tbuckley/cabot-search huggingface dataset:
Antioxidants plus corticosteroids in the treatment of severe acute alcoholic hepatitis: The question is still open
Authors: Eric Nguyen-Khac, Thierry Thevenot, Marie-Astrid Piquet, Said Benferhat, Abdelhamid Hezam, Odile Goria, Blaise Tramier, Denis Chatelain, Jean Louis Dupas
Journal: Journal of Hepatology (2008)

We read with interest the article by Stewart et al. [[1]Stewart S. Prince M. Bassendine M. Hudson M. James O. Jones D. et al.A randomized trial of antioxidant therapy alone or with corticosteroids in acute alcoholic hepatitis.J Hepatol. 2007; 47: 277-283Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar]. The authors concluded that the treatment of severe acute alcoholic hepatitis (AAH) with antioxidants (AO) alone or with corticosteroids (C) did not improve survival at 6 months. Combining AO with C is attractive, since excessive TNFα levels in AAH are more damaging on hepatocytes when glutathione reserves are depleted by chronic alcohol intake [[2]Colell A. Garcia-Ruiz C. Miranda M. Ardite E. Mari M. Morales A. et al.Selective glutathione depletion of mitochondria by ethanol sensitizes hepatocytes to tumor necrosis factor.Gastroenterology. 1998; 115: 1541-1551Abstract Full Text Full Text PDF PubMed Scopus (312) Google Scholar]. The negative results of this work should not oblige us to hastily abandon this strategy. The study had several limits: (i) Sample size calculation was based on the hypothesis of a 40% survival improvement with AO, which seems to be much too optimistic; (ii) AAH was only histologically confirmed in 63% of the cases; (iii) surprisingly, 44% (n = 34/77) of the patients with a Maddrey score ⩾32 were not treated with corticosteroids, for reasons not specified; and (iv) two stratifications (gender and corticosteroids) were applied prior to randomization for AO, resulting in eight small groups, with two without any treatment. Assessment of survival was performed by pooling 34 patients treated by C or not treated, compared with 36 patients treated with AO or placebo, plus C or no treatment. This boils down to testing two hypotheses at the same time (AO vs. C and AO + C vs. C), which is not appropriate – especially since the C vs. AO strategy has been shown to be ineffective [[3]Phillips M. Curtis H. Portmann B. Donaldson N. Bomford A. O’Grady J. Antioxidants versus corticosteroids in the treatment of severe alcoholic hepatitis – a randomised clinical trial.J Hepatol. 2006; 44: 784-790Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar]. Hence, we believe that it is still worth performing a study which compares a combination therapy (C + AO) with C alone in severe AAH patients.
Opportunistic Infections of the Retina in Patients With Aquaporin-4 Antibody Disease
Authors: Jithin S. George, Maria Isabel Leite, Joanna L. Kitley, Nicola Jones, Nicholas Cortes, Matthew Donati, Bethan Non Matthews, Daniel Calladine, Charles Hillier, Imran H. Yusuf, Robert Munneke, Chetan K. Patel, Jacqueline A. Palace, John S. Elston
Journal: JAMA Neurology (2014)

<h3>Importance</h3> Patients with neuromyelitis optica who have aquaporin-4 antibodies are being identified and receiving immunosuppressant treatment earlier and more aggressively as a result of increasing awareness of the importance of preventing relapses responsible for the high morbidity and mortality associated with the disease. To our knowledge, opportunistic retinal infection in patients with aquaporin-4 antibodies who are receiving immunosuppressants has not been reported to date. <h3>Observations</h3> We describe 2 patients with aquaporin-4 antibodies who were receiving conventional doses of first-line immunosuppressive therapy. Both patients presented with vision loss that was initially thought to be optic neuritis attacks. The subsequent diagnoses were ocular toxoplasmosis and cytomegalovirus retinitis. <h3>Conclusions and Relevance</h3> Retinal opportunistic infections can occur in patients with aquaporin-4 antibodies who are receiving relatively low levels of immunosuppression, may mimic optic neuritis, and are a potentially reversible cause of vision loss when treated promptly.
Isoniazid therapy in relation to later occurrence of cancer in adults and in infants.
Authors: E. C. Hammond, I. J. Selikoff, E. H. Robitzek
Journal: BMJ (1967)

JOURNAL (Knox, 1966) and provide a firmer base for decision on long- term planning and development.Thus whatever approach is made to immediate provision of services, the more intensive local study of communities large enough to produce definitive answers (Lawson, 1966) remains an essential component of any general screening programme. SummaryComparison has been made between biochemical (6-phospho- gluconate dehydrogenase activity) and cytological methods of cervical screening in a survey of 4,385 married women attending hospital and general practice clinics.The survey detected 28 cases of carcinoma-in-situ, an overall yield of 6.4 per 1,000.Among the 27 patients for whom enzyme assessment was avail- able, 21 (78%) had at least one result showing an enzyme activity of less than 100 units/g.dried weight.Among 15 carcinoma-in-situ patients with more than one enzyme result, 10 (67%/,) were consistently negative by the same standard.With such a high proportion of false-negative results the enzyme test, as at present developed, cannot be regarded as a practical alternative to cytology for detecting preinvasive cervical cancer.The study's experience of general practice clinics confirmed the contrast between popular demand for cervical screening and the relatively low acceptance rate when this service is offered freely.Less than half of the women eligible attended the clinics.Study of response and prevalence rates from individual practices in relation to their respective social class distribution supported the view that acceptance of screening is lowest among the less health-conscious women at greatest risk, and that this differential response represents a major problem in the development of any effective comprehensive service.The more optimistic hopes for such a service have yet to be realized, and, whatever approach is made to immediate provision of screening facilities, doubts and uncertainties which remain point to the need for supplementing any general pro- gramme with more intensive population studies at a local level.
Hepatic artery pump infusion: toxicity and results in patients with metastatic colorectal carcinoma.
Authors: N Kemeny, J Daly, P Oderman, M Shike, H Chun, G Petroni, N Geller
Journal: Journal of Clinical Oncology (1984)

5-Fluorodeoxyuridine (FUDR) was infused continuously into the hepatic artery for 14 days a month at an initial dose of 0.3 mg/kg per day in 45 patients with liver metastases from colorectal carcinoma. In 41 adequately treated patients, partial responses (greater than 50% tumor regression) were observed in 12 (52%) of 23 previously untreated patients, and three (17%) of 18 previously treated patients. Severe gastrointestinal toxicity was endoscopically documented in 19 (46%) patients; 12 (29%) had discrete ulcers, and seven had diffuse gastritis or duodenitis. Significant hepatic-enzyme abnormality was seen in 29 patients (71%) and an elevated serum bilirubin in nine (22%). A significant factor influencing survival was the extent of tumor involvement in the liver; patients with less than 20% involvement have not yet reached a median survival at 13 months versus six months for patients with greater than 60% involvement (p less than 0.001). Studies comparing regional to systemic chemotherapy and stratifying patients according to the extent of hepatic tumor burden are needed to assess the true impact of hepatic infusion on response and survival.
Helper T cells for cytotoxic T lymphocytes need not be I region restricted
Authors: DH Raulet, MJ Bevan
Journal: The Journal of Experimental Medicine (1982)

We investigated the antigenic requirements for restimulation of H-2- restricted cytolytic T lymphocytes (CTL) in vitro to determine whether H-2 I region-restricted helper T cells are required in these responses. In one set of experiments, we studied the in vitro response of (responder x nonresponder)F(1) female T cells to the male antigen H-Y. We chose to examine this response because it has been suggested that the defect in nonresponder strains is a failure of helper T cells to recognize H-Y in association with nonresponder I region determinants. However, we find that nonresponder male stimulator cells are as effective as F(1) male stimulator cells at inducing H-Y-specific CTL responses. This finding calls into question reports that secondary CTL responses to H-Y are dependent upon the activation of H-Y- specific helper T cells restricted to responder type I region determinants. In a second set of experiments, we examined the requirements for restimulation of H-2-restricted T cells specific for minor-histocompatibility antigens from long-term mixed lymphocyte cultures. These cultures were established by repeatedly restimulating cultures of specific T cells with H- 2-matched stimulator cells expressing foreign minor histocompatibility antigens. We found that H-2D-restricted T ceils, including CTL, could be restimulated with cells that were matched with the responding cells at only the D region genes. This response did not appear to result from positive allogeneic effects or from antigen processing and "representation" by responder type APC that might contaminate the cultures. Thus, we find no evidence for a requirement for I region-restricted helper T cells in these CTL responses. However, helper T cells are required because we find that CTL lines derived by limit-dilution cloning from these long-term MLC are absolutely dependent upon exogenous helper factors for growth. The most simple interpretation of these results is that the helper cells are restricted to H-2 antigens other than I region antigens or to antigens that code outside of the H-2 complex. Finally, we show that factor-dependent CTL lines must recognize their specific antigen to proliferate, even in the presence of exogenous factors. The requirement of activated CTL for antigen to proliferate provides an explanation for how specific CTL can be selectively enriched in MLC by specific antigen stimulation. Furthermore, it is at variance with reports that memory CTL or activated CTL require only interleukin 2 for restimulation.
Change in lung tumor volume as a biomarker of treatment response: a critical review of the evidence
Authors: P.D. Mozley, L.H. Schwartz, C. Bendtsen, B. Zhao, N. Petrick, A.J. Buckler
Journal: Annals of Oncology (2010)

To review the evidence indicating that volumetric image analysis of computed tomography scans meets specifications for qualification as a biomarker in clinical trials or the management of individual patients with lung cancer.Claims of value were broken down into questions about technical feasibility, accuracy, the precision of measurement, sensitivity, the correlations with health outcomes, and the risks of producing misleading information. For each claim, the pertinent literature was reviewed.Technical feasibility has now been shown, but only in limited contexts. Accuracy has been demonstrated, but only for tumors with favorable anatomical features. Measurement error still makes the assessment of change in small nodules precarious in diagnostic settings unless rigorous image acquisition and analysis procedures are followed. Precision is sufficient in some larger masses to make volumetrics a sensitive biomarker. In a few trials, correlations with clinical outcomes have been higher for volumetric-based measures than for unidimensional or bidimensional diameters. Value in clinical practice settings and clinical trials has been suggested, but not proven.The weight of the evidence indicates there are circumstances in which volumetric image analysis adds value to clinical trial science and the practice of medicine.
Inhibition of food-stimulated gastric acid secretion by cimetidine.
Authors: R E Pounder, J G Williams, R C Russell, G J Milton-Thompson, J J Misiewicz
Journal: Gut (1976)

The effect of cimetidine, a new histamine H2-receptor antagonist, on gastric acid secretion stimulated by a homogenised meal was studied in six normal volunteers using an in vivo intragastric titration technique. The subjects were studied twice, no more than 48 h apart, receiving either cimetidine 200 mg or placebo in random order. Cimetidine administered either 32 men before (three subjects) or with the meal (three subjects) significantly inhibited gastric acid secretion in all the subjects throughout the period of study; 96 min after food, total acid secretion decreased by 67 and 57% respectively. When the drug was taken with the meal absorption was slower (mean peak blood level 2-34 mumol/l, 80-128 min after dosing) than when administered on an empty stomach (mean peak blood level 5-08 mumol/l, 48-64 min after dosing). Blood cimetidine concentration correlated significantly (P less than 0-01) with percentage inhibition of acid output and the calculated concentration resulting in 50% inhibition of gastric acid secretion (IC50) was 1-6 mumol/l. Secretion of gastrin in response to food was unaffected by cimetidine. The results suggest that 200 mg cimetidine effectively inhibits food-stimulated acid secretion and that the bioavailability of the drug may be affected by the timing of dosage in relation to meals. No unwanted effect were observed.
The Changing Nature of Rural Health Care
Authors: Thomas C. Ricketts
Journal: Annual Review of Public Health (2000)

▪ Abstract The rural health care system has changed dramatically over the past decade because of a general transformation of health care financing, the introduction of new technologies, and the clustering of health services into systems and networks. Despite these changes, resources for rural health systems remain relatively insufficient. Many rural communities continue to experience shortages of physicians, and the proportion of rural hospitals under financial stress is much greater than that of urban hospitals. The health care conditions of selected rural areas compare unfavorably with the rest of the nation. The market and governmental policies have attempted to address some of these disparities by encouraging network development and telemedicine and by changing the rules for Medicare payments to providers. The public health infrastructure in rural America is not well understood but is potentially the most fragile aspect of the rural health care continuum.
518. Long-Term Lentiviral Vector-Mediated Transgene Expression in Neural Progenitor Cells Following Implantation into the Injured Rat Spinal Cord
Authors: Hiromi Koike, Akihiko Ishida, Munehisa Shimamura, Naoyuki Sato, Naruya Tomita, Yasufumi Kaneda, Ryuichi Morishita
Journal: Molecular Therapy (2004)

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons (DAN) in the substantia nigra (SNi). The ultimate treatment of PD is to prevent DAN from the cell death. We previously showed that hepatocyte growth factor (HGF) resulted in effective prevention of DAN from cell death and remarkable behavioral recovery in 6-hydroxy-dopamine-lesioned parkinsonian rats. In this study, we have extend the preclinical exploration to primate model of PD. Seven days after stereotaxic transfection of human HGF plasmid or pVAX1 control plasmid into the unilateral striatum, infusion of MPTP into the right internal carotid artery of animals produces toxin-induced injury to the right nigro-striatal pathway with sparing of other dopaminergic neurons on the infused side and with negligible or little injury to the opposite, untreated side. After 2 to 3 weeks period, animals exhibited stable moderate parkinsonian features. But animals transfecterd with human HGF plasmid showed normal states. Interestingly, animals transfected with pVAX1 plasmid demonstrated the apomorphine and amphetamine-induced rotational asymmetry. However, the transfection of human HGF plasmid resulted in a significant inhibition of abnormal rotation over 3 months. In immunohistochemistry, more than 90% doperminergic neurons of PD model animals transfecred with pVAX1 plasmid were lost, while more than 70% those of animals transfected with human HGF plasmid were survived. Microdialysis demonstrated that concentrations of dopamine in striatum and SNi in animals transfected with human HGF plasmid were higher compared with PD model. Overall, the present study demonstrated that over-expression of human HGF prevented neuronal death in primate PD model, providing a potential of novel gene therapy for PD using human HGF plasmid.
Strep's key to the brain
Authors: Amy Maxmen
Journal: The Journal of Experimental Medicine (2009)

Meningitis sets in when certain bacteria breach the barrier protecting the brain. [Uchiyama et al.][1] now identify the key protein that Streptococcus pneumoniae (pneumococcus) uses to penetrate that barrier, unleashing a potentially lethal form of meningitis.

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Transactivation of the <b> <i>EGR1</i> </b> Gene Contributes to Mutant p53 Gain of Function
Authors: Lilach Weisz, Amir Zalcenstein, Perry Stambolsky, Yehudit Cohen, Naomi Goldfinger, Moshe Oren, Varda Rotter
Journal: Cancer Research (2004)

Abstract Tumor-associated mutants of the p53 tumor suppressor protein exert biological activities compatible with an oncogenic gain of function. To explore the underlying molecular mechanism, we performed microarray analysis, comparing p53-null cells to mutant p53-expressing cells. One of the genes up-regulated in the presence of mutant p53 was EGR1, a transcription factor implicated in growth control, apoptosis, and cancer. EGR1 induction by various types of stress is markedly augmented in cells expressing mutant p53. Moreover, chromatin immunoprecipitation analysis indicates that mutant p53 is physically associated with the EGR1 promoter. Functional assays indicate that induction of EGR1 by mutant p53 contributes to enhanced transformed properties and resistance to apoptosis. We propose that EGR1 is a significant contributor to mutant p53 gain of function.
Rapid generation of mature hepatocyte-like cells from human induced pluripotent stem cells by an efficient three-step protocol
Authors: Yu-Fan Chen, Chien-Yu Tseng, Hsei-Wei Wang, Hung-Chih Kuo, Vincent W. Yang, Oscar K. Lee
Journal: Hepatology (2011)

Liver transplantation is the only definitive treatment for end-stage cirrhosis and fulminant liver failure, but the lack of available donor livers is a major obstacle to liver transplantation. Recently, induced pluripotent stem cells (iPSCs) derived from the reprogramming of somatic fibroblasts, have been shown to resemble embryonic stem (ES) cells in that they have pluripotent properties and the potential to differentiate into all cell lineages in vitro, including hepatocytes. Thus, iPSCs could serve as a favorable cell source for a wide range of applications, including drug toxicity testing, cell transplantation, and patient-specific disease modeling. Here, we describe an efficient and rapid three-step protocol that is able to rapidly generate hepatocyte-like cells from human iPSCs. This occurs because the endodermal induction step allows for more efficient and definitive endoderm cell formation. We show that hepatocyte growth factor (HGF), which synergizes with activin A and Wnt3a, elevates the expression of the endodermal marker Foxa2 (forkhead box a2) by 39.3% compared to when HGF is absent (14.2%) during the endodermal induction step. In addition, iPSC-derived hepatocytes had a similar gene expression profile to mature hepatocytes. Importantly, the hepatocyte-like cells exhibited cytochrome P450 3A4 (CYP3A4) enzyme activity, secreted urea, uptake of low-density lipoprotein (LDL), and possessed the ability to store glycogen. Moreover, the hepatocyte-like cells rescued lethal fulminant hepatic failure in a nonobese diabetic severe combined immunodeficient mouse model.We have established a rapid and efficient differentiation protocol that is able to generate functional hepatocyte-like cells from human iPSCs. This may offer an alternative option for treatment of liver diseases.
Ultrasonography in screening for developmental dysplasia of the hip in newborns: systematic review
Authors: Nerys F Woolacott, Milo A Puhan, Johann Steurer, Jos Kleijnen
Journal: BMJ (2005)

<h3>Abstract</h3> <b>Objective</b> To assess the accuracy and effectiveness of the screening of all newborn infants for developmental dysplasia of the hip (DDH) using ultrasound imaging, as is standard practice in some European countries but not in the United Kingdom, the United States, or Scandinavia. <b>Design</b> Systematic review. <b>Data sources</b> Twenty three medical, economic, and grey literature databases (to March 2004), with no limitations of design or language; some references were provided by experts. <b>Selection of studies</b> Only diagnostic accuracy studies and comparative studies conducted in an unselected newborn population were eligible for the review. Two reviewers independently selected the studies and performed the quality assessment. <b>Results</b> The review identified one diagnostic accuracy study, and this was of limited quality. In this study the reference standard was treatment up to age of 8 months or an abnormal ultrasound finding at age 8 months. Ultrasound screening had a sensitivity of 88.5% (95% confidence interval 84.1% to 92.1%), specificity of 96.7% (96.4% to 97.4%), a positive predictive value of 61.6% and a negative predictive value of 99.4%. Ten studies evaluated the impact of ultrasound in screening, but these too had various methodological weaknesses, limiting the reliability of their findings. Compared with clinical screening, general ultrasound screening in newborns may increase overall treatment rates, but ultrasound screening seems to be associated with shorter and less intrusive treatment. <b>Conclusions</b> Clear evidence is lacking either for or against general ultrasound screening of newborn infants for DDH. Studies that investigate the natural course of the disorder, the optimal treatment for DDH, and the best strategy for ultrasound screening are needed.