tbuckley/cabot-search huggingface dataset:
Pharmacological Inhibition of Na/Ca Exchange Results in Increased Cellular Ca <sup>2+</sup> Load Attributable to the Predominance of Forward Mode Block
Authors: Semir Ozdemir, Virginie Bito, Patricia Holemans, Laurent Vinet, Jean-Jacques Mercadier, Andras Varro, Karin R. Sipido
Journal: Circulation Research (2008)

Block of Na/Ca exchange (NCX) has potential therapeutic applications, in particular, if a mode-selective block could be achieved, but also carries serious risks for disturbing the normal Ca2+ balance maintained by NCX. We have examined the effects of partial inhibition of NCX by SEA-0400 (1 or 0.3 micromol/L) in left ventricular myocytes from healthy pigs or mice and from mice with heart failure (MLP-/-). During voltage clamp ramps with [Ca2+](i) buffering, block of reverse mode block was slightly larger than of forward mode (by 25+/-5%, P<0.05). In the absence of [Ca2+](i) buffering and with sarcoplasmic reticulum (SR) fluxes blocked, rate constants for Ca2+ influx and Ca2+ efflux were reduced to the same extent (to 36+/-6% and 32+/-4%, respectively). With normal SR function the reduction of inward NCX current (I(NCX)) was 57+/-10% (n=10); during large caffeine-induced Ca2+ transients, it was larger (82+/-3%). [Ca2+](i) transients evoked during depolarizing steps increased (from 424+/-27 to 994+/-127 nmol/L at +10 mV, P<0.05), despite a reduction of I(CaL) by 27%. Resting [Ca2+](i) increased; there was a small decrease in the rate of decline of [Ca2+](i). SR Ca2+) content increased more than 2-fold. Contraction amplitude of field-stimulated myocytes increased in healthy myocytes but not in myocytes from MLP-/- mice, in which SR Ca2+ content remained unchanged. These data provide proof-of-principle that even partial inhibition of NCX results in a net gain of Ca2+. Further development of NCX blockers, in particular, for heart failure, must balance potential benefits of I(NCX) reduction against effects on Ca2+ handling by refining mode dependence and/or including additional targets.
Repaglinide/Bedtime NPH Insulin Is Comparable to Twice-Daily NPH Insulin
Authors: Araceli Panelo, Jeffrey Robert Wing
Journal: Diabetes Care (2005)

The combination of oral antidiabetic drugs and bedtime insulin is currently regarded as the first-line therapy in type 2 diabetes. Repaglinide is an insulin secretatogue with a rapid onset and relatively short duration of action (1–3) that was developed for prandial glucose regulation. The prandial glucose regulation strategy attempts to synchronize availability of insulin to the physiological need by stimulating endogenous insulin output in line with glucose intake. In type 2 diabetes, flexible prandial glucose regulation with repaglinide is well tolerated and safe, irrespective of the number of meals consumed per day (4,5). Repaglinide/NPH insulin combination has shown improved glycemic control in type 2 diabetic subjects inadequately controlled by sulfonylureas alone or in combination with metformin (6) or insulin monotherapy (7). However, no direct comparison between repaglinide and NPH insulin combination with NPH twice daily in type 2 diabetic subjects has been reported.

This trial was conducted in 12 sites in Southeast Asia and South Africa. Inclusion criteria included having type 2 diabetes, age ≥18 years, BMI ≤35 kg/m2, HbA1c (A1C) ≥7.5 and ≤13%, previous treatment with sulfonylurea and/or metformin therapy for at least 3 months before study onset (for subjects on sulfonylurea and metformin therapy, metformin dose …
Prevalence of Rheumatoid Arthritis
Authors: J. S. Lawrence
Journal: Annals of the Rheumatic Diseases (1961)

From the Empire Rheumatism Council Field Unit, based on the University of Manchester In 1956, a committee of the American Rheumatism Association was formed to investigate diagnostic criteria for rheumatoid arthritis.They recommended that the disease should be classified into three categories: definite, probable, and possible, the classification being based on a points system.The eleven points used for this classification included symptoms, physical signs, radiographic appearances, and laboratory tests (Ropes, Bennett, Cobb, Jacox, and Jessar, 1956, 1957, 1959).Though possessing certain limitations, particularly in relation to population studies in which the results of histological and synovial fluid examination are seldom available, these criteria do offer certain theoretical advantages over a simple clinical grading for rheumatoid arthritis.It was felt, therefore, that the publication of data on the American Rheumatism Association criteria in population samples drawn from an urban and a rural area in England might be of value to research workers in this country who desired a standard for comparison with their own findings.Methods of Survey The data used in this paper are drawn from two surveys: one in Leigh, Lancashire, based on a 1 in 30 random sample of persons aged 15 and over (Lawrence and Bennett, 1960); the other in Wensleydale, in the North Riding of Yorkshire, based on an area sample, including half the town of Hawes and half the villages in the area with their surrounding farms.In the Leigh sample there were 751 males and 814 females, in the Wensleydale sample 485 males and 540 females.Thus there was a total of 1,236 males and 1,354 females in the combined sample of whom 1,060 and 1,174 respectively were actually examined.The age and sex distribution was similar in these two areas and the completion rate (proportion of available persons having x rays or a blood test or both) was also alike (86 per cent. in Leigh and 87 per cent. in Wensleydale).The clinical, radiological, and serological examination was based on the same routine procedure in Wensleydale and in Leigh, all persons having x rays of the hands, feet, and cervical spine.All x rays of the cervical spine were read by at least two observers.* "Classical" rheumatoid arthritis has been included in the "definite" group.11
Treatment of Advanced Head and Neck Cancer: What Lessons Have We Learned?
Authors: Barbara A. Conley
Journal: Journal of Clinical Oncology (2006)

Treatment of advanced squamous cell cancers of the head and neck (HNSCC) can be a frustrating endeavor. Early diagnosis may be missed by delay on the part of patients or their physicians and dentists. Patients are often elderly and have multiple medical or social comorbidities. HNSCC is an interdisciplinary disease, with optimum management requiring the input of the medical, radiation, and surgical oncologist, as well as pathologist, dentist, speech pathologist, social worker, and a dedicated home caregiver. The necessary specialists for optimum management may not be present near the patient’s home, necessitating ad hoc clinical teams or further delay and dislocation of the patient and caregiver for an extended treatment period. Numerous phase II and phase III studies have been performed with the hope of improving survival and preserving organ function in locally advanced disease. We now know that survival is improved by radiation administered concurrent with chemotherapy, but there are added toxicities. 1 We also know that radiation with chemotherapy can result in survival that approximates the survival obtained by radical surgery followed by radiation therapy, especially if surgical salvage is performed at early signs of residual or recurrent disease. 2,3 We know less about what the optimal radiation regimen or chemotherapy regimen should be for an individual patient. Currently, standard therapy for locally advanced HNSCC could be radiation administered daily, twice daily, or in a concomitant boost regimen, with or without intensity-modulated radiation therapy, together with a platinum-based chemotherapy. When complete response is obtained, a planned neck dissection is often performed in those patients whose disease was at least N2 at presentation. If complete response is not obtained, resection of the primary and/or regional nodes is performed as is feasible. Standard care could also be surgery, followed by radiation therapy with or without concurrent chemotherapy. These modalities generally result in a 5-year survival rate of 20% to 65%, depending on stage and primary site. The choice of treatment is often dictated by the primary site, patient preferences (eg, organ preservation), and the experience of the treatment team.
The influence of patent foramen ovale on oxygen desaturation in obstructive sleep apnoea
Authors: M. C. Johansson, P. Eriksson, Y. Peker, J. Hedner, L. Råstam, U. Lindblad
Journal: European Respiratory Journal (2006)

Obstructive sleep apnoea (OSA) is associated with oxygen desaturation to a varying degree. A patent foramen ovale (PFO) may allow interatrial right-to-left shunting. The hypothesis of the current study was that oxygen desaturation will occur more often, in proportion to the frequency of respiratory disturbances, in OSA subjects with PFO than in those without. In a group of 209 subjects diagnosed with OSA, the proportion of desaturation to respiratory events was calculated as the ratio of oxygen desaturation index (ODI)/apnoea–hypopnoea index (AHI). A total of 15 cases with high proportional desaturation (ODI/AHI ≥0.66) were individually matched with 15 controls with low proportional desaturation (ODI/AHI ≤0.33), all without pulmonary disease. PFO was assessed with contrast transoesophageal echocardiography and considered large when ≥20 bubbles passed over from the right to the left atrium after a single injection. The prevalence of large PFO was nine out of 15 (60%) in the high proportional desaturation group versus two out of 15 (13%) in the low proportional desaturation group. The median number of passing bubbles was positively correlated to minimum oxygen saturation among those with PFO. In conclusion, oxygen desaturation occurs more often, in proportion to the frequency of respiratory disturbances, in obstructive sleep apnoea subjects with a patent foramen ovale than in those without.
Branched-chain amino acids in the treatment of chronic hepatic encephalopathy.
Authors: L S Eriksson, A Persson, J Wahren
Journal: Gut (1982)

The therapeutic efficacy of orally administered branched-chain amino acids in patients with liver cirrhosis and chronic encephalopathy was examined in a double blind, randomised crossover study. Seven patients with manifest hepatic cirrhosis and encephalopathy of six months9 duration or longer ingested 30 g branched-chain amino acids or placebo during two 14-day periods. Psychometric tests and electroencephalograms were used to evaluate cerebral function. Neither clinical observations nor psychometric testing or electroencephalogram indicated a significant difference in the patients9 response to branched-chain amino acids as compared with placebo. In four patients given branched-chain amino acids for longer periods (five to 22 weeks), psychometric tests also remained unchanged. The plasma concentrations of these acids after oral intake increased significantly, demonstrating adequate absorption. Basal plasma amino acid concentrations were unchanged, however, after branched-chain amino acid therapy. No side-effects were seen, which indicates that these amino acids are well tolerated as an extra protein supply in patients with chronic hepatic encephalopathy. As compared with placebo, however, no effect of branched-chain amino acids on the encephalopathy could be detected.
Alcohol consumption in patients with colorectal adenomatous polyps.
Authors: G F Cope, J I Wyatt, I F Pinder, P N Lee, R V Heatley, J Kelleher
Journal: Gut (1991)

The risk of developing colorectal adenomatous polyps is probably increased by a variety of dietary and environmental factors. We found an association with current alcohol and cigarette consumption. The risk of polyps was increased three times in drinkers who did not smoke and two times in smokers who did not drink, with those who both drank and smoked having 12 times the risk of total abstainers. Since colonic adenomatous polyps are generally regarded as premalignant lesions, these results lend support to the view that alcohol consumption may be an important factor in the pathogenesis of colorectal neoplasia, thus reinforcing the proposed polyp/carcinoma sequence in colorectal carcinogenesis. The role of smoking, however, is less clear particularly since the lack of association of colorectal carcinoma and smoking has been reported in many other studies.
Advances in Autism
Authors: Daniel H. Geschwind
Journal: Annual Review of Medicine (2009)

Autism is a common childhood neurodevelopmental disorder with strong genetic liability. It is not a unitary entity but a clinical syndrome, with variable deficits in social behavior and language, restrictive interests, and repetitive behaviors. Recent advances in the genetics of autism emphasize its etiological heterogeneity, with each genetic susceptibility locus accounting for only a small fraction of cases or having a small effect. Therefore, it is not surprising that no unifying structural or neuropathological features have been conclusively identified. Given the heterogeneity of autism spectrum disorder (ASD), approaches based on studying heritable components of the disorder, or endophenotypes, such as language or social cognition, provide promising avenues for genetic and neurobiological investigations. Early intensive behavioral and cognitive interventions are efficacious in many cases, but autism does not remit in the majority of children. Therefore, development of targeted therapies based on pathophysiologically and etiologically defined subtypes of ASD remains an important and achievable goal of current research.
Non-Q-Wave Myocardial Infarction: Pathophysiology, Prognosis, and Therapeutic Strategy
Authors: R S Gibson
Journal: Annual Review of Medicine (1989)

Non-Q-wave infarction, formerly referred to as nontransmural infarction, is usually associated with less myocardial necrosis and a lower in-hospital mortality than Q-wave or transmural infarction. Despite the initially favorable prognosis, however, long-term survival of patients after non-Q-wave infarction is similar to or even shorter than that after Q-wave infarction. It is now well documented that patients with non-Q-wave infarction are more prone to reinfarction, which usually occurs in the same area as the original injury. Since extensive damage from recurrent myocardial necrosis has a considerable deleterious effect on long-term survival, patients with non-Q-wave infarction would be expected to benefit from prophylactic treatment that prevents reinfarction. Indeed, this subset of patients appears to provide a unique opportunity to modify favorably the natural history of ischemic heart disease.
Discovery of novel immune checkpoint regulators in a comprehensive library of human extracellular proteins
Authors: Nathan A Sallee, Ernestine Lee, Andrew Rankin, Robert Halenbeck, Arthur Brace, Lewis T Williams, Brian Wong, W Michael Kavanaugh
Journal: Journal for ImmunoTherapy of Cancer (2014)

Meeting abstracts Identification of novel targets in cancer immunotherapy is needed to address the significant number of patients that either do not respond to current therapies or encounter unacceptable toxicities. The discovery of such targets, including novel checkpoint regulators and the
Simple heuristics could make us smart; but which heuristics do we apply when?
Authors: Richard Cooper
Journal: Behavioral and Brain Sciences (2000)

Simple heuristics are clearly powerful tools for making near optimal decisions, but evidence for their use in specific situations is weak. Gigerenzer et al. (1999) suggest a range of heuristics, but fail to address the question of which environmental or task cues might prompt the use of any specific heuristic. This failure compromises the falsifiability of the fast and frugal approach.
Endometriosis: hormone regulation and clinical consequences of chemotaxis and apoptosis
Authors: Fernando M. Reis, Felice Petraglia, Robert N. Taylor
Journal: Human Reproduction Update (2013)

The recruitment of immune cells by chemokines and the regulation of endometrial cell apoptosis are critical aspects of endometriosis biology. Here, we review the local (paracrine) and systemic hormone (endocrine) modulation of these two specific, but highly related phenomena. We searched Pubmed for items published in English between September 1991 and September 2011 and selected the studies evaluating the effects of hormones on chemokines or apoptosis in normal human endometrium and endometriosis. Estradiol has proinflammatory and antiapoptotic effects in endometrial cells, and these effects appear to be exacerbated in women with endometriosis. In these women, physiological estradiol concentrations are able to induce an enhanced inflammatory response mediated by local chemokine production and to reinforce mechanisms of cell survival mediated by extracellular signal-regulated kinases and Bcl-2. The main effect of progestogens is to inhibit interleukin-8 and other chemokines in stromal cells from both eutopic and ectopic endometrium. Progesterone is also effective in inducing apoptosis in endometrial and endometriotic cells through the inhibition of Bcl-2 and nuclear factor-κB. Estrogens and progestogens modulate chemotaxis and apoptosis in human endometrium and endometriotic cells and tissues. These endocrine and paracrine pathways are perturbed in women with endometriosis, contributing to inflammatory responses, abnormal tissue remodeling, therapeutic refractoriness and disease persistence. Ultimately, they promote adhesion formation and the clinical symptoms of pelvic pain and infertility. A more detailed understanding of the molecular mechanisms involved will offer new opportunities for novel pharmacological strategies to diagnose and treat endometriosis.
The role of presenilins in Alzheimer’s disease
Authors: Gopal Thinakaran
Journal: Journal of Clinical Investigation (1999)

Figure 1 Schematic diagram of PS1 based on the 8 transmembrane domain model.A circle represents each amino acid of PS1, and residues mutated in FAD are depicted as closed circles.Predicted transmembrane domains are shaded.The arrow indicates the major site of regulated endoproteolysis (position 292-293); the arrowhead indicates the caspase cleavage site (position 344-345).
Uricosuric agents in uremic sera. Identification of indoxyl sulfata and hippuric acid.
Authors: E F Boumendil-Podevin, R A Podevin, G Richet
Journal: Journal of Clinical Investigation (1975)

Serum and urine from chronically uremic patients and normal individuals were subjected to gel filtration of Sephadex-G10. The effects of the eluted fractions on the uptake of urate and para-aminohippurate by isolated cortical tubules of rabbit kidney were investigated. According to the origin of the samples, one to three major groups of fractions inhibiting both urate and para-aminohippurate transport were disclosed. The first eluted group occurred for all the samples under study. The second one was demonstrated in both sera and urines from uremic patients but only in urines from normal individuals. The third one was exclusively detected in uremic sera and urines. Among all the compounds identified, only hippuric acid, eluted in the fractions of the second group, was capable of inhibiting the uptake of urate and para-aminohippurate in vitro. The concentration for which this inhbiitory effect of hippuric acid occurred was in the range of that existing in uremic sera. Indoxyl sulfate, which accumulates to very high concentrations in uremic serum, could not be disclosed in the above-mentioned fractions. This is explained by the strong adsorption of this indole derivative to Sephadex gel. Potassium indoxyl sulfate, when tested in vitro at the concentration existing in uremic serum, substantially inhibited the uptake of both urate and para-aminohippurate. In normal subjects, ingestion of hippuric acid or potassium indoxyl sulfate significantly increased fractional urinary excretion of uric acid. On the basis of these results, it is suggested that progressive retention of hippuric acid, indoxyl sulfate, and other yet unidentified inhibitors may explain the gradual increase in urinary fractional excretion of urate observed in uremia. The present results may be viewed as an example of a mechanism in which retention of normally excreted end products is responsible for adaptation of tubular transport in uremic subjects.
Statins and Musculoskeletal Adverse Events
Authors: Rene Baudrand, Gordon H. Williams
Journal: JAMA Internal Medicine (2014)

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