tbuckley/cabot-search huggingface dataset:
Functional Profile of the Isolated Uremic Nephron
Authors: Walter Trizna, Norimoto Yanagawa, Yaacov Bar-Khayim, Barbara Houston, Leon G. Fine
Journal: Journal of Clinical Investigation (1981)

In experimental models of glomerular and nonglomerular renal disease, single nephron filtration rate and proximal tubular reabsorption of fluid decrease or increase in parallel in the same nephron. To assess whether intrinsic adaptations in proximal tubular function, i.e., changes that are independent of the peritubular or humoral milieu, contribute to this phenomenon, segments of rabbit late superficial proximal convoluted tubules (PCT) were studied by in vitro perfusion. PCT were obtained from normal kidneys, from remnant kidneys, and from kidneys embolized with microspheres. Single nephron filtration rates are increased in the remnant and decreased in the embolized kidneys. Whereas the embolized-kidney rabbits were nonazotemic (the contralateral kidney was left in situ), the remnant-kidney animals were uremic. In order to study a nonazotemic model of increased single nephron filtration rate, PCT were also obtained from uninephrectomized rabbits.
Abstract 5071: Suppression of Macrophage Recruitment, Foam Cell Formation and Atherogenesis by the Negative Regulator of Cytokine Signaling SOCS-1
Authors: Christina Grothusen, Harald Schuett, Stefan Lumpe, Maren Luchtefeld, Karsten Grote, Helmut Drexler, Bernhard Schieffer
Journal: Circulation (2009)

Introduction: Inflammation is the hallmark of atherosclerosis leading to myocardial infarction, sudden cardiac death or stroke. While pro-inflammatory signaling pathways have been studied extensively, the impact of negative regulators of cytokine signalling i.e. suppressor of cytokine signaling (SOCS)-1 remains unclear. We postulated that a systemic SOCS-1 deficiency (socs-1 −/− ) in the atherosclerosis prone low density lipoprotein receptor (ldlr −/− ) mouse results in a pre-mature, aggravated atherogenesis. Methods and Results: Since systemic deletion of SOCS-1 is lethal within 3 weeks post partum due to a systemic inflammation mainly caused by uncontrolled signalling of interferon- γ (IFNG), we used mice lacking mature lymphocytes (rag2 −/− ), the major source for interferon- γ . Thus, socs-1 −/− , rag2 −/− mice were crossed with ldlr −/− mice and fed a high-cholesterol western diet for 30 days. Even though serum lipid levels did not differ between the groups, triple-KO mice (s ocs-1 −/− , rag2 −/− , ldlr −/− ) showed enhanced atherosclerotic plaque formation (en face: oil red O staining/aortic root: oil red O staining, N=8 –15 animals/group, P&lt;0.05) that was mainly due to enhanced accumulation of macrophages (aortic root: MOMA-2 immunohistochemistry, N=6 –15 animals/group, P&lt;0.05). In-vitro, s ocs-1 −/− bone-marrow derived macrophages (BMDM) exhibited increased migration towards CCL-2 associated with enhanced secretion of CCL-2 (transwell assay, ELISA, N=8, P&lt;0.05). Furthermore, s ocs-1 −/− BMDM showed enhanced foam cell formation when stimulated with oxidized(ox)LDL (oil red O staining, N=8, P&lt;0.05). Summary and Conclusion: SOCS-1 deficiency combined with a pro-atherogenic background results in increased atherosclerotic plaque formation. The underlying mechanism involves an enhanced oxLDL uptake and migration capacity of s ocs-1 −/− macrophages as well as enforced recruitment of inflammatory cells by increased secretion of CCL-2. Thus, SOCS-1 seems to represent a molecular brake controlling macrophage recruitment and foam cell formation in atherogenesis and thereby may evolve as a suitable target for future therapeutic strategies.
Abstract 3789: Induction of Murf-1 is Required for Tnf-alpha Induced Loss of Skeletal Muscle Function
Authors: Volker Adams, Norman Magner, Axel Linke, Alexander Gasch, Stephanie Hirner, Stephan Gielen, Siegfried Labeit, Gerhard Schuler
Journal: Circulation (2008)

Background: Inflammatory cytokines like tumor necrosis factor alpha (TNF-α) are known to impair skeletal muscle (SM) function. Furthermore, TNF-α induces the expression of atrogin-like muscle specific ubiquitin E3-ligases, presumed to mediate muscle atrophy. The relative contributions of respective ubiquitin ligases, like MuRF1 for the TNF-α induced reduction in muscle function are not known. Methods: TNF-α or saline was injected either into C57Bl6 or MuRF1 −/− mice. After 16 –24h the expression of MuRF1 in the SM was quantified by qRT-PCR and western blot. Muscle function was measured in an organ bath. To obtain a broader overview on potential alterations, 2D-gel electrophoresis was performed. Results: WT animals injected with TNF-α had higher MuRF1 mRNA (saline: 56.6±12.1 vs. TNF-α: 133.6±30.3 arb. Units; p&lt;0.05) and protein expression (saline: 0.38±0.11 vs. TNF-α: 1.07±0.25 arb. Units; p&lt;0.05) as compared to saline injected littermates. However, TNF- α was unable to induce MurRF1 expression in MuRF1 −/− mice. Furthermore, TNF- α reduced force development at 150Hz by 25% in C57Bl6 animals (saline: 2412±120 vs. TNF-α: 1799±114 g/cm2; p&lt;0.05), but not in MuRF1 −/− mice (saline: 2424±198 vs. TNF-α: 2431±180 g/cm2; p=NS). The proteome analysis revealed a significant down-regulation of fast skeletal muscle troponin T (TNNT3) in WT animals treated with TNF- α as compared to MuRF1 −/− mice receiving TNF-α . In addition, TNF-α injection into C57Bl6 animals resulted in a down-regulation of eEF1γ ( WT: 0.60±0.02 vs. WT+TNF-α: 0.39±0.05 arb. Units; p&lt;0.05). This reduction was not seen in MuRF1 −/− mice receiving TNF- α (KO: 0.59±0.03 vs. KO+TNF-α: 0.68±0.01 arb. Units; p&lt;0.05) Conclusion: The results of this study demonstrate for the first time, that the TNF- α induced reduction in SM force development depends on the induction of the atrophy related E3-ubiquitin ligase MuRF1. A link for the reduction in muscle force may be the TNF-α-MuRF1-mediated down-regulation of TNNT3 and the elongation factor eEF1γ.
Axitinib (AG-013736; AG) combined with chemotherapy in patients (pts) with advanced non-small cell lung cancer (NSCLC) and other solid tumors
Authors: L. P. Martin, M. F. Kozloff, M. Krzakowski, T. A. Samuel, T. A. Rado, J. Tarazi, B. Rosbrook, M. Tortorici, A. J. Olszanski, R. B. Cohen
Journal: Journal of Clinical Oncology (2009)

3559 Background: AG is an oral, potent and selective inhibitor of VEGFRs 1, 2, 3. Anti-VEGF therapies combined with chemotherapy improve survival vs chemotherapy alone in pts with advanced solid tumors, including NSCLC. This phase I trial assessed AG combined with chemotherapy. Methods: Pts with advanced solid tumors without prior treatment with platins or taxanes received paclitaxel/carboplatin (P: 200 mg/m 2 / C: AUC 6 mg*min/mL) every 3 weeks + AG at lead-in doses of 1, 3 or 5 mg BID. AG was increased to 5 mg BID post lead-in. Another cohort of pts with any prior chemotherapy for metastatic disease received AG 5 mg BID + gemcitabine/cisplatin (G: 1250 mg/m 2 on days 1 and 8 / Cis: 80 mg/m 2 on day 1) in 3-week cycles. For all cohorts, cycle 1 consisted of a 3–5-day lead-in period followed by AG for 18 days. On day 19, AG was held and then continued without interruption on day 3, cycle 2. Following determination of the maximum tolerated doses (MTDs) of AG + P/C or G/Cis, pts with squamous NSCLC were enrolled into an expansion cohort (prior anti-VEGF therapy not permitted) and received AG 5 mg BID + P/C. Dose-limiting toxicities (DLTs), adverse events (AEs), objective response rate (ORR), and pharmacokinetics (PK) were evaluated. Results: A total of 47 pts were enrolled; 26 pts were evaluable in the P/C cohort (including 12 pts with squamous NSCLC) and 21 pts in the G/Cis cohort. The MTD for AG in combination with standard doses of P/C and G/Cis was 5 mg BID. DLTs included fatigue, proteinuria and rash (1 each). Treatment-related AEs included hypertension (42%), diarrhea (35%) and fatigue (35%) in the P/C cohort, and headache (29%), hypertension (29%) and fatigue (24%) in the G/Cis cohort. There was no grade ≥3 hemoptysis among 12 pts with squamous NSCLC. The ORR was 29% and 26% for P/C (n = 24) and G/Cis (n = 19) cohorts, respectively. AG, P, C, G and Cis PK parameters and profiles were similar when administered alone and in combination (eg P: mean (%CV) AUC inf 20,822 (21) and 20,596 (21) ng.h/mL, respectively). Conclusions: AG 5 mg BID can be combined with standard P/C and G/Cis regimens with no apparent overlapping toxicities and unaltered PK. Both combinations have antitumor activity. In pts with squamous NSCLC, AG + P/C was well tolerated with no evidence of grade ≥3 hemoptysis. [Table: see text]
Optimizing Outcome After Unrelated Marrow Transplantation by Comprehensive Matching of HLA Class I and II Alleles in the Donor and Recipient
Authors: Effie W. Petersdorf, Theodore A. Gooley, Claudio Anasetti, Paul J. Martin, Anajane G. Smith, Eric M. Mickelson, Ann E. Woolfrey, John A. Hansen
Journal: Blood (1998)
Abstract 14632: Poor Health Status is Associated with Increased Mortality and Direct Medical Costs in Community Heart Failure Patients
Authors: Shannon M Dunlay, Nilay D Shah, John A Spertus, Sheila M McNallan, Holly K Van Houten, Veronique L Roger
Journal: Circulation (2012)

Background: Health status assessed with the Kansas City Cardiomyopathy Questionnaire (KCCQ) has been shown to predict healthcare resource use in trial participants with reduced ejection fraction (EF) following myocardial infarction. However; these associations have not been studied in community heart failure (HF) populations or in those with preserved EF. Methods: We evaluated 12-month mortality and direct medical costs among HF patients enrolled in a community study from October 2007 to December 2011. Costs were obtained using population-based administrative data and inflated to 2011 U.S. dollars using the General Consumer Price Index. Health status was assessed by the KCCQ and patients were categorized according to their score with scores of 0 to <25 reflecting the worst health status, 25 to <50 poor, 50 to <75 fair, and 75 to 100 good health status. Preserved EF was defined as ≥50%. Cox proportional hazard regression models were used to examine mortality and generalized linear models to predict costs. ...
REM sleep dreams and the activation-synthesis hypothesis
Authors: Robert W. McCarley, Edward Hoffman
Journal: American Journal of Psychiatry (1981)

The authors studied 104 dreams obtained from 14 subjects and quantified the formal aspects of the subjects' dream experiences by the following categories: movement in dreams, sensation, affect, dream bizarreness, and dream lucidity. Their results are compared with the predictions of the activation-synthesis hypothesis, which postulates that the characteristic formal aspects of dreams correspond to characteristic aspects of physiological activation during REM sleep. Although further experimental work is needed, the authors show that their results are consistent with and supportive of the activation-synthesis hypothesis.
Abstract 2483: Revisit of Typical Atrial Flutter Wave in the ECG: Electroanatomical Analysis of the Component Between the Negative Deflections of Flutter Wave in Isthmus-Dependent Counterclockwise Atrial Flutter
Authors: Kenichi Sasaki
Journal: Circulation (2009)

Typical cavotricuspid isthmus (CTI)-dependent atrial flutter (AFL) is characterized by flutter wave (F-wave) with negative saw-tooth morphology. It was reported that there are three types of F-wave...
Abstract 1036: Impact Of Emotions On Triggering Of Atrial Fibrillation
Authors: Rachel Lampert, Matthew Burg, Cynthia Brandt, James Dziura, Haibei Liu, Theresa Donovan, Robert Soufer, Larry Jamner
Journal: Circulation (2008)

Small case-series suggest the possibility of “adrenergically-mediated” atrial fibrillation (AF) in humans, and pharmacological autonomic manipulations can alter atrial electrophysiology. Whether AF can be triggered by emotional arousal is unknown. In this prospective, controlled, electronic-diary-based study of emotions preceding AF, patients with a history of paroxysmal or persistent AF, (N=75, mean age 58 years, 60% male, 60% taking beta-blocking medications) recorded their rhythm on event-monitor at the time of AF symptoms, and completed a diary entry querying mood states for the preceding 30 minutes (pre-AF “case period”) over a one-year follow-up. Also, patients underwent monthly 24-hour holter-monitoring, and were prompted by the diary to complete an entry twice per hour. Diaries recorded during sinus comprise the controls. Further, patients completed a diary each night. Patients’ exposure to each emotion was compared between the pre-AF case period and control periods using GEE modeling. Similarly, emotion on a nightly diary preceding AF on the following day was compared to that emotion on other nightly diaries. 119 AF episodes, (in 23 subjects), and 5796 holter-confirmed sinus rhythm control-periods had associated diary data. 95 pre-AF nightly diaries and 9306 control nightly diaries were completed. The likelihood of an AF episode was increased by negative emotions and decreased by happiness whether reported immediately preceding an AF episode, or the night before (table ). Impact of emotion was gender-specific: anger increased the odds of subsequent AF for men, worry for women. In stratified analysis, emotion triggered AF only in those not taking beta-blockers (data not shown). Negative emotions can trigger AF, while happiness is protective. Whether interventions aimed at reducing the physiological effects of emotional stress may lessen AF burden requires further study.
Elevated Plasma B-Type Natriuretic Peptide Concentrations Directly Inhibit Circulating Neprilysin Activity in Heart Failure
Authors: Nicolas Vodovar, Marie-France Séronde, Said Laribi, Etienne Gayat, Johan Lassus, James L. Januzzi, Riadh Boukef, Semir Nouira, Philippe Manivet, Jane-Lise Samuel, Damien Logeart, Alain Cohen-Solal, A. Mark Richards, Jean-Marie Launay, Alexandre Mebazaa
Journal: JACC Heart Failure (2015)

This study sought to hypothesize that elevated B-type natriuretic peptide (BNP) could act as an endogenous neprilysin inhibitor. A hallmark of acute decompensated heart failure (ADHF) is the overproduction of natriuretic peptides (NPs) by stretched cardiomyocytes. Various strategies have been developed to potentiate the beneficial effect of the NPs, including the recent use of neprilysin angiotensin receptor inhibitors. Contrary to rodents, human BNP is poorly sensitive to neprilysin degradation while retaining affinity to neprilysin. We enrolled 638 patients presenting to the emergency department with acute dyspnea of which 468 had ADHF and 169 had dyspnea of noncardiac origin. We also included 46 patients with stable chronic heart failure (HF) and 10 age-matched healthy subjects. Plasma samples were collected within 4 h after emergency department admission. BNP, neprilysin concentration and activity, and the neprilysin substrate substance P concentration were measured. We found that when plasma BNP rose above 916 pg/ml, neprilysin activity was markedly reduced (p < 0.0001) and stratified 95% of the population into 2 groups: BNP <916 pg/ml/neprilysin activity ≥ 0.21 nmol/ml/min and BNP ≥916 pg/ml/neprilysin activity <0.21 nmol/ml/min with very different prognoses. In vitro, BNP was responsible for neprilysin inhibition. Neprilysin activity was inversely correlated with the concentration of substance P (ρ = −0.80; p < 0.0001). Besides being an effector of the cardiac response to cardiomyocyte stretching in ADHF, elevated plasma BNP is also an endogenous neprilysin inhibitor. A biologically relevant BNP threshold discriminates 2 populations of HF patients with different vasoactive peptide profiles and outcome. If confirmed, this may identify an important threshold for managing HF patients.
Fatal anthrax infection in a heroin user from southern Germany, June 2012
Authors: T Holzmann, D Frangoulidis, M Simon, P Noll, S Schmoldt, M Hanczaruk, G Grass, M Pregler, A Sing, S Hörmansdorfer, H Bernard, R Grunow, R Zimmermann, W Schneider-Brachert, A Gessner, U Reischl
Journal: Eurosurveillance (2012)

Blood cultures from a heroin user who died in June 2012, a few hours after hospital admission, due to acute septic disease, revealed the presence of Bacillus anthracis. This report describes the extended diagnosis by MALDI-TOF and real-time PCR and rapid confirmation of the anthrax infection through reference laboratories. Physicians and diagnostic laboratories were informed and alerted efficiently through the reporting channels of German public health institutions, which is essential for the prevention of further cases.
Erythrocytosis Secondary to Increased Oxygen Affinity of a Mutant Hemoglobin, Hemoglobin Kempsey
Authors: CON S. REED, ROGER HAMPSON, SUSAN GORDON, RICHARD T. JONES, MILES J. NOVY, BERNADINE BRIMHALL, MILES J. EDWARDS, ROBERT D. KOLER
Journal: Blood (1968)
The Remote Effects of Cancer on the Nervous System.
Authors: K G Braund
Journal: Annals of Internal Medicine (1965)

The veterinary literature suggests that malignant tumors can induce clinical and subclinical paraneoplastic neurological syndromes, especially involving the PNS. Further studies should help to clarify the intensity and prevalence of polyneuropathy with specific tumor types; however, the true prevalence may always be uncertain because it will vary with the stage and duration of the illness, the diligence with which it is sought, the techniques of investigation used, and the criteria for diagnosis. Finally, the development of polyneuropathy as well as any other neurological syndromes in older dogs and cats should alert the clinician and pathologist to search carefully for an underlying malignancy.
&lt;emph type="bdit"&gt;Helicobacter pylori&lt;/emph&gt;
Authors: Carolyn J. Hildreth
Journal: JAMA (2008)

Helicobacter pyloriH elicobacter pylori (H pylori) is a common bacterium that is present in millions of people worldwide.In the United States, more than 50% of people older than 60 years are affected.Helicobacter pylori is found in the mucous lining of the stomach.It is known to be responsible for 60% to 80% of gastric ulcers (those occurring in the stomach) and 70% to 90% of duodenal ulcers (those occurring in the first part of the small intestine).The recognition of an association between this bacterium and peptic ulcer disease (occurring in the stomach or duodenum) by Dr Barry J. Marshall and Dr John R. Warren, both from Australia, was made in 1983, and they were awarded the Nobel prize in physiology (how the body works internally) and medicine in 2005.It is now understood that peptic ulcer disease is not caused by stress or by eating foods high in acid.It is often caused by the H pylori bacterium.Although the infection typically is acquired in childhood, it may continue without any problem throughout a person' s lifetime.Only 15% to 20% of those who carry this bacterium ever develop symptoms related to an ulcer.Treatment is recommended only for people who have an ulcer as a consequence of the bacterium' s presence.Treatment is important because people who have ulcers tend to have recurrent problems, and eliminating the H pylori infection prevents relapses.Patients infected with H pylori are more likely than others to develop certain types of cancer of the stomach, so testing and treatment for H pylori infection is recommended in patients with a family history of gastric cancer.This issue of JAMA includes a Commentary about a new treatment option for H pylori.
Abstract 19025: A Signaling Complex of HCN2/HCN4/Cav3 Resides in Caveolae of Cardiac Cells
Authors: Nian-Qing Shi, Jessie Ou, Jessie Yang, Xi-Yong Yu, Bin Ye
Journal: Circulation (2012)

Macromolecular signaling complexes including ion channels present in the caveolar micro-domains can provide highly specific and localized regulation of cell function. The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are key constituents of the cardiac pacemaker, regulating the rate of diastolic depolarization and cardiac rhythm. HCN4 and HCN2 are the major HCN isoforms found in cardiac tissues. HCN4 is physically associated with Caveolin-3 (Cav3), the “coat protein” for caveolae in cardiac cells. In this report, we dissected the regulation of Cav3 on HCN2. Cardiac HCN2 (60-kDa, HCN2s) or HCN4 was co-localized with Cav3 in mouse LV membrane fractions. A dominant-negative P104L-Cav3 mutation was used to “probe” the association of HCN2/Cav3. HCN2s itself does not encode currents but HCN2s/HCN4 channels generated currents resembled to those recorded from native cells. HEK293 cells expressing full-length-HCN2 (HCN2f)/WTCav3 showed comparable HCN2 density and channel activity to those cells expressing HCN2f/P104L or HCN2 alone. Bioluminescence Resonance Energy Transfer (BRET) assays in conjunction with stable HCN cell lines and lipid raft inhibitors were used to quantify the intra-molecular interactions of each HCN form and Cav3. WTCav3 or P104L was fused to a Renilla Luciferase (Rluc) as the “donor” while each HCN form was fused to YFP as the “acceptor”. All HCN/Cav3 pairs displayed positive BRET ratios, suggesting that HCN and Cav3 were within a 10-100 Å distance to permit energy transfer from RLuc (470-nm) to YFP (530-nm) in the presence of coelenterazine-h. We did not record positive BRET ratios from samples containing no assay substrate. Average BRET ratio data (n=6, p&lt;0.05) suggested that the association for HCN2s/Cav3 is the strongest. The P104L study showed that aa104 is involved in the interactions of HCN2s/Cav3 or HCN4/Cav3 but not HCN2f/Cav3. Our results indicate that Cav3 interacts with HCN4 via HCN2s to form a HCN2s/HCN4/Cav3/caveolae complex, and it may play an important role in cardiac signaling.
How to be a Good Enough GP: Surviving and Thriving in the New Primary Care Organisations
Authors: Abi Berger
Journal: BMJ (2001)

Gerhard Wilke with Simon Freeman 

Radcliffe Medical Press, £19.95, pp 224

ISBN 1 85775 358 5

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One day GPs will no longer be surprised or thrown off track by political change. One day we will come to embrace change with the same guarded conviction we show when we learn about new drugs. We may pause and resist, but rather than oppose we shall come to listen, learn, digest, and finally accept.

Accepting change without experiencing …

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Association of subjective memory complaints with subsequent cognitive decline in community-dwelling elderly individuals with baseline cognitive impairment
Authors: P W Schofield, K Marder, G Dooneief, D M Jacobs, M Sano, Y Stern
Journal: American Journal of Psychiatry (1997)

The validity of subjective memory complaints has been questioned by clinical studies that have shown little relationship between memory complaints and objective memory performance. These studies often have been cross-sectional in design, have excluded individuals with cognitive impairment, or have lacked a comparison group. The authors conducted a study that attempted to avoid these limitations.Memory complaints of 364 nondemented, community-dwelling elderly individuals were recorded as present or absent at the baseline evaluation. After 1 year, 169 subjects were reevaluated. Standardized neurologic and neuropsychological evaluations were used at each assessment to classify subjects as normal or cognitively impaired.At baseline, 31% of the normal subjects and 47% of those with cognitive impairment had memory complaints. Subjects with memory complaints had higher Hamilton depression scale scores than subjects without memory complaints but equivalent scores on a measure of total recall. At follow-up, multivariate analyses showed that subjects with baseline memory complaints had significantly greater decline in memory and cognition than subjects without memory complaints. Secondary analyses showed this effect to be confined to subjects with baseline cognitive impairment.Memory complaints may lack validity in subjects with normal cognition, but in nondemented individuals with cognitive impairment, memory complaints may predict subsequent cognitive decline.