tbuckley/cabot-search huggingface dataset:
Strategic challenges in the prevention of cardiovascular disease
Authors: Kiran CR Patel, Rubin Minhas, Paul Lincoln, Ranjit K Dhillon
Journal: Journal of the Royal Society of Medicine (2008)

The momentum for strategies to prevent cardiovascular disease is gathering pace in an attempt to reduce health inequalities not only in the UK but globally. The medical profession as well as governments are realizing that prevention is not only better than cure, but in most cases, more cost-effective than dealing with consequent morbidity and mortality. Modelling data suggests that in the last two decades of the 20th century, the UK experienced almost 70,000 fewer myocardial infarcts than predicted,1 the majority of which was driven by primary prevention, with smoking cessation accounting for 41% of the decline.
CNI-1493, an inhibitor of proinflammatory cytokines, retards cartilage destruction in rats with collagen induced arthritis
Authors: E Larsson
Journal: Annals of the Rheumatic Diseases (2004)

<b>Objective:</b> To investigate if administration of CNI-1493, an inhibitor of the synthesis of proinflammatory cytokines and NO, protects against development of joint destruction in collagen induced arthritis (CIA) in rats. <b>Methods:</b> In a placebo controlled experiment, CNI-1493 was given once daily intraperitoneally after onset of clinical arthritis in DA rats. Disease progression was studied by clinical scoring of arthritis, serial measurement of serum levels of COMP, and histological examination of joints. <b>Results:</b> Clinical signs of arthritis were significantly reduced in the CNI-1493 treated group of rats in comparison with the placebo treated group. Histological examinations of paws demonstrated a significant reduction of cartilage destruction in the CNI-1493 treated group, but marked destruction of cartilage in the placebo group. Serum levels of COMP increased in the placebo group, whereas in the CNI-1493 treated group levels were low and decreased significantly during the observation time. <b>Conclusions:</b> Treatment with CNI-1493 provides efficient protection against synovial inflammation and cartilage destruction when used therapeutically in CIA. The protective effect against cartilage destruction can be monitored by measuring serum COMP. These observations make CNI-1493 an attractive candidate for therapeutic studies in human arthritis, and COMP an attractive serum marker for monitoring joint protective effects.
The Impact of Mental and Physical Illness on Family Life
Authors: E. JAMES ANTHONY
Journal: American Journal of Psychiatry (1970)

With the breakdown of the mentally ill parent, there is generally a disruption in family members and the family as a whole, followed by re-integration or disintegration depending on the family's premorbid adjustment, their previous socioeconomic and cultural level, and the severity of the parent's illness. The changes brought about by a physical illness (in this case tuberculosis) follow a similar course; in addition, the fear of contamination created in the family may result in severe disturbances in interpersonal relationships.
Characterizing Affective Instability in Borderline Personality Disorder
Authors: Harold W. Koenigsberg, Philip D. Harvey, Vivian Mitropoulou, James Schmeidler, Antonia S. New, Marianne Goodman, Jeremy M. Silverman, Michael Serby, Frances Schopick, Larry J. Siever
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: This study sought to understand affective instability among patients with borderline personality disorder by examining the degree of instability in six affective domains. The authors also examined the subjective intensity with which moods are experienced and the association between instability and intensity of affect. METHOD: In a group of 152 patients with personality disorders, subjective affective intensity and six dimensions of affective instability were measured. The mean scores for lability and intensity for each affective domain for patients with borderline personality disorder were compared with those of patients with other personality disorders through analyses that controlled for other axis I affective disorders, age, and sex. RESULTS: Greater lability in terms of anger and anxiety and oscillation between depression and anxiety, but not in terms of oscillation between depression and elation, was associated with borderline personality disorder. Contrary to expectation, the experience of an increase in subjective affective intensity was not more prominent in patients with borderline personality disorder than in those with other personality disorders. CONCLUSIONS: By applying a finer-grained perspective on affective instability than those of previous personality disorder studies, this study points to patterns of affective experience characteristic of patients with borderline personality disorder.
Meta-analysis of data on costs from trials of counselling in primary care: using individual patient data to overcome sample size limitations in economic analyses
Authors: P. Bower
Journal: BMJ (2003)

<h3>Abstract</h3> <b>Objective</b> To assess the feasibility of overcoming sample size limitations in economic analyses of clinical trials through meta-analysis of data on individual patients from multiple trials. <b>Design</b> Meta-analysis of individual patient data from trials of counselling in primary care compared with usual care by a general practitioner. <b>Setting</b> Primary care. <b>Patients</b> People with mental health problems. <b>Main outcome measures</b> Direct treatment costs, depressive symptoms, and cost effectiveness. <b>Results</b> Meta-analysis of individual patient data proved feasible. The results showed that the previous analyses of individual trials were underpowered to provide useful conclusions about the cost comparisons. The results are sensitive to assumptions made about the costs of sessions with a counsellor and the management of patients by a general practitioner. <b>Conclusions</b> Meta-analysis of individual patient data may assist in overcoming sample size limitations in economic analyses. Although feasible, such analysis has shortcomings that may limit the validity of the results. The relative costs and benefits of this method, as opposed to further collection of primary data, are as yet unclear.
Oncosome Formation in Prostate Cancer: Association with a Region of Frequent Chromosomal Deletion in Metastatic Disease
Authors: Dolores Di Vizio, Jayoung Kim, Martin H. Hager, Matteo Morello, Wei Yang, Christopher J. Lafargue, Lawrence D. True, Mark A. Rubin, Rosalyn M. Adam, Rameen Beroukhim, Francesca Demichelis, Michael R. Freeman
Journal: Cancer Research (2009)

Oncosomes have recently been described as membrane-derived microvesicles secreted by cancer cells, which transfer oncogenic signals and protein complexes across cell boundaries. Here, we show the rapid formation and secretion of oncosomes from DU145 and LNCaP human prostate cancer cells. Oncosome formation was stimulated by epidermal growth factor receptor activation and also by overexpression of membrane-targeted Akt1. Microvesicles shed from prostate cancer cells contained numerous signal transduction proteins and were capable of activating rapid phospho-tyrosine and Akt pathway signaling, and stimulating proliferation and migration, in recipient tumor cells. They also induced a stromal reaction in recipient normal cells. Knockdown of the actin nucleating protein Diaphanous Related Formin 3 (DRF3/Dia2) by RNA interference enhanced rates of oncosome formation, indicating that these structures resemble, and may be identical to, nonapoptotic membrane blebs, a feature of the amoeboid form of cell motility. Analysis of primary and metastatic human prostate tumors using 100K single nucleotide polymorphism arrays revealed a significantly higher frequency of deletion of the locus encoding DRF3 (DIAPH3) in metastatic tumors (P = 0.001) in comparison with organ-confined tumors. Fluorescence in situ hybridization confirmed increased chromosomal loss of DIAPH3 in metastatic tumors in a different cohort of patients (P = 0.006). These data suggest that microvesicles shed from prostate cancer cells can alter the tumor microenvironment in a manner that may promote disease progression. They also show that DRF3 is a physiologically relevant protein that seems to regulate this process.
Activity of IPI-504, a Novel Heat-Shock Protein 90 Inhibitor, in Patients With Molecularly Defined Non–Small-Cell Lung Cancer
Authors: Lecia V. Sequist, Scott Gettinger, Neil N. Senzer, Renato G. Martins, Pasi A. Jänne, Rogerio Lilenbaum, Jhanelle E. Gray, A. John Iafrate, Ryohei Katayama, Nafeeza Hafeez, Jennifer Sweeney, John R. Walker, Christian Fritz, Robert W. Ross, David Grayzel, Jeffrey A. Engelman, Darrell R. Borger, Guillermo Paez, Ronald Natale
Journal: Journal of Clinical Oncology (2010)

Purpose IPI-504 is a novel, water-soluble, potent inhibitor of heat-shock protein 90 (Hsp90). Its potential anticancer activity has been validated in preclinical in vitro and in vivo models. We studied the activity of IPI-504 after epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy in patients with advanced, molecularly defined non–small-cell lung cancer (NSCLC). Patients and Methods Patients with advanced NSCLC, prior treatment with EGFR TKIs, and tumor tissue available for molecular genotyping were enrolled in this prospective, nonrandomized, multicenter, phase II study of IPI-504 monotherapy. The primary outcome was objective response rate (ORR). Secondary aims included safety, progression-free survival (PFS), and analysis of activity by molecular subtypes. Results Seventy-six patients were enrolled between December 2007 and May 2009 from 10 United States cancer centers. An ORR of 7% (five of 76) was observed in the overall study population, 10% (four of 40) in patients who were EGFR wild-type, and 4% (one of 28) in those with EGFR mutations. Although both EGFR groups were below the target ORR of 20%, among the three patients with an ALK gene rearrangement, two had partial responses and the third had prolonged stable disease (7.2 months, 24% reduction in tumor size). The most common adverse events included grades 1 and 2 fatigue, nausea, and diarrhea. Grade 3 or higher liver function abnormalities were observed in nine patients (11.8%). Conclusion IPI-504 has clinical activity in patients with NSCLC, particularly among patients with ALK rearrangements.
Combining incretin-based therapies with insulin: realizing the potential in type 2 diabetes. Diabetes Care 2013;36(Suppl. 2):S226–S232
Authors: J Vora
Journal: Diabetes Care (2013)

Vora J. Combining incretin-based therapies with insulin: realizing the potential in type 2 diabetes. Diabetes Care 2013;36(Suppl. 2): …
Reflux oesophagitis and oesophageal transit: evidence for a primary oesophageal motor disorder.
Authors: C A Eriksen, S A Sadek, C Cranford, D Sutton, N Kennedy, A Cuschieri
Journal: Gut (1988)

Patients with reflux oesophagitis have a diminished capacity for distal oesophageal clearance. This is considered to be secondary to acid reflux damage to the oesophageal wall. We have postulated that the observed oesophageal dysmotility is a primary phenomenon. Using 24 hour oesophageal pH monitoring and the solid bolus oesophageal egg transit test, we evaluated the oesophageal transit of 55 patients, with symptomatic reflux oesophagitis, and 16 healthy volunteers. The transit for the entire oesophagus was significantly prolonged in the patient group. This delay was evident in all three segments of the oesophagus. Amongst the patients, there was significant correlation between the oesophageal transit time and the number of prolonged reflux events. No correlation was found, however, between symptom score or severity of endoscopic oesophagitis and transit time. These results would indicate that the oesophageal dysmotility is an integral part of gastrooesophageal reflux disease, and is more of a cause than an effect.
Is inflammation good, bad or irrelevant for skeletal muscles in COPD?
Authors: D. D Sin, W D. Reid
Journal: Thorax (2007)

Skeletal muscle weakness is a common and serious finding in patients with advanced chronic obstructive pulmonary disease (COPD) and contributes to their morbidity and mortality, increasing the risk of exacerbations, hospitalisations and death by 3–4-fold.1 2 The treatment for muscle dysfunction of COPD is extremely limited, and the multitude of interventions to address poor muscle performance has not been fully explored in these patients. Over the past decade, there has been an explosion of interest and research on this topic. Despite that, the pathophysiological mechanisms linking the lung disease of COPD with skeletal muscle dysfunction remains largely unknown. Identifying a link between lung disease and muscle performance might indeed be a daunting task because of the influence of other comorbid conditions (and medications), previous musculoskeletal injury and the history of physical activity that might influence the current status of skeletal muscle in this condition. There are, however, several observations that are widely known and accepted. Firstly, skeletal muscle weakness increases with progression of disease. Secondly, histologically, biopsies of large limb muscles consistently demonstrate a reduction in muscle mass, especially of the anaerobic type-IIx fibres, a shift of fibre type from type 1 fibres to a predominance of type 2 fibres and the depletion of mitochondrial oxidative enzymes leading to uncoupling of oxidative phosphorylation and reduced aerobic capacity.3 Interestingly, these muscles also demonstrate increased oxidative stress and accelerated …
Histone Deacetylase Inhibitors Reverse SS18-SSX–Mediated Polycomb Silencing of the Tumor Suppressor <i>Early Growth Response 1</i> in Synovial Sarcoma
Authors: Joanna M. Lubieniecka, Diederik R.H. de Bruijn, Le Su, Anke H.A. van Dijk, Subbaya Subramanian, Matt van de Rijn, Neal Poulin, Ad Geurts van Kessel, Torsten O. Nielsen
Journal: Cancer Research (2008)

Abstract Synovial sarcoma is a soft tissue malignancy characterized by the fusion of SS18 to either SSX1, SSX2, or SSX4 genes. SS18 and SSX are transcriptional cofactors involved in activation and repression of gene transcription, respectively. SS18 interacts with SWI/SNF, whereas SSX associates with the polycomb chromatin remodeling complex. Thus, fusion of these two proteins brings together two opposing effects on gene expression and chromatin structure. Recent studies have shown that a significant number of genes are down-regulated by the SS18-SSX fusion protein and that the clinically applicable histone deacetylase (HDAC) inhibitor romidepsin inhibits synovial sarcoma growth. Therefore, we set out to identify direct targets of SS18-SSX among genes down-regulated in synovial sarcoma and investigated if romidepsin can specifically counteract SS18-SSX–mediated transcriptional dysregulation. Here, we report that the tumor suppressor early growth response 1 (EGR1) is repressed by the SS18-SSX protein through a direct association with the EGR1 promoter. This SS18-SSX binding correlates with trimethylation of Lys27 of histone H3 (H3K27-M3) and recruitment of polycomb group proteins to this promoter. In addition, we found that romidepsin treatment reverts these modifications and reactivates EGR1 expression in synovial sarcoma cell models. Our data implicate polycomb-mediated epigenetic gene repression as a mechanism of oncogenesis in synovial sarcoma. Furthermore, our work highlights a possible mechanism behind the efficacy of a clinically applicable HDAC inhibitor in synovial sarcoma treatment. [Cancer Res 2008;68(11):4303–10]
Regulation of adenosine formation by the heart.
Authors: H V Sparks, H Bardenheuer
Journal: Circulation Research (1986)

We think that the available data on adenosine formation suggest the two signals are responsible for adenosine release from cardiac myocytes: (1) the ratio of oxygen supply to demand and (2) agonist-triggered release of extracellular adenine nucleotides. We do not believe that the available data support the oxygen consumption hypothesis. The few studies which allow us to judge the relative importance of these two signals suggest that both hypoxia and sympathetic nerve stimulation release adenosine primarily by decreasing O2 supply:demand. Agonist triggered nucleotide release may be quantitatively important in situations in which decreased O2 supply/demand cannot explain increased release, i.e., isoproterenol and acetylcholine administration.
Therapeutic effect of urocortin and adrenomedullin in a murine model of Crohn's disease
Authors: E Gonzalez-Rey
Journal: Gut (2006)

<b>Background and aim:</b> Urocortin 1 (UCN) and adrenomedullin (AM) are two recently discovered neuropeptides that, due to their distribution and binding to receptors in immune cells, have emerged as potential endogenous anti-inflammatory factors. Crohn’s disease is a chronic debilitating disease characterised by a Th1 driven severe inflammation of the gastrointestinal tract. This study investigated the therapeutic effect of UCN and AM in a murine model of colitis. <b>Methods and results:</b> Treatment with UCN or AM ameliorated significantly the clinical and histopathological severity of the inflammatory colitis, abrogating body weight loss, diarrhoea, and inflammation, and increased the survival rate of colitic mice. The therapeutic effect was associated with downregulation of both inflammatory and Th1 driven autoimmune responses, including regulation of a wide spectrum of inflammatory mediators. In addition, partial involvement of interleukin 10 secreting regulatory cells in this therapeutic effect was demonstrated. Importantly, UCN or AM treatments were therapeutically effective in established colitis and avoided recurrence of the disease. <b>Conclusions:</b> This work identifies UCN and AM as two potent anti-inflammatory factors with the capacity to deactivate the intestinal inflammatory response and restore mucosal immune tolerance at multiple levels. Consequently, both peptides represent novel multistep therapeutic approaches for the treatment of Crohn’s disease and other Th1 mediated inflammatory diseases.
Exposure to Persistent Organic Pollutants: Relationship With Abnormal Glucose Metabolism and Visceral Adiposity
Authors: Eveline L. Dirinck, Alin C. Dirtu, Malarvannan Govindan, Adrian Covaci, Luc F. Van Gaal, Philippe G. Jorens
Journal: Diabetes Care (2014)

OBJECTIVE The contribution of persistent organic pollutants (POPs) to the pandemic of type 2 diabetes mellitus and obesity has been assumed but remains speculative. Our study aimed at investigating the relationship of POP levels with detailed markers of glucose metabolism and body composition. RESEARCH DESIGN AND METHODS Glucose tolerance was determined in a group of normal-weight and obese individuals. Fat distribution was assessed with abdominal computed tomography (CT) scanning, determining subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT). Selected POPs (28 polychlorinated biphenyls [PCBs] and the pesticide p,p’-dichlorodiphenyldichloroethylene [p,p’-DDE]) were measured in serum. In a subset of obese individuals undergoing bariatric surgery, POPs were also measured in adipose tissue. RESULTS Among obese participants, serum and adipose tissue levels of POPs were significantly correlated to glucose levels during an oral glucose tolerance test. Logistic regression using a model including age, age2, sex, family history of diabetes, BMI, CT-VAT, smoking behavior, physical activity level score, and a POP level identified serum levels of PCB153, the sum of PCBs and p,p’-DDE as significant predictors of abnormal glucose tolerance (odds ratio 4.6, 4.8, and 3.4, respectively; P &amp;lt; 0.05). Adipose tissue levels of p,p’-DDE were also significant predictors (odds ratio 81.6; P &amp;lt; 0.05). Serum levels of PCBs were inversely related to BMI, while serum and adipose tissue levels of all POPs were positively related to the CT-VAT/SAT ratio, suggesting an important role for the visceral fat compartment in POP dynamics. CONCLUSIONS Our findings further sustain the theory that exposure to environmentally relevant levels of POPs may exert both a diabetogenic and obesogenic effect.
The Male Predisposition to Pharyngeal Collapse
Authors: Atul Malhotra, Yaqi Huang, Robert B. Fogel, Giora Pillar, Jill K. Edwards, Ron Kikinis, Stephen H. Loring, David P. White
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Obstructive sleep apnea is an important disorder because of both its prevalence and its cardiovascular and neurocognitive sequelae. Despite the fact that male sex is a major risk factor for this disorder, the mechanisms underlying this predisposition are unclear. To understand the pathophysiologic basis of the male predisposition for pharyngeal collapse, we performed a detailed analysis of the anatomic and physiologic features of the upper airway in a cohort of normal and near-normal subjects (equal number of men and women). Although no important physiologic (genioglossal electromyogram, airflow resistance) differences were observed between sexes, a number of anatomic differences were apparent. The pharyngeal airway length was substantially longer in men compared with women. There was also an increased cross-sectional area of the soft palate and an increased airway volume in men compared with women. Using signal-averaged anatomic data from male and female subjects, we developed representative male and female finite element airway models. This model demonstrated the male airway to be substantially more collapsible than the female airway, solely on the basis of anatomic differences. This study suggests that the male predisposition to pharyngeal collapse is anatomically based, primarily as the result of an increased length of vulnerable airway as well as increased soft palate size.
İntertrijinöz psoriazis'in tedavisi: Ulusal Psoriazis Kurumunun Tıbbi Heyetinden
Authors: Robert E. Kalb, Jerry Bagel, Neil J. Korman, Mark G. Lebwohl, Melodie Young, Elizabeth J. Horn, Abby S. Van Voorhees
Journal: Journal of the American Academy of Dermatology (2009)
Allergens of <i>Pityrosporum ovale</i> and <i>Candida albicans</i>
Authors: G. Doekes, A. G. van Ieperen‐van Dijk
Journal: Allergy (1993)

In atopic dermatitis (AD), a high prevalence has been reported of type I reactions and specific IgE to extracts of the commensal lipophilic skin yeast Pityrosporum ovale. In the present study, a highly significant correlation (r = 0.77) was found between levels of anti-P. ovale IgE and of IgE reacting with extracts of Candida albicans, both measured by a sensitive ELISA method. In a series of 128 AD sera, 34 sera reacted positively with both yeast extracts, 38 reacted with P. ovale but not with C. albicans, and only one of the 56 anti-P. ovale-negative sera showed a very weak reaction with C. albicans. The correlation was due to a marked cross-reactivity, as shown by inhibition ELISA. Fluid-phase preincubation of double-positive sera with either of the two yeast extracts resulted in a dose-dependent, and at high concentrations complete, inhibition of the IgE reactions with both coated P. ovale and C. albicans allergens. Mutual inhibition of IgE-binding could also be achieved with pools of glycoproteins and/or polysaccharides isolated from the crude extracts by Con A affinity chromatography. P. ovale allergens were, however, more potent fluid-phase inhibitors than the corresponding C. albicans components. The apparently higher avidity for P. ovale allergens suggests that these antiyeast IgE antibodies in AD result from sensitization to P. ovale and cross-react with C. albicans.