tbuckley/cabot-search huggingface dataset:
Twin Boys with Major Histocompatibility Complex Class II Deficiency but Inducible Immune Responses
Authors: Hermann M. Wolf, Ilona Hauber, Heinz Gulle, Vojtech Thon, Heinz Eggenbauer, Michael B. Fischer, Sabine Fiala, Martha M. Eibl
Journal: New England Journal of Medicine (1995)

The major histocompatibility complex (MHC) class II molecules are composed of two polypeptide chains (α and β). In humans the three distinct isotypes are designated HLA-DR, DP, and DQ. The different isotypes serve similar functions, and their expression on cells is regulated in coordinated fashion.1 MHC class II molecules are expressed on the surface of certain cells of the immune system, such as monocytes and macrophages, B cells, and dendritic cells, where they play an important part in the immune response.2 MHC class II deficiency is an autosomal recessive disease characterized by cellular and humoral immunodeficiency.3 Family studies show that . . .
Few people seek addiction treatment after Bihar introduces alcohol ban
Authors: Priyanka Pulla
Journal: BMJ (2016)

Fewer people than expected have sought treatment for alcohol dependence in Bihar since the north Indian state imposed a liquor ban on 5 April, doctors administering the treatments have said.

The ban on the sale of alcohol was imposed in response to demands from women who had experienced alcohol fuelled abuse by their husbands and male relatives.1

Jitendra Srivastava, executive director at Bihar’s State Health Society, said that, after the ban, roughly 1300 alcohol users had approached de-addiction centres across the state as outpatients and that 200 had been admitted for further treatment.

This number is much smaller than the estimated number of people with alcohol dependence. World Health …
PTH-094 Are megamitochondria a cellular survival strategy for ethanol-induced liver toxicity?
Authors: E Palma, A Riva, R Williams, S Chokshi
Journal: Gut (2015)

<h3>Introduction</h3> A characteristic histological feature of alcoholic liver disease (ALD), known since the 1970s, is the presence of megamitochondria (MM) in hepatocytes. In a recent study conducted in more than 100 patients, the presence of MM was associated with a lower risk of death within 90 days.<sup>1</sup>Mitochondria are dynamic organelles and their shape is intimately involved with their function, under physiological conditions the changes in mitochondrial morphology are regulated by mitochondrial-shaping proteins (MSP). However, the mechanisms driving MM formation, their role, function and involvement in the pathogenesis of ALD is currently unknown, which is the aim of this study. <h3>Method</h3> Human precision cut liver slices (PCLS) and hepatoma cells VL-17A (positive for ADH/CYP2E1) were cultured with EtOH alone or in combination with FFA, to induce hepatotoxicity. Cell viability was evaluated by FACS (AnnexinV/PI positive cells) or ATP quantification. Post-treatment, changes in the mitochondrial shape were assessed by confocal and electron microscopy; MSP expression and activation was also analysed by Western blot on isolated mitochondria. Additionally, mitochondrial functionality was evaluated in intact cells using the Seahorse Bioscience analyser. Changes in inflammatory cytokine production were assessed by Cytokine Bead Array. <h3>Results</h3> The toxic effect of EtOH (+/-FFA) was confirmed by an increase in the percentage of dead cells or a reduction in ATP levels. Cells that survived the toxic insult showed a dramatically increased proportion of MM; however they also had a compromised ability to grow. Mitochondrial functionality, in terms of coupling efficiency and spare respiratory capacity, was also impaired. Pro inflammatory cytokine profile was found in the supernatants of these cultures. This was associated with a reduced activity in the MSP related to mitochondrial fragmentation. <h3>Conclusion</h3> Cellular survival strategies, in the face of a chronic toxic stimulus, are a necessary requirement to ensure continuing functionality of the organ. We show here that growth retarded hepatocytes, which survived the EtOH insult, are characterised by a dramatic formation of MM, suggesting this as a mechanism to avoid death. We also show for the first time the involvement of MSP in this pathway, raising the potentiality for the use of these proteins as therapeutic targets and biomarkers in ALD. <h3>Disclosure of interest</h3> None Declared. <h3>Reference</h3> Altamirano, <i><i>et al</i>.</i><i>Gastroenterology</i>, 2014;146(5):1231–1239
Case 13-1992
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, A.R. Stark, E.J. Mark
Journal: New England Journal of Medicine (1992)

Presentation of CaseA newborn boy was admitted to the hospital because of respiratory distress and a "ground-glass" appearance on an x-ray film of the chest.The child was born at 38 1/2 weeks of the first pregnancy of a mother 26 years of age whose blood type was O, Rh positive. The child was conceived while his father, 30 years old, was taking doxorubicin for treatment of a relapse of acute lymphocytic leukemia of three years' duration. An amniocentesis, performed at approximately 13 weeks of gestation, was said to show a translocation of chromosomes 16 and 9. Repeated ultrasonographic . . .
Accuracy of the Ventricular Tachycardia-Induction Study for Predicting Long-Term Efficacy and Inefficacy of Antiarrhythmic Drugs
Authors: Jay W. Mason, Roger A. Winkle
Journal: New England Journal of Medicine (1980)

We evaluated the prophylactic effect of antiarrhythmic agents against induction of ventricular tachycardia by extrastimulation in 51 patients with recurrent ventricular tachycardia. These patients subsequently underwent 58 long-term trials with tested agents. In 39 trials an agent predicted to be effective by electrophysiologic study was administered, and in 19 a drug predicted to be ineffective was used. There were no clinical differences between the two treatment groups. During a mean follow-up period of 8.2 months, arrhythmias recurred significantly less frequently in the group treated with drugs predicted to be effective than in the other group (P < 0.001); at six months 80 per cent of the patients in the former group were successfully treated, as compared with 33 per cent in the latter group. At 18 months the corresponding figures were 68 per cent and 11 per cent. We conclude that the arrhythmia-induction technique accurately predicts the clinical effectiveness of drugs used in the long-term treatment of recurrent ventricular tachycardia.
Physical and neurobehavioral determinants of reproductive onset and success
Authors: Felix R Day, Hannes Helgason, Daniel I Chasman, Lynda M Rose, Po-Ru Loh, Robert A Scott, Agnar Helgason, Augustine Kong, Gisli Masson, Olafur Th Magnusson, Daniel Gudbjartsson, Unnur Thorsteinsdottir, Julie E Buring, Paul M Ridker, Patrick Sulem, Kari Stefansson, Ken K Ong, John R B Perry
Journal: Nature Genetics (2016)
The Association Between Survival and Maximum Standardized Uptake Value of Liver Metastases Detected By 18-Fluoro-2-Deoxy-D-Glucose Positron Emission Tomography-Computed Tomography in Patients with Adenocarcinoma of Unknown Primary Origin
Authors: E. Algin, A. Ozet, O. Gumusay, B. Cetin, U.O. Akdemir, M. Benekli, U. Coskun, A. Uner, O. Kapucu, S. Buyukberber
Journal: Annals of Oncology (2014)
Neurology team finalists
Authors: Nigel Hawkes
Journal: BMJ (2016)

Nigel Hawkes finds out how the nominated teams have redesigned services to improve care 

Children born with cerebral palsy in Northern Ireland faced a fragmented pattern of care when Claire Lundy was appointed consultant in paediatric neurodisability at Belfast Health and Social Care Trust in 2011. “Individually they were probably being treated pretty well, though they were ricocheting between services,” she says. “But there was a real challenge for the more able children. They were seen when quite young but then forgotten about, with their needs unmet.”

The best approach, and the one approved by the National Institute for Health and Care Excellence (NICE), is multidisciplinary care by teams incorporating clinicians, occupational therapists, and others. No such service then existed for the 1000 people below the age of 20 years in Northern Ireland recorded as having cerebral palsy. She had worked at the Evelina London Children’s Hospital and had the skills and experience to set up such a service. “They told me, ‘There you go, get on with it.’”

Pilot funding was provided for a clinic designed to provide assessment and initial treatment in one appointment. Within six months 139 children had been seen, with strongly positive feedback from doctors and families. A separate pilot clinic for children with upper limb disorders led to the creation of a network of occupational therapists and standardised pathway for children having treatment with botulinum toxin.

What may seem like small changes can transform lives for the better. Lundy remembers a boy of 14 who desperately wanted to be able to tie his own shoelaces and open a packet of crisps like his friends. “With help, he achieved it—it sounds really simple but it transformed that boy’s life,” she says.

Forth Valley Royal Hospital, opened in 2011, is a new hospital that has adapted …
Cancer Mortality Risk Among Japanese in the United States&lt;xref ref-type="fn" rid="FN1"&gt;1&lt;/xref&gt;
Authors: Frances B. Locke, Haltung King
Journal: JNCI Journal of the National Cancer Institute (1980)

Earlier findings on cancer mortality experiences of Nisei and Issei were updated to around 1970. Compared with U.S. whites, Japanese in Japan had a high standardized mortality ratio (SMR) for cancers of the esophagus, stomach, biliary passages, and cervix, whereas they had low ratios for cancers of most other sites. Among U.S. Japanese, the direction and magnitude of tne SMR transition varied by site, but generally the SMR moderated toward that of U.S. whites. Specifically, mortality from stomach cancer was elevated though the ratio has been reduced, in addition, mortality from cancers of the liver and biliary passages remained high. In contrast to a sharp decline in the SMR for esophageal cancer, the SMR for cancer of the colon and lymphomas rose closer to the levels for whites. The SMR for cancers of the ovary and prostate gland represented a rise above that of Japan. A higher Issei than Nisei SMR was observed for most cancer sites, regardless of the risk level in Japan. The reverse was true for cancers of the liver and nasopharynx among males, cancers of the breast and ovary among females, and lymphosarcoma and leukemia among both sexes.
AB0089 The Role of the Serotonin Receptor Sert in Bone Remodeling
Authors: R. Chen, Y. Chabbi-Achengli, C. Marty, M. Cohen-Solal, M.-C. de Vernejoul, C. Collet
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Inhibitors of the SERT (SSRIs), the specific serotonin transporter, are efficient to treat depression. A decrease in bone formation has been reported in SERT-/- mice but their effects in bone remodelling are unclear. We have demonstrated that the osteoclast precursor needed serotonin to differentiate while SSRI Paroxetine was responsible for a decreased osteoclast differentiation. <h3>Objectives</h3> We here aimed to study the bone phenotype and bone remodelling of SERT-/- mice in 129/Sv background, known to display an appropriate serotonin metabolism unlike C57BL/6J mice. The second aim was to evaluate the capacity of differentiation of precursors of bone cells in the absence of SERT. <h3>Methods</h3> Bone histomorphometry was performed in 6 week-, 16 week- and 8 month-old SERT-/- mice. E<i>x vivo</i> experiment analyses were conducted to assess the capacity of bone forming and resorbing cells from the bone marrow as well as the expression of differentiating factors. <h3>Results</h3> Compared to WT mice, SERT-/- mice had a decreased bone formation as shown by a lower bone formation rate and lower level of P1NP at 6 weeks, 16 weeks and 8 months. At 6 weeks of age only, lower osteoclast number was counted at femur level and lower level of TRAP in SERT-/- mice as compared to WT mice, suggesting a diminished bone resorption in SERT-/-only in the postnatal period. Moreover, we found a decreased number of osteoclasts, osteoblasts and osteoprogenitors in SERT-/- primary cultures. These results were confirmed in primary cells derived from WT mice cultured in the presence of Paroxetine. Furthermore, SERT-/- osteoblasts had a lower expression of RANKL and a higher expression of OPG to WT osteoblasts. Also, a diminution of the ratio RANKL/OPG was observed in SERT-/-mice leading to a blunted osteoclast differentiation. <h3>Conclusions</h3> Our results indicate that the SERT favors bone formation and resorption. The inhibition of SERT might therefore conduct to a low bone mass and promote the development of bone fragility. <h3>Disclosure of Interest</h3> None declared
137O: Nivolumab in patients (pts) with advanced refractory squamous (SQ) non-small cell lung cancer (NSCLC): 2-year follow-up from CheckMate 063 and exploratory cytokine profling analyses
Authors: H. Lena, N.A. Rizvi, J. Wolf, F. Cappuzzo, G. Zalcman, P. Baas, J. Mazieres, B. Farsaci, M.A. Blackwood-Chirchir, S. Ramalingam
Journal: Journal of Thoracic Oncology (2016)
Preoperative docetaxel and gemcitabine in resectable non-small cell lung cancer: A phase II trial of the Minnie Pearl Cancer Research Network
Authors: D. S. Thompson, D. R. Spigel, F. A. Greco, D. A. Yardley, H. A. Burris, E. Vazquez, J. Erland, D. L. Shipley, E. Spremulli, J. D. Hainsworth
Journal: Journal of Clinical Oncology (2007)

18100 Background: Preoperative chemotherapy may improve outcomes for patients (pts) with resectable non-small cell lung cancer (NSCLC) compared with surgery alone. This multicenter community-based phase II trial examined the role of preoperative gemcitabine (G) and docetaxel (D) in pts with resectable NSCLC. Methods: The primary endpoint was to assess the pathologic response rate of G/D in pts with potentially resectable clinical stages IB, II, and selected III NSCLC [T 3 N 1 , T 1–3 N 2 (1 nodal station = 2 cm), T 4 N 0, T 4 N 1 excluding vascular, tracheal, esophageal, vertebral disease, or malignant effusions]. Additional eligibility criteria: measurable disease, ECOG PS 0–1, and informed consent. Treatment: G 1,000 mg/m 2 and D 30 mg/m 2 days 1, 8 every 21 days x 3 cycles. Pts were restaged after treatment and resected 3–6 weeks later. If pts were inoperable, had incomplete resections, or N2 disease, D 20 mg/m 2 , carboplatin AUC=1.5 weekly x 7, and radiation to 63 Gy were administered. Analysis was by intent to treat. Results: Between April 2004 and September 2005, 75 pts were enrolled. Median age was 62 years. 92% of planned preoperative therapy was administered and 38 pts (51%) underwent resection. The clinical objective response rate was 30% (95% CI 20%-42%). No pathological complete responses were observed. 26 pts went on to receive chemoradiotherapy. Median progression-free survival was 9.8 months (95% CI 5.9–13.9). Median overall survival was 18 months (95% CI 14.8- 21.3). 71% of pts were alive at 1 year. Grade 3/4 hematologic toxicity with preoperative therapy included neutropenia (28%), anemia (4%), and thrombocytopenia (7%). Grade 3/4 non-hematologic toxicity was limited. Conclusions: G/D is a well tolerated preoperative regimen for pts with resectable NSCLC, however did not result in pathologic complete responses. There is no suggestion that G/D is more active than other tested combined modality regimens. The role of preoperative therapy in NSCLC remains undefined. Additional studies comparing preoperative and adjuvant treatment are warranted. No significant financial relationships to disclose.
Metabolic Effects of Anesthesia in Man. IV. a Comparison of the Effects of Certain Anesthetic Agents on the Normal Liver
Authors: C. W. Fairlie, T. P. Barss, A. B. French, C. M. Jones, H. K. Beecher
Journal: New England Journal of Medicine (1951)

THE toxic effects of chloroform on the liver are well known and feared. Studies on animals have suggested a similar role for other anesthetic agents, particularly the ethers. Goldschmidt, Ravdin and Lucké1 showed that in dogs three hours of anesthesia with divinyl ether or chloroform produced central necrosis of the liver in a large proportion of the animals studied. Diethyl ether produced similar changes, not quite so severe or frequent. The same workers2 showed the dangers inherent in translation of results from one species to another when they repeated these experiments in monkeys. Here they found histologic changes only with . . .
PTH-092 Discovery and quantitation of novel liver fibrosis biomarkers using proteomics
Authors: B Gangadharan, A Kumar, E Barnes, P Klenerman, N Zitzmann
Journal: Gut (2015)

<h3>Introduction</h3> Liver biopsy is the reference standard for assessing liver fibrosis and serum biomarkers can be used as a less invasive approach. Various antibody-based assays for serum biomarkers are currently in use to help diagnose fibrosis stage. However, these immunoassays have potential disadvantages such as the inability to detect degraded proteins and often these assays are time consuming. We have developed an antibody-free method to detect and quantify novel liver fibrosis biomarkers in human plasma/serum which overcomes these disadvantages. <h3>Method</h3> Novel liver fibrosis biomarkers were identified by analysing proteins in plasma/serum samples from controls and patients with varying stages of liver fibrosis using a proteomics technique: two dimensional gel electrophoresis (2DE). For the most promising liver fibrosis biomarkers, an antibody-free assay (parallel reaction monitoring using mass spectrometry) was used which detects tryptic peptides of the biomarkers and their fragments. A calibration curve, established from known amounts of synthetic isotopically labelled peptides, was used to determine the concentrations of our biomarkers in serum/plasma samples from patients with varying stages of liver fibrosis. <h3>Results</h3> Several candidate biomarkers for hepatic fibrosis were identified using 2DE. Our best biomarkers were promising when compared by Western blotting to the proteins used in existing serum biomarker tests for liver fibrosis. Using parallel reaction monitoring, antibody-free assays were developed for our most promising biomarkers which were able to successfully discriminate between neighbouring stages of liver fibrosis. <h3>Conclusion</h3> We have developed a fast, sensitive and robust antibody-free method to detect and quantify novel liver fibrosis biomarkers in human plasma/serum. Unlike immunoassays which are restricted on the number of biomarkers due to antibody cost, our method can successfully detect and quantify more than 50 biomarkers in a single 30 min run. This novel assay may help clinicians to assess hepatic fibrosis and reduce the need for invasive liver biopsies. <h3>Disclosure of interest</h3> None Declared. <h3>References</h3> Bevin Gangadharan <i>et al</i>. Discovery of novel biomarker candidates for liver fibrosis in hepatitis C patients. PLoS One 2012;7:e39603 Bevin Gangadharan <i>et al</i>. Two dimensional gel electrophoresis using pH3-5.6 immobilised pH gradient strips identifies potential novel disease biomarkers. <i>Nature Protocol Exchange</i>, 2011:doi:10.1038/protex.2011.261 Bevin Gangadharan <i>et al</i>. New approaches for biomarker discovery: The search for liver fibrosis markers in hepatitis C patients. J Proteome Res 2011;10:2643 Bevin Gangadharan <i>et al</i>. Novel serum biomarker candidates for liver fibrosis in hepatitis C patients. Clin Chem 2007;53:1792
S3 Reduced BMPR2 expression potentiates a pulmonary artery smooth muscle cell specific IL-1ß response
Authors: J Pickworth, S Shay, S Gladson, J Iremonger, AMK Rothman, S Francis, J West, A Lawrie
Journal: Thorax (2015)

<h3>Introduction and objectives</h3> Bone morphogenetic protein receptor type 2 (BMPR2) mutations are found in heritable and idiopathic pulmonary arterial hypertension however penetrance is incomplete implying necessity for a ‘second hit’. IL-1ß and IL-6 are increased in PAH patients and animal models and are thought to have a role in disease. We aimed to determine pulmonary specific interplay between BMPR2 and IL-1ß signalling through assessing IL-1ß responsiveness of pulmonary artery and aortic smooth muscle cells (Ao/PA SMC) and determine the effects of reduced BMPR2. <h3>Methods</h3> Microarray analysis of PASMC and AoSMC mRNA was performed using microarray on mRNA isolated from cells cultured in SMGM-2 (Lonza) +/- functional BMPR2 (by use of siRNA) and stimulation with 10 ng/ml IL-1ß for 6 h. Subsequent bioinformatics was performed using R. Findings were validated using quantitative PCR and western blotting. Furthermore R899X<sup>+/-</sup> BMPR2 transgenic mice were fed western diet for six weeks and injected daily with IL-1ß then assessed for inflammatory activation and PAH phenotype (catheter/echo). mRNA and protein changes were measured by TaqMan PCR, western blotting and serum ELISA. Immuno-staining of paraffin embedded lung sections assessed pulmonary vascular remodelling. <h3>Results</h3> Array data shows reduced inflammatory activation in response to IL-1ß in PASMC compared with AoSMCs, analysis of cells lacking functional BMPR2 identified an exaggerated inflammatory response to IL-1ß in PASMC lacking BMPR2 (siRNA). Significant up-regulation of IL-6, IL-1α and adhesion molecules (&gt;2-fold) shown by array analysis was validated by qPCR. In the absence of BMPR2 a 1.5 fold increase in proliferation was observed in response to IL-1ß compared to PASMC with functional BMPR2. Mice treated with IL-1ß show higher white blood cell counts (1.7-fold), and protein levels of OPG and IL-6 (serum) matching <i>in vitro</i> data. <h3>Conclusion</h3> IL-1ß induces a pulmonary specific transcriptome altered by suppression of BMPR2 signalling indicating cross-talk between the pathways. In the presence of BMPR2, PASMCs show limited response to IL-1ß however reducing BMPR2 exacerbated this response increasing the likelihood of a PAH phenotype in PASMCs. This highlights a mechanism that increased IL-1ß may provide “second hit” to reduced BMPR2 to stimulate development of PAH.