tbuckley/cabot-search huggingface dataset:
Evidence of a Role for Fibroblast Transient Receptor Potential Canonical 3 Ca2+ Channel in Renal Fibrosis
Authors: Youakim Saliba, Ralph Karam, Viviane Smayra, Georges Aftimos, Joel Abramowitz, Lutz Birnbaumer, Nassim Farès
Journal: Journal of the American Society of Nephrology (2014)

Transient receptor potential canonical (TRPC) Ca(2+)-permeant channels, especially TRPC3, are increasingly implicated in cardiorenal diseases. We studied the possible role of fibroblast TRPC3 in the development of renal fibrosis. In vitro, a macromolecular complex formed by TRPC1/TRPC3/TRPC6 existed in isolated cultured rat renal fibroblasts. However, specific blockade of TRPC3 with the pharmacologic inhibitor pyr3 was sufficient to inhibit both angiotensin II- and 1-oleoyl-2-acetyl-sn-glycerol-induced Ca(2+) entry in these cells, which was detected by fura-2 Ca(2+) imaging. TRPC3 blockade or Ca(2+) removal inhibited fibroblast proliferation and myofibroblast differentiation by suppressing the phosphorylation of extracellular signal-regulated kinase (ERK1/2). In addition, pyr3 inhibited fibrosis and inflammation-associated markers in a noncytotoxic manner. Furthermore, TRPC3 knockdown by siRNA confirmed these pharmacologic findings. In adult male Wistar rats or wild-type mice subjected to unilateral ureteral obstruction, TRPC3 expression increased in the fibroblasts of obstructed kidneys and was associated with increased Ca(2+) entry, ERK1/2 phosphorylation, and fibroblast proliferation. Both TRPC3 blockade in rats and TRPC3 knockout in mice inhibited ERK1/2 phosphorylation and fibroblast activation as well as myofibroblast differentiation and extracellular matrix remodeling in obstructed kidneys, thus ameliorating tubulointerstitial damage and renal fibrosis. In conclusion, TRPC3 channels are present in renal fibroblasts and control fibroblast proliferation, differentiation, and activation through Ca(2+)-mediated ERK signaling. TRPC3 channels might constitute important therapeutic targets for improving renal remodeling in kidney disease.
Safety and Immunogenicity Trial in Adult Volunteers of a Human Papillomavirus 16 L1 Virus-Like Particle Vaccine
Authors: C D Harro, Y Y Pang, R B Roden, A Hildesheim, Z Wang, M J Reynolds, T C Mast, R Robinson, B R Murphy, R A Karron, J Dillner, J T Schiller, D R Lowy
Journal: JNCI Journal of the National Cancer Institute (2001)

Background: Studies in animal models have shown that systemic immunization with a papillomavirus virus-like particle (VLP) vaccine composed of L1, a major structural viral protein, can confer protection against subsequent experimental challenge with the homologous virus. Here we report results of a double-blind, placebo-controlled, dose-escalation trial to evaluate the safety and immunogenicity of a human papillomavirus (HPV) type 16 (HPV16) L1 VLP vaccine in healthy adults. Methods: Volunteers were given intramuscular injections with placebo or with 10- or 50-μg doses of HPV16 L1 VLP vaccine given without adjuvant or with alum or MF59 as adjuvants at 0, 1, and 4 months. All vaccine recipients were monitored for clinical signs and symptoms for 7 days after each inoculation. Immune responses were measured by an HPV16 L1 VLP-based enzyme-linked immunosorbent assay (ELISA) and by an HPV16 pseudovirion neutralization assay. The antibody titers were given as the reciprocals of the highest dilution showing positive reactivity in each assay. All statistical tests were two-sided. Results: The prevaccination geometric mean ELISA titer for six seropositive individuals was 202 (range, 40–640). All vaccine formulations were well tolerated, and all subjects receiving vaccine seroconverted. Serum antibody responses at 1 month after the third injection were dose dependent in recipients of vaccine without adjuvant or with MF59 but were similar at both doses when alum was the adjuvant. With the higher dose, the geometric means of serum ELISA antibody titers (95% confidence intervals) to purified VLP 1 month after the third injection were as follows: 10 240 (1499 to 69 938) without adjuvant, 10 240 (1114 to 94 145) with MF59, and 2190 (838 to 5723) with alum. Responses of subjects within each group were similar. Neutralizing and ELISA antibody titers were highly correlated (Spearman correlation = .85), confirming that ELISA titers are valid proxies for neutralizing antibodies. Conclusions: The HPV16 L1 VLP vaccine is well tolerated and is highly immunogenic even without adjuvant, with the majority of the recipients achieving serum antibody titers that were approximately 40-fold higher than what is observed in natural infection.
Sudden death and epilepsy
Authors: S.W. Brown, G.E. Mawer, W. Lawler, D.C. Taylor, S. Shorvon, T.A. Betts, M.J. Noronha, A. Richens, D. Chadwick, F.M.C. Besag, P.B.C. Fenwick
Journal: The Lancet (1990)
Glucose and glycogen metabolism in erythrocytes from normal and glycogen storage disease type III subjects
Authors: Shimon W. Moses, Reuben Chayoth, Stanley Levin, Ela Lazarovitz, David Rubinstein
Journal: Journal of Clinical Investigation (1968)

Active glycogen metabolism has been demonstrated in both normal and glycogen-rich erythrocytes taken from patients with type III glycogen storage disease. Activity of all enzymes catalyzing the reactions required for the synthesis and degradation of glycogen have been demonstrated in the mature erythrocytes. Uniformly labeled glucose-(14)C is incorporated into glycogen in intact cells of both types during incubation. Replacement of the glucose-(14)C by unlabeled glucose in the medium resulted in a significant loss of radioactivity from cellular glycogen. In the absence of the substrate a progressive shortening of outer branches occurred during incubation of intact glucogen-rich cells. Using cells from patients with type III glycogen storage disease, which have sufficient glycogen content to be analyzed by beta-amylolysis, we demonstrated that the glucosyl units are first incorporated in the outer tiers, then transferred to the core where they tend to accumulate due to the absence of amylo-1,6-glucosidase. The glycogen-rich cells have a more rapid rate of glucose utilization upon incubation which is not reflected by a higher lactate production. The increased rate of glucose utilization did not result from an increased rate of glucose incorporation into glycogen in affected cells. The rate of (14)CO(2) production from glucose-1-(14)C during incubation was not significantly different in the two types of cells unless methylene blue was added as an electron acceptor, in which case the glycogen-rich cells oxidized glucose to CO(2) more rapidly.
A Molecular Signature of Depression in the Amygdala
Authors: Etienne Sibille, Yingjie Wang, Jennifer Joeyen-Waldorf, Chris Gaiteri, Alexandre Surget, Sunghee Oh, Catherine Belzung, George C Tseng, David A Lewis
Journal: American Journal of Psychiatry (2009)

Objective: Major depressive disorder is a heterogeneous illness with a mostly uncharacterized pathology. Recent gene array attempts to identify the molecular underpinnings of the illness in human postmortem subjects have not yielded a consensus. The authors hypothesized that controlling several sources of clinical and technical variability and supporting their analysis with array results from a parallel study in the unpredictable chronic mild stress (UCMS) rodent model of depression would facilitate identification of the molecular pathology of major depression. Method: Large-scale gene expression was monitored in postmortem tissue from the anterior cingulate cortex and amygdala in paired male subjects with familial major depression and matched control subjects without major depression (N=14–16 pairs). Area dissections and analytical approaches were optimized. Results from the major depression group were compared with those from the UCMS study and confirmed by quantitative polymerase chain reaction and Western blot. Gene coexpression network analysis was performed on transcripts with conserved major depression-UCMS effects. Results: Significant and bidirectional predictions of altered gene expression were identified in amygdala between major depression and the UCMS model of depression. These effects were detected at the group level and also identified a subgroup of depressed subjects with a more homogeneous molecular pathology. This phylogenetically conserved "molecular signature" of major depression was reversed by antidepressants in mice, identified two distinct oligodendrocyte and neuronal phenotypes, and participated in highly cohesive and interactive gene coexpression networks. Conclusions: These studies demonstrate that the biological liability to major depression is reflected in a persistent molecular pathology that affects the amygdala, and support the hypothesis of maladaptive changes in this brain region as a putative primary pathology in major depression.
Malignant Occlusion of the Pulmonary Artery in Bronchial Carcinoma: Pre-operative Diagnosis by Bronchospirometry
Authors: J. G. Stevenson, J. M. Reid
Journal: Thorax (1957)

<h3>Background</h3> Frailty describes a decline in resilience to physical, physiological and emotional stressors, and is linked to increased risk of disability, morbidity and mortality. Neighbourhood features are important risk factors of frailty; however, evidence mainly relies on studies with lack of repeated measurement of neighbourhood. We assessed whether exposure to neighbourhood deprivation across the life course (childhood to late adulthood) was related to the risk and progression of frailty in older age. <h3>Methods</h3> Lifetime residential addresses were collected for participants of the Lothian Birth Cohort 1936 at the age of 78. Edinburgh-based addresses were linked to historical measure of neighbourhood deprivation in childhood (1936–1955), early adulthood (1956–1975) and mid-to-late adulthood (1976–2015). Frailty was measured using the Frailty Index in five consecutive waves between the ages of 70 and 82. Linear mixed effects models were fitted for male (n=161) and female (n=162) participants separately. First, we detected the most appropriate life course model compared to a saturated model. Second, we adjusted selected models with a set of nested confounders (age, childhood IQ, father’s occupational social class, childhood smoking, years of education, adult occupational social class, smoking, living alone). Third, we explored accelerated frailty by imputing the product term of age and neighbourhood deprivation in the selected models. In a sensitivity analysis, we restricted the sample to those with Edinburgh-based addresses in every decades of their life (n=240). Analyses were conducted using R. <h3>Results</h3> In the male subsample, relaxed accumulation provided the best model fit whereby periods contributed independently to the risk of frailty; preliminary results indicated increased risk of frailty by higher childhood (b=0.004; p=0.041) and mid-to-late adulthood neighbourhood deprivation (b=0.005; p=0.014). In the female subsample, mid-to-late adulthood sensitive period was deemed as best fitting with increased risk of frailty in the adjusted model (b=0.005; p=0.014). Importantly, we identified accelerated frailty among woman in deprived neighbourhoods during mid-to-late adulthood (p=0.002). Sensitivity analysis were consistent with the main results. <h3>Conclusion</h3> Our study presents the first investigation of life course impact of neighbourhood deprivation on frailty and frailty trajectories; despite the small sample size limiting the generalisability of our findings. Life course models differed across gender and accelerated frailty was only present in the female subgroup. Future research should explore mediating pathways, and potential opportunities to buffer against the detrimental effect of neighbourhood deprivation on frailty. Policy should focus on tackling neighbourhood inequalities throughout the lifecourse to support healthy population ageing.
Diagnostic tests in jaundice: WHO is to choose, the doctor or the computer?
Authors: K. W. O'Connor
Journal: Hepatology (1986)

A model has been developed for ordering diagnostic tests in jaundiced patients. The system proceeds in two steps: (i) diagnostic hypotheses are calculated for each patient from the results of physical examination and routine biological investigations; (ii) given these hypotheses, the most efficient test (out of 22) for reaching the final diagnosis is selected using four criteria: diagnostic value, risk, financial cost, and time in obtaining the result. This model was tested in 62 patients. In 43 of them (69%), the selected test was sufficient for reaching a diagnostic accuracy of 100%. In this group of patients, a mean of 3.7 (range 1-6) tests per patient was ordered by physicians. In the 19 remaining patients, the selected test was not sufficient for the final diagnosis, thus requiring a multiple choice process. It is suggested that such a system could help physicians to improve the care of patients by more efficient ordering of diagnostic tests.
Effectiveness of an Antimicrobial Stewardship Approach for Urinary Catheter–Associated Asymptomatic Bacteriuria
Authors: Barbara W. Trautner, Larissa Grigoryan, Nancy J. Petersen, Sylvia Hysong, Jose Cadena, Jan E. Patterson, Aanand D. Naik
Journal: JAMA Internal Medicine (2015)

Overtreatment of asymptomatic bacteriuria (ASB) in patients with urinary catheters remains high. Health care professionals have difficulty differentiating cases of ASB from catheter-associated urinary tract infections.To evaluate the effectiveness and sustainability of an intervention to reduce urine culture ordering and antimicrobial prescribing for catheter-associated ASB compared with standard quality improvement methods.A preintervention and postintervention comparison with a contemporaneous control group from July 2010 to June 2013 at 2 Veterans Affairs health care systems. Study populations were patients with urinary catheters on acute medicine wards and long-term care units and health care professionals who order urine cultures and prescribe antimicrobials.A multifaceted guidelines implementation intervention.The primary outcomes were urine cultures ordered per 1000 bed-days and cases of ASB receiving antibiotics (overtreatment) during intervention and maintenance periods compared with baseline at both sites. Patient-level analysis of inappropriate antimicrobial use adjusted for individual covariates.Study surveillance included 289,754 total bed-days. The overall rate of urine culture ordering decreased significantly during the intervention period (from 41.2 to 23.3 per 1000 bed-days; incidence rate ration [IRR], 0.57; 95% CI, 0.53-0.61) and further during the maintenance period (to 12.0 per 1000 bed-days; IRR, 0.29; 95% CI, 0.26-0.32) (P < .001 for both). At the comparison site, urine cultures ordered did not change significantly across all 3 periods. There was a significant difference in the number of urine cultures ordered per month over time when comparing the 2 sites using longitudinal linear regression (P < .001). Overtreatment of ASB at the intervention site fell significantly during the intervention period (from 1.6 to 0.6 per 1000 bed-days; IRR, 0.35; 95% CI, 0.22-0.55), and these reductions persisted during the maintenance period (to 0.4 per 1000 bed-days; IRR, 0.24; 95% CI, 0.13-0.42) (P < .001 for both). Overtreatment of ASB at the comparison site was similar across all periods (odds ratio, 1.32; 95% CI, 0.69-2.52). When analyzed by type of ward, the decrease in ASB overtreatment was significant in long-term care.A multifaceted intervention targeting health care professionals who diagnose and treat patients with urinary catheters reduced overtreatment of ASB compared with standard quality improvement methods. These improvements persisted during a low-intensity maintenance period. The impact was more pronounced in long-term care, an emerging domain for antimicrobial stewardship.
Tree-Based Model for Breast Cancer Prognostication
Authors: Mousumi Banerjee, Julie George, Eun Young Song, Anuradha Roy, William Hryniuk
Journal: Journal of Clinical Oncology (2004)

To define prognostic groups for recurrence-free survival in breast cancer, assess relative effects of prognostic factors, and examine the influence of treatment variations on recurrence-free survival in patients with similar prognostic-factor profiles.We analyzed 1,055 patients diagnosed with stage I-III breast cancer between 1990 and 1996. Variables studied included socioeconomic factors, tumor characteristics, concurrent medical conditions, and treatment. The primary end point was recurrence-free survival (RFS). Multivariable analyses were performed using recursive partitioning and Cox proportional hazards regression.The most significant difference in prognosis was between patients with fewer than four and those with at least four positive nodes (P <.0001). Four distinct prognostic groups (5-year RFS, 97%, 78%, 58%, and 27%) were developed, defined by the number of positive nodes, tumor size, progesterone receptor (PR) status, differentiation, race, and marital status. Patients with fewer than four positive nodes and tumor < or = 2 cm, PR positive, and well or moderately differentiated had the best prognosis. RFS in this group was unaffected by type of adjuvant therapy (P =.38). Patients with at least four positive nodes and PR-negative tumors had the worst prognosis, and those treated with tamoxifen plus chemotherapy had the best outcome in this group (P =.0001). Among patients in the two intermediate-risk groups, those treated with tamoxifen or a combination of tamoxifen and chemotherapy had the best outcome.Lymph node status, PR status, tumor size, differentiation, race, and marital status are valuable for prognostication in breast cancer. The prognostic groups derived can provide guidance for clinical trial design, patient management, and future treatment policy.
Covarion Structure in Plastid Genome Evolution: A New Statistical Test
Authors: C. Ane
Journal: Molecular Biology and Evolution (2004)

Covarion models of molecular evolution allow the rate of evolution of a site to vary through time. There are few simple and effective tests for covarion evolution, and consequently, little is known about the presence of covarion processes in molecular evolution. We describe two new tests for covarion evolution and demonstrate with simulations that they perform well under a wide range of conditions. A survey of covarion evolution in sequenced plastid genomes found evidence of covarion drift in at least 26 out of 57 genes. Covarion evolution is most evident in first and second codon positions of the plastid genes, and there is no evidence of covarion evolution in third codon positions. Therefore, the significant covarion tests are likely due to changes in the selective constraints of amino acids. The frequency of covarion evolution within the plastid genome suggests that covarion processes of evolution were important in generating the observed patterns of sequence variation among plastid genomes.
Bypassing Big Pharma
Authors: James M. Downey, Michael V. Cohen
Journal: Circulation (2007)

T here have been many resounding victories in the war against coronary artery disease.Among those are antiarrhythmic drugs, pacemakers, coronary bypass surgery, coronary angioplasty, reperfusion therapy, and statins.But the one goal that has continuously eluded us has been the clinical availability of an effective cardioprotective agent.Although reperfusion therapy has partially achieved the goal of limiting infarct size in the setting of acute myocardial infarction, the logistics usually prevent restoration of perfusion until after a significant amount of myocardium has been lost to infarction.In 1974, when Braunwald 1 proposed that priority should be given to the identification of interventions that would make the myocardium resistant to infarction, nobody knew what an arduous task that would be.In the beginning, "big pharma" was a strong partner in this quest, and many drugs were evaluated.The first wave of drugs like ␤-blockers and calcium antagonists were examined because it was believed that they would reduce oxygen consumption and that an improvement in the supply-demand relationship in the heart would suppress infarction.Unfortunately, the determinants of oxygen consumption in the ischemic heart are very different from those in the well-perfused heart, and not surprisingly, these drugs were ineffective.Then, the focus shifted to antioxidants and antiinflammatory agents.Their preclinical performance was inconsistent, and the clinical trials that they spawned were all decidedly negative.Most recently, a great deal of money was spent on the development of the sodiumhydrogen exchange blocker cariporide, which again failed in clinical trials.Adenosine and insulin suffered similar fates.With each negative trial, the industry has become increasingly leery of cardioprotective interventions, and most companies are now very reluctant to include primary cardioprotectants in their development pipelines.Nobody knows for sure why there has been such a dismal track record in the cardioprotection trials.One possibility may be that the animal models do not accurately mimic ischemia/reperfusion in humans.It is our opinion, however, that it was probably a case of the wrong drugs being tested because all of the above agents yielded very discrepant results in animal models.
Treatment of hiccups by pharyngeal stimulation in anesthetized and conscious subjects
Authors: M. R. Salem
Journal: JAMA (1967)

Stimulation of the pharynx with a catheter introduced through the nose appears to be a valuable method for managing hiccups in conscious and anesthetized man. Immediate inhibition of hiccups occurred in 84 of 85 patients treated in this manner, of whom 65 were anesthetized. Hiccups recurred in some patients, but were successfully managed with the same maneuver. The area responding to stimulation is the middle of the pharynx, opposite the body of the second cervical vertebra, which is innervated by the pharyngeal plexus. The suggested mechanism of action is impulses arising in response to pharyngeal stimulation which may block or inhibit afferent impulses being transmitted through the vagi thus interrupting the hiccup reflex. No undesirable effects have been encountered as a result of pharyngeal stimulation.
Systemic inflammation and decline in lung function in a general population: a prospective study
Authors: A. W Fogarty, S. Jones, J. R Britton, S. A Lewis, T. M McKeever
Journal: Thorax (2007)

An increase in levels of C-reactive protein (CRP), a marker of systemic inflammation, is associated with reduced forced expiratory volume in 1 s (FEV1), supporting the hypothesis that the pathophysiology of chronic obstructive pulmonary disease has a systemic inflammatory component. However, few large studies have assessed the relationship between systemic inflammation as measured by CRP and decline in lung function prospectively in a randomly selected population.In 1991, data were collected on FEV1 and forced vital capacity (FVC) and a blood sample was taken from 2442 randomly selected adults in a community-based cohort. In 2000 these measures were repeated in 1301 individuals. The level of serum CRP was analysed in these samples from 1991 and 2000.In cross-sectional analyses of data from 1991 and 2000, serum CRP levels were inversely related to FEV1 and FVC. After adjustment for smoking and other confounders, the difference in FEV1 was reduced by -9 ml (95% CI -13 to -5) and -7 ml (95% CI -13 to -2) for each mg/l increment in serum CRP in 1991 and 2000, respectively. There was no significant association between baseline serum CRP levels and decline in FEV1 and FVC over 9 years.Although serum CRP levels are inversely associated with lung function in cross-sectional studies, there was no effect of a marker of systemic inflammation on decline in lung function over 9 years.