tbuckley/cabot-search huggingface dataset:
Diplopia and Ataxia in a Heavy Smoker
Authors: Yuanquan Yang, Missak Haigentz, Mary Welch
Journal: JAMA (2015)

A64-year-oldmanwith coronary artery disease and an 80 pack-year smoking habit presented with 2 weeks of gait instability leading to frequent falls and 8weeks of vertigo and double vision. He reported unintentional weight loss without fevers or decreased appetite. He denied any history of alcohol abuse. Medications includedmetoprolol and aspirin.Onexamination, he was alert and oriented and vital signs were normal; body mass index was 24. Neurologic examination revealed right eyeheterotropia andnasal upshoot indicative of a fourth cranial nerve palsy (Figure 1A), left ptosis, flatteningof the rightnasolabial fold (Figure 1B), andbilateral restrictedupgazeandataxia (Video). Strengthand reflexeswerepreserved.Results of abasicmetabolic panel andcomplete blood cell count were normal. Screening for human immunodeficiency virus, Lyme disease, anddrugusewasnegative. Contrast-enhancedmagnetic resonance imaging (MRI) of the brain was unremarkable. Cerebrospinal fluid (CSF) sampling revealed elevated protein (75 mg/dL [reference range, 10-42]), lymphocyte predominant pleocytosis (21-66 cells/uL [reference range, 0-11]), and oligoclonal bands (OCBs). Pleural thickening was seen on routine chest radiography; chest computed tomography (CT) revealedmediastinal lymphadenopathy, subcentimeterpulmonarynodules, andcalcifiedpleural plaques. Video at jama.com
Bcl-2 Expression as a Predictive Marker of Hormone-Refractory Prostate Cancer Treated with Taxane-Based Chemotherapy
Authors: Tateki Yoshino, Hiroaki Shiina, Shinji Urakami, Nobuyuki Kikuno, Tatsuaki Yoneda, Kazushi Shigeno, Mikio Igawa
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Bcl-2 inhibits apoptosis, and its overexpression is associated with hormone refractory prostate cancer (HRPC). Bak and Bax are in the Bcl-2 family and counteract the antiapoptotic function of Bcl-2. Taxane-induced (paclitaxel and its analogue docetaxel) phosphorylation of Bcl-2 abolishes the potential antiapoptotic effect of Bcl-2. We hypothesized that (a) survival benefit in HRPC patients treated with taxanes is determined by the presence of Bcl-2 protein and (b) altered expression of Bak and Bax protein caused by genetic mutation is associated with biological aggressiveness of prostate cancer. Experimental Design: Forty localized prostate cancer and 30 HRPC cases were used in this study. Surgical specimens of localized prostate cancer and biopsy specimens of HRPC were used for immunostaining of Bcl-2, Bak, and Bax as well as DNA extraction. Mutations in the Bak and Bax genes were screened by single-strand conformational polymorphism, and confirmed by direct DNA sequencing. Results: Bcl-2–positive HRPC showed longer cause-specific survival in comparison with the counterparts. Multivariate analysis revealed that the level of Bcl-2 expression before treatment with taxane-based chemotherapy was an independent predictor for cause-specific survival (P &amp;lt; 0.01) and baseline prostate-specific antigen level was an independent predictor for progression-free survival (P &amp;lt; 0.01). Bax gene mutation was found in only one HRPC specimen. Conclusions: Bcl-2 expression in addition to prostate-specific antigen measurement before treatment could identify HRPC patients who may benefit from taxane-based chemotherapy. Mutation of the Bak and Bax genes is a rare event in prostate cancer.
Chronic selective hypertriglyceridemia impairs endothelium-dependent vasodilatation in rats
Authors: K Kusterer
Journal: Cardiovascular Research (1999)

Objective/Methods: In order to investigate whether selective hypertriglyceridemia impairs endothelium-dependent vasodilatation in the rat hindlimb, rats were selectively bred to establish two strains, one with a pronounced hypertriglyceridemia (HT) and the other with normal plasma levels of triglycerides (LT). Results: Carotid arteries and aortae removed from 3, 6, 9 and 12 month old LT- and HT-rats exhibited a normal morphology. However, marked morphological differences were observed between vessels from 18–20 month old HT- and LT-rats. The endothelium-dependent vasodilator acetylcholine (2 to 50 μg/kg), administered into the iliac artery, elicited a concentration-dependent increase in hindlimb blood flow which was not different in 3, 6 and 9 month old LT- or HT-rats but was impaired in 12 and 18–20 month old HT-rats. In contrast the endothelium-independent vasodilator sodium nitroprusside enhanced blood flow in both strains to a similar extent. Neither administration of the nitric oxide (NO) synthase (NOS) substrate, l-arginine, nor the NOS inhibitor NGnitro-l-arginine, affected the responsiveness to endothelium-dependent vasodilators in 12 month old HT-rats. These attenuated responses could not be attributed to a decrease in endothelial NOS expression as Western blot analysis revealed identical levels of this enzyme in the aortae and carotid arteries from LT- and HT-rats. Determination of superoxide anion (O2−) formation however, demonstrated a markedly elevated production of O2− in aortae from HT-rats. Conclusion: We conclude that chronic selective hypertriglyceridemia, an independent risk factor in the development and progression of atherosclerosis, leads to an endothelial dysfunction which is associated with an increased vascular O2− production and a subsequent decrease in bioavailable NO.
Adipose tissue at entheses: the rheumatological implications of its distribution. A potential site of pain and stress dissipation?
Authors: M Benjamin
Journal: Annals of the Rheumatic Diseases (2004)

<b>Objectives:</b> To describe the distribution of adipose tissue within and adjacent to entheses in order to assess its functional significance at attachment sites. <b>Methods:</b> Entheses were removed from 29 different sites in the limbs of formalin fixed, elderly, dissecting room cadavers and the samples prepared for paraffin and/or methylmethacrylate histology. Entheses from four young volunteers with no history of significant musculoskeletal injury were examined by magnetic resonance imaging using T<sub>1</sub> weighted sequences. <b>Results:</b> Adipose tissue was present at several different sites at numerous entheses. Many tendons/ligaments lay on a bed of well vascularised, highly innervated, "insertional angle fat". Endotenon fat was striking between fascicles, where entheses flared out at their attachments. It was also characteristic of the epitenon, where it occurred in conjunction with lamellated and Pacinian corpuscles. Fat filled, meniscoid folds often protruded into joint cavities, immediately adjacent to attachment sites. <b>Conclusion:</b> Adipose tissue is a common feature of normal entheses and should not be regarded as a sign of degeneration. It contributes to the increase in surface area of attachment sites, promotes movement between tendon/ligament and bone, and forms part of an enthesis organ that dissipates stress. The presence of numerous nerve endings in fat at attachment sites suggests that it has a mechanosensory role and this could account for the rich innervation of many entheses. Because damage to fat is known to lead to considerable joint pain, our findings may be important for understanding the site of pain in enthesopathies.
Assessing Long-Term Effects of Trauma: Diagnosing Symptoms of Avoidance and Numbing
Authors: Richard G. Honig, Mary C. Grace, Jacob D. Lindy, C. Janet Newman, James L. Titchener
Journal: American Journal of Psychiatry (1999)

OBJECTIVE: This study compared the discovery of posttraumatic stress disorder (PTSD) symptoms by means of the Structured Clinical Interview for DSM-III-R (SCID) with a semistructured, psychodynamic clinical interview in a long-term follow-up of the survivors of the Buffalo Creek (W.Va.) flood. METHOD: Videotaped semistructured, psychodynamic clinical interviews of a small group of survivors (N=6) were compared with the results obtained in a prior group-level SCID investigation. RESULTS: Seventy-two percent of the total PTSD symptoms for the subjects studied were elicited exclusively by the psychodynamic clinical interview. PTSD cluster C symptoms of avoidance and numbing of general responsiveness were especially sensitive to discovery by this method. CONCLUSIONS: The psychodynamic clinical interview should be included in the design of studies that seek to investigate long-term effects of trauma, which are especially likely to be manifest in negative symptoms and subtle character change. (Am J Psychiatry 1999; 156:483–485)
Gestational Diabetes Mellitus in Mothers as a Diabetes Predictor in Fathers: A Retrospective Cohort Analysis
Authors: Kaberi Dasgupta, Nancy Ross, Sara Meltzer, Deborah Da Costa, Meranda Nakhla, Youssef Habel, Elham Rahme
Journal: Diabetes Care (2015)

In women, there is a sevenfold risk increase for type 2 diabetes in the years following a pregnancy complicated by gestational diabetes mellitus (GDM) (1,2). We hypothesized that GDM also signals diabetes risk in men. Consistent with this possibility, prior studies demonstrate partners to be concordant for changes in weight (3) and physical activity (4), as well as for diabetes (5). No previous study has assessed a link between GDM in mothers and diabetes incidence in fathers.

This retrospective cohort study combined information from health administrative, birth, and death registry data from the Canadian province of Quebec (universal health insurance). Randomly selected singleton live births (1 April 1990 to 31 December 2007) with two or more diagnostic codes for GDM in mothers (ICD-9 and -10) were matched to births without GDM (year of delivery, mother’s age-group, health region). Incident diabetes in …
Pharmacogenomic Analysis of Cytogenetic Response in Chronic Myeloid Leukemia Patients Treated with Imatinib
Authors: Lee Anne McLean, Insa Gathmann, Renaud Capdeville, Mihael H. Polymeropoulos, Marlene Dressman
Journal: Clinical Cancer Research (2004)

Abstract Purpose: To better understand the molecular basis of cytogenetic response in chronic myeloid leukemia patients treated with imatinib, we studied gene expression profiles from a total of 100 patients from a large, multinational Phase III clinical trial (International Randomized Study of IFN-α versus STI571). Experimental Design: Gene expression data for &amp;gt;12,000 genes were generated from whole blood samples collected at baseline (before imatinib treatment) using Affymetrix oligonucleotide microarrays. Cytogenetic response was determined based on the percentage of Ph+ cells from bone marrow following a median of 13 months of treatment. Results: A genomic profile of response was developed using a subset of individuals that exhibited the greatest divergence in cytogenetic response; those with complete response (0% Ph+ cells; n = 53) and those with minimal or no response (&amp;gt;65% Ph+ cells; n = 13). A total of 55 genes was identified that were differentially expressed between these two groups. Using a “leave-one-out” strategy, we identified the optimum 31 genes from this list to use as our genomic profile of response. Using this genomic profile, we were able to distinguish between individuals that achieved major cytogenetic response (0–35% Ph+ cells) and those that did not, with a sensitivity of 93.4% (71 of 76 patients), specificity of 58.3% (14 of 24 patients), positive predictive value of 87.7%, and negative predictive value of 73.7%. Conclusions: Interestingly, many of the genes identified appear to be strongly related to reported mechanisms of BCR-ABL transformation and warrant additional research as potential drug targets. The validity and clinical implications of these results should be explored in future studies.
Differential Regulation of Proteasome Function in Isoproterenol-Induced Cardiac Hypertrophy
Authors: Oliver Drews, Osamu Tsukamoto, David Liem, John Streicher, Yibin Wang, Peipei Ping
Journal: Circulation Research (2010)

Proteasomal degradation is altered in many disease phenotypes including cardiac hypertrophy, a prevalent condition leading to heart failure. Our recent investigations identified heterogeneous subpopulations of proteasome complexes in the heart and implicated multiple mechanisms for their regulation.The study aimed at identification of molecular mechanisms changing proteasome function in the hypertrophic heart.Proteasome function, expression, and assembly were analyzed during the development of cardiac hypertrophy induced by β-adrenergic stimulation. The analysis revealed, for the first time, divergent regulation of proteasome function in cardiac hypertrophy. Proteasome complexes have 3 different proteolytic activities, which are ATP-dependent for 26S complexes (19S assembled with 20S) and ATP-independent for 20S core particles. The 26S activities were enhanced in hypertrophic hearts, partially because of increased expression and assembly of 19S subunits with 20S core complexes. In contrast, caspase- and trypsin-like 20S activities were significantly decreased. Activation of endogenous cAMP-dependent protein kinase (PKA) rescued the depressed 20S functions, supporting the notion that PKA signaling is a positive regulator of protein degradation in the heart. Chymotrypsin-like 20S activity was stably maintained during cardiac remodeling, indicating a switch in proteasome subpopulations, which was supported by altered expression and incorporation of inducible β subunits.Three novel mechanisms for the regulation of proteasome activities were discovered in the development of cardiac hypertrophy: (1) increased incorporation of inducible subunits in 20S proteasomes; (2) enhanced 20S sensitivity to PKA activation; and (3) increased 26S assembly. PKA modulation of proteasome complexes may provide a novel therapeutic avenue for restoration of cardiac function in the diseased myocardium.
Urinary 8-iso-Prostaglandin F <sub>2α</sub> as a Risk Marker in Patients With Coronary Heart Disease
Authors: Edzard Schwedhelm, Asja Bartling, Henrike Lenzen, Dimitrios Tsikas, Renke Maas, Jens Brümmer, Frank-Mathias Gutzki, Jürgen Berger, Jürgen C. Frölich, Rainer H. Böger
Journal: Circulation (2004)

Oxidative stress is involved in the pathophysiology of atherosclerosis, diabetes mellitus, hypertension, obesity, and cigarette smoking, all of these being risk factors for coronary heart disease (CHD). We tested the hypothesis that risk factors of CHD are associated with abundant systemic oxidative stress.We conducted a case-control study with 93 CHD patients and 93 control subjects frequency-matched by age and sex. Urinary excretion of the F2-isoprostane 8-iso-prostaglandin (PG) F2alpha and its major urinary metabolite, 2,3-dinor-5,6-dihydro-8-iso-PGF2alpha, were measured by gas chromatography-tandem mass spectrometry. Body mass index, systolic blood pressure, and C-reactive protein were elevated in CHD patients (P<0.01). Urinary 8-iso-PGF2alpha and 2,3-dinor-5,6-dihydro-8-iso-PGF2alpha also differed, from 77 (interquartile range, 61-101) to 139 (93-231) pmol/mmol creatinine and from 120 (91-151) to 193 (140-275) pmol/mmol in control subjects and case subjects, respectively (P<0.001). 8-iso-PGF2alpha and its metabolite were highly correlated (Spearman's rho=0.664, P<0.001). HDL cholesterol was diminished in CHD patients (P<0.001). All of these characteristics predicted CHD in univariate analysis. In a multivariate model, the odds ratios were increased only for 8-iso-PGF2alpha (> or =131 pmol/mmol, P<0.001) and C-reactive protein (>3 mg/L, P<0.01), ie, by 30.8 (95% CI, 7.7-124) and 7.2 (1.9-27.6), respectively. 8-iso-PGF2alpha was found to be a novel marker in addition to known risk factors of CHD, ie, diabetes mellitus, hypercholesterolemia, hypertension, and smoking. Urinary excretion of 8-iso-PGF2alpha correlated with the number of risk factors for all subjects (P<0.001 for trend).8-iso-PGF2alpha is a sensitive and independent risk marker of CHD.
Earthquake rattled Christchurch residents reach for cigarettes
Authors: Lutz Beckert, Nick Erskine, Bonwen Rhodes, Sue Stevenson, Vivien Daley
Journal: European Respiratory Journal (2012)

The magnitude 7.1 Canterbury earthquake in September 2010 and associated aftershocks have caused untold damage, drastically changed residents9 living, working, social conditions and taken the lives of 184 people.   Aim : To assess the impact of the Christchurch earthquakes on changes in smoking status and tobacco consumption of current smokers.   Methods : Semi-structured interviews in public locations with high pedestrian flow, including two city malls and the central bus exchange. The interviews were carried out 15 months after the first major earthquake. A total of 1001 people were interviewed.   Results : At the August 2010 point (prior to any earthquakes) 589 (58.9%) had smoked cigarettes or tobacco at some point in their lives; 400 (40.9%) never smoked and three participants (0.3%) were not sure. Of the 319 people who were not smoking in August 2010, 76 (23.8%) had smoked at least one cigarette since the September earthquake, 29 (38.2%) of whom had smoked more than 100 cigarettes. Of the 273 participants smoking in August 2010, 86 (31.5%) had since decreased consumption, 94 (34.4%) had not changed, deletion and 93 (34.1%) had increased consumption. Of the 86 people who decreased, six (7.0%) attributed the earthquake and subsequent lifestyle as a reason to reduce smoking. Of the 93 people who increased, 53 (57.0%) attributed the earthquake and subsequent lifestyle changes as a reason to increase smoking.   Conclusion:  The prevalence of smoking in Christchurch has increased in the 15 months following the first major quake in Sept 2010. 28% of people not smoking prior to the earthquakes smoked one or more cigarettes and people smoking prior to the earthquakes increased their consumption.
A Phase I, Pharmacokinetic and Pharmacodynamic Study on Vorinostat in Combination with 5-Fluorouracil, Leucovorin, and Oxaliplatin in Patients with Refractory Colorectal Cancer
Authors: Marwan G. Fakih, Lakshmi Pendyala, Gerald Fetterly, Karoli Toth, James A. Zwiebel, Igor Espinoza-Delgado, Alan Litwin, Youcef M. Rustum, Mary Ellen Ross, Julianne L. Holleran, Merrill J. Egorin
Journal: Clinical Cancer Research (2009)

We conducted a phase I study to determine the maximum tolerated dose of vorinostat in combination with fixed doses of 5-fluorouracil (FU), leucovorin, and oxaliplatin (FOLFOX).Vorinostat was given orally twice daily for 1 week every 2 weeks. FOLFOX was given on days 4 and 5 of vorinostat. The vorinostat starting dose was 100 mg twice daily. Escalation occurred in cohorts of three to six patients. Pharmacokinetics of vorinostat, FU, and oxaliplatin were studied.Twenty-one patients were enrolled. Thrombocytopenia, neutropenia, gastrointestinal toxicities, and fatigue increased in frequency and severity at higher dose levels of vorinostat. Two of 4 evaluable patients at dose level 4 (vorinostat 400 mg orally twice daily) developed dose-limiting fatigue. One of 10 evaluable patients at dose level 3 (vorinostat 300 mg orally twice daily) had dose-limiting fatigue, anorexia, and dehydration. There were significant relationships between vorinostat dose and the area under the curve on days 1 and 5 (Pearson, < 0.001). The vorinostat area under the curve increased (P = 0.005) and clearance decreased (P = 0.003) on day 5 compared with day 1. The median C(max) of FU at each dose level increased significantly with increasing doses of vorinostat, suggesting a pharmacokinetic interaction between FU and vorinostat. Vorinostat-induced thymidylate synthase (TS) modulation was not consistent; only two of six patients had a decrease in intratumoral TS expression by reverse transcription-PCR.The maximum tolerated dose of vorinostat in combination with FOLFOX is 300 mg orally twice daily x 1 week every 2 weeks. Alternative vorinostat dosing schedules may be needed for optimal down-regulation of TS expression.
Valvular heart disease: A study of mortality in the Sheffield population
Authors: S. Talbot
Journal: Thorax (1973)

<b>Talbot, S. (1973).</b><i>Thorax</i>, <b>28</b>, 622-626. <b>Valvular heart disease: a study of mortality in the Sheffield population</b>. A study of deaths due to valve disease in the community and in hospital showed that aortic valve disease was a more common cause of sudden death than was mitral valve disease. Mitral valve disease was a frequent cause of death in the elderly, but all valve lesions in the elderly were found more often in the community than in the hospital series; these were often (66%) undiagnosed prior to death, particularly in men. Evidence of combined aortic and mitral valve disease was less often overlooked. Systemic embolism was an important factor influencing admission to hospital and was often the presenting feature. The absence of physical findings was probably not responsible for the poor diagnostic rate in the community series. Auscultation of the heart in asymptomatic men and women over the age of 40 years must become widespread before there will be an improvement in mortality and morbidity of these conditions.
Essential Role of Smad3 in Angiotensin II–Induced Vascular Fibrosis
Authors: Wansheng Wang, Xiao R. Huang, Ellery Canlas, Kazuhiro Oka, Luan D. Truong, Chuxia Deng, Neil A. Bhowmick, Wenjun Ju, Erwin P. Bottinger, Hui Y. Lan
Journal: Circulation Research (2006)

Angiotensin II (Ang II) plays a pivotal role in vascular fibrosis, which leads to serious complications in hypertension and diabetes. However, the underlying signaling mechanisms are largely unclear. In hypertensive patients, we found that arteriosclerosis was associated with the activation of Smad2/3. This observation was further investigated in vitro by stimulating mouse primary aorta vascular smooth muscle cells (VSMCs) with Ang II. There were several novel findings. First, Ang II was able to activate an early Smad signaling pathway directly at 15 to 30 minutes. This was extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) dependent but transforming growth factor-β (TGF-β) independent because Ang II–induced Smad signaling was blocked by addition of ERK1/2 inhibitor and by dominant-negative (DN) ERK1/2 but not by DN-TGF-β receptor II (TβRII) or conditional deletion of TβRII. Second, Ang II was also able to activate the late Smad2/3 signaling pathway at 24 hours, which was TGF-β dependent because it was blocked by the anti–TGF-β antibody and DN-TβRII. Finally, activation of Smad3 but not Smad2 was a key and necessary mechanism of Ang II–induced vascular fibrosis because Ang II induced Smad3/4 promoter activities and collagen matrix expression was abolished in VSMCs null for Smad3 but not Smad2. Thus, we concluded that Ang II induces vascular fibrosis via both TGF-β–dependent and ERK1/2 MAPK-dependent Smad signaling pathways. Activation of Smad3 but not Smad2 is a key mechanism by which Ang II mediates arteriosclerosis.