tbuckley/cabot-search huggingface dataset:
Pharmacogenetics of Antidepressant Medication Intolerance
Authors: Greer M. Murphy, Charlotte Kremer, Heidi E. Rodrigues, Alan F. Schatzberg
Journal: American Journal of Psychiatry (2003)

The authors sought to identify genetic markers for antidepressant medication intolerance. Genetic variation in drug metabolizing enzymes such as cytochrome P450 2D6 (CYP2D6) has been postulated to underlie antidepressant intolerance (pharmacokinetic effect). However, variation in genes encoding serotonin receptors could also explain antidepressant side effects (pharmacodynamic effect).An 8-week, double-blind, randomized pharmacogenetic study compared the widely prescribed antidepressants paroxetine (a selective serotonin reuptake inhibitor [SSRI]) and mirtazapine (not an SSRI) in 246 elderly patients with major depression. Genotypes were determined for the 102 T/C single nucleotide polymorphism (SNP) in the serotonin 2A (5-HT(2A)) locus (HTR2A), previously associated with psychotropic medication treatment outcome. Oligonucleotide microarrays were used to extensively characterize variation in the CYP2D6 gene. Clinical outcomes included treatment discontinuations, adverse events, medication compliance, and change in mood.Survival analysis showed discontinuations due to paroxetine-induced side effects were strongly associated with the HTR2A C/C genotype. There was a significant linear relationship between the number of C alleles and the probability of discontinuation. Side effect severity in paroxetine-treated patients with the C/C genotype was also greater. In contrast, HTR2A 102 T/C genotype had no effect on mirtazapine side effects. CYP2D6 genotype did not predict treatment outcome for either medication.Pharmacodynamic differences among patients due to variant 5-HT(2A) receptors appear to be more important than pharmacokinetic variation in determining paroxetine intolerance. Pharmacogenetic markers may be useful in predicting antidepressant treatment outcome.
Loss of Properdin Exacerbates C3 Glomerulopathy Resulting from Factor H Deficiency
Authors: Marieta M. Ruseva, Katherine A. Vernon, Allison M. Lesher, Wilhelm J. Schwaeble, Youssif M. Ali, Marina Botto, Terence Cook, Wenchao Song, Cordula M. Stover, Matthew Caleb Pickering
Journal: Journal of the American Society of Nephrology (2012)

Complement factor H (CFH) is a negative regulator of the alternative pathway of complement, and properdin is the sole positive regulator. CFH-deficient mice (CFH(-/-)) develop uncontrolled C3 activation and spontaneous renal disease characterized by accumulation of C3 along the glomerular basement membrane, but the role of properdin in the pathophysiology is unknown. Here, we studied mice deficient in both CFH and properdin (CFH(-/-).P(-/-)). Although CFH(-/-) mice had plasma depleted of both C3 and C5, CFH(-/-).P(-/-) animals exhibited depletion of C3 predominantly, recapitulating the plasma complement profile observed in humans with properdin-independent C3 nephritic factors. Glomerular inflammation, thickening of the capillary wall, and glomerular C3 staining were significantly increased in CFH(-/-).P(-/-) compared with CFH(-/-) mice. We previously reported that exogenous CFH ameliorates C3 staining of the glomerular basement membrane and triggers the appearance of mesangial C3 deposits in CFH(-/-) mice; here, we show that these effects require properdin. In summary, during uncontrolled activation of C3 driven by complete CFH deficiency, properdin influences the intraglomerular localization of C3, suggesting that therapeutic inhibition of properdin would be detrimental in this setting.
Effectiveness of soft tissue massage and exercise for the treatment of non-specific shoulder pain: a systematic review with meta-analysis
Authors: Paul Andrew van den Dolder, Paulo H Ferreira, Kathryn M Refshauge
Journal: British Journal of Sports Medicine (2012)

Objective To determine the effectiveness of exercise and soft tissue massage either in isolation or in combination for the treatment of non-specific shoulder problems. Methods Database searches for articles from 1966 to December 2011 were performed. Studies were eligible if they investigated ‘hands on’ soft tissue massage performed locally to the shoulder or exercises aimed at improving strength, range of motion or coordination; non-surgical painful shoulder disorders; included participants aged 18–80 years and outcomes measured included pain, disability, range of motion, quality of life, work status, global perceived effect, adverse events or recurrence. Results Twenty-three papers met the selection criteria representing 20 individual trials. We found low-quality evidence that soft tissue massage was effective for producing moderate improvements in active flexion and abduction range of motion, pain and functional scores compared with no treatment, immediately after the cessation of treatment. Exercise was shown by meta-analysis to produce greater improvements than placebo, minimal or no treatment in reported pain (weighted mean=9.8 of 100, 95% CI 0.6 to 19.0) but these changes were of a magnitude that was less than that considered clinically worthwhile. Exercise did not produce greater improvements in shoulder function than placebo, minimal or no treatment (weighted mean=5.7 of 100, 95% CI −3.3 to 14.7). Conclusion There is low-quality evidence that soft tissue massage is effective for improving pain, function and range of motion in patients with shoulder pain in the short term. Exercise therapy is effective for producing small improvements in pain but not in function or range of motion.
First-Trimester Screening for Trisomies 21 and 18
Authors: Ronald Wapner, Elizabeth Thom, Joe Leigh Simpson, Eugene Pergament, Richard Silver, Karen Filkins, Lawrence Platt, Maurice Mahoney, Anthony Johnson, W. Allen Hogge, R. Douglas Wilson, Patrick Mohide, Douglas Hershey, David Krantz, Julia Zachary, Rosalinde Snijders, Naomi Greene, Rudy Sabbagha, Scott MacGregor, Lyndon Hill, Alain Gagnon, Terrence Hallahan, Laird Jackson
Journal: New England Journal of Medicine (2003)

Screening for aneuploid pregnancies is routinely performed after 15 weeks of gestation and has a sensitivity of approximately 65 percent, with a false positive rate of 5 percent. First-trimester markers of aneuploidy have been developed, but their use in combination has not been adequately evaluated in clinical practice.We conducted a multicenter study of screening for trisomies 21 and 18 among patients with pregnancies between 74 and 97 days of gestation, based on maternal age, maternal levels of free beta human chorionic gonadotropin and pregnancy-associated plasma protein A, and ultrasonographic measurement of fetal nuchal translucency. A screening result was considered to be positive for trisomy 21 if the calculated risk was at least 1 in 270 pregnancies and positive for trisomy 18 if the risk was at least 1 in 150.Screening was completed in 8514 patients with singleton pregnancies. This approach to screening identified 85.2 percent of the 61 cases of Down's syndrome (95 percent confidence interval, 73.8 to 93.0), with a false positive rate of 9.4 percent (95 percent confidence interval, 8.8 to 10.1). At a false positive rate of 5 percent, the detection rate was 78.7 percent (95 percent confidence interval, 66.3 to 88.1). Screening identified 90.9 percent of the 11 cases of trisomy 18 (95 percent confidence interval, 58.7 to 99.8), with a 2 percent false positive rate. Among women 35 years of age or older, screening identified 89.8 percent of fetuses with trisomy 21, with a false positive rate of 15.2 percent, and 100 percent of fetuses with trisomy 18.First-trimester screening for trisomies 21 and 18 on the basis of maternal age, maternal levels of free beta human chorionic gonadotropin and pregnancy-associated plasma protein A, and measurement of fetal nuchal translucency has good sensitivity at an acceptable false positive rate.
Immunologic and Clinical Effects of Injecting Mature Peptide-Loaded Dendritic Cells by Intralymphatic and Intranodal Routes in Metastatic Melanoma Patients
Authors: Thierry Lesimple, Eve-Marie Neidhard, Virginie Vignard, Claudia Lefeuvre, Henri Adamski, Nathalie Labarrière, André Carsin, Delphine Monnier, Brigitte Collet, Gilles Clapisson, Brigitte Birebent, Irène Philip, Louis Toujas, Mohamed Chokri, Véronique Quillien
Journal: Clinical Cancer Research (2006)

Abstract Purpose: A phase I/II trial was conducted to evaluate clinical and immunologic responses after intralymphatic and intranodal injections of mature dendritic cells. Experimental Design: Fourteen patients with a metastatic melanoma received matured dendritic cells, loaded with Melan-A/MART-1 and/or NA17-A peptides and keyhole limpet hemocyanin. The cells were matured overnight with Ribomunyl, a toll-like receptor ligand, and IFN-γ, which ensured the production of high levels of interleukin-12p70. Dendritic cells were injected at monthly intervals, first into an afferent lymphatic and then twice intranodally. Immunologic responses were monitored by tetramer staining of circulating CD8+ lymphocytes and delayed-type hypersensitivity tests. Results: Dendritic cell vaccination induced delayed-type hypersensitivity reactivity toward NA17-A-pulsed, keyhole limpet hemocyanin–pulsed, and Melan-A-pulsed dendritic cells in 6 of 10, 4 of 11, and 3 of 9 patients, respectively. Four of the 12 patients analyzed by tetramer staining showed a significantly increased frequency of Melan-A-specific T cells, including one patient vaccinated only with NA17-A-pulsed dendritic cells. Furthermore, 2 of the 12 analyzed patients had a significant increase of NA17-A-specific T cells, including one immunized after an optional additional treatment course. No objective clinical response was observed. Two patients were stabilized at 4 and 10 months and three patients are still alive at 30, 39, and 48 months. Conclusions: Injections into the lymphatic system of mature peptide-loaded dendritic cells with potential TH1 polarization capacities did not result in marked clinical results, despite immunologic responses in some patients. This highlights the need to improve our understanding of dendritic cell physiology.
The usefulness of monitoring WT1 gene transcripts for the prediction and management of relapse following allogeneic stem cell transplantation in acute type leukemia
Authors: Hiroyasu Ogawa, Hiroya Tamaki, Kazuhiro Ikegame, Toshihiro Soma, Manabu Kawakami, Akihiro Tsuboi, Eui Ho Kim, Naoki Hosen, Masaki Murakami, Tatsuya Fujioka, Tomoki Masuda, Yuki Taniguchi, Sumiyuki Nishida, Yusuke Oji, Yoshihiro Oka, Haruo Sugiyama
Journal: Blood (2003)
Divorce among physicians and other healthcare professionals in the United States: analysis of census survey data
Authors: D. P. Ly, S. A. Seabury, A. B. Jena
Journal: BMJ (2015)

<b>Objectives</b> To estimate the prevalence and incidence of divorce among US physicians compared with other healthcare professionals, lawyers, and non-healthcare professionals, and to analyze factors associated with divorce among physicians. <b>Design</b> Retrospective analysis of nationally representative surveys conducted by the US census, 2008-13. <b>Setting</b> United States. <b>Participants</b> 48 881 physicians, 10 086 dentists, 13 883 pharmacists, 159 044 nurses, 18 920 healthcare executives, 59 284 lawyers, and 6 339 310 other non-healthcare professionals. <b>Main outcome measures</b> Logistic models of divorce adjusted for age, sex, race, annual income, weekly hours worked, number of years since marriage, calendar year, and state of residence. Divorce outcomes included whether an individual had ever been divorced (divorce prevalence) or became divorced in the past year (divorce incidence). <b>Results</b> After adjustment for covariates, the probability of being ever divorced (or divorce prevalence) among physicians evaluated at the mean value of other covariates was 24.3% (95% confidence interval 23.8% to 24.8%); dentists, 25.2% (24.1% to 26.3%); pharmacists, 22.9% (22.0% to 23.8%); nurses, 33.0% (32.6% to 33.3%); healthcare executives, 30.9% (30.1% to 31.8%); lawyers, 26.9% (26.4% to 27.4%); and other non-healthcare professionals, 35.0% (34.9% to 35.1%). Similarly, physicians were less likely than those in most other occupations to divorce in the past year. In multivariable analysis among physicians, divorce prevalence was greater among women (odds ratio 1.51, 95% confidence interval 1.40 to 1.63). In analyses stratified by physician sex, greater weekly work hours were associated with increased divorce prevalence only for female physicians. <b>Conclusions</b> Divorce among physicians is less common than among non-healthcare workers and several health professions. Female physicians have a substantially higher prevalence of divorce than male physicians, which may be partly attributable to a differential effect of hours worked on divorce.
Combination of vorinostat with whole-brain radiotherapy in the treatment of brain metastases.
Authors: Y. R. Lawrence, R. M. Pfeffer, M. Werner-Wasik, H. Choy, A. Dicker
Journal: Journal of Clinical Oncology (2010)

TPS181 Background: A third of patients with solid malignancies develop brain metastases. Expected overall survival is 4-7 months depending on age, performance status, and extracranial disease. Standard treatment is controversial; however, the majority of patients receive whole-brain radiation therapy at some point. Vorinostat (suberoylanilide hydroxamic acid, SAHA), an FDA-approved HDAC inhibitor, has been demonstrated to radiosensitize tumor cells in vitro, as assessed by both radiation-induced DNA damage and clonogenic cell survival (Munshi et al. Molecular Cancer Therapeutics 5, 1967-1974, 2006). We have shown that vorinostat downregulates key genes involved in double-strand DNA repair (Rad50, Rad51, XRCC2, XRCC3, XRCC6), as assessed by quantitative PCR. This suggests that the drug's mechanism of radiosensitization is epigenetic coordinated inhibition of the DNA repair process. We hypothesize that the combination of vorinostat with whole-brain radiation therapy will be both safe and efficacious. Methods: This is a dose escalation phase I investigational trial, based on Fibonacci 3+3 design. Whole-brain radiation is delivered in daily fractions of 2.5 Gy over 3 weeks (total dose 37.5 Gy) delivered through parallel opposed fields. Vorinostat is delivered once daily on days of radiation therapy. Dose levels: increase from 200 mg PO qd to 400 mg PO qd in subsequent patient cohorts, with an option de-escalate if 200 mg is found overly toxic. Expected total accrual: 9-18 patients. Primary endpoint is tolerability; secondary endpoint is overall survival. Open to accrual at Thomas Jefferson University, Philadelphia PA; UT Southwestern Medical Center, TX and Sheba Medical Center, Tel Aviv. Study is supported by Merck. ClinicalTrials.gov Identifier: NCT00838929. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck
Analysis of coronary blood flow velocity dynamics in angiographicaily normal and stenosed arteries before and after endolumen enlargement by angioplasty
Authors: Elizabeth O. Ofili, Morton J. Kern, Arthur J. Labovitz, Jeanette A. St. Vrain, Jerome Segal, Frank V. Aguirre, Ramon Castello
Journal: Journal of the American College of Cardiology (1993)
Spontaneous pneumothorax – How long should we keep a chest drain?
Authors: Margarida Dias, Daniel Coutinho, Maria João Oliveira, Daniel Vaz, Teresa Shiang, Maria Céu Brito, Ana Antunes
Journal: European Respiratory Journal (2014)

Background: British Thoracic Society guidelines for management of spontaneous pneumothorax (SP) state that surgical treatment or medical pleurodesis should be considered if there is a persistent air leak despite 7 days of chest tube drainage.

Objectives : To investigate the need of surgery or medical pleurodesis when pneumothorax persists more than 7 days after chest drain insertion.

Methods: We included patients admitted in a Pulmonology ward between January 2011 and October 2013 due to a SP initially treated with a chest drain. Demographic and anthropometric data, pneumothorax characteristics and outcomes were analysed.

Results: We included 80 patients; 27 needed a surgical treatment or medical pleurodesis. Mean age was 34±15years old and 85% were male. Pneumothorax was primary in 62 patients.

Gender, age, smoke status, height, BMI, pneumothorax size, side and classification were not statistically different between patients who needed or not surgical intervention.

The longer the duration (in days) of chest tube drainage, the greater the likelihood of surgery being required (HR: 1.352, p<0.001). However, 50% of primary and 38% of secondary SP with persistent air leak at day 7 of chest drainage had resolved at day 15. There was no mortality in the primary SP group and 1 patient died in the secondary SP group due to complications of previous diseases.

Conclusions: We didn't find predictive factors for surgical treatment of SP, besides the persistence of air leak. Nevertheless, a persistent air leak at day 7 might be resolved at day 15, suggesting that a watch and wait approach might be appropriate, deferring the surgery.
New Treatments for Neuropathic Pain
Authors: Andrew S.C. Rice, Raymond G. Hill
Journal: Annual Review of Medicine (2006)

Existing treatments for neuropathic pain deliver inadequate pain relief, unacceptable side effects, or both. The unmet medical need for more effective treatment is driving a large volume of research to discover new drugs. Most existing treatments are drugs introduced to treat other pain conditions or other medical conditions, such as antidepressants and anticonvulsants, which were found empirically to be effective for neuropathic pain. Only recently have drug discovery efforts have become mechanistically driven, addressing targets identified by a molecular neurobiological approach to the pathophysiology of neuropathic states.
Jet‐nebulized beclomethasone dipropionate in the management of bronchial asthma
Authors: W. Pedersen, P. Prahl
Journal: Allergy (1987)

The efficacy of jet nebulized beclomethasone dipropionate (BDP) in the management of asthma was evaluated in 18 children, 2–26 months old (mean 10 months). The children were selected on the basis of the severity of their symptoms and the lack of effect of conventional treatment. The effect of BDP was evaluated by comparing clinical data before and after the initiation of treatment. Fifteen of the 18 patients experienced a significant clinical improvement during treatment with BDP. BDP “nebulizer solution” is a valuable contribution to the management of severe asthma in young asthmatics.
Activation of cellular immunity and marked inhibition of liver cancer in a mouse model following gene therapy and tumor expression of GM-SCF, IL-21, and Rae-1
Authors: Mingrong Cheng, Kangkang Zhi, Xiaoyan Gao, Bing He, Yingchun Li, Jiang Han, Zhiping Zhang, Yan Wu
Journal: Molecular Cancer (2013)

Cancer is both a systemic and a genetic disease. The pathogenesis of cancer might be related to dampened immunity. Host immunity recognizes nascent malignant cells – a process referred to as immune surveillance. Augmenting immune surveillance and suppressing immune escape are crucial in tumor immunotherapy. A recombinant plasmid capable of co-expressing granulocyte-macrophage colony- stimulating factor (GM-SCF), interleukin-21 (IL-21), and retinoic acid early transcription factor-1 (Rae-1) was constructed, and its effects determined in a mouse model of subcutaneous liver cancer. Serum specimens were assayed for IL-2 and INF-γ by ELISA. Liver cancer specimens were isolated for Rae-1 expression by RT-PCR and Western blot, and splenocytes were analyzed by flow cytometry. The recombinant plasmid inhibited the growth of liver cancer and prolonged survival of tumor-loaded mice. Activation of host immunity might have contributed to this effect by promoting increased numbers and cytotoxicity of natural killer (NK) cells and cytotoxic T lymphocytes (CTL) following expression of GM-SCF, IL-21, and Rae-1. By contrast, the frequency of regulatory T cells was decreased, Consequently, activated CTL and NK cells enhanced their secretion of INF-γ, which promoted cytotoxicity of NK cells and CTL. Moreover, active CTL showed dramatic secretion of IL-2, which stimulates CTL. The recombinant expression plasmid also augmented Rae-1 expression by liver cancer cells. Rae-1 receptor expressing CTL and NK cells removed liver cancer. The recombinant expression plasmid inhibited liver cancer by a mechanism that involved activation of cell-mediated immunity and Rae-1 in liver cancer.
TAK1 Suppresses a NEMO-Dependent but NF-κB-Independent Pathway to Liver Cancer
Authors: Kira Bettermann, Mihael Vucur, Johannes Haybaeck, Christiane Koppe, Jörn Janssen, Felix Heymann, Achim Weber, Ralf Weiskirchen, Christian Liedtke, Nikolaus Gassler, Michael Müller, Rita de Vos, Monika Julia Wolf, Yannick Boege, Gitta Maria Seleznik, Nicolas Zeller, Daniel Erny, Thomas Fuchs, Stefan Zoller, Stefano Cairo, Marie-Annick Buendia, Marco Prinz, Shizuo Akira, Frank Tacke, Mathias Heikenwalder, Christian Trautwein, Tom Luedde
Journal: Cancer Cell (2010)
Daxx Represses Expression of a Subset of Antiapoptotic Genes Regulated by Nuclear Factor-κB
Authors: Rhonda Croxton, Lorena A. Puto, Ian de Belle, Michael Thomas, Seiji Torii, Farid Hanaii, Michael Cuddy, John C. Reed
Journal: Cancer Research (2006)

Abstract Daxx is a nuclear protein that localizes to PML oncogenic domains, sensitizes cells to apoptosis, and functions as a transcriptional repressor. We found that Daxx represses the expression of several antiapoptotic genes regulated by nuclear factor-κB, including cIAP2, in human tumor cell lines. Daxx interacts with RelB and inhibits RelB-mediated transcriptional activation of the human cIAP2 gene promoter. Daxx also forms complexes with RelB while bound to its target sites in the cIAP2 promoter, as shown by electrophoretic mobility shift assays and chromatin immunoprecipitation experiments. Using cells from daxx−/− mouse embryos, we observed that levels of the corresponding murine c-IAP mRNA and protein are increased in cells lacking Daxx. Conversely, c-IAP mRNA and protein levels were reduced in relB−/− cells. Taken together, these observations provide a mechanism that links two previously ascribed functions of Daxx: transcriptional repression and sensitization to apoptosis. (Cancer Res 2006; 66(18): 9026-35)
The tumor necrosis factor family member LIGHT is a target for asthmatic airway remodeling
Authors: Taylor A Doherty, Pejman Soroosh, Naseem Khorram, Satoshi Fukuyama, Peter Rosenthal, Jae Youn Cho, Paula S Norris, Heonsik Choi, Stefanie Scheu, Klaus Pfeffer, Bruce L Zuraw, Carl F Ware, David H Broide, Michael Croft
Journal: Nature Medicine (2011)