tbuckley/cabot-search huggingface dataset:
Patterns of Metabolic Progression to Type 1 Diabetes in the Diabetes Prevention Trial–Type 1
Authors: Jay M. Sosenko, Jerry P. Palmer, Carla J. Greenbaum, Jeffrey Mahon, Catherine Cowie, Jeffrey P. Krischer, H. Peter Chase, Neil H. White, Bruce Buckingham, Kevan C. Herold, David Cuthbertson, Jay S. Skyler
Journal: Diabetes Care (2006)

OBJECTIVE—There is little information regarding the pattern of metabolic deterioration before the onset of type 1 diabetes. The goal of this study was to utilize data from the Diabetes Prevention Trial–Type 1 (DPT-1) to obtain a picture of the metabolic progression to type 1 diabetes over a period of approximately 2.5 years before its diagnosis. RESEARCH DESIGN AND METHODS—Fifty-four DPT-1 participants (22 in the parenteral trial and 32 in the oral trial) were studied. All had oral glucose tolerance tests (OGTTs) at 6-month intervals from approximately 30 to 6 months before diagnosis. The vast majority also had OGTTs at diagnosis. Changes in OGTT glucose and C-peptide indexes from 30 to 6 months before diagnosis were examined by calculating slopes of the indexes for each individual over that time period. Changes from 6 months before diagnosis to diagnosis were examined by paired comparisons of the OGTT metabolic indexes between the time points. RESULTS—Glucose levels increased gradually from 30 to 6 months before diagnosis in both the parenteral and oral groups (P &amp;lt; 0.001 for all indexes). Area under the curve (AUC) C-peptide (P &amp;lt; 0.05) and AUC C-peptide–to–AUC glucose ratio (P &amp;lt; 0.001) values decreased in the oral group; peak C-peptide–to–2-h glucose ratio values decreased in both groups (P &amp;lt; 0.001). In participants who also had OGTTs at diagnosis, AUC C-peptide (parenteral group, P &amp;lt; 0.05) and peak C-peptide (oral group, P &amp;lt; 0.05) values decreased from the last 6 months before diagnosis; stimulated C-peptide–to–glucose ratio values decreased in both groups (P &amp;lt; 0.001). Conversely, fasting C-peptide levels increased in both groups (oral group, P &amp;lt; 0.01). Fasting C-peptide–to–fasting glucose ratio values remained constant throughout the 30-month follow-up. CONCLUSIONS—These data indicate that over a period of at least 2 years, glucose tolerance gradually deteriorates as stimulated C-peptide levels slowly decline in a substantial number of individuals who develop type 1 diabetes. However, fasting C-peptide levels are maintained, even at diagnosis.
Do overweight children necessarily make overweight adults? Repeated cross sectional annual nationwide survey of Japanese girls and women over nearly six decades
Authors: I. Funatogawa, T. Funatogawa, E. Yano
Journal: BMJ (2008)

<b>Objective</b> To compare growth curves of body mass index from children to adolescents, and then to young adults, in Japanese girls and women in birth cohorts born from 1930 to 1999. <b>Design</b> Retrospective repeated cross sectional annual nationwide surveys (national nutrition survey, Japan) carried out from 1948 to 2005. <b>Setting</b> Japan. <b>Participants</b> 76 635 females from 1 to 25 years of age. <b>Main outcome measure</b> Body mass index. <b>Results</b> Generally, body mass index decreased in preschool children (2-5 years), increased in children (6-12 years) and adolescents (13-18 years), and slightly decreased in young adults (19-25 years) in these Japanese females. However, the curves differed among birth cohorts. More recent cohorts were more overweight as children but thinner as young women. The increments in body mass index in early childhood were larger in more recent cohorts than in older cohorts. However, the increments in body mass index in adolescents were smaller and the decrease in body mass index in young adults started earlier, with lower peak values in more recent cohorts than in older cohorts. The decrements in body mass index in young adults were similar in all birth cohorts. <b>Conclusions</b> An overweight birth cohort in childhood does not necessarily continue to be overweight in young adulthood. Not only secular trends in body mass index at fixed ages but also growth curves for wide age ranges by birth cohorts should be considered to study obesity and thinness. Growth curves by birth cohorts were produced by a repeated cross sectional annual survey over nearly six decades.
Impact of chronic illness on the family
Authors: A. Frank
Journal: Journal of the Royal Society of Medicine (2002)

Whilst I welcome very much the importance Mr Rees and his co-workers give to understanding and measuring the strains born by partners of those with chronic illness or disability (November 2001 JRSM, pp. 563-566), I hope that it is not felt that partners are the only groups affected. These effects cross generations, depending on the age of the disabled individual. Thus, in addition to the partner, those involved in sharing the burden include: in the older generation, adult children; in the middle generation, both parents and children; and in children, parents and siblings1.

There has been a natural concern for children who provide care2 even though they themselves may be profoundly affected by their parent's disability3,4. The effects on parents of children with disabilities or illness are also profound, emotionally and physically5 as well as financially6.

Regrettably these areas appear to be under-researched and it is to be hoped that Mr Rees and his colleagues will find this a challenging area for further study.
P1125 PHARMACOKINETIC-RESPONSE ANALYSIS OF FALDAPREVIR IN TREATMENT-NAIVE PATIENTS WITH CHRONIC HCV GENOTYPE-1 INFECTION: A POOLED ANALYSIS OF TWO PHASE III TRIALS
Authors: G.R. Foster, C. Cooper, D. Dieterich, P. Ferenci, J. Crespo, M. Diago, J.-F. Dufour, W.M. Lee, M. Maevskaya, B. Müllhaupt, D. Wright, M. Schuchmann, M. Wright, M. Bourlière, S. Nishiguchi, A. Abergel, A. Streinu-Cercel, Y. Tanaka, E. Tomita, J.O. Stern, J. Scherer, S. Olson, J.-P. Gallivan, D.M. Jensen
Journal: Journal of Hepatology (2014)
Francis Robert Stanley Knight
Journal: BMJ (2004)

General practitioner Cranleigh, Surrey, 1949-85 (b Lewisham, London, 1920; q Guy's Hospital, London, 1944), d 28 January 2004 after a stroke.

During the second world war Bob joined the Royal Army Medical Corps and served in west Africa. Following house jobs he started general practice in Cranleigh. After retirement Bob continued to contribute to the health care of Cranleigh through the League of Friends, St John Ambulance, the Cranleigh Village Hospital Trust, and Ewhurst's Duke of Kent School. He leaves a wife, Grace; four children; and 12 grandchildren.
Increased Carotid Wall Stress in Vascular Ehlers-Danlos Syndrome
Authors: Pierre Boutouyrie, Dominique P. Germain, Jean-Noël Fiessinger, Brigitte Laloux, Jérôme Perdu, Stéphane Laurent
Journal: Circulation (2004)

Vascular Ehlers-Danlos syndrome (vEDS), also known as EDS type IV, an inherited disorder of connective tissue, results from mutations in the gene encoding type III procollagen (COL3A1). Affected patients are at risk for arterial dissection or rupture, the main cause of death. To understand the pathogenesis of the vascular lesions, we used a biomechanical approach and determined steady and pulsatile wall stress.Sixteen patients with vEDS and 16 age-, gender-, and blood pressure-matched control subjects were included in this cross-sectional noninvasive study. Circumferential wall stress was determined under steady and pulsatile conditions at the site of an elastic (common carotid) and a muscular (radial) artery from the measurements of intima-media thickness and internal diameter with high-resolution echo-tracking systems and either mean blood pressure or pulse pressure, respectively. At the site of the carotid artery, steady circumferential wall stress was 43% higher in vEDS patients than in control subjects (68.9+/-14.3 versus 48.2+/-12.1 kPa, P<0.001), and pulsatile circumferential wall stress was 22% higher (28.2+/-7.7 versus 23.1+/-5.7 kPa, P<0.001). Carotid intima-media thickness was 32% lower (408+/-56 versus 598+/-171 microm, P<0.001) in vEDS patients, and internal diameter was not different between groups. Radial artery parameters were not significantly different between groups.In vEDS patients, an abnormally low intima-media thickness generates a higher wall stress than in control subjects at the site of an elastic artery, which may increase the risk of arterial dissection and rupture.
The effect of endocrine responsiveness on high-risk breast cancer treated with dose-intensive chemotherapy: results of International Breast Cancer Study Group Trial 15-95 after prolonged follow-up
Authors: M. Colleoni, Z. Sun, G. Martinelli, R.L. Basser, A.S. Coates, R.D. Gelber, M.D. Green, F. Peccatori, S. Cinieri, S. Aebi, G. Viale, K.N. Price, A. Goldhirsch
Journal: Annals of Oncology (2009)
Localization of Ventricular Irritability by Epicardial Mapping
Authors: JOHN A. KASTOR, JOSEPH F. SPEAR, E. NEIL MOORE
Journal: Circulation (1972)

Epicardial mapping technics were used to locate the origin of ventricular ectopic beats produced by pacing and by the administration of ouabain and acetylstrophanthidin in pentobarbital-anesthetized open-chest dogs. The sequence of epicardial depolarization was determined with close bipolar reference and roving electrodes. The wave of excitation spread in concentric manner from driven points with the origin having the earliest time. Nonparasystolic unifocal ventricular tachycardia (UVT) was then aroused in nine dogs with ouabain or acetylstrophanthidin. Plunge electrodes were inserted for recording and stimulating of bundle of His and Purkinje fibers. Earliest epicardial ventricular activation of the UVT beats always occurred at or near the apex of the left ventricle. Purkinje fiber (PF) spikes from the region of earliest epicardial depolarization appeared just prior to ventricular activation. Pacing at this point produced QRS configuration almost identical to that during UVT. His bundle pacing normalized QRS configuration and suppressed UVT. Isolated right ventricular and left ventricular PF were perfused in the same tissue bath for microelectrode impalement. Infusion of ouabain increased the rate of automatic discharge of left ventricular PF before those from the right ventricle in each of five preparations. These studies suggest that digitalis-induced unifocal ventricular tachycardia originates below the His bundle from Purkinje tissue supplying the left ventricle and demonstrate that automaticity of canine PF from the left ventricle is preferentially enhanced by ouabain.
Hypoxia inducible factor-1α in human emphysema lung tissue
Authors: M. Yasuo, S. Mizuno, D. Kraskauskas, H.J. Bogaard, R. Natarajan, C.D. Cool, M. Zamora, N.F. Voelkel
Journal: European Respiratory Journal (2010)

The pathobiology of chronic obstructive pulmonary disease (COPD) is not completely understood. The aim of this study was to assess the expression of hypoxia inducible factor (HIF)-1α in lung tissue from patients with COPD/emphysema. Lung tissue samples from 26 patients were included in this study. Seven samples were obtained from patients with normal lung function, the remainder of the samples were taken from patients with moderate COPD (n = 6; stage I and II Global Initiative for Chronic Obstructive Lung Disease classification) and severe COPD (n = 13; stage III and IV). We analysed mRNA and protein expression in the lung tissue samples and found that: 1) HIF-1α and histone deacetylase 2 proteins were significantly decreased and were correlated; 2) HIF-1α and vascular endothelial growth factor (VEGF) proteins, and forced expiratory volume in 1 s % predicted were correlated in all patients; 3) the changes in VEGF and HIF-1α protein levels in all patients were not age-related and not related to the pack-yr smoking history; and 4) the reduced HIF-1α protein expression was seen in lung endothelial cells and alveolar septal cells by immunohistochemistry. In conclusion, reduced expression of HIF-1α protein in severe COPD is consistent with the concept of a lung structure maintenance programme which is impaired on a molecular level.
Poly(ADP-Ribose) Polymerase Inhibition: “Targeted” Therapy for Triple-Negative Breast Cancer
Authors: Carey K. Anders, Eric P. Winer, James M. Ford, Rebecca Dent, Daniel P. Silver, George W. Sledge, Lisa A. Carey
Journal: Clinical Cancer Research (2010)

Abstract In contrast to endocrine-sensitive and human epidermal growth factor receptor 2 (HER2)–positive breast cancer, novel agents capable of treating advanced triple-negative breast cancer (TNBC) are lacking. Poly(ADP-ribose) polymerase (PARP) inhibitors are emerging as one of the most promising “targeted” therapeutics to treat TNBC, with the intended “target” being DNA repair. PARPs are a family of enzymes involved in multiple cellular processes, including DNA repair. TNBC shares multiple clinico-pathologic features with BRCA-mutated breast cancers, which harbor dysfunctional DNA repair mechanisms. Investigators hypothesized that PARP inhibition, in conjunction with the loss of DNA repair via BRCA-dependent mechanisms, would result in synthetic lethality and augmented cell death. This hypothesis has borne out in both preclinical models and in clinical trials testing PARP inhibitors in both BRCA-deficient and triple-negative breast cancer. The focus of this review includes an overview of the preclinical rationale for evaluating PARP inhibitors in TNBC, the presumed mechanism of action of this novel therapeutic class, promising results from several influential clinical trials of PARP inhibition in advanced breast cancer (both TNBC and BRCA deficient), proposed mechanisms of acquired resistance to PARP inhibitors, and, finally, concludes with current challenges and future directions for the development of PARP inhibitors in the treatment of breast cancer. Clin Cancer Res; 16(19); 4702–10. ©2010 AACR.
Antiviral therapy in management of chronic hepatitis B viral infection in children: A systematic review and meta‐analysis
Authors: Maureen M. Jonas, Anna S.F. Lok, Brian J. McMahon, Robert S. Brown, John B. Wong, Ahmed T. Ahmed, Wigdan Farah, Mohamed A. Mouchli, Siddharth Singh, Larry J. Prokop, Mohammad Hassan Murad, Khaled Mohammed
Journal: Hepatology (2015)

Most individuals with chronic hepatitis B viral (HBV) infection acquired the infection around the time of birth or during early childhood. We aimed to synthesize evidence regarding the effectiveness of antiviral therapy in the management of chronic HBV infection in children. We conducted a comprehensive search of multiple databases from 1988 to December 2, 2014, for studies that enrolled children (&lt;18 years) with chronic HBV infection treated with antiviral therapy. We included observational studies and randomized controlled trials (RCTs). Two independent reviewers selected studies and extracted data. In the 14 included studies, two cohort studies showed no significant reduction in the already low risk of hepatocellular carcinoma or cirrhosis and 12 RCTs reported intermediate outcomes. In RCTs with posttreatment follow‐up &lt;12 months, antiviral therapy compared to placebo improved alanine aminotransferase normalization (risk ratio [RR] = 2.3, 95% confidence interval [CI] 1.7‐3.2), hepatitis B e antigen (HBeAg) clearance/loss (RR = 2.1, 95% CI 1.5‐3.1), HBV DNA suppression (RR = 2.9, 95% CI 1.8‐4.6), HBeAg seroconversion (RR = 2.1, 95% CI 1.4‐3.3), and hepatitis B surface antigen clearance (RR = 5.8, 95% CI 1.1‐31.5). In RCTs with posttreatment follow‐up ≥12 months, antiviral therapy improved cumulative HBeAg clearance/loss (RR = 1.9, 95% CI 1.7‐3.1), HBeAg seroconversion (RR = 2.1, 95% CI 1.3‐3.5), alanine aminotransferase normalization (RR = 1.4, 95% CI 1.1‐1.7), and HBV DNA suppression (RR = 1.4, 95% CI 1.1‐1.8) but not hepatitis B surface antigen clearance or seroconversion. Conclusion: In children with chronic HBV infection, antivirals compared to no antiviral therapy improve HBV DNA suppression and frequency of alanine aminotransferase normalization and HBeAg seroconversion. (H epatology 2016;63:307–318)
Vascular endothelial growth factor regulates myeloid cell leukemia-1 expression through neuropilin-1-dependent activation of c-MET signaling in human prostate cancer cells
Authors: Shumin Zhang, Haiyen E Zhau, Adeboye O Osunkoya, Shareen Iqbal, Xiaojian Yang, Songqing Fan, Zhengjia Chen, Ruoxiang Wang, Fray F Marshall, Leland WK Chung, Daqing Wu
Journal: Molecular Cancer (2010)

Abstract Background Myeloid cell leukemia-1 (Mcl-1) is a member of the Bcl-2 family, which inhibits cell apoptosis by sequestering pro-apoptotic proteins Bim and Bid. Mcl-1 overexpression has been associated with progression in leukemia and some solid tumors including prostate cancer (PCa). However, the regulatory mechanism for Mcl-1 expression in PCa cells remains elusive. Results Immunohistochemical analyses revealed that Mcl-1 expression was elevated in PCa specimens with high Gleason grades and further significantly increased in bone metastasis, suggesting a pivotal role of Mcl-1 in PCa metastasis. We further found that vascular endothelial growth factor (VEGF) is a novel regulator of Mcl-1 expression in PCa cells. Inhibition of endogenous Mcl-1 induced apoptosis, indicating that Mcl-1 is an important survival factor in PCa cells. Neuropilin-1 (NRP1), the "co-receptor" for VEGF 165 isoform, was found to be highly expressed in PCa cells, and indispensible in the regulation of Mcl-1. Intriguingly, VEGF 165 promoted physical interaction between NRP1 and hepatocyte growth factor (HGF) receptor c-MET, and facilitated c-MET phosphorylation via a NRP1-dependent mechanism. VEGF 165 induction of Mcl-1 may involve rapid activation of Src kinases and signal transducers and activators of transcription 3 (Stat3). Importantly, NRP1 overexpression and c-MET activation were positively associated with progression and bone metastasis in human PCa specimens and xenograft tissues. Conclusions This study demonstrated that Mcl-1 overexpression is associated with PCa bone metastasis. Activation of VEGF 165 -NRP1-c-MET signaling could confer PCa cells survival advantages by up-regulating Mcl-1, contributing to PCa progression.
Can exercise advice be 'made to stick'? Combining psychology and technology to improve patient uptake of physical activity prescription
Authors: Erin M Macri, Vanessa C Young, Karim M Khan
Journal: British Journal of Sports Medicine (2010)

We are clinicians with various degrees of experience, training in three different countries, and a compelling goal of promoting physical activity. However, the physicians feel (shh!) less than expert at confidently prescribing exercise and the physiotherapist feels concerned that inappropriate prescription could lead to a major adverse event. Professor Garry Jennings (see page 994) provides a practical eight-step programme that will allow you to prescribe exercise with confidence.1 These were not things learnt from a textbook or in medical school: they were learnt at UWE, the University of Wealth of Experience.

We would love to see his tips shared during medical school training and in all physiotherapy courses. We particularly appreciated the point that ‘good communication’ …
Causal Inference for Definitive Clinical End Points in a Randomized Clinical Trial With Intervening Nonrandomized Treatments
Authors: Edward L. Korn, Boris Freidlin
Journal: Journal of Clinical Oncology (2010)

trials in oncology in the United States.Thirteen years ago, the Armitage report 9 highlighted the need to reduce the "Tower of Babel" in clinical cancer research, which, unfortunately, the most recent report from the Institute of Medicine also highlights.Again, the history of the US automobile industry shows an eerily similar situation.In the 1980s, the US auto industry received the first of many early warnings of a major challenge from overseas. 10In the early 1990s, the industry received additional warnings that were only partially heeded. 11Fewer than two decades later, two of the Big Three were bankrupt.Let us hope that oncology clinical trials in the United States do not follow the same path.Finally, it will take more than evidence, recommendations, and hope to solve the existing problematic situation with clinical cancer research in the United States.The early warning signs are there; the canary is not looking at all well.Other seemingly dying industries have overcome major international competition to come back even stronger, semiconductor chip manufacturers being one example.Oncology clinical research in the United States can choose to follow this path instead of that of the US automakers.But it will take commitment from all major stakeholders to set aside differences and to concentrate on finding practical solutions that work for all.
Issues in adolescent asthma: what are the needs?
Authors: J F Price
Journal: Thorax (1996)

In the UK most children with asthma do not attend hospital clinics and continuity of care is provided by their general practitioner. However, those with severe asthma, most of whom will not grow out of their symptoms, need hospital-based care as well. As they progress through adolescence teenagers become increasingly uncomfortable in paediatric wards and outpatient clinics. They need clinics where they can meet the chest physician who will take on their care before they transfer to a clinic for adults (table 5). Adolescent asthmatic patients are a distinct group of patients with different treatment requirements from either paediatric or adult patients. It is important that physicians recognise adolescent needs and the importance of regular health checks, smoking, peer pressure, and the negotiation of treatment plans in this group of patients.
In vitro effects of bicarbonate and bicarbonate-lactate buffered peritoneal dialysis solutions on mesothelial and neutrophil function.
Authors: N Topley, D Kaur, M M Petersen, A Jörres, J D Williams, D Faict, C J Holmes
Journal: Journal of the American Society of Nephrology (1996)

The inclusion of bicarbonate in the formulation of peritoneal dialysis solutions may avoid the in vitro impairment of certain cell functions seen with acidic lactate-based fluids. The supranormal physiological levels of HCO3- and PCO2 inherent in such formulations may, however, not be biocompatible. This study compared the in vitro biocompatibility of a pH 5.2 lactate-based formulation with formulations containing either 40 mM lactate at pH 7.4, 38 mM HCO3- at pH 6.8 (PCO2 at approximately 240 mm Hg) or 7.4 (PCO2 at approximately 60 mm Hg), and 25 mM HCO3- plus 15 mM lactate at pH 6.8 (PCO2 at approximately 160 mm Hg) or 7.4 (PCO2 at approximately 40 mm Hg). Significant release of lactate dehydrogenase or decreases in ATP content by human peritoneal mesothelial cells (HPMC) and human peripheral polymorphonuclear leukocytes (PMN) after a 30-min exposure to each test solution was only seen with the pH 5.2 lactate-based fluid. The ATP content of HPMC exposed to this fluid returned to control levels after 30 min of recovery in M199 control medium but showed a trend toward decreasing ATP content at 240 min. Similarly, interleukin (IL)-1 beta-induced IL-6 synthesis by HPMC was also only significantly reduced by the pH 5.2 lactate solution. PMN chemiluminescence was unaffected by 30-min exposure to all test solutions except for the pH 5.2 lactate formulation. Staphylococcus epidermidis phagocytosis was reduced to between 46 to 57% of control with all test solutions except the pH 5.2 lactate solution, which further suppressed the chemiluminescence response to 17% of control. These data suggest that short exposure to supranormal physiological levels of HCO3- and PCO2 does not impair HPMC or PMN viability and function. Furthermore, neutral pH lactate-containing solutions show equivalent biocompatibility to bicarbonate-based ones.