tbuckley/cabot-search huggingface dataset:
A retrospective analysis of quinolone prescriptions for tuberculosis in two North Birmingham hospitals
Authors: Guy Hagan, Dwight McLeod, Nazim Nathani
Journal: European Respiratory Journal (2013)

Introduction  Few guidelines exist on appropriate use of quinolones in TB management; American and British guidelines suggest a role in liver and renal disease. Ongoing phase III trials may further define their role. Advantages include once daily dosing and no cross-resistance, however inappropriate quinolone use may compromise MDRTB treatment.  Aims and objectives  We sought to analyse the reasons and duration of quinolone prescription for TB in our two hospitals.  Methods  Pharmacy prescriptions from 1 st  Nov 2010 to 1 st  Nov 2012 for quinolones were analysed and TB patients identified. Information was obtained from case note review. Follow up was until 1 st  Dec 2012.  Results  33 patients were identified. Mean age was 46.9(+/- 16.4) years. 23 were male, 2 patients HIV+ve. 31/33 TB cases were confirmed on culture; 4 had mono-resistance, and 5 were MDRTB. Sites were pulmonary(13), miliary(8), lymph node(5), meningitis(2), peritoneal(2), spinal(2) and a cold abscess(1). Reasons for quinolone prescription are below:  Quinolones were well tolerated and no patients suffered adverse effects. 30 patients were prescribed moxifloxacin and 3 levofloxacin. 4 patients died during the follow up period, 2 from TB and 2 from malignancy.  Conclusions  Quinolone use for TB in our hospitals is appropriate; duration of quinolone prescription could be reduced to preserve the efficacy of this important drug class.
Pulmonary hypertension associated with POEMS syndrome
Authors: S Ribadeau-Dumas, I Tillie-Leblond, C Rose, F Saulnier, JL Wemeau, PY Hatron, B Wallaert
Journal: European Respiratory Journal (1996)

Pulmonary hypertension (PH) is an uncommon but lethal complication of some connective tissue diseases. We describe two cases of PH associated with plasma cell dyscrasia, with polyneuropathy (P), organomegaly (O), endocrinopathy (E), M protein (P) and skin changes (S) described as POEMS syndrome. Two patients, one female and one male, were hospitalized for dyspnoea. Both had a history of POEMS syndrome a few years previously. PH was diagnosed from cardiac catherization, and complete investigations did not reveal other underlying disease. In Case No. 1, mean pulmonary artery pressure was 40 mmHg and pulmonary vascular resistance was 775 dyne x s x cm-5 x m2, with a significant reversibility to vasodilators. Nifedipine and fluindrone treatment was initiated. The patient was still alive 18 months later. In Case No. 2, mean pulmonary artery pressure was 28 mmHg and pulmonary vascular resistance was 243 dyne x s x cm-5x m2, with a slight reversibility to vasodilators. The patient died 6 months later. Our observations suggest that pulmonary hypertension (PH) may be associated with the POEMS syndrome, and that patients suffering from the POEMS syndrome and dyspnoea should be tested for PH.
A population-based study on the prevalence of NASH using scores validated against liver histology
Authors: Jenni Hyysalo, Ville T. Männistö, You Zhou, Johanna Arola, Vesa Kärjä, Marja Leivonen, Anne Juuti, Nabil Jaser, Susanna Lallukka, Pirjo Käkelä, Sari Venesmaa, Marko Simonen, Juha Saltevo, Leena Moilanen, Eeva Korpi-Hyövalti, Sirkka Keinänen-Kiukaanniemi, Heikki Oksa, Marju Orho-Melander, Luca Valenti, Silvia Fargion, Jussi Pihlajamäki, Markku Peltonen, Hannele Yki-Järvinen
Journal: Journal of Hepatology (2013)
Microarray Technology: A Review of New Strategies to Discover Candidate Vulnerability Genes in Psychiatric Disorders
Authors: William E. Bunney, Blynn G. Bunney, Marquis P. Vawter, Hiroaki Tomita, Jun Li, Simon J. Evans, Prabhakara V. Choudary, Richard M. Myers, Edward G. Jones, Stanley J. Watson, Huda Akil
Journal: American Journal of Psychiatry (2003)

An international effort is in progress to discover candidate genes and pathways associated with psychiatric disorders, including two of the most serious diseases, schizophrenia and mood disorders, through the use of new technology-microarrays. Instead of studying one gene at a time, microarrays provide the opportunity to analyze thousands of genes at once.This article reviews the steps in this discovery process, including the acquisition and characterization of high-quality postmortem brain tissue, RNA extraction, and preparation and use of microarray technology. Two alternative microarray methods and factors affecting the quality of array data are reviewed.New analytical strategies are being developed to process the massive data sets generated by microarray studies and to define the significance of implicated genes. Array results must be validated by other methods, including in situ hybridization and real-time polymerase chain reaction. Identified genes can also be evaluated in terms of their chromosomal locations and possible overlap with regions of suggestive linkage or association identified with genome-wide linkage analysis in psychiatry and in terms of overlap with genes identified by microarray studies in animals administered psychoactive drugs. Microarray studies are only the first major step in the process. Further efforts in the investigation involve multiple strategies for studying function and gene structure, including transgenic and knockout animal studies.Microarrays present a methodology that can identify genes or pathways for new and unique potential drug targets, determine premorbid diagnosis, predict drug responsiveness for individual patients, and, eventually, initiate gene therapy and prevention strategies.
Molecular Pathways: Understanding the Role of Rad52 in Homologous Recombination for Therapeutic Advancement
Authors: Benjamin H. Lok, Simon N. Powell
Journal: Clinical Cancer Research (2012)

The Rad52 protein was largely ignored in humans and other mammals when the mouse knockout revealed a largely "no-effect" phenotype. However, using synthetic lethal approaches to investigate context-dependent function, new studies have shown that Rad52 plays a key survival role in cells lacking the function of the breast cancer type 1 susceptibility protein (BRCA1)-BRCA2 pathway of homologous recombination. Biochemical studies also showed significant differences between yeast and human Rad52 (hRad52), in which yeast Rad52 can promote strand invasion of replication protein A (RPA)-coated single-stranded DNA (ssDNA) in the presence of Rad51 but hRad52 cannot. This results in the paradox of how is hRad52 providing Rad51 function: presumably there is something missing in the biochemical assays that exists in vivo, but the nature of this missing factor is currently unknown. Recent studies have suggested that Rad52 provides back-up Rad51 function for all members of the BRCA1-BRCA2 pathway, suggesting that Rad52 may be a target for therapy in BRCA pathway-deficient cancers. Screening for ways to inhibit Rad52 would potentially provide a complementary strategy for targeting BRCA-deficient cancers in addition to poly (ADP-ribose) polymerase (PARP) inhibitors.
A new animal model of postsurgical bowel inflammation and fibrosis: the effect of commensal microflora
Authors: R. J. Rigby, M. R. Hunt, B. P. Scull, J. G. Simmons, K. E. Speck, M. A. Helmrath, P. K Lund
Journal: Gut (2009)

<h3>Objective:</h3> Ileocaecal resection (ICR) is common in Crohn’s disease. Inflammation and fibrosis frequently recur at the site of anastomosis or in the small intestine (SI). No animal models of postsurgical inflammation and fibrosis exist. A model of ICR was developed in interleukin 10 (IL10) null and wild-type (WT) mice to test the hypothesis that ICR promotes postsurgical inflammation and fibrosis in the SI or anastomosis of genetically susceptible IL10 null, but not WT or germ-free (GF)-IL10 null mice. <h3>Methods:</h3> GF-IL10 null mice were conventionalised (CONV) and 3 weeks later randomised to ICR, transection (T) or no treatment (NoTx). Age-matched conventionally raised (CONV) WT and GF-IL10 null mice received ICR, T or NoTx. Animals were killed 28 days later. Histological scoring, real-time PCR for tumour necrosis factor α and collagen, and immunostaining for CD3<sup>+</sup> T cells assessed inflammation and fibrosis. <h3>Results:</h3> After ICR, CONV-IL10 null, but not CONV-WT mice, developed significant inflammation and fibrosis in the SI and inflammation in anastomosis compared with NoTx or T controls. Fibrosis occurred in the anastomosis of both CONV-IL10 null and CONV-WT mice following ICR. GF-IL10 null mice developed little or no inflammation or fibrosis in the SI or anastomosis after ICR. <h3>Conclusions:</h3> ICR in CONV-IL10 null mice provides a new animal model of postsurgical inflammation and fibrosis in the SI and anastomosis. Absence of inflammation and fibrosis in the SI of CONV-WT and GF-IL10 null mice following ICR indicates that postsurgical small bowel disease occurs only in genetically susceptible IL10 null mice and is bacteria dependent.
Phylogenetic Relationships and Molecular Adaptation Dynamics of Human Rhinoviruses
Authors: N. Lewis-Rogers, M. L. Bendall, K. A. Crandall
Journal: Molecular Biology and Evolution (2009)

Human rhinoviruses (HRVs) are responsible for nearly 50% of all common cold infections. Ordinarily, HRV infections are mild and self-limiting; nonetheless, every year they result in significant loss of economic productivity and substantial inappropriate antibiotic use. Development of effective vaccine and antiviral prophylaxis against HRV has been hampered by the extensive antigenic diversity present among the nearly 100 serotypes. To gain new insights into the evolutionary processes that create the genetic diversity present among HRVs, we tested for recombination and selection for individual genes and the coding genome for 45 HRV serotypes using estimated phylogenetic relationships. Although the structural capsid genes and nonstructural genes recovered incongruent tree topologies, no recombination was detected using substitution methods. Therefore, the coding genome was determined to be appropriate for phylogenetic tests. Results of the Shimodaira–Hasegawa (SH) test support the hypothesis that the capsid genes recover a different evolutionary history than the nonstructural genes. Our best phylogenetic estimate based on the coding genome suggests that HRV-B is more closely related to enterovirus than to HRV-A; however, several alternative phylogenetic hypotheses were not rejected by the SH test. Positive selection was examined by using two different approaches; dN/dS rate ratio and the physicochemical phenotypes for 31 amino acid properties. Analyses using dN/dS failed to detect positive selection. However, protein phenotypic expression appears to be a more sensitive approach. There was extensive stabilizing and destabilizing positive selection in HRV-A major and HRV-B serotypes for all proteins, except in 3A in HRV-B, which overlapped with functional, structural, and to a greater extent in uncharacterized genomic regions. In contrast, the evolution of HRV-A minor serotypes appears to be driven primarily by destabilizing selection. Our results demonstrate that HRV-A major, HRV-A minor, and HRV-B serotypes have not been similarly influenced by purifying selection.
The Carboxyl Terminal Domain Regulates the Unitary Conductance and Voltage Dependence of Connexin40 Gap Junction Channels
Authors: Justus M. B. Anumonwo, Steven M. Taffet, Hong Gu, Marc Chanson, Alonso P. Moreno, Mario Delmar
Journal: Circulation Research (2001)

Abstract —Chemical regulation of connexin (Cx) 40 and Cx43 follows a ball-and-chain model, in which the carboxyl terminal (CT) domain acts as a gating particle that binds to a receptor affiliated with the pore. Moreover, Cx40 channels can be closed by a heterodomain interaction with the CT domain of Cx43 and vice versa. Here, we report similar interactions in the establishment of the unitary conductance and voltage-dependent profile of Cx40 in N2A cells. Two mean unitary conductance values (“lower conductance” and “main”) were detected in wild-type Cx40. Truncation of the CT domain at amino acid 248 (Cx40tr248) caused the disappearance of the lower-conductance state. Coexpression of Cx40tr248 with the CT fragment of either Cx40 (homodomain interactions) or Cx43 (heterodomain interactions) rescued the unitary conductance profile of Cx40. In the N2A cells, the time course of macroscopic junctional current relaxation was best described by a biexponential function in the wild-type Cx40 channels, but it was reduced to a single-exponential function after truncation. However, macroscopic junctional currents recorded in the oocyte expression system were not significantly different between the wild-type and mutant channels. Concatenation of the CT domain of Cx43 to amino acids 1 to 248 of Cx40 yielded a chimeric channel with unitary conductance and voltage-gating profile indistinguishable from that of wild-type Cx40. We conclude that residence of Cx40 channels in the lower-conductance state involves a ball-and-chain type of interaction between the CT domain and the pore-forming region. This interaction can be either homologous (Cx40 truncation with Cx40CT) or heterologous (with the Cx43CT).
Blocking the mitochondrial apoptotic pathway preserves motor neuron viability and function in a mouse model of amyotrophic lateral sclerosis
Authors: Nichole A. Reyes, Jill K. Fisher, Kathryn Austgen, Scott VandenBerg, Eric J. Huang, Scott A. Oakes
Journal: Journal of Clinical Investigation (2010)

Apoptosis of motor neurons is a well-documented feature in amyotrophic lateral sclerosis (ALS) and related motor neuron diseases (MNDs). However, the role of apoptosis in the pathogenesis of these diseases remains unresolved. One possibility is that the affected motor neurons only succumb to apoptosis once they have exhausted functional capacity. If true, blocking apoptosis should confer no therapeutic benefit. To directly investigate this idea, we tested whether tissue-specific deletion in the mouse CNS of BCL2-associated X protein (BAX) and BCL2-homologous antagonist/killer (BAK), 2 proapoptotic BCL-2 family proteins that together represent an essential gateway to the mitochondrial apoptotic pathway, would protect against motor neuron degeneration. We found that neuronal deletion of Bax and Bak in a mouse model of familial ALS not only halted neuronal loss, but prevented axonal degeneration, symptom onset, weight loss, and paralysis and extended survival. These results show that motor neurons damaged in ALS activate the mitochondrial apoptotic pathway early in the disease process and that apoptotic signaling directly contributes to neuromuscular degeneration and neuronal dysfunction. Hence, inhibiting apoptosis upstream of mitochondrial permeabilization represents a possible therapeutic strategy for preserving functional motor neurons in ALS and other MNDs.
The Long-Term Effects of Conventional and Atypical Antipsychotics in Patients With Probable Alzheimer’s Disease
Authors: Oscar L. Lopez, James T. Becker, Yue-Fang Chang, Robert A. Sweet, Howard Aizenstein, Beth Snitz, Judith Saxton, Eric McDade, M. Ilyas Kamboh, Steven T. DeKosky, Charles F. Reynolds, William E. Klunk
Journal: American Journal of Psychiatry (2013)

Objective The authors sought to determine the effects of conventional and atypical antipsychotic use on time to nursing home admission and time to death in a group of outpatients with mild to moderate probable Alzheimer’s disease. Method The authors examined time to nursing home admission and time to death in 957 patients with the diagnosis of probable Alzheimer’s disease who had at least one follow-up evaluation (mean follow-up time, 4.3 years [SD=2.7]; range, 0.78–18.0 years) using Cox proportional hazard models adjusted for age, gender, education level, dementia severity, hypertension, diabetes mellitus, heart disease, extrapyramidal signs, depression, psychosis, aggression, agitation, and dementia medication use. Results A total of 241 patients (25%) were exposed to antipsychotics at some time during follow-up (conventional, N=138; atypical, N=95; both, N=8). Nursing home admission (63% compared with 23%) and death (69% compared with 34%) were more frequent in individuals taking conventional than atypical antipsychotics. In a model that included demographic and cognitive variables, hypertension, diabetes mellitus, heart disease, incident strokes, and extrapyramidal signs, only conventional antipsychotic use was associated with time to nursing home admission. However, the association was no longer significant after adjustment for psychiatric symptoms. Psychosis was strongly associated with nursing home admission and time to death, but neither conventional nor atypical antipsychotics were associated with time to death. Conclusions The use of antipsychotic medications, both conventional and atypical, was not associated with either time to nursing home admission or time to death after adjustment for relevant covariates. Rather, it was the presence of psychiatric symptoms, including psychosis and agitation, that was linked to increased risk of institutionalization and death after adjustment for exposure to antipsychotics.
The prospective evaluation of the TB strain typing service in England: a mixed methods study
Authors: J Mears, E Vynnycky, J Lord, M W Borgdorff, T Cohen, D Crisp, J A Innes, M Lilley, H Maguire, T D McHugh, G Woltmann, I Abubakar, P Sonnenberg
Journal: Thorax (2015)

<h3>Background</h3> In response to rising TB notification rates in England, universal strain typing was introduced in 2010. We evaluated the acceptability, effectiveness and cost-effectiveness of the TB strain typing service (TB-STS). <h3>Methods</h3> We conducted a mixed-methods evaluation using routine laboratory, clinic and public health data. We estimated the effect of the TB-STS on detection of false positive <i>Mycobacterium tuberculosis</i> diagnoses (2010–2012); contact tracing yield (number of infections or active disease per pulmonary TB case); and diagnostic delay. We developed a deterministic age-structured compartmental model to explore the effectiveness of the TB-STS, which informed a cost-effectiveness analysis. <h3>Results</h3> Semi-structured interviews explored user experience. Strain typing identified 17 additional false positive diagnoses. The TB-STS had no significant effect on contact tracing yield or diagnostic delay. Mathematical modelling suggested increasing the proportion of infections detected would have little value in reducing TB incidence in the white UK-born population. However, in the non-white UK-born and non-UK-born populations, over 20 years, if detection of latent infection increases from 3% to 13% per year, then TB incidence would decrease by 11%; reducing diagnostic delay by one week could lead to 25% reduction in incidence. The current TB-STS was not predicted to be cost-effective over 20 years (£95 628/quality-adjusted life-years). Interviews found people had mixed experiences, but identified broader benefits, of the TB-STS. <h3>Conclusions</h3> To reduce costs, improve efficiency and increase effectiveness, we recommend changes to the TB-STS, including discontinuing routine cluster investigations and focusing on reducing diagnostic delay across the TB programme. This evaluation of a complex intervention informs the future of strain typing in the era of rapidly advancing technologies.
Interpreting exercise treadmill tests needs scoring system
Authors: S K S Lairikyengbam
Journal: BMJ (2002)

EDITOR—In their article on exercise tolerance testing in the ABC of electrocardiography Hill and Timmis emphasised that ST segment depression (horizontal or downsloping) is the most reliable indicator of exercise induced ischaemia.1 The overall accuracy of the exercise induced ST segment depression is only about 65%. 2 3 This has led to intense …
Alcohol and absorption from the small intestine. 1. Impairment of absorption from the small intestine in alcoholics.
Authors: N Krasner, K M Cochran, R I Russell, H A Carmichael, G G Thompson
Journal: Gut (1976)

An absorption screen was performed in 10 chronic alcoholic patients within a few days of admission due to an acute alcoholic episode. Impaired absorption of d-Xylose was noted in three patients and low leucocyte ascorbic acid and serum folate levels in five. No abnormality was detected in jejunal histology. The absorption of water and electrolytes from the jejunum was studied in these patients using a triple-lumen tube perfusion system. The mean rate of absorption of water in the alcoholic subjects (50-0 +/- 2-3 ml/h) was significantly lower (P less than 0-001) than the mean value in 14 healthy control subjects (205 +/- 15-9 ml/h). A significant reduction of Na+ and Cl-absorption was also demonstrated in the alcoholic subjects. These results indicate that patients with acute-on-chronic alcoholism may have a function impairment of water and electrolyte absorption from the jejunum. This may, in part, account for some of the nutritional deficiencies in such patients and for symptoms such as diarrhoea which may be present.
Glucocorticoids increase interleukin-6-dependent gene induction by interfering with the expression of the suppressor of cytokine signaling 3 feedback inhibitor
Authors: Anna Dittrich, Christina Khouri, Sara Dutton Sackett, Christian Ehlting, Oliver Böhmer, Ute Albrecht, Johannes G. Bode, Christian Trautwein, Fred Schaper
Journal: Hepatology (2011)

Glucocorticoids are known to be potent regulators of inflammation and have been used pharmacologically against inflammatory, immune, and lymphoproliferative diseases for more than 50 years. Due to their possible and well–documented side effects, it is crucial to understand the molecular mechanisms and targets of glucocorticoid action in detail. Several modes of action have been discussed; nevertheless, none of them fully explain all the functions of glucocorticoids. Therefore, we analyzed the cross–talk between glucocorticoids and interleukin–6 (IL–6) in the liver. IL–6 exerts pro–inflammatory as well as anti–inflammatory properties and is a main inducer of the acute–phase response. The balance between the proinflammatory and anti–inflammatory activities of IL–6 is tightly regulated by suppressor of cytokine signaling 3 (SOCS3), a well–known feedback inhibitor of IL–6 signaling. Here, it is demonstrated that glucocorticoids enhance IL–6–dependent γ–fibrinogen expression. Studying of the underlying mechanism revealed prolonged activation of signal transducer and activator of transcription 3 (STAT3) caused by down–regulation of SOCS3 protein expression. Consequently, in SOCS3–deficient cells glucocorticoids do not affect IL–6–induced signal transduction. Moreover, in hepatocytes lacking the SOCS3 recruiting motif within gp130, IL–6–dependent γ–fibrinogen expression is not influenced by glucocorticoid treatment. Conclusion: Glucocorticoids interfere with IL–6–induced expression of the feedback inhibitor SOCS3, thereby leading to enhanced expression of acute–phase genes in hepatocytes. This mechanism contributes to the explanation of how glucocorticoids affect inflammation and acute–phase gene induction. (Hepatology 2012;55:256–266)
Reaginic antibody produced in mice with contact sensitivity.
Authors: W R Thomas, G L Asherson, M C Watkins
Journal: The Journal of Experimental Medicine (1976)

Mice produced reaginic antibody within 1 wk of painting with the contact sensitizing agent picryl chloride. The titers, measured by passive cutaneous anaphylaxis in rats, increased after repeated applications of picryl chloride. In contrast, serum agglutinins did not increase after two applications of picryl chloride. Reagin was also elicited by another contact sensitizing agent, oxazolone. Some strain variation of the response to picryl chloride was found, with CBA mice being good responders and BALB/c and C57BL/10 mice being poor responders.