High prevalence of bronchiectasis is linked to HTLV-1-associated inflammatory disease.

BACKGROUND: Human T-lymphotropic virus type 1 (HTLV-1), a retrovirus, is the causative agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukaemia/lymphoma (ATLL). The reported association with pulmonary disease such as bronchiectasis is less certain. METHODS: A retrospective case review of a HTLV-1 seropositive cohort attending a national referral centre. The cohort was categorised into HTLV-1 symptomatic patients (SPs) (ATLL, HAM/TSP, Strongyloidiasis and HTLV associated inflammatory disease (HAID)) and HTLV-1 asymptomatic carriers (ACs). The cohort was reviewed for diagnosis of bronchiectasis. RESULT: 34/246 ACs and 30/167 SPs had been investigated for respiratory symptoms by computer tomography (CT) with productive cough +/- recurrent chest infections the predominant indications. Bronchiectasis was diagnosed in one AC (1/246) and 13 SPs (2 HAID, 1 ATLL, 10 HAM/TSP) (13/167, RR 19.2 95 % CI 2.5-14.5, p = 0.004) with high resolution CT. In the multivariate analysis ethnicity (p = 0.02) and disease state (p < 0.001) were independent predictors for bronchiectasis. The relative risk of bronchiectasis in SPs was 19.2 (95 % CI 2.5-14.5, p = 0.004) and in HAM/TSP patients compared with all other categories 8.4 (95 % CI 2.7-26.1, p = 0.0002). Subjects not of African/Afro-Caribbean ethnicity had an increased prevalence of bronchiectasis (RR 3.45 95 % 1.2-9.7, p = 0.02). CONCLUSIONS: Bronchiectasis was common in the cohort (3.4 %). Risk factors were a prior diagnosis of HAM/TSP and ethnicity but not HTLV-1 viral load, age and gender. The spectrum of HTLV-associated disease should now include bronchiectasis and HTLV serology should be considered in patients with unexplained bronchiectasis

Changing treatment patterns for coronary artery revascularization in Canada: the projected impact of drug eluting stents

BACKGROUND: To evaluate current treatment patterns for coronary artery revascularization in Canada and explore the potential impact of drug eluting stents (DES) on these treatment patterns. METHODS: Eleven cardiologists at multiple Canadian academic centers completed a questionnaire on coronary artery revascularization rates and treatment patterns. RESULTS: Participating physicians indicated slightly higher rates of PTCA, CABG, and stent implantation than reported in CCN publications. Participants estimated that 24% of all patients currently receiving bare metal stents (BMS) would receive DES in the first year following DES approval in Canada, although there was a large range of estimates around this value (5% to 65%). By the fifth year following DES approval, it was estimated that 85% of BMS patients would instead receive DES. Among diabetic patients, estimates ranged from 43% in the first year following approval to 91% in the fifth year. For all patients currently receiving CABG, mean use of DES instead was estimated at 12% in the first year to 42% at five years; rates among diabetic patients currently undergoing CABG were 17% in the first year to 49% in the fifth year. CONCLUSIONS: These results suggest a continued increase in revascularization procedures in Canada. Based on the panel's responses, it is likely that a trend away from CABG towards PTCA will continue in Canada, and will be augmented by the availability of DES as a treatment option. The availability of DES as a treatment option in Canada may change the threshold at which revascularization procedures are considered

Copy number variation in Parkinson's disease

A central theme of human genetic studies is to understand genomic variation and how this underlies the inherited basis of disease. Genomic variation can provide increased biological understanding of disease processes, which is necessary to develop future treatments. Recent technological advances have highlighted the role of copy number variants in normal and pathological phenotypic expression. These applications have been used in studies of Parkinson's disease, a common, late-onset, progressive neurodegenerative disorder. At present the main therapeutic approach is administration of symptom-alleviating drugs, which neither reverses the disease process nor halts its progression. However, the generation of in vivo model systems and development of novel disease intervention strategies for Parkinson's disease have come from research on monogenic forms of the disorder, including those caused by copy number variants. Here, we review the role of copy number variants and the mechanistic insights they have provided on the pathogenesis of Parkinson's disease

Ultrasound enhanced prehospital thrombolysis using microbubbles infusion in patients with acute ST elevation myocardial infarction: Rationale and design of the Sonolysis study

Contains fulltext : 70525.pdf (publisher's version ) (Open Access)ABSTRACT: BACKGROUND -: Experimental studies have shown that ultrasound contrast agents enhance the effectiveness of thrombolytic agents in the presence of ultrasound in vitro and in vivo. Recently, we have launched a clinical pilot study, called "Sonolysis", to study this effect in patients with ST-elevation myocardial infarction based on proximal lesions of the infarct-related artery. METHODS/DESIGN -: In our multicenter, randomized, placebo controlled clinical trial we will include patients between 18 and 80 years of age with their first ST-elevation myocardial infarction based on a proximal lesion of the infarct-related artery. After receiving a single bolus alteplase 50 mg IV (Actilyse(R) Boehringer Ingelheim GmbH), a loading dose of aspirin 500 mg, and heparin 5000 IU in the ambulance according to the prehospital thrombolysis protocol, patients, following oral informed consent, are randomized to undergo 15 minutes of pulsatile ultrasound with intravenous administration of ultrasound contrast agent or placebo without ultrasound. Afterwards coronary angiography and, if indicated, percutaneous coronary intervention will take place. A total of 60 patients will be enrolled in approximately 1 year.The primary endpoints are based on the coronary angiogram and consist of TIMI flow, corrected TIMI frame count, and myocardial blush grade. Follow-up includes 12-lead ECG, 2D-echocardiography, cardiac MRI, and enzyme markers to obtain our secondary endpoints, including the infarct size, wall motion abnormalities, and the global left ventricular function. DISCUSSION -: The Sonolysis study is the first multicenter, randomized, placebo controlled clinical trial investigating the therapeutic application of ultrasound and microbubbles in acute ST-elevation myocardial infarction patients. A positive finding may stimulate further research and technical innovations to implement the treatment in the ambulance and maybe obtain even more patency at an earlier stage. TRIAL REGISTRATION -: Trialregister NTR161

Insights into the pathogenesis of vein graft disease: lessons from intravascular ultrasound

The success of coronary artery bypass grafting (CABG) is limited by poor long-term graft patency. Saphenous vein is used in the vast majority of CABG operations, although 15% are occluded at one year with as many as 50% occluded at 10 years due to progressive graft atherosclerosis. Intravascular ultrasound (IVUS) has greatly increased our understanding of this process. IVUS studies have shown that early wall thickening and adaptive remodeling of vein grafts occurs within the first few weeks post implantation, with these changes stabilising in angiographically normal vein grafts after six months. Early changes predispose to later atherosclerosis with occlusive plaque detectable in vein grafts within the first year. Both expansive and constrictive remodelling is present in diseased vein grafts, where the latter contributes significantly to occlusive disease. These findings correlate closely with experimental and clinicopathological studies and help define the windows for prevention, intervention or plaque stabilisation strategies. IVUS is also the natural tool for evaluating the effectiveness of pharmacological and other treatments that may prevent or slow the progression of vein graft disease in clinical trials

HER2 expression in cervical cancer as a potential therapeutic target

BACKGROUND: Trastuzumab, a humanized monoclonal antibody against the HER2 receptor is currently being used in breast and other tumor types. Early studies have shown that a variable proportion of cervical carcinoma tumors overexpress the HER2 receptor as evaluated by diverse techniques and antibodies. Currently it is known that a tumor response to trastuzumab strongly correlates with the level of HER2 expression evaluated by the Hercep Test, thus, it seems desirable to evaluate the status of expression of this receptor using the FDA-approved Hercep Test and grading system to gain insight in the feasibility of using trastuzumab in cervical cancer patients. METHODS: We analyzed a series of cervical cancer cell lines, the primary tumors of 35 cases of cervical cancer patients and four recurrent cases, with the Hercep Test in order to establish whether this tumor type overexpress HER2 at level of 2+/3+ as trastuzumab is currently approved for breast cancer having such level of expression. RESULTS: The results indicate that only 1 out of 35 primary tumors cases overexpress the receptor at this level, however, two out of four recurrent tumors that tested negative at diagnosis shifted to Hercep Test 2+ and 3+ respectively. CONCLUSIONS: The low frequency of expression in primary cases suggests that trastuzumab could have a limited value for the primary management of cervical cancer patients, however, the finding of "conversion" to Hercep Test 2+ and 3+ of recurrent tumors indicates the need to further evaluate the expression of HER2 in the metastatic and recurrent cases

Overexpression of CDC25B, CDC25C and phospho-CDC25C (Ser216) in vulvar squamous cell carcinomas are associated with malignant features and aggressive cancer phenotypes

<p>Abstract</p> <p>Background</p> <p>CDC25 phosphatases are important regulators of the cell cycle. Their abnormal expression detected in a number of tumors implies that their dysregulation is involved in malignant transformation. However, the role of CDC25s in vulvar cancer is still unknown. To shed light on their roles in the pathogenesis and to clarify their prognostic values, expression of CDC25A, CDC25B and CDC25C in a large series of vulvar squamous cell carcinomas were examined.</p> <p>Methods</p> <p>Expression of CDC25A, CDC25B, CDC25C and phosphorylated (phospho)-CDC25C (Ser216) were examined in 300 vulvar carcinomas using immunohistochemistry. Western blot analysis was utilized to demonstrate CDC25s expression in vulvar cancer cell lines. Kinase and phosphatase assays were performed to exclude cross reactivity among CDC25s isoform antibodies.</p> <p>Results</p> <p>High nuclear CDC25A and CDC25B expression were observed in 51% and 16% of the vulvar carcinomas, respectively, whereas high cytoplasmic CDC25C expression was seen in 63% of the cases. In cytoplasm, nucleus and cytoplasm/nucleus high phospho-CDC25C (Ser216) expression was identified in 50%, 70% and 77% of the carcinomas, respectively. High expression of CDC25s correlated significantly with malignant features, including poor differentiation and infiltration of vessel for CDC25B, high FIGO stage, presence of lymph node metastases, large tumor diameter, poor differentiation for CDC25C and high FIGO stage, large tumor diameter, deep invasion and poor differentiation for phospho-CDC25C (Ser216). In univariate analysis, high expression of phospho-CDC25C (Ser216) was correlated with poor disease-specific survival (p = 0.04). However, such an association was annulled in multivariate analysis.</p> <p>Conclusions</p> <p>Our results suggest that CDC25C and phospho-CDC25C (Ser216) play a crucial role and CDC25B a minor role in the pathogenesis and/or progression of vulvar carcinomas. CDC25B, CDC25C and phospho-CDC25C (Ser216) were associated with malignant features and aggressive cancer phenotypes. However, the CDC25s isoforms were not independently correlated to prognosis.</p

Bivalent-Like Chromatin Markers Are Predictive for Transcription Start Site Distribution in Human

Deep sequencing of 5′ capped transcripts has revealed a variety of transcription initiation patterns, from narrow, focused promoters to wide, broad promoters. Attempts have already been made to model empirically classified patterns, but virtually no quantitative models for transcription initiation have been reported. Even though both genetic and epigenetic elements have been associated with such patterns, the organization of regulatory elements is largely unknown. Here, linear regression models were derived from a pool of regulatory elements, including genomic DNA features, nucleosome organization, and histone modifications, to predict the distribution of transcription start sites (TSS). Importantly, models including both active and repressive histone modification markers, e.g. H3K4me3 and H4K20me1, were consistently found to be much more predictive than models with only single-type histone modification markers, indicating the possibility of “bivalent-like” epigenetic control of transcription initiation. The nucleosome positions are proposed to be coded in the active component of such bivalent-like histone modification markers. Finally, we demonstrated that models trained on one cell type could successfully predict TSS distribution in other cell types, suggesting that these models may have a broader application range

Perturbation of lipids and glucose metabolism associated with previous 2,4-D exposure: a cross-sectional study of NHANES III data, 1988-1994

<p>Abstract</p> <p>Background</p> <p>Results from previous population studies showed that mortality rates from acute myocardial infarction and type-2 diabetes during the 1980s and 1990s in rural, agricultural counties of Minnesota, Montana, North and South Dakota, were higher in counties with a higher level of spring wheat farming than in counties with lower levels of this crop. Spring wheat, one of the major field crops in these four states, was treated for 85% or more of its acreage with chlorophenoxy herbicides. In the current study NHANES III data were reviewed for associations of 2,4-dichlorophenoxy acetic acid (2,4-D) exposure, one of the most frequently used chlorophenoxy herbicides, with risk factors that are linked to the pathogenesis of acute myocardial infarction and type-2 diabetes, such as dyslipidemia and impaired glucose metabolism.</p> <p>Methods</p> <p>To investigate the toxicity pattern of chlorophenoxy herbicides, effects of a previous 2,4-D exposure were assessed by comparing levels of lipids, glucose metabolism, and thyroid stimulating hormone in healthy adult NHANES III subjects with urinary 2,4-D above and below the level of detection, using linear regression analysis. The analyses were conducted for all available subjects and for two susceptible subpopulations characterized by high glycosylated hemoglobin (upper 50^thpercentile) and low thyroxine (lower 50^thpercentile).</p> <p>Results</p> <p>Presence of urinary 2,4-D was associated with a decrease of HDL levels: 8.6% in the unadjusted data (p-value = 0.006), 4.8% in the adjusted data (p-value = 0.08), and 9% in the adjusted data for the susceptible subpopulation with low thyroxine (p-value = 0.02). An effect modification of the inverse triglycerides-HDL relation was observed in association with 2,4-D. Among subjects with low HDL, urinary 2,4-D was associated with increased levels of triglycerides, insulin, C-peptide, and thyroid stimulating hormone, especially in the susceptible subpopulations. In contrast, subjects with high HDL did not experience adverse 2,4-D associated effects.</p> <p>Conclusions</p> <p>The results indicate that exposure to 2,4-D was associated with changes in biomarkers that, based on the published literature, have been linked to risk factors for acute myocardial infarction and type-2 diabetes.</p

Mutational Analysis of Photosystem I of Synechocystis sp. PCC 6803: The Role of Four Conserved Aromatic Residues in the j-helix of PsaB

Photosystem I is the light-driven plastocyanin-ferredoxin oxidoreductase in the photosynthetic electron transfer of cyanobacteria and plants. Two histidyl residues in the symmetric transmembrane helices A-j and B-j provide ligands for the P700 chlorophyll molecules of the reaction center of photosystem I. To determine the role of conserved aromatic residues adjacent to the histidyl molecule in the helix of B-j, we generated six site-directed mutants of the psaB gene in Synechocystis sp. PCC 6803. Three mutant strains with W645C, W643C/A644I and S641C/V642I substitutions could grow photoautotrophically and showed no obvious reduction in the photosystem I activity. Kinetics of P700 re-reduction by plastocyanin remained unaltered in these mutants. In contrast, the strains with H651C/L652M, F649C/G650I and F647C substitutions could not grow under photoautotrophic conditions because those mutants had low photosystem I activity, possibly due to low levels of proteins. A procedure to select spontaneous revertants from the mutants that are incapable to photoautotrophic growth resulted in three revertants that were used in this study. The molecular analysis of the spontaneous revertants suggested that an aromatic residue at F647 and a small residue at G650 may be necessary for maintaining the structural integrity of photosystem I. The (P700+ - P700) steady-state absorption difference spectrum of the revertant F647Y has a ∼5 nm narrower peak than the recovered wild-type, suggesting that additional hydroxyl group of this revertant may participate in the interaction with the special pair while the photosystem I complexes of the F649C/G650T and H651Q mutants closely resemble the wild-type spectrum. The results presented here demonstrate that the highly conserved residues W645, W643 and F649 are not critical for maintaining the integrity and in mediating electron transport from plastocyanin to photosystem I. Our data suggest that an aromatic residue is required at position of 647 for structural integrity and/or function of photosystem I