tbuckley/cabot-search huggingface dataset:
Assessment of Second-Line Antiretroviral Regimens for HIV Therapy in Africa
Authors: Nicholas I. Paton, Cissy Kityo, Anne Hoppe, Andrew Reid, Andrew Kambugu, Abbas Lugemwa, Joep J. van Oosterhout, Mary Kiconco, Abraham Siika, Raymond Mwebaze, Mary Abwola, George Abongomera, Aggrey Mweemba, Hillary Alima, Dickens Atwongyeire, Rose Nyirenda, Justine Boles, Jennifer Thompson, Dinah Tumukunde, Ennie Chidziva, Ivan Mambule, Jose R. Arribas, Philippa J. Easterbrook, James Hakim, A. Sarah Walker, Peter Mugyenyi
Journal: New England Journal of Medicine (2014)

The efficacy and toxic effects of nucleoside reverse-transcriptase inhibitors (NRTIs) are uncertain when these agents are used with a protease inhibitor in second-line therapy for human immunodeficiency virus (HIV) infection in resource-limited settings. Removing the NRTIs or replacing them with raltegravir may provide a benefit.In this open-label trial in sub-Saharan Africa, we randomly assigned 1277 adults and adolescents with HIV infection and first-line treatment failure to receive a ritonavir-boosted protease inhibitor (lopinavir-ritonavir) plus clinician-selected NRTIs (NRTI group, 426 patients), a protease inhibitor plus raltegravir in a superiority comparison (raltegravir group, 433 patients), or protease-inhibitor monotherapy after 12 weeks of induction therapy with raltegravir in a noninferiority comparison (monotherapy group, 418 patients). The primary composite end point, good HIV disease control, was defined as survival with no new World Health Organization stage 4 events, a CD4+ count of more than 250 cells per cubic millimeter, and a viral load of less than 10,000 copies per milliliter or 10,000 copies or more with no protease resistance mutations at week 96 and was analyzed with the use of imputation of data (≤4%).Good HIV disease control was achieved in 60% of the patients (mean, 255 patients) in the NRTI group, 64% of the patients (mean, 277) in the raltegravir group (P=0.21 for the comparison with the NRTI group; superiority of raltegravir not shown), and 55% of the patients (mean, 232) in the monotherapy group (noninferiority of monotherapy not shown, based on a 10-percentage-point margin). There was no significant difference in rates of grade 3 or 4 adverse events among the three groups (P=0.82). The viral load was less than 400 copies per milliliter in 86% of patients in the NRTI group, 86% in the raltegravir group (P=0.97), and 61% in the monotherapy group (P<0.001).When given with a protease inhibitor in second-line therapy, NRTIs retained substantial virologic activity without evidence of increased toxicity, and there was no advantage to replacing them with raltegravir. Virologic control was inferior with protease-inhibitor monotherapy. (Funded by European and Developing Countries Clinical Trials Partnership and others; EARNEST Current Controlled Trials number, ISRCTN37737787, and ClinicalTrials.gov number, NCT00988039.).
The Origins of Schizophreniaedited by BrownAlan S., M.D., M.P.H., and PattersonPaul H., Ph.D. New York, Columbia University Press, 2011, 448 pp., $80.00.<b>Infectious Behavior: Brain-Immune Connections in Autism, Schizophrenia, and Depression</b>, by PattersonPaul H., Ph.D. Cambridge, Mass., MIT Press, 2011, 176, pp., $24.95.
Authors: Dolores Malaspina
Journal: American Journal of Psychiatry (2012)
Effect of Simvastatin on Cetuximab Resistance in Human Colorectal Cancer With KRAS Mutations
Authors: Jeeyun Lee, Inkyoung Lee, Boram Han, Joon Oh Park, Jiryeon Jang, Chaehwa Park, Won Ki Kang
Journal: JNCI Journal of the National Cancer Institute (2011)

Metastatic colorectal cancer (CRC) patients with v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are resistant to treatment with cetuximab, a monoclonal antibody that targets the epidermal growth factor receptor. Statins have reported antitumor activity, but it is unknown whether simvastatin can reverse cetuximab resistance in KRAS mutant CRC. Human CRC cell lines with KRAS mutations (LS153, LS174T, DLD1, LoVo, SW403, SW480, SNU175, and LS1034) or with v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations (DiFi, SW48, HT29, and RKO) were used to test the effect of cetuximab, simvastatin, and cetuximab plus simvastatin on cell proliferation and apoptosis in vitro. Because BRAF V600E mutant may be responsible for cetuximab resistance in KRAS wild-type cells, we measured the growth of xenograft tumors originating from KRAS mutant and BRAF mutant cells in mice treated with cetuximab alone or plus simvastatin (n = 5 mice per treatment group). We used immunoblot assays to study RAS-regulated activation of BRAF protein after simvastatin treatment. All statistical tests were two-sided. Addition of simvastatin (0.2 μM) to cetuximab (0.03–1.0 μM) reduced cell proliferation of KRAS mutant ( P < .001) but not of BRAF mutant CRC cells in vitro. Treatment of KRAS mutant cells with simvastatin reduced BRAF activity and induced apoptosis. Treatment with cetuximab and simvastatin reduced the growth of xenograft tumors originating from KRAS mutant cells compared with cetuximab alone (eg, for tumors originating from DLD1 cells, cetuximab vs cetuximab + simvastatin, mean tumor volume = 49.4 vs 20.2 cm 3 , mean difference = 29.2 cm 3 , 95% confidence interval = 19.7 to 38.5, P < .001); treatment with cetuximab alone or in combination with simvastatin had no effect on the growth of BRAF mutant tumors. Simvastatin may overcome cetuximab resistance in colon cancer cells with KRAS mutations by modulating BRAF activity and inducing apoptosis.
Neutrophils, interleukin-17A and lung disease
Authors: A. Linden
Journal: European Respiratory Journal (2005)

It is now established that an excessive and sustained mobilisation of neutrophils is a hallmark of several chronic inflammatory lung disorders, including severe obstructive lung disease. This article reviews evidence that the cytokine interleukin (IL)-17A is a major orchestrator of sustained neutrophilic mobilisation. Current evidence suggests that IL-17A is produced by T-lymphocytes, and that it exerts an orchestrating effect on the accumulation and associated activity of neutrophils in the bronchoalveolar space indirectly, through an induced release of specific cytokines and colony-stimulating factors in resident lung cells. Although the involvement of IL-17A in inflammatory lung disorders is supported by several recent studies, its causative role is still uncertain. However, the unique position of interleukin-17A at the interface between acquired and innate immunity puts this cytokine forward as an important signal for the reinforcement of host defence; it also implies that interleukin-17A may constitute a useful target for pharmacotherapeutic intervention.
Increased Number of Subcortical Hyperintensities on MRI in Children and Adolescents With Tourette’s Syndrome, Obsessive-Compulsive Disorder, and Attention Deficit Hyperactivity Disorder
Authors: Jose A. Amat, Richard A. Bronen, Sanjay Saluja, Noriko Sato, Hongtu Zhu, Daniel A. Gorman, Jason Royal, Bradley S. Peterson
Journal: American Journal of Psychiatry (2006)

Objective: To investigate whether cerebral hyperintensities on T 2 -weighted magnetic resonance images (MRI) are associated with childhood neuropsychiatric disorders. Method: The authors compared the frequency of cortical and subcortical cerebral hyperintensities in 100 children and adolescents with Tourette's syndrome, obsessive-compulsive disorder (OCD), or attention deficit hyperactivity disorder (ADHD) and 32 healthy comparison subjects. Results: The frequency of cerebral hyperintensities was significantly higher in subjects with Tourette's syndrome, OCD, or ADHD than in healthy comparison subjects; each diagnostic group seemed to contribute to this effect. Among the patient groups, the likelihood of detecting cerebral hyperintensities in the subcortex (primarily the basal ganglia and thalamus) was significantly greater than in the cortex. Conclusions: A childhood diagnosis of Tourette's syndrome, OCD, or ADHD significantly increased the likelihood of detecting cerebral hyperintensities, particularly in the subcortex, supporting the notion that subcortical injury may play a role in the pathophysiology of these conditions.
Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials
Authors: L.E. Brattstrom, M. den Heijer, H.J. Blom, G. Bos, A.P. Spaans, F.R. Rosendaal, C.M.G. Thomas, H.L. Haak
Journal: BMJ (1998)

<h3>Abstract</h3> <b>Objective:</b> To determine the size of reduction in homocysteine concentrations produced by dietary supplementation with folic acid and with vitamins B-12 or B-6. <b>Design:</b> Meta-analysis of randomised controlled trials that assessed the effects of folic acid based supplements on blood homocysteine concentrations. Multivariate regression analysis was used to determine the effects on homocysteine concentrations of different doses of folic acid and of the addition of vitamin B-12 or B-6. <b>Subjects:</b> Individual data on 1114 people included in 12 trials. <b>Findings:</b> The proportional and absolute reductions in blood homocysteine produced by folic acid supplements were greater at higher pretreatment blood homocysteine concentrations (P&lt;0.001) and at lower pretreatment blood folate concentrations (P&lt;0.001). After standardisation to pretreatment blood concentrations of homocysteine of 12 μmol/l and of folate of 12 nmol/l (approximate average concentrations for Western populations), dietary folic acid reduced blood homocysteine concentrations by 25% (95% confidence interval 23% to 28%; P&lt;0.001), with similar effects in the range of 0.5-5 mg folic acid daily. Vitamin B-12 (mean 0.5 mg daily) produced an additional 7% (3% to 10%) reduction in blood homocysteine. Vitamin B-6 (mean 16.5 mg daily) did not have a significant additional effect. <b>Conclusions:</b> Typically in Western populations, daily supplementation with both 0.5-5 mg folic acid and about 0.5 mg vitamin B-12 would be expected to reduce blood homocysteine concentrations by about a quarter to a third (for example, from about 12 μmol/l to 8-9 μmol/l). Large scale randomised trials of such regimens in high risk populations are now needed to determine whether lowering blood homocysteine concentrations reduces the risk of vascular disease. <h3>Key messages</h3> Higher blood homocysteine concentrations seem to be associated with higher risks of occlusive vascular disease and with lower blood concentrations of folate and vitamins B-12 and B-6 Proportional and absolute reductions in blood homocysteine concentrations with folic acid supplements are greater at higher pretreatment blood homocysteine concentrations and at lower pretreatment blood folate concentrations In typical Western populations, supplementation with both 0.5-5 mg daily folic acid and about 0.5 mg daily vitamin B-12 should reduce blood homocysteine concentrations by about a quarter to a third Large scale randomised trials of such regimens in people at high risk are now needed to determine whether lowering blood homocysteine concentrations reduces the risk of vascular disease
HLA-Derived Peptides as Novel Immunomodulatory Therapeutics
Authors: BARBARA MURPHY, ALAN M. KRENSKY
Journal: Journal of the American Society of Nephrology (1999)

Abstract. A growing body of experimental evidence demonstrates that synthetic peptides corresponding to linear sequences of MHC (HLA in humans) proteins have immunomodulatory effects in vitro and in vivo in animal models and in humans. Although the original concept was that these peptides inhibited antigen recognition at the MHC-T cell receptor interface via physical blockade, it is now clear that the mechanisms responsible for the myriad of functional effects are more complex. Recent findings show that some peptides affect signal transduction and cell cycle progression. Fragments of MHC molecules can dampen or downregulate immune responses via a variety of mechanisms. Some soluble MHC molecules or synthetic peptides are capable of inducing and maintaining immunologic tolerance in animals. This information suggests that synthetic peptides themselves or drugs mimicking their effects may represent a new class of immunotherapeutics.
Amantadine in the Treatment of Cocaine-Dependent Patients With Severe Withdrawal Symptoms
Authors: Kyle M. Kampman, Joseph R. Volpicelli, Arthur I. Alterman, James Cornish, Charles P. O’Brien
Journal: American Journal of Psychiatry (2000)

OBJECTIVE: The study examined the effectiveness of amantadine in reducing cocaine withdrawal symptoms and improving treatment outcome among cocaine-dependent patients in outpatient treatment. METHOD: Sixty-one cocaine-dependent subjects participated in a double-blind, placebo-controlled trial of amantadine. RESULTS: Among subjects with severe cocaine withdrawal symptoms at the start of treatment, those who received amantadine used significantly less cocaine during the trial than did subjects who received placebo. Compared to subjects who received placebo, subjects who received amantadine submitted significantly more benzoylecgonine-negative urine samples and used cocaine on significantly fewer days during the trial. CONCLUSIONS: Amantadine may be an effective treatment for cocaine-dependent patients with severe cocaine withdrawal symptoms.
An Expanded Peripheral T Cell Population to a Cytotoxic T Lymphocyte (Ctl)-Defined, Melanocyte-Specific Antigen in Metastatic Melanoma Patients Impacts on Generation of Peptide-Specific Ctls but Does Not Overcome Tumor Escape from Immune Surveillance in Metastatic Lesions
Authors: Andrea Anichini, Alessandra Molla, Roberta Mortarini, Gabrina Tragni, Ilaria Bersani, Massimo Di Nicola, Alessandro M. Gianni, Silvana Pilotti, Rod Dunbar, Vincenzo Cerundolo, Giorgio Parmiani
Journal: The Journal of Experimental Medicine (1999)

It is not known if immune response to T cell–defined human histocompatibility leukocyte antigen (HLA) class I–restricted melanoma antigens leads to an expanded peripheral pool of T cells in all patients, affects cytotoxic T lymphocyte (CTL) generation, and correlates with anti-tumor response in metastatic lesions. To this end, a limiting dilution analysis technique was developed that allowed us to evaluate the same frequency of peptide-specific T cells as by staining T cells with HLA–peptide tetrameric complexes. In four out of nine patients, Melan-A/Mart-127–35–specific CTL precursors (CTLp) were ≥1/2,000 peripheral blood lymphocytes and found mostly or only in the CD45RO+ memory T cell subset. In the remaining five patients, a low (&amp;lt;1/40,000) peptide-specific CTLp frequency was measured, and the precursors were only in the CD45RA+ naive T cell subset. Evaluation of CTL effector frequency after bulk culture indicated that peptide-specific CTLs could be activated in all patients by using professional antigen-presenting cells as dendritic cells, but CTLp frequency determined the kinetics of generation of specificity and the final number of effectors as evaluated by both limiting dilution analysis and staining with HLA-A*0201–Melan-A/Mart-1 tetrameric complexes. Immunohistochemical analysis of 26 neoplastic lesions from the nine patients indicated absence of tumor regression in most instances, even in patients with an expanded peripheral T cell pool to Melan-A/Mart-1 and whose neoplastic lesions contained a high frequency of tetramer-positive Melan-A/Mart-1–specific T cells. Furthermore, frequent lack of a “brisk” or “nonbrisk” CD3+CD8+ T cell infiltrate or reduced/absent Melan-A/Mart-1 expression in several lesions and lack of HLA class I antigens were found in some instances. Thus, expansion of peripheral immune repertoire to Melan-A/Mart-1 takes place in some metastatic patients and leads to enhanced CTL induction after antigen-presenting cell–mediated selection, but, in most metastatic lesions, it does not overcome tumor escape from immune surveillance.
Higher Gestational Weight Gain Is Associated With Increasing Offspring Birth Weight Independent of Maternal Glycemic Control in Women With Type 1 Diabetes
Authors: Anna L. Secher, Clara B. Parellada, Lene Ringholm, Björg Ásbjörnsdóttir, Peter Damm, Elisabeth R. Mathiesen
Journal: Diabetes Care (2014)

OBJECTIVE We evaluate the association between gestational weight gain and offspring birth weight in singleton term pregnancies of women with type 1 diabetes. RESEARCH DESIGN AND METHODS One hundred fifteen consecutive women referred at &amp;lt;14 weeks were retrospectively classified as underweight (prepregnancy BMI &amp;lt;18.5 kg/m2; n = 1), normal weight (18.5–24.9; n = 65), overweight (25.0–29.9; n = 39), or obese (≥30.0; n = 10). Gestational weight gain was categorized as excessive, appropriate, or insufficient according to the Institute of Medicine recommendations for each BMI class. Women with nephropathy, preeclampsia, and/or preterm delivery were excluded because of restrictive impact on fetal growth and limited time for total weight gain. RESULTS HbA1c was comparable at ∼6.6% (49 mmol/mol) at 8 weeks and ∼6.0% (42 mmol/mol) at 36 weeks between women with excessive (n = 62), appropriate (n = 37), and insufficient (n = 16) gestational weight gain. Diabetes duration was comparable, and median prepregnancy BMI was 25.3 (range 18–41) vs. 23.5 (18–31) vs. 22.7 (20–30) kg/m2 (P = 0.05) in the three weight gain groups. Offspring birth weight and birth weight SD score decreased across the groups (3,681 [2,374–4,500] vs. 3,395 [2,910–4,322] vs. 3,295 [2,766–4,340] g [P = 0.02] and 1.08 [−1.90 to 3.25] vs. 0.45 [−0.83 to 3.18] vs. −0.02 [−1.51 to 2.96] [P = 0.009], respectively). In a multiple linear regression analysis, gestational weight gain (kg) was positively associated with offspring birth weight (g) (β = 19; P = 0.02) and birth weight SD score (β = 0.06; P = 0.008) when adjusted for prepregnancy BMI, HbA1c at 36 weeks, smoking, parity, and ethnicity. CONCLUSIONS Higher gestational weight gain in women with type 1 diabetes was associated with increasing offspring birth weight independent of glycemic control and prepregnancy BMI.
Increased coronary heart disease in Japanese-American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels.
Authors: S Zhong, D S Sharp, J S Grove, C Bruce, K Yano, J D Curb, A R Tall
Journal: Journal of Clinical Investigation (1996)

Plasma high density lipoprotein (HDL) levels are strongly genetically determined and show a general inverse relationship with coronary heart disease (CHD). The cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl esters from HDL to other lipoproteins and is a key participant in the reverse transport of cholesterol from the periphery to the liver. A high prevalence of two different CETP gene mutations (D442G, 5.1%; intron 14G:A, 0.5%), was found in 3,469 men of Japanese ancestry in the Honolulu Heart Program and mutations were associated with decreased CETP (-35%) and increased HDL chol levels (+10% for D442G). However, the overall prevalence of definite CHD was 21% in men with mutations and 16% in men without mutations. The relative risk (RR) of CHD was 1.43 in men with mutations (P < .05); after adjustment for CHD risk factors, the RR was 1.55 (P = .02); after additional adjustment for HDL levels, the RR was 1.68 (P = .008). Similar RR values were obtained for the D442G mutation alone. Increased CHD in men with mutations was primarily observed for HDL chol 41-60 mg/dl; for HDL chol > 60 mg/dl men with and without mutations had low CHD prevalence. Thus, genetic CETP deficiency appears to be an independent risk factor for CHD, primarily due to increased CHD prevalence in men with the D442G mutation and HDL cholesterol between 41 and 60 mg/dl. The findings suggest that both HDL concentration and the dynamics of cholesterol transport through HDL (i.e., reverse cholesterol transport) determine the anti-atherogenicity of the HDL fraction.
The Effects of Colestipol Resin and of Colestipol Plus Clofibrate on the Turnover of Plasma Cholesterol in Man
Authors: DeWitt S. Goodman, Robert P. Noble, Ralph B. Dell
Journal: Journal of Clinical Investigation (1973)

Studies were conducted to determine the effects of colestipol hydrochloride, a new bile acid-sequestrant resin, on some of the parameters of cholesterol turnover and metabolism in man. Three normal volunteers and eight hyperlipidemic patients participated in three sets of cholesterol turnover studies carried out at intervals of approximately 1 yr. The effects of colestipol were assessed by comparing the results obtained before therapy with those obtained on repeat study after several months of resin therapy. Colestipol treatment significantly reduced the serum cholesterol concentration (mean reduction 21%), and produced a large increase in the production rate of cholesterol (mean 86%) and in the turnover rate of cholesterol in pool 1 (mean 46%). The values of the intercompartmental rate constants and of the size of the rapidly exchangeable pool were unchanged with therapy. The turnover studies were carried out for 12-13 wk, and were analyzed according to a two-pool model. Although long-term studies of cholesterol turnover conform to a three-pool, rather than a two-pool model, the present studies probably provide a valid estimate of the effects of therapy on certain parameters, namely the production rate, the size, and the turnover rate of pool 1. Repeated studies in four untreated subjects showed a striking constancy with time for the kinetic parameters for each subject. The production rate was particularly constant from year to year for a given subject, and showed a pooled standard deviation of only 3%. The findings suggest that the total body turnover of cholesterol is under close homeostatic control in an integrated manner. Combined drug therapy with colestipol plus clofibrate further reduced the serum cholesterol level in three of four patients, and reduced the triglyceride level in all four patients. Addition of clofibrate to the treatment program produced only small decreases in the production rate, which were not significantly different from the small decreases seen in two patients who were continued (and restudied) on colestipol alone. The findings do not support the suggestion that clofibrate can block the increased rate of cholesterol synthesis and turnover resulting from bile acid-sequestrant treatment. The effects on serum lipids, however, make the combined drug therapy potentially quite useful.
Review of Inmaculada de Melo-Martin, Taking Biology Seriously: What Biology Can &amp; Cannot Tell Us About Moral &amp; Public Policy Issues<sup>1</sup>
Authors: Suzanne Holland, Stephanie M. Fullerton
Journal: The American Journal of Bioethics (2007)

Earlier this year, newspapers across the country featured a series of articles about a Texas “garage operation” that had been advertising ready-made embryos for sale on the Internet. Jennalee Ryan,...