tbuckley/cabot-search huggingface dataset:
Mitochondria, Energetics, Epigenetics, and Cellular Responses to Stress
Authors: Daniel T. Shaughnessy, Kimberly McAllister, Leroy Worth, Astrid C. Haugen, Joel N. Meyer, Frederick E. Domann, Bennett Van Houten, Raul Mostoslavsky, Scott J. Bultman, Andrea A. Baccarelli, Thomas J. Begley, Robert W. Sobol, Matthew D. Hirschey, Trey Ideker, Janine H. Santos, William C. Copeland, Raymond R. Tice, David M. Balshaw, Frederick L. Tyson
Journal: Environmental Health Perspectives (2014)

Background: Cells respond to environmental stressors through several key pathways, including response to reactive oxygen species (ROS), nutrient and ATP sensing, DNA damage response (DDR), and epigenetic alterations. Mitochondria play a central role in these pathways not only through energetics and ATP production but also through metabolites generated in the tricarboxylic acid cycle, as well as mitochondria–nuclear signaling related to mitochondria morphology, biogenesis, fission/fusion, mitophagy, apoptosis, and epigenetic regulation.Objectives: We investigated the concept of bidirectional interactions between mitochondria and cellular pathways in response to environmental stress with a focus on epigenetic regulation, and we examined DNA repair and DDR pathways as examples of biological processes that respond to exogenous insults through changes in homeostasis and altered mitochondrial function.Methods: The National Institute of Environmental Health Sciences sponsored the Workshop on Mitochondria, Energetics, Epigenetics, Environment, and DNA Damage Response on 25–26 March 2013. Here, we summarize key points and ideas emerging from this meeting.Discussion: A more comprehensive understanding of signaling mechanisms (cross-talk) between the mitochondria and nucleus is central to elucidating the integration of mitochondrial functions with other cellular response pathways in modulating the effects of environmental agents. Recent studies have highlighted the importance of mitochondrial functions in epigenetic regulation and DDR with environmental stress. Development and application of novel technologies, enhanced experimental models, and a systems-type research approach will help to discern how environmentally induced mitochondrial dysfunction affects key mechanistic pathways.Conclusions: Understanding mitochondria–cell signaling will provide insight into individual responses to environmental hazards, improving prediction of hazard and susceptibility to environmental stressors.Citation: Shaughnessy DT, McAllister K, Worth L, Haugen AC, Meyer JN, Domann FE, Van Houten B, Mostoslavsky R, Bultman SJ, Baccarelli AA, Begley TJ, Sobol RW, Hirschey MD, Ideker T, Santos JH, Copeland WC, Tice RR, Balshaw DM, Tyson FL. 2014. Mitochondria, energetics, epigenetics, and cellular responses to stress. Environ Health Perspect 122:1271–1278; http://dx.doi.org/10.1289/ehp.1408418
STUDIES ON ENDEMIC PNEUMONIA OF THE ALBINO RAT
Authors: John B. Nelson
Journal: The Journal of Experimental Medicine (1948)

An attempt was made to reestablish the virus-like agent associated with rat pneumonia by the nasal instillation of the infectious material into supposedly normal young rats from the selected Princeton colony. The incidence of the pneumonia in these animals after the injection of suspensions of pneumonic lungs from either rats or mice was not significantly greater than the incidence under natural conditions. In attempting to account for the refractory state of the immature rats it was found that the agent was widely dispersed through the breeding colony at an early age. Detailed tests of many litters indicated that the agent was acquired shortly after birth by way of the upper air passages as the result of maternal contact. In most instances it was so well tolerated by young rats during the suckling period and for several months thereafter that its presence was recognized only by nasal transfer to mice. There is every indication that the rate of infection of rats in the breeding colony approaches 100 per cent by the time the animals are old enough to be used experimentally.
Risperidone in Treatment-Refractory Schizophrenia
Authors: D A Wirshing, B D Marshall, M F Green, J Mintz, S R Marder, W C Wirshing
Journal: American Journal of Psychiatry (1999)

The purpose of this study was to evaluate the clinical safety and efficacy of risperidone compared to haloperidol in patients with treatment-refractory schizophrenia.Sixty-seven medication-unresponsive subjects were randomly assigned to treatment with risperidone (N = 34) or haloperidol (N = 33). After a 3-7 day-placebo washout period, there was a 4-week, double-blind, fixed-dose comparison trial that was followed by a 4-week, flexible-dose phase. Measures of clinical change were quantified by standard psychopathologic and neuromotor instruments.Risperidone demonstrated clinical efficacy superior to that of haloperidol on the total Brief Psychiatric Rating Scale (BPRS) after the first 4 weeks of treatment. Risperidone did not show any advantage over haloperidol after an additional 4 weeks. Overall improvement on the BPRS at 4 weeks was significantly better for the risperidone group (24%) than for the haloperidol group (11%). Risperidone-treated subjects were significantly less likely than haloperidol-treated subjects to require concomitant anticholinergic medication after 4 weeks (20% versus 63%); they also had significantly les observable akathisia (24% versus 53%) and significantly less severe tardive dyskinesia. Baseline characteristics that correlated significantly with risperidone response were positive symptoms, conceptual disorganization, akathisia, and tardive dyskinesia.Risperidone was better tolerated and more effective in a subset of patients with treatment-refractory schizophrenia. Positive psychotic symptoms and extrapyramidal side effects at baseline appear to be powerful predictors of subsequent response to risperidone.
Gemcitabine Plus<i>nab</i>-Paclitaxel Is an Active Regimen in Patients With Advanced Pancreatic Cancer: A Phase I/II Trial
Authors: Daniel D. Von Hoff, Ramesh K. Ramanathan, Mitesh J. Borad, Daniel A. Laheru, Lon S. Smith, Tina E. Wood, Ronald L. Korn, Neil Desai, Vuong Trieu, Jose L. Iglesias, Hui Zhang, Patrick Soon-Shiong, Tao Shi, N.V. Rajeshkumar, Anirban Maitra, Manuel Hidalgo
Journal: Journal of Clinical Oncology (2011)

Purpose The trial objectives were to identify the maximum-tolerated dose (MTD) of first-line gemcitabine plus nab-paclitaxel in metastatic pancreatic adenocarcinoma and to provide efficacy and safety data. Additional objectives were to evaluate positron emission tomography (PET) scan response, secreted protein acidic and rich in cysteine (SPARC), and CA19-9 levels in relation to efficacy. Subsequent preclinical studies investigated the changes involving the pancreatic stroma and drug uptake. Patients and Methods Patients with previously untreated advanced pancreatic cancer were treated with 100, 125, or 150 mg/m 2 nab-paclitaxel followed by gemcitabine 1,000 mg/m 2 on days 1, 8, and 15 every 28 days. In the preclinical study, mice were implanted with human pancreatic cancers and treated with study agents. Results A total of 20, 44, and three patients received nab-paclitaxel at 100, 125, and 150 mg/m 2 , respectively. The MTD was 1,000 mg/m 2 of gemcitabine plus 125 mg/m 2 of nab-paclitaxel once a week for 3 weeks, every 28 days. Dose-limiting toxicities were sepsis and neutropenia. At the MTD, the response rate was 48%, with 12.2 median months of overall survival (OS) and 48% 1-year survival. Improved OS was observed in patients who had a complete metabolic response on [ 18 F]fluorodeoxyglucose PET. Decreases in CA19-9 levels were correlated with increased response rate, progression-free survival, and OS. SPARC in the stroma, but not in the tumor, was correlated with improved survival. In mice with human pancreatic cancer xenografts, nab-paclitaxel alone and in combination with gemcitabine depleted the desmoplastic stroma. The intratumoral concentration of gemcitabine was increased by 2.8-fold in mice receiving nab-paclitaxel plus gemcitabine versus those receiving gemcitabine alone. Conclusion The regimen of nab-paclitaxel plus gemcitabine has tolerable adverse effects with substantial antitumor activity, warranting phase III evaluation.
Inflammatory gradient in Barrett's oesophagus: implications for disease complications
Authors: R C Fitzgerald
Journal: Gut (2002)

<b>Introduction:</b> Barrett’s oesophageal epithelium (BE) is clinically important due to the associated inflammatory and malignant complications which are unevenly distributed throughout the BE segment. As the immunoregulatory environment may influence disease manifestations, we analysed the inflammatory and cytokine responses throughout the BE mucosa. We then investigated whether the inflammatory gradient is related to the distribution of metaplastic cell subtypes, epithelial exposure to the components of refluxate, or squamocolumnar cell interactions. <b>Methods:</b> Fifty consecutive patients with long segment BE were recruited. The segmental degree of endoscopic and histopathological inflammation was graded, and expression of interleukin (IL)-1β, IL-8, IL-4, and IL-10 were determined by ELISA following organ culture with or without addition of acid or bile salts. Mucin staining and IL-10 immunohistochemistry were performed. The effect of squamocolumnar interactions on cytokine expression were analysed using cocultures of squamous (OE-21) and BE (TE7) carcinoma cell lines. <b>Results:</b> There was a histopathological inflammatory gradient in BE. Inflammation was maximal at the new squamocolumnar junction with ≥2-fold increase in proinflammatory IL-8 and IL-1β expression. The proximal proinflammatory response could not be explained by the distribution of metaplastic subtypes. Pulsatile exposure of BE to acid and bile, as well as juxtaposition of BE to squamous epithelial cells in culture, increased expression of IL-1β. In contrast, inflammation was minimal distally with a significant increase in anti-inflammatory IL-10 expression and 4/6 cancers occurred distally. <b>Conclusions:</b> Specific cytokine responses may contribute to the localisation of inflammatory and malignant complications within BE.
Simulation Technology for Health Care Professional Skills Training and Assessment
Authors: S. Barry Issenberg
Journal: JAMA (1999)

Changes in medical practice that limit instruction time and patient availability, the expanding options for diagnosis and management, and advances in technology are contributing to greater use of simulation technology in medical education. Four areas of high-technology simulations currently being used are laparoscopic techniques, which provide surgeons with an opportunity to enhance their motor skills without risk to patients; a cardiovascular disease simulator, which can be used to simulate cardiac conditions; multimedia computer systems, which includes patient-centered, case-based programs that constitute a generalist curriculum in cardiology; and anesthesia simulators, which have controlled responses that vary according to numerous possible scenarios. Some benefits of simulation technology include improvements in certain surgical technical skills, in cardiovascular examination skills, and in acquisition and retention of knowledge compared with traditional lectures. These systems help to address the problem of poor skills training and proficiency and may provide a method for physicians to become self-directed lifelong learners.
Interpreting HIV Serodiagnostic Test Results in the 1990s: Social Risks of HIV Vaccine Studies in Uninfected Volunteers
Authors: R B Belshe, M L Clements, M C Keefer, B S Graham, L Corey, R Sposto, S Wescott, D Lawrence
Journal: Annals of Internal Medicine (1994)

Objective: To evaluate the influence of a human immunodeficiency virus (HIV) vaccine given to uninfected volunteers on the interpretation of serodiagnostic HIV test results. Design: Retrospective cohort study. Setting: 5 AIDS Vaccine Evaluation Units funded by the National Institute of Allergy and Infectious Diseases. Participants: The first 266 healthy adult volunteers (aged 18 to 60 years) who did not have HIV infection and whose history suggested that they were at low risk for acquiring HIV infection. Measurements: HIV antibody was measured by enzyme-linked immunosorbent assay (ELISA) and Western blot test, the results of which were interpreted on the basis of four different published criteria. Results: At some time during the first 12 months of the vaccine studies, 68% of volunteers were positive for HIV antibodies by ELISA. Depending on criteria used to interpret Western blot test results, 0% to 44% of volunteers had positive results that might have caused them to be incorrectly labeled as HIV infected. Conclusions: Significant social risks to volunteers participating in HIV vaccine studies were identified. Persons interpreting HIV serodiagnostic test results must consider that an HIV vaccine can cause a positive result in persons who are not infected.
Does Fetal Exposure to SSRIs or Maternal Depression Impact Infant Growth?
Authors: Katherine L. Wisner, Debra L. Bogen, Dorothy Sit, Mary McShea, Carolyn Hughes, David Rizzo, Andrea Confer, James Luther, Heather Eng, Stephen W. Wisniewski
Journal: American Journal of Psychiatry (2013)

In utero exposure to a mother's untreated major depression or SSRI antidepressants did not affect infant weight, length, or head circumference in the first year of life, suggesting that factors regulating infant growth are robust enough not to be perturbed by either option.
Complement Regulator CD59 Protects Against Atherosclerosis by Restricting the Formation of Complement Membrane Attack Complex
Authors: Gongxiong Wu, Weiguo Hu, Aliakbar Shahsafaei, Wenping Song, Martin Dobarro, Galina K. Sukhova, Rod R. Bronson, Guo-ping Shi, Russell P. Rother, Jose A. Halperin, Xuebin Qin
Journal: Circulation Research (2009)

Complement is a central effector system within the immune system and is implicated in a range of inflammatory disorders. CD59 is a key regulator of complement membrane attack complex (MAC) assembly. The atherogenic role of terminal complement has long been suspected but is still unclear. Here, we demonstrate that among mice deficient in apolipoprotein (Apo)E, the additional loss of murine CD59 (mCd59ab(-/-)/ApoE(-/-)) accelerated advanced atherosclerosis featuring occlusive coronary atherosclerosis, vulnerable plaque, and premature death and that these effect could be attenuated by overexpression of human CD59 in the endothelium. Complement inhibition using a neutralizing anti-mouse C5 antibody attenuated atherosclerosis in mCd59ab(-/-)/ApoE(-/-) mice. Furthermore, MAC mediated endothelial damage and promoted foam cell formation. These combined results highlight the atherogenic role of MAC and the atheroprotective role of CD59 and suggest that inhibition of MAC formation may provide a therapeutic approach for the treatment of atherosclerosis.
The Modern Treatment of Myoma
Authors: W. S. Thomson
Journal: BMJ (1892)

Reproductive health care of adolescent women is focused on prevention of disease. Adolescents are at higher risk for pelvic inflammatory disease than adult women; therefore, screening regularly for sexually transmitted infections is important. Immunization for human papillomavirus is the primary means of cervical cancer prevention because new guidelines recommend not initiating Papanicolaou smears until the age of 21. Contraception for adolescents is a challenge, and clinicians should focus on long-acting, reversible contraception in this group. The treatment of pelvic pain and menstrual disorders in adolescent women is distinct from adult women and is related to differing prevalence of conditions. Lastly, this article discusses the importance of confidential care when treating adolescent women.
Mortality and Hospitalization in Patients After Amputation
Authors: Christopher J. Schofield, Gillian Libby, Geraldine M. Brennan, Ritchie R. MacAlpine, Andrew D. Morris, Graham P. Leese
Journal: Diabetes Care (2006)

We sought to compare the risk of mortality and hospitalization between patients with and without diabetes following incident lower-extremity amputation (LEA).We performed a retrospective data-linkage review of all incident amputations between 1 January 1992 and 31 December 1995. Patients were categorized according to their diabetes status. Follow-up for mortality was until 1 January 2005 and until 31 March 1996 for hospitalization.Of 390 major-incident LEAs performed during the study period, 119 (30.5%) were in patients with diabetes and 271 (69.5%) were in nondiabetic subjects. The median time to death was 27.2 months in patients with diabetes compared with 46.7 months for patients without (P = 0.01). Diabetic subjects had a 55% greater risk of death than those without diabetes. The risk of developing congestive cardiac failure with diabetes was 2.26 (95% CI 1.12-4.57) and of further amputation was 1.95 (1.14-3.33) times that of a patient without diabetes after incident LEA.After LEA, patients with diabetes have an increased risk of death compared with nondiabetic patients. Efforts should be made to minimize these risks with aggressive treatment of cardiovascular risk factors and management of cardiac failure.
Loss of Bcl-2 expression correlates with tumour recurrence in colorectal cancer
Authors: M Ilyas, X-P Hao, K Wilkinson, I P M Tomlinson, A M Abbasi, A Forbes, W F Bodmer, I C Talbot
Journal: Gut (1998)

To investigate the association between immunohistochemical expression of Bcl-2 and p53 in colorectal cancer and tumour recurrence following surgery.Sixty six cases of Dukes' B colorectal carcinoma were studied. All tumours were moderately differentiated and were shown to be histologically clear of the resection margins. Immunohistochemistry was performed on formalin fixed paraffin wax embedded tissue using monoclonal antibodies for p53 and Bcl-2. The Bcl-2 staining was assessed separately for relative intensity of staining and percentage of positive tumour cells and given a final score which combined the two factors. The p53 staining was assessed on number of positive tumour cells only. The patterns of immunostaining of those cases in which there had been tumour recurrence were compared with those cases in which there was no tumour recurrence (controls).A statistically significant inverse association was found between Bcl-2 score and tumour recurrence (median Bcl-2 score of 6 (interquartile range (IQR) 2-9) in patients with recurrent disease; median Bcl-2 score of 8 (IQR 6-10) in those without recurrence; p = 0.03). When examined separately, both the intensity of expression and percentage of positive tumour cells were significantly associated with tumour recurrence (p = 0.04 in each case). There was no association between p53 staining and tumour recurrence.Results suggest that, when controlled for differentiation, Bcl-2 expression is a prognostic marker and may be useful as an adjunctive test in clinical decision making.
Murine interstitial nephritis. I. Analysis of disease susceptibility and its relationship of pleiomorphic gene products defining both immune-response genes and a restrictive requirement for cytotoxic T cells at H-2K.
Authors: E G Neilson, S M Phillips
Journal: The Journal of Experimental Medicine (1982)

Anti-tubular basement membrance (alpha TBM) disease-producing interstitial nephritis in mice is not dependent on the generation of alpha TBM antibodies. Susceptibility seems to be defined by very private specificities in H-2K. These specificities are pleiomorphic, providing both immune-response genes and identity restrictions for cytotoxic effector functions expressed by a Thy-1.2+, Lyt-2,3+ T cell. These studies establish a role for T cells in the pathogenesis in interstitial nephritis as well as providing further evidence for the role of H-2K in the expression of an autoimmune disease.
Poor quality water is among the WHO's concerns for Palestinians' health
Authors: Lynn Eaton
Journal: BMJ (2002)

The quality of water and poor standards of sanitation in the Palestinian territories occupied by Israel are a cause of “grave concern,” according to the director general of the World Health Organization.

In a report published last week Dr Gro Harlem Brundtland said that, despite a resolution passed by the WHO assembly in May calling on her to visit the territories to assess the situation, she has “not been given the opportunity to pay a visit.” According to a spokeswoman the Israeli government had made it clear that it would not let Dr Brundtland visit to carry out her investigation, although discussions were ongoing.

However, she has based her latest report, which takes account of the escalation of the conflict in the area since March and further …
Risk Factors for Active Tuberculosis after Antiretroviral Treatment Initiation in Abidjan
Authors: Catherine Seyler, Siaka Toure, Eugène Messou, Dominique Bonard, Delphine Gabillard, Xavier Anglaret
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

In sub-Saharan Africa: (1) tuberculosis is the first cause of HIV-related mortality; (2) the incidence of tuberculosis in adults receiving highly active antiretroviral therapy (HAART) is lower than in untreated HIV-infected adults but higher than in HIV-negative adults; and (3) factors associated with the occurrence of tuberculosis in patients receiving HAART have never been described.To look for the risk factors for active tuberculosis in HIV-infected adults receiving HAART in Abidjan.Seven-year prospective cohort of HIV-infected adults, with standardized procedures for documenting morbidity. We analyzed the incidence of active tuberculosis in patients who started HAART and the association between the occurrence of tuberculosis and the characteristics of these patients at HAART initiation.A total of 129 adults (median baseline CD4 count 125/mm(3)) started HAART and were then followed for 270 person-years (P-Y). At HAART initiation, 31 had a history of tuberculosis and none had current active tuberculosis. During follow-up, the incidence of active tuberculosis was 4.8/100 P-Y (95% confidence interval [CI], 2.5-8.3) overall, 3.0/100 P-Y (95% CI, 1.1-6.6) in patients with no tuberculosis history, and 11.3/100 P-Y (95% CI, 4.1-24.5) in patients with a history of tuberculosis (adjusted hazard ratio, 4.64; 95% CI, 1.29-16.62, p = 0.02).The risk of tuberculosis after HAART initiation was significantly higher in patients with a history of tuberculosis than in those with no tuberculosis history. If confirmed by others, this finding could lead to assessment of new patterns of time-limited tuberculosis secondary chemoprophylaxis during the period of initiation of HAART in sub-Saharan African adults.