tbuckley/cabot-search huggingface dataset:
Discovering Genes Essential to the Hypothalamic Regulation of Human Reproduction Using a Human Disease Model: Adjusting to Life in the “-Omics” Era
Authors: M. I. Stamou, K. H. Cox, William F. Crowley
Journal: Endocrine Reviews (2015)

The neuroendocrine regulation of reproduction is an intricate process requiring the exquisite coordination of an assortment of cellular networks, all converging on the GnRH neurons. These neurons have a complex life history, migrating mainly from the olfactory placode into the hypothalamus, where GnRH is secreted and acts as the master regulator of the hypothalamic-pituitary-gonadal axis. Much of what we know about the biology of the GnRH neurons has been aided by discoveries made using the human disease model of isolated GnRH deficiency (IGD), a family of rare Mendelian disorders that share a common failure of secretion and/or action of GnRH causing hypogonadotropic hypogonadism. Over the last 30 years, research groups around the world have been investigating the genetic basis of IGD using different strategies based on complex cases that harbor structural abnormalities or single pleiotropic genes, endogamous pedigrees, candidate gene approaches as well as pathway gene analyses. Although such traditional approaches, based on well-validated tools, have been critical to establish the field, new strategies, such as next-generation sequencing, are now providing speed and robustness, but also revealing a surprising number of variants in known IGD genes in both patients and healthy controls. Thus, before the field moves forward with new genetic tools and continues discovery efforts, we must reassess what we know about IGD genetics and prepare to hold our work to a different standard. The purpose of this review is to: 1) look back at the strategies used to discover the "known" genes implicated in the rare forms of IGD; 2) examine the strengths and weaknesses of the methodologies used to validate genetic variation; 3) substantiate the role of known genes in the pathophysiology of the disease; and 4) project forward as we embark upon a widening use of these new and powerful technologies for gene discovery.
Risk-Adjusted Short- and Long-Term Outcomes for On-Pump Versus Off-Pump Coronary Artery Bypass Surgery
Authors: Matthew L. Williams, Lawrence H. Muhlbaier, Jacob N. Schroder, Jonathan A. Hata, Eric D. Peterson, Peter K. Smith, Kevin P. Landolfo, Robert H. Messier, R. Duane Davis, Carmelo A. Milano
Journal: Circulation (2005)

Background— Surgeons have adopted off-pump coronary artery bypass grafting (OPCAB) in an effort to reduce the morbidity of surgical revascularization. However, long-term outcome of OPCAB compared with conventional coronary artery bypass grafting (CABG) remains poorly defined. Methods and Results— Using logistic regression analysis and proportional hazards modeling, short-term and long-term outcomes (perioperative mortality and complications, risk-adjusted survival, and survival/freedom from revascularization) were investigated for patients who underwent OPCAB (641 patients) and CABG-cardiopulmonary bypass (5026 patients) from 1998 to 2003 at our institution. For these variables, follow-up was 98% complete. OPCAB patients were less likely to receive transfusion (odds ratio for OPCAB, 0.80; P =0.037), and there were trends toward improvement in other short-term outcomes compared with CABG-cardiopulmonary bypass. Long-term outcomes analysis demonstrated no difference in survival, but OPCAB patients were more likely to require repeat revascularization (OPCAB hazard ratio, 1.29; P =0.020). Conclusions— OPCAB patients were less likely to receive transfusion during their hospitalization for surgery but had higher risk for revascularization in follow-up. These results highlight the need for a large randomized, controlled trial to compare these 2 techniques.
Tubal sterilization and its reversal.
Authors: Vartan K
Journal: BMJ (1973)

study of five chronic schizophrenics we found that DL-a-methyltyrosine 2 g daily reinforced the antipsychotic action of pheno- thiazines, so that the dosage needed to con- trol the schizophrenic symptoms was much reduced.4We have now seen a case in which the extrapyramidal action of haloperidol was greatly potentiated by a-methyltyrosine.A 38-year-old woman, who had suffered for many years from severe phobia and anxiety, had been treated with chlorpromazine (up to 800 mg daily), haloperidol (up to 3 mg daily), and antidepressants of the monoamine oxidase inhibitor or tricyclic type without any extrapyramidal side effects.To try to control her symptoms she was given a-methyltyrosine (125 mg daily gradually increasing to 1 g daily) combined with haloperidol 1.5 mg daily.There was no therapeutic response or side effects.The dose of haloperidol was then gradually increased to 2.5 mg daily.About 24 hours after this dose level was reached a severe extrapyramidal syn- drome developed, with general muscular rigidity, cogwheel phenomenon, coarse tremors, oral dyskinesia, and restlessness.Intravenous biperi- den chloride quickly controlled the symptoms.
Abstract 2895: Targeted Ultrasound Imaging of Apoptosis with Annexin-A5 Microbubbles in Acute Doxorubicin-induced Cardiotoxicity
Authors: Pil-Ki Min, Soyeon Lim, Soo-Jung Kang, Sung-Yu Hong, Ki-Chul Hwang, Kwang-Hoe Chung, Namsik Chung
Journal: Circulation (2007)

Background Recently, apoptosis has been suggested as a common mechanism of myocardial loss in doxorubicin-induced cardiomyopathy. The aim of this study was to assess the feasibility of targeted ultrasound imaging of apoptosis with annexin-A5 microbubbles (A5MB) in acute doxorubicin-induced cardiotoxicity. Method Avidinated and octafluoropropan-filled phospholipid microbubbles were conjugated with biotinylated annexin-A5. To confirm the specific binding ability of A5MB, flow cytometry was performed with hydrogen peroxide induced apoptosis of rat aorta smooth muscle cells incubated with FITC-labeled annexin-A5 and A5MB. Adult male rats were injected with 5mg/kg doxorubicin IP weekly for 3 weeks (n=5). Control rats were injected with normal saline (n=2). At 24h after the final treatment, triggering imaging was done at a MI of 0.8 using 15MHz linear probe 15 minutes after IV bolus injection of A5MB for wash-out of freely circulating microbubbles. After the contrast echocardiography, the heart was isolated for histological detection of apoptosis (TUNEL assay). Result In in vitro test, fluorescence intensity was low for the healthy cells and high for the apoptotic cells when incubated with FITC-labeled annexin A5 and A5MB. Rats treated with doxorubicin showed significant contrast opacification of myocardium in contrast echocardiography using A5MB (Fig A, B ). However, no opacification was observed in control rats (Fig C, D ). Late apoptosis was confirmed by TUNEL assay in doxorubicin treated rats. Conclusion Acute doxorubicin induced cardiomyopathy based on early apoptosis can be assessed and imaged with targeted ultrasound imaging using A5MB in rats.
AIDS/HIV risk behavior among the chronic mentally ill
Authors: J A Kelly, D A Murphy, G R Bahr, T L Brasfield, D R Davis, A C Hauth, M G Morgan, L Y Stevenson, M K Eilers
Journal: American Journal of Psychiatry (1992)

There is growing concern that chronic mentally ill adults living in the community have a high risk for HIV infection. The purpose of this study was to identify risk knowledge, high-risk behaviors, and risk-related encounters of chronic psychiatric outpatients.Detailed information on high-risk behaviors and risk-related situations during the past 12 months was collected from 60 outpatients appearing for regular visits at inner-city community mental health clinics.Of the 60 outpatients, 37 (62%) had been sexually active during the past year, and 42% of the men and 19% of the women reported multiple sexual contacts and infrequent use of condoms during intercourse. Assessments of the patients' knowledge of AIDS risks revealed substantial deficits in their practical understanding of AIDS and risk reduction measures. Although use of intravenous drugs was uncommon in this group, many subjects reported histories of 1) trading sex for money, drugs, or a place to stay, 2) coercion to engage in unwanted sex, 3) causal sexual encounters, and 4) sexual activity after use of drugs or intoxicants. Twenty percent of the subjects had met their sexual partners on the streets, in parks, or in other public places. One-third had been treated for sexually transmitted diseases other than AIDS.These findings underscore the need for AIDS risk assessment, counseling, and prevention programs for the chronic mentally ill.
Abstract LB-198: Molecular drivers of metabolic reprogramming during EMT
Authors: Zi Qiang Teo, Ming Keat Sng, Jeremy CHAN, Nguan Soon Tan
Journal: Cancer Research (2015)

Abstract The reprogrammed cancer metabolism is an emerging cancer hallmark pervasive in many cancers and is fundamental to neoplastic progression. Many key cancer-promoting pathways are known to converge on the regulation of cellular metabolism. Besides providing basic sustenance to fuel cancer cells limitless replicative potential, emerging data reveals critical roles for the reprogammed metabolism during maglignant progression. Metastasis is often regarded as the end-stage of malignancy and majority of cancer mortality is attributed to the metastatic dissemination of the malignant cancer cells. The initiation of metastasis has been pinpointed as pivotal event, without which, the malignant cancer cells loses their motility and invasive capabilities for distal dissemination. This initiation event highly resembles epithelial-mesenchymal transition (EMT) process that occurs during embryogenesis and wound healing. Microenvironmental signals such as hypoxia and the inflammatory milleu that initiate EMT, interestingly, are also shown to be critical in rewiring cancer metabolism. Thus, it is conceivable that the manipulation of cancer metabolism can impact EMT. Furthermore, whether such metabolic reprogramming is a functional pre-requisite for the initiation of EMT remains unclear. Using three distinct in vitro EMT models, we show that EMT is an energy-demanding process. Comparative microarray analysis of the EMT models reveals that genes involved in fatty acid, glucose and ROS metabolism are altered. We went further to show that cancer cells undergoing EMT, derives much of the ATP/energy from glucose and lipid metabolism. Importantly, we identified several key molecular drivers that coordinate EMT and cellular bioenergetics, which is validated by our in vivo EMT model. Citation Format: Zi Qiang Teo, Ming Keat Sng, Jeremy CHAN, Nguan Soon Tan. Molecular drivers of metabolic reprogramming during EMT. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-198. doi:10.1158/1538-7445.AM2015-LB-198
Observations of interactions of depressed women with their children
Authors: D Gordon, D Burge, C Hammen, C Adrian, C Jaenicke, D Hiroto
Journal: American Journal of Psychiatry (1989)

Dysfunctional interactions between mothers with major affective disorders and their children may contribute to the children's high risk of disorder. This study investigated the behavior of mothers with recurrent unipolar depression, bipolar disorder, or chronic medical illness and of normal subjects toward their children during a directly observed conflict discussion task. In addition, lifetime history of depression, current mood, and chronic stress were investigated as predictors of maternal interaction. Unipolar depressed women displayed relatively more negative, less positive, and less task-focused behaviour toward their children. Current mood and chronic stress, more than psychiatric history, contributed to the prediction of interaction style.
Anticholinergic Use With Incident Dementia—Reply
Authors: Shelly L. Gray, Melissa Anderson, Rebecca Hubbard
Journal: JAMA Internal Medicine (2015)

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Back Pain during Pregnancy and after Childbirth: An Unusual Cause not to Miss
Authors: Keyoumars Ashkan, Adrian T H Casey, Michael Powell, H Alan Crockard
Journal: Journal of the Royal Society of Medicine (1998)

Figure 1 T2 weighted axial magnetic resonance image of the pelvis showing a gadolinium enhancing lesion within the piriformis muscle. The lesion can be seen in the piriformis as it passes through the sciatic notch (open black arrow). The muscle is distended by the abscess (solid black arrow), displacing the sacral plexus (open white arrow) and superior gluteal vessels (solid white arrow) anteriorly
Cost-Effectiveness of Revascularization Strategies
Authors: Zugui Zhang, Paul Kolm, Maria V. Grau-Sepulveda, Angelo Ponirakis, Sean M. O’Brien, Lloyd W. Klein, Richard E. Shaw, Charles McKay, David M. Shahian, Frederick L. Grover, John E. Mayer, Kirk N. Garratt, Mark Hlatky, Fred H. Edwards, William S. Weintraub
Journal: Journal of the American College of Cardiology (2015)
Abstract 19603: Incidence and Predictors of Peri-procedure Complications with Transvenous Lead Extractions in the Real World: Data from NCDR ICD Registry
Authors: Nitesh Sood, David Martin, Jude Clancy, Jeptha Curtis, Craig S Parzynski, Rachel Lampert
Journal: Circulation (2014)

Introduction:  Transvenous lead extraction (TLE) is integral to device management. The incidence and predictors of peri-procedural complications in a large cohort undergoing TLE in the “real world” is not yet reported.   Methods:  Data from NCDR ICD Registry Version 2.0 (both implant and lead-only procedures, 4/10-6/12) was analyzed. “Lead Extraction” was defined as removal of leads implanted for > 1 year. Clinical characteristics were available for 8228 patients. High-voltage (HV) leads were analyzed separately for lead related factors predicting major complications. Major complications were defined as any of: cardiac arrest, cardiac perforation, coronary venous dissection, conduction block, hemothorax, pericardial tamponade, pneumothorax, urgent cardiac surgery and death. Multivariable logistic regression analyses were performed to evaluate for predictors of peri-procedural complications.   Results:  Among 11,304 patients, 8362 (74%) had HV +/-pacing lead/s, and 2942 (26%) pacing-lead/s only, extracted at 762 centers. There were 258 (2.3%) major peri-procedural complications reported: 200 in patients undergoing HV TLE (2.39%), and 58 in patients with pacing (2%) lead TLE. Urgent cardiac surgery was required in 41 patients (16%). Of the 41 patients undergoing cardiac surgery, 14 (34%) died either intra- or post-operatively. There were 98 (0.9%) in-hospital deaths reported with 18 (0.16%) of these occurring during TLE. Female sex, infection leading to extraction, ≥3 leads extracted, lead dislodgement during procedure, history of heart failure, and older lead age were significant multivariate predictors of major peri-procedural complications. Smaller lead diameter, flat vs. round coil shape and greater proximal surface coil area were multivariate predictors of major peri-procedural complications specific to HV leads.   Conclusion:  Many US centers are now performing TLE. The rate of major complications and mortality is higher in this “real world” population than that reported in studies/series from high volume specialized extraction centers. Urgent cardiac surgery is frequently required in patients with major complications during TLE and it is imperative for centers to plan for immediately available cardiothoracic surgical support.
Abstract 2434: The anticancer activity of Japonicone A is mediated by inhibiting NFAT1-MDM2 pathway
Authors: Sukesh Voruganti, Jiang-Jiang Qin, Wei Wang, Ruiwen Zhang
Journal: Cancer Research (2015)

Abstract NFAT1 plays a crucial role in cancer development and progression and has been suggested as a novel target for cancer therapy. We recently report NFAT1 promotes the expression of the MDM2 oncogene, independent of p53. The present study was designed to elucidate the mechanisms of action for a newly identified NFAT1 inhibitor, Japonicone A (JapA), and demonstrate the value of targeting NFAT1-MDM2 signaling in cancer therapy. JapA was identified as a novel NFAT1 inhibitor from our initial screening of a natural product library. Its effects on NFAT1 expression and stability were analyzed in several human breast cancer cell lines with different genetic background, including MCF-7 (estrogen receptor (ER) positive and p53 wild-type), MCF-7 p53−/− (ER positive and p53 knockout), MDA-MB-231 (triple negative and p53 mutant), and MDA-MB-468 (triple negative and p53 mutant) cell lines. The effects of JapA on NFAT1 expression were also determined in MCF-7 and MDA-MB-231 xenograft tumors in vivo. To further demonstrate the specificity of JapA in targeting NFAT1-MDM2 pathway and the importance of NFAT1-MDM2 inhibition in JapA's anticancer activity, MCF7 NFAT1 overexpression (OE) and knockdown (KD) cell lines, as well as pharmacological activators and inhibitors of NFAT1 signaling were used in this study. Our results indicated that JapA showed a significant, specific inhibition of NFAT1 in breast cancer cells in vitro and in vivo. It induced NFAT1 protein ubiquitination and proteasomal degradation, and inhibited NFAT1 nuclear translocation. JapA also disrupted the binding of NFAT1 to the MDM2 P2 promoter, leading to the inhibition of MDM2 transcription. Furthermore, the inhibition of NFAT1 and the NFAT1-MDM2 signaling are critical for JapA's anticancer activity, as shown in NFAT1 OE and KD cell lines. In conclusion, JapA represents a new class of NFAT1 inhibitor. It exerts its anticancer activity through inhibiting NFAT1 and the NFAT1-MDM2 pathway, providing evidence for the value of NFAT1 as a novel target in developing effective targeted therapy for cancers. (Supported by NIH R01 CA112029, R01 CA121211, and R01 CA186662) Citation Format: Sukesh Voruganti, Jiang-Jiang Qin, Wei Wang, Ruiwen Zhang. The anticancer activity of Japonicone A is mediated by inhibiting NFAT1-MDM2 pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2434. doi:10.1158/1538-7445.AM2015-2434
VEGFR2 Gene Polymorphisms and Response to Anti–Vascular Endothelial Growth Factor Therapy in Age-Related Macular Degeneration
Authors: Stephanie A. Hagstrom, Gui-shuang Ying, Maureen G. Maguire, Daniel F. Martin, Jane Gibson, Andrew Lotery, Usha Chakravarthy
Journal: Ophthalmology (2015)
Phase I trial of a humanized anti-CD40 monoclonal antibody (SGN-40) in the treatment of multiple myeloma
Authors: M. A. Hussein, J. R. Berenson, R. Niesvizky, N. C. Munshi, K. C. Anderson, K. L. Ryan, K. T. Baumgartner, D. M. Miller, J. G. Drachman, M. McDonald
Journal: Journal of Clinical Oncology (2005)

6581 Background: CD40 is a member of the Tumor Necrosis Factor (TNF) family of receptors and is expressed on the surface of B lymphocytes as well as B cell-derived tumors, including multiple myeloma, non-Hodgkin’s lymphoma, and chronic lymphocytic leukemia. Because of the potential for immunotherapy, a humanized anti-CD40 monoclonal antibody was developed (SGN-40). Preclinical data demonstrated that this antibody inhibits malignant cell growth by both antibody-induced cell death (AICD) and antibody-dependent cell-mediated cytotoxicity (ADCC). Safety data in cynomolgous monkeys treated with repeated doses up to 100 mg/kg/week were acceptable. Methods: Based on these encouraging results, a phase I trial was initiated at multiple clinical sites, using dose-escalation of SGN-40 (0.5–16 mg/kg/week x 4 weeks) to treat patients with refractory and recurrent multiple myeloma. At this time, thirteen individuals have completed treatment at 0.5, 1.0, and 2.0 mg/kg. Results: On average, patients had received 5 previous therapies for myeloma (range 3–9). Grade three toxicities included: anemia (3), thrombocytopenia (1), neutropenia (1), and hypercalcemia (2). In each case, these were secondary to advanced disease. Lymphocyte subset analysis showed that CD19+ B cells were selectively decreased during treatment with SGN-40. Despite treatment at the low end of predicted effective dosing, three patients demonstrated stable M-protein in the blood and urine through day 43. Conclusions: This study represents the first clinical trial of an anti-CD40 antibody in humans and demonstrates that the therapy is well-tolerated and safe. Preliminary evidence for antitumor activity in this heavily pretreated myeloma population is encouraging. Accrual of patients at higher dose levels is ongoing as the maximum tolerated dose has not yet been reached. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Seattle Genetics Seattle Genetics Seattle Genetics Seattle Genetics
Effectiveness of airstack technique training in a longitudinal cohort study in ALS population without any other respiratory support
Authors: Erik de Smit, Marianne Zijnen-Suyker, Ries van den Biggelaar
Journal: European Respiratory Journal (2014)

Background:  Amyotrophic Lateral Sclerosis (ALS) is a severely debilitating neuromuscular disorder in which frequently respiratory functions are affected. Weakening of the respiratory muscles leads to decreased cough strength, and consequently risk of developing respiratory infections. Air stack technique is a lung volume recruitment method to support cough effectively in order to sputum expectoration.  Hypothesis:  Does air stack technique improves or maintains the coughing strength in ALS population, without any other respiratory support, and as a result less respiratory complications.  Method:  The study was conducted from January 2013 to May 2013 at the Erasmus MC in Rotterdam and 41 ALS patients without respiratory support were included. The study was designed as a longitudinal cohort study with a maturity of three months. At baseline patient were teached the air stack technique and outcome parameters as Peak Cough Flow measurement (PCF l/m) and inventory of pulmonary complications three months prior to baseline were performed.  Results:  24 patients were evaluated, 17 were dropped out for various reasons. The mean PCF was 277,5 +/-50-800 l/m . After three months of airstack technique training the PCF (l/m) value increased by an average of 4.17 (l/m), and no change in pulmonary complication was measured.  Conclusion:  Air stack technique training preserves PCF and stabilizes the number of pulmonary complications in ALS patient without any other respiratory support.