tbuckley/cabot-search huggingface dataset:
The Oral Neurokinin-1 Antagonist Aprepitant for the Prevention of Chemotherapy-Induced Nausea and Vomiting: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial in Patients Receiving High-Dose Cisplatin—The Aprepitant Protocol 052 Study Group
Authors: Paul J. Hesketh, Steven M. Grunberg, Richard J. Gralla, David G. Warr, Fausto Roila, Ronald de Wit, Sant P. Chawla, Alexandra D. Carides, Juliana Ianus, Mary E. Elmer, Judith K. Evans, Klaus Beck, Scott Reines, Kevin J. Horgan
Journal: Journal of Clinical Oncology (2003)

In early clinical trials with patients receiving highly emetogenic chemotherapy, the neurokinin antagonist aprepitant significantly enhanced the efficacy of a standard antiemetic regimen consisting of a type-three 5-hydroxytryptamine antagonist and a corticosteroid. This multicenter, randomized, double-blind, placebo-controlled phase III study was performed to establish definitively the superiority of the aprepitant regimen versus standard therapy in the prevention of chemotherapy-induced nausea and vomiting (CINV).Patients receiving cisplatin > or = 70 mg/m2 for the first time were given either standard therapy (ondansetron and dexamethasone on day 1; dexamethasone on days 2 to 4) or an aprepitant regimen (aprepitant plus ondansetron and dexamethasone on day 1; aprepitant and dexamethasone on days 2 to 3; dexamethasone on day 4). Patients recorded nausea and vomiting episodes in a diary. The primary end point was complete response (no emesis and no rescue therapy) on days 1 to 5 postcisplatin, analyzed by a modified intent-to-treat approach. Treatment comparisons were made using logistic regression models. Tolerability was assessed by reported adverse events and physical and laboratory assessments.The percentage of patients with complete response on days 1 to 5 was significantly higher in the aprepitant group (72.7% [n = 260] v 52.3% in the standard therapy group [n = 260]), as were the percentages on day 1, and especially on days 2 to 5 (P <.001 for all three comparisons).Compared with standard dual therapy, addition of aprepitant was generally well tolerated and provided consistently superior protection against CINV in patients receiving highly emetogenic cisplatin-based chemotherapy.
Accuracy of Screening for Fecal Occult Blood on a Single Stool Sample Obtained by Digital Rectal Examination: A Comparison with Recommended Sampling Practice
Authors: Judith F. Collins, David A. Lieberman, Theodore E. Durbin, David G. Weiss
Journal: Annals of Internal Medicine (2005)

Many expert panels recommend colorectal cancer screening for average-risk asymptomatic individuals older than 50 years of age. Recent studies have found that 24% to 64% of primary care providers use only the digital fecal occult blood test (FOBT) as their primary screening test. The effectiveness of a single digital FOBT is unknown.To compare the sensitivity and specificity of digital FOBT and the recommended 6-sample at-home FOBT for advanced neoplasia in asymptomatic persons.Prospective cohort study.13 Veterans Affairs medical centers.3121 asymptomatic patients 50 to 75 years of age.2665 patients had 6-sample at-home FOBT and digital FOBT, followed by complete colonoscopy.We measured the sensitivity of digital and 6-sample FOBT for advanced neoplasia and the specificity for no neoplasia. We calculated predictive values and likelihood ratios for advanced neoplasia, defined as tubular adenomas 10 mm or greater, adenomas with villous histology or high-grade dysplasia, or invasive cancer.Of all participants, 96.8% were men; their average age was 63.1 years. The 6-sample FOBT and the single digital FOBT had specificities of 93.9% and 97.5%, respectively, as defined by studying 1656 patients with no neoplasia. Sensitivities for detection of advanced neoplasia in 284 patients were 23.9% for the 6-sample FOBT and 4.9% for the digital FOBT. The likelihood ratio for advanced neoplasia was 1.68 (95% CI, 0.96 to 2.94) for positive results on digital FOBT and 0.98 (CI, 0.95 to 1.01) for negative results.Most patients were men.Single digital FOBT is a poor screening method for colorectal neoplasia and cannot be recommended as the only test. When digital FOBT is performed as part of a primary care physical examination, negative results do not decrease the odds of advanced neoplasia. Persons with these results should be offered at-home 6-sample FOBT or another type of screening test.
Prostaglandin E2 systemic production in patients with asthma with and without aspirin hypersensitivity
Authors: L Mastalerz, M Sanak, A Gawlewicz-Mroczka, A Gielicz, A Cmiel, A Szczeklik
Journal: Thorax (2007)

<h3>Background:</h3> A special regulatory role for prostaglandin E<sub>2</sub> has been postulated in aspirin-induced asthma. A study was undertaken to investigate the effects of aspirin on the systemic production of prostaglandin E<sub>2</sub> and cysteinyl leucotrienes in patients with asthma. <h3>Methods:</h3> The urinary concentrations were determined of two main prostaglandin E<sub>2</sub> metabolites (13,14-dihydro-15keto-PGE<sub>2</sub> using a commercial enzyme immunoassay and 9,15-dioxo-11α-hydroxy-2,3,4,5-tetranor-prostane-1,20-dioic acid by gas chromatography/mass spectrometry) and leucotriene E<sub>4</sub> using an immunoassay. Determinations were performed at baseline and following oral aspirin and celecoxib challenges in two well-defined asthma phenotypes: aspirin-sensitive and aspirin-tolerant patients. <h3>Results:</h3> Aspirin precipitated bronchial reactions in all aspirin-sensitive patients but in none of the aspirin-tolerant patients. Celecoxib 400 mg was well tolerated by all patients except for one with aspirin-induced asthma. At baseline, the mean levels of prostaglandin E<sub>2</sub> metabolites did not differ between the groups. Following different aspirin provocation doses, the mean levels of the two main prostaglandin E<sub>2</sub> metabolites were decreased in the aspirin-tolerant group but remained unchanged in the aspirin-sensitive group. The dose of aspirin had no effect on the magnitude of the response on the prostaglandin E<sub>2</sub> metabolites and its duration. In both groups, urinary prostaglandin E<sub>2</sub> metabolites decreased following celecoxib challenge. No correlation was found between prostaglandin E<sub>2</sub> metabolites and leucotriene E<sub>4</sub>. <h3>Conclusions:</h3> Aspirin-precipitated asthmatic attacks are not associated with changes in the systemic production of prostaglandin E<sub>2</sub>. In contrast, the systemic production of prostaglandin E<sub>2</sub> becomes depressed by aspirin in non-sensitive patients. This different response might indicate COX-1-dependent prostaglandin E<sub>2</sub> control of inflammatory cells in aspirin-induced asthma. Thus, PGE<sub>2</sub> is released during the clinical reactions to aspirin through an alternative COX-2 pathway. The clinical implications of this finding are in line with current observations of good tolerance of the selective COX-2 inhibitors in aspirin-sensitive patients.
"It's make your mind up time" on social care funding, MPs are told
Authors: A. O'Dowd
Journal: BMJ (2012)

Reform of social care in England is taking far too long, and delay will seriously affect people’s health and quality of life, experts have told MPs.

The government’s plans for a white paper on social care have been delayed, despite a large scale independent review on funding of social care for adults in England, the Dilnot report, being published almost a year ago, with specific recommendations.1

All four witnesses appearing before the parliamentary health select committee on 19 June for the first evidence session of its new inquiry into social care condemned ongoing delays in publishing the white paper.

After the publication of Dilnot’s review in July 2011, the health committee conducted an inquiry into social care, publishing its report in February this year. …
Residual Type 1 Immunity in Patients Genetically Deficient for Interleukin 12 Receptor β1 (IL-12Rβ1)
Authors: Claudia E. Verhagen, Tjitske de Boer, Hermelijn H. Smits, Frank A.W. Verreck, Eddy A. Wierenga, M. Kurimoto, D. Anthony Lammas, Dinakanthe S. Kumararatne, Ozden Sanal, Frank P. Kroon, Jaap T. van Dissel, Francesco Sinigaglia, Tom H.M. Ottenhoff
Journal: The Journal of Experimental Medicine (2000)

Genetic lack of interleukin 12 receptor β1 (IL-12Rβ1) surface expression predisposes to severe infections by poorly pathogenic mycobacteria or Salmonella and causes strongly decreased, but not completely abrogated, interferon (IFN)-γ production. To study IL-12Rβ1–independent residual IFN-γ production, we have generated mycobacterium–specific T cell clones (TCCs) from IL-12Rβ1–deficient individuals. All TCCs displayed a T helper type 1 phenotype and the majority responded to IL-12 by increased IFN-γ production and proliferative responses upon activation. This response to IL-12 could be further augmented by exogenous IL-18. IL-12Rβ2 was found to be normally expressed in the absence of IL-12Rβ1, and could be upregulated by IFN-α. Expression of IL-12Rβ2 alone, however, was insufficient to induce signal transducer and activator of transcription (Stat)4 activation in response to IL-12, whereas IFN-α/IFN-αR ligation resulted in Stat4 activation in both control and IL-12Rβ1–deficient cells. IL-12 failed to upregulate cell surface expression of IL-18R, integrin α6, and IL-12Rβ2 on IL-12Rβ1–deficient cells, whereas this was normal on control cells. IL-12–induced IFN-γ production in IL-12Rβ1–deficient T cells could be inhibited by the p38 mitogen-activated protein kinase (MAP) kinase inhibitor SB203580 and the MAP kinase kinase (MEK) 1/2 inhibitor U0126, suggesting involvement of MAP kinases in this alternative, Stat4-independent, IL-12 signaling pathway. Collectively, these results indicate that IL-12 acts as a partial agonist in the absence of IL-12Rβ1. Moreover, the results reveal the presence of a novel IL-12Rβ1/Stat4–independent pathway of IL-12 responsiveness in activated human T cells involving MAP kinases. This pathway is likely to play a role in the residual type 1 immunity in IL-12Rβ1 deficiency.
Early Detection of Small-Fiber Neuropathy in Diabetes
Authors: Giuseppe Pozzessere, Paolo Rossi, Annarita Gabriele, Rosalba Cipriani, Antonino Morocutti, Umberto Di Mario, Susanna Morano
Journal: Diabetes Care (2002)

Over the last 15 years, many authors have pointed out that small nerve fibers may be selectively damaged in the early stages of diabetes, leading to an early impairment of pain and temperature sensations and to a decline in autonomic nervous function (1,2).

The CO2 pain-induced laser somatosensory-evoked potential (pSEP) evaluation may represent a new quantitative and objective approach to evaluate pain and temperature sensation functions (3–8). Recently, Agostino et al. (9) reported small-fiber dysfunction assessed by pSEPs in diabetic patients with different degrees of peripheral nerve damage.

A total of 27 diabetic patients (12 type 1 [group 1] and 15 type 2 [group 2]) and 27 age-, sex-, and height-matched control subjects were included in the study. In group 1 (6 men and 6 women), the mean age was 33.6 ± 9 years, the duration of diabetes was 13.5 ± 6.7 years, and the glycated hemoglobin was 6.1 ± 1.3%; two patients had nephropathy and three had background retinopathy. In group 2 (7 men and 8 women), the mean age was 55.3 ± 8.8 years, the duration of diabetes was 8.2 ± 6.2 years, and the glycated hemoglobin was 6.8 ± 1.5%; three patients had nephropathy and four had background retinopathy. The patients reported no history of autonomic and somatic neuropathy and had negative clinical examinations (evaluated using the Neuropathy Symptom Score [NSS], the Neurological Symptom Profile [NSP], and the Neurologic Disability Score [NDS]) (10); normal nerve conduction velocity and P100 latency at visual-evoked potentials (VEPs) recording; no severe diabetic retinopathy or other opthalmological diseases; no recurrent ketoacidosis, ketonuria, or hypoglycemia; no psychiatric disorders or alcohol consumption; no cognitive impairment; and no other diseases or treatment with medications known to influence nervous system function. Two control groups (groups 3 and 4) were included …
Comparison of Viral Load in Individuals with and without Asthma during Infections with Rhinovirus
Authors: Joshua L. Kennedy, Marcus Shaker, Victoria McMeen, James Gern, Holliday Carper, Deborah Murphy, Wai-Ming Lee, Yury A. Bochkov, Rose F. Vrtis, Thomas Platts-Mills, James Patrie, Larry Borish, John W. Steinke, William A. Woods, Peter W. Heymann
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Rationale: Most virus-induced attacks of asthma are caused by rhinoviruses (RVs).Objectives: To determine whether people with asthma are susceptible to an increased viral load during RV infection.Methods: Seventy-four children (4–18 yr old) were enrolled; 28 with wheezing, 32 with acute rhinitis, and 14 without respiratory tract symptoms. Nasal washes were evaluated using quantitative polymerase chain reaction for RV to judge viral load along with gene sequencing to identify strains of RV. Soluble intercellular adhesion molecule-1, IFN-λ1, and eosinophil cationic protein in nasal washes, along with blood eosinophil counts and total and allergen-specific IgE in sera, were also evaluated. Similar assessments were done in 24 young adults (16 with asthma, 8 without) who participated in an experimental challenge with RV (serotype 16).Measurements and Main Results: Fifty-seven percent of wheezing children and 56% with acute rhinitis had nasal washes testing positive for RV. The geometric mean of viral loads by quantitative polymerase chain reaction in washes from wheezing children was 2.8-fold lower, but did not differ significantly from children with rhinitis (7,718 and 21,612 copies of viral RNA per microliter nasal wash, respectively; P = 0.48). The odds for wheezing were increased if children who tested positive for RV were sensitized to one or more allergens (odds ratio, 3.9; P = 0.02). Similarly, neither peak nor cumulative viral loads differed significantly in washes from adults with asthma compared with those without asthma during the experimental RV challenge.Conclusions: During acute symptoms, children infected with RV enrolled for wheezing or acute rhinitis had similar viral loads in their nasal washes, as did adults with and without asthma infected with RV-16 experimentally.
Hepatitis C virus infection in hemodialysis patients
Authors: K al Meshari, O Alfurayh, M Al Ahdal, W Qunibi, G Kessie, E De Vol
Journal: Journal of the American Society of Nephrology (1995)

The performance of two new hepatitis C virus antibody (anti-HCV) assays (a third-generation immunoglobulin (Ig)G recombinant immunoblot assay (RIBA 3.0) and hepatitis C virus core IgM (HCV IgM) in the prediction of hepatitis C viremia in hemodialysis patients was compared with that of a second-generation IgG recombinant immunoblot assay (RIBA 2.0). Forty-three patients on maintenance hemodialysis were studied. Aliquots of sera were tested prospectively for anti-HCV by RIBA 2.0, RIBA 3.0, and HCV IgM and for HCV RNA by polymerase chain reaction. Thirty-eight patients were HCV RNA positive. Among those, 7 (18%) were HCV IgM positive, 22 (58%) were RIBA 2.0 positive, and 29 (76%) were RIBA 3.0 positive. All but one viremic patients detected by HCV IgM were also detected by RIBA 2.0 and RIBA 3.0. All viremic patients detected by RIBA 2.0 were also detected by RIBA 3.0. RIBA 3.0 was more sensitive than RIBA 2.0 and HCV IgM in the detection of viremic patients (P = 0.0156 and < 0.0001, respectively). The positive predictive value for HCV IgM was 100% as compared with 96 and 97% for RIBA 2.0 and RIBA 3.0, respectively. The negative predictive value for RIBA 3.0 was 36% as compared with 24 and 14% for RIBA 2.0 and HCV IgM, respectively. At 6-months follow-up of the eight viremic patients without a detectable IgM or IgG anti-HCV response, all patients remained RIBA 2.0 nonreactive, one became RIBA 3.0 indeterminate, and one became HCV IgM positive. These data suggest that HCV IgM has poor sensitivity in the detection of hepatitis C viremia and RIBA 3.0 improves the sensitivity of IgG anti-HCV assays in the early detection of hepatitis C viremia in hemodialysis patients.
Increased susceptibility of<i>Trpv4</i>-deficient mice to obesity and obesity-induced osteoarthritis with very high-fat diet
Authors: Christopher J O'Conor, Timothy M Griffin, Wolfgang Liedtke, Farshid Guilak
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objective</h3> To test the hypotheses that: (1) the transient receptor potential vanilloid 4 (TRPV4) ion channel is protective in the obesity model of osteoarthritis (OA), resulting in more severe obesity-induced OA in <i>Trpv4</i> knockout (<i>Trpv4<sup>−/−</sup></i>) mice; and (2) loss of TRPV4 alters mesodermal stem cell differentiation. <h3>Methods</h3> Male <i>Trpv4<sup>−/−</sup></i> and wild-type (<i>Trpv4</i><sup>+/+</sup>) mice were fed a control or high-fat diet (10% kcal and 60% kcal from fat, respectively) for 22 weeks, at which time spontaneous cage activity and severity of knee OA were evaluated. In addition, the adipogenic, osteogenic and chondrogenic potential of bone marrow-derived (MSC) and adipose-derived (ASC) stem cells from <i>Trpv4<sup>−/−</sup></i> and <i>Trpv4</i><sup>+/+</sup> mice were compared. <h3>Results</h3> A high-fat diet significantly increased knee OA scores and reduced spontaneous cage activity in <i>Trpv4<sup>−/−</sup></i> mice, while also increasing weight gain and adiposity. MSCs from <i>Trpv4<sup>−/−</sup></i> mice had decreased adipogenic and osteogenic differentiation potential versus <i>Trpv4<sup>+/+</sup></i> MSCs. ASCs from <i>Trpv4<sup>−/−</sup></i> mice had increased adipogenic and osteogenic and reduced chondrogenic differentiation potential versus <i>Trpv4<sup>+/+</sup></i> ASCs. <h3>Conclusions</h3> Pan-<i>Trpv4<sup>−/−</sup></i> mice develop more severe OA with high-fat feeding, potentially due to more severe diet-induced obesity. The altered differentiation potential of <i>Trpv4<sup>−/−</sup></i> progenitor cells may reflect the importance of this ion channel in the maintenance and turnover of mesodermally-derived tissues.
Cognitive Interventions Targeting Brain Plasticity in the Prodromal and Early Phases of Schizophrenia
Authors: Melissa Fisher, Rachel Loewy, Kate Hardy, Danielle Schlosser, Sophia Vinogradov
Journal: Annual Review of Clinical Psychology (2013)

Several important paradigm shifts have occurred in the field of schizophrenia treatment, including an increased focus on early detection, the development of preemptive interventions, and the view of schizophrenia as a neurodevelopmental disease characterized by decreased efficiency and abnormal connectivity in cortical and subcortical neural networks. In this review, we briefly describe some of the neural impairments that contribute to the development of schizophrenia, with an emphasis on the impact of stress and trauma on cognitively vulnerable neural systems. We then present current data on two behavioral interventions that target these critical risk factors and that aim to preempt the onset of schizophrenia in vulnerable individuals or improve the clinical course in recent-onset schizophrenia: cognitive therapy and computerized cognitive training.
Kinesin Family Member 12 Is a Candidate Polycystic Kidney Disease Modifier in the cpk Mouse
Authors: Michal Mrug, Renhua Li, Xiangqin Cui, Trenton R Schoeb, Gary A Churchill, Lisa M Guay-Woodford
Journal: Journal of the American Society of Nephrology (2005)

The cpk mouse is the most extensively characterized model of autosomal recessive polycystic kidney disease (ARPKD). The major ARPKD-related renal and biliary phenotypes are modulated in F2 mutants by genetic background, suggesting that quantitative trait loci (QTL) modulate disease severity. In 461 F2 cpk mice, kidney length, weight, and volume were scored as quantitative traits (QT), and a semiquantitative method to assess biliary duct number, area (BDA), portal vein area, and total area of each portal field, as well as the severity of cholangitis, was developed. QTL mapping was performed with Pseudomarker v1.02. Candidate genes were identified within the QTL intervals on the basis of expression profiling, reverse transcriptase-PCR, haplotypes, and sequence analysis. The renal QT were normally distributed in the F2 cohort and strongly correlated (P < 0.001). Among the biliary QT, only BDA correlated with the renal QT (P < 0.01). Genome-wide scan identified a major effect QTL on chromosome (Chr) 4 for the renal traits, adjusted BDA, and cholangitis with logarithm of odds scores of 18, 8, and 5, respectively. Regression modeling refined the Chr 4 main effect into an approximately 50-cM region with three distinct QTL peaks at 16, 34, and 54 cM. Kif12, a gene encoding a novel kinesin, mapped beneath the 34 cM QTL peak and has expression level variants and strain-specific sequences that were associated with renal disease severity in affected mice. Therefore, the positional candidate gene, Kif12, fulfills the major criteria for QTL gene discovery established by the Complex Trait Consortium, and, thus, it is proposed that Kif12 is a cpk modifier gene.
Radiation Oncology Research in the Cancer and Leukemia Group B
Authors: Jeffrey A. Bogart, Stephen L. Seagren, Arvin Glicksman
Journal: Clinical Cancer Research (2006)

Abstract Radiation oncology initiatives have been an integral component in the evolution of multidisciplinary research in the Cancer and Leukemia Group B. Although early studies in the Group primarily focused on chemotherapy for hematologic and pediatric malignancies, the Radiation Oncology Committee was established in 1972, reflecting the broadening scope of clinical investigation with an increased emphasis on solid tumor research. A major early contribution of the Radiation Oncology Committee was the recognition of the importance of formalized radiation quality review, which led to the development of the Quality Assurance Review Center. The committee has been instrumental in designing trials, in conjunction with our medical oncology and surgical oncology colleagues, to assess multimodality therapy. The results of many of these studies have had important implications for clinical practice. Recent efforts have explored our major research theme of treatment intensification via radiotherapy dose modulation and novel combinations of radiotherapy with sensitizing agents, with an emphasis on safely implementing advanced technologies in the cooperative group setting.
Peers call for UK to harness "enormous" potential of regenerative medicine
Authors: A. O'Dowd
Journal: BMJ (2013)

Regenerative medicine has “enormous” potential to help people with chronic disease, but the United Kingdom is currently unprepared to harness its possibilities, peers have claimed.

Regenerative medicine, which involves replacing or regenerating cells, tissues, or organs in the human body to restore or establish normal function, includes cell therapy, gene therapy, and tissue engineering.

A report published on 1 July by the House of Lords …