tbuckley/cabot-search huggingface dataset:
Immune selection and genetic sequence variation in core and envelope regions of hepatitis C virus
Authors: John M. Christie, Helen Chapel, Roger W. Chapman, William M. Rosenberg
Journal: Hepatology (1999)

How Hepatitis C Virus (HCV) causes persistent infection is unknown. One hypothesis is that HCV evades the host immune response through mutation in immune epitopes. We have investigated mutations in the HCV genome to see if they cluster within immune epitopes; and we have studied the effect of antibody deficiency on mutation rates. We studied patients with chronic hepatitis C, 3 with antibody deficiency and 3 with normal immunity. Regions of the core and envelope genes of HCV, encoding cytotoxic (CTL), and B cell epitopes were sequenced at 2 time points, 2 years apart. The diversity of quasispecies increased with time. The HCV genetic mutation rate was higher than previously predicted. The cryptic nucleotide mutation rate in core was similar to that observed in envelope, suggesting that the error rate of the HCV RNA polymerase is similar in both regions. In contrast, the coding mutation rate was decreased in core and increased in envelope. No genetic mutation was seen in any of the core CTL epitopes despite detectable cellular responses. All patients had mutations within a previously described envelope CTL epitope but did not exhibit immune responses to either index or mutated peptides. There was no difference in mutation rates in any cellular or humoral epitopes between patients with antibody deficiency and normal immunity. Thus we have found no evidence that mutations were selected by T-lymphocytes or antibodies. These findings implicate alternative virus-host interactions in the selection of HCV mutations.
Clinical significance of Clostridium difficile and its toxins in faeces of immunocompromised children.
Authors: M J Wolfhagen, K Meijer, A C Fluit, R Torensma, R A Bruinsma, A Fleer, J Verhoef
Journal: Gut (1994)

In this study, clinical and laboratory findings were tested for correlation with the presence of Clostridium difficile. The toxigenicity of the isolated strains and the toxins were determined in faecal samples of immunocompromised children admitted to a single room for protective isolation. Using the toxin assay as the gold standard, the culture sensitivity of toxigenic C difficile was 94.1%, the specificity 93.8%, the positive predictive value 62.8%, and the negative predictive value 99.3%. Correction for stools with a positive culture of toxigenic C difficile preceding detection of toxin, resulted in a positive prediction value of 78.4%. A statistically significant association was found between a positive faecal toxin assay and fever, and between a positive culture of toxigenic C difficile and abdominal pain: 42% of the patients with positive toxin assays had fever versus 21% with negative toxin assays, and 66% of the patients with a positive culture for toxigenic C difficile had abdominal pain, versus 22% with negative cultures. Further analysis of the cultures and toxin assays showed no statistically significant association with diarrhoea, fever, white blood cell count, C reactive protein concentrations, or abdominal pain. Based on these findings, it is suggested that immunocompromised children should be treated when toxigenic C difficile is cultured or when toxin is detected in stool samples.
Suicidal and self harming behaviours may be distinct
Authors: Philip V Dutton, Andrew J Ashworth
Journal: BMJ (2007)

suicide riskBipolarity is important during treatment with antidepressants Rubino et al have identified that most (if not all) of the excess risk of suicide in a group of patients treated with venlafaxine could be explained by a higher burden of risk factors for suicide.It may be true that this group of patients had more severe or "difficult to treat" unipolar depression, but it is also possible that bipolar features in this group may be responsible for the observed raised rates of suicidality.Perhaps because of limitations of space, the authors do not discuss this as a possibility, despite an adjusted relative risk of completed suicide of 4.94 (95% confidence interval 1.30 to 18.84) for "past history of bipolar disorder" (table 3). 1 Recent work shows that at least 50% of difficult to treat unipolar depressed patients may have an undetected bipolar disorder, 2 and it is now well documented that antidepressant monotherapy for bipolar depression runs a high risk of precipitating hypomanic or mixed affective states, 3 which have been strongly associated with self harm and completed suicide. 4 It is also the case that venlafaxine seems more likely than other antidepressants to precipitate a switch into hypomania or mania in bipolar depression. 5Furthermore, many of the variables reported by Rubino et al could be considered to point towards high levels of bipolarity in the venlafaxine treated group, including higher rates of a family history of psychiatric disorder, more frequent prescription of antipsychotics and mood stabilisers, a history of non-response to several different antidepressants, and more frequent lifetime depressive episodes.
Host Defenses and Immunologic Alterations Associated with Chronic Hemodialysis
Authors: SIMEON E. GOLDBLUM
Journal: Annals of Internal Medicine (1980)

Many of the complications experienced by patients undergoing hemodialysis can be attributed to their altered host defenses. Increased cutaneous staphylococcal carriage along with repeated intravascular cannulation and defective mucocutaneous barriers lead to frequent invasion by infectious agents. Pathogens encounter granulocytes with subnormal locomotion, phagocytosis, and intracellular killing. Depressed cell-mediated immunity may be explained by shortened lymphocyte survival, lymphopenia, inhibition of lymphocyte transformation, and suppressor T-cell activity. This is manifested by cutaneous anergy, prolonged graft survival, altered tumor surveillance, and abnormal responses to hepatitis B and tuberculosis. Host interaction with the hemodialysis membrane leads to cellular disruption, which may induce autoantibodies. Activation of the alternate complement pathway during hemodialysis leads to granulocyte sequestration in small vessels, specifically within the lungs. These hemodialysis-induced alterations along with the manifestations of underlying chronic renal insufficiency may obscure clinical evaluation of these patients.
Application of Ultrasonic Probes Prior to Endoscopic Resection of Early Gastric Cancer
Authors: T. Takemoto, H. Yanai, M. Tada, T. Aibe, H. Fujimura, N. Murata, M. Karita, K. Okita
Journal: Endoscopy (1992)

The development of a new strip biopsy technique for endoscopic mucosectomy utilizing endoscopic saline injection and a double-channel endoscope permits the safe and simple resection of superficial type early gastric cancer which has been difficult to perform with conventional poylpectomy techniques. Preresection assessment of the depth of invasion and postresection assessment of efficacy are important with regard to treatment of early gastric cancer, but conventional endoscopic ultrasonography employed for this purpose requires special equipment and involves intricate procedures. An ultrasonic probe which can be used endoscopically has recently been developed and is currently in the trial stage. The authors have conducted studies with respect to a 7.5 MHz radial scanning type Miniature Ultrasonic Probe as well as a 20 MHz manual linear scanning type Sonoprobe System. Experimental studies indicated that the former type is capable of delineating postresection ulcers, while the latter permitted delineation of tumors as hypoechoic images in 9 of 11 cases of early gastric cancer.
Remarkable Sequence Conservation of the Last Intron in the PKD1 Gene
Authors: M. Rodova
Journal: Molecular Biology and Evolution (2003)

The last intron of the PKD1 gene (intron 45) was found to have exceptionally high sequence conservation across four mammalian species: human, mouse, rat, and dog. This conservation did not extend to the comparable intron in pufferfish. Pairwise comparisons for intron 45 showed 91% identity (human vs. dog) to 100% identity (mouse vs. rat) for an average for all four species of 94% identity. In contrast, introns 43 and 44 of the PKD1 gene had average pairwise identities of 57% and 54%, and exons 43, 44, and 45 and the coding region of exon 46 had average pairwise identities of 80%, 84%, 82%, and 80%. Intron 45 is 90 to 95 bp in length, with the major region of sequence divergence being in a central 4-bp to 9-bp variable region. RNA secondary structure analysis of intron 45 predicts a branching stem-loop structure in which the central variable region lies in one loop and the putative branch point sequence lies in another loop, suggesting that the intron adopts a specific stem-loop structure that may be important for its removal. Although intron 45 appears to conform to the class of small, G-triplet–containing introns that are spliced by a mechanism utilizing intron definition, its high sequence conservation may be a reflection of constraints imposed by a unique mechanism that coordinates splicing of this last PKD1 intron with polyadenylation.
Bile acids modulate the interferon signalling pathway
Authors: Philippe Podevin, Olivier Rosmorduc, Filomena Conti, Yvon Calmus, Peter J. Meier, Raoul Poupon
Journal: Hepatology (1999)

We have previously shown that cholestasis and bile acids inhibit 2′,5′ oligoadenylate synthetase (OAS) activity in the liver and in primary hepatocyte cultures. Here, we assessed the influence of bile acids on interferon (IFN) pathway activation in three hepatoma cell lines. In HepG2 cells, bile acids (100–200 μmol/L) inhibited IFN–induced 2′,5′ OAS activity to an extent depending on their surface activity index. In Western blot analysis, IFN–induced expression of two major antiviral proteins, MxA and OAS p100, was reduced by 54% ± 8% and 44% ± 12%, respectively, when cells were preincubated for 4 hours with 100 μmol/L chenodeoxycholic acid (CDCA). In the same conditions, CDCA did not modify the IFN–induced signal transducers and activators of transcription (STAT)s tyrosine phosphorylation. In contrast, it reduced IFN–induced MxA promoter activity by 60%. The inhibitory effect of CDCA was not mediated by a 4β–phorbol 12β–myristate 13α–acetate (PMA)–sensitive protein kinase C (PKC)–dependent pathway. Finally, using CHO cells stably expressing a functional human bile acid carrier (Na + –dependent taurocholate cotransporting polypeptide [NTCP]), we found that bile acid inhibition of the IFN pathway occurred in the range of more physiological concentrations (12–50 μmol/L). In summary, our results provide strong evidence that bile acids inhibit the induction of proteins involved in the antiviral activity of IFN. This might partly explain the lack of responsiveness to IFN therapy in some patients with advanced chronic viral liver diseases.
A general practitioner in an ophthalmology accident and emergency department.
Authors: M Price, C I Phillips
Journal: BMJ (1976)

After a short period of intensive training, a general practitioner successfully replaced a senior house officer (SHO) in the accident and emergency department of an eye hospital on one morning a week for a year. An unbiased observer compared the performance of the general practitioner after one year with that of a full-time SHO who had had 17 months' experience; their performances were about equal. Although a sessional general practitioner costs about 28% more than an SHO, the real cost is much less because undue length of service as an SHO or change to another specialty (because of the SHO surplus) delays achievement of a permanent grade. Continuity is a great advantage of the general practitioner. Replacement of some SHOs by general practitioners would reduce the surplus of SHOs with poor promotion prospects. The commonest diagnoses were Meibomian cysts (18%), corneal foreign bodies (20%), corneal abrasions (12%), and conjunctivitis (8%).
Salmeterol resolves airway obstruction but does not possess anti-eosinophil efficacy in newly diagnosed asthma: A randomized, double-blind, parallel group biopsy study comparing the effects of salmeterol, fluticasone propionate, and disodium cromoglycate
Authors: Ari Lindqvist, Eeva-Maija Karjalainen, Lauri A. Laitinen, Tuomo Kava, Alan Altraja, Markku Pulkkinen, Maija Halme, Annika Laitinen
Journal: Journal of Allergy and Clinical Immunology (2003)
Psychiatrist admits plagiarism but denies dishonesty
Authors: Owen Dyer
Journal: BMJ (2008)

Five years after a major reorganisation of England's neonatal services, large and unexplained variations between regions in mortality among neonates still exist, concludes a new report from the House of Commons Public Accounts Committee.England's 178 neonatal care units were ordered in 2003 to reorganise into 23 regional networks.But that reorganisation has failed to address discrepancies between regions; and two regions, Essex and the Northern, have still not formally merged into unified organisations after five years.In 2005 the neonatal mortality rate among babies born at more than 22 weeks' gestation varied from 1.8 deaths per 1000 live births in the Surrey and Sussex region to 4.8 in the South West Midlands.The Conservative MP Edward Leigh, who chairs the Public Accounts Committee, said that the 2003 reorganisation "has had limited effect in reducing regional variations in mortality rates of babies born prematurely or suffering an illness [and] needing specialist care."The Department of Health was unable to confirm whether these discrepancies were due to disparities in care or to demographic factors, he said.Primary care trusts, Mr Leigh added, "need to improve their understanding of the Reorganisation of neonatal service in England fails to iron out regional variation in death rates UK NEWS Regulation of alternative medicine faces more delays, p 1395 WoRld NEWS dutch doctors make advice on suicide available to public, p 1394 bmj.com Germany promises protection to hospital doctors over longer working hours
Genomic modulators of the immune response
Authors: Julian C. Knight
Journal: Trends in Genetics (2012)

Our understanding of immunity has historically been informed by studying heritable mutations in both the adaptive and innate immune responses, including primary immunodeficiency and autoimmune diseases. Recent advances achieved through the application of genomic and epigenomic approaches are reshaping the study of immune dysfunction and opening up new avenues for therapeutic interventions. Moreover, applying genomic techniques to resolve functionally important genetic variation between individuals is providing new insights into immune function in health. This review describes progress in the study of rare variants and primary immunodeficiency diseases arising from whole-exome sequencing (WES), and discusses the application, success, and challenges of applying genome-wide association studies (GWAS) to disorders of immune function and how they may inform more rational use of therapeutics. In addition, the application of expression quantitative-trait mapping to immune phenotypes, progress in understanding MHC disease associations, and insights into epigenetic mechanisms at the interface of immunity and the environment are reviewed.
Merging Hospitals and Physician Support
Authors: Lawrence Tremonti
Journal: JAMA (1983)

This study gives empirical documentation of physician support for a recent hospital merger. Results indicated that physicians from private practice, from the medical specialty of anesthesiology, and those least satisfied with hospital administration were also the least supportive of the merger. Formal involvement in the merger process, via task force membership, did relatively little to increase physician support for the merger. However, a significant correlation between perceived input into the merger process and support for the merger indicates positive aspects of involvement, even though this may not have occurred through the formal structure of task forces. Implications for managing physicians and hospital mergers is discussed.
Nitric oxide amplifies interleukin 1-induced cyclooxygenase-2 expression in rat mesangial cells.
Authors: T Tetsuka, D Daphna-Iken, B W Miller, Z Guan, L D Baier, A R Morrison
Journal: Journal of Clinical Investigation (1996)

Interleukin 1 and nitric oxide (NO) from infiltrating macrophages and activated mesangial cells may act in concert to sustain and promote glomerular damage. To evaluate if such synergy occurs, we evaluated the effect if IL-1 beta and NO on the formation of prostaglandin (PG)E2 and cyclooxygenase (COX) expression. The NO donors, sodium nitroprusside and S-nitroso-N-acetylpenicillamine, alone did not increase basal PGE2 formation. However, these compounds amplified IL-1 beta-induced PGE2 production. Similarly, sodium nitroprusside and S-nitroso-N-acetylpenicillamine by themselves did not induce mRNA and protein for COX-2, the inducible isoform of COX; however, they both potentiated IL-1 beta-induced mRNA and protein expression of COX-2. The stimulatory effect of NO is likely to be mediated by cGMP since (a) an inhibitor of the soluble guanylate cyclase, methylene blue, reversed the stimulatory effect of NO donors on COX-2 mRNA expression; (b) the membrane-permeable cGMP analogue, 8-Br-cGMP, mimicked the stimulatory effect of NO donors on COX-2-mRNA expression; and (c) atrial natriuretic peptide, which increases cellular cGMP by activating the membrane-bound guanylate cyclase, also amplified IL-1 beta-induced COX-2 mRNA expression. These data indicate a novel interaction between NO and COX pathways.
Maximal Treadmill Stress Test Correlated with Postexercise Phonocardiogram in Normal Subjects
Authors: WILBERT S. ARONOW, NICHOLAS P. PAPAGEORGE'S, RONALD R. UYEYAMA, JOHN CASSIDY
Journal: Circulation (1971)

One hundred normal subjects, mean age 51, who had had a simultaneous phonocardiogram and electrocardiogram at rest and after a double Master's test had a maximal treadmill stress test. Thirteen of 100 normal people (13%) had an abnormal maximal treadmill stress test with at least 1.0 mm of ischemic ST-segment depression. Ten of 29 normal subjects (34%) with a fourth heart sound and four of 11 normal people (36%) with a third heart sound after their double Master's test had an abnormal maximal treadmill stress test. Three of 71 normal subjects (4%) without a fourth heart sound and nine of 89 normal people (10%) without a third heart sound after their double Master's test had an abnormal maximal treadmill stress test. Normal subjects with an abnormal maximal treadmill stress test had a significantly higher incidence of fourth heart sounds ( P &lt;0.001) and third heart sounds ( P &lt;0.02) than normals with a normal maximal treadmill stress test.
Tissue plasminogen activator: Toronto (TPAT) placebo-controlled randomized trial in acute myocardial infarction
Authors: Paul W. Armstrong, Ronald S. Baigrie, Paul A. Daly, Aminul Haq, Michael Gent, Robin S. Roberts, Michael R. Freeman, Robert Burns, Peter Liu, Christopher D. Morgan
Journal: Journal of the American College of Cardiology (1989)
Chaperone Nanobodies Protect Gelsolin Against MT1-MMP Degradation and Alleviate Amyloid Burden in the Gelsolin Amyloidosis Mouse Model
Authors: Wouter Van Overbeke, Adriaan Verhelle, Inge Everaert, Olivier Zwaenepoel, Joël Vandekerckhove, Claude Cuvelier, Wim Derave, Jan Gettemans
Journal: Molecular Therapy (2014)

Gelsolin amyloidosis is an autosomal dominant incurable disease caused by a point mutation in the GSN gene (G654A/T), specifically affecting secreted plasma gelsolin. Incorrect folding of the mutant (D187N/Y) second gelsolin domain leads to a pathological proteolytic cascade. D187N/Y gelsolin is first cleaved by furin in the trans-Golgi network, generating a 68 kDa fragment (C68). Upon secretion, C68 is cleaved by MT1-MMP-like proteases in the extracellular matrix, releasing 8 kDa and 5 kDa amyloidogenic peptides which aggregate in multiple tissues and cause disease-associated symptoms. We developed nanobodies that recognize the C68 fragment, but not native wild type gelsolin, and used these as molecular chaperones to mitigate gelsolin amyloid buildup in a mouse model that recapitulates the proteolytic cascade. We identified gelsolin nanobodies that potently reduce C68 proteolysis by MT1-MMP in vitro. Converting these nanobodies into an albumin-binding format drastically increased their serum half-life in mice, rendering them suitable for intraperitoneal injection. A 12-week treatment schedule of heterozygote D187N gelsolin transgenic mice with recombinant bispecific gelsolin-albumin nanobody significantly decreased gelsolin buildup in the endomysium and concomitantly improved muscle contractile properties. These findings demonstrate that nanobodies may be of considerable value in the treatment of gelsolin amyloidosis and related diseases.
Predominance of Brain and Lung Metastases in Triple-Negative Breast Cancer Patients.
Authors: V. Gadiyaram, S. Kurian, J. Abraham, G. Hobbs, L. Vona-Davis, L. Vona-Davis
Journal: Cancer Research (2009)

Abstract Background: Patients with triple-negative breast cancer have an increased likelihood of recurrence compared to other types of breast cancer, however, little is known about their pattern of metastatic spread. Our object was to evaluate the metastatic patterns of women diagnosed with triple-negative breast cancer compared to other subtypes. Methods: We studied a cohort of 572 white patients diagnosed with invasive breast cancer at West Virginia University Hospital between 1999 and 2004. Hospital registry, charts, and pathology records provided clinical data including tumor receptor status and biopsy-proven metastatic spread to bone, brain, liver and lung. Breast cancers that were negative for estrogen, progesterone, and HER2neu, otherwise known as triple-negative were compared with HER2neu-postive and HER2neu-negative (endocrine receptor positive) disease. Body mass index was calculated and a value of ≥30 considered indicative of obesity. Specimens of primary carcinoma were available for analysis of Ki67 mitotic index and expression of p53. Results: 134/572 (23.4%) had triple-negative breast cancer, while the frequencies were 108/572 (18.9%) and 330/572 (57.7%) in HER2neu-positive and HER2neu-negative (endocrine receptor positive) groups. Women with triple-negative disease were more likely to have brain-metastasizing breast cancer; 10.5% versus 4.6% for HER2neu-positive and 3.3% for HER2neu-negative (P&amp;lt;0.05). They were also more likely to have metastasis to the lung; 10.5% versus 2.8% for HER2neu-positive and 7.0% for HER2neu-negative (P&amp;lt;0.05). Triple-negative breast cancer patients who developed brain and lung metastases were younger &amp;lt;50 years and significantly more obese (P=0.0236). High Ki67 labeling index and p53 expression were associated with more advanced disease indicating an aggressive phenotype for this group.Patterns of metastasis in breast cancer subtypesSite of metastasisTriple-negativeHER2-positiveHER2-negativeP valueBone20/134 (14.9)7/108 (6.5)38/330 (11.5)0.1037Brain14/134 (10.5)5/108 (4.6)11/330 (3.3)0.0136*Liver11/134 (8.2)4/108 (3.7)22/330 (6.7)0.3261Lung14/134 (10.5)3/108 (2.8)23/330 (6.9)0.0507*Other5/134 (3.7)3/108 (2.8)3/330 (0.91)0.1093 Conclusion: The excess risk of brain and lung metastasis in women with triple-negative breast cancers versus other subtypes needs further validation. The unique biology of triple-negative tumors may explain this pattern of metastatic spread. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6159.