tbuckley/cabot-search huggingface dataset:
ACE inhibitors may reduce muscle loss
Authors: D. Spurgeon
Journal: BMJ (2002)

Angiotensin converting enzyme (ACE) inhibitors, when taken regularly, show promise for delaying muscle loss and disability, report researchers at Wake Forest University Baptist Medical Center, Winston Salem, North Carolina, who studied 641 older women with hypertension ( Lancet 2002;359:926-30).

Participants who took the drug continually had a significantly lower average decline in muscle strength over three years, compared with continual, intermittent users of other antihypertensive drugs …
Sickling in an African Community
Authors: W. Brass
Journal: BMJ (1956)

<h3>Abstract</h3> Regulation of energy metabolism and response to cold are intimately linked in mammals. Central to these two processes are the mitochondrial uncoupling proteins (UCPs), which by promoting proton leakage across the inner mitochondrial membrane lead to the generation of heat instead of ATP synthesis. In addition to heat generation, UCPs also influence energy storage and can protect against obesity and diabetes. Cold-blooded animals like flies also contain UCPs that protect from cold, however their regulations are poorly understood. We find that <i>Drosophila UCP4b</i> is induced by cold in a cell-intrinsic manner and protects against cold and obesity in fly models. Mechanistically, cold regulates <i>UCP4b</i> expression through calcium signaling and Spargel (Srl), the <i>Drosophila</i> ortholog of mammalian PGC1α. To the opposite, MAD, acting downstream of the BMP branch of the TGFβ signaling pathway, represses <i>UCP4b</i> expression independently of cold. Interestingly, the two mechanisms of <i>UCP4b</i> regulation are integrated as MAD binding to the <i>UCP4b</i> promoter is displaced by cold in a <i>Srl-</i>dependent manner. We discuss the similarities between the regulation of mammalian and <i>Drosophila</i> UCPs. <h3>Significance</h3> Mitochondrial uncoupling proteins (UCPs) that uncouple the mitochondrial respiration from ATP synthesis regulate energy metabolism, non-shivering thermogenesis, and redox balance in vertebrates and invertebrates. However, their regulation in <i>Drosophila</i> is poorly understood. We found that <i>Drosophila</i> uncoupling protein UCP4b is induced by cold in a cell-autonomous fashion. Conversely, MAD, acting downstream of BMP signaling, inhibits <i>UCP4b</i> expression. MAD is displaced from the upstream regions of the <i>UCP4b</i> gene by cold. UCP4b protects <i>Drosophila</i> against cold and diet-induced obesity. The regulation of UCP4b by cold and BMP signaling is reminiscent of the regulation of mammalian uncoupling protein UCP1. Altogether, we discovered an important regulator of <i>Drosophila</i> energy metabolism which is controlled by regulatory processes that are similar between <i>Drosophila</i> and mammals.
Effect of Clopidogrel on Early Failure of Arteriovenous Fistulas for Hemodialysis
Authors: Laura M. Dember, Gerald J. Beck, Michael Allon, James A. Delmez, Bradley S. Dixon, Arthur Greenberg, Jonathan Himmelfarb, Miguel A. Vazquez, Jennifer J. Gassman, Tom Greene, Milena K. Radeva, Gregory L. Braden, T. Alp Ikizler, Michael V. Rocco, Ingemar J. Davidson, James S. Kaufman, Catherine M. Meyers, John W. Kusek, Harold I. Feldman, for the Dialysis Access Consortium Study Group
Journal: JAMA (2008)

<h3>Context</h3>The arteriovenous fistula is the preferred type of vascular access for hemodialysis because of lower thrombosis and infection rates and lower health care expenditures compared with synthetic grafts or central venous catheters. Early failure of fistulas due to thrombosis or inadequate maturation is a barrier to increasing the prevalence of fistulas among patients treated with hemodialysis. Small, inconclusive trials have suggested that antiplatelet agents may reduce thrombosis of new fistulas.<h3>Objective</h3>To determine whether clopidogrel reduces early failure of hemodialysis fistulas.<h3>Design, Setting, and Participants</h3>Randomized, double-blind, placebo-controlled trial conducted at 9 US centers composed of academic and community nephrology practices in 2003-2007. Eight hundred seventy-seven participants with end-stage renal disease or advanced chronic kidney disease were followed up until 150 to 180 days after fistula creation or 30 days after initiation of dialysis, whichever occurred later.<h3>Intervention</h3>Participants were randomly assigned to receive clopidogrel (300-mg loading dose followed by daily dose of 75 mg; n = 441) or placebo (n = 436) for 6 weeks starting within 1 day after fistula creation.<h3>Main Outcome Measures</h3>The primary outcome was fistula thrombosis, determined by physical examination at 6 weeks. The secondary outcome was failure of the fistula to become suitable for dialysis. Suitability was defined as use of the fistula at a dialysis machine blood pump rate of 300 mL/min or more during 8 of 12 dialysis sessions.<h3>Results</h3>Enrollment was stopped after 877 participants were randomized based on a stopping rule for intervention efficacy. Fistula thrombosis occurred in 53 (12.2%) participants assigned to clopidogrel compared with 84 (19.5%) participants assigned to placebo (relative risk, 0.63; 95% confidence interval, 0.46-0.97; P = .018). Failure to attain suitability for dialysis did not differ between the clopidogrel and placebo groups (61.8% vs 59.5%, respectively; relative risk, 1.05; 95% confidence interval, 0.94-1.17; P = .40).<h3>Conclusion</h3>Clopidogrel reduces the frequency of early thrombosis of new arteriovenous fistulas but does not increase the proportion of fistulas that become suitable for dialysis.<h3>Trial Registration</h3>clinicaltrials.gov Identifier: NCT00067119
In vitro parasite-monocyte interactions in human leishmaniasis. Evidence for an active role of the parasite in attachment.
Authors: D J Wyler
Journal: Journal of Clinical Investigation (1982)

Leishmania are obligate intracellular parasites of mononuclear phagocytes in the mammalian host. To more clearly define features of the early events in host-parasite interaction, human monocytes were so-cultured with Leishmania tropica amastigotes in vitro. Infection of monocytes was time dependent and inhibited at 4 degrees C and in the presence of cytochalasin B. Pretreatment of amastigotes with cytochalasins prevented their attachment to normal monocytes. Untreated amastigotes attached normally but could not enter cytochalasin-pretreated monocytes. This suggests that amastigotes actively participate in attachment but require host cell participation for interiorization.
A RENAL CYST CAUSING CHRONIC INTESTINAL OBSTRUCTION
Authors: E. C. Bevers
Journal: BMJ (1914)

microscope there are to be seen bacteria, minute fat globules, anid cellular detritus.The tluid is practically free from albumini.The fermentative action of the fluid has been tested upon fibrin, egg albumen, starch, and butter fat, with the following results:1 There is slight but quite definite proteolytic action upon the fibriin and coagulated albumin.2. There is marked diastatic action uiponi starch, wlich is coniverted into a reducing sugar which yields the osazone of iso-maltose.3. Butter fat is emulsified, but does not undergo sufficient splitting withini two lhours to show any acid productioin by the litmus test.From its general characters and reactions there is goo(d reason for believing that the fluid is from a panlereatic cyst.Oii F'ebruary 17tli, 1939, the patient was again seized with violenit pain in the epigastrium withl vomiting anid constipation; the vomit consiste(d of bile-stainied mucus.No food could be retained in the stomach.The pain, wlhich was spasmodic, and passed through to the back, passed off in about three days, and the bowels were well openied by castor oil anid magnesium sulphate.The ingestioni of food wvas associated with dis- comfort about half ani hour after, and there were occasional attacks of pain at otlher times.Some thickening was niow
Pharmacological Modulation of Cardiac Gap Junctions to Enhance Cardiac Conduction
Authors: Benjamin C. Eloff, Eran Gilat, Xiaoping Wan, David S. Rosenbaum
Journal: Circulation (2003)

Disease-induced alterations of cardiac gap junctions lead to intercellular uncoupling, which is an important mechanism of arrhythmogenesis. Therefore, drugs that selectively open gap junctions potentially offer a novel strategy for antiarrhythmic therapy. Because the peptide ZP123 was found to increase conductance between paired myocytes, we hypothesized that ZP123 would suppress acidosis-induced gap junction closure in the intact heart.High-resolution optical mapping was used to measure conduction velocity (CV) and action potential duration from ventricular epicardium of Langendorff-perfused guinea pig hearts at baseline (pH 7.4) and during 45 minutes of perfusion with acidotic (pH 6.0) Tyrode's solution with (n=8) and without (control, n=7) ZP123 (80 nmol/L). Acidosis produced conduction slowing transverse (29.1+/-0.1 to 16.8+/-0.2 cm/s, P<0.0001) and longitudinal (47.2+/-2.4 to 33.2+/-4.8 cm/s, P<0.0001) to cardiac fibers. Importantly, ZP123 inhibited conduction slowing during acidosis by approximately 60%. The peak effect of ZP123 was achieved after 16 minutes of acidosis, consistent with inhibition of uncoupling. ZP123 did not affect Na+ current in isolated myocytes, additionally affirming that preservation of CV was attributable to the compound's action on gap junctions. ZP123 had no effect on CV in the absence of acidosis, suggesting that drug activity targets gap junctions under metabolic stress. Action potential duration heterogeneity was significantly reduced by ZP123 (6.7+/-0.8 ms) compared with controls (9.7+/-3.1 ms, P<0.05), presumably by enhancing cell-to-cell coupling.These data suggest that ZP123 significantly attenuates gap junction closure during acidosis. Preservation of intercellular coupling diminished CV slowing and heterogeneous repolarization, eliminating arrhythmogenic substrates.
Characterization of glycosylated hemoglobins. Relevance to monitoring of diabetic control and analysis of other proteins.
Authors: R L Garlick, J S Mazer, P J Higgins, H F Bunn
Journal: Journal of Clinical Investigation (1983)

Boronate affinity chromatography and ion exchange chromatography were used to measure the levels of glycosylated hemoglobins in normal and diabetic hemolysates, as well as the distribution of glucose adducts on alpha-NH2-valine and epsilon-NH2-lysine residues. When analyzed by ion exchange chromatography on BioRex 70 resin, the Hb Alc peak comprised 4.4 +/- 0.6% of 15 normal hemolysates and 9.1 +/- 2.1% of 15 diabetic hemolysates. The "Hb Alc" was rechromatographed on GlycoGel B boronate affinity resin that binds vicinal hydroxyl groups of covalently linked sugars. Only 70 +/- 5% of the hemoglobin adhered to the resin. Analysis by the thiobarbituric acid colorimetric test confirmed that the affinity resin effectively separated glycosylated from nonglycosylated hemoglobin. When corrected for nonglycosylated contaminants, the mean level of Hb Alc in normal hemolysates was 2.9 +/- 0.4%, a value considerably lower than those previously reported. In addition to Hb Alc, 5.2 +/- 0.5% of the remaining hemoglobin (Hb Ao) was glycosylated. In diabetics, glycosylated Ao was increased in parallel with Hb Alc. After reduction with [3H]borohydride and acid hydrolysis, glycosylated amino acids were first purified on Affi-Gel boronate affinity resin and then analyzed by ion exchange chromatography. The glucose adducts on Hb Ao were distributed as follows: alpha-chain N-terminal valine, 14%; alpha-chain lysines, 40%; beta-chain lysines, 46%. This study has revealed several pitfalls in the analysis of nonenzymatically glycosylated proteins. Peaks isolated by ion exchange chromatography or electrophoresis are likely to be contaminated by nonglycosylated proteins. Furthermore, both the thiobarbituric acid test and [3H]borohydride reduction show variable reactivity depending upon the site of the ketoamine-linked glucose.
Liposome-encapsulated vincristine, vinblastine and vinorelbine: A comparative study of drug loading and retention
Authors: Igor V. Zhigaltsev, Norbert Maurer, Quet-Fah Akhong, Robert Leone, Esther Leng, Jinfang Wang, Sean C. Semple, Pieter R. Cullis
Journal: Journal of Controlled Release (2005)
Abstract 5187: Urokinase plasminogen activator receptor (uPAR) and integrin α5β1 regulate plasminogen activator inhibitor-1 (PAI-1) activity in medulloblastoma cells
Authors: Arun Kumar Nalla, Swapna Asuthkar, Meena Gujrati, Dzung H. Dinh, Jasti S. Rao
Journal: Cancer Research (2012)

Abstract The urokinase plasminogen activator (uPA) system is a dynamic extracellular protease system that regulates both proteolytic and non-proteolytic events associated with cancer progression. In earlier studies, we have demonstrated that radiation-induced cell adhesion was associated with uPAR expression and downregulation of uPAR effectively inhibited radiation-induced cell adhesion of medulloblastoma cells. Herein, we further investigated the impact of uPAR downregulation on plasminogen activator inhibitor (PAI-1), a key regulator component of the uPA system, and its role in cell adhesion. With radiation treatment, the levels of uPAR and PAI-1 increased in D283 and UW228 cells. Surprisingly, knockdown of uPAR elevated the levels of PAI-1. The increase in PAI-1 levels in uPAR-knocked down cells was regulated by activation of cJUN/CREB signaling molecules. Moreover, studies show that the reduced interaction between uPAR and integrin α5β1 plays a critical role in PAI-1 release into the extracellular matrix, thereby enhancing the cell detachment process. Incubation of medulloblastoma cells with Tiplaxtinin-PAI-039, a potent PAI-1 activity inhibitor, increased the association of uPAR with integrin α5β1 and cell adhesion. Interestingly, prolonged inhibition of PAI-1 activity adversely affected cell viability; we were able to revert this effect by exogenously supplementing cells with recombinant PAI-1. Moreover r-PAI-1 showed no significant effect on cell adhesion whereas it increased the association of uPAR with integrin α5β1. Expression of full-length (FL) uPAR elevated uPA and PAI-1 levels both at the transcriptional and the translational levels. These increased PAI-1 levels play a pivotal role in regulating uPA activity by binding and translocating integrin α5β1 towards the uPA/uPAR complex. Taken together, the results of the present study lead us to conclude that levels of uPAR and integrin α5β1, and their association on the cell surface dictate the function of PAI-1 to maintain extracellular homeostasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5187. doi:1538-7445.AM2012-5187
Distinction awards and racial discrimination
Authors: P. Rubin
Journal: BMJ (1998)

Distinction awards are as old as the NHS. They were established in 1948 to reward specialists for “more than ordinary ability and effort”1 by increasing their salaries, and this aim has remained essentially unchanged. Any system that tries to identify and then reward distinction is likely to have its critics, and distinction awards are no exception. Suggestions that the system favoured men and certain specialties were made long ago,2 and now Esmail and Everington add the accusation of racial bias (p 193).3

Most consultants don’t have a distinction award.4 Those who do have achieved wide recognition in their specialty, often nationally or internationally, and receive a pensionable salary enhancement of £22 590 to £53 645, subject to review every five years. The system is run by the Advisory Committee on Distinction Awards, which has 33 members, most of them doctors, with a few NHS managers. The committee receives nominations from the royal colleges and faculties, other professional organisations, national employers such as the Medical Research Council, and regional committees of …
Electropathological Substrate of Longstanding Persistent Atrial Fibrillation in Patients With Structural Heart Disease
Authors: Natasja M.S. de Groot, Richard P.M. Houben, Joep L. Smeets, Eric Boersma, Ulrich Schotten, Martin J. Schalij, Harry Crijns, Maurits A. Allessie
Journal: Circulation (2010)

During persistent atrial fibrillation (AF), waves with a focal spread of activation are frequently observed. The origin of these waves and their relevance for the persistence of AF are unknown.In 24 patients with longstanding persistent AF and structural heart disease, high-density mapping of the right and left atria was performed during cardiac surgery. In a reference group of 25 patients, AF was induced by rapid pacing. For data analysis, a mapping algorithm was developed that separated the fibrillatory process into its individual wavelets and identified waves with a focal origin. During persistent AF, the incidence of focal fibrillation waves in the right atrium was almost 4-fold higher than during acute AF (median, 0.46 versus 0.12 per cycle per 1 cm² (25th to 75th percentile, 0.40 to 0.77 and 0.01 to 0.27; P<0.0001). They were widely distributed over both atria and were recorded at 46 ± 18 of all electrodes. A large majority (90.5) occurred as single events. Repetitive focal activity (>3) happened in only 0.8. The coupling interval was not more than 11 ms shorter than the average AF cycle length (P=0.04), and they were not preceded by a long interval. Unipolar electrograms at the site of origin showed small but clear R waves. These data favor epicardial breakthrough rather than a cellular focal mechanism as the underlying mechanism. Often, conduction from a site of epicardial breakthrough was blocked in 1 or more directions. This generated separate multiple wave fronts propagating in different directions over the epicardium.Focal fibrillation waves are due to epicardial breakthrough of waves propagating in deeper layers of the atrial wall. In patients with longstanding AF, the frequency of epicardial breakthroughs was 4 times higher than during acute AF. Because they provide a constant source of independent fibrillation waves originating over the entire epicardial surface, they offer an adequate explanation for the high persistence of AF in patients with structural heart disease.
An Unusual Case of Synchronous Renal Cell Carcinoma in a Horseshoe Kidney and Intrahepatic Cholangiocarcinoma
Authors: Marina-Portia Anthony, Henry Mak, Pek-Lan Khong
Journal: Clinical Nuclear Medicine (2009)

We report an unusual FDG-PET/CT case of synchronous renal cell carcinoma of a horseshoe kidney and intrahepatic cholangiocarcinoma. A 70-year-old man presented with 1 day of frank hematuria, on a background of 4 months’ treatment for polycythemia. CT identified the horseshoe kidney and isthmic tumor, with the renal lesion considered to be the primary neoplasm, and the hepatic lesion considered metastatic. FDG-PET/CT was performed to exclude further metastases. Histopathologic assessment revealed synchronous primary renal cell carcinoma (RCC) of the horseshoe kidney isthmus and intrahepatic cholangiocarcinoma. The polycythemia was attributed to a paraneoplastic effect of the RCC. Helpful factors in identifying synchronous primary tumors in this case were the absence of multiple metastases, and in more typical locations (bone for RCC; lymph nodes for cholangiocarcinoma) and the morphologic feature of minor capsular retraction adjacent to the liver lesion.
Mumps Meningo-encephalitis
Authors: H. G. S. Murray, C. M. B. Field, W. J. McLeod
Journal: BMJ (1960)

Histological examination of brains of four children and one man dying with encephalitic symptoms within a few days of an attack of Asian influenza showed, in the children, scanty microglial infiltrations principally in the cerebellar cortex and also in the spinal cord; in the man, an acute haemorrhagic leuco-encephalitis.In one brain no abnormality other than congestion could be found.The remainder showed also slight lympho- cytic infiltration of the perivascular spaces and meninges.We are indebted to those physicians named in our last paper who allowed us to report their cases and supplied us with clinical details; to Professor Stuart-Harris for reading our draft, and especially to Dr. A. L. Woolf for his helpful comments and criticisms, and for drawing our attention to the nuclear changes in the Purkinje cells.
Raising price of alcohol in one Canadian province led to fall in drinking, finds study
Authors: J. H. Tanne
Journal: BMJ (2012)

When the Canadian province of Saskatchewan increased the minimum price of alcohol by 10% in April 2010, consumption of all alcoholic drinks fell by 8.4%, a study shows. Over the same period consumption of alcohol did not change in the neighboring province of Alberta, which does not have minimum prices.

The Saskatchewan Liquor and Gaming Authority has a monopoly on the distribution of alcohol and a partial monopoly on the sale of alcohol in liquor stores. The authority’s minimum prices apply to liquor store prices and to …
Dilemmas and Solutions
Authors: Kurt H. Stenzel
Journal: JAMA (1975)

<h3>To the Editor.—</h3> The thoughtful commentary "Dilemmas and Solutions" (230:401, 1974), by Harrison, contains an unfortunate and often repeated fallacy. The following is given as the second example of a moral dilemma: "Two persons need a kidney transplant in order to survive, but there is only one kidney available. How can the surgeon determine which candidate will undergo surgery?" Statistics reveal that mortality following transplantation is no better than after dialysis, and is often worse. An individual, therefore, does not "<i>need</i>a kidney transplant in order to survive." He does need a program of treatment for chronic renal disease that will include whatever type of therapy is best suited to his particular medical and social requirements. Institutional, self-care, and home dialysis are all viable treatment methods. Transplantation is an elective procedure, and should only be done in cases that have been fully evaluated by the transplant team for medical, surgical,
Good genes and parental care in human evolution
Authors: Frank Marlowe
Journal: Behavioral and Brain Sciences (2000)

Prior to agriculture, human societies were small, with little variation for good genes sexual selection (GGSS) to work on. Across cultures, variation in paternal care makes the benefits of GGSS highly variable. Despite these caveats, female preferences for traits like male body symmetry suggest one reason for female short-term mating is gene shopping.
Confusing signals: Recent progress in CTLA-4 biology
Authors: Lucy S.K. Walker, David M. Sansom
Journal: Trends in Immunology (2015)

The mechanism of action of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) remains surprisingly unclear. Regulatory T (Treg) cells can use CTLA-4 to elicit suppression; however, CTLA-4 also operates in conventional T cells, reputedly by triggering inhibitory signals. Recently, interactions mediated via the CTLA-4 cytoplasmic domain have been shown to preferentially affect Treg cells, yet other evidence suggests that the extracellular domain of CTLA-4 is sufficient to elicit suppression. Here, we discuss these paradoxical findings in the context of CTLA-4-mediated ligand regulation. We propose that the function of CTLA-4 cytoplasmic domain is not to transmit inhibitory signals but to precisely control the turnover, cellular location, and membrane delivery of CTLA-4 to facilitate its central function: regulating the access of CD28 to their shared ligands.