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25,165,824
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In vivo high-resolution 7 Tesla MRI shows early and diffuse cortical alterations in CADASIL.
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Recent data suggest that early symptoms may be related to cortex alterations in CADASIL (Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), a monogenic model of cerebral small vessel disease (SVD). The aim of this study was to investigate cortical alterations using both high-resolution T2* acquisitions obtained with 7 Tesla MRI and structural T1 images with 3 Tesla MRI in CADASIL patients with no or only mild symptomatology (modified Rankin's scale ≤1 and Mini Mental State Examination (MMSE) ≥24). Complete reconstructions of the cortex using 7 Tesla T2* acquisitions with 0.7 mm isotropic resolution were obtained in 11 patients (52.1±13.2 years, 36% male) and 24 controls (54.8±11.0 years, 42% male). Seven Tesla T2* within the cortex and cortical thickness and morphology obtained from 3 Tesla images were compared between CADASIL and control subjects using general linear models. MMSE, brain volume, cortical thickness and global sulcal morphology did not differ between groups. By contrast, T2* measured by 7 Tesla MRI was significantly increased in frontal, parietal, occipital and cingulate cortices in patients after correction for multiple testing. These changes were not related to white matter lesions, lacunes or microhemorrhages in patients having no brain atrophy compared to controls. Seven Tesla MRI, by contrast to state of the art post-processing of 3 Tesla acquisitions, shows diffuse T2* alterations within the cortical mantle in CADASIL whose origin remains to be determined.
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27,262,978
|
Superficial warming and cooling of the leg affects walking speed and neuromuscular impairments in people with spastic paraparesis.
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People with hereditary and spontaneous spastic paraparesis (HSSP) report that their legs are stiffer and walking is slower when their legs are cold. This study explored the effects of prolonged superficial cooling and warming of the lower leg on walking speed and local measures of neuromuscular impairments. This was a randomised pre- and post-intervention study of 22 HSSP participants and 19 matched healthy controls. On 2 separate occasions, one lower leg was cooled or warmed. Measurements included walking speed and measures of lower limb impairment: ankle movement, passive muscle stiffness, spasticity (stretch reflex size), amplitude and rate of force generation in dorsi- and plantarflexors and central and peripheral nerve conduction time/velocity. For both participants and controls, cooling decreased walking speed, especially for HSSP participants. For both groups, cooling decreased the dorsiflexor rate and amplitude of force generation and peripheral nerve conduction velocity and increased spasticity. Warming increased dorsiflexor rate of force generation and nerve conduction velocity and decreased spasticity. Superficial cooling significantly reduced walking speed for people with HSSP. Temperature changes were associated with changes in neuromuscular impairments for both people with spastic paraparesis and controls. This study does not support the use of localised cooling in rehabilitation for people with spastic paraparesis as reported in other neurological conditions. Rehabilitation interventions that help prevent heat loss (insulation) or improve limb temperature via passive or active means, particularly when the legs and/or environment are cool, may benefit people with spastic paraparesis.
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10,485,769
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Tourniquet constriction exacerbates hyperalgesia-related pain induced by intradermal capsaicin injection.
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When capsaicin is injected intradermally, hyperalgesia develops around the injection site. The authors observed that volunteers report painful sensations in the skin remote from the injection site during tourniquet constriction of the affected extremity. Each volunteer received an intradermal injection of capsaicin on the volar forearm, followed by intermittent tourniquet constriction of the extremity. In some participants, the tourniquet position was rotated between different sites on the upper extremities. Laser Doppler measurements were made in the skin to measure capillary blood flow during pain magnification. Hyperalgesia developed in the volunteers who were tested after the capsaicin injection. Blood flow increased three times in the dermal capillaries remote from the injection site after capsaicin injection. The tourniquet-induced pain reached peak intensity soon after tourniquet inflation. Tourniquet constriction of the arm on the affected side reliably induced painful exacerbation in each person tested. The quality of the sensation was described as burning and extended across the arm in most volunteers. Only when pinprick hyperalgesia was detectable did the volunteers experience the diffuse, immediate pain sensation. The pain initiated by the tourniquet constriction likely is related to changes in skin capillary blood flow. Low cutaneous blood perfusion is related to the intensity of ongoing, spontaneous pain when secondary hyperalgesia is present. The specific trigger(s) have yet to be identified.
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25,690,125
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Comparing the performance of the Charlson/Deyo and Elixhauser comorbidity measures across five European countries and three conditions.
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The Charlson and Elixhauser comorbidity measures are commonly used methods to account for patient comorbidities in hospital-level comparisons of clinical quality using administrative data. Both have been validated in North America, but there is less evidence of their performance in Europe and in pooled cross-country data, which are features of the European Collaboration for Healthcare Optimization (ECHO) project. This study compares the performance of the Charlson/Deyo and Elixhauser comorbidity measures in predicting in-hospital mortality using data from five European countries in three inpatient groups. Administrative data is used from five countries in 2008-2009 for three indicators commonly used in hospital quality comparisons: mortality rates following acute myocardial infarction, coronary artery bypass graft surgery and stroke. Logistic regression models are constructed to predict mortality controlling for age, gender and the relevant comorbidity measure. Model discrimination is evaluated using c-statistics. Model calibration is evaluated using calibration slopes. Overall goodness-of-fit is evaluated using Nagelkerke's R(2) and the Akaike information criterion. All models are validated internally by using bootstrapping and externally by using the 2009 model parameters to predict mortality in 2008. The Elixhauser measure has better overall predictive ability in terms of discrimination and goodness-of-fit than the Charlson/Deyo measure or the age-sex only model. There is no clear difference in model calibration. These findings are robust to the choice of country, to pooling all five countries and to internal and external validation. The Elixhauser list contains more comorbidities, which may enable it to achieve better discrimination than the Charlson measure. Both measures achieve similar calibration, so for the purpose of ECHO we judged the Elixhauser measure to be preferable.
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19,398,670
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Acute kidney injury is associated with increased long-term mortality after cardiothoracic surgery.
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Long-term survival after acute kidney injury (AKI) is poorly studied. We report the relationship between long-term mortality and AKI with small changes in serum creatinine during hospitalization after various cardiothoracic surgery procedures. This was a retrospective study of 2973 patients with no history of chronic kidney disease who were discharged from the hospital after cardiothoracic surgery between 1992 and 2002. AKI was defined by the RIFLE classification (Risk, Injury, Failure, Loss, and End stage), which requires at least a 50% increase in serum creatinine and stratifies patients into 3 grades of AKI: Risk, injury, and failure. Patient survival was determined through the National Social Security Death Index. Long-term survival was analyzed with a risk-adjusted Cox proportional hazards regression model. Survival was worse among patients with AKI and was proportional to its severity, with an adjusted hazard ratio of 1.23 (95% CI 1.06 to 1.42) for the least severe RIFLE risk class and 2.14 (95% CI 1.73 to 2.66) for the RIFLE failure class compared with patients without AKI. Survival was worse among all subgroups of cardiothoracic surgery with AKI except for valve surgery. Patients with complete renal recovery after AKI still had an increased adjusted hazard ratio for death of 1.28 (95% CI 1.11 to 1.48) compared with patients without AKI. The risk of death associated with AKI after cardiothoracic surgery remains high for 10 years regardless of other risk factors, even for those patients with complete renal recovery. Improved renal protection and closer postdischarge follow-up of renal function may be warranted.
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19,398,671
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Basal and oxidative stress-induced expression of metallothionein is decreased in ascending aortic aneurysms of bicuspid aortic valve patients.
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Bicuspid aortic valve (BAV) is a heritable condition that has been linked by an unknown mechanism to a predisposition for ascending aortic aneurysm. Matrix metalloproteinases have been implicated in this predisposition. Metallothionein is a poorly characterized, metal-binding protein that regulates matrix metalloproteinases and is an antioxidant known to be upregulated under oxidative stress. To determine putative factors involved in the pathogenesis of aortic aneurysm in BAV patients, our first goal was to identify genes that are dysregulated in ascending aortic aneurysms of BAV patients compared with tricuspid aortic valve patients and nondiseased (control) donors. By microarray analysis (22,000 probe sets), 110 dysregulated genes were identified in BAV compared with tricuspid aortic valve patients and control donors; 8 were genes of the metallothionein family. Metallothionein gene expression and protein expression were significantly lower in aortic tissue and cultured aortic smooth muscle cells from BAV patients compared with control subjects. Matrix metalloproteinase-9 expression was increased in BAV aortic samples relative to controls. BAV aorta was more susceptible to oxidative stress, and induction of metallothionein under oxidative stress was reduced in BAV patients compared with control subjects. These results demonstrate dysregulated metallothionein expression in ascending aortic smooth muscle cells of BAV patients that may contribute to an inadequate response to oxidative stress and provoke aneurysm formation. We hypothesize that metallothionein plays a pivotal role in the response of ascending aortic smooth muscle cells to oxidative stress cues normally involved in the maintenance of the extracellular matrix, including the regulation of matrix metalloproteinase expression.
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17,825,806
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Microsomal triglyceride transfer protein 493-T variant is associated with resistin levels and C-reactive protein.
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The microsomal triglyceride transfer protein (MTP) is a heterodimeric lipid transfer protein that consists of a large unique 97-kDA subunit and protein disulfide isomerase. MTP is involved in the assembly of apoB-containing lipoprotein and enables the secretion of VLDLs by the liver and chylomicrons by the intestine. The MTP gene is highly polymorphic. The less common T variant has been associated with the reduction of plasma LDL-cholesterol levels and with an increased risk in coronary heart disease. We hypothesized that MTP polymorphism could be associated to LDL-cholesterol levels and proinflammatory cytokines, such as resistin. The -493G/T MTP gene polymorphism was investigated in 290 subjects. Subjects carrying the TT genotype had lower level of LDL-cholesterol and higher serum resistin levels than individual carrying one or two copies of the -493G allele. After adjustments for age, BMI, waist circumference, alcohol intake and exercise levels, a significant direct association was evident between hs-CRP and resistin levels and the presence of the TT genotype in a multiple regression model. This study supports the notion that the rare MTP-493T/T genotype is associated both with higher levels of inflammatory parameters and with low levels of LDL-cholesterol. Prospective data are needed to investigate if the association between CVD and the MTP-493T/T genotype might be due to the increased sub-clinical proinflammatory state associated with this mutation.
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15,204,373
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Alarm treatment is successful in children with day- and night-time wetting.
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To assess the effect of alarm treatment in children with day- and night-time wetting compared to those with night-time wetting only. A total of 37 consecutive children (25 boys, 12 girls), all of whom suffered from both day- and night-time wetting, were compared to a group of 21 boys and 16 girls with nocturnal enuresis only. In both groups the age range was 5-13 years. Inclusion criteria were at least two wet nights a week in the previous 4 weeks combined with day-time wetting. The parents were asked to complete a diary during the study period. Sixty-five percent of the children with day- and night-time wetting became dry at night, the average time needed being 49 days (range 22-134 days). Seventy-six percent of the children with only night-time wetting became dry at night, the average time needed being 52 days (range 22-121 days). No significant differences were found between the success rates for the two groups or between the different age groups in the two groups. Of the children with day- and night-time wetting who became dry at night after alarm treatment, 42% also became dry during the day-time. Two years after alarm treatment, 15/16 traced children were still dry at night and all 10 traced children were still dry during the day-time. As with children with only night-time wetting, the majority of children with day- and night-time wetting become dry at night with the use of an enuresis alarm. The results are good compared to the spontaneous cure rate. By using alarm treatment at night, children often also become dry during the day.
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10,485,786
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High-dose nitric oxide inhalation increases lung injury after gastric aspiration.
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Inhaled nitric oxide is often used in patients with adult respiratory distress syndrome. However, nitric oxide also may be significantly toxic, especially if administered concurrently with hyperoxia. The authors evaluated the isolated effect of nitric oxide and the combined effects of nitric oxide and hyperoxia on lung injury in rats after acid aspiration. Animals were injured by instillation of 1.2 ml/kg hydrogen chloride in low-pH saline (the acid group) or acidified gastric particles (the casp group) into the lungs under halothane anesthesia via a tracheal catheter. Controls received no injury vehicle but rather underwent the surgical process. After recovery from anesthesia, the animals were exposed to 20% or 90% oxygen with or without 20, 40, or 80 ppm nitric oxide for 5 h. The permeability index, alveolar-arterial oxygen difference, the ratio of oxygen pressure to the inspired fraction of oxygen, and the ratio of wet to dry weight were assessed 5 h after injury as indices of lung injury. Data were assessed using analysis of variance. Each group included 6-10 rats. Exposure to nitric oxide (80 ppm) in air increased protein permeability in the lungs to a permeability index of 1.42+/-0.12 after acid aspiration. The combination of nitric oxide (80 ppm) and hyperoxia further increased protein leakage to a permeability index of 2.1+/-0.25. Exposure to lower concentrations of nitric oxide (e.g., 20 and 40 ppm) increased the permeability index of the lungs (1.44+/-0.21, 1.75+/-0.29, respectively) in the presence of hyperoxia, although it did not affect the permeability index of the lungs during exposure to air. Pretreatment of animals with deferoxamine and methylene blue partially inhibited the adverse effect of hyperoxia and nitric oxide, which suggested a complex underlying mechanism involving both reactive-species generation and pulmonary vasomotor changes. These results show that inhaled nitric oxide at 80 ppm for a short duration (5 h) increases the severity of the inflammatory microvascular lung injury after acid aspiration. The pulmonary damage is exacerbated further in the presence of high oxygen concentrations. Although lower concentrations of nitric oxide did not increase the extent of lung injury, longer exposure times need to be assessed.
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25,165,850
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Early exposure to volatile anesthetics impairs long-term associative learning and recognition memory.
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Anesthetic exposure early in life affects neural development and long-term cognitive function, but our understanding of the types of memory that are altered is incomplete. Specific cognitive tests in rodents that isolate different memory processes provide a useful approach for gaining insight into this issue. Postnatal day 7 (P7) rats were exposed to either desflurane or isoflurane at 1 Minimum Alveolar Concentration for 4 h. Acute neuronal death was assessed 12 h later in the thalamus, CA1-3 regions of hippocampus, and dentate gyrus. In separate behavioral experiments, beginning at P48, subjects were evaluated in a series of object recognition tests relying on associative learning, as well as social recognition. Exposure to either anesthetic led to a significant increase in neuroapoptosis in each brain region. The extent of neuronal death did not differ between groups. Subjects were unaffected in simple tasks of novel object and object-location recognition. However, anesthetized animals from both groups were impaired in allocentric object-location memory and a more complex task requiring subjects to associate an object with its location and contextual setting. Isoflurane exposure led to additional impairment in object-context association and social memory. Isoflurane and desflurane exposure during development result in deficits in tasks relying on associative learning and recognition memory. Isoflurane may potentially cause worse impairment than desflurane.
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21,495,837
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Statin therapy is associated with decreased pulmonary vascular pressures in severe COPD.
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Pulmonary hypertension (PH) in COPD carries a poor prognosis. Statin therapy has been associated with numerous beneficial clinical effects in COPD, including a possible improvement in PH. We examined the association between statin use and pulmonary hemodynamics in a well-characterized cohort of patients undergoing evaluation for lung transplantation. We conducted a cross-sectional analysis of 112 subjects evaluated for lung transplant with a diagnosis of COPD. Clinical characteristics, pulmonary function, cardiac catheterization findings and medical comorbidities were compared between statins users and non-users. Thirty-four (30%) subjects were receiving statin therapy. Statin users were older and had an increased prevalence of systemic hypertension and coronary artery disease (CAD). Mean pulmonary arterial pressure (mPAP) in the statin group was lower [26 ± 7 vs 29 ± 7 mmHg, p = 0.02], as was pulmonary artery wedge pressure (PAWP) [12 ± 5 vs. 15 ± 6 mmHg, p = 0.02]. Pulmonary vascular resistance did not differ between the groups. In multiple regression analysis, statin use was associated with a 4.2 mmHg (95% CI: 2 to 6.4, p = <0.001) lower PAWP and a 2.6 mmHg (95% CI: 0.3 to 4.9, p = 0.03) reduction in mPAP independent of PAWP. In patients with severe COPD, statin use is associated with significantly lower PAWP and mPAP. These finding should be evaluated prospectively.
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17,825,830
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Coronary flow reserve is impaired in patients with aortic valve calcification.
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Calcific aortic valve disease is an active and progressive condition. Data indicate that aortic valve calcification (AVC) is associated with endothelial dysfunction and accepted as a manifestation of atherosclerosis. Coronary flow reserve (CFR) determined by transthoracic echocardiography has been introduced as a reliable indicator for coronary microvascular function. In this study we aimed to evaluate CFR in patients with AVC. Eighty patients, aged more than 60 years, without coronary heart disease or diabetes mellitus were included: 40 had AVC without significant stenosis (peak gradient across the valve <25 mm Hg) and 40 had normal aortic valves (controls). Using transthoracic Doppler echocardiography, we measured coronary diastolic peak flow velocities (PFV) at baseline and after dipyridamole infusion. CFR was calculated as the ratio of hyperemic to baseline diastolic PFV and was compared between groups. Mean ages for patients with AVC and controls were 68.9+/-6.2 and 67.6+/-5.9 years (P=.3). There were no significant differences regarding clinical characteristics, laboratory findings, ejection fraction, or peak aortic valve gradients. Mean diastolic PFV at baseline and during hyperemia were 28.4+/-4.2 and 59.2+/-7.8 cm/s for AVC and 27.7+/-3.9 and 68.5+/-10.5 cm/s for controls. Compared with controls, patients with AVC had significantly lower CFR values (2.12+/-0.41 versus 2.51+/-0.51; P<.0001). CFR is impaired in patients with AVC before valve stenosis develops, suggesting that microvascular-endothelial dysfunction is present during the early stages of the calcific aortic valve disease.
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19,398,704
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Neuropathologic intermediate phenotypes enhance association to Alzheimer susceptibility alleles.
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The identification of susceptibility alleles to risk of Alzheimer disease (AD) is a major public health priority. Using apolipoprotein E genotype (APOE), we examined whether neuropathologic intermediate phenotypes, the pathology underlying clinical AD that presumably lies intermediate in the causal chain, would increase power for genetic associations. More than 700 older persons underwent annual evaluation and organ donation as part of the Religious Orders Study or Rush Memory and Aging Project. A total of 536 autopsied persons with clinical AD or without dementia with APOE genotyping and a quantitative measure of AD pathology were analyzed. Regression analyses were used to examine the relation of APOE to clinical AD, to the level of cognitive function proximate to death, and to measures of AD neuropathology. APOE epsilon4 was associated with increased odds of clinical AD (p = 3 x 10(-7)), and its association with level of cognition was stronger (p = 8 x 10(-12)). However, the use of quantitative measures of AD pathology markedly enhanced the association (p = 9 x 10(-24)). The APOE epsilon2 was not associated with either AD (p = 0.69) or level of cognition (p = 0.82). However, its association with AD pathology (p = 1 x 10(-5)) was sufficiently strong that it would have warranted follow-up if discovered in a genome-wide association study. Power calculations demonstrate that a sample size of 625 subjects with our measure of AD pathology would be required to meet genome-wide significance of p = 5 x 10(-8) for epsilon2. Discovery efforts for susceptibility loci for Alzheimer disease could benefit from the use of neuropathologic intermediate phenotypes as a complement to other approaches.
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15,204,401
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Single-dose orally administered quinolone appears to be sufficient antibiotic prophylaxis for radical retropubic prostatectomy.
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To evaluate a new prophylaxis routine, which was introduced at our clinic in December 1998, comprising a single oral dose of antibiotic given prior to radical retropubic prostatectomy (RRP). A total of 60 men scheduled to undergo RRP were included in a prospective study and received antibiotic prophylaxis in the form of a single oral dose of quinolone. Cultures were made from the tip of the catheter and from urine sampled at the time of extraction as well as 1 and 2 weeks post-extraction. The outcome of this prospective study of 60 men was then compared to the total numbers of patients operated on in 1998 (n = 103) and 1999 (n = 140) by means of a retrospective analysis of clinical files. No cases of sepsis occurred. Two weeks after catheter removal, 15/60 patients had persisting bacteriuria. No other signs of infection were detected. Six patients developed a stricture of the anastomotic area during follow-up (mean duration 18.9 months). When the study group was compared to all patients operated on in 1998 and 1999 no increases in the incidence of anastomotic strictures or serious infections or in the length of hospitalization could be detected. A single dose of antibiotic given before RRP appears to be sufficient prophylaxis.
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9,437,234
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Hormonal replacement therapy affects calcitonin gene-related peptide and atrial natriuretic peptide secretion in postmenopausal women.
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Menopause is associated with critical changes in the cardiovascular system, and the possible effect of hormonal replacement therapy (HRT) on these changes is under investigation. The aim of our study was to evaluate in postmenopausal women the effects of HRT and clonidine on the response of plasma calcitonin gene-related peptide (CGRP) and plasma atrial natriuretic peptide (ANP) to the upright posture test and the saline infusion test respectively. CGRP and ANP levels were measured with specific radioimmunological assays and expressed in pmol/l (means +/- S.E.M). Postmenopausal women (age 46-53 years) (n = 18) were studied before and after 3 months of HRT (n = 13) or clonidine treatment (n = 5). After HRT or clonidine treatment plasma CGRP levels (14.9 +/- 1.6 and 15.9 +/- 3.8 pmol/l) were significantly higher than before (9.8 +/- 0.6 and 10.5 +/- 1.6 pmol/l) (P < 0.01). The assumption of upright posture caused no change in plasma CGRP levels before treatment, while after HRT, but not after clonidine treatment, an increase in plasma CGRP levels was observed (P < 0.01 at 5 and 20 min). Basal plasma ANP levels significantly decreased after both HRT and clonidine treatment (P < 0.01). In untreated women the saline infusion test did not induce any change in plasma ANP levels; a significant response to the test was restored after HRT but not after clonidine treatment (P < 0.01 at 90 and 120 min). The results show that some of the adaptive responses modified by menopausal changes are restored by HRT but not clonidine treatment, suggesting a modulatory role for sex steroid hormones in cardiovascular function and salt and water balance.
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15,728,691
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Participation in leanness sports but not training volume is associated with menstrual dysfunction: a national survey of 1276 elite athletes and controls.
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To examine the prevalence of menstrual dysfunction in the total population of Norwegian elite female athletes and national representative controls in the same age group. A detailed questionnaire that included questions on training and/or physical activity patterns, menstrual, dietary, and weight history, oral contraceptive use, and eating disorder inventory subtests was administered to all elite female athletes representing the country at the junior or senior level (aged 13-39 years, n = 938) and national representative controls in the same age group (n = 900). After exclusion, a total of 669 athletes (88.3%) and 607 controls (70.2%) completed the questionnaire satisfactorily. Age at menarche was significantly (p<0.001) later in athletes (13.4 (1.4) years) than in controls (13.0 (1.3) years), and differed among sport groups. A higher percentage of athletes (7.3%) than controls (2.0%) reported a history of primary amenorrhoea (p<0.001). A similar percentage of athletes (16.5%) and controls (15.2%) reported present menstrual dysfunction, but a higher percentage of athletes competing in leanness sports reported present menstrual dysfunction (24.8%) than athletes competing in non-leanness sports (13.1%) (p<0.01) and controls (p<0.05). These novel data include virtually all eligible elite athletes, and thus substantially extend previous studies. Age at menarche occurred later and the prevalence of primary amenorrhoea was higher in elite athletes than in controls. A higher percentage of athletes competing in sports that emphasise thinness and/or a specific weight reported present menstrual dysfunction than athletes competing in sports focusing less on such factors and controls. On the basis of a comparison with a previous study, the prevalence of menstrual dysfunction was lower in 2003 than in 1993.
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26,738,740
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ELF5 isoform expression is tissue-specific and significantly altered in cancer.
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E74-like factor 5 (ELF5) is an epithelial-specific member of the E26 transforming sequence (ETS) transcription factor family and a critical regulator of cell fate in the placenta, pulmonary bronchi, and milk-producing alveoli of the mammary gland. ELF5 also plays key roles in malignancy, particularly in basal-like and endocrine-resistant forms of breast cancer. Almost all genes undergo alternative transcription or splicing, which increases the diversity of protein structure and function. Although ELF5 has multiple isoforms, this has not been considered in previous studies of ELF5 function. RNA-sequencing data for 6757 samples from The Cancer Genome Atlas were analyzed to characterize ELF5 isoform expression in multiple normal tissues and cancers. Extensive in vitro analysis of ELF5 isoforms, including a 116-gene quantitative polymerase chain reaction panel, was performed in breast cancer cell lines. ELF5 isoform expression was found to be tissue-specific due to alternative promoter use but altered in multiple cancer types. The normal breast expressed one main isoform, while in breast cancer there were subtype-specific alterations in expression. Expression of other ETS factors was also significantly altered in breast cancer, with the basal-like subtype demonstrating a distinct ETS expression profile. In vitro inducible expression of the full-length isoforms 1 and 2, as well as isoform 3 (lacking the Pointed domain) had similar phenotypic and transcriptional effects. Alternative promoter use, conferring differential regulatory responses, is the main mechanism governing ELF5 action rather than differential transcriptional activity of the isoforms. This understanding of expression and function at the isoform level is a vital first step in realizing the potential of transcription factors such as ELF5 as prognostic markers or therapeutic targets in cancer.
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19,398,706
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Near-infrared spectroscopy in carotid artery stenting predicts cerebral hyperperfusion syndrome.
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Cerebral hyperperfusion syndrome (CHS) following carotid artery stenting (CAS) or carotid endarterectomy (CEA) is rare but often fatal once intracranial hemorrhage has occurred. In particular, CHS occurs significantly earlier after CAS than after CEA. Thus a monitoring method for early detection of CHS is required. Near-infrared spectroscopy (NIRS) provides a noninvasive monitoring technique for assessing regional cerebral oxygen saturation (rSO2). This study evaluated the usefulness of transcranial NIRS during CAS for prediction of CHS. Periprocedural rSO2 was monitored in 64 cases of CAS (52 men, 12 women; 71 +/- 6.6 years). The average degree of carotid stenosis was 76.8 +/- 11.3% by North American Symptomatic Carotid Endarterectomy Trial criteria. Bifrontal rSO2 was monitored during the procedure using NIRS. Seventeen patients were symptomatic and 47 were asymptomatic. CHS was diagnosed by increased cerebral blood flow by SPECT performed on the day after treatment with deterioration of neurologic symptoms. CHS was observed in two cases (3.1%). In the CHS group, post-reperfusion rSO2 values increased >24% from baseline until 3 minutes after reperfusion. In the non-CHS group, the normal upper limit (NUL) of the rSO2 change was set at 10.0% at 3 minutes after reperfusion. In the CHS group, rSO2 at 3 minutes after reperfusion was markedly higher than the NUL. In patients showing an rSO2 at 3 minutes after reperfusion increased by more than 10.0%, CHS following CAS could be predicted. Periprocedural increases in regional cerebral oxygen saturation measured by near- infrared spectroscopy can be an excellent predictor of cerebral hyperperfusion syndrome after carotid artery stenting.
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24,641,590
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Higher plasma vitamin D is associated with reduced risk of Clostridium difficile infection in patients with inflammatory bowel diseases.
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Patients with inflammatory bowel diseases (IBD) have an increased risk of clostridium difficile infection (CDI). Cathelicidins are anti-microbial peptides that attenuate colitis and inhibit the effect of clostridial toxins. Plasma calcifediol [25(OH)D] stimulates production of cathelicidins. To examine the association between plasma 25(OH)D and CDI in patients with IBD. From a multi-institutional IBD cohort, we identified patients with at least one measured plasma 25(OH)D. Our primary outcome was development of CDI. Multivariate logistic regression models adjusting for potential confounders were used to identify independent effect of plasma 25(OH)D on risk of CDI. We studied 3188 IBD patients of whom 35 patients developed CDI. Patients with CDI-IBD were older and had greater co-morbidity. The mean plasma 25(OH)D level was significantly lower in patients who developed CDI (20.4 ng/mL) compared to non-CDI-IBD patients (27.1 ng/mL) (P = 0.002). On multivariate analysis, each 1 ng/mL increase in plasma 25(OH)D was associated with a 4% reduction in risk of CDI (OR 0.96, 95% CI 0.93-0.99, P = 0.046). Compared to individuals with vitamin D >20 ng/mL, patients with levels <20 ng/mL were more likely to develop CDI (OR 2.27, 95% CI 1.16-4.44). The mean plasma 25(OH)D in patients with CDI who subsequently died was significantly lower (12.8 ± 8.1 ng/mL) compared to those who were alive at the end of follow-up (24.3 ± 13.2 ng/mL) (P = 0.01). Higher plasma calcifediol [25(OH)D] is associated with reduced risk of C. difficile infection in patients with IBD. Further studies of therapeutic supplementation of vitamin D in patients with inflammatory bowel disease and C. difficile infection may be warranted.
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25,690,167
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Women Build Long Bones With Less Cortical Mass Relative to Body Size and Bone Size Compared With Men.
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The twofold greater lifetime risk of fracturing a bone for white women compared with white men and black women has been attributed in part to differences in how the skeletal system accumulates bone mass during growth. On average, women build more slender long bones with less cortical area compared with men. Although slender bones are known to have a naturally lower cortical area compared with wider bones, it remains unclear whether the relatively lower cortical area of women is consistent with their increased slenderness or is reduced beyond that expected for the sex-specific differences in bone size and body size. Whether this sexual dimorphism is consistent with ethnic background and is recapitulated in the widely used mouse model also remains unclear. We asked (1) do black women build bones with reduced cortical area compared with black men; (2) do white women build bones with reduced cortical area compared with white men; and (3) do female mice build bones with reduced cortical area compared with male mice? Bone strength and cross-sectional morphology of adult human and mouse bone were calculated from quantitative CT images of the femoral midshaft. The data were tested for normality and regression analyses were used to test for differences in cortical area between men and women after adjusting for body size and bone size by general linear model (GLM). Linear regression analysis showed that the femurs of black women had 11% lower cortical area compared with those of black men after adjusting for body size and bone size (women: mean=357.7 mm2; 95% confidence interval [CI], 347.9-367.5 mm2; men: mean=400.1 mm2; 95% CI, 391.5-408.7 mm2; effect size=1.2; p<0.001, GLM). Likewise, the femurs of white women had 12% less cortical area compared with those of white men after adjusting for body size and bone size (women: mean=350.1 mm2; 95% CI, 340.4-359.8 mm2; men: mean=394.3 mm2; 95% CI, 386.5-402.1 mm2; effect size=1.3; p<0.001, GLM). In contrast, female and male femora from recombinant inbred mouse strains showed the opposite trend; femurs from female mice had a 4% larger cortical area compared with those of male mice after adjusting for body size and bone size (female: mean=0.73 mm2; 95% CI, 0.71-0.74 mm2; male: mean=0.70 mm2; 95% CI, 0.68-0.71 mm2; effect size=0.74; p=0.04, GLM). Female femurs are not simply a more slender version of male femurs. Women acquire substantially less mass (cortical area) for their body size and bone size compared with men. Our analysis questions whether mouse long bone is a suitable model to study human sexual dimorphism. Identifying differences in the way bones are constructed may be clinically important for developing sex-specific diagnostics and treatment strategies to reduce fragility fractures.
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17,301,562
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Polymorphisms in Toll-like receptor 9 influence the clinical course of HIV-1 infection.
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The clinical course of HIV-1 infection is highly variable among individuals, at least in part as a result of genetic polymorphisms in the host. Toll-like receptors (TLRs) have a key role in innate immunity and mutations in the genes encoding these receptors have been associated with increased or decreased susceptibility to infections. To determine whether single-nucleotide polymorphisms (SNPs) in TLR2-4 and TLR7-9 influenced the natural course of HIV-1 infection. Twenty-eight SNPs in TLRs were analysed in HAART-naive HIV-positive patients from the Swiss HIV Cohort Study. The SNPs were detected using Sequenom technology. Haplotypes were inferred using an expectation-maximization algorithm. The CD4 T cell decline was calculated using a least-squares regression. Patients with a rapid CD4 cell decline, less than the 15th percentile, were defined as rapid progressors. The risk of rapid progression associated with SNPs was estimated using a logistic regression model. Other candidate risk factors included age, sex and risk groups (heterosexual, homosexual and intravenous drug use). Two SNPs in TLR9 (1635A/G and +1174G/A) in linkage disequilibrium were associated with the rapid progressor phenotype: for 1635A/G, odds ratio (OR), 3.9 [95% confidence interval (CI),1.7-9.2] for GA versus AA and OR, 4.7 (95% CI,1.9-12.0) for GG versus AA (P = 0.0008). Rapid progression of HIV-1 infection was associated with TLR9 polymorphisms. Because of its potential implications for intervention strategies and vaccine developments, additional epidemiological and experimental studies are needed to confirm this association.
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15,728,698
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Enhancing the efficacy of the 20 m multistage shuttle run test.
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Maximal oxygen uptake (Vo(2max)) of 44 ml kg(-1) min(-1) is an accepted criterion (Vo(2CR)) below which health and fitness for young male adults may be compromised. New algorithms validated for Vo(2CR) screening using the 20 m multistage shuttle run test (20mMST) were developed. Vo(2max) was assessed in 110 males using a stationary gas analyser in a treadmill test (TT) and in 40 of these subjects using a portable gas analyser in the 20mMST. Vo(2max) predicted from the 20mMST in 70 subjects was used for cross validation. Two equations predicting Vo(2max) during 20mMST (EQ(MST)) and TT (EQ(TT)) were developed. Significant energy cost variance (EC(V)) was detected between TT and 20mMST (p<0.001), correlated significantly with subject height, and was a significant predictor of Vo(2max) differences between TT and 20mMST. The r(2) of EQ(MST) was 0.92 (p<0.001). Predicted Vo(2max) values from EQ(MST) correlated with directly measured 20mMST Vo(2max) at r = 0.96 (p<0.001). ANOVA detected no mean difference (p>0.05) between predicted and measured values. Prevalence of low fitness based on Vo(2CR) was 0.37. McNemar chi(2) indicated significant differences in sensitivity (p<0.001) and specificity (p<0.05) between the original 20mMST equation (EQ(LEG)) and EQ(TT), regarding Vo(2CR) screening. Cohen's kappa demonstrated higher agreement with TT Vo(2max) for EQ(TT) (p<0.001) than EQ(LEG) (p<0.05). TT Vo(2max) correlated with the end result of both EQ(LEG) and EQ(TT) at r = 0.75 (p<0.001). Unlike EQ(TT) (p>0.05), mean predicted Vo(2max) from EQ(LEG) was significantly higher compared to TT Vo(2max) (p<0.001). These algorithms increase the efficacy of 20mMST to accurately evaluate aspects of health and fitness.
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25,690,170
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Platelet-rich concentrates differentially release growth factors and induce cell migration in vitro.
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Platelet-rich concentrates are used as a source of growth factors to improve the healing process. The diverse preparation protocols and the gaps in knowledge of their biological properties complicate the interpretation of clinical results. In this study we aimed to (1) analyze the concentration and kinetics of growth factors released from leukocyte- and platelet-rich fibrin (L-PRF), leukocyte- and platelet-rich plasma (L-PRP), and natural blood clot during in vitro culture; (2) investigate the migration of mesenchymal stem cells (MSCs) and human umbilical vein endothelial cells (HUVECs) as a functional response to the factors released; and (3) uncover correlations between individual growth factors with the initial platelet/leukocyte counts or the induced cell migration. L-PRF, L-PRP, and natural blood clot prepared from 11 donors were cultured in vitro for 28 days and media supernatants collected after 8 hours and 1, 3, 7, 14, and 28 days. Released transforming growth factor β1 (TGF-β1), vascular endothelial growth factor (VEGF), insulin growth factor (IGF-1), platelet-derived growth factor AB (PDGF-AB), and interleukin-1β (IL-1β) were measured in the supernatants with enzyme-linked immunosorbent assay. Migration of MSC and HUVEC induced by the supernatants was evaluated in Boyden chambers. More TGF-ß1 was released (mean ± SD in pg/mL of blood) from L-PRF (37,796 ± 5492) compared with L-PRP (23,738 ± 6848; p < 0.001) and blood clot (3739 ± 4690; p < 0.001), whereas more VEGF and IL-1ß were released from blood clot (1933 ± 704 and 2053 ± 908, respectively) compared with both L-PRP (642 ± 208; p < 0.001 and 273 ± 386; p < 0.001, respectively) and L-PRF (852 ± 376; p < 0.001 and 65 ± 56, p < 0.001, respectively). No differences were observed in IGF-1 and PDGF-AB released from any of the concentrates. TGF-β1 release peaked at Day 7 in L-PRF and at 8 hours and Day 7 in L-PRP and 8 hours and Day 14 in blood clot. In all concentrates, main release of VEGF occurred between 3 and 7 days and of IL-1β between Days 1 and 7. IGF-1 and PDGF-AB were released until Day 1 in L-PRP and blood clot, in contrast to sustained release over the first 3 days in L-PRF. The strongest migration of MSC occurred in response to L-PRF, and more HUVEC migration was seen in L-PRF and blood clot compared with L-PRP. TGF-β1 correlated with initial platelet counts in L-PRF (Pearson r = 0.66, p = 0.0273) and initial leukocyte counts in L-PRP (Pearson r = 0.83, p = 0.0016). A positive correlation of IL-1β on migration of MSC and HUVEC was revealed (Pearson r = 0.16, p = 0.0208; Pearson r = 0.31, p < 0.001). In comparison to L-PRP, L-PRF had higher amounts of released TGF-β1, a long-term release of growth factors, and stronger induction of cell migration. Future preclinical studies should confirm these data in a defined injury model. By characterizing the biologic properties of different platelet concentrates in vitro, we may gain a better understanding of their clinical effects and develop guidelines for specific future applications.
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17,301,565
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PRO 2000 elicits a decline in genital tract immune mediators without compromising intrinsic antimicrobial activity.
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Vaginal microbicides should protect against infection without disrupting the mucosal environment or its mediators of host defense. The objective of this study was to examine the effect of 14 daily applications of 0.5% PRO 2000 or placebo gel on mediators of mucosal immunity and intrinsic antimicrobial activity. A randomized, prospective, double-blind, placebo-controlled study was conducted among 24 healthy, abstinent women. Levels of cytokines, chemokines, defensins, and other protective factors and intrinsic antimicrobial activity were determined in cervicovaginal lavage samples collected on study days 0, 7, 14, and 21. No increase in pro-inflammatory cytokines was observed. Rather cytokines and protective factors including interleukin (IL)-1 receptor antagonist, immunoglobulins and human beta-defensin 2 were lower in the drug compared with the placebo group. All of the mediators returned towards baseline on day 21. Women who were cycling had lower levels of most proteins on study days 7 and/or 14 compared with women on oral contraceptives; however, the magnitude of decline was greater in women who received PRO 2000 compared with placebo gel. The reduction in protective factors was not associated with a loss in the intrinsic anti-viral (HIV or herpes simplex virus) activity or anti-bacterial activity (Escherichia coli or Staphylococcus aureus). In contrast to experience with nonoxynol-9, PRO 2000 did not trigger an inflammatory response in cervicovaginal secretions. There was a modest reduction in mucosal immune mediators, but this loss was not associated with a reduction in intrinsic antimicrobial activity.
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17,301,569
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Initiation of antiretroviral therapy leads to a rapid decline in cervical and vaginal HIV-1 shedding.
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Antiretroviral therapy (ART) may decrease HIV-1 infectivity in women by reducing genital HIV-1 shedding. To evaluate the time course and magnitude of decay in cervical and vaginal HIV-1 shedding as women initiate ART. This prospective, observational study of 20 antiretroviral-naive women initiating ART with stavudine, lamivudine, and nevirapine measured HIV-1 RNA in plasma, cervical secretions, and vaginal secretions. Qualitative polymerase chain reaction estimated HIV-1 DNA in cervical and vaginal samples. Perelson's two-phase viral decay model and non-linear random effects were used to compare RNA decay rates. Decreases in proviral DNA were evaluated using logistic regression and generalized estimating equations. Significant decreases in the quantity of HIV-1 RNA were observed by day 2 in plasma (P < 0.001), day 2 in cervical secretions (P = 0.001), and day 4 in vaginal secretions (P < 0.001). Modeled initial and subsequent RNA decay rates in plasma, cervical secretions, and vaginal secretions were 0.6, 0.8, and 1.2 log10 virions/day, and 0.04, 0.05, and 0.06 log10 virions/day, respectively. The initial decay rate for vaginal HIV-1 RNA was more rapid than for plasma RNA (P = 0.02). Detection of HIV-1 DNA decreased significantly in vaginal secretions during the first week (P < 0.001). At day 28, 10 women had detectable HIV-1 RNA or proviral DNA in genital secretions. Genital HIV-1 shedding decreased rapidly after ART initiation, consistent with a rapid decrease in infectivity. However, incomplete viral suppression in half of these women may indicate an ongoing risk of transmission.
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26,738,757
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Non-adherence to Anti-TNF Therapy is Associated with Illness Perceptions and Clinical Outcomes in Outpatients with Inflammatory Bowel Disease: Results from a Prospective Multicentre Study.
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Non-adherence to anti-tumour necrosis factor [TNF] agents in patients with inflammatory bowel disease [IBD] is a serious problem. In this study, we assessed risk factors for non-adherence and examined the association between adherence to anti-TNF agents and loss of response [LOR]. In this multicentre, 12-month observational study, outpatients with IBD were included. Demographic and clinical characteristics were recorded. Adherence was measured with the Modified Morisky Adherence Scale-8 [MMAS-8] and 12-month pharmacy refills [medication possession ratio, MPR]. Risk factors included demographic and clinical characteristics, medication beliefs, and illness perceptions. Cox regression analysis was performed to determine the association between MPR and LOR to anti-TNF, IBD-related surgery or hospitalisation, dose intensification, or discontinuation of anti-TNF. In total, 128 patients were included [67 infliximab, 61 adalimumab], mean age 37 ( ± standard deviation [SD] 14) years, 71 [56%] female. Median disease duration was 8 (interquartile range [IQR] 4-14) years. Clinical disease activity was present in 41/128 [32%] patients, 36/127 [28%] patients had an MMAS-8 < 6 ['low adherence'], and 25/99 [25%] patients had an MPR < 80% [non-adherence]. Risk factors for non-adherence included adalimumab use (odds ratio [OR] 10.1, 95% confidence interval [CI] 2.62-40.00), stronger emotional response [OR 1.16, 95% CI 1.02-1.31], and shorter timeline perception, i.e. short perceived illness duration [OR 0.60, 95% CI 0.38-0.96]. Adherence is linearly and negatively [OR 0.14, 95% CI 0.03-0.63] associated with LOR. Non-adherence to anti-TNF agents is strongly associated with LOR to anti-TNF agents, adalimumab use, and illness perceptions. The latter may provide an important target for interventions aimed at improving adherence and health outcomes.
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25,165,894
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A solitary positive prostate cancer biopsy does not predict a unilateral lesion in radical prostatectomy specimens.
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Prostate cancer (PCa) may be a multifocal and bilateral disease. Patients with low-risk PCa and a low number of positive biopsy cores may choose to undergo active surveillance or focal therapy. The aim of this study was to determine the correlation between a solitary positive prostate biopsy core and the pathological outcome after radical prostatectomy (RP). The Michinoku Japan Urological Cancer Study Group database contains data, including preoperative and postoperative information, on 1268 consecutive patients with PCa treated with RP alone at four institutions. This study focused on 151 patients with a single positive biopsy core, preoperative prostate-specific antigen (PSA) level less than 10 ng/ml, biopsy Gleason score less than 8, and clinical stage T1c/T2a/T2b disease. Potential preoperative predictors of unilateral PCa were age, preoperative PSA level, biopsy Gleason score and clinical T stage. The median age and preoperative PSA level were 65 years (range 47-76 years) and 6.00 ng/ml (range 0.50-9.80 ng/ml), respectively. Unilateral PCa was identified in 41% of the patients. Extraprostatic extension or seminal vesicle invasion was observed in 26% of all patients. Serum PSA levels were significantly higher in the bilateral PCa group than in the unilateral PCa group in the current study. For patients with PCa having a solitary positive prostate biopsy core, definitive therapy such as RP should be considered.
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18,350,152
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The assembly of the plasmodial PLP synthase complex follows a defined course.
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Plants, fungi, bacteria and the apicomplexan parasite Plasmodium falciparum are able to synthesize vitamin B6 de novo, whereas mammals depend upon the uptake of this essential nutrient from their diet. The active form of vitamin B6 is pyridoxal 5-phosphate (PLP). For its synthesis two enzymes, Pdx1 and Pdx2, act together, forming a multimeric complex consisting of 12 Pdx1 and 12 Pdx2 protomers. Here we report amino acid residues responsible for stabilization of the structural and enzymatic integrity of the plasmodial PLP synthase, identified by using distinct mutational analysis and biochemical approaches. Residues R85, H88 and E91 (RHE) are located at the Pdx1:Pdx1 interface and play an important role in Pdx1 complex assembly. Mutation of these residues to alanine impedes both Pdx1 activity and Pdx2 binding. Furthermore, changing D26, K83 and K151 (DKK), amino acids from the active site of Pdx1, to alanine obstructs not only enzyme activity but also formation of the complex. In contrast to the monomeric appearance of the RHE mutant, alteration of the DKK residues results in a hexameric assembly, and does not affect Pdx2 binding or its activity. While the modelled position of K151 is distal to the Pdx1:Pdx1 interface, it affects the assembly of hexameric Pdx1 into a functional dodecamer, which is crucial for PLP synthesis. Taken together, our data suggest that the assembly of a functional Pdx1:Pdx2 complex follows a defined pathway and that inhibition of this assembly results in an inactive holoenzyme.
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18,350,153
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Multiple oncogenic pathway signatures show coordinate expression patterns in human prostate tumors.
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Gene transcription patterns associated with activation of oncogenes Myc, c-Src, beta-catenin, E2F3, H-Ras, HER2, EGFR, MEK, Raf, MAPK, Akt, and cyclin D1, as well as of the cell cycle and of androgen signaling have been generated in previous studies using experimental models. It was not clear whether genes in these "oncogenic signatures" would show coordinate expression patterns in human prostate tumors, particularly as most of the signatures were derived from cell types other than prostate. The above oncogenic pathway signatures were examined in four different gene expression profile datasets of human prostate tumors (representing approximately 250 patients in all), using both Q1-Q2 and one-sided Fisher's exact enrichment analysis methods. A significant fraction (approximately 5%) of genes up-regulated experimentally by Myc, c-Src, HER2, Akt, or androgen were co-expressed in human tumors with the oncogene or biomarker corresponding to the pathway signature. Genes down-regulated experimentally, however, did not show anticipated patterns of anti-enrichment in the human tumors. Significant subsets of the genes in these experimentally-derived oncogenic signatures are relevant to the study of human prostate cancer. Both molecular biologists and clinical researchers could focus attention on the relatively small number of genes identified here as having coordinate patterns that arise from both the experimental system and the human disease system.
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22,020,171
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Regression of early diabetic macular oedema is associated with prevention of dark adaptation.
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Dark-adapted rods consume oxygen at high rates and light adaptation decreases this oxygen burden and can have therapeutic effects on diabetic macular oedema (DMO). Patients with mild non-proliferative diabetic retinopathy (DR) and early, untreated non-sight-threatening DMO slept for 6 months wearing masks that illuminated the eyelid of one closed eye by 505 nm light. Exclusion criteria were any concomitant eye disease, DR >ETDRS grade 35, and other systemic diseases. change of OCT retinal thickness in the local region where oedema was present. A total of 34 out of 40 patients completed the study. Mean baseline OCT macular cube thickness was equivalent for study and fellow eyes. But study eyes had a greater mean thickness in the central subfield zone 1 (282±53 μm) vs (256±19 μm) the fellow eyes. Twenty-eight study eyes showed intraretinal cysts compared with nine in the fellow eyes. At 6 months, only 19 study eyes had cysts while cysts were seen in 20 fellow eyes. After 6 months, the worst affected ETDRS zone and the central subfield zone 1 reduced in thickness in study eyes only by 12 μm (95% CI 20 to -7, P=0.01). The secondary outcomes of change in visual acuity, achromatic contrast sensitivity, and microperimetric thresholds improved significantly in study eyes and deteriorated in fellow eyes. Sleeping in dim light that can keep rods light adapted may reverse the changes of DMO.
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18,350,156
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Catechol-o-methyltransferase gene polymorphism is associated with skeletal muscle properties in older women alone and together with physical activity.
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Muscle strength declines on average by one percent annually from midlife on. In postmenopausal women this decrement coincides with a rapid decline in estrogen production. The genetics underlying the effects of estrogen on skeletal muscle remains unclear. In the present study, we examined whether polymorphisms within COMT and ESR1 are associated with muscle properties and assessed their interaction and their combined effects with physical activity. A cross-sectional data analysis was conducted with 434 63-76-year-old women from the population-based Finnish Twin Study on Aging. Body anthropometry, muscle cross-sectional area (mCSA), isometric hand grip and knee extension strengths, and leg extension power were measured. COMT Val158Met and ESR1 PvuII genotypes were determined by the RFLP method. mCSA differed by COMT genotypes (p = 0.014) being significantly larger in LL than HL individuals in unadjusted (p = 0.001) and age- and height-adjusted model (p = 0.004). When physical activity and age were entered into GEE model, COMT genotype had a significant main effect (p = 0.038) on mCSA. Furthermore, sedentary individuals with the HH genotype had lower muscle mass, strength and power, but they also appeared to benefit the most from physical activity. No association of ESR1 PvuII polymorphism with any of the muscle outcomes was observed. The present study suggests that the COMT polymorphism, affecting the activity of the enzyme, is associated with muscle mass. Furthermore, sedentary individuals with potential high enzyme activity were the weakest group, but they may potentially benefit the most from physical activity. This observation elucidates the importance of both environmental and genetic factors in muscle properties.
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24,117,326
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Plasma anandamide and related n-acylethanolamide levels are not elevated in pregnancies complicated by hyperemesis gravidarum.
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Cannabinoids are effective antiemetics and the "endogenous cannabinoids" (endocannabinoids) are thought to modulate emesis in both humans and animal models. Endocannabinoids, their receptors and their metabolising enzymes are present in peripheral blood and a reduction in blood endocannabinoid concentration has been observed in individuals with excessive nausea and vomiting following parabolic flight manoeuvres. We tested the hypothesis that plasma endocannabinoid levels are similarly perturbed in women with hyperemesis gravidarum (HG), a condition where the aetiopathogenesis is still unknown, compared to normal pregnant controls. Plasma N-arachidonoylethanolamine (anandamide), N-oleoylethanolamide and N-palmitoylethanolamide were quantified in women with HG (n = 15) and matched normal pregnant controls (n = 30) using UHPLC-ESI-MS/MS utilising an isotope dilution method and selective ion monitoring. No significant differences in anandamide, oleoylethanolamide and palmitoylethanolamide levels were observed between the two groups. There were no significant correlations between these endocannabinoids and plasma haematocrit and serum urea or sodium concentrations. These results would suggest that either the circulating endocannabinoids quantified may not be key modulating factors in HG or that the expected endocannabinoid system response to the stress induced by nausea and vomiting of early pregnancy remain unchanged in women with HG.
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18,350,162
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CD44v4 is a major E-selectin ligand that mediates breast cancer cell transendothelial migration.
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Endothelial E-selectin has been shown to play a pivotal role in mediating cell-cell interactions between breast cancer cells and endothelial monolayers during tumor cell metastasis. However, the counterreceptor for E-selectin and its role in mediating breast cancer cell transendothelial migration remain unknown. By assessing migration of various breast cancer cells across TNF-alpha pre-activated human umbilical vein endothelial cells (HUVECs), we found that breast cancer cells migrated across HUVEC monolayers differentially and that transmigration was E-selectin dependent. Cell surface labeling with the E-selectin extracellular domain/Fc chimera (exE-selectin/Fc) showed that the transmigration capacity of breast cancer cells was correlated to both the expression level and localization pattern of E-selectin binding protein(s) on the tumor cell surface. The exE-selectin/Fc strongly bound to metastatic MDA-MB-231, MDA-MB-435 and MDA-MB-468 cells, but not non-metastatic MCF-7 and T47D cells. Binding of exE-selectin/Fc was abolished by removal of tumor cell surface sialyl lewis x (sLe(x)) moieties. Employing an exE-selectin/Fc affinity column, we further purified the counterreceptor of E-selectin from metastatic breast cancer cells. The N-terminal protein sequence and cDNA sequence identified this E-selectin ligand as a approximately 170 kD human CD44 variant 4 (CD44v4). Purified CD44v4 showed a high affinity for E-selectin via sLe(x) moieties and, as expected, MDA-MB-231 cell adhesion to and migration across HUVEC monolayers were significantly reduced by down-regulation of tumor cell CD44v4 via CD44v4-specific siRNA. We demonstrated, for the first time, that breast cancer cell CD44v4 is a major E-selectin ligand in facilitating tumor cell migration across endothelial monolayers. This finding offers new insights into the molecular basis of E-selectin-dependent adhesive interactions that mediate breast cancer cell transendothelial metastasis.
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24,117,332
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Mean platelet volume predicts outcome in patients with asymptomatic carotid artery disease.
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Platelets play a pivotal role in atherothrombosis and are potentially involved in the pathogenesis of atherosclerosis. We investigated whether mean platelet volume (MPV) predicts clinical outcome and progression of atherosclerosis in patients with asymptomatic carotid artery disease. We studied 1006 of 1268 prospectively collected consecutive patients with asymptomatic carotid atherosclerosis who were evaluated by duplex sonography. Patients were followed up clinically for the occurrence of a major adverse cardiovascular event (MACE), a composite of myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft, stroke and death. During a median follow-up of 3.1 years (interquartile range, 2.5-3.5), a total of 316 (31.5%) MACEs were recorded. Increased levels of MPV were significantly associated with increased risk of the occurrence of MACEs (adjusted hazard ratio [HR] for an increase in one standard deviation [SD] of MPV 1.22, confidence interval [CI] 1.05-1.35, P < 0.01). Patients with MPV levels above 11.8 femtolitre (= fifth quintile) had a significantly higher event rate (41.3% vs. 29.3%, P < 0.001) with an adjusted HR for MACEs of 1.65 (95% CI 1.26-2.16, P < 0.001) compared with patients with MPV levels in the first to fourth quintile. No significant association was found between baseline MPV levels with either baseline degree or progression during a 6-month follow-up of carotid stenosis. Mean platelet volume was independently and significantly associated with adverse cardiovascular outcome in patients with asymptomatic carotid atherosclerosis.
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18,350,168
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Nitric oxide antagonizes the acid tolerance response that protects Salmonella against innate gastric defenses.
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Reactive nitrogen species (RNS) derived from dietary and salivary inorganic nitrogen oxides foment innate host defenses associated with the acidity of the stomach. The mechanisms by which these reactive species exert antimicrobial activity in the gastric lumen are, however, poorly understood. The genetically tractable acid tolerance response (ATR) that enables enteropathogens to survive harsh acidity was screened for signaling pathways responsive to RNS. The nitric oxide (NO) donor spermine NONOate derepressed the Fur regulon that controls secondary lines of resistance against organic acids. Despite inducing a Fur-mediated adaptive response, acidified RNS largely repressed oral virulence as demonstrated by the fact that Salmonella bacteria exposed to NO donors during mildly acidic conditions were shed in low amounts in feces and exhibited ameliorated oral virulence. NO prevented Salmonella from mounting a de novo ATR, but was unable to suppress an already functional protective response, suggesting that RNS target regulatory cascades but not their effectors. Transcriptional and translational analyses revealed that the PhoPQ signaling cascade is a critical ATR target of NO in rapidly growing Salmonella. Inhibition of PhoPQ signaling appears to contribute to most of the NO-mediated abrogation of the ATR in log phase bacteria, because the augmented acid sensitivity of phoQ-deficient Salmonella was not further enhanced after RNS treatment. Since PhoPQ-regulated acid resistance is widespread in enteric pathogens, the RNS-mediated inhibition of the Salmonella ATR described herein may represent a common component of innate host defenses.
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17,301,597
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Low plasma glutathione levels after reperfused acute myocardial infarction are associated with late cardiac events.
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To clarify whether an altered redox state persists in the subacute phase of myocardial infarction and if specific redox patterns are associated with later cardiac events. Ninety-seven patients [80 men, median 63 (interquartile range, 53, 69) years] with a first acute myocardial infarction, with (53%) or without ST segment elevation, treated with successful percutaneous interventions, were tested at 5-6 days after admission for plasma alpha-tocopherol, ascorbic acid, total and reduced homocysteine, cysteine, glutathione, cysteinylglycine and blood-reduced glutathione, all assessed by high-pressure liquid chromatography. Free malondialdehyde was evaluated by gas chromatography. A subgroup of 14 patients had adjunctive blood samples within 1 h and at 72 h after angioplasty. Blood samples from 44 patients matched for age, sex, and risk factors served as controls. Patients were followed up for median 15 (interquartile range, 9, 17) months for cardiac events. All plasma-reduced aminothiols, vitamins and plasma total glutathione were significantly lower in myocardial infarction at 5-6 days than in controls. In the 14 myocardial infarction patients sampled repeatedly, plasma-reduced glutathione, cysteinylglycine, total glutathione, and alpha-tocopherol significantly decreased, whereas blood-reduced glutathione, total homocysteine, and cysteine significantly increased over time. During follow-up, 20 of 97 (21%) patients had adverse cardiac events. Multivariate analysis revealed that only plasma-reduced glutathione was independently associated with events (hazard ratio 0.42, 95% confidence interval 0.18-0.99, P=0.04). Acute myocardial infarction patients have an altered redox state at 5-6 days after successful reperfusion with respect to controls. Low plasma levels of reduced glutathione at discharge are associated with cardiac events at follow-up.
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17,301,598
|
Ischemia-modified albumin is a highly sensitive serum marker of transient myocardial ischemia induced by coronary vasospasm.
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Ischemia-modified albumin, a new marker of myocardial ischemia, is known to elevate during ischemia induced by percutaneous coronary intervention. It is, however, not known whether ischemia-modified albumin also elevates during transient coronary vasospasm. We evaluated ischemia-modified albumin in patients undergoing intracoronary ergonovine spasm provocation test (n=26). For additional comparison, ischemia-modified albumin was also evaluated in elective percutaneous coronary intervention patients (n=18) and in patients with normal coronary angiography (n=10). Blood samples were taken from the arterial sheath before the procedure, just after procedural completion, or balloon inflation. Median ischemia-modified albumin level elevated significantly in patients with positive provocation test compared with baseline [n=16, 106.0 (interquartile range 96.5, 115.5) versus 128.5 (114.8, 171.8) U/ml, P<0.001], whereas it did not change in patients with negative provocation test [n=10, 109.5 (103.3, 115.0) versus 113.5 (104.0, 118.3) U/ml, P=0.108]. Ischemia-modified albumin was also higher after percutaneous coronary intervention [113.5 (101.0, 131.5) versus 151.0 (129.3, 231.0) U/ml, P<0.0001] and did not change in patients with normal coronary angiography [108.5 (99.3, 114.0) versus 110.0 (108.0, 114.0) U/ml, P=0.085]. Ischemia-modified albumin elevation higher than 9 U/ml after provocation test could detect the presence of coronary vasospasm, with an area under the receiver operating characteristic curve of 0.975 (95% confidence interval 0.921-1.000), with a sensitivity of 94% and a specificity of 99%. Serum albumin levels were within reference range for all patients and there was no significant relationship between albumin and baseline ischemia-modified albumin or postischemic ischemia-modified albumin. Thus, ischemia-modified albumin may have a role as a biochemical marker for transient myocardial ischemia induced by coronary vasospasm.
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17,825,886
|
Resveratrol inhibits glucose metabolism in human ovarian cancer cells.
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Resveratrol is a phytoalexin found in grapes that inhibits the in vitro growth of multiple tumor cell types. We showed previously that resveratrol induces autophagic cell death in ovarian cancer cells. Because autophagy is typically an adaptive response to nutrient starvation, we hypothesized that autophagy would also be triggered when ovarian cancer cells are nutrient deprived and that resveratrol could in fact be acting by inducing a starvation-like signaling response. Ovarian cancer cells were incubated with normal media, media containing resveratrol, glucose free media, or media lacking amino acids. Growth inhibition was determined using the sulforhodamine assay. Cells were evaluated for autophagocytosis by analyzing cleavage of LC3. Glucose uptake, lactate production, and activation of glycolytic regulators pAkt and pmTOR were analyzed following resveratrol treatment. We show here that epithelial ovarian cancer cells are highly sensitive to glucose-deprivation-induced cell death and like resveratrol, glucose deprivation induces caspase-independent cell death with hallmarks of autophagy. Consistent with the hypothesis that resveratrol treatment results in biochemical conditions that mirror a nutrient deprived state, we found that resveratrol dramatically reduces glucose uptake and lactate production. Moreover, resveratrol reduces the levels of phosphorylated Akt and mTOR, two signals that increase glucose uptake and the rate limiting steps in glycolysis. Our findings are consistent with the hypothesis that resveratrol-induced changes in glucose utilization comprise the mechanism that underlies resveratrol-induced autophagocytosis in ovarian cancer. Inhibition of glycolysis in ovarian cancer with resveratrol or other compounds may be effective therapy for ovarian cancer.
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17,301,600
|
Reduced low-frequency heart rate variability relates to greater intimal-medial thickness of the carotid wall in two samples.
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We investigated the relationship between heart rate variability and preclinical carotid intima-media thickening, a putative index of atherosclerosis. A sample of 350 men and women (mean age 56.8 years) selected for the presence or absence of untreated hypertension was assessed for heart rate variability at rest and separately for carotid intima-media thickness using duplex ultrasonography (Pittsburgh study). Findings from this sample were cross-validated in a subsample of 68 men drawn from the Kuopio Ischemic Heart Disease Risk Factor trial and selected for the presence or absence of angina. In both samples, regression analyses, controlling for known risk factors, showed a significant negative relationship between mean carotid intima-media thickness and low-frequency (0.05-0.15 Hz) heart rate variability, but not high-frequency variability. The mechanism underlying this relationship remains unclear. The absence of difference in high-frequency variation questions any interpretation in terms of vagal function; the difference in low-frequency variation may implicate vessel wall characteristics or decreased sympathetic nervous system influence. Decreased amplitude of low-frequency heart rate variability seems associated with a preclinical atherosclerotic index.
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27,263,072
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Different reserve proxies confer overlapping and unique endurance to cortical thinning in healthy middle-aged adults.
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To investigate different proxies of brain and cognitive reserve as potential mediators of the effect of cortical thinning on cognition in healthy middle-aged adults. Eighty-two middle-aged individuals were included (mean(SD) age=45.1(3.9)years). Cortical thickness was calculated for multiple brain regions using FreeSurfer. Cognitive measures sensitive to early cognitive decline were selected, including Block Design from the Wechsler Adult Intelligence Scale-III (WAIS-III), Judgment of Line Orientation Test (JLOT), Color Trails Test (CTT), and first learning trial of TAVEC (the Spanish version of the California Verbal Learning Test, CVLT). Brain reserve was operationalized as total intracranial volume (TIV); and cognitive reserve was estimated by means of Years of Education, WAIS-III Vocabulary subtest, WAIS-III Information subtest, and a Cognitive Reserve Questionnaire (CRQ). Mediation effects were investigated with multiple linear regression and bootstrapping analysis. Information and Vocabulary showed the greatest mediation capacity. All the observed mediations were positive indicating that higher levels of reserve attenuate the effect of reduced cortical thickness on cognition. Information, Vocabulary and TIV buffered the effect of frontal thinning on Block Design; Vocabulary and Years of Education buffered the effect of frontal thinning on JLOT; and CRQ buffered the effect of temporal thinning on CTT. Higher reserve buffers the effect of cortical thinning on cognition in healthy middle-aged adults. The investigated proxies might be underpinned by slightly different neural networks. Advancing in the understanding of the influences of reserve in healthy middle-aged adults is crucial to facilitate early interventions.
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24,117,347
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AMPA receptor antagonist NBQX attenuates later-life epileptic seizures and autistic-like social deficits following neonatal seizures.
|
To determine whether AMPA receptor (AMPAR) antagonist NBQX can prevent early mammalian target of rapamycin (mTOR) pathway activation and long-term sequelae following neonatal seizures in rats, including later-life spontaneous recurrent seizures, CA3 mossy fiber sprouting, and autistic-like social deficits. Long-Evans rats experienced hypoxia-induced neonatal seizures (HS) at postnatal day (P)10. NBQX (20 mg/kg) was administered immediately following HS (every 12 h × 4 doses). Twelve hours post-HS, we assessed mTOR activation marker phosphorylated p70-S6 kinase (p-p70S6K) in hippocampus and cortex of vehicle (HS + V) or NBQX-treated post-HS rats (HS + N) versus littermate controls (C + V). Spontaneous seizure activity was compared between groups by epidural cortical electroencephalography (EEG) at P70-100. Aberrant mossy fiber sprouting was measured using Timm staining. Finally, we assessed behavior between P30 and P38. Postseizure NBQX treatment significantly attenuated seizure-induced increases in p-p70S6K in the hippocampus (p < 0.01) and cortex (p < 0.001). Although spontaneous recurrent seizures increased in adulthood in HS + V rats compared to controls (3.22 ± 1 seizures/h; p = 0.03), NBQX significantly attenuated later-life seizures (0.14 ± 0.1 seizures/h; p = 0.046). HS + N rats showed less aberrant mossy fiber sprouting (115 ± 8.0%) than vehicle-treated post-HS rats (174 ± 10%, p = 0.004), compared to controls (normalized to 100%). Finally, NBQX treatment prevented alterations in later-life social behavior; post-HS rats showed significantly decreased preference for a novel over a familiar rat (71.0 ± 12 s) compared to controls (99.0 ± 15.6 s; p < 0.01), whereas HS + N rats showed social novelty preference similar to controls (114.3 ± 14.1 s). Brief NBQX administration during the 48 h postseizure in P10 Long-Evans rats suppresses transient mTOR pathway activation and attenuates spontaneous recurrent seizures, social preference deficits, and mossy fiber sprouting observed in vehicle-treated adult rats after early life seizures. These results suggest that acute AMPAR antagonist treatment during the latent period immediately following neonatal HS can modify seizure-induced activation of mTOR, reduce the frequency of later-life seizures, and protect against CA3 mossy fiber sprouting and autistic-like social deficits.
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17,825,892
|
Multivariate statistical analysis of large-scale IgE antibody measurements reveals allergen extract relationships in sensitized individuals.
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Many allergenic sources are reportedly cross-reactive because of protein structural similarities. Although several aggregations are well characterized, no holistic mapping of IgE reactivity has hitherto been reported. The aim of this study was to disclose relevant associations within a large set of allergen preparations, as revealed by specific IgE antibody levels in blood sera of multireactive human donors. A dataset of recorded IgE antibody serum concentrations of 1011 nonidentifiable multireactive individuals (devoid of clinical records) to 89 allergen extracts was compiled for in silico analysis. Various algorithms were used to identify specific multivariate dependencies between the IgE antibody levels. Exhaustive cluster analysis demonstrates that IgE antibody responses to the 89 extracts can be aggregated into 12 stable formations. These clusters hold both well-known relationships, unexpected patterns, and unknown patterns, the latter categories being exemplified by the coclustering of wasp and certain seafood and a clear differentiation among pollen allergens. Identified relationships within several well-known groups of cross-reactive allergen extracts confirm the applicability of dedicated multivariate data analysis within the allergology field. Moreover, some of the unexpected IgE reactivity associations in sensitized human subjects might help in identifying new relationships with potential importance to allergy. Although clinical implications from this study should be validated in subsequent investigations with documentation on symptoms included, we believe this seminal approach is a key step toward the development of new analysis tools for interpretation of allergy data generated by using high-throughput recording systems.
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17,301,605
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Antioxidant is a useful supportive agent for the treatment of coronary vasospasm with endothelial dysfunction in pig.
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Recently, many antioxidants have been tested in cardiovascular disease. The effect of antioxidants on alleviation of coronary vasospasm, however, remains unclear. We investigated whether chronic administration of ascorbic acid and glutathione prevents coronary vasospasm in pigs. Balloon-induced endothelial injury in the left anterior descending coronary artery was performed every 2 weeks until 6 weeks (0, 2, 4, 6 weeks). Ten micrograms per kilogram serotonin-induced vasoconstriction was assessed before each endothelial injury and at eighth week by coronary angiography. In endothelial injury without antioxidant group (ED group, n=12), serotonin-induced left anterior descending coronary artery vasoconstriction was augmented from 7+/-4% (0 week) to 88+/-8% (8th week, P<0.01) with electrocardiogram-ST elevation, and an increase of cyclooxygenase-2 expression and a decrease of endothelial nitric oxide synthase expression was observed at the spasm portion removed from the endothelial denuded site. In the endothelial injury group with oral administration of ascorbic acid 3 g/day and glutathione 1 g/day after the first endothelial injury (ASC+GSH group, n=12), serotonin-induced vasoconstriction was suppressed (8th week, 60+/-6%, P<0.01 vs. ED group) and endothelial nitric oxide synthase expression was fairly well maintained. Intimal thickening was observed at the left anterior descending artery spasm portion in the endothelial injury without antioxidant group but not at the corresponding portion in the ASC+GSH group. Antioxidant therapy was partially effective to prevent coronary vasospasm, whereas intimal thickening after endothelial injury was nearly restored. From these results, chronic antioxidant therapy may well be a useful supportive therapy for the treatment of coronary vasospasm, although it has limited availability despite amelioration of endothelial dysfunction.
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27,263,078
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High shear stress relates to intraplaque haemorrhage in asymptomatic carotid plaques.
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Carotid artery plaques with vulnerable plaque components are related to a higher risk of cerebrovascular accidents. It is unknown which factors drive vulnerable plaque development. Shear stress, the frictional force of blood at the vessel wall, is known to influence plaque formation. We evaluated the association between shear stress and plaque components (intraplaque haemorrhage (IPH), lipid rich necrotic core (LRNC) and/or calcifications) in relatively small carotid artery plaques in asymptomatic persons. Participants (n = 74) from the population-based Rotterdam Study, all with carotid atherosclerosis assessed on ultrasound, underwent carotid MRI. Multiple MRI sequences were used to evaluate the presence of IPH, LRNC and/or calcifications in plaques in the carotid arteries. Images were automatically segmented for lumen and outer wall to obtain a 3D reconstruction of the carotid bifurcation. These reconstructions were used to calculate minimum, mean and maximum shear stresses by applying computational fluid dynamics with subject-specific inflow conditions. Associations between shear stress measures and plaque composition were studied using generalized estimating equations analysis, adjusting for age, sex and carotid wall thickness. The study group consisted of 93 atherosclerotic carotid arteries of 74 participants. In plaques with higher maximum shear stresses, IPH was more often present (OR per unit increase in maximum shear stress (log transformed) = 12.14; p = 0.001). Higher maximum shear stress was also significantly associated with the presence of calcifications (OR = 4.28; p = 0.015). Higher maximum shear stress is associated with intraplaque haemorrhage and calcifications.
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26,738,805
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A common TLR1 polymorphism is associated with higher parasitaemia in a Southeast Asian population with Plasmodium falciparum malaria.
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The factors leading to poor outcomes in malaria infection are incompletely understood. Common genetic variation exists in the human genes for Toll like receptors (TLRs) that alter host responses to pathogen-associated molecular patterns. Genetic variation in TLR1 and TLR6 could alter the risk of development of complicated malaria and ability of the host to control the parasite burden during acute Plasmodium falciparum infection. Five single nucleotide polymorphisms in TLR1 and TLR6 in 432 patients with clinical P. falciparum monoinfection acquired on the Thai-Myanmar border were genotyped. Using logistic regression, associations with the development of complicated malaria and the percentage of infected erythrocytes (parasitaemia) on the day of presentation to clinical care (day zero) were tested. Genotypes carrying the T (major) allele of TLR1 rs5743551--an allele associated with improved outcomes in sepsis--were associated with higher parasitaemia measured on day zero (p = 0.03). Since malaria exerts strong genetic pressure on the human genome, protection from parasitaemia associated with TLR1 rs5743551 may account for the maintenance of an allele associated with poor outcomes in Caucasians with sepsis. These data suggest that genetic variation in TLR1 has effects on the host response to Plasmodium falciparum malaria in Asian populations. Genotypes from TLR6 showed no evidence of association with either complicated malaria or parasite burden.
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17,301,625
|
Gender differences in health-related quality of life following ST-elevation myocardial infarction: women and men do not benefit from primary percutaneous coronary intervention to the same degree.
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There is limited evidence whether women benefit to the same degree as men from treatment of myocardial infarction with percutaneous coronary intervention (PCI) when compared to fibrinolysis. This study compares health-related quality of life (HRQoL) outcomes for men and women randomized to primary PCI and fibrinolysis. A questionnaire-based study in 1351 patients with ST-elevation myocardial infarction (STEMI), assessed at 1 and 12 months after the infarction. HRQoL was measured with the Medical Outcomes Study Short Form (SF-36), the Hospital Anxiety and Depression Scale (HADS), Rose's angina and dyspnoea questionnaire and global QoL questions. Women had a worse score than men on all endpoints at 1 month and at several endpoints at 12 months. In analyses of gender differences in benefits of PCI 1 month after the STEMI, significant gender differences were found in the SF-36 mental component summary scale, with men having better scores after primary PCI and women having better scores after fibrinolysis (P=0.03). At 12 months, similar gender differences in treatment benefit were found in the SF-36 scales for general health (P=0.01), mental health (P<0.01), and the mental component summary scale (P=0.01), as well as in the scales for anxiety (P=0.04), depression (P=0.02), and global quality of life (P<0.01); men had better scores after primary-PCI and women had better scores after fibrinolysis. Compared to fibrinolysis treatment in patients with ST-elevation myocardial infarction, women do not seem to benefit from primary PCI to the same degree as men. Since previous studies have found no gender differences in clinical outcomes, this result may be specific to HRQoL.
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24,117,380
|
Hypoxia modulates the activity of a series of clinically approved tyrosine kinase inhibitors.
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Hypoxia in tumours is known to cause resistance to conventional chemotherapeutic drugs. In contrast, little is known about the effects of hypoxia on targeted anti-cancer drugs. This study evaluated the effect of hypoxia on a series of clinically approved tyrosine kinase inhibitors (TKIs). The effect of hypoxia (0.1% oxygen) on the activity of conventional cytotoxic drugs (5-fluorouracil, doxorubicin and vinblastine), the hypoxia-activated prodrug tirapazamine and 9 TKIs was determined in a panel of cell lines. Where hypoxia had a marked effect on chemosensitivity, Western blot analysis was conducted to determine the effect of hypoxia on target expression and the effect of TKIs on cell signalling response under aerobic and hypoxic conditions. Three patterns of chemosensitivity were observed: resistance under hypoxia, equitoxic activity against hypoxic and aerobic cells, and preferential cytotoxicity to hypoxic cells. Significant hypoxia selectivity (independent of HIF1) was observed in the case of dasatinib and this correlated with the ability of dasatinib to inhibit phosphorylation of Src at tyrosine 530. Sorafenib was significantly less effective under hypoxic conditions but resistance did not correlate with hypoxia-induced changes in Raf/MEK/ERK signalling. Hypoxia influences the activity of TKIs but in contrast to conventional cytotoxic drugs, preferential activity against hypoxic cells can occur. The search for hypoxia-targeted therapies has been long and fruitless and this study suggests that some clinically approved TKIs could preferentially target the hypoxic fraction of some tumour types.
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24,641,672
|
Heparin binding VEGF isoforms attenuate hyperoxic embryonic lung growth retardation via a FLK1-neuropilin-1-PKC dependent pathway.
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Previous work in our laboratory demonstrated that hyperoxia suppressed the expression of vascular endothelial growth factor (VEGF) by the embryonic lung, leading to increased epithelial cell apoptosis and failure of explant airway growth and branching that was rescued by the addition of Vegf165. The aims of this study were to determine protective pathways by which VEGF isoforms attenuate hyperoxic lung growth retardation and to identify the target cell for VEGF action. Timed pregnant CD-1 or fetal liver kinase (FLK1)-eGFP lung explants cultured in 3% or 50% oxygen were treated ± Vegf121, VEGF164/Vegf165 or VEGF188 in the presence or absence of anti-rat neuropilin-1 (NRP1) antibody or GO6983 (protein kinase C (PKC) pan-inhibitor) and lung growth and branching quantified. Immunofluorescence studies were performed to determine apoptosis index and location of FLK1 phosphorylation and western blot studies of lung explants were performed to define the signaling pathways that mediate the protective effects of VEGF. Heparin-binding VEGF isoforms (VEGF164/Vegf165 and VEGF188) but not Vegf121 selectively reduced epithelial apoptosis and partially rescued lung bud branching and growth. These protective effects required NRP1-dependent FLK1 activation in endothelial cells. Analysis of downstream signaling pathways demonstrated that the VEGF-mediated anti-apoptotic effects were dependent on PKC activation. Vegf165 activates FLK1-NRP1 signaling in endothelial cells, leading to a PKC-dependent paracrine signal that in turn inhibits epithelial cell apoptosis.
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9,437,321
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Autosomal dominant iris hypoplasia is caused by a mutation in the Rieger syndrome (RIEG/PITX2) gene.
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To determine whether autosomal dominant iris hypoplasia is caused by mutations in the newly described gene for Rieger syndrome (RIEG/PITX2). Mutation screening and sequence analysis was performed in a single family. A novel mutation in the RIEG/PITX2 gene was found in all affected but no unaffected individuals. This mutation would be expected to result in an arginine to tryptophan amino acid change in the homeodomain of solurshin, the RIEG/ITX2 gene product. Autosomal dominant iris hypoplasia is caused by a defect in the same gene that is defective in many cases of Rieger syndrome.
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17,301,644
|
Acetic acid allows effective selection of areas for obtaining biopsy samples in Barrett's esophagus.
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The aim of this study was to determine whether macroscopic changes resulting from acetic acid application on the surface of columnar-lined esophagus allow regular, nonmagnifying, endoscopic identification of areas presenting dysplasia and/or cancer in Barrett's esophagus. A total of 100 patients (mean age, 53 years; range, 27-86 years) under surveillance because of short-segment (n=71) and long-segment (n=29) Barrett's esophagus, with no alterations of columnar-lined esophagus on standard endoscopy, were enrolled. After endoscopic examination, 3% acetic acid was sprayed on columnar-lined esophagus. The subsequent appearance of the mucosa was classified as: (1) Normal pattern: uniform reticulum along the entire columnar-lined esophagus. (2) Abnormal pattern: reticulum presenting areas of rough or irregular appearance. Biopsy samples were obtained from areas of normal and abnormal patterns, and the results of the corresponding histological studies were compared. All endoscopies were performed by the same investigator. The endoscopic appearance, after acetic acid application, corresponded to a normal pattern in 85% of cases and an abnormal pattern in 15%. The percentage of dysplasia and adenocarcinoma in biopsy specimens was significantly higher in patients with rough or irregular areas (86.7%) than in those with normal uniform reticulum (0%) (P< 0.001). Sensitivity for the identification of areas of dysplasia or adenocarcinoma was 100% (95% confidence interval: 71.7-100%). Specificity was 97.7% (95% confidence interval: 91.2-99.6%). This prospective study shows that acetic acid test is useful for standard, nonmagnifying, endoscopic detection of dysplasia and cancer in Barrett's esophagus.
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26,214,540
|
Changes in posttraumatic cognitions predict changes in posttraumatic stress disorder symptoms during cognitive processing therapy.
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Although cognitive processing therapy (CPT) has strong empirical support as a treatment for posttraumatic stress disorder (PTSD), studies have not directly examined the proposed change mechanisms that underlie CPT-that change in trauma-related cognitions produces change in PTSD and depression symptoms. To improve the understanding of underlying mechanisms of psychotherapeutic change, this study investigated longitudinal association between trauma-related cognitions, PTSD, and depression among veterans receiving CPT during a 7-week residential PTSD treatment program. All 195 veterans met DSM-IV-TR diagnosis for PTSD. The sample was 53% male with a mean age of 48 years. Self-reported race was 50% White and 45% African American. The Posttraumatic Cognitions Inventory was used to assess trauma-related cognitions. The PTSD Checklist and Beck Depression Inventory-II were used to assess PTSD and depression, respectively. Cross-lagged panel models were used to test the longitudinal associations between trauma-related cognitions, PTSD, and depression. Measures were administered at three time points: pre-, mid-, and posttreatment. Change in posttraumatic cognitions (self-blame; negative beliefs about the self) preceded change in PTSD. In addition, (a) change in negative beliefs about the self preceded change in depression, (b) change in depression preceded change in self-blame cognitions, and (c) change in depression preceded change in PTSD. Findings support the hypothesized underlying mechanisms of CPT in showing that change in trauma-related cognitions precedes change in PTSD symptoms. Results suggest that reduction of depression may be important in influencing reduction of PTSD among veterans in residential PTSD treatment.
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26,214,541
|
Testing gene × environment moderation of tobacco and marijuana use trajectories in adolescence and young adulthood.
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This study examines the main and interaction effects of known social risk factors for substance use (inadequate parental monitoring and substance using friends) in adolescence and a polygenic score in predicting marijuana and tobacco use in adolescence and young adulthood. Phenotypic and genetic data were derived from a longitudinal study of a cohort of urban, predominately African American youth. Last year substance-use measures were collected annually from 8th grade through age 22. Participant self-reports of substance-using friends and parent monitoring were obtained yearly from Grades 8 to 12. Using longitudinal latent class analysis, the authors identified parallel developmental trajectories of tobacco and marijuana use and parent monitoring and the proportion of substance-using friends. Two trajectories were identified for tobacco and marijuana use, characterized by moderate versus little-to-no use. Additionally, 2 latent profiles were found for the social environment profiles: those characterized by higher parent monitoring and a lower proportion of substance-using friends versus lower parent monitoring and a higher proportion of substance-using friends. We found main and interaction effects for the polygenic score and social environment profile in predicting the longitudinal classes of marijuana and tobacco use. With respect to the interaction effect, membership in the moderate-use classes of marijuana and tobacco use was highest among those in the social environment profile characterized by lower parent monitoring and a higher proportion of substance-using friends.
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18,350,224
|
Messages about dual contraception in areas of high HIV prevalence are not heeded.
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Dual protection is recommended for prevention of unwanted pregnancies and protection against sexually transmitted infections, including HIV. It is critical for HIV-negative women to prevent seroconversion and HIV transmission to their infants during pregnancy and breastfeeding. Women were followed up after delivery, monthly for the first 9 months and then 3-monthly to 24 months, in a cohort study investigating postnatal HIV transmission. Study nurses discussed family planning, including condom use, at each visit. Contraceptive methods used since the last visit were recorded. All women knew their HIV status, and most women breastfed for a minimum of 6 months. Among 1,137 HIV-positive and 1 220 HIV-negative women the most common contraceptive method was the hormonal injectable; few women used condoms alone or as dual contraception (0-3 months 6.8%; 7-12 months 16.3%; 19-24 months 14.4%). Compared with uninfected women, HIV-positive women were more likely to use condoms in years 1 and 2 after delivery (adjusted odds ratio (AOR) 1.72, 95% confidence interval (CI) 1.38-2.14, p<0.001; AOR 1.61, 95% CI 1.15-2.25, p=0.006 respectively). Compared with women with a flush toilet, those with a pit latrine were less likely to use condoms in years 1 and 2 (AOR 0.22, 95% CI 01.7-0.28, p<0.001; AOR 0.27, 95% CI 0.19-0.39, p<0.001). Older women were more likely to use condoms in the first postpartum year (AOR 1.78, 95% CI 1.03-3.09, p=0.040). More creative ways of promoting condoms and dual contraception need to be found if new HIV infections, in women and children, are to be prevented.
|
25,165,972
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Endoscopy findings affect subjective smell rehabilitation in post-laryngectomy patients using the nasal airflow-inducing manoeuvre.
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To evaluate the characteristics of post-laryngectomy patients, including nasal endoscopy findings, that affect subjective smell improvement in the post-surgical period. Thirty patients who had undergone total laryngectomy participated in at least three sessions of a smell rehabilitation programme involving the nasal airflow-inducing manoeuvre, under the supervision of a speech-language pathologist. Patient characteristics and nasal endoscopy findings were evaluated. Participants experienced a mean improvement in sense of smell of 61 per cent (p < 0.001) and a significant improvement in appetite (p = 0.002). Male patients and patients with a nasal discharge had a significantly better outcome. The nasal airflow-inducing manoeuvre is an effective method for improving smell perception and appetite in laryngectomy patients. There was no relationship between nasal endoscopy findings and outcome of the nasal airflow-inducing manoeuvre rehabilitation programme in our case series.
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18,350,230
|
Phototherapy causes DNA damage in peripheral mononuclear leukocytes in term infants.
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Our aim was to determine whether endogenous mononuclear leukocyte DNA strand is a target of phototherapy. The study included 65 term infants aged between 3-10 days that had been exposed to intensive (n = 23) or conventional (n = 23) phototherapy for at least 48 hours due to neonatal jaundice, and a control group (n = 19). DNA damage was assayed by single-cell alkaline gel electrophoresis (comet assay). Plasma total antioxidant capacity and total oxidant status levels were also measured, and correlation between DNA damage and oxidative stress was investigated. Mean values of DNA damage scores in both the intensive and conventional phototherapy groups were significantly higher than those in the control group (p < 0.001). Mean values and standard deviation were 32 (9), 28 (9), 21 (7) arbitrary unit, respectively. Total oxidant status levels in both the intensive and conventional phototherapy groups were significantly higher than those in the control group (p = 0.005). Mean (standard deviation) values were 18.1 (4.2), 16.9 (4.4), 13.5 (4.2) micromol H2O2 equivalent/L, respectively. Similarly, oxidative stress index levels in both the intensive and conventional phototherapy groups were significantly higher than those in the control group (p = 0.041). Plasma total antioxidant capacity and total bilirubin levels did not differ between the groups (p > 0.05). There were no significant correlations between DNA damage scores and bilirubin, total oxidant status and oxidative stress levels in either phototherapy group (p > 0.05). Both conventional phototherapy and intensive phototherapy cause endogenous mononuclear leukocyte DNA damage in jaundiced term infants.
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16,777,368
|
Depth of invasion is the most significant histological predictor of subclinical cervical lymph node metastasis in early squamous carcinomas of the oral cavity.
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Cervical node metastasis is the single most important prognostic factor in head and neck squamous carcinomas. Taking a homogenous patient population, applying stringent selection criteria, and standard pathological evaluation methods, this retrospective study aims to establish histological predictors of subclinical cervical node metastasis in early (T1-T2/N0) squamous carcinomas of the oral cavity, thereby identifying a subset of patients who are at an increased risk for cervical node metastasis. Forty-eight previously untreated patients with clinically T1 or T2, and N0, squamous carcinomas of the oral cavity who were treated with primary excision of the tumour and elective neck node dissection were selected. Various histological factors including T size, gross and microscopic tumour depth and thickness, grade of differentiation, pattern of invasion, inflammatory response, perineural and lymphovascular invasion were studied. The statistical significance of various parameters as predictors of subclinical node metastasis was determined using logistic regression analysis. Of all the parameters studied, microscopic tumour depth and thickness were the only significant factors (P value=0.026 and 0.046, respectively) which correlated with cervical node metastasis, on univariate analysis. Tumour depth emerged as a single most significant predictor on multivariate analysis. Majority of patients with node metastasis had a tumour depth of more than or equal to 5 mm. Depth is the most significant predictor of cervical node metastasis in early squamous carcinomas of the oral cavity. Patients with a tumour depth of more than or equal to 5 mm are at an increased risk of harbouring node metastasis, hence should be taken up for elective node dissection.
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7,864,473
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Home use of syrup of ipecac is associated with a reduction in pediatric emergency department visits.
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To determine whether home use of syrup of ipecac is safe and effective in reducing pediatric emergency department visits. Retrospective, multicenter comparison based on secondary use of a large database. Children younger than 6 years after acute, accidental ingestion of a pharmaceutical product. 1990 Data corresponding to the study patients from seven regional poison centers were obtained from the American Association of Poison Control Centers. Poison center management choices (particularly use of syrup of ipecac for home decontamination) and characteristics (distribution of pharmaceutical ingestions managed, work volume per staff, staff experience, and training of decision-making director) were analyzed for their impact on the decision to refer a patient to a health care facility or to manage the patient at home. Statistical techniques included weighted least-squares regression analysis using logistic transformation of dependent variables and the forward selection procedure. Adverse patient outcome was defined as moderate effect, major effect, or death (American Association of Poison Control Centers coding criteria). In all, 55,436 children were included in the analysis (range, 3,839 to 12,691 per poison center). The distribution of medications ingested was similar among centers. Increased home use of syrup of ipecac, decreased frequency of ingestion of "high-risk" drugs, and increased staff experience were associated with decreased referral to a health care facility (P < .0001 for each variable). The forward selection procedure determined that syrup of ipecac use explained 45% of the variation in the poison center referral rates. The percentage of drugs defined as high-risk accounted for an additional 31%, and staff experience accounted for another 10% of the variation. Outcome of patients was excellent. No child died. Two home-managed patients had a major effect, and 26 had a moderate effect. Centers that recommended home use of syrup of ipecac more frequently were able to manage childhood poisoning more cost-effectively, without a decrease in safety. Although increased home management was strongly associated with syrup of ipecac use, the reason for this relationship cannot be determined from the data. Management by experienced professionals also contributed to cost-effectiveness.
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24,117,403
|
Sleep apnoea patients have higher mortality when confronting sepsis.
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Sleep is essential for the maintenance of an intact immune function. Patients with sleep apnoea experience frequent sleep interruption due to apnoea-related arousals, possibly adversely impacting their immunity and affecting their outcomes when confronting sepsis. This case-control study aimed to compare the outcomes of sepsis patients with and without sleep apnoea. From 2000 to 2009, 168 sleep apnoea patients who were first admitted for sepsis were identified from the Taiwan National Health Insurance Research Database. Also, 672 sepsis patients without sleep apnoea, who were matched by age, gender and Charlson's comorbidity index scores, served as controls. Hospital outcomes of the two groups were compared. Binary logistic regression was employed for multivariate analysis. The mortality rates of sepsis patients with and without sleep apnoea were 60.1% and 47.9%, respectively (P = 0. 005). After multivariate adjustment, sleep apnoea (OR: 1.805, 95% CI: 1.227-2.656, P = 0.003), presence of shock (OR: 3.600, 95% CI: 2.144-6.046, P < 0.001) and number of organs with dysfunction (OR: 1.591, 95% CI: 1.087-2.329, P = 0.017) were found to be independently associated with mortality. Sleep apnoea patients who needed continuous positive airway pressure treatment had an even higher risk of mortality. Sepsis patients with sleep apnoea may have poorer hospital outcomes than those without sleep apnoea.
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16,253,083
|
Gingipain-specific IgG in the sera of patients with periodontal disease is necessary for opsonophagocytosis of Porphyromonas gingivalis.
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Porphyromonas gingivalis is a primary etiologic agent of generalized aggressive periodontitis (GAgP), and gingipains, a group of cysteine proteinases, are critical virulence factors expressed by this organism. GAgP patients develop specific antibodies to gingipains; however, the function of these antibodies in the clearance of P. gingivalis infection is poorly understood. In this study, we defined the levels of gingipain-specific antibodies in GAgP patient sera and examined the ability of gingipain-specific antibodies to facilitate opsonophagocytosis of P. gingivalis by human polymorphonuclear leukocytes (PMNs) using a fluorescent phagocytosis assay. GAgP patient sera possessed elevated levels of P. gingivalis-, arginine-gingipain (Rgp)A-, RgpB-, and lysine-gingipain (Kgp)-specific IgG (Kgp > RgpA > P. gingivalis > RgpB). Adsorption of GAgP sera with P. gingivalis whole organisms, RgpA, RgpB, and Kgp conjugated to sepharose beads reduced opsonophagocytosis of P. gingivalis by PMNs. Our studies demonstrate that GAgP patient sera possess elevated levels of P. gingivalis- and gingipain-specific IgG. Furthermore, we show that gingipain antibodies promote uptake of P. gingivalis by PMNs, and our data suggest that gingipain-specific antibodies may be important for the control of P. gingivalis infections.
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16,253,089
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T cells support osteoclastogenesis in an in vitro model derived from human periodontitis patients.
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Periodontitis is characterized by alveolar bone destruction; however, the mechanisms responsible for bone damage are poorly understood. It has been reported that T cells are implicated in the pathogenesis of periodontitis. It has been also demonstrated that activated T lymphocytes secrete receptor activator of nuclear factor-kappa B ligand (RANKL) and can support the differentiation of monocytes into resorbing osteoclasts (OCs). Therefore, the purpose of this study was to examine the OC formation in periodontitis patients (PP) and the role of T cells in osteoclastogenesis. To study OC formation, we used an in vitro model consisting of unstimulated and unfractionated peripheral blood mononuclear cells (PBMCs) from PP and controls. In parallel, T-cell-depleted PBMCs from the same patients were also established. The expression of RANKL and tumor necrosis factor-alpha (TNF-alpha) was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot in fresh T cells isolated from PP and controls. Functional antibodies, anti-RANKL and anti-TNF-alpha, were utilized to study osteoclastogenesis in PBMC cultures from PP. We showed that, in unfractionated PBMCs from PP, the OCs spontaneously developed in a T-cell-dependent way. The addition of macrophage colony stimulating factor (MCSF) and RANKL was necessary to promote the osteoclastogenesis in T-cell-depleted PBMC cultures from PP and in unfractionated PBMCs from periodontally healthy controls. Moreover, freshly isolated T cells from PBMCs of PP overexpressed RANKL and TNF-alpha. Finally, functional anti-RANKL and anti-TNF-alpha antibodies significantly inhibited osteoclastogenesis. Our data suggest that T cells support spontaneous osteoclastogenesis in PP via RANKL and TNF-alpha overexpression.
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16,253,097
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Human gingival fibroblast integrin subunit expression on titanium implant surfaces.
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Implant surface characteristics have been shown to modify cell behavior and regulate integrin expression. Integrin expression and resultant integrin-mediated cellular activity are essential components of tissue healing and homeostasis. Although both osseous and soft tissue healing around dental implants are critical to clinical success, there is limited information available on the effect of implant surfaces on integrin expression in soft tissues. Therefore, the aim of this study was to examine integrin expression for gingival fibroblasts on titanium surfaces and the influence of titanium surface roughness on integrin expression and cell morphology. Human gingival fibroblasts were cultured on smooth (polished) and rough (sand-blasted acid-etched) titanium surfaces and a cell culture plastic (control) surface. To analyze integrin expression, total RNA was isolated from experimental and control cells, and levels of integrin subunit mRNA were assessed by reverse transcription-polymerase chain reaction (RT-PCR) using primers specific for the alpha2, alpha4, alpha5, alpha(v), and beta1 integrin subunits and aldolase (internal control). PCR products were analyzed by polyacrylamide gel electrophoresis (PAGE), confirmed via DNA sequencing, and quantified using computer-assisted densitometry. The expression of the integrin subunits was analyzed at the protein level using flow cytometry, as well as fluorescence and confocal laser microscopy. Cell morphology was evaluated using scanning electron microscopy (SEM). Our experiments demonstrated cellular expression of the alpha2, alpha4, alpha5, alpha(v), and beta1 integrin subunits at both mRNA and protein levels on all surfaces. In addition, the alpha4 and beta1 mRNA levels were significantly increased on smooth titanium relative to plastic surfaces (P <.05) with intermediate mRNA levels found on the rough titanium surfaces. The smooth titanium surfaces exhibited a flat monolayer of cells, while rough titanium surfaces showed cells orienting themselves along surface irregularities. These results demonstrate the presence of multiple integrin subunits in human gingival fibroblasts grown in contact with titanium implant surfaces and that titanium surface roughness alters cellular morphology but appears to have limited effects on integrin expression. This study provides insight into the complicated cellular and molecular events occurring at the implant surface that may be critical to optimizing the soft tissue interactions with the soft tissue-implant interface.
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22,020,265
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Sphingosine-kinase 1 and 2 contribute to oral sensitization and effector phase in a mouse model of food allergy.
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Sphingosine-1-phosphate (S1P) influences activation, migration and death of immune cells. Further, S1P was proposed to play a major role in the induction and promotion of allergic diseases. However, to date only limited information is available on the role of S1P in food allergy. We aimed to investigate the role of sphingosine-kinase (SphK) 1 and 2, the enzymes responsible for endogenous S1P production, on the induction of food allergy. Human epithelial colorectal CaCo2 cells stimulated in vitro with S1P revealed a decrease of transepithelial resistance and enhanced transport of FITC labeled OVA. We studied the effect of genetic deletion of the enzymes involved in S1P production on food allergy induction using a mouse model of food allergy based on intragastrically (i.g.) administered ovalbumin (OVA) with concomitant acid-suppression. Wild-type (WT), SphK1(-/-) and SphK2(-/-) mice immunized with OVA alone i.g. or intraperitoneally (i.p.) were used as negative or positive controls, respectively. SphK1- and SphK2-deficient mice fed with OVA under acid-suppression showed reduced induction of OVA specific IgE and IgG compared to WT mice, but had normal responses when immunized by the intraperitoneal route. Flow cytometric analysis of spleen cells revealed a significantly reduced proportion of CD4(+) effector T-cells in both SphK deficient animals after oral sensitization. This was accompanied by a reduced accumulation of mast cells in the gastric mucosa in SphK-deficient animals compared to WT mice. Furthermore, mouse mast cell protease-1 (mMCP-1) levels, an IgE-mediated anaphylaxis marker, were reliably elevated in allergic WT animals. Modulation of the S1P homeostasis by deletion of either SphK1 or SphK2 alters the sensitization and effector phase of food allergy.
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25,165,998
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Spinal cord stimulation suppresses focal rapid firing-induced atrial fibrillation by inhibiting atrial ganglionated plexus activity.
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This study was designed to demonstrate that spinal cord stimulation (SCS) could suppress high-frequency stimulation (HFS)-induced focal atrial fibrillation (AF) at atrial and pulmonary vein (PV) sites by inhibiting atrial ganglionated plexus (GP) activity. Multielectrode catheters were attached to atria and all PV sites. SCS was performed at the T1-T5 spinal region for 1 hour. At the baseline state and the end of 1 hour of SCS, 40 milliseconds of HFS was delivered 2 milliseconds after atrial pacing to determine the AF threshold at each site. One electrode was attached to the superior left GP so that HFS to this site induced sinus rate slowing. Microelectrodes inserted into the anterior right GP recorded neural firing. SCS induced a significant increase in AF threshold at all sites (all P < 0.05). The sinus rate slowing response induced by superior left GP stimulation was blunted by SCS (17% ± 3.6% vs. 39% ± 3.8%, P < 0.05). The frequency (32 ± 4 vs. 87 ± 6 impulses per minute, P < 0.05) and amplitude (0.16 ± 0.02 vs. 0.42 ± 0.04 mv, P < 0.05) of the neural activity recorded from the anterior right GP were markedly inhibited by SCS. SCS may prevent episodic AF caused by rapid PV and non-PV firing through modulating GP activity.
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27,787,448
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SMOKING IS A RISK FACTOR FOR PROLIFERATIVE VITREORETINOPATHY AFTER TRAUMATIC RETINAL DETACHMENT.
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To determine the incidence of retinal redetachment due to proliferative vitreoretinopathy after open-globe trauma in smokers and nonsmokers. A total of 892 patients comprising 893 open-globe injuries, in whom 255 eyes were diagnosed with a retinal detachment, and 138 underwent surgical repair were analyzed in a retrospective case-control study. Time to redetachment was examined using the Kaplan-Meier method and analysis of risk factors was analyzed using Cox proportional hazards modeling. Within one year after retinal detachment surgery, 47% (95% CI, 39-56%) of all 138 repaired retinas redetached because of proliferative vitreoretinopathy. Being a smoker was associated with a higher rate of detachment (adjusted hazard ratio 1.96, P = 0.01). As shown in previous studies, the presence of proliferative vitreoretinopathy at the time of surgery was also an independent risk factor for failure (adjusted hazard ratio 2.13, P = 0.005). Treatment with vitrectomy-buckle compared favorably to vitrectomy alone (adjusted hazard ratio 0.58, P = 0.04). Only 8% of eyes that redetached achieved a best-corrected visual acuity of 20/200 or better, in comparison to 44% of eyes that did not redetach (P < 0.001). Proliferative vitreoretinopathy is a common complication after the repair of retinal detachment associated with open-globe trauma, and being a smoker is a risk factor for redetachment. Further study is needed to understand the pathophysiologic mechanisms underlying this correlation.
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17,301,689
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CYP2D6 worldwide genetic variation shows high frequency of altered activity variants and no continental structure.
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CYP2D6, a member of the cytochrome P450 superfamily, is responsible for the metabolism of about 25% of the commonly prescribed drugs. Its activity ranges from complete deficiency to excessive activity, potentially causing toxicity of medication or therapeutic failure with recommended drug dosages. This study aimed to describe the CYP2D6 diversity at the global level. A total of 1060 individuals belonging to 52 worldwide-distributed populations were genotyped at 12 highly informative variable sites, as well as for gene deletion and duplications. Phenotypes were predicted on the basis of haplotype combinations. Our study shows that (i) CYP2D6 diversity is far greater within than between populations and groups thereof, (ii) null or low-activity variants occur at high frequencies in various areas of the world, (iii) linkage disequilibrium is lowest in Africa and highest in the Americas. Patterns of variation, within and among populations, are similar to those observed for other autosomal markers (e.g. microsatellites and protein polymorphisms), suggesting that the diversity observed at the CYP2D6 locus reflects the same factors affecting variation at random genome markers.
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24,641,725
|
The active form of MMP-3 is a marker of synovial inflammation and cartilage turnover in inflammatory joint diseases.
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Matrix metalloproteinase-3 (MMP-3) plays an important role in the pathology of rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Measurement of active MMP-3 in clinical samples could provide information about progression of rheumatoid diseases, and potentially response to treatment. Hence, we aimed to develop a sensitive assay specifically measuring the active form of MMP-3 (act-MMP-3) both in ex vivo models and in human sera. A monoclonal antibody against the first 6 amino acids of act-MMP-3 was developed, and the specificity was carefully tested by comparing total and active MMP-3. A technically robust act-MMP-3 ELISA was produced. For biological validation, human synovial membrane and human cartilage explant (HEX) culture models were measured and compared by ELISA and immunoblots. For clinical relevance, the serum levels of act-MMP-3 in AS and RA patients before and after anti-TNF-α treatment were evaluated. A highly specific and technically robust ELISA detecting act-MMP-3 in serum was developed. The lower limit of detection was 33.7 pg/mL. The dilution and spiking recovery of human serum was within 100 ± 20%. The average intra- and inter-assay variations were 3.1% and 13.5% respectively.High levels of act-MMP-3 expression were observed in human synovial membrane culture and oncostatin M and TNF-α stimulated human cartilage. In a cross-sectional study of both AS and RA patients, serum act-MMP-3 level was correlated with C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). In addition, in patients receiving anti-TNF-α treatment, the serum level of act-MMP-3 was significantly reduced compared to baseline level reflecting the anti-inflammatory effects of the treatment. We have successfully developed an assay measuring act-MMP-3 in human serum showing correlation to inflammatory markers. Further studies are required to clarify, whether act-MMP-3 can serve as a predictive marker for outcome in chronic rheumatoid disorders.
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19,398,848
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The association between maternal smoking during pregnancy and childhood obesity persists to the age of 9-10 years.
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We previously reported that a number of factors related to maternal lifestyle during early pregnancy, including smoking, are associated with childhood obesity at 5 years of age. In the present study, we investigated whether the association with maternal smoking persisted to the age of 9-10 years. The study population comprised children born between April 1, 1991 and March 31, 1999, and their mothers. The dependent variables--childhood overweight and obesity at 5 and 9-10 years of age--were defined according to internationally acknowledged cut-off values. Maternal smoking during early pregnancy was used as the independent variable. Mothers who completed a specifically designed questionnaire gave birth to a total of 1644 infants during the study period. Anthropometric data were collected from 1302 of these children during medical checkups at 9-10 years of age (follow-up rate: 79.2%). Maternal smoking during early pregnancy was associated with obesity in 9- to 10-year-old children (adjusted odds ratio, 1.91; 95% confidence interval, 1.03-3.53). However, the point estimates at the age of 9-10 years were considerably lower than those at the age of 5 years. Our results suggest that fetal environment, including exposure to maternal smoking, continues to be associated with childhood obesity at the age of 9-10 years.
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18,350,273
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Moderate and severe traumatic brain injury induce early overexpression of systemic and brain gelatinases.
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Recent experimental evidence suggests that matrix metalloproteinases (MMPs) are implicated in the pathophysiology of traumatic brain injury (TBI) by increasing blood-brain barrier permeability and exacerbating posttraumatic edema. We examined the acute profile of MMP-2 and MMP-9 in the plasma of patients with moderate or severe TBI and in the brain extracellular fluid (ECF). Prospective observational study. Neurotraumatology intensive care unit of a tertiary university hospital. Twenty patients with moderate or severe TBI were included and three groups were used as controls: 20 patients with a mild head injury and normal CT scan, 15 moderate polytrauma patients without TBI, and 20 healthy volunteers. Plasma samples were collected within the first 12[Symbol: see text]h and at 24[Symbol: see text]h post-injury. Simultaneous brain microdialysate and plasma samples were obtained in four moderate-severe TBI patients at additional timepoints: 48, 72, and 96[Symbol: see text]h post-TBI. Gelatinases (MMP-2 and MMP-9) were measured by gelatin zymography. A significant increase in plasma gelatinases was observed at baseline when compared with healthy volunteers in the study group. This early increase was followed by a significant decrease at 24[Symbol: see text]h post-injury. Brain microdialysis samples presented a similar time profile as plasma samples for both gelatinases. High levels of gelatinases were found in plasma and brain ECF in the early phase of TBI, indicating that both local and systemic trauma-induced upregulation of gelatinases in the acute phase might play an important role in the pathophysiology of TBI and could be a future therapeutic target.
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25,166,018
|
Racial difference in cochlear pigmentation is associated with hearing loss risk.
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The goals of this study are to characterize the distribution of melanin pigmentation in the human cochlea and to investigate differences in pigment content between races. Human temporal bone specimens from the Johns Hopkins Temporal Bone Collection were examined. Demographic, clinical, and audiometric data were analyzed. Melanin pigmentation in the cochlea was quantified in each specimen. Nineteen African-American (AA) and 27 Caucasian specimens were selected for the study. The mean ages were 64 and 70 years for AA and Caucasian specimens, respectively (p = 0.21). At all cochlear turns, AA specimens contained significantly more pigmentation in the stria vascularis (p = 0.0003) and Rosenthal's canal (p < 0.0001) compared with Caucasian specimens. Strial melanin content increased significantly with age. Cochlear pigmentation content was not associated with sex or hearing thresholds. Melanin pigmentation is significantly more abundant in AA cochleae than in Caucasian cochleae. This study provides a detailed description of pigmentation in the cochlea and may help to explain the observed racial differences in hearing thresholds.
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24,117,444
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Dermoscopy uncovers clinically undetectable pigmentation in basal cell carcinoma.
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The presence of pigmentation might influence the management of basal cell carcinoma (BCC), with pigmented BCC responding poorly to certain treatments. Clinical studies report on a generally lower frequency of pigmentation compared with dermoscopic and histopathological studies, but the true frequency at which pigmentation occurs in clinically nonpigmented BCC has not been studied in detail. To compare the clinical and dermoscopic frequency of pigmentation in a series of histopathologically diagnosed BCCs and to correlate it with patient demographics, tumour location and histopathological subtype. Clinical and dermoscopic images of histopathologically confirmed BCCs were retrospectively evaluated for the presence of pigmentation. Dichotomous outcome variables were clinically pigmented and dermoscopically pigmented BCC. All separate dermoscopic variables were included in the analysis. Differences in proportions were evaluated using Pearson's chi-square test. Five hundred and seven BCCs from 507 patients with a mean age of 67 years and a male-to-female ratio of 1.35 : 1 were included in the study. Clinically, 295 tumours were judged as nonpigmented. Of those, dermoscopy disclosed pigmentation in 88 cases (29.8%). Overall, blue-grey ovoid nests were the most frequent dermoscopic pattern (n = 184, 36.3%), followed by multiple blue-grey dots/globules (n = 147, 29%) and maple-leaf-like areas (n = 70, 13.8%). Superficial tumours exhibited mainly maple-leaf-like areas, spoke-wheel areas and brown dots, whereas pigmented nodular BCC was most frequently typified by the presence of blue-grey ovoid nests. Dermoscopy allows detection of pigmentation in about 30% of clinically nonpigmented BCCs, providing additional information that may aid the clinical choice of adequate treatment modalities.
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10,485,960
|
Fluoxetine blocks expression but not development of sensitization to morphine-induced oral stereotypy in rats.
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Repeated high doses of morphine in the rat cause stereotypic gnawing behavior that can be re-expressed by a low dose of morphine weeks and even months after the initial treatment. The determination of the role of serotonin in this sensitized morphine-induced behavior has both empirical and theoretical relevance. To determine whether the serotonin-reuptake blocker fluoxetine will block the development and/or the expression of this opiate-induced stereotypy. Rats were given four 10-mg/kg injections of morphine alone or with 5.0 mg/kg fluoxetine over a 36-h period. At weekly intervals for 6 weeks after the last of the sensitizing morphine doses, all rats were challenged with 4.0 mg/kg morphine. At week 2 and week 4, however, the morphine was co-administered with fluoxetine. Fluoxetine completely blocked the expression of the morphine-induced stereotypy; however, when the morphine/fluoxetine-treated rats were challenged with morphine alone, they expressed similar degrees of stereotypy as the rats that initially only received morphine. The results indicate that increasing synaptic serotonin will block the expression but not the development of sensitization to the oral stereotypic effects of repeated high doses of morphine. Also, despite the complete blocking of the morphine effect by fluoxetine during the sensitization phase, the presence of significant biting by these rats during the challenge with morphine alone argues that conditioning factors are not a necessary component for the morphine sensitization to develop.
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18,350,281
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An extract of Salvia (sage) with anticholinesterase properties improves memory and attention in healthy older volunteers.
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Species of Salvia (sage) have a long-standing reputation in European medical herbalism, including for memory enhancement. In recent controlled trials, administration of sage extracts with established cholinergic properties improved cognitive function in young adults. This randomised, placebo-controlled, double-blind, balanced, five-period crossover study investigated the acute effects on cognitive performance of a standardised extract of Salvia officinalis in older adults. Twenty volunteers (>65 years of age, mean = 72.95) received four active doses of extract (167, 333, 666 and 1332 mg) and a placebo with a 7-day wash-out period between visits. Assessment involved completion of the Cognitive Drug Research computerised assessment battery. On study days, treatments were administered immediately following a baseline assessment with further assessment at 1, 2.5, 4 and 6 h post treatment. Compared with the placebo condition (which exhibited the characteristic performance decline over the day), the 333-mg dose was associated with significant enhancement of secondary memory performance at all testing times. The same measure benefited to a lesser extent from other doses. There also were significant improvements to accuracy of attention following the 333-mg dose. In vitro analysis confirmed cholinesterase inhibiting properties for the extract. The overall pattern of results is consistent with a dose-related benefit to processes involved in efficient stimulus processing and/or memory consolidation rather than retrieval or working memory efficiency. These findings extend those of the memory-enhancing effects of Salvia extracts in younger populations and warrant further investigation in larger series, in other populations and with different dosing regimes.
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10,485,963
|
Sensitization of apomorphine-induced stereotyped behavior in mice is context dependent.
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The role of the environment in the sensitization of the stereotyped behavioral effects of apomorphine is unclear, since sensitization of this drug effect has either been difficult to demonstrate or has been shown to occur with a low but not a higher dose of apomorphine. The present study was designed to determine whether sensitization of the stereotyped behavioral effects induced by a single dose of apomorphine is dependent on environmental context. CF-1 mice were pretreated with apomorphine or vehicle under different environmental conditions and tested for stereotyped behavior after apomorphine challenge. Animals were scored positively for stereotyped behavior if they remained stationary and exhibited repetitive head and/or fore-limb movements, and data are reported as the percentage of mice rated as positive for stereotyped behavior. When mice were pretreated with 40 mg/kg apomorphine and later tested in the same environment, the dose-response curve for stereotyped behavior elicited by apomorphine was shifted threefold to the left 48 h after pretreatment, and this sensitization persisted for at least 28 days after pretreatment. Mice pretreated with apomorphine did not have higher brain levels of apomorphine after administration of the test dose of apomorphine. When the pretreatment environment was different from the test environment, mice did not exhibit sensitization to apomorphine. These results show that pre-exposure to a single high dose of apomorphine induces a long-lasting sensitization of apomorphine-induced stereotyped behavior that is context dependent. Since apomorphine directly activates dopamine receptors, these observations suggest that a mechanism located postsynaptic to dopamine neurons may be responsible for sensitization of stereotyped behavior.
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10,485,967
|
Genetic differences in cocaine-induced conditioned place preference in mice depend on conditioning trial duration.
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In previous comparisons with C57BL/6J mice, DBA/2J mice have been characterized as "hyporesponsive" to cocaine's rewarding effect in the conditioned place-preference paradigm. This finding contrasts with other studies showing greater sensitivity of DBA/2J mice to the rewarding effects of ethanol and morphine in the place conditioning task. The purpose of the present study was to examine cocaine- induced place conditioning in both strains using apparatus and procedures similar to those used previously to assess ethanol and morphine preference conditioning. Mice from both strains were exposed to an unbiased place-conditioning procedure using 1, 10, or 30 mg/kg cocaine. Conditioning trial duration was 15, 30, or 60 min. In general, C57BL/6J mice displayed a significant conditioned place preference that was relatively unaffected by cocaine dose or trial duration. In contrast, DBA/2J mice showed no place conditioning at the shortest trial duration, but an increasing level of preference as trial duration increased. At the longest trial duration, both strains showed similar levels of place preference. Genetic differences in sensitivity to cocaine's rewarding effect depend critically on temporal parameters of the place-conditioning procedure. One possible interpretation of these findings is that short trial durations produce conditioned activity responses that interfere more with expression of conditioned place preference in DBA/2J mice than in C57BL/6J mice. More generally, these findings underscore the need for caution when drawing conclusions about genetic differences in place conditioning, especially when using this paradigm to evaluate the effects of gene knockouts or insertions on drug reward.
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26,738,899
|
Diabetes Is Related to Worse Patient-Reported Outcomes at Two Years Following Spine Surgery.
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Diabetes has been associated with poor outcomes following elective spine surgery. The purpose of our study was to determine if diabetes predicts worse patient-reported outcomes at two years postoperatively and to evaluate the effect of perioperative blood glucose levels and control on patient-reported outcomes in patients with diabetes. One thousand and five patients undergoing elective spine surgery were included in this prospective cohort study. The presence of diabetes and baseline and one and two-year patient-reported outcomes (Short Form-12 [SF-12], EuroQol-5D [EQ-5D], Oswestry Disability Index [ODI] or Neck Disability Index [NDI], and Numeric Rating Scale [NRS] pain scores) were recorded. The mean blood glucose measurements in patients with diabetes were collected during the postoperative period. Multivariable linear regression analyses were performed to determine predictors of one and two-year outcomes as well as the relationship between perioperative blood glucose and patient-reported outcomes in patients with diabetes. Four hundred and thirty-four patients (43%) had diabetes. When compared with patients without diabetes at two years, patients with diabetes had lower SF-12 Physical Component Summary scores (34.4 points for the diabetic group compared with 38.6 points for the non-diabetic group), lower EQ-5D scores (0.67 for the diabetic group compared with 0.74 for the non-diabetic group), higher ODI or NDI scores (32.1 points for the diabetic group compared with 26.8 points for the non-diabetic group), and higher NRS scores (5.1 points for the diabetic group compared with 4.3 points for the non-diabetic group) (p < 0.05 for all). Although patients with diabetes improved significantly over time, they did not improve to the extent that patients without diabetes did in the ODI or NDI and EQ-5D scores (p < 0.05). Diabetes and preoperative opioid use were independent predictors of decreased SF-12 scores, decreased EQ-5D scores, increased ODI or NDI scores, and increased NRS scores (p < 0.05). Diabetes was associated with increased ODI or NDI (by 6.6 points) and decreased EQ-5D (by 0.1) at two years. Perioperative blood glucose control did not predict outcomes at either one or two years in patients with diabetes. Diabetes was associated with worse patient-reported outcomes when patients with diabetes were compared with patients without diabetes at two years following elective spine surgery. Although patients with diabetes improved when compared from baseline to the time following elective spine surgery, they did not improve to the same extent as patients without diabetes in the ODI or NDI and EQ-5D scores. Providers may use this information to counsel patients with diabetes on expectations following spine surgery.
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26,738,904
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Changes in Muscle Oxygen Saturation Have Low Sensitivity in Diagnosing Chronic Anterior Compartment Syndrome of the Leg.
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Near-infrared spectroscopy measures muscle oxygen saturation (StO2) in the skeletal muscle and has been proposed as a noninvasive tool for diagnosing chronic anterior compartment syndrome (CACS). The purpose of this study was to investigate the diagnostic value of changes in StO2 during and after exercise in patients with CACS. The study comprised 159 consecutive patients with exercise-induced leg pain. Near-infrared spectroscopy was used to measure StO2 continuously before, during, and after an exercise test. One minute post-exercise, intramuscular pressure was recorded in the same muscle. The cohort was divided into patients with CACS (n = 87) and patients without CACS (n = 72) according to the CACS diagnostic criteria. Reoxygenation at rest after exercise was calculated as the time period required for the level of muscular StO2 to reach 50% (T50), 90% (T90), and 100% (T100) of the baseline value. The lowest level of StO2 during exercise was 1% (range, 1% to 36%) in the patients with CACS and 3% (range, 1% to 54%) in the patients without CACS. The sensitivity was 34% and the specificity was 43% when an StO2 level of ≤8% at peak exercise was used to indicate CACS. The sensitivity and the specificity were only 1% when an StO2 level of ≤50% at peak exercise was used to indicate CACS. The time period for reoxygenation was seven seconds (range, one to forty-three seconds) at T50, twenty-eight seconds (range, seven to seventy-seven seconds) at T90, and forty-two seconds (range, seven to 200 seconds) at T100 in the patients with CACS and ten seconds (range, one to forty-nine seconds) at T50, thirty-two seconds (range, four to 138 seconds) at T90, and forty-eight seconds (range, four to 180 seconds) at T100 in the patients without CACS. When thirty seconds or more at T90 was set as the cutoff value for a prolonged time for reoxygenation, indicating a diagnosis of CACS, the sensitivity was 38% and the specificity was 50%. Changes in muscle oxygen saturation during and after an exercise test that elicits leg pain cannot be used to distinguish between patients with CACS and patients with other causes of exercise-induced leg pain.
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27,787,485
|
Moyamoya vasculopathy shows a genetic mutational gradient decreasing from East to West.
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Moyamoya disease (MMD) is a chronic, occlusive cerebrovascular disease characterized by bilateral steno-occlusive changes at the terminal portion of the internal carotid arteries and an abnormal vascular network at the base of the brain determining stroke in children. Patients with a similar vasculopathy and associated conditions are affected by the moyamoya syndrome (MMS). Most of the studies focused on MMD were carried out on East-Asian population. Ring Finger 213 (RNF213) has been identified as the strongest susceptibility gene for MMD in East-Asian people. Overall, 74.5% of the East-Asian patients carry the founder variant p.Arg4810Lys of RNF213 never reported in Caucasians. A different genetic landscape among the diverse ethnic populations seems to exist. We sequenced the coding sequence region of RNF213, TGFB1 and PDGFRB in 21 ethnically homogeneous Italian children with moyamoya; comprehensive sequencing data are available from parents of eight of them. The analyses were carried out by NGS on Thermo-fisher PGM platform. We also performed a comprehensive review of the literature about the variations of these three genes in Caucasian patients. Several new variants of RNF213 gene were detected, in particular, two new pathogenic mutations on RNF213 (p.Trp4677Leu and p.Cys4017Ser) were identified in one MMS case and in one MMD case, respectively. Moreover, in a MMS case a new probably causing disease mutation p.Pro1063Thr of PDGFRB was detected. The genetic susceptibility of Asian moyamoya vasculopathy seems to differ from the Caucasian disease. No additional differences seem to exist between MMD and MMS.
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9,437,408
|
Cisapride increases peak plasma and saliva ethanol levels under fasting conditions.
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Alcohol absorption is influenced by gastric first-pass metabolism through an alcohol dehydrogenase and the gastric emptying time. Whilst an influence of antisecretory drugs and aspirin on gastric alcohol metabolism has been described, the role of prokinetic drugs has not been determined. A randomized, placebo-controlled double-blind cross-over study was performed. Out-patient facilities of a referral hospital. Eight male volunteers (age range 25-46 years). Treatment with two doses of either placebo or cisapride 150 micrograms/kg 7 h and 20 min before drinking 0.5 g/kg alcohol either in a fasting state or during a standardized meal (12 kcal/kg). Plasma and saliva ethanol concentrations were measured during 4 h. Cisapride increased peak plasma ethanol levels in fasting subjects from 15.6 (SD 1.4, 95%-KI 14.7;16.6) to 17.8 (SD 2.7, 95%-KI 15.9;19.7) mmol/L and saliva ethanol 30 min after alcohol ingestion from 11.4 (SD 2.2. 95%-KI 9.9;12.9) to 15.9 (SD 4.3, 95%-KI 12.9;18.8) mmol/L. A significant interaction between fasting state and drug intake was found for the 30 min saliva ethanol values (P < 0.05, ANOVA for repeated measurements). Cisapride may increase ethanol levels under fasting conditions. Patients treated with prokinetic drugs should be informed about this possibility.
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16,777,443
|
Routine completion angiography during carotid endarterectomy is not mandatory.
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Intraoperative quality control after carotid endarterectomy (CEA) has been advocated to improve the results of surgical treatment of extracranial carotid artery disease. The aim of this study was to evaluate the usefulness of completion angiography (CA) in prevention of stroke and restenosis after CEA in a single center experience. Data concerning 914 consecutive CEAs performed in 3 years (2000-2002) were prospectively collected in a dedicated database. Patients were divided into two groups: in the first group (mandatory-CA group; 430 cases) CA was routinely carried out, except in presence of contraindications to iodinate contrast agents; in the second group (selective-CA group, 484 cases) CA was performed only in selected cases, at surgeon's discretion. There were no significant differences between the two groups in terms of neurological complications at awakening (0.5% in mandatory-CA group and 0.4% in selective-CA group; p=n.s.) and in 30-day stroke and death rate (1.9% and 1.4%, respectively; p=n.s.). A surgical revision on the basis of CA findings was performed in 5 cases in mandatory-CA group and in 2 cases in selective-CA group (1.2% and 0.4%, respectively; p=n.s.). In the second group, the conditions significantly associated with the need for CA examination were internal carotid near-occlusion, preoperative symptoms, shunt insertion, kind of surgical reconstruction, redo surgery. Estimated absence of ipsilateral stroke and absence of restenosis at 18 months was 98.9% and 89.7% in mandatory-CA group and 99.3% and 93.4% in selective-CA group (p=n.s.) respectively. Based on our experience, routine CA following CEA is not suggested. A policy of selected CA at the surgeon's discretion seems to make the intervention safe and durable as well.
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11,534,563
|
The development of ventilator-associated pneumonia does not change aspects of mechanical ventilation.
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To evaluate whether the development of ventilator-associated pneumonia (VAP) is associated with changes in ventilation parameters. Matched case-control study. Mixed intensive care unit of a university hospital. From a large database we selected 33 patients with VAP, diagnosed with quantitative cultures of bronchoscopically obtained specimens. In addition, 33 other mechanically ventilated patients who did not develop VAP were selected (controls). Patients with VAP and controls were matched on seven variables representing severity of illness: duration of ventilation until matching, diagnosis on admission, renal function, liver function, preceding infection, preceding surgery and immunosuppressive therapy. Each patient with VAP was matched to a single control. Variables regarding type and mode of ventilation and interpretation of chest radiographs were not included in the matching procedure. Characteristics of mechanical ventilation (mode of ventilation, tidal volume, expired minute ventilation, peak airway pressures, mean airway pressures, level of positive end-expiratory pressure, arterial oxygen tension(PaO2)/fractional inspired oxygen (FIO2) ratio), were compared on the day of diagnosis of VAP (or matching for controls) and 2 and 4 days before. Although there was a significant difference in PaO2/FIO2 ratios between cases and controls on the day of diagnosis of VAP, the change in PaO2/FIO2 ratios during the days of study were not statistically different between patients developing VAP and controls. No significant differences were found for any of the other variables of ventilation at any of the three time points studied, nor were there significant differences in changes of these parameters within individual patients. Characteristics and parameters of mechanical ventilation are not influenced by the development of VAP. It is, therefore, unlikely that these variables are useful in the diagnostic work-up of VAP.
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11,534,567
|
Macrophage migration inhibitory factor is a critical mediator of systemic inflammatory response syndrome.
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To determine the relations between macrophage migration inhibitory factor (MIF), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and cortisol in patients with systemic inflammatory response syndrome (SIRS) and to determine whether their levels correlate with patient survival. Prospective, observational, cohort study. General intensive care unit in a university hospital. The study included 17 consecutive patients who met the criteria for SIRS; the patients were classified into subgroups, survivors (n = 8) and nonsurvivors (n = 9); eight healthy volunteers served as control subjects. None. Serum MIF, TNF-alpha, IFN-gamma, and cortisol levels were measured serially when the patients were first identified as having SIRS (day 0), and on days 1-4. Except for the high tendency of acute respiratory distress syndrome in nonsurvivors (44%) compared to survivors (13%), there were no differences in the clinical backgrounds of the patients between the two groups. All patients had multiple organ dysfunction syndrome. The values of MIF and TNF-alpha in the nonsurvivors were significantly more elevated than those cytokines measured in the survivors and control subjects. Peak MIF levels significantly correlated with peak TNF-alpha levels (r2 = 0.448, P = 0.002), but did not correlate with peak levels of cortisol and IFN-gamma. Although the levels of IFN-gamma and cortisol showed a marked increase compared to those of the control subjects, we could not find differences in these variables between the survivors and the nonsurvivors. High MIF and TNF-alpha levels are closely linked with poor outcome in patients with SIRS. MIF and TNF-alpha may act together and have pathogenic roles in SIRS.
|
8,913,128
|
The flashlight test and van Herick's test are poor predictors for occludable angles.
|
To determine the reliability and validity of the flashlight test and van Herick's test in detecting occludable anterior chamber angles. The flashlight test, van Herick's test and gonioscopy were performed independently by two observers on 96 consecutive new patients in our outpatient clinic. Interobserver agreement was determined using the weighted Kappa statistic. Using the glaucoma specialist's assessment of occludability of the angle (assessed by gonioscopy) as a gold standard, the sensitivities and specificities of the two tests were calculated. All three tests showed good agreement (Kappa more than 0.75). The sensitivity and specificity on the flashlight test were 45.5% and 82.7% respectively. For the van Herick's test they were 61.9% and 89.3%. The flashlight test and van Herick's test are of limited use as screening tests for occludable angles.
|
24,641,770
|
Preoperative platelet lymphocyte ratio (PLR) is superior to neutrophil lymphocyte ratio (NLR) as a predictive factor in patients with esophageal squamous cell carcinoma.
|
Recent studies have shown that the presence of systemic inflammation correlates with poor survival in various cancers. The aim of this study was to determinate the prognostic value of the neutrophil lymphocyte ratio (NLR) and the platelet lymphocyte ratio (PLR) in patients with esophageal squamous cell carcinoma (ESCC). Preoperative NLR and PLR were evaluated in 483 patients undergoing esophagectomy for ESCC from January 2005 to December 2008. The prognostic significance of both markers was then determined by both uni- and multivariate analytical methods. Receiver operating characteristic (ROC) curves were also plotted to verify the accuracy of NLR and PLR for survival prediction. High preoperative NLR (≥3.5 versus < 3.5, P = 0.039) and PLR (≥150 versus < 150, P < 0.001) were significantly associated with poor overall survival in multivariate analysis. However, our study demonstrated a better discrimination for the PLR in terms of hazard ratio(HR) than the NLR (HR = 1.840 versus HR = 1.339). Patients with NLR ≥3.5 had significantly poorer overall survival compared to NLR <3.5 (35.4% versus 57.7%, P < 0.001). Patients with PLR ≥150 also had significantly poorer overall survival compared to patients with PLR <150 (32.7% versus 63.5%, P < 0.001). The area under the curve (AUC) was 0.658 (95% confidence interval (CI): 0.610 to 0.706, P < 0.001) for NLR and 0.708 (95% CI: 0.662 to 0.754, P < 0.001) for PLR, indicating that PLR was superior to NLR as a predictive factor in ESCC. Preoperative NLR and PLR were significant predictors of overall survival in patients with ESCC. However, PLR is superior to NLR as a predictive factor in patients with ESCC.
|
26,214,633
|
Early initiation of fluorouracil-based adjuvant chemotherapy improves survival in patients with resectable gastric cancer.
|
Several clinical trials have suggested that adjuvant chemotherapy improves the survival of patients with resected gastric cancer, but the optimal time at which to initiate post-operative adjuvant chemotherapy has not been studied. This study investigated the association between time to adjuvant chemotherapy and survival in gastric cancer. We retrospectively identified 266 patients with stage IB-IIIC gastric cancer who received fluorouracil-based adjuvant chemotherapy after radical gastrectomy. Overall survival (OS) was compared between patients grouped according to time from surgery to adjuvant chemotherapy (<45 and ≥45 days). The Cox proportional hazards model was used to analyze the effects of time to initiation of chemotherapy and other clinical covariates on survival. Of 266 patients, 141 (53%) started adjuvant chemotherapy within 45 days after surgery and 125 (47%) started adjuvant chemotherapy more than 45 days after surgery. The 3-year OS rates were 81.2 and 65.8% for patients starting chemotherapy within 45 days and after 45 days, respectively (p=0.006). Multivariate analysis identified early initiation of adjuvant chemotherapy, completion of the planned chemotherapy, and early-stage disease as favorable prognostic factors in terms of OS (p<0.05). Subgroup analysis suggested that starting chemotherapy within 45 days after surgery was associated with significant OS benefit compared with initiation of chemotherapy after 45 days from surgery in most subgroups. This retrospective analysis suggests that delaying adjuvant chemotherapy for longer than 45 days after surgery may be associated with poorer survival in patients with resected gastric cancer.
|
24,117,485
|
Corneal nerve fibre damage precedes diabetic retinopathy in patients with type 2 diabetes mellitus.
|
To quantify the morphological alterations in corneal nerve fibres and cells in patients with type 2 diabetes mellitus in relation to the severity of diabetic retinopathy. One hundred and thirty-two eyes of 132 patients with type 2 diabetes and 32 eyes of 32 healthy control subjects were evaluated with in vivo corneal confocal microscopy. Patients with diabetes were classified into three groups: patients without diabetic retinopathy, patients with non-proliferative diabetic retinopathy and patients with proliferative diabetic retinopathy. Anterior and posterior stromal keratocyte, endothelial cell and basal epithelial cell densities and sub-basal nerve fibre structure were evaluated. Significant reductions in basal epithelial cell, anterior stromal keratocyte and endothelial cell densities were observed only in patients with diabetic retinopathy. However, nerve fibre density, nerve branch density and nerve fibre length were reduced in patients without diabetic retinopathy and worsened progressively with increasing severity of retinopathy. Corneal cell pathology occurs in patients with diabetic retinopathy, but corneal nerve fibre damage seems to precede the development of diabetic retinopathy.
|
20,971,758
|
Age at onset predicts good seizure outcome in sporadic non-lesional and mesial temporal sclerosis based temporal lobe epilepsy.
|
To study prognosis and prognostic predictors of sporadic non-lesional temporal lobe epilepsy (TLE). 474 patients with TLE were consecutively seen from April 1987 to April 2004. 190 had a sporadic non-lesional TLE and a follow-up longer than 2 years. 284 patients were excluded because of family history for TLE, incomplete history, poor compliance with treatment, psychogenic seizures, no brain MRI study, presence of intracranial lesions except for scattered T2 hyperintense spots on hemispheric white matter or mesial temporal sclerosis (MTS). The following prognostic predictors were considered: age at onset of epilepsy, gender, family history of non-TLE or febrile seizures, perinatal factors, history of febrile seizures, ictal phenomena, MTS and interictal EEG. The end point was time to 24 month seizure freedom after treatment onset. The χ(2) test, Student's t test, Kaplan-Meier survival curves with log rank test (univariate analysis) and Cox proportional hazards regression models (multivariate analysis) were used to assess seizure prognosis and prognostic predictors. At univariate analysis, patients achieving 24 month seizure freedom had a significantly older age at onset of epilepsy (33.5 ± 19.9 vs 17.2 ± 14.4 years), and lower occurrence of febrile seizures (11.0% vs 24.4%) and MTS (19.0% vs 35.6%). The chance of remission was directly correlated to age at onset of seizures and inversely correlated to a history of febrile seizures and to the presence of MTS. At multivariate analysis, age at onset of epilepsy was the only significant prognostic predictor. Older age at onset predicts better prognosis in sporadic non-lesional TLE.
|
20,971,757
|
Pedunculopontine nucleus deep brain stimulation produces sustained improvement in primary progressive freezing of gait.
|
To assess the efficacy of bilateral pedunculopontine nucleus (PPN) deep brain stimulation (DBS) as a treatment for primary progressive freezing of gait (PPFG). A patient with PPFG underwent bilateral PPN-DBS and was followed clinically for over 14 months. The PPFG patient exhibited a robust improvement in gait and posture following PPN-DBS. When PPN stimulation was deactivated, postural stability and gait skills declined to pre-DBS levels, and fluoro-2-deoxy-d-glucose positron emission tomography revealed hypoactive cerebellar and brainstem regions, which significantly normalised when PPN stimulation was reactivated. This case demonstrates that the advantages of PPN-DBS may not be limited to addressing freezing of gait (FOG) in idiopathic Parkinson's disease. The PPN may also be an effective DBS target to address other forms of central gait failure.
|
26,738,931
|
Molecular identification of tobacco leaf curl disease in Sichuan province of China.
|
Tobacco leaf curl disease (TLCD) is caused by begomoviruses in Geminiviridae, and infected plants exhibit leaf thickening, downward leaf curling, vein swelling as well as stunting symptoms. It is one of the economically important diseases in tropical and subtropical tobacco-growing areas. Seven monopartite begomoviruses have been identified causing TLCD in China. In this study, two begomoviruses were identified, characterized and polygenetically analyzed to be responsible for TLCD in Sichuan province, China. The complete genomes of two isolates SC230 and SC379 from diseased tobacco samples were cloned and sequenced to be 2738 nucleotides (nts) and 2748 nts in size, respectively. Sequence alignment indicated that SC230 and SC379 were most closely related to Tomato yellow leaf curl China virus (TYLCCNV-CN[CN:Sc226:Mal:12]) and Papaya leaf curl China virus (PaLCuCNV-CN[CN:Gx30:Lyc:03]), with a sequence identity of 99.2 and 99.2 %, respectively. The infection rate of TYLCCNV and PaLCuCNV was 100 and 34.78 %, respectively and the co-infection rate was 34.78 % in fields. Betasatellites of SC230 and SC379 share the highest sequence identity with Tomato yellow leaf curl China betasatellite (TYLCCNB-CN[CN:Sc176:Malva:12]) and TYLCCNB-CN[CN:Yn149:Tom:09], with a sequence identity of 95.2 and 97.2 % respectively. Sequence identity between betasatellites of SC230 and SC379 was 89.6 %. And TYLCCNB was detected in all the samples. Co-infection of TYLCCNV and PaLCuCNV was identified in tobacco plants with typical symptoms of TLCD from Sichuan province in China, and this is the first report of PaLCuCNV infecting tobacco in China. TYLCCNV/TYLCCNB disease complex is widespread in tobacco-growing areas in Panzhihua city of Sichuan.
|
19,398,901
|
Pancreatic tumor motion on a single planning 4D-CT does not correlate with intrafraction tumor motion during treatment.
|
To quantify pancreas tumor motion on both a planning 4D-CT and during a single fraction treatment using the CyberKnife linear accelerator and Synchrony respiratory tracking software, and to investigate whether a single 4D-CT study is reliable for determining radiation treatment margins for patients with locally advanced pancreas cancer. Twenty patients underwent fiducial placement, biphasic pancreatic protocol CT scan and 4D-CT scan in the treatment position while free-breathing. Patients were then treated with a single 25 Gy fraction of stereotactic body radiotherapy. Predicted pancreas motion in the superior-inferior (SI), left-right (LR), and anterior-posterior (AP) directions was calculated from the maximum inspiration and maximum expiration 4D-CT scan. For CyberKnife treatments, mean respiratory cycle motion and maximum respiratory cycle motion was determined in the SI, LR, and AP directions. The range of centroid movement based on 4D-CT in the SI, LR, and AP directions were 0.9 to 28.8 mm, 0.1 to 13.7 mm, and 0.2 to 7.6 mm, respectively. During CyberKnife treatment, in the SI direction, the mean motion of the centroid ranged from 0.5 to 12.7 mm. In the LR direction, the mean motion range was 0.4 to 9.4 mm. In the AP direction, the mean motion range was 0.6 to 5.5 mm. The maximum range of movement (mean) during CyberKnife treatment in the SI, LR, and AP directions were 4.5 to 48.8 mm (mean 20.8 mm), 1.5 to 41.3 mm (mean 11.3 mm), and 1.6 to 68.1 mm (mean 13.4 mm), respectively. Neither the maximum or mean motion correlated with the 4D-CT movement. There is substantial respiratory associated motion of pancreatic tumors. The 4D-CT planning scans cannot accurately predict the movement of pancreatic tumors during actual treatment on CyberKnife.
|
19,398,902
|
Excellent results from high dose rate brachytherapy and external beam for prostate cancer are not improved by androgen deprivation.
|
Prostate cancer patients treated with high dose rate brachytherapy and external beam radiation therapy were stratified by risk group for analysis to determine whether androgen deprivation therapy (ADT) affected outcome. From 1991 through 1998, 411 patients were treated with 4 fractions of 5.5 to 6.0 Gy high dose rate brachytherapy and a total of 36.0 to 39.6 Gy external beam radiation therapy (dose escalation over time). The dataset was prospective. Administration of ADT was not randomized, but it was the primary study variable. During this period, ADT was administered across all risk groups for various indications. It did not necessarily reflect advanced disease or large prostate size. There were 200 patients in the "ADT Group" (20% low, 48% intermediate, and 32% high risk) and 211 in the "No ADT Group" (33% low, 44% intermediate, 23% high risk). The median follow-up was 6.4 years. Cases were grouped according to low, intermediate, and high risk groups to reduce the effects of unrecognized selection bias for or against the ADT group. The prostate specific antigen (PSA) nadir plus 2.0 ng/ml (nadir + 2) was used as the biochemical control end point. Local control, PSA progression-free survival, distant metastasis free survival, and cause-specific survival were compared. The 10 year PSA-PFS (nadir + 2) for all 411 patients was 81%. The results stratified by risk group were: low 92%, intermediate 87%, and high 63%. The low and intermediate risk groups were not statistically different from one another but they were both significantly better than the high risk group. ADT versus No ADT 10-year survival showed no significant differences for any outcome variable: PSA-PFS (83% vs. 81% ns), local control (97% vs. 99%), distant metastasis free survival (94% vs. 97%), and cause-specific survival (97% vs. 97%). A subset analysis of PSA-PFS (nadir + 2) stratified by risk group revealed no difference between the ADT and No ADT groups. high dose rate brachytherapy and external beam radiation therapy resulted in high rates of local control, PSA progression-free survival, distant metastasis free survival, and cause-specific survival in all risk groups. Improved outcome from the use of androgen deprivation was not observed.
|
26,214,645
|
Gefitinib causes growth arrest and inhibition of metastasis in human chondrosarcoma cells.
|
Chondrosarcomas are primary malignant cartilage-forming tumors of bone which are not responsive either to chemotherapy or radiation treatment and display potent capacity to invade locally and cause distant metastasis. Epidermal growth factor receptor (EGFR) pathway plays an important role in the development and progression of many cancers. However, the effect of EGFR inhibitor gefitinib on cell growth and metastasis in human chondrosarcoma cells is largely unknown. Features of the protein expression of EGFR in 3 human chondrosarcoma cell lines JJ2012, SW1353 and OUMS27 were analyzed. The inhibitory effects of EGFR inhibitor gefitinib on cell proliferation, cell cycle and metastasis were assessed by using MTS, flow cytometry and migration assays, respectively. The expression of metastasis-related proteins was evaluated by western blotting. All the three human chondrosarcoma cell lines expressed EGFR protein. Gefitinib significantly inhibited the growth, induced cell cycle arrest and decreased the migra- tion ability of human chondrosarcoma cells. In addition, gefitinib also reduced the expression of metastasis-related proteins, basic fibroblast growth factor (bFGF), matrix metalloproteinases-2 (MMP-2) and matrix metalloproteinases-9 (MMP-9). The discovery that gefitinib inhibited the proliferation and reduced the metastatic capacity of chondrosarcoma cells may help increase the understanding of the mechanism underlying human chondrosarcoma growth and metastasis. Thus, gefitinib may represent a promising agent for controlling chondrosarcoma proliferation and metastasis.
|
22,020,349
|
Polymorphisms of INSIG2, MC4R, and LEP are associated with obesity- and metabolic-related traits in schizophrenic patients.
|
Schizophrenic patients have a high prevalence of metabolic adversities. Previous studies have suggested some candidate genes for obesity- and metabolic-related traits, including the insulin-induced gene (INSIG2), melanocortin 4 receptor gene (MC4R), and leptin and leptin receptor genes (LEP and LEPR). We aimed to investigate the associations between these genes and metabolic disturbances in patients with schizophrenia in Taiwan. Patients with a diagnosis of schizophrenia or schizoaffective disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, were recruited from 36 community psychiatric rehabilitation centers or hospitals in Taipei. A total of 650 subjects were enrolled, and 577 were included in the genetic analyses. The anthropometric (body mass index, waist circumference [WC], and blood pressure) and biochemical measurements (fasting plasma glucose, insulin, triglyceride, high-density lipoprotein cholesterol, and Homeostasis Model of Assessment - Insulin Resistance index [HOMA-IR]) were assessed. Seven loci in the 4 genes were genotyped using standard TaqMan assays. Genetic association analyses were conducted for binary and quantitative measurements of the previously mentioned traits. Obese patients with schizophrenia exhibited more metabolic disturbances than nonobese patients. Our data showed that INSIG2 was significantly associated with fasting plasma glucose (for rs17587100, P < 0.0001), MC4R was associated with WC (for rs2229616, P = 0.005), and LEP was associated with body mass index and WC (for rs7799039, P < 0.01). In addition, these loci showed suggestive associations with traits including high-density lipoprotein cholesterol and triglyceride, metabolic syndrome, insulin level, and HOMA-IR index (P = 0.05). In addition to the effect from antipsychotic medications and an unhealthy lifestyle, genetic factors also contribute to the high prevalence of obesity and metabolic disturbances in patients with schizophrenia, especially genes involved in metabolic-related pathways.
|
12,058,882
|
Type 2 diabetes is not a risk factor for asymptomatic ischemic brain lesion--the Funagata study.
|
The purpose of this study is to clarify whether type 2 diabetes (DM) is a risk factor for asymptomatic (silent) ischemic brain lesion, which is controversial at present. The subjects (n=187), who showed normal results on both neurological and neuropsychological examinations, underwent a 75-g OGTT and were examined by brain MRI on T1-weighted, T2-weighted, and FLAIR (fluid-attenuated inversion recovery) images. Their brain MRIs were evaluated quantitatively with the ischemia rating scale defined here. The subjects were grouped based on their glucose tolerance: normal glucose tolerance (NGT) (n=48), impaired glucose tolerance (IGT) (n=62), and DM (n=65). The subjects with DM were further divided based on their duration of illness: 20 with short duration (short DM: 1.3+0.8 years) and 45 with long duration (long DM; 8.9+/-5.4 years). Ages were matched among the groups. The percentages of individuals with asymptomatic ischemic brain lesion were 81% in NGT, 74% in IGT, 65% in short DM, and 78% in long DM. No significant difference was observed among the groups in terms of the percentage. Namely, even in individuals with a long history of DM without clinical stroke, the prevalence of asymptomatic ischemic brain lesion was not different from that of the other groups. Multiple regression and multiple logistic regression analyses showed that age and hypertension were significant independent risk factors for asymptomatic ischemic brain lesion, whereas hypercholesterolemia, smoking, and glucose intolerance, including IGT, short DM and long DM, were not. DM is not a risk factor for asymptomatic ischemic brain lesion.
|
18,350,343
|
The increase in serum visfatin after bariatric surgery in morbidly obese women is modulated by weight loss, waist circumference, and presence or absence of diabetes before surgery.
|
Previous studies addressing the changes in serum visfatin levels after bariatric surgery yielded conflicting results. We measured serum visfatin levels in 41 morbidly obese women before bariatric surgery and after losing at least 15% of the initial weight, and analyzed the results taking into account the type of surgery, reproductive and diabetic status, among others. Body mass index, waist circumference, lipid profile, and insulin resistance determined by homeostasis model assessment (HOMA-IR) were also measured. Patients lost 30.3 +/- 6.1% of the initial body weight, and serum visfatin levels increased from 22.2 +/- 20.9 to 32.2 +/- 27.6 ng/ml (P = 0.031). A multiple regression model (R (2) = 0.314, F = 3.555, P = 0.017) including the percentage of weight loss, changes in waist circumference, HOMA-IR, high-density lipoprotein-cholesterol, and triglycerides (also expressed as percentage from baseline), the surgical procedure, time elapsed since surgery, and previous diabetic status as independent variables showed that weight loss (beta = -0.670, P = 0.010), previous diabetic status (beta = -0.330, P = 0.036), and change in waist circumference (beta = 0.556, P = 0.031) were the main determinants of the percentual increase in serum visfatin levels observed after bariatric surgery. Serum visfatin increased after bariatric surgery in relation to the amount of weight lost and to the changes in waist circumference, and this increase was higher in diabetic patients.
|
24,117,513
|
Determination of sIgE to rPhl p 1 is sufficient to diagnose grass pollen allergy.
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New diagnostic tools such as the basophil activation test (BAT) and component-resolved diagnosis (CRD) are promising for Hymenoptera venom or food allergy. A clear benefit for inhalant allergens has not yet been shown. Our aim was to compare new and established tests for grass pollen allergy. Forty-nine patients with grass pollen allergy and 47 controls were prospectively enrolled in the study. A symptom score was calculated for each patient. Conjunctival provocation tests (CPT), skin prick tests (SPT), BAT, and sIgE determination including CRD were performed. Sensitivity and specificity were compared and results were correlated with the symptom score. Single determination of sIgE to rPhl p 1 showed the best balance between sensitivity (98%) and specificity (92%). Use of additional components, such as rPhl p 2 and 5, did not increase sensitivity. Generally, sensitivity of tests was high: SPT 100%, ISAC-112 100%, sIgE to timothy grass 98%, BAT 98%, ISAC-103 84%, and CPT 83%. Specificity ranged from 79% (SPT) to 96% (CPT). All test results and calculated values (e.g. ratio sIgE/tIgE) did not correlate with symptom severity. Asymptomatic sensitization to timothy grass in controls was rare in the CAP (11%) and predominantly due to Phl p 1 sensitization. rPhl p 1 was sufficient to diagnose grass pollen allergy, and sIgE patterns were the same in symptomatically and asymptomatically sensitized subjects. The testing of multiple components was of minor importance, and no test correlated with symptom severity.
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24,641,801
|
MicroRNA-484 is more highly expressed in serum of early breast cancer patients compared to healthy volunteers.
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Previous studies have profiled breast cancer compared to normal breast tissue and identified differentially expressed microRNAs (miRNAs). These miRNAs are then assessed in serum of breast cancer patients compared to healthy volunteers. MiRNAs in serum however do not always reflect what is in tissue and important serum miRNAs may be missed. PCR arrays were therefore performed on serum samples from breast cancer patients compared to healthy volunteers with the aim of identifying circulating miRNAs that are more highly expressed in serum from early breast cancer patients compared to controls. Taqman low density array (TLDA) cards were used to profile serum miRNAs in a discovery cohort of serum from 39 early breast cancer patients compared to 10 healthy volunteers. The results were confirmed in a validation cohort of serum from 98 early breast cancer patients compared to 25 healthy volunteers using customized qPCR plates. Seventeen miRNAs were found to have significantly higher levels in breast cancer serum compared to serum of healthy volunteers in the discovery cohort. Fourteen of these miRNAs were studied in the validation cohort and serum miR-484 was found to be at a significantly higher level in breast cancer serum compared to healthy volunteers. In this study, we found that miR-484 is significantly differentially expressed in serum of early breast cancer patients compared to healthy volunteers. We did not however find any correlation between miR-484 levels with histopathological parameters of the breast cancers. With further studies, miR-484 may prove useful as an adjunct to mammography for detection of early breast cancer.
|
17,826,059
|
Egg retrieval with cryopreservation does not delay breast cancer treatment.
|
Infertility is a concern to young women diagnosed with breast cancer. Advances in fertility technology have made it possible to bank fertilized embryos. Twenty-three women, ages 27 to 40 years, underwent stimulation/oocyte retrieval before the start of adjuvant therapies. Time intervals between retrieval and therapeutic procedures were analyzed. The average stimulation to egg retrieval was 11.5 days (range 9-20 d). The average time interval from first evaluation to oocyte retrieval was 33.3 days (range 10-65 d). Overall, the mean time from definitive surgery to initiation of chemotherapy was 46.8 days (n = 20). For 6 patients referred by surgeons, the mean time from fertility consult to retrieval was 48.8 days (range 16-118 d), and from definitive surgery to initiation of chemotherapy was 45 days (range 15-93 d). Egg retrieval cryopreservation can be integrated with breast cancer work-up and surgical procedures. Early referrals to a fertility specialist by surgeons will help patients' safeguard future childbearing.
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24,641,804
|
Silencing of hepcidin enforces the apoptosis in iron-induced human cardiomyocytes.
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Iron is essential not only for erythropoisis but also for several bioenergetics' processes in myocardium. Hepcidin is a well-known regulator of iron homeostasis. Recently, researchers identified low hepcidin was independently associated with increased 3-year mortality among systolic heart failure patients. In addition, our previous in vivo study revealed that the left ventricular mass index increased in chronic kidney disease patients with lower serum hepcidin. We hypothesize that hepcidin interacts with the apoptotic pathway of cardiomyocytes during oxidative stress conditions. To test this hypothesis, human cardiomyocytes were cultured and treated with ferrous iron. The possible underlying signaling pathways of cardiotoxicity were examined following knockdown studies using siRNAs of hepcidin (siRNA1 was used as a negative control and siRNA2 was used to silence hepcidin). We found that ferrous iron induces apoptosis in human cardiomyocytes in a dose-dependent manner. This iron-induced apoptosis was linked to enhanced caspase 8, reduced Bcl-2, Bcl-xL, phosphorylated Akt and GATA-4. Hepcidin levels increased in human cardiomyocytes pretreated with ferrous iron and returned to non-iron treated levels following siRNA2 transfection. In iron pretreated cardiomyocytes, the siRNA2 transfection further increased caspase 8 expression and decreased the expression of GATA-4, Bcl-2, Bcl-xL and phosphorylated Akt than iron pretreatment alone, but caspase 9 levels remained unchanged. Our findings suggest that hepcidin can rescue human cardiomyocytes from iron-induced apoptosis through the regulation of GATA-4/Bcl-2 and the extrinsic apoptotic pathway.
|
19,398,924
|
Increased body mass index after H. pylori eradication for duodenal ulcer predisposes to erosive reflux esophagitis.
|
A higher body mass index (BMI) may lead to a more adverse outcome of reflux esophagitis. The study aimed to determine whether increased BMI after H. pylori eradication in duodenal ulcer patients predisposes to erosive reflux esophagitis. Four hundred fifty-nine patients with Helicobacter pylori-positive duodenal ulcers but without reflux esophagitis were evaluated. Serial BMIs were collected before therapy and on the 2nd, 6th, and 12th months after H. pylori eradication. New-onset reflux esophagitis was recorded. In 350 patients with complete follow-up, mean BMI increased from the second month after H. pylori eradication (P<0.001). H. pylori eradication also led to a net increase of BMI >1.5 kg/m in nearly 20% of patients in the 12-month follow-up, whereas new-onset of reflux esophagitis was noted in 16.3% (57/350). Baseline BMI, prevalence rate of hiatus hernia, and net increase of BMI were higher in patients with new-onset reflux than in those without (P<0.05). Multiple logistic regression confirmed higher baseline BMI, hiatus hernia, and net BMI increase >1.5 kg/m after H. pylori eradication were independently associated with new-onset reflux esophagitis (P<0.05). Eradication of H. pylori may lead to a significant net increase of BMI in patients with duodenal ulcers. Such BMI gain, as well as higher baseline BMI and hiatus hernia, predisposes to new-onset reflux esophagitis after H. pylori eradication.
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21,496,085
|
Dynamic mobilisation exercises increase cross sectional area of musculus multifidus.
|
In human subjects with back pain, the deep spinal stabiliser m. multifidus is inhibited ipsilaterally leading to atrophy, asymmetry and intervertebral instability. Specific physiotherapeutic exercises are required to reactivate m. multifidus. This study assesses the effect of dynamic mobilisation exercises on size and symmetry of m. multifidus in the equine caudal thoracic and lumbar spine. Regular performance of dynamic mobilisation exercises over a period of 3 months increases cross sectional area (CSA) and left-right symmetry of m. multifidus muscles in the caudal thoracic and lumbar spine. Eight horses performed dynamic mobilisation exercises (3 cervical flexions, one cervical extension and 3 lateral bending exercises to the left and right sides) with 5 repetitions/exercise/day on 5 days/week for 3 months during which time they were not ridden. Left and right m. multifidus CSA was measured ultrasonographically at 6 levels from T10 to L5 at the start (initial evaluation) and end (final evaluation) of the 3 month study. Changes in CSA of the right and left m. multifidus muscles and symmetry of m. multifidus CSA on the right and left sides between the 2 evaluations were sought using analysis of variance (P<0.05). Between the initial evaluation and final evaluation m. multifidus CSA increased significantly at all 6 spinal levels on both right and left sides. Asymmetries in m. multifidus CSA between the right and left sides decreased between the initial and final evaluations. Hypertrophy of multifidus occurred over a 3 month period during which dynamic mobilisation exercises were the only exercise performed. Dynamic mobilisation exercises maybe a useful rehabilitative technique for horses in which m. multifidus has atrophied in response to back pain.
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