tbuckley/cabot-search huggingface dataset:
Effect of Potent γ-Secretase Modulator in Human Neurons Derived From Multiple Presenilin 1–Induced Pluripotent Stem Cell Mutant Carriers
Authors: Qing Liu, Shannon Waltz, Grace Woodruff, Joe Ouyang, Mason A. Israel, Cheryl Herrera, Floyd Sarsoza, Rudolph E. Tanzi, Edward H. Koo, John M. Ringman, Lawrence S. B. Goldstein, Steven L. Wagner, Shauna H. Yuan
Journal: JAMA Neurology (2014)

Although considerable effort has been expended developing drug candidates for Alzheimer disease, none have yet succeeded owing to the lack of efficacy or to safety concerns. One potential shortcoming of current approaches to Alzheimer disease drug discovery and development is that they rely primarily on transformed cell lines and animal models that substantially overexpress wild-type or mutant proteins. It is possible that drug development failures thus far are caused in part by the limits of these approaches, which do not accurately reveal how drug candidates will behave in naive human neuronal cells.To analyze purified neurons derived from human induced pluripotent stem cells from patients carrying 3 different presenilin 1 (PS1) mutations and nondemented control individuals in the absence of any overexpression. We tested the efficacy of γ-secretase inhibitor and γ-secretase modulator (GSM) in neurons derived from both normal control and 3 PS1 mutations (A246E, H163R, and M146L).Adult human skin biopsies were obtained from volunteers at the Alzheimer Disease Research Center, University of California, San Diego. Cell cultures were treated with γ-secretase inhibitor or GSM. Comparisons of total β-amyloid (Aβ) and Aβ peptides 38, 40, and 42 in the media were made between vehicle- vs drug-treated cultures.Soluble Aβ levels in the media were measured by enzyme-linked immunosorbent assay.As predicted, mutant PS1 neurons exhibited an elevated Aβ42:Aβ40 ratio (P < .05) at the basal state as compared with the nondemented control neurons. Treatment with a potent non-nonsteroidal anti-inflammatory druglike GSM revealed a new biomarker signature that differs from all previous cell types and animals tested. This new signature was the same in both the mutant and control neurons and consisted of a reduction in Aβ42, Aβ40, and Aβ38 and in the Aβ42:Aβ40 ratio, with no change in the total Aβ levels.This biomarker discrepancy is likely due to overexpression of amyloid precursor protein in the transformed cellular models. Our results suggest that biomarker signatures obtained with such models are misleading and that human neurons derived from human induced pluripotent stem cells provide a unique signature that will more accurately reflect drug response in human patients and in cerebrospinal fluid biomarker changes observed during GSM treatment.
Pre-transjugular intrahepatic portosystemic shunts (TIPS) prediction of post-TIPS overt hepatic encephalopathy: The Critical Flicker Frequency is more accurate than psychometric tests
Authors: Pierre Berlioux, Marie Angèle Robic, Hélène Poirson, Sophie Métivier, Philippe Otal, Carine Barret, Frédéric Lopez, Jean Marie Péron, Jean Pierre Vinel, Christophe Bureau
Journal: Hepatology (2013)

Transjugular intrahepatic portosystemic shunts (TIPS) is a second-line treatment because of an increased incidence of overt hepatic encephalopathy (OHE). A better selection of patients to decrease this risk is needed and one promising approach could be the detection of minimal hepatic encephalopathy (MHE). The aim of the present prospective study was to determine whether pre-TIPS minimal hepatic encephalopathy was predictive of post-TIPS OHE and to compare Psychometric Hepatic Encephalopathy Sum Score (PHES) and the Critical Flicker Frequency (CFF) in this setting. From May 2008 to January 2011, 54 consecutive patients treated with TIPS were included. PHES and CFF were performed 1 to 7 days before and after TIPS at months 1, 3, 6, 9, and 12 or until liver transplantation or death. Before TIPS, MHE was detected by PHES and CFF in 33% and 39% of patients, respectively. After the TIPS procedure, 19 patients (35%) experienced a total of 64 episodes of OHE. OHE developed significantly more often in patients for whom an indication for TIPS had been refractory ascites, with a history of OHE or of renal failure, lower hemoglobin level, or MHE as diagnosed by CFF. Post-TIPS OHE was more accurately predicted by CFF than by PHES. Absence of MHE at CFF had a good negative predictive value (91%) for the risk of post-TIPS recurrent OHE, defined as the occurrence of three or more episodes of OHE or of one episode which lasted more than 15 days. The absence of pre-TIPS history of OHE and a CFF value equal to or greater than 39 Hz had a 100% negative predictive value for post-TIPS recurrent OHE. Conclusion : Aiming to decrease the rate of post-TIPS HE, the use of CFF could help selecting patients for TIPS. (Hepatology 2014;59:622–629)
Points from Letters: Chloroquine Prophylaxis in East Africa
Authors: A. R. Shaw
Journal: BMJ (1975)

autonomy, heads of departments may be able, for example, to finance replacement equipment from money saved during periods when there are unfilled posts in a department.It might also make more sense to use cheaper analytical methods and reagents.Such. a policy might enable a measure of Mr. Crossman's redeployment of money to take place without crippling the existing service.However, only departmental man- agers can make their services more efficient.It cannot be properly or safely done by remote administrators making arbitrary and swingeing cuts based on ill-conceived ideas or inadequate information.If financial stringency is to be the com- pulsory order of the day it should be applied impartially throughout the N.H.S.Let us renmember that few ordinary doctors have ever been convinced of the need for the new enlarged administration required to run the Health Service reorganization.In some areas of activity the region now wields more power than it did before 1 April 1974, and the area is left like a castrato tenor warbling in- effectually between the baritone soloist at the district and the bass obligato at the region.The new management system has yet to prove both its own effectiveness and cost- benefit to the community.Perhaps some of these less than essential gentlemen should recll Cromwell's famous assessment of the Rump
Exenatide blocks JAK1-STAT1 in pancreatic beta cells
Authors: Francesca M. Couto, Alexandra H. Minn, Cynthia A. Pise-Masison, Mike Radonovich, John N. Brady, Matthew Hanson, Luis A. Fernandez, Ping Wang, Christina Kendziorski, Anath Shalev
Journal: Metabolism (2007)
Local Postural Vasomotor Reflexes Arising from the Limb Veins
Authors: PETER GASKELL, ALAN C. BURTON
Journal: Circulation Research (1953)

Blood flow of the toes and fingers was studied plethysmographically with the level of the blood vessels below or above the heart, using the contralateral digit as control. The apparent flow is a maximum when the vessels are near the heart level. The decrease of flow when the vessels are raised is explained on the basis of narrowing and closure of vessels when the hydrostatic pressure within them falls. The decrease in flow when the limb is lowered is interpreted as evidence of a vasoconstriction elicited by distension of the local veins. This raises serious doubt about the classic flow method.
Multisociety Task Force Recommendations of Competencies in Pulmonary and Critical Care Medicine
Authors: John D. Buckley, Doreen J. Addrizzo-Harris, Alison S. Clay, J. Randall Curtis, Robert M. Kotloff, Scott M. Lorin, Susan Murin, Curtis N. Sessler, Paul L. Rogers, Mark J. Rosen, Antoinette Spevetz, Talmadge E. King, Atul Malhotra, Polly E. Parsons
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Numerous accrediting organizations are calling for competency-based medical education that would help define specific specialties and serve as a foundation for ongoing assessment throughout a practitioner's career. Pulmonary Medicine and Critical Care Medicine are two distinct subspecialties, yet many individual physicians have expertise in both because of overlapping content. Establishing specific competencies for these subspecialties identifies educational goals for trainees and guides practitioners through their lifelong learning.To define specific competencies for graduates of fellowships in Pulmonary Medicine and Internal Medicine-based Critical Care.A Task Force composed of representatives from key stakeholder societies convened to identify and define specific competencies for both disciplines. Beginning with a detailed list of existing competencies from diverse sources, the Task Force categorized each item into one of six core competency headings. Each individual item was reviewed by committee members individually, in group meetings, and conference calls. Nominal group methods were used for most items to retain the views and opinions of the minority perspective. Controversial items underwent additional whole group discussions with iterative modified-Delphi techniques. Consensus was ultimately determined by a simple majority vote.The Task Force identified and defined 327 specific competencies for Internal Medicine-based Critical Care and 276 for Pulmonary Medicine, each with a designation as either: (1) relevant, but competency is not essential or (2) competency essential to the specialty.Specific competencies in Pulmonary and Critical Care Medicine can be identified and defined using a multisociety collaborative approach. These recommendations serve as a starting point and set the stage for future modification to facilitate maximum quality of care as the specialties evolve.
Small‐colony variants and phenotype switching of intracellular <i><scp>S</scp>taphylococcus aureus</i> in chronic rhinosinusitis
Authors: N. C.‐W. Tan, C. M. Cooksley, E. Roscioli, A. J. Drilling, R. Douglas, P.‐J. Wormald, S. Vreugde
Journal: Allergy (2014)

Abstract Background Chronic rhinosinusitis ( CRS ) has been linked to the gram‐positive bacteria Staphylococcus aureus ( S. aureus ) in its biofilm or intracellular forms. Recent evidence suggests that S. aureus also exists in a small‐colony variant ( SCV ) form as a mechanism of altering its virulence capabilities. The aim of this study was to investigate the presence of SCV s in sinonasal mucosa of CRS patients and whether the phenomenon of phenotype switching can be applied to intracellular epithelial infections. Methods Sinonasal specimens were examined for the presence of intramucosal S. aureus and characterized to the strain level. An airway epithelial cell culture infection model was utilized to investigate whether bacteria were capable of alterations in virulence phenotype. Results Intramucosal organisms harvested from sinonasal biopsies demonstrate phenotypic growth patterns and lack of coagulase activity consistent with SCV s. Intracellular infection of airway epithelial cell cultures with S. aureus led to decreased secretion of enterotoxins and phenotypic growth alterations consistent with SCV s. Conclusions Regulation of S. aureus virulence factors is a dynamic process, and exposure to the intracellular environment appears to provide the necessary conditions to enable these alterations in an attempt for the bacterium to survive and persist within host tissues. Further work is required to ascertain whether SCV s in CRS hold a clinically relevant pathogenic role in recalcitrant disease.
ABC of nutrition. Adults young and old.
Authors: A S Truswell
Journal: BMJ (1985)

Adults should eat enough ofthe essential nutrients by eating a healthy varied diet.This is more difficult to achieve ifpeople have a low energy intake and ifmuch oftheir diet consists offats, alcohol, and sugar, which provide empty calories but little or no protein or micronutrients.The triple table shows three recent sets ofBritish recommendations, two by the DHSS and one by the Health Education Council.These mostly give advice about how that part ofthe diet that provides energy-fats, carbohydrates, protein, etc-should be divided up.These dietary guidelines or goals give advice to the general public expressed in terms of averages.The average person, eating the average amount of(say) fat, should reduce this by or to a new national average.The advice has to be modified for individuals.Jack Sprat should not reduce fat intake as much as his wife.There is much consistency and reiteration between the three sets of recommendations, though they were prepared by different people from different viewpoints and given in different sequence.More regular exercise; less fat, alcohol, sugar, and salt; more cereals (preferably wholegrain), vegetables, and fruit are the recurring themes.The same themes appear too in contemporary dietary guidelines in the USA, Canada, Scandinavia, West Germany, Australia, and New Zealand.Other aspects ofa healthy diet, sometimes taken for granted, are that food should be wholesome and not contaminated with pathogenic micro- organisms or their toxins or with other toxins (see later article on food poisoning).Some ofour foods are routinely enriched with micronutrients- for example, B vitamins in white flour, vitamins A and D in margarine.The municipal drinking water should likewise be nearly chemically pure.Calcium, magnesium, sodium, and fluoride concentrations vary from place to place.There is suggestive-but not conclusive-evidence that hard water (more calcium or magnesium, or both), is associated with lower cardiovascular mortality.Fluoridation at 1 ppm is recommended by all orthodox medical and dental authorities.Are vegetarians more healthy or less?The answer depends first on the degree ofvegetarianism.Vegans, who eat no animal products, are at risk ofvitamin B-12 deficiency.Supplements are essential during pregnancy and for infants of vegans.Vegans lack the best dietary sources ofcalcium-milk, yoghurt, and cheese.Lacto-ovo-vegetarians have no absolute nutritional risk.They miss the best absorbed form ofiron in the diet, haem iron, but may largely compensate because ascorbic acid enhances the absorption ofnon-haem iron.* Muscle mass declines from 450 g/kg to 300 g/kg.* Body density goes down from 1-072 to 1-041 in men and from 1-040 to 1-016 in women.* Body fat (as % ofbody weight) increases from about 20% to 30% in men and from 27% to 40% in women.* Liver weight falls from about 25 g to 20 g/kg body weight.* Basal metabolic rate goes down proportionally with lean body mass.
RANTES and Monocyte Chemoattractant Protein–1 (MCP-1) Play an Important Role in the Inflammatory Phase of Crescentic Nephritis, but Only MCP-1 Is Involved in Crescent Formation and Interstitial Fibrosis
Authors: Clare M. Lloyd, Andrew W. Minto, Martin E. Dorf, Amanda Proudfoot, Timothy N.C. Wells, David J. Salant, Jose-Carlos Gutierrez-Ramos
Journal: The Journal of Experimental Medicine (1997)

The involvement of chemokines in inflammation is well established, but their functional role in disease progression, and particularly in the development of fibrosis, is not yet understood. To investigate the functional role that the chemokines monocyte chemoattractant protein-1 (MCP-1) and RANTES play in inflammation and the progression to fibrosis during crescentic nephritis we have developed and characterized a murine model for this syndrome. Significant increases in T-lymphocytes and macrophages were observed within glomeruli and interstitium, paralleled by an induction of mRNA expression of MCP-1 and RANTES, early after disease initiation. Blocking the function of MCP-1 or RANTES resulted in significant decreases in proteinuria as well as in numbers of infiltrating leukocytes, indicating that both MCP-1 and RANTES (regulated upon activation in normal T cells expressed and secreted) play an important role in the inflammatory phase of crescentic nephritis. In addition, neutralization of MCP-1 resulted in a dramatic decrease in both glomerular crescent formation and deposition of type I collagen. These results highlight a novel role for MCP-1 in crescent formation and development of interstitial fibrosis, and indicate that in addition to recruiting inflammatory cells this chemokine is critically involved in irreversible tissue damage.
Manipulation effects of prior exercise intensity feedback by the Borg scale during open-loop cycling
Authors: Flávio Oliveira Pires, John Hammond
Journal: British Journal of Sports Medicine (2011)

To verify the effects of exercise intensity deception by the Borg scale on the ratings of perceived exertion (RPE), heart rate (HR) and performance responses during a constant power output open-loop exercise.Eight healthy men underwent a maximal incremental test on a cycle ergometer to identify the peak power output (PPO) and heart rate deflection point (HRDP). Subsequently, they performed a constant power output trial to exhaustion set at the HRDP intensity, in deception (DEC) and informed (INF) conditions: DEC--subjects were told that they would be cycling at an intensity corresponding to two categories below the RPE quantified at the HRDP; INF--subjects were told that they would cycle at the exact intensity corresponding to the RPE quantified at the HRDP.The PPO and power output at the HRDP obtained in maximal incremental tests were 247.5 ± 32.1 W and 208.1 ± 27.1 W, respectively. No significant difference in the time to exhaustion was found between DEC (525 ± 244 s) or INF (499 ± 224 s) trials. The slope and the first and second measurements of the RPE and HR parameters showed no significant difference between trials.Psychophysiological variables such as RPE and HR as well as performance were not affected when exercise intensity was deceptively manipulated via RPE scores. This may suggest that unaltered RPE during exercise is a regulator of performance in this open-loop exercise.
Vitamin D receptor gene polymorphism: association with Crohn's disease susceptibility
Authors: J D Simmons
Journal: Gut (2000)

The vitamin D receptor (VDR) gene represents a strong positional candidate susceptibility gene for inflammatory bowel disease (IBD). The VDR gene maps to a region on chromosome 12 that has been shown to be linked to IBD by genome screening techniques. It is the cellular receptor for 1,25(OH)(2) vitamin D(3) (calcitriol) which has a wide range of different regulatory effects on the immune system. IBD is characterised by activation of the mucosal immune system.To determine if polymorphisms in the VDR gene are associated with susceptibility to IBD SUBJECTS: European Caucasoids: 158 patients with ulcerative colitis, 245 with Crohn's disease, and 164 cadaveric renal allograft donor controls.Single nucleotide polymorphisms (TaqI, ApaI, and FokI) in VDR were typed in patients with Crohn's disease, ulcerative colitis, and controls by polymerase chain reaction with sequence specific primers.There were significantly more homozygotes for the TaqI polymorphism at codon 352 of exon 8 (genotype "tt") among patients with Crohn's disease (frequency 0.22) than patients with ulcerative colitis (0.12) or controls (0.12) (odds ratio 1.99; 95% confidence interval 1.14-3.47; p=0.017).This study provides preliminary evidence for a genetic association between Crohn's disease susceptibility and a gene that lies within one of the candidate regions determined by linkage analysis.
Adolescent Hypertension
Authors: MARGARET M. KILCOYNE, RALPH W. RICHTER, PEGGY A. ALSUP
Journal: Circulation (1974)

Blood pressure screening of 3537 high school students in the Harlem community was performed to determine the frequency distribution of blood pressures in this age group and to investigate the prevalence of hypertension in adolescence. The major inscription of the frequency distributions of both systolic and diastolic blood pressures was comparable among black, latin, and white students. However, female students of all races had lower systolic pressures than males. An over-all prevalence of 5.4% systolic and 7.8% diastolic hypertension was observed during the initial screening, and no significant difference in prevalence among the races was detected. With follow-up screening of those students with elevated blood pressures (BP ≧ 140/90 mm Hg) prevalence declined markedly to 1.2% systolic and 2.4% diastolic hypertension and showed that black males had a higher prevalence of persistent diastolic hypertension (3.7%) than all other groups. This difference did not achieve statistical significance; however, the racial comparison was not wholly satisfactory because of the limited sample of white students. Nevertheless, the observed prevalence in black males was more than twice that reported in the National Health Survey during a single screening. The data suggest two features of adolescent blood pressure which should be taken into account in hypertension detection programs for this age group: 1) the criteria selected to define blood pressure elevations in a maturing circulation would be more meaningful if related to the observed frequency distributions of blood pressure in an adolescent sample population. Values exceeding one standard deviation above the means reported herein are recommended (males: 132/85 mm Hg; females: 123/82 mm Hg); and 2) serial measurements of blood pressure appear to be required to detect the potentially hypertensive adolescent as well as to determine prevalence rates with accuracy. A finding which deserves further study is the striking increase in the percent of elevated blood pressures noted between the ages of 17 and 18 years, particularly in black males. Black males represent a vulnerable segment of the adult hypertensive population as well. The results indicate that over-all, contrary to traditional views, the development of hypertension may begin in adolescence and that methods of detection which appear satisfactory in adulthood are insufficient to uncover the true prevalence rates of hypertension in this age group.
Cardiac Myosin-Binding Protein-C Phosphorylation and Cardiac Function
Authors: Sakthivel Sadayappan, James Gulick, Hanna Osinska, Lisa A. Martin, Harvey S. Hahn, Gerald W. Dorn, Raisa Klevitsky, Christine E. Seidman, Jonathan G. Seidman, Jeffrey Robbins
Journal: Circulation Research (2005)

The role of cardiac myosin binding protein-C (cMyBP-C) phosphorylation in cardiac physiology or pathophysiology is unclear. To investigate the status of cMyBP-C phosphorylation in vivo, we determined its phosphorylation state in stressed and unstressed mouse hearts. cMyBP-C phosphorylation is significantly decreased during the development of heart failure or pathologic hypertrophy. We then generated transgenic (TG) mice in which the phosphorylation sites of cMyBP-C were changed to nonphosphorylatable alanines (MyBP-C(AllP-)). A TG line showing &40% replacement with MyBP-C(AllP-) showed no changes in morbidity or mortality but displayed depressed cardiac contractility, altered sarcomeric structure and upregulation of transcripts associated with a hypertrophic response. To explore the effect of complete replacement of endogenous cMyBP-C with MyBP-C(AllP-), the mice were bred into the MyBP-C(t/t) background, in which less than 10% of normal levels of a truncated MyBP-C are present. Although MyBP-C(AllP-) was incorporated into the sarcomere and expressed at normal levels, the mutant protein could not rescue the MyBP-C(t/t) phenotype. The mice developed significant cardiac hypertrophy with myofibrillar disarray and fibrosis, similar to what was observed in the MyBP-C(t/t) animals. In contrast, when the MyBP-C(t/t) mice were bred to a TG line expressing normal MyBP-C (MyBP-CWT), the MyBP-C(t/t) phenotype was rescued. These data suggest that cMyBP-C phosphorylation is essential for normal cardiac function.