tbuckley/cabot-search huggingface dataset:
Thyrotropin receptor-associated diseases: from adenomata to Graves disease
Authors: T. F. Davies
Journal: Journal of Clinical Investigation (2005)

The thyroid-stimulating hormone receptor (TSHR) is a G protein-linked, 7-transmembrane domain (7-TMD) receptor that undergoes complex posttranslational processing unique to this glycoprotein receptor family. Due to its complex structure, TSHR appears to have unstable molecular integrity and a propensity toward over- or underactivity on the basis of point genetic mutations or antibody-induced structural changes. Hence, both germline and somatic mutations, commonly located in the transmembrane regions, may induce constitutive activation of the receptor, resulting in congenital hyperthyroidism or the development of actively secreting thyroid nodules. Similarly, mutations leading to structural alterations may induce constitutive inactivation and congenital hypothyroidism. The TSHR is also a primary antigen in autoimmune thyroid disease, and some TSHR antibodies may activate the receptor, while others inhibit its activation or have no influence on signal transduction at all, depending on how they influence the integrity of the structure. Clinical assays for such antibodies have improved significantly and are a useful addition to the investigative armamentarium. Furthermore, the relative instability of the receptor can result in shedding of the TSHR ectodomain, providing a source of antigen and activating the autoimmune response. However, it may also provide decoys for TSHR antibodies, thus influencing their biological action and clinical effects. This review discusses the role of the TSHR in the physiological and pathological stimulation of the thyroid.
TCR binding differs for a bacterial superantigen (SEE) and a viral superantigen (Mtv-9).
Authors: L Liao, A Marinescu, A Molano, C Ciurli, R P Sekaly, J D Fraser, A Popowicz, D N Posnett
Journal: The Journal of Experimental Medicine (1996)

Both superantigens (SAG) and many anti-TCR monoclonal antibodies (mAb) have specificity for the V beta region of the TCR encoded by TCRBV genes. For instance the bacterial SAG staphylococcal enterotoxin E (SEE), the retroviral SAG MTV-9 and the mAb OT145 each react with human T cells expressing BV6S7. This BV gene encodes two common alleles. We found that SEE and the mAb preferentially activate T cells expressing BV6S7*1 as opposed to BV6S7*2, but Mtv-9 activates T cells expressing either allele. Thus binding to the TCR differs between the two SAGs. A mutation in the TCR HVR-4 region of BV6S7*1 (G72E), where the two BV6S7 alleles differ, indicated that HVR-4 is a component of the binding site for SEE and for the mAb OT145. BV6S7*2 has a charged E72 which may result in electrostatic repulsion of SEE, as SEE contains a similarly acidic aspartic acid residue at a TCR interaction site (204D).
High alpha 1-adrenoceptor occupancy decreases relaxing potency of nifedipine by increasing myosin light chain phosphorylation.
Authors: P H Ratz
Journal: Circulation Research (1993)

It has been proposed that the decreased potency of Ca2+ channel blockers to produce relaxation in vascular tissues contracted at high alpha 1-adrenoceptor occupancy may be caused by activation of spare receptors. Results from the present study using isolated strips of rabbit renal arteries contracted with the alpha 1-adrenoceptor agonist phenylephrine (PhE) support this hypothesis and provide a cellular explanation for the phenomenon. PhE at 1 microM activated only 23% of the total alpha 1-adrenoceptor pool but produced maximum stress while increasing the extent of myosin light chain phosphorylation to 35%. Activation of additional (spare) alpha 1-adrenoceptors with 100 microM PhE produced an additional increase in the extent of myosin light chain phosphorylation, which reached 45%, but did not produce an additional increase in stress above that produced by 1 microM PhE. A complete [PhE]-response curve revealed a quasihyperbolic dependency of stress on myosin light chain phosphorylation; i.e., a roughly linear relation existed at [PhE] values below that producing maximum stress, and at higher concentrations, phosphorylation was further increased but stress was not. Interestingly, the Ca2+ channel blocker nifedipine (0.1 microM) reduced the increases in myosin light chain phosphorylation produced by both 1 and 100 microM PhE by the same amount, approximately 12%. Nifedipine also reduced the increases in [Ca2+]i produced by 1 and 100 microM PhE by the same amount. However, nifedipine reduced the level of stress produced by 100 microM PhE by only 17%, whereas the level of stress produced by 1 microM PhE was reduced by 63%.(ABSTRACT TRUNCATED AT 250 WORDS)
Diseases of the Retina
Authors: D J D'Amico
Journal: New England Journal of Medicine (1994)

The retina, the transparent neural tissue lining the interior of the eye, is the initial receptor for visual stimuli. Exciting progress has been made in many areas of retinal investigation, from genetic breakthroughs in retinoblastoma and retinitis pigmentosa to sophistication in the medical and surgical therapy of retinal diseases. This article reviews recent clinical developments in diabetic retinopathy, retinal detachment, retinal manifestations of the acquired immunodeficiency syndrome (AIDS), and age-related macular degeneration.Classically, the retina is separated into 10 layers on light microscopy (Figure 1)1. The photoreceptors, consisting of rod and cone cells, are located near the outer surface . . .
John Beasley William Arthur Llewellyn Bowen Stefan Janikiewicz Robert John Rhys Lewis James Gareth Longhurst Asif Omar Qureshi Joseph Cecil Turton Roberts Jonathan Harold Rosenberg Robert Henry Stewart Thompson Charles Henry Townsend Wade Margaret Jean Wharton Desmond Gilbert Cromie Whyte
Authors: I F Brockington, D. Bowen, S Janikiewicz, J. Jenkins, K. Raza, J. Rowe, J. Laszlo, D. W Roberts, S. Thomas, A. Cohen, P. Williams, J R Lisle, P T W Cohen, P. Mcwilliam, R. Forster, D A J Keegan
Journal: BMJ (1998)

Former consultant community physician west Midlands (q UCH 1951; FFCM), died suddenly on
Early Identification of Resistance to First-Line Single-Agent Methotrexate in Patients With Persistent Trophoblastic Disease
Authors: Nienke E. van Trommel, Leon F. Massuger, Charles P. Schijf, Marianne J. ten Kate-Booij, Fred C. Sweep, Chris M. Thomas
Journal: Journal of Clinical Oncology (2005)

Purpose A generally accepted definition for resistance to first-line single-agent chemotherapy for persistent trophoblastic disease (PTD) is lacking. In the present study, a normogram for serum human chorionic gonadotropin (hCG) from patients with normalization of serum hCG after first-line single-agent chemotherapy for PTD was constructed to identify patients resistant to this chemotherapy. Patients and Methods Between 1987 and 2004, data from 2,132 patients were registered at the Dutch Central Registry for Hydatidiform Moles. A normal serum hCG regression corridor was constructed for 79 patients with low-risk PTD who were cured by single-agent methotrexate (MTX) chemotherapy (control group). Another group of 29 patients with low-risk PTD needed additional alternative therapies (dactinomycin and multiagent chemotherapy) for failure of serum hCG to normalize with single-agent chemotherapy (study group). Results Serum hCG measurement preceding the fourth and sixth single-agent chemotherapy course proved to have excellent diagnostic accuracy for identifying resistance to single-agent chemotherapy, with an area under the curve (AUC) for receiver operating characteristic curve analysis of 0.949 and 0.975, respectively. At 97.5% specificity, serum hCG measurements after 7 weeks showed 50% sensitivity. Conclusion In the largest study to date, we describe the regression of serum hCG levels in patients with low-risk PTD successfully treated with MTX. At high specificity, hCG levels in the first few courses of MTX can identify half the number of patients who are extremely likely to need alternative chemotherapy to cure their disease and for whom further treatment with single-agent chemotherapy will be ineffective.
Muscle wasting and changes in muscle protein metabolism in chronic obstructive pulmonary disease
Authors: R.T. Jagoe, M.P.K.J. Engelen
Journal: European Respiratory Journal (2003)

Loss of skeletal muscle mass is now recognised as an important feature of chronic obstructive pulmonary disease (COPD) which contributes to symptoms and influences prognosis. The changes in skeletal muscle remain poorly understood, largely because only a few studies have been performed to define the adaptations in whole body and muscle protein metabolism in COPD. The first sections of this review summarise background information about skeletal muscle wasting in COPD, and focuses on the studies concerned with amino acid profiles and protein synthesis and degradation rates. To aid interpretation some discussion of the techniques commonly used is included. A variety of different catabolic factors may determine whether chronic obstructive pulmonary disease patients become cachectic. The precise role for each one of these factors as well as the intracellular pathways activated in muscle as a result of chronic obstructive pulmonary disease are unknown and remain to be defined. Details of the actions of a range of different catabolic factors and potential mechanisms will be discussed.
The Evolution of <i>Drosophila melanogaster</i> as a Model for Alcohol Research
Authors: Anita V. Devineni, Ulrike Heberlein
Journal: Annual Review of Neuroscience (2013)

Animal models have been widely used to gain insight into the mechanisms underlying the acute and long-term effects of alcohol exposure. The fruit fly Drosophila melanogaster encounters ethanol in its natural habitat and possesses many adaptations that allow it to survive and thrive in ethanol-rich environments. Several assays to study ethanol-related behaviors in flies, ranging from acute intoxication to self-administration and reward, have been developed in the past 20 years. These assays have provided the basis for studying the physiological and behavioral effects of ethanol and for identifying genes mediating these effects. In this review we describe the ecological relationship between flies and ethanol, the effects of ethanol on fly development and behavior, the use of flies as a model for alcohol addiction, and the interaction between ethanol and social behavior. We discuss these advances in the context of their utility to help decipher the mechanisms underlying the diverse effects of ethanol, including those that mediate ethanol dependence and addiction in humans.
Fundamental Relations Between Short-term RR Interval and Arterial Pressure Oscillations in Humans
Authors: J. Andrew Taylor, Dwain L. Eckberg
Journal: Circulation (1996)

Background One of the principal explanations for respiratory sinus arrhythmia is that it reflects arterial baroreflex buffering of respiration-induced arterial pressure fluctuations. If this explanation is correct, then elimination of RR interval fluctuations should increase respiratory arterial pressure fluctuations. Methods and Results We measured RR interval and arterial pressure fluctuations during normal sinus rhythm and fixed-rate atrial pacing at 17.2±1.8 (SEM) beats per minute greater than the sinus rate in 16 healthy men and 4 healthy women, 20 to 34 years of age. Measurements were made during controlled-frequency breathing (15 breaths per minute or 0.25 Hz) with subjects in the supine and 40° head-up tilt positions. We characterized RR interval and arterial pressure variabilities in low-frequency (0.05 to 0.15 Hz) and respiratory-frequency (0.20 to 0.30 Hz) ranges with fast Fourier transform power spectra and used cross-spectral analysis to determine the phase relation between the two signals. As expected, cardiac pacing eliminated beat-to-beat RR interval variability. Against expectations, however, cardiac pacing in the supine position significantly reduced arterial pressure oscillations in the respiratory frequency (systolic, 6.8±1.8 to 2.9±0.6 mm Hg 2 /Hz, P =.017). In contrast, cardiac pacing in the 40° tilt position increased arterial pressure variability (systolic, 8.0±1.8 to 10.8±2.6, P =.027). Cross-spectral analysis showed that 40° tilt shifted the phase relation between systolic pressure and RR interval at the respiratory frequency from positive to negative (9±7° versus −17±11°, P =.04); that is, in the supine position, RR interval changes appeared to lead arterial pressure changes, and in the upright position, RR interval changes appeared to follow arterial pressure changes. Conclusions These results demonstrate that respiratory sinus arrhythmia can actually contribute to respiratory arterial pressure fluctuations. Therefore, respiratory sinus arrhythmia does not represent simple baroreflex buffering of arterial pressure.
Epigenetic silencing contributes to frequent loss of the fragile histidine triad tumour suppressor in basal cell carcinomas
Authors: M. Goldberg, C. Rummelt, A. Laerm, P. Helmbold, L.M. Holbach, W.G. Ballhausen
Journal: British Journal of Dermatology (2006)

Background Extensive exposure to ultraviolet radiation is associated with genetic alterations in basal cell carcinomas (BCCs), which represent some 75% of skin cancers. Objectives As recent data suggested the fragile histidine triad (FHIT) gene product to participate in DNA damage responses we wished to address whether functional deletion of this tumour suppressor participates in the development of BCC. Our study focused on epigenetic inactivation of the FHIT gene. Methods Paraffin-embedded specimens from 17 patients with BCC were available for methylation-specific polymerase chain reaction (MSP), combined bisulphite-dependent restriction analysis (COBRA) of the FHIT gene and immunohistochemistry of its product. Results We report for the first time that 100% of BCCs are negative for FHIT by immunostaining. Aberrant methylation of the FHIT promoter occurred in a significant portion of BCCs. MSP detected hypermethylation of the FHIT/FRA3B locus in nine of nine (100%) periocular BCCs and in six of eight (75%) BCCs from other body regions. COBRA yielded similar results, confirming that some 88% of the 17 BCCs analysed harbour epigenetic silencing of the FHIT gene. Loss of FHIT protein was demonstrated immunohistochemically, confirming that promoter hypermethylation correlated with loss of gene expression. Conclusions We have identified epigenetic silencing of the FHIT tumour suppressor gene as a frequent inactivation mechanism which is likely to contribute to functional deficiencies in DNA damage response of BCCs.
Determinants of Modality Selection among Incident US Dialysis Patients
Authors: Austin G. Stack
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Few studies have comprehensively addressed the association of social factors and elements of pre–end-stage renal disease (ESRD) care with the selection of dialysis modality. This study examines the relative contribution of demographic, medical, social, pre-ESRD, and geographic factors to modality assignment among new ESRD patients. Data were collected from the Dialysis Mortality and Morbidity Wave 2 Study, a national random sample of 4025 patients in 1996 and 1997. In multivariate analyses, the selection of peritoneal dialysis (PD) over hemodialysis (HD) was significantly associated with younger age, white race, fewer comorbid conditions, and lower serum albumin. Greater use of PD was seen in patients who were employed, married, and living with someone before the start of ESRD and in those who were more autonomous and more accomplished educationally. Patients referred earlier to a nephrologist (&gt;4 mo versus ≤4 mo) and seen more frequently by a nephrologist (≥2 visits versus &lt;2 visits) in the pre-ESRD period had greater PD use. Of the factors listed, 25% of the variability (R 2 ) in PD use was explained by demographic (4.1%), comorbid (1.2%), social/pre-ESRD (14.5%), and geographic (5.2%) factors. This study identifies several clinical, social, and pre-ESRD factors with the selection of PD, and it underscores the importance of patient education, autonomy, and a strong social support system in improving rates of PD use in the United States. As pre-ESRD patient care is an important contributor to PD use in the United States, greater efforts should be expended in improving its delivery earlier in the pre-ESRD period.
Acquired C3 deficiency in patients with alcoholic cirrhosis predisposes to infection and increased mortality.
Authors: C Homann, K Varming, K Hogasen, T E Mollnes, N Graudal, A C Thomsen, P Garred
Journal: Gut (1997)

BACKGROUND: Acquired deficiencies of certain complement proteins and impaired opsonisation activity have been implicated in the pathogenesis of the increased susceptibility to infections of patients with alcoholic cirrhosis. METHODS: Serum concentrations of C3 and C4, plasma concentrations of C3bc, C9, and the terminal C5b-9 complement complex (TCC), and haemolytic complement activity (classic and alternative pathway) of serum, and serum opsonic activity were determined in 46 patients with compensated alcoholic cirrhosis, 31 who were decompensated, and in 15 healthy subjects. After 19 months (median) the investigated variables were analysed for their use in prognosis of recurrent infections and survival. RESULTS: C3 and C4 concentrations and the haemolytic complement activity of the alternative pathway were decreased in decompensated cirrhotic patients compared with controls (p &lt; 0.01). Univariate analysis (log rank test) showed that low concentrations (&lt; or = lower quartile) of C3 (p &lt; 0.001) and C3bc (p &lt; 0.05), haemolytic complement activity of the alternative pathway (p &lt; 0.01) and classic pathway (p &lt; 0.05), and decompensated cirrhosis (p &lt; 0.001) were associated with an increased risk of infection and increased mortality. Multivariate (Cox) analysis showed that low C3 concentrations and decompensation of cirrhosis were significant predictors of infections and mortality (p &lt; 0.02). CONCLUSIONS: Low serum C3 concentrations and decreased haemolytic complement function predisposes to infection and increased mortality in patients with alcoholic cirrhosis.
James Tulloch Brown
Authors: D. L. H. J. Graham
Journal: BMJ (2015)

James Tulloch Brown was born in Hamilton, Lanarkshire, and educated at Hamilton Academy before studying medicine He did house jobs at Glasgow’s Victoria Infirmary before joining the Royal Army Medical Corps in 1939. His initial posting to France ended with the Dunkirk evacuation, and in 1940 he was attached to the 21st mobile casualty clearing station. This unit supported the 7th Armoured Division (the Desert Rats) in its north African campaign through Egypt, Sicily, and the Italian landings. By 1944 he was graded as surgeon and attached to the 5th Orthopaedic Centre, involved in treating the …
457 THE QUALITY OF LIVER SPECIMEN USING TWO DIFFERENT LARGE NEEDLE BIOPSY DEVICES: A PROSPECTIVE RANDOMIZED-CONTROLLED STUDY
Authors: M. Garcovich, L. Riccardi, F.M. Vecchio, V. Arena, I. Pennacchia, F. Pizzolante, A. Grieco, A. Gasbarrini, G.L. Rapaccini, M. Pompili
Journal: Journal of Hepatology (2013)
Prevalence of Intimate Partner Abuse in Women Treated at Community Hospital Emergency Departments
Authors: Stephen R. Dearwater
Journal: JAMA (1998)

Context.-The majority of prior studies examining intimate partner abuse in the emergency department (ED) setting have been conducted in large, urban tertiary care settings and may not reflect the experiences of women seen at community hospital EDs, which treat the majority of ED patients in the United States.Objective.-Todetermine the prevalence of intimate partner abuse among female patients presenting for treatment in community hospital EDs and describe their characteristics.Design.-An anonymous survey conducted from 1995 through 1997 inquiring about physical, sexual, and emotional abuse.Setting.-Eleven community EDs in Pennsylvania and California.Participants.-Allwomen aged 18 years or older who came to the ED during selected shifts.Main Outcome Measures.-Reportedacute trauma from abuse, past-year physical or sexual abuse, and lifetime physical or emotional abuse.Results.-Surveys were completed by 3455 (74%) of 4641 women seen.The prevalence of reported abuse by an intimate partner was 2.2% (95% confidence interval [CI], 1.7%-2.7%)for acute trauma from abuse, 14.4% (95% CI, 13.2%-15.6%)for past-year physical or sexual abuse, and 36.9%(95% CI, 35.3%-38.6%)for lifetime emotional or physical abuse.California had significantly higher reported rates of past-year physical or sexual abuse (17% vs 12%, PϽ.001) and lifetime abuse (44% vs 31%, PϽ.001) than Pennsylvania.Logistic regression modeling identified 4 risk factors for reported physical, sexual, or acute trauma from abuse within the past year: age, 18 to 39 years (odds ratio [OR], 2.2; 95% CI, 1.7-3.0);monthly income less than $1000 (OR, 1.7; 95% CI, 1.3-2.1);children younger than 18 years living in the home (OR, 2.0; 95% CI, 1.5-2.6);and ending a relationship within the past year (OR, 7.0; 95% CI, 5.5-8.9).Conclusion.-If the prevalence of abuse in community hospitals throughout the United States is similar to the range of prevalence estimates found in this study, then heightened awareness of intimate partner abuse is warranted for patients presenting to the ED.
Osteoblast-Derived Factors Induce an Expression Signature that Identifies Prostate Cancer Metastasis and Hormonal Progression
Authors: Gang Wang, Simon Haile, Barbara Comuzzi, Amy H. Tien, Jun Wang, Theresa M.K. Yong, Anca E. Jelescu-Bodos, Natalie Blaszczyk, Robert L. Vessella, Bassam A. Masri, Marianne D. Sadar
Journal: Cancer Research (2009)

Identification of gene expression signatures associated with metastases provides a tool to discern mechanisms and potential therapeutic targets and may lead toward a molecular classification system in pathology. Prostate cancer (CaP) frequently metastasizes to the bone to form osteoblastic lesions. Correlative clinical data and in vitro evidence have led to the hypothesis that osteoblast-derived factors promote hormonal progression of CaP cells. Here, the gene expression signature of CaP exposed to osteoblast-derived factors was identified. This signature included known androgen-regulated genes, oncogenes, tumor suppressors, and genes whose products are involved in apoptosis and cell cycle. A comparative functional genomic approach involved the application of this responsive gene expression signature to clinical samples of human CaP, melanomas, and oral cancers. Cluster analysis revealed that this gene expression signature had specificity for CaP and could resolve clinical specimens according to stage (benign, localized, and metastatic) and androgen sensitivity with an accuracy of 100% and 80%, respectively. Together, these results suggest that factors derived from osteoblasts induce a more advanced phenotype of CaP and promotes hormonal progression.
Autophagy induced by valproic acid is associated with oxidative stress in glioma cell lines
Authors: J. Fu, C.-J. Shao, F.-R. Chen, H.-K. Ng, Z.-P. Chen
Journal: Neuro-Oncology (2009)

Autophagy represents an alternative tumor-suppressing mechanism that overcomes the dramatic resistance of malignant gliomas to radiotherapy and proapoptotic-related chemotherapy. This study reports that valproic acid (VPA), a widely used anti-epilepsy drug, induces autophagy in glioma cells. Autophagy, crucial for VPA-induced cell death, is independent of apoptosis, even though apoptotic machinery is proficient. Oxidative stress induced by VPA occurs upstream of autophagy. Oxidative stress also activates the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway, whereas blocking this pathway inhibits autophagy and induces apoptosis. VPA-induced autophagy cannot be alleviated by inositol, suggesting a mechanism different from that for lithium. Moreover, VPA potentiates autophagic cell death, but not apoptosis, when combined with other autophagy inducers such as rapamycin, Ly294002, and temozolomide in glioma cells both in vitro and in vivo, which may warrant further investigation toward possible clinical application in patients with malignant gliomas.