tbuckley/cabot-search huggingface dataset:
Pharmacogenomics of heart failure - focus on drug disposition and action*1
Authors: I CASCORBI
Journal: Cardiovascular Research (2004)

Heart failure represents the composite endpoint of various cardiovascular disorders. Advanced pharmacotherapy resulted in significant improvement of overall survival, however with highly variable outcome, possibly due to genetic modification of drug disposition and action. This review highlights the role of genetic polymorphisms in systems responsible for disposition of drugs, used in heart failure patients (e.g. the polymorphic drug metabolizing enzymes such as cytochrome P450 enzymes, as well as polymorphic ATP-membrane transporters like P-glycoprotein (P-gp)). In addition, genetic variants in physiological systems, being target of drug action, particularly beta-adrenergic receptors, the renin–angiotensin–aldosterone system (RAAS)- and endothelin system, and the endothelial nitrogene monoxide (NO) synthase are reviewed. The current situation in pharmacogenomics of heart failure with respect to drug disposition and action is characterized by multiple studies investigating single components of a complex system. Therefore, overall conclusions regarding treatment and/or outcome of heart failure patients based on individual genetic traits require large prospective trials allowing for simultaneous assessment of multiple genetic variants in different systems. Using advanced screening technologies, such trials can be carried out in the near future.
Conduction Slowing and Sudden Arrhythmic Death in Mice With Cardiac-Restricted Inactivation of Connexin43
Authors: David E. Gutstein, Gregory E. Morley, Houman Tamaddon, Dhananjay Vaidya, Michael D. Schneider, Ju Chen, Kenneth R. Chien, Heidi Stuhlmann, Glenn I. Fishman
Journal: Circulation Research (2001)

Abstract —Cardiac arrhythmia is a common and often lethal manifestation of many forms of heart disease. Gap junction remodeling has been postulated to contribute to the increased propensity for arrhythmogenesis in diseased myocardium, although a causative role in vivo remains speculative. By generating mice with cardiac-restricted knockout of connexin43 (Cx43), we have circumvented the perinatal lethal developmental defect associated with germline inactivation of this gap junction channel gene and uncovered an essential role for Cx43 in the maintenance of electrical stability. Mice with cardiac-specific loss of Cx43 have normal heart structure and contractile function, and yet they uniformly (28 of 28 conditional Cx43 knockout mice observed) develop sudden cardiac death from spontaneous ventricular arrhythmias by 2 months of age. Optical mapping of the epicardial electrical activation pattern in Cx43 conditional knockout mice revealed that ventricular conduction velocity was significantly slowed by up to 55% in the transverse direction and 42% in the longitudinal direction, resulting in an increase in anisotropic ratio compared with control littermates (2.1±0.13 versus 1.66±0.06; P &lt;0.01). This novel genetic murine model of primary sudden cardiac death defines gap junctional abnormalities as a key molecular feature of the arrhythmogenic substrate.
Na+ channel regulation by Ca2+/calmodulin and Ca2+/calmodulin-dependent protein kinase II in guinea-pig ventricular myocytes†
Authors: Takeshi Aiba, Geoffrey G. Hesketh, Ting Liu, Rachael Carlisle, Maria Celeste Villa-Abrille, Brian O'Rourke, Fadi G. Akar, Gordon F. Tomaselli
Journal: Cardiovascular Research (2009)

Calmodulin (CaM) regulates Na+ channel gating through binding to an IQ-like motif in the C-terminus. Ca2+/CaM-dependent protein kinase II (CaMKII) regulates Ca2+ handling, and chronic overactivity of CaMKII is associated with left ventricular hypertrophy and dysfunction and lethal arrhythmias. However, the acute effects of Ca2+/CaM and CaMKII on cardiac Na+ channels are not fully understood. Purified NaV1.5–glutathione-S-transferase fusion peptides were phosphorylated in vitro by CaMKII predominantly on the I–II linker. Whole-cell voltage-clamp was used to measure Na+ current (INa) in isolated guinea-pig ventricular myocytes in the absence or presence of CaM or CaMKII in the pipette solution. CaMKII shifted the voltage dependence of Na+ channel availability by ≈+5 mV, hastened recovery from inactivation, decreased entry into intermediate or slow inactivation, and increased persistent (late) current, but did not change INa decay. These CaMKII-induced changes of Na+ channel gating were completely abolished by a specific CaMKII inhibitor, autocamtide-2-related inhibitory peptide (AIP). Ca2+/CaM alone reproduced the CaMKII-induced changes of INa availability and the fraction of channels undergoing slow inactivation, but did not alter recovery from inactivation or the magnitude of the late current. Furthermore, the CaM-induced changes were also completely abolished by AIP. On the other hand, cAMP-dependent protein kinase A inhibitors did not abolish the CaM/CaMKII-induced alterations of INa function. Ca2+/CaM and CaMKII have distinct effects on the inactivation phenotype of cardiac Na+ channels. The differences are consistent with CaM-independent effects of CaMKII on cardiac Na+ channel gating.
Short-Term Acute Psychiatric Care: A Follow-Up Study
Authors: S. B. PENICK, NANCY BUONPANE, R. N. CARRIER
Journal: American Journal of Psychiatry (1971)

Every fourth patient from the total of 1,571 patients admitted to the Carrier Clinic during 1967 (with a mean hospital stay of 25 days) was followed up 2.5 years later. Ninety percent of the study group, whether or not they had been rehospitalized in the interim, gave evidence of adequate social functioning. A relatively small number were regularly followed by physicians; these tended to be sicker and had a higher readmission rate than the rest of the study group.
Junior doctors will not re-enter contract negotiations with government
Authors: Abi Rimmer
Journal: BMJ (2015)

The BMA’s Junior Doctors Committee has voted not to re-enter negotiations with NHS Employers on a new contract.

The BMA said that junior doctors had rejected the government’s attempts to “force through a new contract” and called on the government to “reverse their hardline stance and work with junior doctors in a genuine negotiation without artificial deadlines.”

Last month the Review Body on Doctors’ and Dentists’ Remuneration (DDRB) published a report on reform of the contracts for consultants and junior doctors.1 The DDRB was asked to review the contracts after negotiations between the BMA and …
Antibody and CD8+ T Cell Responses against HER2/neu Required for Tumor Eradication after DNA Immunization with a Flt-3 Ligand Fusion Vaccine
Authors: Francesca Orlandi, Franco M. Venanzi, Antonio Concetti, Hanako Yamauchi, Shakuntala Tiwari, Larry Norton, Jedd D. Wolchok, Alan N. Houghton, Polly D. Gregor
Journal: Clinical Cancer Research (2007)

Abstract Purpose: HER2/neu is frequently overexpressed in breast cancer. In a mouse model, vaccination with HER2/neu DNA elicits antibodies that confer partial protection against tumor challenge. Experimental Design: To enhance antitumor immunity, we fused cDNA encoding Flt-3 ligand (FL) to the rat HER2/neu extracellular domain (neu), generating a chimeric FLneu molecule. FLneu and neu DNA vaccines were compared for immunogenicity and their ability to protect mice from tumor challenge. Results: The neu vaccine generated a HER2/neu-specific antibody response. In contrast, vaccination with FLneu induced CD8+ T cells specific for HER2/neu but a negligible anti-HER2/neu antibody response. The switch from an antibody-mediated to T cell–mediated response was due to different intracellular localization of neu and FLneu. Although the neu protein was secreted, the FLneu protein was retained inside the cell, co-localizing with the endoplasmic reticulum, facilitating processing and presentation to T cells. The neu and FLneu vaccines individually conferred only weak tumor immunity. However, efficient tumor rejection was seen when neu and FLneu were combined, inducing both strong anti-HER2/neu-specific antibody and T cell responses. Adoptive transfer of both immune CD8+ T cells and immune sera from immunized mice was required to confer tumor immunity in naïve hosts. Conclusions: These results show that active induction of both humoral and cellular immunity to HER2/neu is required for efficient tumor protection, and that neither response alone is sufficient.
Apelin Enhances Cardiac Neovascularization After Myocardial Infarction by Recruiting Aplnr+ Circulating Cells
Authors: Dennie Tempel, Martine de Boer, Elza D. van Deel, Remco A. Haasdijk, Dirk J. Duncker, Caroline Cheng, Stefan Schulte-Merker, Henricus J. Duckers
Journal: Circulation Research (2012)

Neovascularization stimulated by local or recruited stem cells after ischemia is a key process that salvages damaged tissue and shows similarities with embryonic vascularization. Apelin receptor (Aplnr) and its endogenous ligand apelin play an important role in cardiovascular development. However, the role of apelin signaling in stem cell recruitment after ischemia is unknown.To investigate the role of apelin signaling in recruitment after ischemia.Aplnr was specifically expressed in circulating cKit+/Flk1+ cells but not in circulating Sca1+/Flk1+ and Lin+ cells. cKit+/Flk1+/Aplnr+ cells increased significantly early after myocardial ischemia but not after hind limb ischemia, indicative of an important role for apelin/Aplnr in cell recruitment during the nascent biological repair response after myocardial damage. In line with this finding, apelin expression was upregulated in the infarcted myocardium. Injection of apelin into the ischemic myocardium resulted in accelerated and increased recruitment of cKit+/Flk1+/Aplnr+ cells to the heart. Recruited Aplnr+/cKit+/Flk1+ cells promoted neovascularization in the peri-infarct area by paracrine activity rather than active transdifferentiation, resulting into cardioprotection as indicated by diminished scar formation and improved residual cardiac function. Aplnr knockdown in the bone marrow resulted in aggravation of myocardial ischemia-associated damage, which could not be rescued by apelin.We conclude that apelin functions as a new and potent chemoattractant for circulating cKit+/Flk1+/Aplnr+ cells during early myocardial repair, providing myocardial protection against ischemic damage by improving neovascularization via paracine action.
Subtypes of Australia antigen and hepatitis-B virus
Authors: G. L. Le Bouvier
Journal: JAMA (1972)

Infection with type-B-hepatitis virus causes Australia antigen (HB Ag) to appear in the serum. This antigen possesses the "group" specificity,<i>a</i>, common to all HB Ag-positive sera; and one or other of two mutually exclusive subspecificities,<i>d</i>or<i>y</i>, which distinguish the two antigenic subtypes, D and Y. We hypothesize that these determinants,<i>d</i>and<i>y</i>, reflect the activity of two distinct genotypes of hepatitis-B virus (HBV), provisionally designated HBV-D and HBV-Y. Transmission experiments have shown that these viral subtypes "breed true." Their separate identity is further attested by the usual finding of only one subtype in localized outbreaks of hepatitis B. The clinical expressions of HBV-D and HBV-Y infection are beginning to be studied. Early results suggest significant differences in subtype distribution, such as the marked preponderance of Y in drug-abusers' hepatitis.
Distinction of the memory B cell response to cognate antigen versus bystander inflammatory signals
Authors: Micah J. Benson, Raul Elgueta, William Schpero, Michael Molloy, Weijun Zhang, Edward Usherwood, Randolph J. Noelle
Journal: The Journal of Experimental Medicine (2009)

The hypothesis that bystander inflammatory signals promote memory B cell (BMEM) self-renewal and differentiation in an antigen-independent manner is critically evaluated herein. To comprehensively address this hypothesis, a detailed analysis is presented examining the response profiles of B-2 lineage B220+IgG+ BMEM toward cognate protein antigen in comparison to bystander inflammatory signals. After in vivo antigen encounter, quiescent BMEM clonally expand. Surprisingly, proliferating BMEM do not acquire germinal center (GC) B cell markers before generating daughter BMEM and differentiating into plasma cells or form structurally identifiable GCs. In striking contrast to cognate antigen, inflammatory stimuli, including Toll-like receptor agonists or bystander T cell activation, fail to induce even low levels of BMEM proliferation or differentiation in vivo. Under the extreme conditions of adjuvanted protein vaccination or acute viral infection, no detectable bystander proliferation or differentiation of BMEM occurred. The absence of a BMEM response to nonspecific inflammatory signals clearly shows that BMEM proliferation and differentiation is a process tightly controlled by the availability of cognate antigen.
PWE-195 Non-neoplastic diagnoses within the NHS bowel cancer screening programme: Abstract PWE-195 Table 1
Authors: R Bevan, T J W Lee, W S Atkin, C L R Nickerson, G Rubin, C Rees
Journal: Gut (2012)

<h3>Introduction</h3> The aim of the NHS Bowel Cancer Screening Programme (BCSP) is to diagnose colorectal cancer. Small studies have demonstrated a yield of diagnoses other than cancer or adenomas (non-neoplastic diagnoses (NND)) ranging from 11% to 25%. NND may account for false positive FOB test (FOBt) results and may generate a significant workload outside the BCSP. The aim of this study was to evaluate the burden of NND generated by the BCSP. <h3>Methods</h3> Data were obtained from the BCSP national database for all patients with a positive FOBt who subsequently underwent investigation from August 2006 to November 2011. These data included patient demographic data, smoking status, clinical outcome and NND made. Data were analysed using SPSS. <h3>Results</h3> 121 728 patient episodes in the BCSP were included in the analysis. 60.2% of patients were male and the mean age was 65.7 years. In this period 10 836 cancers were detected (8.9%). One or more NND were made in 26 251 patients (21.6%). Patients with a diagnosis of neoplasia (cancer or adenomas) were less likely to have a NND than those without neoplasia (19.8% vs 24.4%, p&lt;0.001). Older age and male gender were, but smoking status was not, associated with a greater likelihood of an NND being made (NND in males 21.8% vs 21.2% in females, p=0.01; NND in those &lt;65 years 20.6% vs 22.3% in those ≥65 years, p&lt;0.001; NND in smokers 21.4% vs 21.7% in non-smokers, p=0.34). After adjustment for confounding using multivariable analysis, older age and male gender were still associated with a small but statistically significant increased risk of a NND. <h3>Conclusion</h3> The BCSP generates a significant volume of Non-Neoplastic Diagnoses. Inflammatory bowel disease is an important and common diagnosis and may have important implications for the management of the patient. Large numbers of patients had diverticulosis and haemorrhoids diagnosed however reporting of these findings may vary. Patients undergoing bowel cancer screening should be aware that a diagnosis other than cancer or polyps may be made. The burden of NND generated by the BCSP nationally has not been investigated and the impact of this on primary and secondary care is not known. <h3>Competing interests</h3> None declared.
Haemoglobin level and its clinical impact in a cohort of patients with COPD
Authors: C. Cote, M. D. Zilberberg, S. H. Mody, L. J. Dordelly, B. Celli
Journal: European Respiratory Journal (2007)

Haemoglobin (Hb) abnormalities in chronic obstructive pulmonary disease (COPD) are not well characterised. The present authors investigated the prevalence and association of abnormal Hb with clinical outcomes. Analysis of a prospective cohort of stable COPD outpatients (n = 683) in a USA Veterans Administration pulmonary clinic was undertaken. Patients were classified as anaemic (Hb &lt;13 g·dL −1 ), polycythemic (Hb ≥17 g·dL −1 and ≥15 g·dL −1 for males and females, respectively) or normal. Demographic characteristics and physiological/functional outcomes were compared between groups. Regression models adjusting for confounders examined the independent association of anaemia with clinical outcomes. Anaemia was present in 116 (17%) patients and polycythemia in 40 (6%). While the only values that differed between polycythemic and nonpolycythemic patients were mean body mass index and Hb, anaemic patients showed a significantly higher modified Medical Research Council dyspnoea scale score (2.8 versus 2.6), lower 6-min walk distance (265 versus 325 m) and shorter median survival (49 versus 74 months) than nonanaemic patients. In regression models, anaemia independently predicted dyspnoea and reduced exercise capacity. Anaemia in chronic obstructive pulmonary disease was an independent risk factor for reduced functional capacity. Polycythemia prevalence was low and had no association with worsened outcomes. Further work is required to evaluate the effect of anaemia correction on outcomes in chronic obstructive pulmonary disease.
Ketosis-Prone Atypical Diabetes: Glucagon Is There, Too
Authors: Pierre Lefèbvre
Journal: Diabetes Care (2012)

As stated by Zimmet et al. (1) in the initial chapter of a classical textbook on diabetes, the major requirement for orderly epidemiologic, genetic, and clinical research on diabetes and glucose intolerance, and indeed for their clinical management, is an appropriate classification. Furthermore, a hallmark in the process of understanding the etiology of a disease and studying its natural history is the ability to identify and differentiate its various forms and place them into a rational etio-pathologic framework. In 1984, Ahren and Corrigan (2) reported the existence of a subgroup of diabetic patients observed in Tanzania where the need for insulin replacement therapy fluctuates with time, waxes and wanes, and transient ketoacidosis develops. This subtype of diabetes is not unusual in African Americans and sub-Saharan Africans and currently recognized under the term of ketosis-prone atypical diabetes (KPD) (review in ref. 3).

Classifying KPD in relation with the other more frequent forms of diabetes is not easy. At the onset, KPD often appears as type 1 diabetes with acute hyperglycemia and ketosis or ketoacidosis and the obvious need for insulin therapy but the signs of autoimmunity against islet β-cells are absent. In contrast, during near-normoglycemic remission, patients with KPD usually display multisite insulin resistance similar to that seen in type 2 diabetes (4,5). In 2008, Sobngwi et al. (6) hypothesized that KPD is a subtype of type 2 diabetes with acute onset at diagnosis as the result of an environmental factor such as a human herpes virus infection that would severely impair glucose-stimulated insulin secretion and favor ketogenesis.

In this issue of Diabetes Care , Choukem et al. (7) present original data on the islet dysfunction present in KPD during remission.

Previous studies have shown severe insulin secretory deficiency during the acute ketotic phase of KPD while during …
An infrequent cause of acute left lower quadrant abdominal pain
Authors: S. Greco, G. Maconi, E. Bareggi, E. Radice, G. B. Porro, A. Norsa
Journal: Gut (2008)

A 65-year-old male patient referred with acute abdominal pain in the left lower quadrant and a low grade fever (38°C) was admitted to the surgical emergency department of our institution. He was haemodynamically stable. His bowel movements were completely normal. …
Synergistic Effect of Persistent <i>Chlamydia pneumoniae</i> Infection, Autoimmunity, and Inflammation on Coronary Risk
Authors: Tiina Huittinen, Maija Leinonen, Leena Tenkanen, Hanna Virkkunen, Matti Mänttäri, Timo Palosuo, Vesa Manninen, Pekka Saikku
Journal: Circulation (2003)

Given the role of chronic infections, autoimmunity, and inflammation in atherosclerosis, we studied the joint effect of chronic Chlamydia pneumoniae infection, persistently elevated human heat-shock protein 60 (hHsp60) antibodies, and C-reactive protein (CRP) on coronary risk.The participants for this prospective nested case-control study were obtained from the Helsinki Heart Study, during which 241 nonfatal myocardial infarctions or coronary deaths occurred among 4081 dyslipidemic middle-aged men. Serum samples taken at baseline and 3 to 6 months before the coronary events that occurred during the 8.5-year period were analyzed for antibodies to C pneumoniae and hHsp60 and the CRP concentration. Compared with persistently low levels, the risk of coronary events was 2-fold for persistently elevated immunocomplex (IC)-bound and/or serum IgA antibodies to C pneumoniae (OR, 1.96; 95% CI, 1.14 to 3.36) and also for serum IgA antibodies to hHsp60 (OR, 2.11; 95% CI, 1.08 to 4.13). The risks associated with elevated antibodies were much higher when CRP was also elevated. Compared with low or transiently elevated levels, the risk of coronary events, with adjustment for age and smoking, was 4.5-fold for persistently elevated CRP and C pneumoniae IC/IgA antibodies together (OR, 4.47; 95% CI, 1.84 to 10.83) and was similar for CRP and hHsp60 IgA antibodies together (OR, 4.36; 95% CI, 1.53 to 12.39).Persistently but not transiently elevated C pneumoniae IC/IgA and hHsp60 IgA antibodies, especially when present together with an elevated CRP level, predicted coronary events.
Denosumab for the prevention of skeletal complications in metastatic castration-resistant prostate cancer: comparison of skeletal-related events and symptomatic skeletal events
Authors: M.R. Smith, R.E. Coleman, L. Klotz, K. Pittman, P. Milecki, S. Ng, K.N. Chi, A. Balakumaran, R. Wei, H. Wang, A. Braun, K. Fizazi
Journal: Annals of Oncology (2014)

In a phase III trial in patients with castration-resistant prostate cancer (CRPC) and bone metastases, denosumab was superior to zoledronic acid in reducing skeletal-related events (SREs; radiation to bone, pathologic fracture, surgery to bone, or spinal cord compression). This study reassessed the efficacy of denosumab using symptomatic skeletal events (SSEs) as a prespecified exploratory end point.Patients with CRPC, no previous bisphosphonate exposure, and radiographic evidence of bone metastasis were randomized to subcutaneous denosumab 120 mg plus i.v. placebo every 4 weeks (Q4W), or i.v. zoledronic acid 4 mg plus subcutaneous placebo Q4W during the blinded treatment phase. SSEs were defined as radiation to bone, symptomatic pathologic fracture, surgery to bone, or symptomatic spinal cord compression. The relationship between SSE or SRE and time to moderate/severe pain was assessed using the Brief Pain Inventory Short Form.Treatment with denosumab significantly reduced the risk of developing first SSE [HR, 0.78; 95% confidence interval (CI) 0.66-0.93; P = 0.005] and first and subsequent SSEs (rate ratio, 0.78; 95% CI 0.65-0.92; P = 0.004) compared with zoledronic acid. The treatment differences in the number of patients with SSEs or SREs were similar (n = 48 and n = 45, respectively). Among patients with no/mild pain at baseline, both SSEs and SREs were associated with moderate/severe pain development (P < 0.0001). Fewer patients had skeletal complications, particularly fractures, when defined as SSE versus SRE.In patients with CRPC and bone metastases, denosumab reduced the risk of skeletal complications versus zoledronic acid regardless of whether the end point was defined as SSE or SRE.