tbuckley/cabot-search huggingface dataset:
Inhibition of Mutated, Activated BRAF in Metastatic Melanoma
Authors: Keith T. Flaherty, Igor Puzanov, Kevin B. Kim, Antoni Ribas, Grant A. McArthur, Jeffrey A. Sosman, Peter J. O'Dwyer, Richard J. Lee, Joseph F. Grippo, Keith Nolop, Paul B. Chapman
Journal: New England Journal of Medicine (2010)

The identification of somatic mutations in the gene encoding the serine-threonine protein kinase B-RAF (BRAF) in the majority of melanomas offers an opportunity to test oncogene-targeted therapy for this disease.We conducted a multicenter, phase 1, dose-escalation trial of PLX4032 (also known as RG7204), an orally available inhibitor of mutated BRAF, followed by an extension phase involving the maximum dose that could be administered without adverse effects (the recommended phase 2 dose). Patients received PLX4032 twice daily until they had disease progression. Pharmacokinetic analysis and tumor-response assessments were conducted in all patients. In selected patients, tumor biopsy was performed before and during treatment to validate BRAF inhibition.A total of 55 patients (49 of whom had melanoma) were enrolled in the dose-escalation phase, and 32 additional patients with metastatic melanoma who had BRAF with the V600E mutation were enrolled in the extension phase. The recommended phase 2 dose was 960 mg twice daily, with increases in the dose limited by grade 2 or 3 rash, fatigue, and arthralgia. In the dose-escalation cohort, among the 16 patients with melanoma whose tumors carried the V600E BRAF mutation and who were receiving 240 mg or more of PLX4032 twice daily, 10 had a partial response and 1 had a complete response. Among the 32 patients in the extension cohort, 24 had a partial response and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months.Treatment of metastatic melanoma with PLX4032 in patients with tumors that carry the V600E BRAF mutation resulted in complete or partial tumor regression in the majority of patients. (Funded by Plexxikon and Roche Pharmaceuticals.)
Modern use of clomiphene citrate in induction of ovulation
Authors: E Kousta
Journal: Human Reproduction Update (1997)

Clomiphene citrate is the treatment of first choice in the management of infertility in normally oestrogenized, anovulatory women (WH0 group II). The majority of women with 'pure' anovulatory infertility respond to treatment with clomiphene citrate. The rates of pregnancy and miscarriage are close to those expected in a normal fertile population. Basal hormone concentrations do not predict outcome. An increased body mass index is the only factor which is consistently associated with a decreased response to clomiphene citrate; it follows therefore, that weight reduction should be an important part of therapy in anovulatory women. According to our data, only an increased luteinizing hormone value immediately post clomiphene citrate predicted an adverse pregnancy outcome in women who conceived. Clomiphene citrate, along with other ovulation induction therapies, can cause multiple follicular development, with a risk of ovarian hyperstimulation and multiple pregnancy. Ultrasound monitoring of treatment is important in order to choose the appropriate dose of clomiphene citrate in subsequent cycles and to minimize the risks of hyperstimulation and multiple pregnancy. When couples with other factors contributing to subfertility are excluded, the cumulative conception rate continues to rise after 6 months of treatment with clomiphene citrate, reaches a plateau by treatment cycle 12 and approaches that of the normal population. It has been reported that prolonged use of clomiphene citrate may be associated with an increased risk of a borderline or invasive ovarian tumour. Taking into consideration these observations, we recommend that anovulatory women responsive to clomiphene citrate should be treated for at least 6 cycles before considering more complex or invasive methods of ovulation induction, and that treatment should probably be limited to a maximum of 12 cycles.
Genomic and post-genomic analyses of human prion diseases
Authors: Maurizio Pocchiari, Anna Poleggi, Serena Principe, Silvia Graziano, Franco Cardone
Journal: Genome Medicine (2009)

Prion diseases share common features of neurodegenerative disorders, infectious diseases and pathologies linked to misfolded proteins. Whether these aspects are independently and fortuitously present in prion diseases or are somewhat linked together remains unsettled, but the contribution of genomic, proteomic, metabolomic and spectroscopic techniques might give insights into this puzzle, and likely give hope for therapy to patients. Although the prion protein gene (PRNP) governs most of the clinical and pathological features of prion diseases and plays a pivotal role in determining host susceptibility, there are still many uncertainties and unknown risk factors that need to be clarified and identified. Several genes, other than PRNP, have recently been found to be associated with a risk of developing sporadic or variant Creutzfeldt-Jakob disease, but these novel data have been produced in a relatively small number of patients and controls and, therefore, need further confirmation. The same criticism applies to the identification of the over 20 new cerebrospinal fluid or plasma markers of disease. Some of these markers seem related to the massive brain damage that occurs, rather than being specific to prion infection. Nevertheless, genomic and post-genomic approaches have shown that these techniques are very powerful, and the best way to overcome the scantiness of samples would be to encourage strong collaboration between different centers of excellence in prion diseases. In this review, we describe the most recent and outstanding advances offered by genomics and post-genomics analyses in the field of human prion diseases.
EPIDEMIOLOGIC REVIEW OF COLLEGIATE ACL INJURY RATES ACROSS 14 SPORTS: NATIONAL COLLEGIATE ATHLETIC ASSOCIATION INJURY SURVEILLANCE SYSTEM DATA 2004-05 THROUGH 2011–12
Authors: J Agel, D Klossner
Journal: British Journal of Sports Medicine (2014)

Background Extensive effort has been put into awareness and prevention programs to decrease the overall rate of injury and the difference between sexes. Objective The objective of this review is to document the rate of ACL injury in 14 collegiate sports over an eight year period and compare it to an earlier 16 year review. Design Descriptive Epidemiology. Setting Universities in the U.S. Participants NCAA athletes. Interventions There was no intervention. Main outcome measures The primary outcome chosen apriori is injury. Results: The majority of ACL injuries to women occurred by a non-contact mechanism of injury while the majority of ACL injuries to men occurred by a contact mechanism. The highest rates of ACL injury for men were found in American football (0.17 per 1000 A-E and wrestling (0.16 per 1000 A-E). The highest rates of ACL injury for women were found in basketball and lacrosse (0.23 per 1000 A-E). Within the 8 year study period men's and women's ice hockey showed the greatest increase over time with an average annual rate of change of 105% and 136% respectively. Mens' baseball and women's lacrosse showed the greatest decrease in average annual rate of change (16.9% and 17% respectively).When comparing the current 8 years of data to previously reported 16 years of data baseball and women's basketball, showed no change, men's basketball, lacrosse, and wrestling along with field hockey showed an increase and American football, men's and women's ice hockey and soccer, women's lacrosse, softball, and volleyball showed a decrease in overall injury rate. Conclusions Despite focused scientific efforts and prevention programs ACL injuries remain a significant injury in collegiate sports. Women continue to sustain ACL injuries at higher rates than men in the comparable sports of soccer, basketball, and lacrosse.
β-catenin is a central mediator of pro-fibrotic Wnt signaling in systemic sclerosis
Authors: Christian Beyer, Amelie Schramm, Alfiya Akhmetshina, Clara Dees, Trayana Kireva, Kolja Gelse, Sonali Sonnylal, Benoit de Crombrugghe, Makoto Mark Taketo, Oliver Distler, Georg Schett, Jörg H W Distler
Journal: Annals of the Rheumatic Diseases (2012)

Objectives Pathologic fibroblast activation drives fibrosis of the skin and internal organs in patients with systemic sclerosis (SSc). β-catenin is an integral part of adherens junctions and a central component of canonical Wnt signaling. Here, the authors addressed the role of β-catenin in fibroblasts for the development of SSc dermal fibrosis. Methods Nuclear accumulation of β-catenin in fibroblasts was assessed by triple staining for β-catenin, prolyl-4-hydroxylase-β and 4′,6-diamidino-2-phenylindole (DAPI). The expression of Wnt proteins in the skin was analysed by real-time PCR and immunohistochemistry. Mice with fibroblast-specific stabilisation or fibroblast-specific depletion were used to evaluate the role of β-catenin in fibrosis. Results The auhors found significantly increased nuclear levels of β-catenin in fibroblasts in SSc skin compared to fibroblasts in the skin of healthy individuals. The accumulation of β-catenin resulted from increased expression of Wnt-1 and Wnt-10b in SSc. The authors further showed that the nuclear accumulation of β-catenin has direct implications for the development of fibrosis: Mice with fibroblast-specific stabilisation of β-catenin rapidly developed fibrosis within 2 weeks with dermal thickening, accumulation of collagen and differentiation of resting fibroblasts into myofibroblasts. By contrast, fibroblast-specific deletion of β-catenin significantly reduced bleomycin-induced dermal fibrosis. Conclusions The present study findings identify β-catenin as a key player of fibroblast activation and tissue fibrosis in SSc. Although further translational studies are necessary to test the efficacy and tolerability of β-catenin/Wnt inhibition in SSc, the present findings may have clinical implications, because selective inhibitors of β-catenin/Wnt signaling have recently entered clinical trials.
Influence of body posture on intestinal transit of gas
Authors: R Dainese
Journal: Gut (2003)

<b>Background:</b> Patients describe that body posture may affect their abdominal bloating, distension, and flatulence, but whether changes in position have objectively demonstrable effects, either beneficial or deleterious, has not been investigated. <b>Aim:</b> To determine the effect of body posture, upright versus supine, on intestinal transit of gas loads. <b>Subjects:</b> Eight healthy subjects without gastrointestinal symptoms. <b>Methods:</b> In each subject a gas mixture was continuously infused into the jejunum (12 ml/min) for three hours, and gas evacuation, clearance of a non- absorbable gaseous marker, perception, and abdominal girth were measured. Paired studies were randomly performed in each subject on separate days in the upright and supine positions. <b>Results:</b> In the upright position, intestinal gas retention was much smaller than when supine (13 (52) ml <i>v</i> 146 (75) ml retention at 60 minutes, respectively; p&lt;0.05), and clearance of the gas marker was expedited (72 (10)% clearance <i>v</i> 49 (16)% at 60 minutes, respectively; p&lt;0.05). The gas challenge test was well tolerated both in the upright and supine positions without abdominal distension. <b>Conclusion:</b> Body posture has a significant influence on intestinal gas propulsion: transit is faster in the upright position than when supine.
Human B1 cells in umbilical cord and adult peripheral blood express the novel phenotype CD20+CD27+CD43+CD70−
Authors: Daniel O. Griffin, Nichol E. Holodick, Thomas L. Rothstein
Journal: The Journal of Experimental Medicine (2011)

B1 cells differ in many ways from conventional B cells, most prominently in the production of natural immunoglobulin, which is vitally important for protection against pathogens. B1 cells have also been implicated in the pathogenesis of autoimmune dyscrasias and malignant diseases. It has been impossible to accurately study B1 cells during health and illness because the nature of human B1 cells has not been successfully defined. This has produced controversy regarding the existence of human B1 cells. Here, we determined the phenotype of human B1 cells by testing sort-purified B cell fractions for three fundamental B1 cell functions based on mouse studies: spontaneous IgM secretion, efficient T cell stimulation, and tonic intracellular signaling. We found that a small population of CD20+CD27+CD43+ cells present in both umbilical cord and adult peripheral blood fulfilled these criteria and expressed a skewed B cell receptor repertoire. These B cells express little or no surface CD69 and CD70, both of which are markedly up-regulated after activation of CD20+CD27−CD43− (naive) and CD20+CD27+CD43− (memory) B cells. This work identifies human B1 cells as CD20+CD27+CD43+CD70−. We determined that the proportion of B1 cells declines with age, which may contribute to disease susceptibility. Identification of human B1 cells provides a foundation for future studies on the nature and role of these cells in human disease.
An independent external validation and evaluation of QRISK cardiovascular risk prediction: a prospective open cohort study
Authors: G. S Collins, D. G Altman
Journal: BMJ (2009)

<b>Objective</b> To independently evaluate the performance of the QRISK score for predicting 10 year risk of cardiovascular disease in an independent UK cohort of patients from general practice and compare the performance with Framingham equations. <b>Design</b> Prospective open cohort study. <b>Setting</b> 274 practices from England and Wales contributing to the THIN database. <b>Participants</b> 1.07 million patients, registered between 1 January 1995 and 1 April 2006, aged 35-74 years (5.4 million person years) with 43 990 cardiovascular events. <b>Main outcome measures</b> First diagnosis of cardiovascular disease (myocardial infarction, coronary heart disease, stroke, and transient ischaemic attack) recorded in general practice records. <b>Results</b> This independent validation indicated that QRISK offers an improved performance in predicting the 10 year risk of cardiovascular disease in a large cohort of UK patients over the Anderson Framingham equation. Discrimination and calibration statistics were better with QRISK. QRISK explained 32% of the variation in men and 37% in women, compared with 27% and 31% respectively for Anderson Framingham. QRISK underpredicted risk by 13% for men and 10% for women, whereas Anderson Framingham overpredicted risk by 32% for men and 10% for women. In total, 85 010 (8%) of patients would be reclassified from high risk (≥20%) with Anderson Framingham to low risk with QRISK, with an observed 10 year cardiovascular disease risk of 17.5% (95% confidence interval 16.9% to 18.1%) for men and 16.8% (15.7% to 18.0%) for women. The incidence rate of cardiovascular disease events among men was 30.5 per 1000 person years (95% confidence interval 29.9 to 31.2) in high risk patients identified with QRISK and 23.7 per 1000 person years (23.2 to 24.1) in high risk patients identified with Anderson Framingham. Similarly, the incidence rate of cardiovascular disease events among women was 26.7 per 1000 person years (25.8 to 27.7) in high risk patients identified with QRISK compared with 22.2 per 1000 person years (21.4 to 23.0) in high risk patients identified with Anderson Framingham. <b>Conclusions</b> The QRISK cardiovascular disease risk equation offers an improvement over the long established Anderson Framingham equation in terms of identifying a high risk population for cardiovascular disease in the United Kingdom. QRISK underestimates 10 year cardiovascular disease risk, but the magnitude of underprediction is smaller than the overprediction with Anderson Framingham.
Sclerosing mediastinitis: a report on 18 cases.
Authors: T M Mole, J Glover, M N Sheppard
Journal: Thorax (1995)

BACKGROUND--Sclerosing mediastinitis is a rare condition which causes dense fibrosis of the mediastinum. Few large studies have been reported to date. The clinical and pathological features of cases have been studied in a specialist referral centre in the UK. METHODS--The pathological files of the Royal Brompton Hospital were examined and 18 cases of sclerosing mediastinitis were identified between 1970 and 1993. The clinical notes were obtained and the pathological specimens analysed. RESULTS--There were 12 men and six women of age range 9-64 years. Twelve patients presented with shortness of breath, six had haemoptysis, three had hoarseness, four had pleuritic chest pain, three general weakness, two had dysphagia, and one was asymptomatic. Nine patients had a previous history of pulmonary tuberculosis. Two had auto-immune disease--one rheumatoid arthritis and the other systemic lupus erythematosus. There were three cases of previous malignancy--two undifferentiated carcinoma of the lung and the other Hodgkin9s disease. Serological tests revealed only one positive reaction to Histoplasma. The erythrocyte sedimentation rate and serum immunoglobulins were raised in nine patients. Diagnosis was usually by thoracotomy with biopsy. All cases had fibrosis and chronic inflammation with no active granulomas. No infective organisms or positive cultures were obtained in any case. Ten of the 18 cases are alive up to 15 years after diagnosis, with only two deaths and six lost to follow up. CONCLUSIONS--Sclerosing mediastinitis is a slowly progressive condition associated with previous tuberculosis, mediastinal malignancy, and autoimmune disease. The outlook is excellent for those cases without underlying malignancy.
Decannulation and NIV in tracheotomized and chronically ventilated patients
Authors: Piero Ceriana, Annalisa Carlucci, Giancarlo Piaggi, Marta Agnesi, Alberto Malovini, Stefano Nava
Journal: European Respiratory Journal (2012)

While non-invasive ventilation (NIV) is a recommended technique for weaning intubated patients after acute hypercapnic respiratory failure, little evidence exists for NIV as a technique for weaning tracheotomized patients undergoing prolonged invasive ventilation (IV). Methods: we prospectively studied a group of tracheotomized and chronically ventilated patients admitted to a weaning centre who could be suitable to decannulation and conversion to NIV because of absence of airway stenosis, normal swallowing function, preserved cough mechanism but unable to sustain a spontaneous breathing for more than 16 hours without increasing PaCO 2 . Data collected for follow-up were: demographic, functional, severity score (SAPSII), need to re-tracheotomy, survival, hospital admissions/year, maintenance of adequate gas exchange. The Fisher exact test and the log-rank test have been employed for statistical analysis. Results: 176 patients with tracheotomy and prolonged IV were evaluated; 26 patients (14 men) met the criteria and were decannulated and converted to NIV (16 obstr. 10 restr.). Mean age was 67.46 years, mean SAPSII score was 26.8, mean follow-up time was 24.8 months; 12 patients had at least 1 new episode of exacerbation, in 5 cases requiring ICU admission, and 2 patients needed re-tracheotomy. Two years-mortality rate was 26%. Age and severity score turned out to be statistically significant predictors of survival. Conclusions: Long-term maintenance of tracheotomy and invasive ventilation makes the patient more fragile and difficult to manage in the domiciliary setting. Decannulation and conversion from IV to NIV is a safe and feasible technique and should be attempted in selected hypercapnic patients.
The six-minute walking test in patients with severe COPD: What conditions are matters?
Authors: Maria Sanzharovskaya, Anna Fisenko, Georgy Chernogoryuk, Konstantin Zavadovskiy
Journal: European Respiratory Journal (2012)

The distance walked during a Six-Minute Walk Test (6 MWD) is used for following the natural history of COPD, for assessing the response to therapeutic interventions, to estimate the prognosis in BODE index, in cardiology it is used to estimation of the chronic heart failure. Normally patients with COPD III and IV stage are patients with polypatology.

Aim: to investigate the pathologic conditions which influence on the 6 MWD in severe COPD patents with and without exacerbation.

Methods : 120 patients were clinically and functionally investigated in the study during and after hospitalization in the pulmonology department. Additionally for 16 patients was performed gated blood pool single photon emission computer tomography (gbSPECT) and proBNP measurement.

Results : 

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Conclusion: in patients with COPD during disease exacerbation the main 6MWD limiting factors are respiratory function failure, hypoxia and muscle dysfunction. In stable state left and right heart dysfunction even without clinically significant heart failure contribute to 6MWD limitation.
Adiponectin and Lipoprotein Particle Size
Authors: Ram Weiss, James D. Otvos, Allan Flyvbjerg, Andre R. Miserez, Jan Frystyk, Ronit Sinnreich, Jeremy D. Kark
Journal: Diabetes Care (2009)

OBJECTIVE Adiponectin has been postulated to affect lipid and insulin signal transduction pathways. We evaluated the relationships of plasma adiponectin with lipoprotein mean particle size and subclass concentrations, independent of obesity and insulin sensitivity. RESEARCH DESIGN AND METHODS A cross-sectional analysis of 884 young Israeli adults who participated in the population-based Jerusalem Lipid Research Clinic (LRC) study was conducted. Lipoprotein particle size was assessed using proton nuclear magnetic resonance. RESULTS In multivariable linear regression models that included sex, BMI, waist circumference, homeostasis model assessment of insulin resistance, and leptin, adiponectin was associated with mean LDL size (standardized regression coefficient B = 0.20; P &amp;lt; 0.001), VLDL size (B = −0.12; P &amp;lt; 0.001), and HDL size (B = 0.06; P = 0.013). Adiponectin was inversely related to large VLDL (P &amp;lt; 0.001) but positively to small VLDL (P = 0.02), inversely related to small LDL (P &amp;lt; 0.006) but positively to large LDL (P &amp;lt; 0.001), and positively related to large HDL (P &amp;lt; 0.001) subclass concentrations. CONCLUSIONS Adiponectin is favorably associated with lipoprotein particle size and subclass distribution independent of adiposity and insulin sensitivity.
Respiratory muscle dysfunction in idiopathic pulmonary arterial hypertension
Authors: F. J. Meyer, D. Lossnitzer, A. V. Kristen, A. M. Schoene, W. Kübler, H. A. Katus, M. M. Borst
Journal: European Respiratory Journal (2005)

Idiopathic pulmonary arterial hypertension (IPAH) is a pulmonary vasculopathy of unknown aetiology. Dyspnoea, peripheral airway obstruction and inefficient ventilation are common in IPAH. Data on respiratory muscle function are lacking. This prospective single-centre study included 26 female and 11 male patients with IPAH in World Health Organization functional classes II–IV. Mean± sd pulmonary artery pressure was 48.6±16.9 in females and 53.1±22.9 mmHg in males; cardiac output was 3.7±1.3 and 4.2±1.7 L·min −1 . Maximal inspiratory pressure ( P I,max) was lower in the female patients than in 20 controls (5.3±2.0 versus 8.2±2.0 kPa). In the male patients, P I,max was lower than in 25 controls (6.8±2.2 versus 10.5±3.7 kPa). Maximal expiratory pressure ( P E,max) was lower in the female patients than in controls (6.2±2.6 versus 9.5±2.1 kPa), and in male patients as compared to controls (7.1±1.6 versus 10.3±3.9 kPa). There was no correlation between P I,max or P E,max and parameters of pulmonary haemodynamics or exercise testing. The ratio of mouth occlusion pressure within the first 0.1 s of inspiration and P I,max was higher in IPAH than in controls (females 0.067±0.066 versus 0.021±0.008; males 0.047±0.061 versus 0.023±0.016). In conclusion, this study provides the first evidence of inspiratory and expiratory muscle weakness in idiopathic pulmonary arterial hypertension. The pathomechanisms and the prognostic significance should be further investigated.