An updated meta-analysis of cardiac resynchronization therapy with or without defibrillation in patients with nonischemic cardiomyopathy

BackgroundCardiac resynchronization therapy (CRT) is a major device therapy used to treat patients suffering from heart failure (HF) and electrical asynchrony. It can improve HF symptoms, reduce HF hospitalization time, and improve long-term survival in HF with and without implantable cardioverter (ICD) therapy. However, the benefit of defibrillator therapy in CRT-eligible patients with nonischemic cardiomyopathy (NICM) remains unknown. As a result, we conducted a systematic review and meta-analysis to compare clinical outcomes in patients with NICM and HF who were treated with implantable CRT defibrillators (CRT-D) vs. a CRT pacemaker (CRT-P) alone.MethodsWe searched the electronic databases PubMed, Embase, and Cochrane for all studies comparing CRT-D vs. CRT-P treatment in patients with NICM. The time frame was from 1990 to September 2022. All-cause mortality and cardiovascular mortality were the primary clinical outcomes of interest to us. To pool adjusted hazard ratios (HRs) and 95% confidence intervals (CIs), a random-effects model with inverse variance was used.ResultsA pooled meta-analysis included two randomized controlled trials (RCTs), each with 1,200 CRT-eligible patients with NICM (592 with CRT-D and 608 with CRT-P) and nine cohort studies representing 27,568 CRT-eligible patients with NICM (16,196 with CRT-D and 11,372 with CRT-P). The adjusted HR for all-cause mortality for CRT-D vs. CRT-P was 0.90 (95% CI, 0.81-0.99). In a subgroup analysis of two RCTs and nine cohort studies, the adjusted HR for all-cause mortality was 0.72 (95% CI, 0.43–1.19) and HR 0.92 (95% CI, 0.83–1.03) for CRT-D vs. CRT-P, respectively.ConclusionWith the addition of defibrillation leads, we found a significantly lower risk of all-cause mortality in patients with NICM, but this association was not found in subgroup analyses of RCTs and observational studies

A novel SLC6A8 mutation associated with intellectual disabilities in a Chinese family exhibiting creatine transporter deficiency: case report

Abstract Background X-linked creatine transporter deficiency (OMIM#300036,CRTR-D) is characterized by cerebral creatine deficiency, intellectual disabilities, severe speech impairment, seizures and behavioral problems. Mutations in the creatine transporter gene SLC6A8, a member of the solute-carrier family 6 mapped to Xq28, have been reported to cause the creatine transporter deficiency. Case presentation The proband presented at 5 yrs. 1 month of age with delays in intellectual and development, seizures and behavioral problems. A novel missense mutation, c.1181C > A (p.Thr394Lys), in the SLC6A8 gene (NM_005629.3) was detected via targeted exome sequencing, and then validated by Sanger sequencing. Multiple in silico variant effect analysis methods, including SIFT, PolyPhen2, PROVEAN, and Mutation Taster predicted that this variant was likely damaging or diseasing-causing. This hemizygous variation was also identified in the affected brother with the same clinical condition and inherited from the heterozygous carrier mother. The diagnosis was suggested by increased urinary creatine/creatinine (Cr:Crn) ratio and markedly reduced creatine content peak by brain proton magnetic resonance spectroscopy (MRS). The proband’s mother became pregnant with a 3rd sibling, in whom the Sanger sequencing result of c.1181C > A was negative. Conclusion The novel mutation c.1181C > A in the SLC6A8 gene reported in a Chinese family has expanded the mutation spectrum of CRTR-D. The combination of powerful new technologies such as targeted exome sequencing with thorough systematic clinical evaluation of patients will improve the diagnostic yield, and assist in genetic counselling and prenatal diagnosis for suspected genetic disorders

De novo paternal origin duplication of chromosome 11p15.5: report of two Chinese cases with Beckwith-Wiedemann syndrome

Abstract Background The molecular etiology of Beckwith-Wiedemann syndrome (BWS) is complex and heterogeneous. Several subtypes of epigenetic-genetic alterations including aberrant methylation patterns, segmental uniparental disomy, single gene mutations, and copy number changes have been described. An integrated molecular approach to analyze the epigenetic-genetic alterations is required for accurate diagnosis of BWS. Case presentation We reported two Chinese cases with BWS detected by genome-wide copy number analysis and locus-specific methylation profiling. Prenatal analysis on cord blood of patient 1 showed a de novo paternal origin duplication spanning 896Kb at 11p15.5. Patient 2 was referred at 2-month old and the genetic analysis showed a de novo 228.8Kb deletion at 11p15.5 telomeric end and a de novo duplication of 2.5 Mb at 11p15.5–15.4. Both the duplications are of paternal origin with gain of methylation at the imprinting center 1 and thus belong to the subgroup of a low tumor risk. Conclusion Results from these two cases and other reported cases from literature indicated that paternally derived duplications at 11p15.5 region cause BWS. Combined chromosome microarray analysis and methylation profiling provided reliable diagnosis for this subtype of BWS. Characterization of genetic defects in BWS patients could lead to better understanding the genetic mechanisms of this clinically and genetically heterogeneous disorder

Ischemic postconditioning decreases cerebral edema and brain blood barrier disruption caused by relief of carotid stenosis in a rat model of cerebral hypoperfusion.

BACKGROUND AND PURPOSE: Complications due to brain edema and breakdown of blood brain barrier are an important factor affecting the treatment effects of patients with severe carotid stenosis. In this study, we investigated the protective effects of ischemic postconditioning on brain edema and disruption of blood brain barrier via establishing rat model of hypoperfusion due to severe carotid stenosis. METHODS: Wistar rat model of hypoperfusion due to severe carotid stenosis was established by binding a stainless microtube to both carotid arteries. Ischemic postconditioning procedure consisted of three cycles of 30 seconds ischemia and 30 seconds reperfusion. Brain edema was evaluated by measuring cerebral water content, and blood brain barrier permeability was assayed by examining cerebral concentration of Evans' Blue (EB) and fluorescein sodium (NaF). ELISA was used to analyze the expression of MMP-9, claudin-5 and occludin. The activity and location of MMP-9 was analyzed by gelatin zymography and in situ zymography, respectively. The distribution of tight junction proteins claudin-5 and occludin was observed by immunohistochemistry. RESULTS: The increased brain water content and cerebral concentration of EB and NaF were suppressed by administration of ischemic postconditioning prior to relief of carotid stenosis. Zymographic studies showed that MMP-9 was mainly located in the cortex and its activity was significantly improved by relief of carotid stenosis and, but the elevated MMP-9 activity was inhibited markedly by ischemic postconditioning. Immunohistochemistry revealed that ischemic postconditioning improved the discontinuous distribution of claudin-5 and occludin. ELISA detected that the expression of up-regulated MMP-9 and down-regulated claudin-5 and occludin caused by carotid relief were all attenuated by ischemic postconditioning. CONCLUSIONS: Ischemic postconditioning is an effective method to prevent brain edema and improve BBB permeability and could be used during relief of severe carotid stenosis

Study on the Temporal and Spatial Evolution of China’s Carbon Dioxide Emissions and Its Emission Reduction Path

Based on the total carbon emission data of 30 provinces and cities in China from 2000 to 2020, this paper used non-parametric kernel density estimation and traditional and spatial Markov probability transfer matrix methods to explore the temporal and spatial dynamic evolution characteristics of carbon dioxide emissions in China and then used a super-SBM model to calculate the carbon emission reduction potential of each province. The results showed that: (1) from 2000 to 2020, the total carbon emissions in China showed an upward trend of fluctuation, from 1.35 Gt to 4.90 Gt year by year, with an annual growth rate of 13.10%. (2) The core density curve showed a double peak form of “main peak + right peak,” indicating that a polarization phenomenon occurred in the region. (3) The overall trend of carbon dioxide emissions shifting to superheavy carbon emissions was significant, and the probability of transition was as high as 74.69%, indicating that it was challenging to achieve leapfrog transition in the short term. (4) Based on the principle of fairness and efficiency of provincial carbon emission reduction, mainland China’s 30 provincial administrative regions can be divided into four types. Finally, the carbon emission reduction path is designed for each province

Long-term effects of shikonin on the cellular viability of C6 glioma cells.

<p>MTT assay showed that the decreased cellular viability of C6 glioma cells caused by shikonin was dependent on shikonin concentration and incubation time. *: <i>p</i><0.01 versus control group.</p

Distribution and expression of tight junction proteins caludin-5 and occludin.

<p>A, distribution of caludin-5 and occludin in cerebral microvessels. Immuno-histochemical images showed that claudin-5 and occludin were located sharply and continuously on cerebral microvessels in the sham and carotid stenosis group. At 2 day following relief of carotid stenosis, their distribution became discontinuous, which was reversed partly by ischemic postconditioning. B, ELISA assay of claudin-5 concentration. C, ELISA assay of occludin concentration. The level of caludin-5 and occludin in stenosis relief group were significantly lower that those in the sham and the carotid stenosis group at each scheduled time point. However, ischemic postconditioning maintained their quantity. *: <i>p</i><0.01, versus carotid stenosis group; #: <i>p</i><0.01, versus stenosis relief group.</p