tbuckley/cabot-search huggingface dataset:
Sympathoadrenal Hyperactivity and the Etiology of Neuroleptic Malignant Syndrome
Authors: Ronald J. Gurrera
Journal: American Journal of Psychiatry (1999)

The author's goal was to develop a pathophysiological model for neuroleptic malignant syndrome with greater explanatory power than the alternative hypotheses of hypothalamic dopamine antagonism (elevated set point) and direct myotoxicity (malignant hyperthermia variant).Published clinical findings on neuroleptic malignant syndrome were integrated with data from human and animal studies of muscle physiology, thermoregulation, and autonomic nervous system function.The data show that the sympathetic nervous system's latent capacity for autonomous activity is expressed when tonic inhibitory inputs from higher central nervous system centers are disrupted. These tonic inhibitory inputs are relayed to preganglionic sympathetic neurons by way of dopaminergic hypothalamospinal tracts. The sympathetic nervous system mediates hypothalamic coordination of thermoregulatory activity and is a primary regulator of muscle tone and thermogenesis, augmenting both of these when stimulated. In addition, the sympathetic nervous system modulates all of the other end-organs that function abnormally in neuroleptic malignant syndrome.There is substantial evidence to support the hypothesis that dysregulated sympathetic nervous system hyperactivity is responsible for most, if not all, features of neuroleptic malignant syndrome. A predisposition to more extreme sympathetic nervous system activation and/or dysfunction in response to emotional or psychological stress may constitute a trait vulnerability for neuroleptic malignant syndrome, which, when coupled with state variables such as acute psychic distress or dopamine receptor antagonism, produces the clinical syndrome of neuroleptic malignant syndrome. This hypothesis provides a more comprehensive explanation for existing clinical data than do the current alternatives.
D2 dopamine receptor occupancy during low-dose treatment with haloperidol decanoate
Authors: S Nyberg, L Farde, C Halldin, M L Dahl, L Bertilsson
Journal: American Journal of Psychiatry (1995)

The aim of this study was to examine the relationships among clinical effects, central D2 dopamine receptor occupancy, and plasma concentrations of haloperidol in eight clinically stabilized schizophrenic outpatients who were responding to treatment with low doses of haloperidol decanoate.During a 4-week interval of haloperidol decanoate dosage (dose range = 30-50 mg), the patients' D2 receptor occupancy was determined with positron emission tomography on two occasions. Plasma concentrations of haloperidol were determined with a sensitive high-performance liquid chromatography method.One week after injection of haloperidol decanoate, the mean D2 receptor occupancy was 73% (range = 60%-82%), and the mean plasma concentration of haloperidol was 4.6 nmol/liter (range = 2.9-9.7). After 4 weeks, the mean D2 receptor occupancy had decreased to 52% (range = 20%-74%), and the mean haloperidol concentration to 2.3 nmol/liter (range = 1.0-4.4).The D2 receptor occupancy 1 week after injection was high and comparable to that previously found in patients responding to acute treatment with classic neuroleptics. Prevention of relapse was maintained despite low D2 receptor occupancy during the latter part of the treatment interval. These observations indicate that continuously high D2 receptor occupancy may not be necessary to prevent schizophrenic relapses. The results emphasize the need for systematic clinical evaluation of intermittent low-dose treatment strategies.
Silicosis and pulmonary tuberculosis in South African gold miners: 1975 – 2012
Authors: Jill Murray, Ntombizodwa Ndlovu
Journal: European Respiratory Journal (2014)

Introduction 

Silicosis and pulmonary tuberculosis (PTB) are major health issues in the South gold mining industry. Exposure to silica dust predisposes individuals to TB. The law allows for autopsy examination of the lungs of deceased miners for the diagnosis of occupational diseases, regardless of the clinical cause of death. Since 1975 the autopsy findings have been stored on a database (PATHAUT). We estimated temporal trends in the relative proportions of silicosis and PTB.

Methods 

We extracted data from all gold miners 1975 - 2012 (n=68 436). The data were stratified by population group because of differences in exposure and autopsy referral. Silicosis and PTB trends, and potential determinants e.g. age, gold mining service duration, year of death and HIV, were evaluated using linear regression.

Results 

Significant changes in disease trends were observed (p<0.0001). The crude proportions of silicosis in white miners decreased from 0.27 in 1975 to 0.18 in 2000 and then increased to 0.34 in 2012. Those in black miners increased from 0.04 in 1975 to 0.40 in 2012. PTB was higher in black than in white miners, increasing from 0.03 in 1975 to 0.35 in 2012 in blacks and from 0.01 to 0.04 in whites. The increasing trends were associated with increasing age, employment duration, year of death and HIV status.

Conclusion 

The high and increasing trends of silicosis and PTB in the South African gold mining industry are fuelled by high silica dust levels. HIV also plays a major role in increasing PTB rates. Measures to control these epidemics have been initiated by the State and industry. The autopsy data can be used to monitor the effectiveness of these interventions over time.
Adoptive transfer of chimeric antigen receptor-T regulatory cells as an effective therapy for allergic asthma
Authors: Jelena Skuljec, Markus Chmielewski, Christine Happle, Mandy Busse, Hinrich Abken, Gesine Hansen
Journal: European Respiratory Journal (2014)

Regulatory T cells (Tregs) are considered as important players in suppressing allergic airway inflammation and inducing immunological tolerance. Impairment in the suppressive capacity of Tregs and/or a decrease in their number have been reported in asthmatic patients. Even though this makes Tregs attractive candidates for the adoptive cellular therapy of asthma, low numbers of antigen-specific Tregs and the variety of asthma-eliciting antigens bring concerns to a potential clinical translation. Carcinoembryonic antigen (CEA) is a glycoprotein present in several human tissues, including lung. We employed a model system consisting of CEA transgenic mice, having similar CEA distribution as in humans, and engineered CD4 + CD25 +  Tregs with a chimeric antigen receptor (CAR) specific for CEA. After sensitization, but prior to intranasal challenge of mice with ovalbumin (OVA), we adoptively transferred CAR-Tregs and investigated if such cells have a higher capacity to suppress the Th2 biased response in asthmatic mice than adoptively transferred non-modified Tregs (WT-Tregs). Both CAR- and WT-Tregs reduced total bronchoalveolar lavage cell numbers and increased CD4 + CD25 + Foxp3 +  Tregs in the lung, draining lymph nodes and spleen. However, CAR-Tregs were more effective in reducing airway hyperresponsiveness, bronchoalveolar eosinophilia, airway inflammation, mucus hyper-production as well as IL-5 and OVA-specific IgE levels in the serum. We conclude that targeting of Tregs to the lung by a specific CAR holds great promise for the efficient treatment of allergic asthma.
Stimulation of Proliferation in Mixed Cultures of Mouse Tumor Cells and Nonimmune Peritoneal Cells. I. Occurrence of Stimulation and Cyclical Variation in Tumor Cell Activity&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: M Nelson, D S Nelson
Journal: JNCI Journal of the National Cancer Institute (1985)

Mixtures of mouse tumor cells and resident peritoneal cells (PC) from nonimmune mice frequently incorporated [methyl-3H]thymidine [( 3H]dThd) in culture to a far greater extent than did either cell population alone. With PC-to-tumor cell ratios of 10:1, stimulation indices of up to 21 were recorded. Syngeneic, semisyngeneic, and allogeneic mixtures were active. PC elicited by thioglycollate or proteose-peptone could participate in the reaction. PC from mice injected with Corynebacterium parvum also could do so, provided they were precultured for 48 hours. Normal mouse spleen cells and fibroblasts and human Chang cells were inactive. There was considerable variation between experiments in the extent of stimulation observed, even with the same tumor. When tumors were cloned in vitro, freshly isolated clones differed widely in the extent of stimulation. Individual clones studied over a period of time varied markedly and cyclically in the degree of stimulation they exhibited in mixed cultures. This variation appeared to be unrelated to the density of the cultures from which the clones were obtained, to the base-line incorporation of [3H]dThd by tumor cells alone, or to the frequency of passage in vitro. It is suggested that the cyclical variation may be related to the generation of variant cells, which could be important in tumor progression and metastasis.
Abstract 14459: Daily Coffe Consumption Does Not Impact All-Cause or Specific Cardiovascular Mortality: Findings from the National Health and Nutrition Examination Survey
Authors: Rohit S Loomba, Saurabh Aggarwal, Alexander Raskin, Rohit R Arora
Journal: Circulation (2012)

Studies have examined the association between the consumption of caffeinated coffee to all cause, and cardiovascular (CV), mortality. This study aimed to delineate this using data from the National...
A summary report from Amsterdam: increase in sexually transmitted diseases and risky sexual behaviour among homosexual men in relation to the introduction of new anti-HIV drugs
Authors: G Stolte, N H T M Dukers, J B F de Wit, H Fennema, R A Coutinho
Journal: Eurosurveillance (2002)

The worrying increase of sexually transmitted diseases (STDs) in Amsterdam was investigated in two studies carried out by the department of AIDS research of the municipal health service. The results indicate that the introduction of Highly Active Antiretroviral Therapies (HAART) may have had an influence on the increase of STDs and risky sexual behaviours in Amsterdam.
Drug Interactions in Palliative Care
Authors: Stephen A. Bernard, Eduardo Bruera
Journal: Journal of Clinical Oncology (2000)

PURPOSE: This review of drug interactions in palliative care examines the relevant literature in this area and summarizes the information on interactions of drugs, nutrients, and natural products that are used in the palliative care setting. Particular emphasis is placed on describing the newer information on the cytochrome P450 (CYP) system and the interactions of opioids, antidepressants, and the antitussive, dextromethorphan. METHODS: We performed a search of the MEDLINE database of the time period from 1966 until April 1998, using medical subject headings such as the names of selective serotonin reuptake inhibitors and other relevant medications in palliative care. Literature reviewed included both human and animal articles as well as non-English literature. Bibliographies of these articles and the personal libraries of several palliative care specialists were reviewed. Software developed by The Medical Letter—The Drug Interaction Program was also used. RESULTS: Drug interactions can be categorized in several ways. Drug-drug interactions are the most well known and can be kinetic, dynamic, or pharmaceutical. Pharmacokinetic interactions can involve CYP 2D6, which acts on drugs such as codeine and is responsible for its conversion to morphine. Poor metabolizers, either genotypic or due to phenocopying, are at risk for undertreatment if not recognized. Pharmacodynamic interactions with dextromethorphan may produce serotonin syndrome. CONCLUSION: Drug interactions are important in palliative care as in other aspects of medicine. These interactions are similar to those seen in other areas of medical care but have significant consequences in pain management. Failure to recognize these interactions can lead to either overdosing or undertreatment.
Synergism of Diethylstilbestrol and Radiation in Mammary Carcinogenesis in Female F344 Rats&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: S Holtzman, J P Stone, C J Shellabarger
Journal: JNCI Journal of the National Cancer Institute (1979)

One compressed 20-mg pellet containing cholesterol only or cholesterol mixed with 0.98, 1.6, 2.6, or 3.9 mg of diethylstilbestrol (DES) was implanted into each of 203 female F344 rats. Two days later, half the animals in each group were exposed to 150 R of X-rays, and the other half were sham irradiated. The rats were maintained until 350 days post implantation. Mortality increased with the higher doses of DES, with or without X-rays. DES at all dose levels, with or without X-rays, produced pituitary tumors and pyometritis. Only rats that received both DES and X-rays had mammary adenocarcinomas (AC). A synergistic AC response was found in the group that received 2.6 mg DES plus X-rays. Synergism was defined as a significantly greater incidence of rats with mammary neoplasia resulting from DES plus X-ray treatment when compared to the summed incidence from comparable individual treatments. For all other groups of rats that received both treatments, synergism was detected only when their data were combined. Synergism was not detected among rats that had fibroadenomas (FA). Both types of neoplasms were independent phenomena because no significant relationship was found between the incidences of FA and AC.
Lung protective ventilator settings for lung transplantation? The Harefield experience
Authors: Rosada Davey, Louit Thakuria, Anna Reed, André Simon, Martin Carby, Nandor Marczin
Journal: European Respiratory Journal (2013)

Lung protective ventilation strategies employing low tidal volumes have been advocated for ARDS and lung transplant donors. There is a paucity of clinical information regarding current ventilation practices in the recipients following lung transplantation (LTx).  The aim of the study was to review early post-operative ventilation strategies and to explore the impact of high tidal volume ventilation on patient outcomes.  Bilateral sequential single lung transplants (n=62) performed in 2010-11 were retrospectively analysed for ventilation strategies and clinical and physiological outcomes.  The majority of patients (>60%) received pressure-controlled ventilation during the first 6 hours post-transplantation. The distribution of resultant tidal volumes and associated median peak inspiratory pressures are shown below.  Median PEEP values were 6 cmH 2 0 [IQR:6-8]. Low tidal volume was mainly employed in patients requiring ECMO. Patients stratified into low ( 8 ml/kg, n=29) tidal volume groups exhibited similar clinical (ventilation duration, ICU stay) and physiological (P/F ratios, inflammatory markers) outcomes, and comparable requirement for vasoactive support.  Our ventilation strategies employed protective PEEP and pressure limitation but frequently resulted in traditionally high tidal volumes. However, clinical and physiological outcomes were not different with higher tidal volumes.
Abstract 12920: Beat-to-Beat QT Interval Variability While Awake, but Not During Sleep, is Associated With All-Cause Mortality
Authors: Sandeep Bansal, Francis P Sgambati, Barry J Fetics, Ronald D Berger, Naresh M Punjabi
Journal: Circulation (2011)

Introduction:  Electrocardiographic markers of autonomic tone, in particular heart rate variability (HRV) and QT-interval variability index (QTVI), have previously been shown to correlate with adverse outcomes. How these metrics perform during wake compared with sleep, when sympathetic tone is lower, is unclear. We assessed the hypothesis that lower HRV and elevated QTVI during wakefulness, but not sleep, would correlate with mortality.   Methods:  We performed a nested case-control analysis within the Sleep Heart Health Study, a prospective study of 6441 subjects who underwent polysomnography, with collection of sleep and ECG data. Cases died of any cause during 8 years of follow-up, and controls were matched for age, gender, race, smoking status, body-mass index, baseline cardiovascular disease, and respiratory-disturbance index. ECGs were analyzed in 5-minute epochs using a previously validated semi-automated method of R-wave detection, with QT-interval matching to a user-defined template. Differences between groups were assessed using a paired t-test.   Results:  A total of 215 case-control pairs were identified. Overnight (wake and sleep), mean heart rate was slightly higher in cases than in controls (67.1 ± 9.6 vs 65.3 ± 8.5 bpm, p = 0.03), but no significant differences were found in measures of HRV (SDNN, RMSSD, or pNN50) or QT variability (QTVI or coherence). During awake periods, cases had higher QTVI (-0.98 ± 0.46 vs -1.11 ± 0.39, p=0.04), and lower coherence (0.31 ± 0.10 vs 0.34 ± 0.11, p=0.008) compared to controls, while HRV measures remained similar. In contrast, during sleep, no significant differences were noted in these measures.   Conclusion:  During periods of wake, but not sleep, increased lability in ventricular repolarization (as measured by high QTVI and low coherence) is associated with all-cause mortality. These data suggest that QT variability during periods of greater sympathetic stimulation may be more predictive of outcomes such as mortality.
Expression of Histocompatibility Antigens and Characterization of Mononuclear Cell Infiltrates in Normal and Neoplastic Colorectal Tissues of Humans
Authors: H C Umpleby, D Heinemann, M O Symes, R C Williamson
Journal: JNCI Journal of the National Cancer Institute (1985)

Serial frozen sections were prepared from 22 colorectal carcinomas. Additional samples were obtained from the adjacent normal bowel in 10 patients, from 6 concomitant adenomas in 5 patients, and from another 4 isolated adenomas. Mononuclear cell infiltrates were stained by the indirect immunoperoxidase technique with the use of a panel of 6 mouse monoclonal antibodies to human leukocyte antigens. The degree of infiltration was graded from 4 (heavy) to 0 (nil). The colorectal carcinomas and adjacent normal bowel showed an equal degree of leukocyte infiltration (HLe-1), graded 3-4 in 8 cases and 2-3 in the other 2 cases. In 7 carcinomas cytotoxic-suppressor T-lymphocytes (UCHT-4) graded 2-3 predominated over helper T-cells (OKT-4) graded 0-1. By contrast, in the adjacent normal bowel cytotoxic and helper cells were present in equal numbers. Among the adenomas leukocyte infiltration was grade 4 in 9 and grade 3 in 1. In 9 of the 10 adenomas cytotoxic cells graded 2 predominated over helper cells graded 0-1. The number of helper cells was equivalent among 6 concomitant adenomas and carcinomas from 5 patients. Adenomatous epithelial cells expressed class II major histocompatibility complex antigens (OKIa-1). However, carcinomatous or normal epithelium showed only faint staining with OKIa-1. The similarity in cell infiltration is consistent with an adenoma-carcinoma sequence. The predominance of cytotoxic cells in carcinomas that expressed class I major histocompatibility complex supports the association between lymphocyte infiltration and a favorable prognosis.
Interaction of Phytohemagglutinin and Concanavalin A With Transplantable Mouse Lymphomas of Differing Malignant Potential1&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: Peter B. Dent, Brian L. Hillcoat
Journal: JNCI Journal of the National Cancer Institute (1972)

Journal Article Interaction of Phytohemagglutinin and Concanavalin A With Transplantable Mouse Lymphomas of Differing Malignant Potential1 Get access Peter B. Dent, M.D., Peter B. Dent, M.D. Department of Pediatrics and Biochemistry, Division of Immunology, McMaster University, Hamilton, Ontario, Canada Search for other works by this author on: Oxford Academic PubMed Google Scholar Brian L. Hillcoat, M.D. Brian L. Hillcoat, M.D. Department of Pediatrics and Biochemistry, Division of Immunology, McMaster University, Hamilton, Ontario, Canada Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 49, Issue 2, August 1972, Pages 373–377, https://doi.org/10.1093/jnci/49.2.372 Published: 01 August 1972 Article history Received: 23 November 1971 Revision received: 24 March 1972 Accepted: 03 April 1972 Published: 01 August 1972
LSC 2013 abstract - Bioavailability of VEGF in idiopathic pulmonary fibrosis
Authors: Shaney Barratt, Caroline Jarrett, Thomas Blythe, Khadija Ourradi, Gavin Welsh, David Bates, Ann Millar
Journal: European Respiratory Journal (2013)

VEGF is both a growth and permeability factor implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). The presence of hypoxia and its treatment with high flow oxygen have been proposed to contribute to lung injury. VEGF gene transcription is tightly regulated by a hypoxia response element. We hypothesised that: 1) VEGF and its receptors would be differentially expressed between normal (NF) and fibrotic fibroblasts (FF) and 2) Hypoxia and hyperoxia would alter fibroblast VEGF expression. Methods: NF(n=5) and FF(n=5)(from patients with proven usual interstitial pneumonia) were extracted from lung biopsies using the explant method. VEGF receptors levels were analysed at the mRNA and protein level (qPCR and western blotting (WB)). Pan VEGF isoforms were detected at the protein level by ELISA. Fibroblasts were grown in culture for 24 hours in normoxic, hyperoxic (90% O2) and hypoxic conditions (21% O2 with CoCl2). Results: Both NF and FF expressed VEGFR1, VEGFR2, NRP-1 and NRP-2. No significant difference was detected in receptor expression at mRNA or protein level. FF expressed significantly more total VEGF than NF by ELISA:(NF 180.5 pg/ml vs FF 332.0 pg/ml, p=0.01). Moreover, a significant increase in VEGF expression was observed in both NF and FF in response to hypoxic growth conditions (NF 205.7 pg/ml vs 1382.0 pg/ml, p = 0.05, FF 394.6 pg/ml vs 1113 pg/ml.0, p = 0.01). A trend towards increased VEGF expression was also seen in FF vs NF exposed to hyperoxic conditions. Conclusion:Differential expression of VEGF between NF and FF suggests a potential role in the development of IPF. Hypoxia and possibly hyperoxia may alter VEGF bioavailability with important implications in the use of oxygen therapy to manage this disease.
A Randomized Trial Testing US Food and Drug Administration “Breakthrough” Language
Authors: Tamar Krishnamurti, Steven Woloshin, Lisa M. Schwartz, Baruch Fischhoff
Journal: JAMA Internal Medicine (2015)

patients with atrial fibrillation with high global cardiovascular risk, the yield for detecting ischemia was 5.2%, and ischemia was not associated with increased mortality in this population.These findings suggest that these asymptomatic patients do not benefit from MPI. Harms of MPI include increased cancer risk from the high radiation burden (6-37 mSv depending on protocol, which is equivalent to hundreds or thousands of chest radiographs).These findings support a change in the AUC rating to the rarely appropriate category for this indication, and because MPI has definite harms without benefits for asymptomatic patients with atrial fibrillation this Research Letter merits the Less is More designation.