tbuckley/cabot-search huggingface dataset:
Cutaneous adverse events associated with vemurafenib in patients with metastatic melanoma: practical advice on diagnosis, prevention and management of the main treatment-related skin toxicities
Authors: R. Sinha, K. Edmonds, J.A. Newton-Bishop, M.E. Gore, J. Larkin, L. Fearfield
Journal: British Journal of Dermatology (2012)

Until recently, no effective treatment was available for patients with metastatic malignant melanoma, and median overall survival was little more than 6 months with the current standard of care, dacarbazine. In 2012, the first specific BRAF mutation inhibitor, vemurafenib, was licensed for the monotherapy of adults with BRAF V600 mutation-positive unresectable or metastatic melanoma. Like other targeted therapies, vemurafenib is associated with a predictable pattern of adverse events, including skin toxicities. We review the most common cutaneous adverse events associated with vemurafenib, based on data from clinical trials, and our own experiences of treating patients in trials and clinical practice. Overall, these toxicities are not preventable, but they rarely necessitate permanent treatment discontinuation and are generally manageable with dose modification and supportive care. We provide a treatment algorithm offering guidance on the most appropriate approach to managing the main skin toxicities to help clinicians unfamiliar with this novel agent to become confident in using vemurafenib effectively in the management of patients with metastatic melanoma.
MPs call for full results of all past clinical trials to be made public
Authors: A. O'Dowd
Journal: BMJ (2014)

The methods and results of all past clinical trials in the United Kingdom, as well as future trials, should be made available to doctors and researchers to ensure the safety of drugs being prescribed by clinicians, MPs have said.

MPs on the parliamentary public accounts committee have also called for further scrutiny of Tamiflu, Roche’s branded form of oseltamivir, which had been used to treat pandemic flu, before more supplies are bought and stockpiled by the government.

A report published by the committee on 3 January on access to clinical trial information and the stockpiling of oseltamivir raises many concerns over how the current system operates.1

It says that information is routinely withheld from doctors and researchers about the methods and results of clinical trials on treatments that are currently prescribed in the UK.

Although the problem has been known about for many years, says the report, action taken by the government, industry, or professional bodies to tackle it has been inadequate.

The MPs recommended that the Department of Health take action to ensure that full methods and results were made available to doctors and researchers from all trials on all uses of all treatments currently being prescribed—from now on and retrospectively—and …
Social determinants of asthma: Results from UK household longitudinal study
Authors: Ivy Shiue
Journal: European Respiratory Journal (2012)

Background  Asthma is a prevalent respiratory disease, but its social determinants are not well investigated in detail.  Aims  It is aimed to explore social determinants of asthma in recent years.  Methods  Data were extracted from UK Household Longitudinal Study (2009-2010). Demographics, family background, migration history, and self-rated health were taken as aspects of social determinants. Deprivation at the regional level was included as well. Asthma was defined according to physician diagnosis by self-reporting. Regression models were performed and 95% confidence intervals were estimated.  Results  Associations among family background, migration history, self-rated health, and asthma were observed (P  Conclusions  The association between social inequality and asthma prevalence is critised not being fully understood until the 21st century and called on for further investigation. This study has tried to answer this with a large national representative sample with complete household conditions. Some shared contributing factors will absolutely need further care to be eliminated across common non-communicable diseases. Then then next step is to communicate with policy makers to generate proper strategies on preventing asthma from childhood to adulthood with a lifetime approach.
Topical applications of chlorhexidine to the umbilical cord for prevention of omphalitis and neonatal mortality in southern Nepal: a community-based, cluster-randomised trial
Authors: Luke C Mullany, Gary L Darmstadt, Subarna K Khatry, Joanne Katz, Steven C LeClerq, Shardaram Shrestha, Ramesh Adhikari, James M Tielsch
Journal: The Lancet (2006)
Real-Time 3-Dimensional Echocardiography
Authors: Victor Mor-Avi, Lissa Sugeng, Roberto M. Lang
Journal: Circulation (2009)

O ne of the most significant developments of the last decade in ultrasound imaging of the heart was the evolution of 3-dimensional (3D) imaging from slow and labor-intense offline reconstruction to real-time volumetric imaging.This imaging modality provides valuable clinical information that empowers echocardiographers with new levels of confidence in the diagnosis of heart disease.We have previously described the technological milestones in the development of real-time 3D echocardiographic (RT3DE) imaging and its major advantages over conventional 2-dimensional echocardiography (2DE) and reviewed the published literature that supported the use of this new methodology in clinical practice. 1Since 2006, the growing availability of RT3DE technology, its ease of use, and its multiple attractive features have sparked significant interest in the research community, resulting in a large number of publications, most of which have endorsed RT3DE imaging for clinical use by demonstrating its unique capabilities in different scenarios.In parallel, the clinical acceptance of this new tool has broadened significantly.The most recent clinically significant addition is matrix-array transesophageal echocardiography (TEE), which provides images of unprecedented quality that aid surgeons and interventional cardiologists in planning and guiding procedures and evaluating their outcomes.The purpose of the present article is to review the most recent RT3DE literature and provide readers with an update on the latest developments and the current status of this noninvasive imaging tool.Because different potential applications of RT3DE imaging have been explored to various extents, they are described here separately, and each is discussed with an emphasis on the scientifically established facts, along with the known stumbling blocks and difficulties.
Altered venous function in hypertensive rats.
Authors: G Simon
Journal: Circulation Research (1976)

The vascular beds of the upper or lower body of rats were perfused through the aorta with oxygenated Krebs-Ringer solution containing dextran (7 g/100 ml), at 37 degrees C. Perfusion was stopped every 10 minutes, and the pressure rise in the jugular or the femoral vein was recorded during rapid infusion (15.3-90.0 ml/min) of Krebs-Ringer solution into the inferior vena cava. The following groups of rats were studied: (1) six male genetically hypertensive rats (GHR), 9-11 months old, New Zealand strain; (2) seven female GHR, 5-6 months old, New Zealand strain; (3) eight male spontaneously hypertensive rats (SHR), 4 months old, Okamoto strain; (4) five male rats with two-kidney Goldblatt hypertension (2-KGH), 30 days postclipping; (5) seven male 2-KGH rats, 65 days postclipping; (6) eight male rats with one-kidney Goldblatt hypertension (1-KGH), 40 days postclipping; (7) weight- and sex-matched normotensive control rats of the appropriate strain; and (8) weight- and sex-matched two-kidney and one-kidney, sham-clipped normotensive rats. Preliminary studies showed that rapid infusion into the venous circulation fills the veins, but there is no entry of fluid into the arterial side of the circulation. Compared to controls, the venous pressure-volume curves of GHR (male and female), SHR, 1-KGH rats and 2-KGH rats, 65 (but not 30) days postclipping, were shifted toward the pressure axis (P less than 0.05). The shift of the venous pressure-volume curves persisted following the reduction of vasoconstrictor tone by killing the rats or by the administration of sodium nitroprusside (0.1 mg/ml perfusate), or by both. The findings suggest decreased venous capacity in hypertensive rats.
Treatment-related myelodysplasia/AML in a patient with a history of breast cancer and an oligodendroglioma treated with temozolomide: Case study and review of the literature1
Authors: Vanita Noronha, Nancy Berliner, Karen K. Ballen, Jill Lacy, Jean Kracher, Joachim Baehring, John W. Henson
Journal: Neuro-Oncology (2006)

The emergence of temozolomide as an effective alkylating agent with little acute toxicity or cumulative myelosuppression has led to protracted courses of chemotherapy for many patients with gliomas. Secondary, or treatment-related, myelodysplasia (t-MDS) and acute myelogenous leukemia (t-AML) are life-threatening complications of alkylating chemotherapy and have been reported in patients with primary brain tumors. We describe a case of temozolomide-related t-MDS/AML and discuss the clinical features of this condition. Administration of an alkylating agent in patient populations with long median survivals must be undertaken with an understanding of the potential for this treatment complication.
Recombinant interferon-alfa therapy in children with chronic hepatitis C
Authors: Flavia Bortolotti, Raffaella Giacchino, Pietro Vajro, Cristiana Barbera, Carlo Crivellaro, Alfredo Alberti, Gabriella Nebbia, Lucia Zancan, Lorena de Moliner, Adalberto Bertolini, Fiorella Balli, Francesco Callea
Journal: Hepatology (1995)

The efficacy of recombinant interferon-alfa therapy in children with chronic hepatitis C has been evaluated in a randomized, controlled pilot study including 27 patients, aged 2 to 14 years, without underlying systemic diseases. On entry, all patients had abnormal alanine transaminase (ALT) levels, 22 were hepatitis C virus (HCV) RNA positive, 19 had mild chronic active hepatitis, and 8 had chronic persistent hepatitis on liver biopsy. Fourteen children received 5 MU/m2 of recombinant interferon-alfa2b thrice weekly for 4 months. If at this time ALT had been reduced to at least 50% the baseline level, treatment was continued up to 12 months. The other 13 children remained untreated. The whole follow-up period lasted 24 months. Interferon was stopped at 4 months in 4 children because of an ALT increase (2 cases), unchanged ALT and febrile convulsions (1 case), and slight ALT decrease (1 case). This latter patient, however, had normal ALT at 6 months and throughout further follow-up, and cleared HCV RNA, thus behaving as a sustained responder. All 10 children treated for 12 months had normal levels of ALT, and 9 were HCV RNA negative at the end of treatment. Of the 9 children who could be followed to 24 months, 4 relapsed soon after therapy withdrawal and 5 maintained a sustained biochemical and virologic response. Overall, 6 (43%) of 14 treated children had a sustained ALT normalization associated with HCV RNA clearance as compared with only 1 (7.5%) untreated child who had a sustained ALT normalization but did not clear HCV RNA.(ABSTRACT TRUNCATED AT 250 WORDS)
Phagocytosis by Human Leucocytes. I. Effect of Fibrin on Phagocytosis of Staphylococci and of Encapsulated Pneumococci by Normal Human Leucocytes1
Authors: Henry H. Balch, Margaret T. Spencer
Journal: Journal of Clinical Investigation (1954)

Resistance to phagocytosis by pathogenic micro- organisms may be due to a variety of mechanisms depending on the species.For example, bacteria may produce substances toxic for leucocytes such as the "leucocidins" produced by staphylococci and hemolytic streptococci.Another mechanism sug- gested by Hale and Smith (1) may operate in the case of pathogenic staphylococci; these bacteria produce an enzyme, coagulase, which acting in concert with a serum factor catalyzes the conversion of fibrinogen to fibrin.According to Hale and Smith, the fibrin meshwork so formed, impedes the activity of the leucocytes, and furthermore, fibrin, intimately deposited about the staphylococci, in some way interferes with their ingestion.Rogers and Tompsett (2), using human leucocytes, confirmed the observation that coagulase- producing staphylococci are less well ingested than coagulase negative strains, but believe that the ob- served difference was not of sufficient magnitude to be a factor of major importance in explaining the difference in pathogenicity between the two species.The production of capsules by certain bacterial species can be correlated with pathogenicity.Spe- cific anticapsular serum renders the encapsulated organism relatively defenseless to leucocyte ac- tivity.Wood, Smith, and Watson (3, 4) have shown, however, that encapsulated pathogens may be ingested in the absence of specific antibody both in vitro and in vivo provided the leucocytes can push the organisms against a nonyielding surface.A fibrin meshwork such as occurs in blood clots or inflammatory exudates offers an excellent matrix
ErbB Receptor Signaling and Therapeutic Resistance to Aromatase Inhibitors
Authors: Incheol Shin, Todd Miller, Carlos L. Arteaga
Journal: Clinical Cancer Research (2006)

Abstract We have investigated the effect of HER-2 overexpression on resistance to the aromatase inhibitor letrozole in MCF-7 breast cancer cells stably expressing cellular aromatase (MCF-7/CA). MCF-7/CA cells overexpressing HER-2 showed a &amp;gt;2-fold increase in estrogen receptor (ER)–mediated transcriptional reporter activity upon treatment with androstenedione compared with vector-only control MCF-7/CA cells. Cotreatment with letrozole did not abrogate androstenedione-induced transcription and cell proliferation in HER-2-overexpressing cells. Chromatin immunoprecipitation assays using cross-linked protein-DNA from MCF-7/CA/HER-2 cells indicated ligand-independent association of the ERα coactivators AIB-1 and CBP to the promoter region of the estrogen-responsive pS2 gene. Upon treatment with androstenedione, there were increased associations of AIB1 and CBP with the pS2 promoter in the HER-2-overexpressing compared with control MCF-7/CA cells. These results suggest that ligand-independent recruitment of coactivator complexes to estrogen-responsive promoters as a result of HER-2 overexpression may play a role in the development of letrozole resistance.
Detecting and characterizing gene conversions between multigene family members
Authors: G. Drouin, F. Prat, M. Ell, G. D. Clarke
Journal: Molecular Biology and Evolution (1999)

We used a variety of methods to detect known gene conversions in the actin gene families of five angiosperm species, the beta-globin gene families of two primate species, and the Zfx/Zfy gene families of seven mammalian species. Our goal was to devise a working strategy which would allow the analysis of the members of a multigene family in order to determine whether there had been gene conversions between its members, identify the genes involved in the gene conversions, establish the lengths of the converted regions, and determine the polarities of the gene conversions. We show that three phylogenetic methods and the homoplasy test of Maynard Smith and Smith perform relatively poorly on our data sets because the sequences we analyzed had large levels of multiple substitutions. The method of Sawyer, the compatibility method of Jakobsen and Easteal, the partition matrix method of Jakobsen, Wilson, and Easteal, and the co-double method of Balding, Nichols, and Hunt can be used to identify the genes which have been involved in gene conversions. The co-double method is more powerful than other methods but requires orthologous sequences from related species. Compatibility, phylogenetic, and nucleotide substitution distribution statistics methods can be used to identify the location of the converted region(s). Site-by-site compatibility analyses can also be used to identify the direction of the conversion event(s). Combinations of these methods can therefore be used to establish the presence, locations, and polarities of gene conversions between multigene family members.
Bowel diversion should be used with caution in stenosing anal Crohn's disease.
Authors: M E Williamson, L E Hughes
Journal: Gut (1994)

Proximal diversion has commonly been used for severe perianal Crohn9s disease in an attempt to relieve local symptoms, whether the primary intestinal disease is in the colon or small bowel. Two patients are presented in whom diversion led to severe symptomatic disease in the previously normal defunctioned bowel. In each case the development of colonic disease was associated with increasing anal stenosis leading to retention of purulent fluid within the bowel lumen. Faecal stream diversion should be used with caution in stenosing anal Crohn9s disease.
Problematic aspects of embodied memory
Authors: Aaron S. Benjamin, Robert A. Bjork
Journal: Behavioral and Brain Sciences (1997)

Glenberg's theory is rich and provocative, in our view, but we find fault with the premise that all memory representations are embodied. We cite instances in which that premise mispredicts empirical results or underestimates human capabilities, and we suggest that the motivation for the embodiment idea – to avoid the symbol-grounding problem – should not, ultimately, constrain psychological theorizing.
Allelic Differences Between Han Chinese and Europeans for Functional Variants in ZNF804A and Their Association With Schizophrenia
Authors: Ming Li, Xiong-jian Luo, Xiao Xiao, Lei Shi, Xing-yan Liu, Li-de Yin, Hong-bo Diao, Bing Su
Journal: American Journal of Psychiatry (2011)

ZNF804A is a schizophrenia risk gene that was recently identified by genome-wide association studies as well as subsequent replications. Although the results are consistent among studies in European populations, there have been conflicting reports in Chinese populations. The authors conducted both association and functional analyses to test whether ZNF804A is a risk gene for schizophrenia in Chinese populations.The authors recruited two case-control samples of independent Han Chinese (a total of 2,207 participants) from southwestern China. A total of six single-nucleotide polymorphisms (SNPs), including the key SNP (rs1344706) that showed significant association with schizophrenia in European populations and the other five promoter SNPs of ZNF804A, were tested. Based on the results of the association analysis, the authors performed two functional assays to test the impact of the risk SNP on transcriptional factor binding affinity and promoter activity.The SNP rs1344706 was not associated with schizophrenia in either of the two Han Chinese groups, and this result was confirmed by meta-analyses in five Han Chinese samples. However, the authors identified two ZNF804A promoter SNPs that were significantly associated with schizophrenia in both samples, and the significance was strengthened in the combined samples and further supported by haplotype analysis. The functional assays demonstrated that the risk SNP (rs359895) can influence Sp1 binding affinity, resulting in a higher promoter activity of the risk allele.Our results suggest that ZNF804A is a common risk gene for schizophrenia in world populations and that the newly identified functional SNP (rs359895) is likely a risk SNP for schizophrenia.
Discussion on: Immunologic Responsiveness and the Induction of Experimental Neoplasms
Authors: John L. Fahey
Journal: Cancer Research (1966)

Several years ago, many articles appeared indicating that neonatal thymectomy induced a profound and generalized effect on immune response and emphasizing that the thymus was an important factor in the development of immune capacity (6). At the same time, we were conducting studies on the immunoglobulins of mice, and extended our investigations to neonatally thymectomized animals. It was postulated, in view of the pro found impairment of immunity originally reported in the neo natally thymectomized mouse, that some significant abnormality in the immunoglobulins would be detected. This postulate was not confirmed in our studies, conducted over a period of years with Dr. Werner Barth and Dr. Lloyd Law (2). Indeed, the effect of neonatal thymectomy on immunity has had to be modi fied as a result of studies in several laboratoreis (1, 2, 4, 5). The 1st phase of our studies undertook to measure the serum level of the major immunoglobulin components in neonatally thymectomized mice. Our initial observations indicated that the 4 major categories of immunoglobulins, i.e., the IgM,1 IgA, 7 871, and 7 872, were all present in these mice, even though they were dying with marked lymphocytopenia and exhibited severe wasting and weight loss. Variations were found in indi vidual mice; i.e., a high level of IgA immunoglobulin was oc casionally seen in some mice and low levels of the two 7 S im munoglobulins were frequently evident. A 2nd phase of the study was concerned with immunoglobulin metabolism. Immunoglobulin turnover and estimates of the rate of immunoglobulin synthesis were conducted with radioiodinelabeled proteins. These studies indicated that immunoglobulin synthesis was normal in neonatally thymectomized mice. When serum immunoglobulin levels were low, the cause was increased catabolism rather than impaired synthesis. The cause of this rapid catabolism has not been ascertained; it is possible that there was excessive leakage of immunoglobulins into the gut. Qualitative characterization of the immunoglobulins consti tuted a 3rd phase of the study. The immunoglobulins of neo natally thymectomized mice were found to have both heavy and light polypeptide chains and to have the antigenic determinants characteristic of these polypeptide chains. Genetically deter mined isoantigens were present. The 7 S immunoglobulins were catabolized in the same manner as normal 7 S immunoglobulins and appeared to be responsive to the regulatory mechanisms which normally adjust catabolic rate to the serum level of 7 S immunoglobulin.
Unbalanced M1/M2 Phenotype of Peripheral Blood Monocytes in Obese Diabetic Patients
Authors: Noriko Satoh, Akira Shimatsu, Akihiro Himeno, Yousuke Sasaki, Hajime Yamakage, Kazunori Yamada, Takayoshi Suganami, Yoshihiro Ogawa
Journal: Diabetes Care (2009)

The monocyte-macrophage system exists in at least two distinct phenotypes of differentiation: proinflammatory (M1) and anti-inflammatory (M2) (1,2). Macrophages, when infiltrated into obese adipose tissue, exhibit a phenotypic switch from M2 to M1 polarization, thereby contributing to obesity-induced adipose tissue inflammation and insulin resistance (1). Expression of both M1 and M2 markers is detected in circulating peripheral blood mononuclear cells as well as in atherosclerotic plaques (3). However, there have been no detailed studies on the M1/M2 phenotype of monocytes and their association with cardiovascular risks in obese subjects with type 2 diabetes. On the other hand, we demonstrated that pioglitazone, a thiazolidinedione class of insulin sensitizer, exerts an antiatherogenic effect independent of its antidiabetic effect …