tbuckley/cabot-search huggingface dataset:
Ziprasidone in the Treatment of Acute Bipolar Mania: A Three-Week, Placebo-Controlled, Double-Blind, Randomized Trial
Authors: Paul E. Keck, Marcio Versiani, Steven Potkin, Scott A. West, Earl Giller, Kathleen Ice
Journal: American Journal of Psychiatry (2003)

The study evaluated the efficacy and tolerability of ziprasidone, compared with placebo, in the treatment of adult patients with acute bipolar mania.Patients with a primary DSM-IV diagnosis of bipolar I disorder and a current manic or mixed episode (confirmed by the Structured Clinical Interview for DSM-IV Axis I Disorders, Patient Edition) (N=210) were randomly assigned in a 2:1 ratio to 3 weeks of double-blind treatment with ziprasidone (40-80 mg twice daily) or placebo. Efficacy was assessed with the Schedule for Affective Disorders and Schizophrenia, Change Version (which contains the Mania Rating Scale), Positive and Negative Syndrome Scale, Clinical Global Impression (CGI) severity scale, CGI improvement scale, and Global Assessment of Functioning Scale. Primary efficacy variables were differences from baseline to endpoint (last observation carried forward) in mean Mania Rating Scale and CGI severity scale scores between the ziprasidone and placebo groups. Safety evaluations included monitoring of adverse events, vital signs, electrocardiogram results, and clinical laboratory values and assessment of movement disorders and akathisia.Ziprasidone produced rapid, sustained improvements relative to baseline and placebo on all primary and most secondary efficacy measures at endpoint. Significant improvements were typically observed within 2 days after treatment commenced and were maintained throughout the 3 weeks. Ziprasidone was well tolerated and associated with a low rate of extrapyramidal symptoms; neither weight gain nor clinically significant changes in vital signs or other safety parameters were observed with ziprasidone.Ziprasidone monotherapy was significantly superior to placebo in reducing symptoms of acute mania in patients with bipolar I disorder. Onset of action was rapid, and tolerability of ziprasidone was generally comparable to that of placebo.
A functional single-nucleotide polymorphism of the G-CSF receptor gene predisposes individuals to high-risk myelodysplastic syndrome
Authors: Albert Wölfler, Stefan J. Erkeland, Claudia Bodner, Marijke Valkhof, Wilfried Renner, Christina Leitner, Werner Olipitz, Michael Pfeilstöcker, Christoph Tinchon, Werner Emberger, Werner Linkesch, Ivo P. Touw, Heinz Sill
Journal: Blood (2005)
Mutations in Cytoplasmic Loops of the KCNQ1 Channel and the Risk of Life-Threatening Events
Authors: Alon Barsheshet, Ilan Goldenberg, Jin O-Uchi, Arthur J. Moss, Christian Jons, Wataru Shimizu, Arthur A. Wilde, Scott McNitt, Derick R. Peterson, Wojciech Zareba, Jennifer L. Robinson, Michael J. Ackerman, Michael Cypress, Daniel A. Gray, Nynke Hofman, Jorgen K. Kanters, Elizabeth S. Kaufman, Pyotr G. Platonov, Ming Qi, Jeffrey A. Towbin, G. Michael Vincent, Coeli M. Lopes
Journal: Circulation (2012)

β-Adrenergic stimulation is the main trigger for cardiac events in type 1 long-QT syndrome (LQT1). We evaluated a possible association between ion channel response to β-adrenergic stimulation and clinical response to β-blocker therapy according to mutation location.The study sample comprised 860 patients with genetically confirmed mutations in the KCNQ1 channel. Patients were categorized into carriers of missense mutations located in the cytoplasmic loops (C loops), membrane-spanning domain, C/N terminus, and nonmissense mutations. There were 27 aborted cardiac arrest and 78 sudden cardiac death events from birth through 40 years of age. After multivariable adjustment for clinical factors, the presence of C-loop mutations was associated with the highest risk for aborted cardiac arrest or sudden cardiac death (hazard ratio versus nonmissense mutations=2.75; 95% confidence interval, 1.29-5.86; P=0.009). β-Blocker therapy was associated with a significantly greater reduction in the risk of aborted cardiac arrest or sudden cardiac death among patients with C-loop mutations than among all other patients (hazard ratio=0.12; 95% confidence interval, 0.02-0.73; P=0.02; and hazard ratio=0.82; 95% confidence interval, 0.31-2.13; P=0.68, respectively; P for interaction=0.04). Cellular expression studies showed that membrane spanning and C-loop mutations produced a similar decrease in current, but only C-loop mutations showed a pronounced reduction in channel activation in response to β-adrenergic stimulation.Patients with C-loop missense mutations in the KCNQ1 channel exhibit a high risk for life-threatening events and derive a pronounced benefit from treatment with β-blockers. Reduced channel activation after sympathetic activation can explain the increased clinical risk and response to therapy in patients with C-loop mutations.
The Treatment of Inguinal Hernia in Children
Authors: W. M. Eccles
Journal: BMJ (1899)

rquent progress was slow, but the temperature did not rise again above .0020,reaching 990 three days later; convalescence was delayed by furuncles, but no abscesses formed.CASE IV.-J.P., a previously healthy man of 20, admitted with initial temperature of ioio.A very severe confluent attack, accompanied by much active delirium and some bronchitis.April 21St.Paolse ii8, weak; respirations 28, irregular, tremulous at times, tries to get out of bed.Patient very weak.Temperature IOI.80; -serum.0O e.cm., injected at 6 P.M.April 22nd.Temperature rose to 0030 at 6 A.M., but gradually declined to I.o00; general condition rather better.April 23rd.Very delirious, had to be tied in bed.In very exhausted condition
Absence of Cross-Reactivity between Sulfonamide Antibiotics and Sulfonamide Nonantibiotics
Authors: Brian L. Strom, Rita Schinnar, Andrea J. Apter, David J. Margolis, Ebbing Lautenbach, Sean Hennessy, Warren B. Bilker, Dan Pettitt
Journal: New England Journal of Medicine (2003)

The safety of sulfonamide nonantibiotics is unclear in patients with prior allergic reactions to sulfonamide antibiotics.
Conflicts and catastrophes: Lessons for medicine
Authors: Kamran Abbasi
Journal: Journal of the Royal Society of Medicine (2007)

War—what is it good for? You will be excused for believing that war has broken out in the pages of the JRSM this month. Alan Maynard's—some might say—unprovoked attack on the Medical Royal Colleges in the July issue (JRSM 2007;100:306-8) prompted a swift reply in defence of their purpose and relevance to their memberships (JRSM 2007;100:410-11). Ian Roberts' target in July was the involvement of Formula One and motoring organizations in road safety, an involvement that makes little sense to him (JRSM 2007;100:360-2). How much control would you allow to the pharmaceutical industry in deciding on the safety of drugs? Or the tobacco industry on the safety of cigarettes? In this issue David Ward, from the FIA Foundation, argues that Roberts misses the point, and possibly several more (JRSM 2007;100:412-13). You decide.
Sporadic Jakob-Creutzfeldt Disease Presenting as Primary Progressive Aphasia
Authors: David Y. Johnson, Diana L. Dunkelberger, Maya Henry, Aissatou Haman, Michael D. Greicius, Katherine Wong, Stephen J. DeArmond, Bruce L. Miller, Maria Luisa Gorno-Tempini, Michael D. Geschwind
Journal: JAMA Neurology (2013)

Objective: To report the clinical, neuropsychological, linguistic, imaging, and neuropathological features of a unique case of sporadic Jakob-Creutzfeldt disease in which the patient presented with a logopenic variant of primary progressive aphasia.Design: Case report.Setting:
Balancing Calcium Signals through TRPC5 and TRPC6 in Podocytes
Authors: Anna Greka, Peter Mundel
Journal: Journal of the American Society of Nephrology (2011)

Calcium (Ca(2+)) ions are important mediators of cellular homeostasis owing to their ability to elicit a dynamic, transient, and tightly regulated range of biochemical responses. More than a decade ago, a nonselective, Ca(2+)-permeable, cationic conductance was identified in podocytes downstream of angiotensin II (Ang II) signaling, but its molecular structure remained elusive. Six years ago, transient receptor potential canonical 6 (TRPC6) mutations were found in families with hereditary FSGS, and TRPC5 and TRPC6 channels are now known as the Ca(2+) influx pathways for this previously described, nonselective, cationic current in podocytes. Ang II activation engages this Ca(2+) influx to modulate the actin cytoskeleton in podocytes. These discoveries dovetail with previously described regulation of actin dynamics by the Ca(2+)-activated phosphatase, calcineurin, and the emergence of Rho GTPases as critical regulators of podocyte function in health and disease. Understanding the interconnected signaling regulated by Ca(2+) currents offers potential new therapeutic targets and highlights the notion that synergistic therapies targeting multiple levels of biochemistry may be useful in treating proteinuric kidney disease.
A Role for Lipid Rafts in B Cell Antigen Receptor Signaling and Antigen Targeting
Authors: Paul C. Cheng, Michelle L. Dykstra, Richard N. Mitchell, Susan K. Pierce
Journal: The Journal of Experimental Medicine (1999)

The B cell antigen receptor (BCR) serves both to initiate signal transduction cascades and to target antigen for processing and presentation by MHC class II molecules. How these two BCR functions are coordinated is not known. Recently, sphingolipid- and cholesterol-rich plasma membrane lipid microdomains, termed lipid rafts, have been identified and proposed to function as platforms for both receptor signaling and membrane trafficking. Here we show that upon cross-linking, the BCR rapidly translocates into ganglioside GM1-enriched lipid rafts that contain the Src family kinase Lyn and exclude the phosphatase CD45R. Both Igα and Lyn in the lipid rafts become phosphorylated, and subsequently the BCR and a portion of GM1 are targeted to the class II peptide loading compartment. Entry into lipid rafts, however, is not sufficient for targeting to the antigen processing compartments, as a mutant surface Ig containing a deletion of the cytoplasmic domain is constitutively present in rafts but when cross-linked does not internalize to the antigen processing compartment. Taken together, these results provide evidence for a role for lipid rafts in the initial steps of BCR signaling and antigen targeting.
Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum
Authors: Mai Yamauchi, Teppei Morikawa, Aya Kuchiba, Yu Imamura, Zhi Rong Qian, Reiko Nishihara, Xiaoyun Liao, Levi Waldron, Yujin Hoshida, Curtis Huttenhower, Andrew T Chan, Edward Giovannucci, Charles Fuchs, Shuji Ogino
Journal: Gut (2012)

Colorectal cancer is typically classified into proximal colon, distal colon and rectal cancer. Tumour genetic and epigenetic features differ by tumour location. Considering a possible role of bowel contents (including microbiome) in carcinogenesis, this study hypothesised that tumour molecular features might gradually change along bowel subsites, rather than change abruptly at splenic flexure.Utilising 1443 colorectal cancers in two US nationwide prospective cohort studies, the frequencies of molecular features (CpG island methylator phenotype (CIMP), microsatellite instability (MSI), LINE-1 methylation and BRAF, KRAS and PIK3CA mutations) were examined along bowel subsites (rectum, rectosigmoid junction, sigmoid, descending colon, splenic flexure, transverse colon, hepatic flexure, ascending colon and caecum). The linearity and non-linearity of molecular relations along subsites were statistically tested by multivariate logistic or linear regression analysis.The frequencies of CIMP-high, MSI-high and BRAF mutations gradually increased from the rectum (<2.3%) to ascending colon (36-40%), followed by falls in the caecum (12-22%). By linearity tests, these molecular relations were significantly linear from rectum to ascending colon (p<0.0001), and there was little evidence of non-linearity (p>0.09). Caecal cancers exhibited the highest frequency of KRAS mutations (52% vs 27-35% in other sites; p<0.0001).The frequencies of CIMP-high, MSI-high and BRAF mutations in cancer increased gradually along colorectum subsites from the rectum to ascending colon. These novel data challenge the common conception of discrete molecular features of proximal versus distal colorectal cancers, and have a substantial impact on clinical, translational and epidemiology research, which has typically been performed with the dichotomous classification of proximal versus distal tumours.
Racial Disparity in Glucagon-Like Peptide 1 and Inflammation Markers Among Severely Obese Adolescents
Authors: Pedro A. Velásquez-Mieyer, Patricia A. Cowan, Sylvia Pérez-Faustinelli, Ramfis Nieto-Martínez, Cesar Villegas-Barreto, Elizabeth A. Tolley, Robert H. Lustig, Bruce S. Alpert
Journal: Diabetes Care (2008)

OBJECTIVE—Compared with Caucasians, obese African-American adolescents have a higher risk for type 2 diabetes. Subclinical inflammation and reduced glucagon-like peptide 1 (GLP-1) concentration are linked to the pathogenesis of the disease. We determined the relationship between insulin resistance, β-cell activity, and subclinical inflammation with GLP-1 concentrations and whether racial disparities in GLP-1 response were present in 49 obese adolescents (14 ± 3 years; 76% African American; 71% female). RESEARCH DESIGN AND METHODS—Subjects underwent physical examination and an oral glucose tolerance test. We measured levels of high-sensitivity CRP (CRPhs), fibrinogen, glucose, GLP-1total, GLP-1active, and insulin. Insulin and glucose area under the curve (AUC), insulinogenic index (ΔI30/ΔG30), and composite insulin sensitivity index (CISI) were computed. Subjects were categorized by race and as inflammation positive (INF+) if CRPhs or fibrinogen were elevated. RESULTS—No racial differences were seen in mean or relative BMI. Thirty-five percent of subjects had altered fasting or 2-h glucose levels (African American vs. Caucasian, NS), and 75% were INF+ (African American vs. Caucasian, P = 0.046). Glucose and insulin, CISI, and ΔI30/ΔG30 values were similar; African Americans had lower GLP-1total AUC (P = 0.01), GLP-1active at 15 min (P = 0.03), and GLP-1active AUC (P = 0.06) and higher fibrinogen (P = 0.01) and CRPhs (NS) compared with Caucasians. CONCLUSIONS—African Americans exhibited lower GLP-1 concentrations and increased inflammatory response. Both mechanisms may act synergistically to enhance the predisposition of obese African Americans to type 2 diabetes. Our findings might be relevant to effective deployment of emerging GLP-1–based treatments across ethnicities.
Testing Hypotheses about the Sister Group of the Passeriformes Using an Independent 30-Locus Data Set
Authors: N. Wang, E. L. Braun, R. T. Kimball
Journal: Molecular Biology and Evolution (2011)

Although many phylogenetic studies have focused on developing hypotheses about relationships, advances in data collection and computation have increased the feasibility of collecting large independent data sets to rigorously test controversial hypotheses or carefully assess artifacts that may be misleading. One such relationship in need of independent evaluation is the position of Passeriformes (perching birds) in avian phylogeny. This order comprises more than half of all extant birds, and it includes one of the most important avian model systems (the zebra finch). Recent large-scale studies using morphology, mitochondrial, and nuclear sequence data have generated very different hypotheses about the sister group of Passeriformes, and all conflict with an older hypothesis generated using DNA–DNA hybridization. We used novel data from 30 nuclear loci, primarily introns, for 28 taxa to evaluate five major a priori hypotheses regarding the phylogenetic position of Passeriformes. Although previous studies have suggested that nuclear introns are ideal for the resolution of ancient avian relationships, introns have also been criticized because of the potential for alignment ambiguities and the loss of signal due to saturation. To examine these issues, we generated multiple alignments using several alignment programs, varying alignment parameters, and using guide trees that reflected the different a priori hypotheses. Although different alignments and analyses yielded slightly different results, our analyses excluded all but one of the five a priori hypotheses. In many cases, the passerines were sister to the Psittaciformes (parrots), and taxa were members of a larger clade that includes Falconidae (falcons) and Cariamidae (seriemas). However, the position of Coliiformes (mousebirds) was highly unstable in our analyses of 30 loci, and this represented the primary source of incongruence among analyses. Mousebirds were united with passerines or parrots in some analyses, suggesting an additional hypothesis that needs to be considered in future studies. There was no clear evidence that base-compositional convergence, saturation, or long-branch attraction affected our conclusions. These results provide independent evidence excluding four major hypotheses about the position of passerines, allowing the extensive studies on this group to be placed in a more rigorous evolutionary framework.
Toxicity profiles of traditional disease modifying antirheumatic drugs for rheumatoid arthritis
Authors: D Aletaha
Journal: Annals of the Rheumatic Diseases (2003)

The progression of rheumatoid arthritis (RA) can be retarded or halted by disease modifying antirheumatic drugs (DMARDs). Next to inefficacy, toxicity limits their use.To explore the toxicity profiles of DMARDs in daily life.Five hundred and ninety three patients with RA charts (>2300 patient years of treatment) were reviewed at two rheumatology outpatient clinics. All recorded data on toxicity and reasons for stopping treatment were collected.Adverse events were common reasons for treatment discontinuation (42% of treatments). In 70% they were subjectively reported at the clinical visit, while substantial laboratory abnormalities were seen relatively rarely (9% of treatments: abnormal liver function tests in 5%; haematological abnormalities in 3%; impaired renal function in 1%). No single case of retinopathy from antimalarial drugs (that is, an incidence of <0.3 events/1000 patient years) was found, although eye examinations by the specialists were abnormal 30 times per 1000 patient years, mostly revealing keratopathy. Most commonly reported symptoms per 1000 patient years were nausea (54 events), abdominal pain (37 events), and rashes (34 events). Adverse events were more likely to occur with increasing number of consecutive DMARD courses.The first DMARD course in a patient seems to be safer than the consecutive ones. In addition, the incidence of adverse events (AEs) seems to be similar for high and low dose treatment. Data are also provided on types and incidence of AEs that are consistent with previous studies in other countries and different settings.
Genistein, a Dietary Isoflavone, Down-Regulates the MDM2 Oncogene at Both Transcriptional and Posttranslational Levels
Authors: Mao Li, Zhuo Zhang, Donald L. Hill, Xinbin Chen, Hui Wang, Ruiwen Zhang
Journal: Cancer Research (2005)

Abstract Although genistein has chemopreventive effects in several human malignancies, including cancers of the breast, colon, and prostate, the mechanisms of action are not fully understood. Herein we report novel mechanisms whereby genistein down-regulates the MDM2 oncogene, perhaps explaining some of its anticancer activities. In a dose- and time-dependent manner, genistein reduced MDM2 protein and mRNA levels in human cell lines of breast, colon, and prostate cancer; primary fibroblasts; and breast epithelial cells. The inhibitory effects were found at both transcriptional and posttranslational levels and were independent of tyrosine kinase pathways. We found that the NFAT transcription site in the region between −132 and +33 in the MDM2 P2 promoter was responsive to genistein. At the posttranslational level, genistein induced ubiquitination of MDM2, which led to its degradation. Additionally, genistein induced apoptosis and G2 arrest and inhibited proliferation in a variety of human cancer cell lines, regardless of p53 status. We further showed that MDM2 overexpression abrogated genistein-induced apoptosis in vitro and that genistein inhibited MDM2 expression and tumor growth in PC3 xenografts. In conclusion, genistein directly down-regulates the MDM2 oncogene, representing a novel mechanism of its action that may have implications for its chemopreventive and chemotherapeutic effects.
Where Does Hematology End and Oncology Begin? Questions of Professional Boundaries and Medical Authority
Authors: Gretchen Krueger, George Canellos
Journal: Journal of Clinical Oncology (2006)

This article recounts the development of the American Society of Clinical Oncology (ASCO) and explores the role of its members in defining oncology's boundaries-boundaries dictated by scientific innovations, major changes in the structure of medical specialization, and the competing efforts of closely related professional groups. Oral histories, journal articles, and unpublished materials from the ASCO History of Oncology Archive were reviewed to analyze these events closely. In 1972, the American Board of Internal Medicine recognized medical oncology as a subspecialty, creating tensions between oncology and hematology as each discipline defended its identity. Drawing on sources produced by hematologists, historian Keith Wailoo (Wailoo, Drawing Blood, 1997) has shown that when medical oncologists claimed wide-ranging expertise over the treatment of all patients suffering from malignant disease in their pursuit of specialty status, the leukemias became contested ground. This article extends this thesis by reviewing the central role of ASCO in these events and recreating the dialogue between members of the two fields as they sought recognition at individual institutions and, more broadly, within American medicine. By acknowledging the contestation of its authority and the results of these prolonged negotiations, we can better understand the current status of oncology and its future outlook.
Outcomes from sudden cardiac arrest in US high schools: a 2-year prospective study from the National Registry for AED Use in Sports
Authors: Jonathan A Drezner, Brett G Toresdahl, Ashwin L Rao, Ella Huszti, Kimberly G Harmon
Journal: British Journal of Sports Medicine (2013)

Sudden cardiac arrest (SCA) is the leading cause of death in athletes during exercise. The effectiveness of school-based automated external defibrillator (AED) programmes has not been established through a prospective study.A total of 2149 high schools participated in a prospective observational study beginning 1 August 2009, through 31 July 2011. Schools were contacted quarterly and reported all cases of SCA. Of these 95% of schools confirmed their participation for the entire 2-year study period. Cases of SCA were reviewed to confirm the details of the resuscitation. The primary outcome was survival to hospital discharge.School-based AED programmes were present in 87% of participating schools and in all but one of the schools reporting a case of SCA. Fifty nine cases of SCA were confirmed during the study period including 26 (44%) cases in students and 33 (56%) in adults; 39 (66%) cases occurred at an athletic facility during training or competition; 55 (93%) cases were witnessed and 54 (92%) received prompt cardiopulmonary resuscitation. A defibrillator was applied in 50 (85%) cases and a shock delivered onsite in 39 (66%). Overall, 42 of 59 (71%) SCA victims survived to hospital discharge, including 22 of 26 (85%) students and 20 of 33 (61%) adults. Of 18 student-athletes 16 (89%) and 8 of 9 (89%) adults who arrested during physical activity survived to hospital discharge.High school AED programmes demonstrate a high survival rate for students and adults who suffer SCA on school campus. School-based AED programmes are strongly encouraged.