tbuckley/cabot-search huggingface dataset:
T1 Matrix metalloproteinase-driven tissue destruction in Human Tuberculosis (TB) is mediated by Th-17 cytokines and the PI3K/p110a/p70S6K cascade
Authors: S. Singh, U. K. Singh, P. T. Elkington, J. S. Friedland
Journal: Thorax (2011)

Mycobacterium tuberculosis (Mtb) kills 1.7 million people annually. The Th1 paradigm does not explain TB-driven cavitation. Current treatment is lengthy with many adverse effects. The Interleukin-23/Th17 axis plays a critical role in early Mtb containment. Respiratory stromal cells are important first-line defence and secrete Matrix metalloproteinases (MMPs). Role of MMPs, which are substrate-specific proteases causing extracellular matrix degradation/remodelling, was investigated in TB. Human bronchoalveolar lavage (BAL) samples from 35 well-characterised TB and control patients were analysed for MMPs and Th17 cytokines. TB/Control lung biopsies were stained for MMPs/IL-17. Primary normal human bronchial epithelial cells (NHBEs) and MRC-5 fibroblasts were stimulated with IL-17/IL-22/IL-23, alone and in combination with conditioned medium from Mtb-infected monocytes (CoMTb). Secretion, gene expression, gene silencing, intracellular signalling were investigated by luminex, ELISA, zymography, dual-luciferase promoter-reporter, realtime RT-PCR, siRNA transfection. MMPs were up-regulated in Human TB BALs (p&lt;0.0001). This positively correlated with cavitation score on CXRs. TIMPs (tissue inhibitor of metalloproteinase) and IL-17/IL-23 were unaltered but IL-22 was increased in TB BAL. IL-17 and MMP-3 were co-expressed in pneumocytes around granulomas in TB lung biopsies. CoMTb (but not direct infection) up-regulated secretion and gene expression of MMP-1 (collagenase, p&lt;0.0001), MMP-3 (stromelysin, p&lt;0.001) and MMP-9 (gelatinase, p&lt;0.0001) from NHBEs. MMP-3 protein and promoter activity in MRC-5s was also increased (p&lt;0.001). AKT inhibition suppressed all MMPs (p&lt;0.01) whereas siRNA and chemical inhibition of the proximal PI3Kp110a subunit abrogated MMP-3 only (p&lt;0.001). Distally, p70S6K (mTOR) blockade with rapamycin abrogated TB-driven MMP-1 and MMP-3 (p&lt;0.001). MMP-9 production was unaffected by proximal/distal inhibition of PI3K.IL-17 independently and also synergistically with CoMTb augmented MMP-3 secretion/gene expression from NHBEs and MRC-5s in a dose-dependent manner (peak 8ng/ml, p&lt;0.0001). This was p38-dependent, confirmed by p38-specific siRNA. In contrast, IL-17 down-regulated CoMTb-driven MMP-9 to baseline (p&lt;0.01). IL-22 augmented MMP-3 from fibroblasts but not from NHBEs. IL-23 did not drive MMPs. <h3>Summary</h3> MMPs are key mediators of tissue damage in human pulmonary TB and are regulated in a cell- and stimulus-specific manner. IL-17 and IL-22 drive MMP-3 but suppress MMP-9 in airway epithelium. The PI3Kinase/p110a/p70S6K pathway is a crucial target and its immuno-modulation (eg, rapamycin) is a potential adjunctive therapy to limit tissue destruction and shorten chemotherapy in TB.
Resolution of liver biopsy alterations in three siblings with bile acid treatment of an inborn error of bile acid metabolism (Δ4-3-oxosteroid 5β-reductase deficiency)
Authors: Ynthia C. Daugherty, Kenneth D. R. Setchell, James E. Heubi, William F. Ballstreri
Journal: Hepatology (1993)

Identical male twins and their brother, cholestatic from birth, with delta 4-3-oxosteroid 5 beta-reductase deficiency, were studied by serial liver biopsy. Spectrometry documented defective primary bile acid synthesis and markedly increased levels of atypical oxo and allo bile acids in urine and serum. Hepatocellular cholestasis and giant-cell transformation resolved in parallel with clinical and biochemical recovery during oral bile acid administration. In the twins, portal fibrosis stabilized at a mild level; they are well as 5-yr-olds at this writing. Follow-up biopsy in their brother at 8 mo was normal, and he is doing well at 3 yr of age. Hepatic ultrastructural alterations in all three were characterized by abnormalities of bile canaliculi including small bile plugs, diverticulae and latticelike elaborations of hepatocellular membranes adjacent to bile canaliculi that were shown to have resolved completely on subsequent biopsies. Eight additional cases have been detected on urine screening; only two of these patients have survived, on bile acid therapy. Early diagnosis and treatment improves the prognosis of this otherwise lethal inborn error of bile acid synthesis.
Miss, Mister, Doctor: Celecoxib
Authors: R. Cheung
Journal: Journal of the Royal Society of Medicine (2006)

How we are titled is of little consequence I found the editorial (April 2006 JRSM 1 ) on how we are titled most interesting.This is a continuation of the debate that the dental profession has been having for many years, fuelled by both an influx of overseas graduates styling themselves as 'Doctor', and by the development of the role of dentists from 'toothwrights' to practitioners with a more holistic approach encompassing the oral health and wellbeing of those in their care.However all of us, physicians, surgeons, general practitioners and dentists have one thing in commonpatients.But that may be about to change.The same week as the editorial appeared, the chief executive of the Sussex Partnership NHS Trust ordered staff not to refer to people receiving medical care as patients but as clients.This not only demonstrates a misunderstanding of our roles but also devalues both practitioners and those that we care for.Patients are not simply clients or users of health services.Patients are those receiving care, who are given time, are listened to and treated with sympathy, understanding and expertise.There is something special about the term patient, and although to give a precise dictionary definition is difficult, it is well understood by those who deliver the care.How we are titled may well, as the editorial states, be of little consequence; far more important is how we refer to, and perceive, those in our care.
Clinical Issues and Research in Respiratory Failure from Severe Acute Respiratory Syndrome
Authors: Mitchell M. Levy, Melisse S. Baylor, Gordon R. Bernard, Rob Fowler, Teri J. Franks, Frederick G. Hayden, Rita Helfand, Stephen E. Lapinsky, Thomas R. Martin, Michael S. Niederman, Gordon D. Rubenfeld, Arthur S. Slutsky, Thomas E. Stewart, Barbara A. Styrt, B. Taylor Thompson, Andrea L. Harabin
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Section:ChooseTop of pageAbstract <<SARS—BACKGROUND AND CLINI...LUNG PATHOLOGY IN SARSSPECIFIC TREATMENTS FOR S...RECOMMENDATIONCLINICAL MANAGEMENT OF SE...PREPARATION OF THE HEALTH...SARS RESEARCH: PROPOSALS ...CONCLUSIONSReferencesCITING ARTICLES
Angiotensin II type 1 receptor blocker inhibits fibrosis in rat nonalcoholic steatohepatitis
Authors: Akira Hirose, Masafumi Ono, Toshiji Saibara, Yasuko Nozaki, Kosei Masuda, Akemi Yoshioka, Masaya Takahashi, Naoaki Akisawa, Shinji Iwasaki, Jude A. Oben, Saburo Onishi
Journal: Hepatology (2007)

Nonalcoholic steatohepatitis (NASH) is now the most frequent cause of chronic liver impairment in developed countries and is a suggested causative factor in the development of cryptogenic cirrhosis and hepatocellular carcinoma. At present there is no effective and accepted therapy for NASH. The renin-angiotensin system is involved in hepatic fibrosis through activation of hepatic stellate cells, major fibrogenic cells in the liver. Hepatic stellate cells are activated by liver injury to express excessive matrix proteins and profibrogenic cytokines such as transforming growth factor–beta 1. Medicines that inhibit this pathway may be of therapeutic potential in NASH. Using a methionine-choline–deficient rat model of NASH, we studied the potential utility of an angiotensin II type 1 receptor blocker (ARB), olmesartan, on biochemical, histologic, and antioxidant measures of disease activity. ARB significantly attenuated increases in aspartate aminotransferase, activation of hepatic stellate cells, oxidative stress, expression of transforming growth factor–beta 1, expression of collagen genes, and liver fibrosis. Conclusion : Our observations strongly suggest a potential preventive role for ARB in the progression of nonalcoholic steatohepatitis. (Hepatology 2007.)
Increasing Disparities in the Age-Related Incidences of Colon and Rectal Cancers in the United States, 1975-2010
Authors: Christina E. Bailey, Chung-Yuan Hu, Y. Nancy You, Brian K. Bednarski, Miguel A. Rodriguez-Bigas, John M. Skibber, Scott B. Cantor, George J. Chang
Journal: JAMA Surgery (2014)

The overall incidence of colorectal cancer (CRC) has been decreasing since 1998 but there has been an apparent increase in the incidence of CRC in young adults.To evaluate age-related disparities in secular trends in CRC incidence in the United States.A retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER) CRC registry. Age at diagnosis was analyzed in 15-year intervals starting at the age of 20 years. SEER*Stat was used to obtain the annual cancer incidence rates, annual percentage change, and corresponding P values for the secular trends. Data were obtained from the National Cancer Institute's SEER registry for all patients diagnosed as having colon or rectal cancer from January 1, 1975, through December 31, 2010 (N = 393 241).Difference in CRC incidence by age.The overall age-adjusted CRC incidence rate decreased by 0.92% (95% CI, -1.14 to -0.70) between 1975 and 2010. There has been a steady decline in the incidence of CRC in patients age 50 years or older, but the opposite trend has been observed for young adults. For patients 20 to 34 years, the incidence rates of localized, regional, and distant colon and rectal cancers have increased. An increasing incidence rate was also observed for patients with rectal cancer aged 35 to 49 years. Based on current trends, in 2030, the incidence rates for colon and rectal cancers will increase by 90.0% and 124.2%, respectively, for patients 20 to 34 years and by 27.7% and 46.0%, respectively, for patients 35 to 49 years.There has been a significant increase in the incidence of CRC diagnosed in young adults, with a decline in older patients. Further studies are needed to determine the cause for these trends and identify potential preventive and early detection strategies.
Impact of Hyperglycemia on the Renin Angiotensin System in Early Human Type 1 Diabetes Mellitus
Authors: JUDITH A. MILLER
Journal: Journal of the American Society of Nephrology (1999)

Abstract. It has been demonstrated previously that moderate hyperglycemia without glucosuria can increase plasma renin activity and mean arterial pressure in young healthy males with early uncomplicated type 1 diabetes mellitus. This study was conducted to extend these observations by testing the hypothesis that mild to moderate hyperglycemia can affect renal function by increasing renin angiotensin system (RAS) activity in diabetic humans. The study included 10 men and women with early, uncomplicated type 1 diabetes (duration &lt;5 yr), all ingesting a controlled sodium and protein diet. They were studied on four separate occasions, during a subdepressor dose of the angiotensin II (AngII) receptor blocker losartan, and during graded AngII infusion, 1.5 and 2.5 ng/kg per min, while euglycemic (blood glucose 4 to 6 mmol/L) and again while hyperglycemic without glucosuria (blood glucose 9 to 11 mmol/L), according to a randomized crossover design. Outcome measures included mean arterial pressure (MAP), GFR, effective renal plasma flow (ERPF), renal vascular resistance (RVR), filtration fraction (FF), and urine sodium excretion (UNaV) at baseline and in response to the above maneuvers. During hyperglycemic conditions, MAP was significantly higher compared with euglycemia, as were RVR and FF. After the administration of losartan, a significant renal and peripheral depressor effect was noted, with decreases in MAP, RVR, and FF, whereas during euglycemia the responses to losartan were minimal. AngII infusion resulted in elevations in MAP, RVR, and FF and a decline in UNaV during both glycemic phases, but the responses during hyperglycemia, most significantly at the 1.5 ng/kg per min infusion rate, were blunted. These data support the hypothesis that hyperglycemia affects renal function by activating the RAS. The mechanism remains obscure, but these contrasting responses may provide a link between the observations that maintenance of euglycemia and blockade of the RAS prevent or delay diabetic kidney disease, and furthermore, may clarify the mechanism whereby high glucose promotes renal disease progression in diabetes.
Hypoglycemia in Type 1 Diabetic Pregnancy
Authors: Simon Heller, Peter Damm, Henriette Mersebach, Trine Vang Skjøth, Risto Kaaja, Moshe Hod, Santiago Durán-García, David McCance, Elisabeth R. Mathiesen
Journal: Diabetes Care (2009)

OBJECTIVE A recent randomized trial compared prandial insulin aspart (IAsp) with human insulin in type 1 diabetic pregnancy. The aim of this exploratory analysis was to investigate the incidence of severe hypoglycemia during pregnancy and compare women enrolled preconception with women enrolled during early pregnancy. RESEARCH DESIGN AND METHODS IAsp administered immediately before each meal was compared with human insulin administered 30 min before each meal in 99 subjects (44 to IAsp and 55 to human insulin) randomly assigned preconception and in 223 subjects (113 for IAsp and 110 for human insulin) randomly assigned in early pregnancy (&amp;lt;10 weeks). NPH insulin was the basal insulin. Severe hypoglycemia (requiring third-party assistance) was recorded prospectively preconception (where possible), during pregnancy, and postpartum. Relative risk (RR) of severe hypoglycemia was evaluated with a gamma frailty model. RESULTS Of the patients, 23% experienced severe hypoglycemia during pregnancy with the peak incidence in early pregnancy. In the first half of pregnancy, the RR of severe hypoglycemia in women randomly assigned in early pregnancy/preconception was 1.70 (95% CI 0.91–3.18, P = 0.097); the RR in the second half of pregnancy was 1.35 (0.38–4.77, P = 0.640). In women randomly assigned preconception, severe hypoglycemia rates occurring before and during the first and second halves of pregnancy and postpartum for IAsp versus human insulin were 0.9 versus 2.4, 0.9 versus 2.4, 0.3 versus 1.2, and 0.2 versus 2.2 episodes per patient per year, respectively (NS). CONCLUSIONS These data suggest that initiation of insulin analog treatment preconception rather than during early pregnancy may result in a lower risk of severe hypoglycemia in women with type 1 diabetes.
Bronchogenic carcinoma between never-smoker and smoker patients: What are the difference?
Authors: Rihab Bay, Soumaya Ben Saad, Hafaoua Daghfous, Hala Cherif, Fatma Tritar
Journal: European Respiratory Journal (2014)

Introduction: Fifteen per cent of bronchogenic carcinoma (BC) occurs in never-smoker which is a defined as a subject who smoked less than 100 cigarettes in his/her lifetime.  Aims: Identify risk factor and overview clinical, therapeutic and prognostic features of BC in never-smoker patients.  Methods: 164 patients were treated for BC between 2006 and 2013: 29 non-smokers (G1) and 135 smokers (G2). The 2 groups (G1 and G2) were compared (age, past history, investigations, interventions, TNM stage and long term survival).  Results: Mean age was 48 years in G1 and 62 years in G2 (p  Conclusion: Because of less comorbidities, better PS and better chemosensitivity.BC in never-smokers have better prognosis than BC in smoker patients.
Serum neopterin concentrations in chronic liver disease.
Authors: A Wilmer, B Nolchen, H Tilg, M Herold, C Pechlaner, G Judmaier, O Dietze, W Vogel
Journal: Gut (1995)

Neopterin is produced by macrophages after stimulation with interferon gamma or lipopolysaccharide. Its production is increased in many infectious, autoimmune, and malignant diseases. The aim of this study was to examine whether, on the basis of neopterin as a marker, liver diseases could be classified according to aetiology and stage of disease. A cohort of 264 patients with chronic liver diseases (viral, metabolic, autoimmune, toxic) and 150 normal controls were studied; 136 of the patients had cirrhosis. Increased serum neopterin concentrations were found in 41% of all patients (controls 6.0 (2.2) nmol/l), with patients in the cirrhotic stage of disease showing higher neopterin values (mean (SD) 15.7 (23.6) nmol/ml) than those in the non-cirrhotic stage (9.9 (5.5)). There were no statistically significant differences in the serum neopterin concentrations that could be considered characteristic for different stages of disease classified according to the Child criteria. Such differences in concentrations of neopterin that were found in patients with liver diseases grouped according to underlying causes were only marginal. Serum neopterin concentrations were found to be significantly lower than in any other disease group only in patients with Wilson's disease. The results suggest that activated macrophages participate in the development of chronic liver disease. Measurement of serum neopterin does not offer a reliable method for differentiating between various aetiologies of chronic liver diseases and does not help to predict severity of cirrhosis.
HÄUFIGKEIT UNO KORRELATIVE BEZIEHUNG VON DIAGNOSTISCHEN KRITERIEN BEI DER TIERSCHUPPENALLERGIE
Authors: G. SCHULTZE‐WERNINCHAUS, E. GONSIOR, C. THIEL, R. KROIDL, J. MEIER‐SYDOW
Journal: Allergy (1976)

355 out-patients with signs of bronchial asthma were studied with special reference to animal dander sensitization. Case histories allowed the clinical diagnosis of an allergy to animal dander in 75 patients (21.1%). Skin testing is a useful means, as large reactions appear in most cases of animal dander allergy (60.7% are greater than or equal to + + + -reactions). Skin reactions, however, often are "false positive" or "false negative". Therefore, bronchial provocation tests are necessary if the case history is doubtful and/or the skin reaction is less than a + + + -reaction. There is a positive correlation between skin reaction and bronchial provocation test. No negative inhalation tests were seen when the skin reaction was greater than + + +. However, a positive inhalation test can be correlated with a negative or weakly positive skin test. The probability of common structural properties of different mammalian dander allergens is discussed. Avoidance of exposure to the animal is recommended as the therapy of choice.
TOLERANCE AND IMMUNITY TO MATERNALLY DERIVED INCOMPATIBLE IgG2a-GLOBULIN IN MICE
Authors: Noel L. Warner, Leonore A. Herzenberg
Journal: The Journal of Experimental Medicine (1970)

Progeny mice were confronted with maternal gamma-globulin of a different allotype by either back-cross mating, intercross mating, or by foster nursing. In all cases, many mice subsequently produced alloantibodies directed against the incompatible maternal type of IgG(2a)-globulin. In one series of experiments, immunologic tolerance to the maternally derived gamma-globulin was demonstrated to exist in the period before formation of spontaneous antibody. The state of tolerance was then lost, unless maintenance injections of foreign gamma-globulin were given. These studies demonstrate in a natural situation that maternally derived foreign proteins can first induce a state of immunological tolerance which is followed, after disappearance of the antigen, by a state of immunity. As such, this parallels the experimental induction of tolerance to foreign proteins by neonatal injections.
Hypoxic-Ischemic Encephalopathy
Authors: Martha Douglas-Escobar, Michael D. Weiss
Journal: JAMA Pediatrics (2015)

Hypoxic-ischemic encephalopathy (HIE) occurs in 1 to 8 per 1000 live births in developed countries. Historically, the clinician has had little to offer neonates with HIE other than systemic supportive care. Recently, the neuroprotective therapy of hypothermia has emerged as the standard of care, and other complementary therapies are rapidly transitioning from the basic science to clinical care.To examine the pathophysiology of HIE and the state of the art for the clinical care of neonates with HIE.We performed a literature review using the PubMed database. Results focused on reviews and articles published from January 1, 2004, through December 31, 2014. Articles published earlier than 2004 were included when appropriate for historical perspective. Our review emphasized evidence-based management practices for the clinician.A total of 102 articles for critical review were selected based on their relevance to the incidence of HIE, pathophysiology, neuroimaging, placental pathology, biomarkers, current systemic supportive care, hypothermia, and emerging therapies for HIE and were reviewed by both of us. Seventy-five publications were selected for inclusion in this article based on their relevance to these topics. The publications highlight the emergence of serum-based biomarkers, placental pathology, and magnetic resonance imaging as useful tools to predict long-term outcomes. Hypothermia and systemic supportive care form the cornerstone of therapy for HIE.The pathophysiology of HIE is now better understood, and treatment with hypothermia has become the foundation of therapy. Several neuroprotective agents offer promise when combined with hypothermia and are entering clinical trials.
Principles of study design in environmental epidemiology.
Authors: H Morgenstern, D Thomas
Journal: Environmental Health Perspectives (1993)

This paper discusses the principles of study design and related methodologic issues in environmental epidemiology. Emphasis is given to studies aimed at evaluating causal hypotheses regarding exposures to suspected health hazards. Following background sections on the quantitative objectives and methods of population-based research, we present the major types of observational designs used in environmental epidemiology: first, the three basic designs involving the individual as the unit of analysis (i.e., cohort, cross-sectional, and case-control studies) and a brief discussion of genetic studies for assessing gene-environment interactions; second, various ecologic designs involving the group or region as the unit of analysis. Ecologic designs are given special emphasis in this paper because of our lack of resources or inability to accurately measure environmental exposures in large numbers of individuals. The paper concludes with a section highlighting current design issues in environmental epidemiology and several recommendations for future work.