Genetic modifiers of Duchenne muscular dystrophy and dilated cardiomyopathy

OBJECTIVE: Dilated cardiomyopathy (DCM) is a major complication and leading cause of death in Duchenne muscular dystrophy (DMD). DCM onset is variable, suggesting modifier effects of genetic or environmental factors. We aimed to determine if polymorphisms previously associated with age at loss of independent ambulation (LoA) in DMD (rs28357094 in the SPP1 promoter, rs10880 and the VTTT/IAAM haplotype in LTBP4) also modify DCM onset. METHODS: A multicentric cohort of 178 DMD patients was genotyped by TaqMan assays. We performed a time-to-event analysis of DCM onset, with age as time variable, and finding of left ventricular ejection fraction 70 mL/m2 as event (confirmed by a previous normal exam < 12 months prior); DCM-free patients were censored at the age of last echocardiographic follow-up. RESULTS: Patients were followed up to an average age of 15.9 \ub1 6.7 years. Seventy-one/178 patients developed DCM, and median age at onset was 20.0 years. Glucocorticoid corticosteroid treatment (n = 88 untreated; n = 75 treated; n = 15 unknown) did not have a significant independent effect on DCM onset. Cardiological medications were not administered before DCM onset in this population. We observed trends towards a protective effect of the dominant G allele at SPP1 rs28357094 and recessive T allele at LTBP4 rs10880, which was statistically significant in steroid-treated patients for LTBP4 rs10880 (< 50% T/T patients developing DCM during follow-up [n = 13]; median DCM onset 17.6 years for C/C-C/T, log-rank p = 0.027). CONCLUSIONS: We report a putative protective effect of DMD genetic modifiers on the development of cardiac complications, that might aid in risk stratification if confirmed in independent cohorts

Short-term Heart Rate Turbulence Analysis Versus Variability and Baroreceptor Sensitivity in Patients With Dilated Cardiomyopathy

New methods for the analysis of arrhythmias and their hemodynamic consequences have been applied in risk stratification, in particular to patients after myocardial infarction. This study investigates the suitability of short-term heart rate turbulence (HRT) analysis in comparison to heart rate and blood pressure variability as well as baroreceptor sensitivity analyses to characterise the regulatory differences between patients with dilated cardiomyopathy (DCM) and healthy controls. In this study, 30 minutes data of non-invasive continuous blood pressure and ECGs of 37 DCM patients and 167 controls measured under standard resting conditions were analysed. The results show highly significant differences between DCM patients and controls in heart rate and blood pressure variability as well as in baroreceptor sensitivity parameters. Applying a combined heart rate-blood pressure trigger, ventricular premature beats were detected in 24.3% (9) of the DCM patients and 11.3% (19) of the controls. This fact demonstrates the limited applicability of short-term HRT analyses. However, the HRT parameters showed significant differences in this subgroup with ventricular premature beats (turbulence onset: DCM: 1.80±2.72, controls: - 4.34±3.10, p<0.001; turbulence slope: DCM: 6.75±5.50, controls: 21.30±17.72, p=0.021). Considering all (including HRT) parameters in the subgroup with ventricular beats, a discrimination rate between DCM patients and controls of 88.0% was obtained (max. 6 parameters). The corresponding value obtained for the total group was 86.3% (without HRT parameters). Comparable classification rates and high correlations between heart rate turbulence and variability and baroreflex parameters point to a more universal applicability of the latter methods

The role of cardiac troponin T quantity and function in cardiac development and dilated cardiomyopathy

Background: Hypertrophic (HCM) and dilated (DCM) cardiomyopathies results from sarcomeric protein mutations, including cardiac troponin T (cTnT, TNNT2). We determined whether TNNT2 mutations cause cardiomyopathies by altering cTnT function or quantity; whether the severity of DCM is related to the ratio of mutant to wildtype cTnT; whether Ca2+ desensitization occurs in DCM; and whether absence of cTnT impairs early embryonic cardiogenesis. Methods and Findings: We ablated Tnnt2 to produce heterozygous Tnnt2+/ mice, and crossbreeding produced homozygous null Tnnt2-/-embryos. We also generated transgenic mice overexpressing wildtype (TGWT) or DCM mutant (TGK210Δ) Tnnt2. Crossbreeding produced mice lacking one allele of Tnnt2, but carrying wildtype (Tnnt2+/-/TGWT) or mutant (Tnnt2+/-/TGK210Δ) transgenes. Tnnt2+/-mice relative to wildtype had significantly reduced transcript (0.82 ± 0.06 [SD] vs. 1.00 ± 0.12 arbitrary units; p = 0.025), but not protein (1.01 ± 0.20 vs. 1.00 ± 0.13 arbitrary units; p = 0.44). Tnnt2+/-mice had normal hearts (histology, mass, left ventricular end diastolic diameter [LVEDD], fractional shortening [FS]). Moreover, whereas Tnnt2+/-/ TGK210Δ mice had severe DCM, TGK210Δ mice had only mild DCM (FS 18 ± 4 vs. 29 ± 7%; p < 0.01). The difference in severity of DCM may be attributable to a greater ratio of mutant to wildtype Tnnt2 transcript in Tnnt2+/-/TGK210Δ relative to TGK210Δ mice (2.42±0.08, p = 0.03). Tnnt2+/-/TGK210Δ muscle showed Ca2+ desensitization (pCa50 = 5.34 ± 0.08 vs. 5.58 ± 0.03 at sarcomere length 1.9 μm. p<0.01), but no difference in maximum force generation. Day 9.5 Tnnt2-/-embryos had normally looped hearts, but thin ventricular walls, large pericardial effusions, noncontractile hearts, and severely disorganized sarcomeres. Conclusions: Absence of one Tnnt2 allele leads to a mild deficit in transcript but not protein, leading to a normal cardiac phenotype. DCM results from abnormal function of a mutant protein, which is associated with myocyte Ca2+ desensitization. The severity of DCM depends on the ratio of mutant to wildtype Tnnt2 transcript. cTnT is essential for sarcomere formation, but normal embryonic heart looping occurs without contractile activity. © 2008 Ahmad et al

Managing the Complex Patient with Degenerative Cervical Myelopathy: How to Handle the Aging Spine, the Obese Patient, and Individuals with Medical Comorbidities.

Degenerative cervical myelopathy (DCM) is the most common cause of nontraumatic spinal cord injury worldwide. Even relatively mild impairment in functional scores can significantly impact daily activities. Surgery is an effective treatment for DCM, but outcomes are dependent on more than technique and preoperative neurologic deficits

The effect of mixed-enzyme addition in anaerobic digestion on methane yield of dairy cattle manure

This study investigates the effect of applying a mixture of enzymes (ME) to dairy cattle manure (DCM) as substrate in anaerobic digestion (AD). The aims of this study were to evaluate different methods of ME application to DCM at different temperatures and to investigate the effect of adding ME during the pre-treatment of the solid fractions of dairy cattle manure (SFDCM). The results showed that there was no positive effect of direct ME addition to substrate at either mesophilic (35 C) or thermophilic (50 ◦ C) process temperatures, but there was a significant 4.44% increase in methane yield when DCM, which had been incubated with ME addition at 50 ◦ C for three days, was fed to a digester when compared to a control digester operating at the same retention time. Methane production was detected during the pre-treatment incubation, and the total sum methane yield during pre-treatment and digestion was found to be 8.33% higher than in the control. The addition of ME to the SFDCM in a pre-incubation stage of 20 h at 35 ◦ C gave a significant increase in methane yield by 4.15% in a digester treating a mixed substrate (30% liquid fractions DCM and 70% enzyme-treated SFDCM) when compared with the control digester treating a similar mixed substrate with inactivated enzyme addition. The results indicate that direct physical contact of enzyme molecules and organic material in DCM prior to AD, without the intervention of extracellular enzymes from the indigenous microorganism population, was needed in order to increase methane yields. Keywords: biogas; mixed enzymes; pre-treatment; incubation; manur

Reaction of N,N-Dimethyltryptamine with Dichloromethane Under Common Experimental Conditions.

A large number of clinically used drugs and experimental pharmaceuticals possess the N,N-dimethyltryptamine (DMT) structural core. Previous reports have described the reaction of this motif with dichloromethane (DCM), a common laboratory solvent used during extraction and purification, leading to the formation of an undesired quaternary ammonium salt byproduct. However, the kinetics of this reaction under various conditions have not been thoroughly described. Here, we report a series of experiments designed to simulate the exposure of DMT to DCM that would take place during extraction from plant material, biphasic aqueous work-up, or column chromatography purification. We find that the quaternary ammonium salt byproduct forms at an exceedingly slow rate, only accumulates to a significant extent upon prolonged exposure of DMT to DCM, and is readily extracted into water. Our results suggest that DMT can be exposed to DCM under conditions where contact times are limited (&lt;30 min) with minimal risk of degradation and that this byproduct is not observed following aqueous extraction. However, alternative solvents should be considered when the experimental conditions require longer contact times. Our work has important implications for preparing a wide-range of pharmaceuticals bearing the DMT structural motif in high yields and purities

Seasonal patterns and interannual variability of phytoplankton in Lake Stechlin

The paper presents results of detailed phytoplankton investigations in Lake Stechlin between 1994 and 2003. The analysis includes the picoplankton fraction (dominated by Cyanobium sp.) that regularly appears as a deep-layer chlorophyll maximum (DCM). Planktothrix and Aulacoseira are successful competitors against Cyanobium in the isothermal period, the consequences differ markedly due to the fact that Planktothrix is able and Aulacoseira is unable to accumulate in the DCM after the onset of thermocline. The „regular-Cyanobium” and „irregular-Planktothrix, -Aulacoseira” patterns of DCM development has a basic influence on ecosystem functioning. Lake Stechlin a pristine, oligo-mesotrophic deep lake, with an established and detailed monitoring system and thus has been an ideal reference site for studying the influence of global climate changes on plankton that may improve our predictive tools for impact assessment

A systematic approach for monitoring and evaluating the construction project progress

A persistent problem in construction is to document changes which occur in the field and to prepare the as-built schedule. In current practice, deviations from planned performance can only be reported after significant time has elapsed and manual monitoring of the construction activities are costly and error prone. Availability of advanced portable computing, multimedia and wireless communication allows, even encourages fundamental changes in many jobsite processes. However a recent investigation indicated that there is a lack of systematic and automated evaluation and monitoring in construction projects. The aim of this study is to identifytechniques that can be used in the construction industry for monitoring and evaluating the physical progress, and also to establish how current computer technology can be utilised for monitoring the actual physical progress at the construction site. This study discusses the results of questionnaire survey conducted within Malaysian Construction Industry and suggests a prototype system, namely Digitalising Construction Monitoring (DCM). DCM prototype system integrates the information from construction drawings, digital images of construction site progress and planned schedule of work. Using emerging technologies and information system the DCM re-engineer the traditional practice for monitoring the project progress. This system can automatically interpret CAD drawings of buildings and extract data on its structural components and store in database. It can also extract the engineering information from digital images and when these two databases are simulated the percentage of progress can be calculated and viewed in Microsoft Project automatically. The application of DCM system for monitoring the project progress enables project management teams to better track and controls the productivity and quality of construction projects. The use of the DCM can help resident engineer, construction manager and site engineer in monitoring and evaluating project performance. This model will improve decision-making process and provides better mechanism for advanced project management