tbuckley/cabot-search huggingface dataset:
Safety profile of protein kinase inhibitors in rheumatoid arthritis: systematic review and meta-analysis
Authors: Eva Salgado, Jose R Maneiro, Loreto Carmona, Juan J Gomez-Reino
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objective</h3> To summarise the adverse events (AE) reported in patients with rheumatoid arthritis (RA) treated with protein kinase inhibitors (PKi), and identify family and molecule-related AEs. <h3>Methods</h3> Systematic review of the PKi used in clinical trials (CTs) in RA. Medline, Embase, Cochrane Library, Web of Knowledge, and international abstracts of congress were reviewed, (up to 31 October 2012). Search was limited to interventional studies of PKi used in CTs in RA, written in English, and reporting frequencies of AE. Diseases with similar comorbidity burden also were included. Frequency of AE, serious AE (SAE), death and discontinuation due to &nbsp;AEs (DCAE) were recorded. Risk of bias was assessed. Meta-analysis was carried using pooled relative risk (RR) with 95% CI as effect measure. <h3>Results</h3> The search produced 4410 hits. Forty-one articles reporting data on 21 PKi of the Janus kinase (JAK), SYK, p38 and cKit families were selected for detailed analysis. In patients treated with p38 inhibitors, RR for dizziness was 2.36 (1.20 to 4.63), and in patients treated with c-Kit inhibitors, RR for oedema was 3.43 (1.58 to 7.42). In patients treated with the JAK inhibitor tofacitinib, RR for hypercholesterolaemia was 1.70 (1.10 to 2.63) that was dose related. In patients treated with the Syk inhibitor fostamatinib, pooled RR for hypertransaminasaemia, hypertension, diarrhoea and neutropenia were 2.93 (1.02 to 8.43), 2.80 (1.58 to 5.99), 5.20 (3.19 to 8.49) and 9.24 (2.22 to 38.42), respectively. Serious infections and malignancies were not significantly more frequent in PKi-treated patients than in comparator groups. <h3>Conclusions</h3> Event rates of serious infections and malignancies with PKi are not different from biologics. In addition, PKi have a unique safety profile related to target and off-target inhibition of kinases, at times dose related.
A Scanographic Assessment of Pulmonary Morphology in Acute Lung Injury
Authors: SILVIA R. R. VIEIRA, LOUIS PUYBASSET, QIN LU, JACK RICHECOEUR, PHILIPPE CLUZEL, PIERRE CORIAT, JEAN-JACQUES ROUBY
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

The goal of this study was to assess lung morphology in patients with acute lung injury according to the presence or the absence of a lower inflection point (LIP) on the lung pressure–volume (P–V) curve and to compare the effects of positive end-expiratory pressure (PEEP). Eight patients with and six without an LIP underwent a spiral thoracic CT scan performed at zero end-expiratory pressure (ZEEP) and at two levels of PEEP: PEEP1 = LIP + 2 cm H2O and PEEP2 = LIP + 7 cm H2O, or PEEP1 = 10 cm H2O and PEEP2 = 15 cm H2O in the absence of an LIP. The volumes of air and tissue within the lungs were measured from the gas–tissue ratio and the volumes of overdistended and normally, poorly, and nonaerated lung areas were determined by the analysis of the frequency histogram distribution. In the ZEEP condition, although total lung volume, volume of gas, and volume of tissue were similar in both groups, the percentage of normally aerated lung was lower (24 ± 22% versus 55 ± 12%, p < 0.05) and the percentage of poorly aerated lung was greater (40 ± 12% versus 23 ± 8%, p < 0.05) in patients with an LIP than in patients without an LIP. Lung density histograms of patients with an LIP showed a unimodal distribution with a peak at 7 Hounsfield units (HU). Lung density histograms of patients without an LIP had a bimodal distribution, with a first peak at − 727 HU and a second peak at 27 HU. Total respiratory system and lung compliances were lower in patients with an LIP whereas all other cardiorespiratory parameters were similar in the two groups. In both groups, PEEP induced an alveolar recruitment that was associated with lung overdistension only in patients without an LIP. The amount of lung overdistension was related to the volume of lung parenchyma, characterized by a CT number less than − 800 HU before PEEP implementation (y = 0.52x + 4, R = 0.87, and p < 0.0001). This study shows that the presence or the absence of an LIP on the lung P–V curve is associated with differences in lung morphology. In patients without an LIP on the lung P–V curve, normally aerated lung areas coexist with nonaerated lung areas and increasing levels of PEEP result in lung overdistension rather than in additional alveolar recruitment. In patients with an LIP, air and tissue are more homogeneously distributed within the lungs and increasing levels of PEEP result in additional alveolar recruitment without lung overdistention.
Increase in viral gastroenteritis outbreaks in Europe and epidemic spread of new norovirus variant
Authors: Ben Lopman, Harry Vennema, Evelyne Kohli, Pierre Pothier, Alicia Sanchez, Anabel Negredo, Javier Buesa, Eckart Schreier, Jim Gray, Chris Gallimore, Blenda Bottiger, Kjell-Olof Hedlund, Maria Torvén, Carl-Henrik von Bonsdorff, Leena Maunula, Mateja Poljsak-Prijatelj, Janet Zimsek, Gábor Reuter, György Szücs, Béla Melegh, Lennart Svennson, Yvonne van Duijnhoven, Marion Koopmans, Mark Reacher, David Brown, Miren Iturriza
Journal: The Lancet (2004)
SUN EXPOSURE AND SKIN DISEASE
Authors: Charles R. Taylor, M.D, Arthur J. Sober, M.D
Journal: Annual Review of Medicine (1996)

▪ Abstract Sunlight exposure produces a variety of adverse cutaneous effects. Erythema, photosensitivity, and immunologic alterations represent acute events, whereas photoaging and carcinogenesis are long-term consequences. These adverse cutaneous sequelae can be minimized by photoprotection in the form of sun avoidance, regular cover-up with clothing, and sunscreen application. This chapter reviews the diagnosis and treatment of sun-related skin disorders and recommendations for reducing photodamage.
Role of hydrogen sulfide in visceral nociception
Authors: M. Schemann, D. Grundy
Journal: Gut (2009)

Hydrogen sulfide (H2S) is a malodorous and toxic gas. Nevertheless, recent evidence suggests that H2S is an endogenous mediator, joining nitric oxide and carbon monoxide as a third gaseous transmitter, and is increasingly being recognised as a key regulator of several cell processes and organ functions under both normal and pathological conditions.

H2S can be generated in mammalian tissues by a number of different processes. It can be enzymatically synthesised from cysteine by cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase in combination with cysteine aminotransferase. There are also inorganic sources of H2S such as the non-enzymatic haem-dependent reduction of sulfur. Also from a gut perspective, H2S can be generated by the colonic microbiota before diffusing from the lumen into the intestinal mucosa to reach subepithelial targets within the gut wall. However, counteracting the build up of endogenous H2S and potential toxic actions are protective mechanisms that degrade H2S, and this is especially true of the intestinal epithelium which is extremely efficient at reducing H2S to thiosulfate.1

Since the first description of a physiological function for H2S in enhancing N -methyl-d-aspartate (NMDA) receptor-mediated responses and facilitating the induction of long-term potentiation in the hippocampus,2 a host of effects have been reported in almost every cell or organ system studied to date.3–5 Inhibitors of CSE and CBS have been used to demonstrate a role for endogenous H2S, and its role as a physiological regulator of blood pressure is apparent in the CSE knockout mouse which develops hypertension.6 In the gastrointestinal (GI) tract H2S-synthesising enzymes have been shown to be expressed in the enteric nervous system,7 and H2S …
Absence of seasonal variation in concentrations of the house dust mite allergen Der p1 in south Manchester homes.
Authors: S Kalra, P Crank, J Hepworth, C A Pickering, A A Woodcock
Journal: Thorax (1992)

House dust mite numbers and the concentration of its main allergen, Der p1, depend on ambient temperature and humidity and have been reported to show a seasonal variation in homes in the United States. A study was designed to find out whether Der p1 concentrations vary with the seasons in dust collected from homes in north west England.The concentration of Der p1 was measured in dust, collected every three months from April 1990 to April 1991, from mattresses and from bedroom and living room carpets in 40 houses in the south Manchester area. Twenty four hour recordings of indoor relative humidity were made in 20 houses during the sampling day.Mean concentrations of Der p1 from all three sources rose two to three fold in October. This was in contrast to the 1000 fold variation in concentrations of Der p1 present between houses within each season's sample and less than the 10 fold change considered to be of clinical importance. The autumn increase was paralleled by a rise in humidity. There was no statistical correlation, however, between Der p1 concentrations and relative humidity, house type, ventilation, or double glazing.The results suggest that seasonal variations in exposure to Der p1 exposure in north west England are small and unlikely to be of major clinical importance. The temperature and humidity data showed that the indoor environment remained relatively constant and conducive to mite growth throughout the year.
An age‐adapted approach for the use of D‐dimers in the exclusion of deep venous thrombosis
Authors: Fred J.L.M. Haas, Roger E.G. Schutgens, Douwe H. Biesma
Journal: American Journal of Hematology (2009)

A normal D-dimer (DD) concentration for the exclusion of deep venous thrombosis (DVT) has a low specificity in older patients and compression ultrasonography is often required. Three D-dimer assays, STA Liatest, Tina-quant, and Innovance, are evaluated in symptomatic outpatients suspected for DVT with emphasis on its performance in older patients by using different cut-off levels. This study includes 466 outpatients suspected for having DVT. The diagnostic accuracy, measured as sensitivity and area under the curve of the receiver operation characteristic curve is good for all DD assays. The specificity of the DD assays combined with a low pretest probability varies from 42.6 to 51.5%. The specificity of the three DD assays in patients > or = 60 years varies, however, between 24.6 and 40.9%. Several cut-off values in different age-subgroups are studied. For patients < 60 years, the most accurate cut-off value is 500 microg/L for all DD assays. For patients > or = 60 years, a threshold of 750 microg/L has the best results with NPV of 100% for all assays and specificity of 48.5% (STA Liatest), 60.6% (Tina-quant), and 49.2% (Innovance), respectively. For the three assays, the number needed to test (NNT) decreases in both subgroups of patients compared to the standard algorithm. A cut-off level of 750 microg/L for patients > or = 60 years improves the clinical performance of DD assays in combination with the PTP score without the loss of NPV. The NNT improves substantially with an age-adapted algorithm.
The role of aminogenic glucagon secretion in blood glucose homeostasis
Authors: Roger H. Unger, Akira Ohneda, Eugenio Aguilar-Parada, Anna M. Eisentraut
Journal: Journal of Clinical Investigation (1969)

Hyperaminoacidemia is a powerful stimulus of pancreatic glucagon secretion. These studies were designed to elucidate the role of aminogenic hyperglucagonemia in glucoregulation. Conscious dogs with previously implanted indwelling venous catheters were employed. The results support the view that a role of glucagon is to limit blood glucose decline during hyperaminoacidemia.First, a significant negative correlation between the area of glucagon increment during the 1st 20 min of a 10 amino acid infusion and the maximum fall in glucose concentration was observed. Second, when endogenous glucagon secretion was suppressed by means of a continuous glucose infusion, hyperaminoacidemia induced a maximal glucose decline which averaged 35 mg/100 ml, differing significantly from mean maximal fall of 3 mg/100 ml, which normally occurs in the presence of endogenous hyperglucagonemia. Third, when, during hyperglycemic suppression of endogenous glucagon secretion, 50 mmug of exogenous glucagon/min was infused via the mesenteric vein with the amino acids, the fall in glucose was reduced to an average of 5 mg/100 ml. Similarly when pancreozymin, administered during the combined infusion of glucose and amino acids, overcame glucose suppression of endogenous glucagon secretion, plasma glucose did not fall. Similar results were obtained when aminogenic hyperglucagonemia was prevented by other means. Hyperlipacidemia, induced by infusing a triglyceride emulsion and giving heparin injections, also suppressed aminogenic hyperglucagonemia in two of four experiments; in these two dogs glucose fell 15 and 11 mg/100 ml. In a final group of experiments, the canine pancreas was resected except for the uncinate process, which is virtually devoid of alpha-cells. In two dogs, in which this procedure resulted in zero portal venous glucagon levels, the administration of amino acids and/or pancreozymin resulted in a glucose decline of 14 and 16 mg/100 ml, despite the reduced beta-cell population resulting from the subtotal pancreotectomy. It thus appears that the secretion of pancreatic glucagon during hyperaminoacidemia in association with insulin secretion, serves to limit the decline of glucose concentration.
Severe back pain - risk factors
Authors: M A Akhtar, A Clark, S Atiya, K Chirputkar, G Ayana, S Smith
Journal: British Journal of Sports Medicine (2011)

Back pain is a common problem in all age groups. Different risk factors have been identified including high BMI, Smoking, alcohol, and psychological history. The aim of our study was to identify if there was a difference in the incidence of these risk factors in different age groups. We collected data prospectively for 26 consecutive patients admitted between January and March 2011 with severe back pain who needed an MRI scan to rule out Cauda equina syndrome or nerve root compression in a district general hospital. Demographic details were recorded along with their occupation, BMI, Smoking status, alcohol intake and psychological history. Group A (Younger Group) had 13 patients with a mean age of 38 y (range 29–44). 7 (54%) were female and 6 (46%) male. 6 (46%) were employed, 4 (30%) unemployed and 2 (15%) housewives. The mean BMI was 29 (range 24–40). 7 patients (54%) were smokers and alcohol users and 6 (46%) were non-smoker and non-alcohol users. 5 patients (38%) had associated psychological history. Group B (Older group) had 13 patients with a mean age of 59 years (range 45–79). 11 (85%) were female and 2 (15%) male. 5 (38%) were employed, 2 (15%) retired and 3 (23%) house-wives. The mean BMI was 21 (range-14–32). 6 patients (46%) were smoker and 7 (54%) enjoyed alcohol. Only 2 patients (15%) had associated psychological history. Younger patients with severe back pain were overweight (mean BMI-29) and had higher incidence of psychological history (38%) as compared to older patients (15%). There was no difference in the occupation status, smoking and alcohol consumption in both groups. Younger patients with severe back pain should be routinely assessed for associated psychological history and appropriate advice on weight management should be given.
Efficacy of Neoadjuvant Cisplatin in Triple-Negative Breast Cancer
Authors: Daniel P. Silver, Andrea L. Richardson, Aron C. Eklund, Zhigang C. Wang, Zoltan Szallasi, Qiyuan Li, Nicolai Juul, Chee-Onn Leong, Diana Calogrias, Ayodele Buraimoh, Aquila Fatima, Rebecca S. Gelman, Paula D. Ryan, Nadine M. Tung, Arcangela De Nicolo, Shridar Ganesan, Alexander Miron, Christian Colin, Dennis C. Sgroi, Leif W. Ellisen, Eric P. Winer, Judy E. Garber
Journal: Journal of Clinical Oncology (2010)

PURPOSE Cisplatin is a chemotherapeutic agent not used routinely for breast cancer treatment. As a DNA cross-linking agent, cisplatin may be effective treatment for hereditary BRCA1-mutated breast cancers. Because sporadic triple-negative breast cancer (TNBC) and BRCA1-associated breast cancer share features suggesting common pathogenesis, we conducted a neoadjuvant trial of cisplatin in TNBC and explored specific biomarkers to identify predictors of response. PATIENTS AND METHODS Twenty-eight women with stage II or III breast cancers lacking estrogen and progesterone receptors and HER2/Neu (TNBC) were enrolled and treated with four cycles of cisplatin at 75 mg/m(2) every 21 days. After definitive surgery, patients received standard adjuvant chemotherapy and radiation therapy per their treating physicians. Clinical and pathologic treatment response were assessed, and pretreatment tumor samples were evaluated for selected biomarkers. Results Six (22%) of 28 patients achieved pathologic complete responses, including both patients with BRCA1 germline mutations;18 (64%) patients had a clinical complete or partial response. Fourteen (50%) patients showed good pathologic responses (Miller-Payne score of 3, 4, or 5), 10 had minor responses (Miller-Payne score of 1 or 2), and four (14%) progressed. All TNBCs clustered with reference basal-like tumors by hierarchical clustering. Factors associated with good cisplatin response include young age (P = .001), low BRCA1 mRNA expression (P = .03), BRCA1 promoter methylation (P = .04), p53 nonsense or frameshift mutations (P = .01), and a gene expression signature of E2F3 activation (P = .03). CONCLUSION Single-agent cisplatin induced response in a subset of patients with TNBC. Decreased BRCA1 expression may identify subsets of TNBCs that are cisplatin sensitive. Other biomarkers show promise in predicting cisplatin response.
The concept of axial spondyloarthritis. Lessons from the INFAST study
Authors: Henning Zeidler
Journal: Annals of the Rheumatic Diseases (2013)

Sieper et al 1 evaluated whether combination therapy with infliximab (IFX) and naproxen (NPX) was superior to treatment with NPX alone in patients who had active moderate-to-severe early (disease duration under 3 years) active axial spondyloarthritis (SpA) and who were naive to non-steroidal anti-inflammatory drugs (NSAIDs) or had only been treated with a submaximal dose of NSAIDs. This study is the first investigation of the potential benefits of early tumour necrosis factor (TNF) antagonist treatment in active axial SpA patients who are not yet refractory to NSAID therapy. Additionally, this represents the first randomised controlled clinical trial to use the imaging portion of the Assessment of SpondyloArthritis International Society criteria for axial SpA with active inflammation of the sacroiliac joints on MRI at baseline. Most importantly, …
Molecular complexity of leukocyte surface glycoproteins related to the macrophage differentiation antigen Mac-1.
Authors: I S Trowbridge, M B Omary
Journal: The Journal of Experimental Medicine (1981)

Monoclonal antibodies have been obtained that react with the murine leukocyte surface glycoproteins bearing the macrophage differentiation antigen Mac-1. Structural and antigenic analysis shows that related glycoproteins are found on other murine hematopoietic cell types. The data not only illustrate the complexity of cell surface structures that can be detected by means of monoclonal antibodies, but also raise questions as to the functional significance of this family of molecules within the hematopoietic system.
Novel recurrently mutated genes and a prognostic mutation signature in colorectal cancer
Authors: Jun Yu, William K K Wu, Xiangchun Li, Jun He, Xiao-Xing Li, Simon S M Ng, Chang Yu, Zhibo Gao, Jie Yang, Miao Li, Qiaoxiu Wang, Qiaoyi Liang, Yi Pan, Joanna H Tong, Ka F To, Nathalie Wong, Ning Zhang, Jie Chen, Youyong Lu, Paul B S Lai, Francis K L Chan, Yingrui Li, Hsiang-Fu Kung, Huanming Yang, Jun Wang, Joseph J Y Sung
Journal: Gut (2014)

<h3>Background</h3> Characterisation of colorectal cancer (CRC) genomes by next-generation sequencing has led to the discovery of novel recurrently mutated genes. Nevertheless, genomic data has not yet been used for CRC prognostication. <h3>Objective</h3> To identify recurrent somatic mutations with prognostic significance in patients with CRC. <h3>Method</h3> Exome sequencing was performed to identify somatic mutations in tumour tissues of 22 patients with CRC, followed by validation of 187 recurrent and pathway-related genes using targeted capture sequencing in additional 160 cases. <h3>Results</h3> Seven significantly mutated genes, including four reported (<i>APC</i>, <i>TP53</i>, <i>KRAS</i> and <i>SMAD4</i>) and three novel recurrently mutated genes (<i>CDH10</i>, <i>FAT4</i> and <i>DOCK2</i>), exhibited high mutation prevalence (6–14% for novel cancer genes) and higher-than-expected number of non-silent mutations in our CRC cohort. For prognostication, a five-gene-signature (<i>CDH10</i>, <i>COL6A3</i>, <i>SMAD4</i>, <i>TMEM132D</i>, <i>VCAN</i>) was devised, in which mutation(s) in one or more of these genes was significantly associated with better overall survival independent of tumor-node-metastasis (TNM) staging. The median survival time was 80.4 months in the mutant group versus 42.4 months in the wild type group (p=0.0051). The prognostic significance of this signature was successfully verified using the data set from the Cancer Genome Atlas study. <h3>Conclusions</h3> The application of next-generation sequencing has led to the identification of three novel significantly mutated genes in CRC and a mutation signature that predicts survival outcomes for stratifying patients with CRC independent of TNM staging.
Cardiac Fgf21 synthesis and release: an autocrine loop for boosting up antioxidant defenses in failing hearts
Authors: Fabio Di Lisa, Nobuyuki Itoh
Journal: Cardiovascular Research (2015)

Fibroblast growth factors (Fgfs) are signalling proteins of ∼150–300 amino acids with diverse functions, mainly in development and metabolism. The human/mouse Fgf family comprises 22 members. Fgfs can be classified as intracellular, paracrine, and endocrine Fgfs by their action mechanisms. Among Fgfs, Fgf2, Fgf16, Fgf21, and Fgf23 have been shown to be cardiomyokines playing pathophysiological roles in the heart.1 Fgf2 and Fgf16 are paracrine Fgfs, which usually function in an autocrine/paracrine manner. In contrast, so far Fgf21 and Fgf23 have been reported to function in an endocrine manner. Cardiac Fgf2 promotes cardiac hypertrophy and fibrosis by activating MAPK signalling through the activation of Fgf receptor (Fgfr). In contrast, cardiac Fgf16 may prevent them by competing with Fgf2 for the binding site of Fgfr. Although Fgf23 is an endocrine Fgf, cardiac Fgf23 induces cardiac hypertrophy by activating calcineurin/NFAT signalling in an autocrine/paracrine manner.1

Fgf21 is usually known to be a hepatic hormone involved in the control of glucose, lipid, and energy metabolism. These actions of Fgf21 are mediated by activating MAPK signalling through the activation of Fgfr in an endocrine manner.2 Fgf21 is also produced in the heart and prevents cardiac hypertrophy by activating MAPK signalling through the activation of Fgfr.3 Cardiac Fgf21 expression is induced by the protein deacetylase Sirt1,3 which protects against hypertrophy, ischaemia–reperfusion injury, and oxidative stress in the …