tbuckley/cabot-search huggingface dataset:
Plasmapheresis for treatment of pulmonary alveolar proteinosis
Authors: M. Luisetti, G. Rodi, C. Perotti, I. Campo, F. Mariani, E. Pozzi, B. C. Trapnell
Journal: European Respiratory Journal (2009)

Whole lung lavage (WLL) is currently the standard therapy for pulmonary alveolar proteinosis (PAP). Nevertheless, some PAP patients respond poorly to WLL or require it frequently. The present paper reports a patient with autoimmune PAP with persistent disease despite three WLL treatments over 10 months. Plasmapheresis with ten 1.5-L plasma exchanges was performed, which lowered the serum granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibody level from 250 μg·mL<sup>−1</sup> to 156 μg·mL<sup>−1</sup> but did not improve respiratory impairment. Further WLL therapy was required and transiently effective. Serum GM-CSF autoantibody levels declined progressively, reaching a value of 56 μg·mL<sup>−1</sup> 80 weeks after completion of plasmapheresis. However, this decrease was not accompanied by clinical improvement and the patient required additional WLL therapy. The results confirm that minor reductions in serum granulocyte-macrophage colony-stimulating factor autoantibody levels from plasmapheresis are not reflected in clinical improvement in the severity of lung disease in pulmonary alveolar proteinosis.
Weight reduction increases adipose tissue lipoprotein lipase responsiveness in obese women.
Authors: R H Eckel, T J Yost
Journal: Journal of Clinical Investigation (1987)

Lipoprotein lipase was measured in gluteal adipose tissue from nine obese (90.6 +/- 2.7 kg) women fasting and after the intravenous infusion of insulin and glucose before, immediately after, and 3 mo subsequent to a 14.0 +/- 1.8% (mean +/- SEM) weight reduction. Fasting adipose tissue lipoprotein lipase activity (ATLPL) decreased from 5.3 to 2.3 nEq FFA/10(6) cells per min (P less than 0.02) immediately after weight reduction, yet after weight maintenance, higher levels were again found (6.1 nEq FFA/10(6) cells per min). Although responsiveness of ATLPL to 40 mU/m2 per min of insulin infusion over 6 h was absent before weight loss, increases were seen immediately after weight loss (delta 0.8, P = 0.05) and more so (delta 7.7, P less than 0.01) after 3 mo. Moreover, whereas before weight loss the ATLPL response to ingested mixed meals (delta 0.9) was minimal, in the maintained reduced-obese state a marked increase was seen (delta 12.6, P = 0.02). Thus, because ATLPL is important to lipid filling in adipose tissue, the maintenance of high levels of fasting ATLPL and the increase in enzyme responsiveness in the reduced-obese state could play an important role in the resumption of the obese state, which so commonly follows weight reduction.
Predictive Value of the Pretreatment Extent of Disease System in Hepatoblastoma: Results From the International Society of Pediatric Oncology Liver Tumor Study Group SIOPEL-1 Study
Authors: Daniël C. Aronson, J. Marco Schnater, Chris R. Staalman, Gerrit J. Weverling, Jack Plaschkes, Giorgio Perilongo, Julia Brown, Angela Phillips, Jean-Bernard Otte, Piotr Czauderna, Gordon MacKinlay, Anton Vos
Journal: Journal of Clinical Oncology (2005)

Preoperative staging (pretreatment extent of disease [PRETEXT]) was developed for the first prospective liver tumor study by the International Society of Pediatric Oncology (SIOPEL-1 study; preoperative chemotherapy and delayed surgery). Study aims were to analyze the accuracy and interobserver agreement of PRETEXT and to compare the predictive impact of three currently used staging systems.Hepatoblastoma (HB) patients younger than 16 years who underwent surgical resection (128 of 154 patients) were analyzed. The centrally reviewed preoperative staging was compared with postoperative pathology (accuracy) in 91 patients (81%), and the local center staging was compared with the central review (interobserver agreement) in 97 patients (86%), using the agreement beyond change method (weighted kappa). The predictive values of the three staging systems were compared in 110 patients (97%) using survival curves and Cox proportional hazard ratio estimates.Preoperative PRETEXT staging compared with pathology was correct in 51%, overstaged in 37%, and understaged in 12% of patients (weighted kappa = 0.44; 95% CI, 0.26 to 0.62). The weighted kappa value of the interobserver agreement was 0.76 (95% CI, 0.64 to 0.88). The Children's Cancer Study Group/Pediatric Oncology Group-based staging system showed no predictive value for survival (P = .516), but the tumor-node-metastasis-based system and PRETEXT system showed good predictive values (P = .0021 and P = .0006, respectively). PRETEXT seemed to be superior in the statistical fit.PRETEXT has moderate accuracy with a tendency to overstage patients, shows good interobserver agreement (reproducibility), shows superior predictive value for survival, offers the opportunity to monitor the effect of preoperative therapy, and can also be applied in patients who have not had operations. For comparability reasons, we recommend that all HB patients included in trials also be staged according to PRETEXT.
Achieving Optimal Outcomes After Radical Prostatectomy
Authors: Jeffery W. Saranchuk, Michael W. Kattan, Elena Elkin, A. Karim Touijer, Peter T. Scardino, James A. Eastham
Journal: Journal of Clinical Oncology (2005)

The most favorable outcome that can be achieved after radical prostatectomy is complete tumor resection without recurrence and full recovery of continence and potency. Risks of erectile dysfunction, incontinence, and disease recurrence are well described, but in isolation, do not adequately inform patients of the possibility of becoming cancer-free while at the same time returning to their preoperative functional state. We sought to determine the frequency of optimal outcomes after radical prostatectomy and the time to such outcomes.Patients who underwent radical prostatectomy performed at a tertiary referral center between July 1998 and July 2003 for clinical stage T1 to T3 prostate cancer were identified. Patients were excluded if they were incontinent or impotent preoperatively, or if they had received radiotherapy or neoadjuvant androgen deprivation therapy previously. Six hundred forty-seven patients were analyzed for time to recovery of full continence and potency without cancer recurrence after surgery. Optimal outcome probability was calculated with a Markov state transition model to simulate clinical outcomes in the first 4 years following radical prostatectomy.Mean patient age was 58 years, and mean pretreatment prostate-specific antigen was 6.9 ng/mL. Cancer-free status with full continence and potency was achieved in 30% of men at 12 months, 42% at 24 months, 47% at 36 months, and 53% at 48 months postoperatively.Optimal outcomes after radical prostatectomy can be achieved in a small majority of cases. Time to full recovery is primarily dictated by recovery of erectile function. This information is helpful for patients interested in their chances of returning to their preoperative functional state.
A urine biomarker for severe obstructive sleep apnoea patients: lipocalin-type prostaglandin D synthase
Authors: Yuichi Chihara, Kazuo Chin, Kosuke Aritake, Yuka Harada, Yoshiro Toyama, Kimihiko Murase, Chikara Yoshimura, Takefumi Hitomi, Toru Oga, Michiaki Mishima, Yoshihiro Urade
Journal: European Respiratory Journal (2012)

Lipocalin-type prostaglandin D synthase (L-PGDS), which is responsible for the biosynthesis of prostaglandin D<sub>2</sub>, has been reported to have a close connection with cardiovascular disease and sleep regulation. This study aimed to test the hypothesis that the L-PGDS level is a useful marker to identify patients with obstructive sleep apnoea. 64 subjects were enrolled in this prospective study. Urinary concentrations of L-PGDS were measured in the morning. Measurements were made every 4 h in 25 of the 64 patients. Endothelial function was assessed by the reactive hyperaemia peripheral arterial tone index. Circadian variations in L-PGDS concentrations had a significant time-dependent fluctuation (p = 0.0002). L-PGDS was higher in the subjects with severe obstructive sleep apnoea (median 784.7 ng per mg of creatinine, n = 23) than in control subjects (262.1 ng per mg of creatinine, n = 16; p = 0.004) and in those with moderate obstructive sleep apnoea (371.7 ng per mg of creatinine, n = 25; p = 0.0008). After 2 days of continuous positive airway pressure treatment, L-PGDS concentrations in severe obstructive sleep apnoea subjects (n = 12) decreased significantly (p = 0.02) to levels present in control subjects whereas endothelial function did not change significantly. Morning urinary L-PGDS concentrations had significant correlations with the apnoea/hypopnoea index (R<sup>2</sup> = 13.9%) and serum high-density lipoprotein cholesterol (R<sup>2</sup> = 6.2%), but not with sleepiness. Urinary L-PGDS might be a moderately useful marker to identify patients with severe obstructive sleep apnoea.
Glycemic control in diabetic American Indians. Longitudinal data from the Strong Heart Study.
Authors: D Hu, J A Henderson, T K Welty, E T Lee, K A Jablonski, M F Magee, D C Robbins, B V Howard
Journal: Diabetes Care (1999)

OBJECTIVE: To describe glycemic control and identify correlates of elevated HbA1c levels in diabetic American Indians participating in the Strong Heart Study, which is a longitudinal study of cardiovascular disease in American Indians in Arizona, Oklahoma, South Dakota, and North Dakota. RESEARCH DESIGN AND METHODS: This analysis is based on data from the baseline (1989-1992) and first follow-up (1994-1995) examinations of the Strong Heart Study. The 1,581 diabetic participants included in this analysis were aged 45-74 years at baseline, were diagnosed with diabetes before and at baseline, and had their HbA1c levels measured at follow-up. HbA1c was used as the index of glycemic control. Characteristics that may affect glycemic control were evaluated for cross-sectional and longitudinal relationships by analysis of covariance and multiple regression. RESULTS: There was no significant difference between median HbA1c at baseline (8.4%) and at follow-up (8.5%). Sex, age (inversely), and insulin and oral hypoglycemic agent therapy were significantly related to HbA1c levels in both the cross-sectional and longitudinal analyses. Current smoking, prior use of alcohol, and duration of diabetes were significant only for the cross-sectional data. Baseline HbA1c significantly and positively predicted HbA1c levels at follow-up. Comparison of HbA1c by therapy type shows that insulin therapy produced a significant decrease in HbA1c between the baseline and follow-up examinations. CONCLUSIONS: Glycemic control was poor among diabetic American Indians participating in the Strong Heart Study. Women, patients taking insulin or oral hypoglycemic agents, and younger individuals had the worst control of all the participants. Baseline HbA1c, and weight loss predicted worsening of control, whereas insulin therapy predicted improvement in control. Additional therapies and/or approaches are needed to improve glycemic control in this population.
Walking and Leisure-Time Activity and Risk of Hip Fracture in Postmenopausal Women
Authors: Diane Feskanich
Journal: JAMA (2002)

ContextPhysical activity can reduce the risk of hip fractures in older women, although the required type and duration of activity have not been determined. Walking is the most common activity among older adults, and evidence suggests that it can increase femoral bone density and reduce fracture risk.ObjectiveTo assess the relationship of walking, leisure-time activity, and risk of hip fracture among postmenopausal women.Design, Setting, and ParticipantsProspective analysis begun in 1986 with 12 years of follow-up in the Nurses' Health Study cohort of registered nurses within 11 US states. A total of 61 200 postmenopausal women (aged 40-77 years and 98% white) without diagnosis of cancer, heart disease, stroke, or osteoporosis at baseline.Main Outcome MeasuresIncident hip fracture resulting from low or moderate trauma, analyzed by intensity and duration of leisure-time activity and by time spent walking, sitting, and standing, measured at baseline and updated throughout follow-up.ResultsFrom 1986 to 1998, 415 incident hip fracture cases were identified. After controlling for age, body mass index, use of postmenopausal hormones, smoking, and dietary intakes in proportional hazards models, risk of hip fracture was lowered by 6% (95% confidence interval [CI], 4%-9%; P&lt;.001) for each increase of 3 metabolic equivalent (MET)–hours per week of activity (equivalent to 1 h/wk of walking at an average pace). Active women with at least 24 MET-h/wk had a 55% lower risk of hip fracture (relative risk [RR], 0.45; 95% CI, 0.32-0.63) compared with sedentary women with less than 3 MET-h/wk. Even women with a lower risk of hip fracture due to higher body weight experienced a further reduction in risk with higher levels of activity. Risk of hip fracture decreased linearly with increasing level of activity among women not taking postmenopausal hormones (P&lt;.001), but not among women taking hormones (P = .24). Among women who did no other exercise, walking for at least 4 h/wk was associated with a 41% lower risk of hip fracture (RR, 0.59; 95% CI, 0.37-0.94) compared with less than 1 h/wk. More time spent standing was also independently associated with lower risks.ConclusionModerate levels of activity, including walking, are associated with substantially lower risk of hip fracture in postmenopausal women.
Defining the Signals that Constitute the Nephron Progenitor Niche
Authors: Thomas J. Carroll, Amrita Das
Journal: Journal of the American Society of Nephrology (2013)

For decades we have known that reciprocal inductive interactions between the embryonic ureteric bud and the metanephric mesenchyme are the basis for kidney development. Signals from the mesenchyme promote the branching of the bud, whereas signals from the bud regulate the survival, proliferation, and differentiation of nephron progenitors. Due to the complex nature of the bud-derived signals, progress in identifying these factors has been slow. However, in the last several years, tremendous advances have been made in identifying specific roles for various secreted proteins in nephron progenitor cell development. Here, we briefly review the roles for Fgfs and Wnts in induction of the nephron progenitors.
A Naturally Selected Dimorphism within the HLA-B44 Supertype Alters Class I Structure, Peptide Repertoire, and T Cell Recognition
Authors: Whitney A. Macdonald, Anthony W. Purcell, Nicole A. Mifsud, Lauren K. Ely, David S. Williams, Linus Chang, Jeffrey J. Gorman, Craig S. Clements, Lars Kjer-Nielsen, David M. Koelle, Scott R. Burrows, Brian D. Tait, Rhonda Holdsworth, Andrew G. Brooks, George O. Lovrecz, Louis Lu, Jamie Rossjohn, James McCluskey
Journal: The Journal of Experimental Medicine (2003)

HLA-B*4402 and B*4403 are naturally occurring MHC class I alleles that are both found at a high frequency in all human populations, and yet they only differ by one residue on the alpha2 helix (B*4402 Asp156-->B*4403 Leu156). CTLs discriminate between HLA-B*4402 and B*4403, and these allotypes stimulate strong mutual allogeneic responses reflecting their known barrier to hemopoeitic stem cell transplantation. Although HLA-B*4402 and B*4403 share >95% of their peptide repertoire, B*4403 presents more unique peptides than B*4402, consistent with the stronger T cell alloreactivity observed toward B*4403 compared with B*4402. Crystal structures of B*4402 and B*4403 show how the polymorphism at position 156 is completely buried and yet alters both the peptide and the heavy chain conformation, relaxing ligand selection by B*4403 compared with B*4402. Thus, the polymorphism between HLA-B*4402 and B*4403 modifies both peptide repertoire and T cell recognition, and is reflected in the paradoxically powerful alloreactivity that occurs across this "minimal" mismatch. The findings suggest that these closely related class I genes are maintained in diverse human populations through their differential impact on the selection of peptide ligands and the T cell repertoire.
National audit shows improving survival rates from bowel cancer but worrying regional variations in case management
Authors: A. O'Dowd
Journal: BMJ (2009)

Survival rates from bowel cancer in England and Wales are improving, but variation in different regions is a cause for concern, states a national audit report published this week.

The audit, produced by the Association of Coloproctology of Great Britain and Ireland (ACPGBI) and the NHS Information Centre, paints an improving picture for patients with this form of cancer, but shows worrying regional variations in how cases are managed.

Bowel cancer is the third most common form of cancer and causes the deaths of about 16 000 people each year in the United Kingdom.

In England 146 of 153 (95%) eligible trusts and all …
The 26-kD transmembrane form of tumor necrosis factor alpha on activated CD4+ T cell clones provides a costimulatory signal for human B cell activation.
Authors: G Aversa, J Punnonen, J E de Vries
Journal: The Journal of Experimental Medicine (1993)

Interleukin 4 (IL-4) induces immunoglobulin (Ig)E and IgG4 synthesis in human B cells. In addition to IL-4, costimulatory signals provided by activated CD4+ T cells are required for productive IgG4 and IgE synthesis. Here we report that the 26-kD transmembrane form of tumor necrosis factor alpha (mTNF-alpha), which is rapidly expressed on CD4+ T cell clones after activation, contributes to the costimulatory signals resulting in IL-4-dependent Ig synthesis by B cells, including IgG4 and IgE production. mTNF-alpha expression was induced on T cell clones within 2 h after activation with concanavalin A. Peak expression was observed at 24 h, followed by a gradual decrease, but appreciable levels of mTNF-alpha were still detectable 72 h after activation. The presence of the 26-kD membrane form of TNF-alpha on activated T cell clones was confirmed by immunoprecipitation. Monoclonal antibodies (mAbs) recognizing mTNF-alpha, or the p55 TNF receptor, inhibited IgM, IgG, IgG4, and IgE synthesis induced by IL-4 and activated CD4+ T cell clones in cultures of highly purified surface IgD+ B cells. The anti-TNF-alpha mAbs also blocked Ig production in cultures in which the activated CD4+ T cell clones were replaced by their plasma membranes. Furthermore, pretreatment of the plasma membranes with anti-TNF-alpha mAbs strongly reduced their capacity to stimulate B cells to produce Ig in the presence of IL-4, indicating that the anti-TNF-alpha mAbs blocked the effects of mTNF-alpha. Anti-TNF-alpha mAbs did not affect IgM, IgG, IgG4, or IgE synthesis induced by anti-CD40 mAbs and IL-4 in the absence of CD4+ T cells, supporting the notion that the anti-TNF-alpha mAbs indeed interfered with the costimulatory, contact-mediated signal provided by T cells, or their membranes. Collectively these results indicate that mTNF-alpha, which is rapidly induced after activation of CD4+ T cells, participates in productive T-B cell interactions resulting in IL-4-induced Ig production. This is a novel property of the T cell membrane form of TNF-alpha.
Treatment of Type 2 Diabetes and Outcomes in Patients With Heart Failure: A Nested Case–Control Study From the U.K. General Practice Research Database
Authors: Michael R. MacDonald, Dean T. Eurich, Sumit R. Majumdar, James D. Lewsey, Sai Bhagra, Pardeep S. Jhund, Mark C. Petrie, John J.V. McMurray, John R. Petrie, Finlay A. McAlister
Journal: Diabetes Care (2010)

Diabetes and heart failure commonly coexist, and prior studies have suggested better outcomes with metformin than other antidiabetic agents. We designed this study to determine whether this association reflects a beneficial effect of metformin or a harmful effect of other agents.We performed a case-control study nested within the U.K. General Practice Research Database cohort in which diagnoses were assigned by each patient's primary care physician. Case subjects were patients 35 years or older, newly diagnosed with both heart failure and diabetes after January 1988, and who died prior to October 2007. Control subjects were matched to case subjects based on age, sex, clinic site, calendar year, and duration of follow-up. Analyses were adjusted for comorbidities, A1C, renal function, and BMI.The duration of concurrent diabetes and heart failure was 2.8 years (SD 2.6) in our 1,633 case subjects and 1,633 control subjects (mean age 78 years, 53% male). Compared with patients who were not exposed to antidiabetic drugs, the current use of metformin monotherapy (adjusted odds ratio 0.65 [0.48-0.87]) or metformin with or without other agents (0.72 [0.59-0.90]) was associated with lower mortality; however, use of other antidiabetic drugs or insulin was not associated with all-cause mortality. Conversely, the use of ACE inhibitors/angiotensin receptor blockers (0.55 [0.45-0.68]) and beta-blockers (0.76 [0.61-0.95]) were associated with reduced mortality.Our results confirm the benefits of trial-proven anti-failure therapies in patients with diabetes and support the use of metformin-based strategies to lower glucose.
Synaptotagmin IV determines the linear Ca2+ dependence of vesicle fusion at auditory ribbon synapses
Authors: Stuart L Johnson, Christoph Franz, Stephanie Kuhn, David N Furness, Lukas Rüttiger, Stefan Münkner, Marcelo N Rivolta, Elizabeth P Seward, Harvey R Herschman, Jutta Engel, Marlies Knipper, Walter Marcotti
Journal: Nature Neuroscience (2009)
Effect of Azithromycin Treatment on Endothelial Function in Patients With Coronary Artery Disease and Evidence of <b> <i>Chlamydia pneumoniae</i> </b> Infection
Authors: Nikhil Parchure, Emmanouil G. Zouridakis, Juan Carlos Kaski
Journal: Circulation (2002)

Background — It has been suggested that infection with Chlamydia pneumoniae ( CPn ) can trigger inflammatory mechanisms that may in turn impair vascular endothelial function. The aim of the present study was to assess whether treatment with the macrolide antibiotic azithromycin improves endothelial function in patients with coronary artery disease and antibodies positive to CPn. Methods and Results — We carried out a randomized, prospective, double-blind, placebo-controlled trial in 40 male patients (mean age, 55±9 years) with documented coronary artery disease and positive CPn -IgG antibody titers. After baseline evaluation, patients were randomized to receive either azithromycin or placebo for 5 weeks. Flow-mediated dilation (FMD) of the brachial artery and E-selectin, von Willebrand factor, and C-reactive protein (CRP) levels were assessed at study entry and at the end of the treatment period. Our results showed that patients who received azithromycin had a significant improvement in FMD (mean change, 2.1±1.1%; P &lt;0.005). In contrast, FMD was not significantly changed in the placebo group (mean change, −0.02±0.2%, P =0.64). Azithromycin therapy also resulted in a significant decrease of E-selectin and von Willebrand factor levels. CRP levels were not significantly altered by treatment with either azithromycin or placebo. Beneficial effects of azithromycin treatment were independent from the presence of low (&lt;1:32) or high (≥1:32) CPn antibody titers. Conclusions — Our findings indicate that treatment with azithromycin has a favorable effect on endothelial function in patients with documented coronary artery disease and evidence of CPn infection irrespective of antibody titer levels. Whether these favorable actions of antibiotic treatment will translate into a beneficial effect on atherogenesis and cardiac events needs further investigation.