tbuckley/cabot-search huggingface dataset:
Determinants of airflow obstruction in severe alpha-1-antitrypsin deficiency
Authors: D. L DeMeo, R. A Sandhaus, A. F Barker, M. L Brantly, E. Eden, N G. McElvaney, S. Rennard, E. Burchard, J. M Stocks, J. K Stoller, C. Strange, G. M Turino, E. J Campbell, E. K Silverman
Journal: Thorax (2007)

<b>Background:</b> Severe α<sub>1</sub>-antitrypsin (AAT) deficiency is an autosomal recessive genetic condition associated with an increased but variable risk for chronic obstructive pulmonary disease (COPD). A study was undertaken to assess the impact of chronic bronchitis, pneumonia, asthma and sex on the development of COPD in individuals with severe AAT deficiency. <b>Methods:</b> The AAT Genetic Modifier Study is a multicentre family-based cohort study designed to study the genetic and epidemiological determinants of COPD in AAT deficiency. 378 individuals (age range 33–80 years), confirmed to be homozygous for the SERPINA1 Z mutation, were included in the analyses. The primary outcomes of interest were a quantitative outcome, forced expiratory volume in 1 s (FEV<sub>1</sub>) percentage predicted, and a qualitative outcome, severe airflow obstruction (FEV<sub>1</sub> &lt;50% predicted). <b>Results:</b> In multivariate analysis of the overall cohort, cigarette smoking, sex, asthma, chronic bronchitis and pneumonia were risk factors for reduced FEV<sub>1</sub> percentage predicted and severe airflow obstruction (p&lt;0.01). Index cases had lower FEV<sub>1</sub> values, higher smoking histories and more reports of adult asthma, pneumonia and asthma before age 16 than non-index cases (p&lt;0.01). Men had lower pre- and post-bronchodilator FEV<sub>1</sub> percentage predicted than women (p&lt;0.0001); the lowest FEV<sub>1</sub> values were observed in men reporting a history of childhood asthma (26.9%). This trend for more severe obstruction in men remained when index and non-index groups were examined separately, with men representing the majority of non-index individuals with airflow obstruction (71%). Chronic bronchitis (OR 3.8, CI 1.8 to 12.0) and a physician's report of asthma (OR 4.2, CI 1.4 to 13.1) were predictors of severe airflow obstruction in multivariate analysis of non-index men but not women. <b>Conclusion:</b> In individuals with severe AAT deficiency, sex, asthma, chronic bronchitis and pneumonia are risk factors for severe COPD, in addition to cigarette smoking. These results suggest that, in subjects severely deficient in AAT, men, individuals with symptoms of chronic bronchitis and/or a past diagnosis of asthma or pneumonia may benefit from closer monitoring and potentially earlier treatment.
Cyclin D3 Immunoreactivity Is an Independent Predictor of Survival in Laryngeal Squamous Cell Carcinoma
Authors: Giancarlo Pruneri, Lorenzo Pignataro, Stefano Valentini, Sonia Fabris, Patrick Maisonneuve, Nadia Carboni, Salvatore Pece, Maria Capra, Barbara Del Curto, Antonino Neri, Giuseppe Viale
Journal: Clinical Cancer Research (2005)

Abstract Purpose: To analyze the prevalence and clinical relevance of cyclin D3 abnormalities in laryngeal squamous cell carcinoma (LSCC). Experimental Design: Cyclin D3 immunoreactivity was evaluated in 223 formalin-fixed and paraffin-embedded samples of LSCC patients with a mean follow-up of 62.8 ± 43.2 months. The occurrence of cyclin D3 extra signals was analyzed by fluorescence in situ hybridization in 47 randomly selected cases collected in a tissue microarray. Cyclin D1 immunoreactivity had been previously investigated in 133 cases. Results: Cyclin D3 immunoreactivity and gene extra signals were found in 39.5% and 42.6% of the cases, respectively, and the concordance between immunohistochemical and fluorescence in situ hybridization results was 70.2% (P = 0.0085). Cyclin D3 immunoreactivity was significantly associated with a high risk of death. Multivariate analysis showed that high tumor grade, exophytic/ulcerating tumor type, low performance status, and cyclin D3 immunoreactivity were the only independent predictors of poor overall survival. In the 133 cases analyzed for both cyclin D1 and cyclin D3, patients with cyclin D1+/cyclin D3+ tumors experienced the worst prognosis, patients with cyclin D1−/cyclin D3− exhibited the most prolonged survival, and with cyclin D1−/cyclin D3+ or cyclin D1+/cyclin D3− tumors an intermediate course was associated. Conclusions: Our data suggest that cyclin D3 immunoreactivity, possibly due to the occurrence of gene extra copies, may represent an adjunct in LSCC patients' prognostication and contribute to identify D-type cyclins as potential targets of newly developed therapies.
Medium term treatment of stable stage cystic fibrosis with recombinant human DNase I.
Authors: P L Shah, S F Scott, H J Fuchs, D M Geddes, M E Hodson
Journal: Thorax (1995)

A phase II multicentre double blind placebo controlled study in 1993 showed that short term treatment (10 days) with recombinant human DNase I (rhDNase) was safe and improved pulmonary function in patients with cystic fibrosis with stable stage lung disease. A six month open label treatment study was conducted in some of the patients who participated in the short term study to assess the medium term effects of rhDNase.Patients who completed the phase II study and were stable for 14 days prior to treatment were eligible. They were treated with rhDNase 2.5 mg twice daily for six months and reviewed at regular intervals to assess safety and efficacy.Fifty nine patients (31M,28F) of age range 16-55 years were recruited. Mean baseline values for forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were 41.5% and 72.4% of predicted, respectively. The mean increase in FEV1 over the first month of treatment was 13.1% (range 12-14.1%) and then stabilised at 6.2% (4.6-7.8%) for the subsequent five months. FVC was similarly improved. Administration of rhDNase improved the severity of dyspnoea, cystic fibrosis related symptoms, and the modified Taussig/NIH score (not statistically significant). Fifty seven of the 59 patients completed the study; two died from progression of their pulmonary disease unrelated to treatment with rhDNase. The adverse events and intercurrent illnesses were no different from those expected in a cystic fibrosis population. Pharyngitis was the only possible drug related adverse event which occurred at least once in 14% of patients during the six month period.Administration of rhDNase was safe, well tolerated, and improved pulmonary function in patients with cystic fibrosis. When rhDNase was stopped at day 169 there was a deterioration in pulmonary function and dyspnoea score.
Novel Therapeutic Strategy for Atherosclerosis
Authors: Ryuichi Morishita, Shingo Yamada, Kei Yamamoto, Naruya Tomita, Iwao Kida, Ikunosuke Sakurabayashi, Akira Kikuchi, Yasufumi Kaneda, Richard Lawn, Jitsuo Higaki, Toshio Ogihara
Journal: Circulation (1998)

Background —Because mechanisms of atherosclerosis by lipoprotein(a) [Lp(a)] have been postulated in the decrease in active transforming growth factor-β conversion by decreased plasmin, selective decrease in apolipoprotein(a) [apo(a)] independent of plasminogen may have therapeutic values. Although antisense can decrease apo(a), its application may be difficult because of very high homology of apo(a) gene to plasminogen. Thus we used ribozyme strategy that actively cleaves targeted genes to selectively inhibit apo(a) expression. Methods and Results —We constructed ribozyme oligonucleotides containing phosphorothioate DNA- and RNA-targeted kringle 4 of the apo(a) gene that showed 80% homology to plasminogen. Transfection of human apo(a) gene produced Lp(a) in medium of HepG2 cells, whereas Lp(a) could not be detected in control cells. Cotransfection of ribozyme and apo(a) gene resulted in the decrease in mRNA of apo(a) but not plasminogen. Moreover, marked decrease in Lp(a) was also observed in the medium transfected with ribozyme and apo(a) gene compared with apo(a) gene alone ( P &lt;0.01), whereas there was no significant change in plasminogen level between ribozyme-transfected and control cells. Incubation of human vascular smooth muscle cells (VSMC) with conditioned medium from apo(a)–transfected HepG2 cells resulted in a significant increase in VSMC number, whereas addition of conditioned medium from cells cotransfected with ribozyme oligonucleotides and apo(a) gene resulted in no VSMC growth ( P &lt;0.01). DNA-based control oligonucleotides and mismatched ribozyme oligonucleotides did not have an inhibitory effect on Lp(a) production. Conclusions —Overall, our data revealed that transfection of ribozyme against the apo(a) gene resulted in the selective inhibition of the apo(a) but not the plasminogen gene, providing novel therapeutic strategy for treatment of high Lp(a), a risk factor for atherosclerosis.
NADH Oxidase Activation Is Involved in Arsenite-Induced Oxidative DNA Damage in Human Vascular Smooth Muscle Cells
Authors: Shugene Lynn, Jia-Ran Gurr, Hsien-Tsung Lai, Kun-Yan Jan
Journal: Circulation Research (2000)

Abstract —Arsenic is atherogenic, carcinogenic, and genotoxic. Because atherosclerotic plaque has been considered a benign smooth muscle cell tumor, we have studied the effects of arsenite on DNA integrity of human vascular smooth muscle cells. By using single-cell alkaline electrophoresis, apparent DNA strand breaks were detected in a 4-hour treatment with arsenite at a concentration above 1 μmol/L. DNA strand breaks of arsenite-treated cells were increased by Escherichia coli formamidopyrimidine–DNA glycosylase and decreased by diphenylene iodinium, superoxide dismutase, catalase, pyruvate, DMSO, or d -mannitol. Extract from arsenite-treated cells showed increased capacity for producing superoxide when NADH was included in the reaction mixture; however, addition of arsenite to extract from untreated cells did not increase superoxide production. The superoxide-producing ability of arsenite-treated cells was also suppressed by diphenylene iodinium, 4,5-dihydroxy-1,2-benzenedisulfonic acid disodium salt (Tiron), or superoxide dismutase. Superoxide production and DNA strand breaks in arsenite-treated cells were also suppressed by transfecting antisense oligonucleotides of p22phox, an essential component of NADH oxidase. Treatment with arsenite also increased the mRNA level of p22phox. These results suggest that arsenite activates NADH oxidase to produce superoxide, which then causes oxidative DNA damage. The result that arsenite at low concentrations increases oxidant levels and causes oxidative DNA damage in vascular smooth muscle cells may be important in arsenic-induced atherosclerosis.
Increased Platelet Binding to Circulating Monocytes in Acute Coronary Syndromes
Authors: Jaydeep Sarma, Caterina A. Laan, Shirjel Alam, Ashwani Jha, Keith A.A. Fox, Ian Dransfield
Journal: Circulation (2002)

Background — Present therapies for acute coronary syndromes aim toward limiting platelet–platelet adhesion and aggregation processes. However, platelet–leukocyte interactions may contribute importantly to disease progression in the arterial wall. Recent studies suggest that prevention of platelet–leukocyte binding via P-selectin glycoprotein ligand-1 (PSGL-1) may be beneficial in animal models of vascular injury. Methods and Results — P-selectin–PSGL-1 interactions were found to account for most platelet–monocyte binding observed in peripheral blood samples from healthy donors. However, a significant component of observed adhesion was calcium independent, involving neither PSGL-1 nor P-selectin. Platelet–monocyte interactions were examined in 52 patients admitted within 14 hours of symptom onset, with acute coronary syndromes defined as unstable angina (n=12) and acute myocardial infarction (n=13) or noncardiac chest pain (n=27). When compared with patients with noncardiac chest pain, significantly elevated levels of platelet–monocyte binding were found in patients with acute myocardial infarction (70.1±15.4% versus 45.4±23.3%; P &lt;0.01) and unstable angina (67.4±12.9% versus 45.4±23.3%; P &gt;0.01). Calcium-independent platelet–monocyte binding was significantly elevated in myocardial infarction patients alone (14.7±7.7% versus 6.1±5.96%; P &lt;0.001). Conclusions — There is evidence for a significant P-selectin–independent molecular component to the platelet–monocyte conjugation observed in peripheral blood. Patients with myocardial infarction and unstable angina demonstrate increased total binding of platelets to monocytes. Additionally, calcium-independent adhesion was significantly elevated in patients with evidence of myocardial infarction. These findings demonstrate that novel cation-independent adhesion mechanisms may mediate platelet–monocyte binding, representing a new therapeutic target after vascular injury associated with myocardial infarction.
Endoscopy assisted microthoracotomy: initial experience.
Authors: R J Donnelly, R D Page, M E Cowen
Journal: Thorax (1992)

BACKGROUND: Although thoracoscopy has been used for diagnostic and minor therapeutic procedures for many years, there have been few reports of its use in performing major intrathoracic procedures, which have traditionally required formal thoracotomy. METHODS: Twenty one patients (M:F 1.2:1; mean (SD) age 47.1 (18.8), range 17-75 years) underwent endoscopic intrathoracic surgery. Eight had unidentified peripheral masses on the chest radiograph, eight required lung biopsy, and five had recurrent or persisting pneumothoraces. Under general anaesthesia a laparoscope attached to a video monitor was introduced into the chest. One or two additional stab incisions were made as needed for the introduction of standard surgical or endoscopic instruments and staplers. RESULTS: There were no complications or deaths, though one patient developed a second pneumothorax seven days after endoscopic pleurectomy, necessitating open pleurodesis. All patients were discharged home from two to six days after surgery (mean (SD) 3.7 (1.2) days). CONCLUSION: Endoscopic thoracic surgery is a safe and useful technique for certain cases. It merits further investigation and assessment.
Inpatient management of patients with skin cancer in Germany: an analysis of the nationwide DRG-statistic 2005-2006
Authors: A. Stang, J. Stausberg
Journal: British Journal of Dermatology (2009)

Background In 2004, Germany introduced a nationwide DRG (Diagnosis Related Groups) based recompensation system for hospitals.The aim of this study was to provide nationwide quantitative information about the in-hospital management of skin cancer patients in Germany based on the DRG statistic of the years 2005 through 2006. Methods We analysed the DRG statistic of the years 2005 and 2006. For each hospitalisation, diagnoses and procedures codes were analysed. The unit of analysis was the hospital admission with a diagnosis of skin melanoma (MEL) or nonmelanoma skin cancer (NMSC) including 151·144 hospitalisations. Results In 60% and 28% of all MEL- and NMSC-related hospitalisations respectively, skin cancers were surgically excised. Local therapies other than surgical excision were more prevalent among hospitalisations for NMSC than for MEL (9% vs. 4%). 22% and 1% of all MEL-related and NMSC-related hospitalisations respectively included a systemic chemotherapy. Plastic surgery was more common among NMSC-related hospitalisations (56%) than among MEL-related hospitalisations (30%). Native CT or MRI scans were coded in 11% and 2% of all MEL- and NMSC-related hospitalisations respectively. Age-standardized hospitalisation rates for MEL and NMSC varied considerably across the 16 Federal States of Germany. However, these rates were neither associated with the number of dermatology hospital beds or number of registered dermatologists. Discussion We provide for the first time nationwide quantitative data on the in-hospital management of skin cancer patients. The observed differences in the management of MEL and NMSC most likely reflect differences of the biology, epidemiology and therapeutic modalities of these cancers.
Patterning the Brain of the Zebrafish Embryo
Authors: Charles B. Kimmel
Journal: Annual Review of Neuroscience (1993)

The brain's default mode network consists of discrete, bilateral and symmetrical cortical areas, in the medial and lateral parietal, medial prefrontal, and medial and lateral temporal cortices of the human, nonhuman primate, cat, and rodent brains. Its ...Read More
The Evolution of the knirps Family of Transcription Factors in Arthropods
Authors: Tal Naggan Perl, Bernhard G.M. Schmid, Jonas Schwirz, Ariel D. Chipman
Journal: Molecular Biology and Evolution (2013)

The orphan nuclear receptor gene knirps and its relatives encode a small family of highly conserved proteins. We take advantage of the conservation of the family, using the recent prevalence of genomic data, to reconstruct its evolutionary history, identifying duplication events and tracing the intron–exon structure of the genes over evolution. Many arthropod species have two or three members of this family, but the orthology between members is unclear. We have analyzed the protein coding sequences of members of this family from 15 arthropod species covering all four main arthropod classes, including a total of 28 genes. All members of the family encode a highly conserved 94 amino acid core sequence, part of which is encoded by a single invariant exon. We find that many of the automated predictions of these genes contain errors, while some copies of the gene were not uncovered by automated pipelines, requiring manual corrections and curation. We use the coding sequences to present a phylogenetic analysis of the knirps family. Our analysis indicates that there was a duplication of a single ancestral gene in the lineage leading to insects, which gave rise to two paralogs, eagle and knirps-related. Descendants of this duplication can be identified by the presence or absence of a short protein-coding motif. Independent, lineage-specific duplications occurred in the two crustaceans we sampled. Within the insects, the knirps-related gene underwent further lineage-specific duplications, giving rise to—among others—the Drosophila gap gene knirps.
Adhesion molecule expression in the synovial membrane of psoriatic arthritis
Authors: V Riccieri
Journal: Annals of the Rheumatic Diseases (2002)

Blockade of tumour necrosis factor alpha (TNFα) using infliximab, a chimeric monoclonal antibody against TNFα, is an effective treatment in rheumatoid arthritis and Crohn's disease. 1 2 Sifikakis reported success using infliximab in sight threatening Behçet's disease. 3 A preliminary study has also reported clinical improvements in the primary systemic vasculitis, Wegener's granulomatosis, with the soluble TNFα receptor etanercept. 4 The benefit of lenercept, a soluble p55 TNFα receptor fusion protein, on digital vasculitis in rheumatoid arthritis has also been reported. 5 We report the compassionate treatment of six patients with refractory vasculitis using infliximab.Diagnoses were Wegener's granulomatosis in three and microscopic polyangiitis in three.Three patients were positive for proteinase-3 antineutrophil cytoplasmic antibodies (PR3-ANCA) and one for myeloperoxidase (MPO)-ANCA.Four were female, with a mean age of 58 years (range 23-77) and mean disease duration of 3.5 years.All had had at least three clinical relapses and had received prolonged treatment with corticosteroids and at least four immunosuppressive drugs.At the time of infliximab treatment the eyes were affected in four patients and the lung in three; in addition, five had profound constitutional symptoms.The mean prednisolone dose was 17 mg.Three intravenous doses of infliximab 200 mg were given at monthly intervals for three months.One patient complained of fatigue, myalgia, and blurred vision 24 hours after the first infusion, which did not recur on rechallenge.Infliximab was otherwise well tolerated.Five patients had remission of their disease, four within two weeks of treatment.This allowed steroid withdrawal in three and reduction by more than 50% in two.Disease activity assessed by the Birmingham Vasculitis Activity Scores (BVAS) improved from a mean of 6.3 to 0.8 at three months (fig 1). 6 One patient receiving continued infliximab for six months relapsed when the treatment interval was extended to two months.Mean falls in erythrocyte sedimentation rate and C reactive protein were 17 mm/1st h and 13 mg/l, respectively.The ANCA status was unchanged.Anti-TNFα treatment heralds a new wave of specifically targeted biological interventions of potential value in the treatment of vasculitis.It offers the hope of improved therapeutic efficacy over current agents and the possibility of reducing exposure to steroids and immunosuppressive drugs.Further studies are warranted to confirm these observations and explore the role of infliximab as a component of initial protocols.. . . . . .
Left atrial myocardial function in either physiological or pathological left ventricular hypertrophy: a two-dimensional speckle strain study
Authors: A D’Andrea, G De Corato, R Scarafile, S Romano, L Reigler, C Mita, F Allocca, G Limongelli, G Gigantino, B Liccardo, S Cuomo, G Tagliamonte, P Caso, R Calbrò
Journal: British Journal of Sports Medicine (2007)

Background: Atrial function is an integral part of cardiac function that is often neglected. The presence of left ventricule hypertrophy (LVH) due to arterial hypertension may impair atrial function. However, it has also been suggested that physical training attenuates the age-associated impairment of diastolic filling. This study investigated whether mechanical dysfunction in the left atrium (LA) is present in patients with either physiological or pathological LVH, using two-dimensional strain rate imaging (2D strain echocardiography; 2DSE). Methods: Standard echocardiography, exercise stress echo and 2DSE of the left atrium were performed in 40 patients with arterial hypertension, 45 age-matched elite athletes (&gt;40 years) and 25 healthy sedentary controls. Atrial longitudinal strain was performed from the apical views for the basal segments of the LA septum, lateral wall and roof. Results: LV mass index and ejection fraction were comparable between patients with either physiological or pathological LVH. Elite athletes showed increased LV end-diastolic diameter, end-diastolic volume and stroke volume, whereas circumferential end-systolic stress was higher in patients with hypertension. LA diameter and maximum volume were increased but similar between the two groups of patients with LVH. LA active emptying volume and fraction were both higher in patients with hypertension. Conversely, peak systolic myocardial atrial strain was significantly reduced in patients with pathological LVH compared with controls and athletes for all the analysed atrial segments (p&lt;0.0001). Using multivariate analysis, LV end-diastolic volume/body surface area (BSA) (β coefficient 0.52; p&lt;0.0001) and LV mass (β = 0.48; p&lt;0.001) in athletes emerged as the only independent determinants of LA lateral wall peak systolic strain. In contrast, in patients with hypertension, an independent negative association of LA lateral wall peak systolic strain with both LV mass (β = −0.42; p&lt;0.001) and circumferential end-systolic stress (β = −0.43; p&lt;0.001) was found. In addition, in the overall population of patients with LVH, LA lateral wall systolic strain (β = 0.49; p&lt;0.0001) was a powerful independent predictor of maximum workload during exercise testing. Conclusions: 2DSE represents a promising, non-invasive, simple and reproducible technique to assess LA myocardial function in patients with either physiological or pathological LVH. LA myocardial deformation is impaired in patients with hypertension compared with age-matched sedentary controls and elite athletes, and is closely associated with functional capacity during effort.