tbuckley/cabot-search huggingface dataset:
Genetic and Family and Community Environmental Effects on Drug Abuse in Adolescence: A Swedish National Twin and Sibling Study
Authors: Kenneth S. Kendler, Hermine H. Maes, Kristina Sundquist, Henrik Ohlsson, Jan Sundquist
Journal: American Journal of Psychiatry (2013)

Objective Using Swedish nationwide registry data, the authors investigated genetic and environmental risk factors in the etiology of drug abuse by twin sibling modeling. The authors followed up with epidemiological analyses to identify shared environmental influences on drug abuse. Method Drug abuse was defined using public medical, legal, or pharmacy records. Twin and sibling pairs were obtained from the national twin and genealogical registers. Information about sibling pair residence within the same household, small residential area, or municipality was obtained from Statistics Sweden. The authors predicted concordance for drug abuse by years of co-residence until the older sibling turned 21 and risk for future drug abuse in adolescents living with parental figures as a function of family-level socioeconomic status and neighborhood social deprivation. Results The best twin sibling fit model predicted substantial heritability for drug abuse in males (55%) and females (73%), with environmental factors shared by siblings operating only in males and accounting for 23% of the variance in liability. For each year of living in the same household, the probability of sibling concordance for drug abuse increased 2%−5%. When not residing in the same household, concordance was predicted from residence in the same small residential area or municipality. Risk for drug abuse was predicted both by family socioeconomic status and neighborhood social deprivation. Controlling for family socioeconomic status, each year of living in a high social deprivation neighborhood increased the risk for drug abuse by 2%. Conclusions Using objective registry data, the authors found that drug abuse is highly heritable. A substantial proportion of the shared environmental effect on drug abuse comes from community-wide rather than household-level influences. Genetic effects demonstrated in twin studies have led to molecular analyses to elucidate biological pathways. In a parallel manner, environmental effects can be followed up by epidemiological studies to clarify social mechanisms.
Airflow obstruction in bronchiectasis: correlation between computed tomography features and pulmonary function tests
Authors: H R Roberts, A U Wells, D G Milne, M B Rubens, J Kolbe, P J Cole, D M Hansell
Journal: Thorax (2000)

<h3>BACKGROUND</h3> An obstructive defect is usual in bronchiectasis, but the pathophysiological basis of airflow obstruction remains uncertain. High resolution computed tomographic (CT) scanning now allows quantitation of static morphological abnormalities, as well as dynamic changes shown on expiratory CT scans. The aim of this study was to determine which static and dynamic structural abnormalities on the CT scan are associated with airflow obstruction in bronchiectasis. <h3>METHODS</h3> The inspiratory and expiratory features on the CT scan of 100 patients with bronchiectasis undergoing concurrent lung function tests were scored semi-quantitatively by three observers. <h3>RESULTS</h3> On univariate analysis the extent and severity of bronchiectasis, the severity of bronchial wall thickening, and the extent of decreased attenuation on the expiratory CT scan correlated strongly with the severity of airflow obstruction; the closest relationship was seen between decreased forced expiratory volume in one second (FEV<sub>1</sub>) and the extent of decreased attenuation on the expiratory CT scan (<i>R</i><sub>s</sub> = –0.55, p&lt;0.00005). On multivariate analysis bronchial wall thickness and decreased attenuation were consistently the strongest independent determinants of airflow obstruction. The extent of decreased attenuation was positively associated with the severity of bronchial wall thickness, but was not independently linked to gas transfer levels. Endobronchial secretions seen on CT scanning had no functional significance; the severity of bronchial dilatation was negatively associated with airflow obstruction after adjustment for other morphological features. <h3>CONCLUSIONS</h3> These findings indicate that airflow obstruction in bronchiectasis is primarily linked to evidence of intrinsic disease of small and medium airways on CT scanning and not to bronchiectatic abnormalities in large airways, emphysema, or retained endobronchial secretions.
Prevalence and classification of rhinitis in the elderly: a nationwide survey in <scp>P</scp>ortugal
Authors: M. Morais‐Almeida, H. Pite, A. M. Pereira, A. Todo‐Bom, C. Nunes, J. Bousquet, J. Fonseca
Journal: Allergy (2013)

Abstract Background Nationwide epidemiologic data on rhinitis in the elderly do not exist. This study aimed to estimate the prevalence of rhinitis in the population aged 65 years or above in mainland P ortugal and to characterize and classify rhinitis in this age group. Methods Cross‐sectional, nationwide, population‐based survey of citizens aged 65 years or above, living in mainland P ortugal. Current rhinitis ( CR ) was defined as the presence of at least two symptoms: ‘repeated sneezing and itchy nose’, ‘blocked nose for more than one whole hour’, or ‘runny nose when not having a cold or flu’, either usually or in the last 12 months. Rhinitis severity was assessed using a visual analogue scale; rhinitis was classified according to ARIA . Results Data were obtained from 3678 responders (92.5% response rate). The prevalence of CR was 29.8% (95% confidence interval (CI): 28.4%–31.3%): 49.1% had mild intermittent, 7.0% mild persistent, 27.5% moderate‐severe intermittent, and 16.4% moderate‐severe persistent rhinitis. Only 38.6% of patients with CR had been physician diagnosed and 38.7% were under treatment for this disease in the previous year. Allergic conjunctivitis symptoms were referred by 68.6% of subjects with CR (rhinoconjunctivitis population prevalence, 20.5% (95% CI : 19.2%–21.8%)). Conclusions Rhinitis and rhinoconjunctivitis are common but underdiagnosed and undertreated diseases in the geriatric population. This was the first nationwide epidemiological survey classifying rhinitis according to ARIA guidelines in this age group. More than 40% of old‐age patients presented moderate‐severe disease.
Spontaneous Rupture of Oesophagus
Authors: J. R. Boulle
Journal: BMJ (1955)

OESOPHAGUSBR 25 include adequate treating of the accompanying empyema.In a late case, with fully established empvema.to attempt to free the oesophagus and perform suture would be un- doubted folly.In an early case, however, possibly up to 48 hours after perforation, the right attitude should be to explore and if possible suture the rent.In this third case-with a long rent-there was a late leak.By performing a gastrostomy as an oesophageal bypass, and thus restricting swallowing purely to saliva, local pleural drainage together with gastrostomy ultimately gave sound closure. Summary and ConclusionsSpontaneous perforation of the oesophagus is an acute emergency which must always be kept in mind and which may simulate many lesions.It can masquerade as coronary thrombosis, or acute abdominal catastrophes, especially perforated gastric ulcer, acute pancreatitis, and acute cholecystitis.Frequently the patient is too dis- tressed to give a rational history.As the oesophagus may perforate into the mediastinum alone, into the right or left pleural cavities, or into both, there is a diversity of signs and symptoms.Convincing chest clinical signs are often hard to elicit.Not all cases have cervical emphysema, but, if present, it is diagnostic.Chest radiographs, including, if necessary, the swallow- ing of radiopaque oil, confirm the diagnosis.Pre-operative management embodies prompt relief of any tension pneumothorax, restriction of all food by mouth, intravenous fluids, passage of a Ryle tube to the stomach, and antibiotics.Thoracotomy is then required, and wherever possible the rent should be sutured.In early cases, healing is sound and convalescence greatly shortened.A plea is made to include a chest radiograph when faced with a difficult diagnosis of the acute abdomen.
Structural Basis for the Binding of the Anticancer Compound 6-(7-Nitro-2,1,3-Benzoxadiazol-4-Ylthio)Hexanol to Human Glutathione <i>S</i>-Transferases
Authors: Luca Federici, Carlo Lo Sterzo, Silvia Pezzola, Adele Di Matteo, Flavio Scaloni, Giorgio Federici, Anna Maria Caccuri
Journal: Cancer Research (2009)

Glutathione S-transferases (GST) constitute a superfamily of enzymes with diversified functions including detoxification from xenobiotics. In many human cancers, Pi class GST (GSTP1-1) is overexpressed and contributes to multidrug resistance by conjugating chemotherapeutics. In addition, GSTP1-1 displays antiapoptotic activity by interacting with c-Jun NH(2)-terminal kinase, a key regulator of apoptosis. Therefore, GSTP1-1 is considered a promising target for pharmaceutical treatment. Recently, a potent inhibitor of GSTs, 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX), was identified and tested on several tumor cell lines demonstrating high antiproliferative activity. To establish the structural basis of NBDHEX activity, we determined the crystal structure of NBDHEX bound to either GSTP1-1 or GSTM2-2 (mu class). NBDHEX in both cases binds to the H-site but occupies different positions. Furthermore, the compound is covalently attached to the GSH sulfur in the GSTM2-2 crystal, forming a sigma-complex, although it is bound but not conjugated in the GSTP1-1 crystal. Several differences in the H-sites of the two isozymes determine the higher affinity of NBDHEX for GSTM2-2 with respect to GSTP1-1. One such difference is the presence of Ile(104) in GSTP1-1 close to the bound NBDHEX, whereas the corresponding position is occupied by an alanine in GSTM2-2. Mutation of Ile(104) into valine is a frequent GSTP1-1 polymorphism and we show here that the Ile(104)Val and Ile(104)Ala variants display a 4-fold higher affinity for the compound. Remarkably, the GSTP1-1/Ile(104)Ala structure in complex with NBDHEX shows a considerable shift of the compound inside the H-site. These data might be useful for the development of new anticancer compounds.
Adalimumab added to a treat-to-target strategy with methotrexate and intra-articular triamcinolone in early rheumatoid arthritis increased remission rates, function and quality of life. The OPERA Study: an investigator-initiated, randomised, double-blind, parallel-group, placebo-controlled trial
Authors: Kim Hørslev-Petersen, Merete Lund Hetland, Peter Junker, Jan Pødenphant, Torkell Ellingsen, Palle Ahlquist, Hanne Lindegaard, Asta Linauskas, Annette Schlemmer, Mette Yde Dam, Ib Hansen, Hans Christian Horn, Christian Gytz Ammitzbøll, Anette Jørgensen, Sophine B Krintel, Johnny Raun, Julia S Johansen, Mikkel Østergaard, Kristian Stengaard-Pedersen
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> An investigator-initiated, double-blinded, placebo-controlled, treat-to-target protocol (Clinical Trials:NCT00660647) studied whether adalimumab added to methotrexate and intra-articular triamcinolone as first-line treatment in early rheumatoid arthritis (ERA) increased the frequency of low disease activity (DAS28CRP&lt;3.2) at 12 months. <h3>Methods</h3> In 14 Danish hospital-based clinics, 180 disease-modifying anti-rheumatic drugs (DMARD)-naïve ERA patients (&lt;6 months duration) received methotrexate 7.5 mg/week (increased to 20 mg/week within 2 months) plus adalimumab 40 mg every other week (adalimumab-group, n=89) or methotrexate+placebo-adalimumab (placebo-group, n=91). At all visits, triamcinolone was injected into swollen joints (max. four joints/visit). If low disease activity was not achieved, sulfasalazine 2 g/day and hydroxychloroquine 200 mg/day were added after 3 months, and open-label biologics after 6–9 months. Efficacy was assessed primarily on the proportion of patients who reached treatment target (DAS28CRP&lt;3.2). Secondary endpoints included DAS28CRP, remission, Health Assessment Questionnaire (HAQ), EQ-5D and SF-12. Analysis was by intention-to-treat with last observation carried forward. <h3>Results</h3> Baseline characteristics were similar between groups. In the adalimumab group/placebo group the 12-month cumulative triamcinolone doses were 5.4/7.0 ml (p=0.08). Triple therapy was applied in 18/27 patients (p=0.17). At 12 months, DAS28CRP&lt;3.2 was reached in 80%/76% (p=0.65) and DAS28CRP was 2.0 (1.7–5.2) (medians (5th/95th percentile ranges)), versus 2.6 (1.7–4.7) (p=0.009). Remission rates were: DAS28CRP&lt;2.6: 74%/49%, Clinical Disease Activity Index≤2.8: 61%/41%, Simplified Disease Activity Index&lt;3.3: 57%/37%, European League Against Rheumatism/American College of Rheumatology Boolean: 48%/30% (0.0008&lt;p&lt;0.014, number-needed-to-treat: 4.0–5.4). Twelve months HAQ, SF12PCS and EQ-5D improvements were most pronounced in the adalimumab group. Treatments were well tolerated. <h3>Conclusions</h3> Adalimumab added to methotrexate and intra-articular triamcinolone as first-line treatment did not increase the proportion of patients who reached the DAS28CRP&lt;3.2 treatment target, but improved DAS28CRP, remission rates, function and quality of life in DMARD-naïve ERA.
Prenatal Screening for Neural Tube Defects
Authors: James E. Haddow
Journal: JAMA (1979)

NEURAL tube defects, including anencephaly and spina bifida, are among the commonest major congenital malformations in the United States.<sup>1</sup>A study in selected Massachusetts hospitals disclosed a combined prevalence rate of 2.24 per 1,000 births during the years 1930 to 1965.<sup>2</sup>Between 1972 and 1975, twenty-six neural tube defects were found among 18,155 consecutive deliveries at the Boston Hospital for Women (1.43 per 1,000).<sup>3</sup>The Center for Disease Control in Atlanta reported an incidence of 2.35 per 1,000 for the white population and 0.9 per 1,000 for the black population.<sup>4</sup>Among the first 6,031 pregnancies screened in Nassau County, NY, ten neural tube defects were prospectively identified. Women who have been delivered of a conceptus with one of these lesions are at approximately 2% risk of having another similarly affected offspring in each succeeding pregnancy.<sup>3</sup>In a given year, however, more than 90% of all
NMS-E973, a Novel Synthetic Inhibitor of Hsp90 with Activity against Multiple Models of Drug Resistance to Targeted Agents, Including Intracranial Metastases
Authors: Gianpaolo Fogliatto, Laura Gianellini, Maria G. Brasca, Elena Casale, Dario Ballinari, Marina Ciomei, Anna Degrassi, Anna De Ponti, Massimiliano Germani, Marco Guanci, Mauro Paolucci, Paolo Polucci, Micaela Russo, Francesco Sola, Barbara Valsasina, Carlo Visco, Fabio Zuccotto, Daniele Donati, Eduard Felder, Enrico Pesenti, Arturo Galvani, Sergio Mantegani, Antonella Isacchi
Journal: Clinical Cancer Research (2013)

Recent developments of second generation Hsp90 inhibitors suggested a potential for development of this class of molecules also in tumors that have become resistant to molecular targeted agents. Disease progression is often due to brain metastases, sometimes related to insufficient drug concentrations within the brain. Our objective was to identify and characterize a novel inhibitor of Hsp90 able to cross the blood-brain barrier (BBB).Here is described a detailed biochemical and crystallographic characterization of NMS-E973. Mechanism-based anticancer activity was described in cell models, including models of resistance to kinase inhibitors. Pharmacokinetics properties were followed in plasma, tumor, liver, and brain. In vivo activity and pharmacodynamics, as well as the pharmacokinetic/pharmacodynamic relationships, were evaluated in xenografts, including an intracranially implanted melanoma model.NMS-E973, representative of a novel isoxazole-derived class of Hsp90 inhibitors, binds Hsp90α with subnanomolar affinity and high selectivity towards kinases, as well as other ATPases. It possesses potent antiproliferative activity against tumor cell lines and a favorable pharmacokinetic profile, with selective retention in tumor tissue and ability to cross the BBB. NMS-E973 induces tumor shrinkage in different human tumor xenografts, and is highly active in models of resistance to kinase inhibitors. Moreover, consistent with its brain penetration, NMS-E973 is active also in an intracranially implanted melanoma model.Overall, the efficacy profile of NMS-E973 suggests a potential for development in different clinical settings, including tumors that have become resistant to molecular targeted agents, particularly in cases of tumors which reside beyond the BBB.
Vascular events following hospitalisation for community acquired pneumonia
Authors: Ahsan R. Akram, James D. Chalmers, Aran Singanayagam, Gillian B. Fleming, Joanne K. Taylor, Duncan Mills, Adam T. Hill
Journal: European Respiratory Journal (2011)

Objective: To determine if patients with community acquired pneumonia (CAP) are at increased risk of vascular events following discharge.

Methods: Patients enrolled in a prospective study for CAP who survived to hospital discharge were followed up at 1 year. A cohort matched to age, sex, co-morbidities and vascular risk factors were included and the incidence of vascular events and mortality were recorded.

Results: 1321 patients were included (50.3% male, median age 65 (IQR 48-77), 23.7% had a prior history cardiovascular events) with 1321 matched controls. 12.3% of CAP patients died after discharge by 1 year, with 28.9% attributed to cardiovascular events or stroke. The incidence increased with age.

156 patients required hospitalisation within 1 year for one or more vascular event; myocardial infarction (MI) n=74, cardiac failure n=61, for cardiac arrhythmia n=31 and stroke n=12. Of the 74 patients with MI, there was a significantly increased incidence when compared to the control group (fig1).

![Figure][1] 



Using multivariate logistic regression analysis, major predictors of cardiovascular deaths following CAP were age (AOR 1.04 95%CI (1.02-1.07), p<0.0001), prior history of cardiovascular events (2.70 (1.47-4.96), p=0.001), ICU admission during hospital admission (1.87 (1.04-3.38), p=0.04) and anaemia (0.98 (0.97-0.99), p=0.0007).

Conclusion: Hospitalisation for CAP is associated with an increased risk of cardiovascular events and mortality at 1 year.

 [1]: pending:yes
International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid Receptors and Their Ligands: Beyond CB<sub>1</sub>and CB<sub>2</sub>
Authors: R. G. Pertwee, A. C. Howlett, M. E. Abood, S. P. H. Alexander, V. Di Marzo, M. R. Elphick, P. J. Greasley, H. S. Hansen, G. Kunos, K. Mackie, R. Mechoulam, R. A. Ross
Journal: Pharmacological Reviews (2010)

There are at least two types of cannabinoid receptors (CB<sub>1</sub> and CB<sub>2</sub>). Ligands activating these G protein-coupled receptors (GPCRs) include the phytocannabinoid Δ<sup>9</sup>-tetrahydrocannabinol, numerous synthetic compounds, and endogenous compounds known as endocannabinoids. Cannabinoid receptor antagonists have also been developed. Some of these ligands activate or block one type of cannabinoid receptor more potently than the other type. This review summarizes current data indicating the extent to which cannabinoid receptor ligands undergo orthosteric or allosteric interactions with non-CB<sub>1</sub>, non-CB<sub>2</sub> established GPCRs, deorphanized receptors such as GPR55, ligand-gated ion channels, transient receptor potential (TRP) channels, and other ion channels or peroxisome proliferator-activated nuclear receptors. From these data, it is clear that some ligands that interact similarly with CB<sub>1</sub> and/or CB<sub>2</sub> receptors are likely to display significantly different pharmacological profiles. The review also lists some criteria that any novel “CB<sub>3</sub>” cannabinoid receptor or channel should fulfil and concludes that these criteria are not currently met by any non-CB<sub>1</sub>, non-CB<sub>2</sub> pharmacological receptor or channel. However, it does identify certain pharmacological targets that should be investigated further as potential CB<sub>3</sub> receptors or channels. These include TRP vanilloid 1, which possibly functions as an ionotropic cannabinoid receptor under physiological and/or pathological conditions, and some deorphanized GPCRs. Also discussed are 1) the ability of CB<sub>1</sub> receptors to form heteromeric complexes with certain other GPCRs, 2) phylogenetic relationships that exist between CB<sub>1</sub>/CB<sub>2</sub> receptors and other GPCRs, 3) evidence for the existence of several as-yet-uncharacterized non-CB<sub>1</sub>, non-CB<sub>2</sub> cannabinoid receptors; and 4) current cannabinoid receptor nomenclature.
Thrombosis following desmopressin for uremic bleeding
Authors: John J. Byrnes, Alberto Larcada, Joel L. Moake
Journal: American Journal of Hematology (1988)

Abstract An elderly patient with evidence of atherosclerosis and uremic bleeding diathesis developed two foci of cerebral thrombosis immediately after an infusion of desmopressin (DDAVP). Because large molecular weight multimers of von Willebrand factor (vWF) have been demonstrated to cause platelet aggregation under conditions of elevated fluid shear stress as occurs in atherosclerotic vessels, we investigated his plasma vWF at the time of the event and compared it to baseline values obtained 2 weeks later. Unusually large vWF multimers induced by the DDAVP infusion were present and likely contributed to the thrombotic process. Consequently, we believe DDAVP should be given with greater caution to patients with atherosclerosis.
Bleeding time in Uremia: A useful test to assess clinical bleeding
Authors: R. W. Steiner, Cecil Coggins, Angelina C. A. Carvalho
Journal: American Journal of Hematology (1979)

Modified Ivy bleeding time (template) and platelet aggregation to ADP, epinephrine, and collagen were studied in 26 uremic patients who had not recently ingested anti-platelet drugs. Regardless of the aggregating agent used, the abnormalities in platelet aggregation were often mild, even with advanced uremia, and frequently less severe than the effects of common anti-platelet drugs. The inhibition of collagen-induced aggregation was significantly correlated with both increased bleeding time and blood urea nitrogen. Platelet aggregation was not discriminative between clinically bleeding and non-bleeding groups of patients, but the bleeding time was helpful in this regard. In certain cases, the aggregometric patterns differed between drug-induced and uremic thrombocytopathies. Platelet aggregometry appears to be of little help clinically in assessing the severity of the uremic bleeding diathesis.
Assumptions in studies of heritability and genotype–phenotype association
Authors: Michael B. Miller, Colin G. DeYoung, Matt McGue
Journal: Behavioral and Brain Sciences (2012)

Abstract Charney's dismissal of well-established methods in behavioral genetic research is misguided. He claims that studies of heritability and genetic association depend for their validity on six assumptions, but he cites no sources to support this claim. We explain why none of the six assumptions is strictly necessary for the utility of either method of genetic analysis.