Genotype-Phenotype Correlations in Charcot-Marie-Tooth Disease Due to MTMR2 Mutations and Implications in Membrane Trafficking

Charcot-Marie-Tooth type 4 (CMT4) is an autosomal recessive severe form of neuropathy with genetic heterogeneity. CMT4B1 is caused by mutations in the myotubularin-related 2 (MTMR2) gene and as a member of the myotubularin family, the MTMR2 protein is crucial for the modulation of membrane trafficking. To enable future clinical trials, we performed a detailed review of the published cases with MTMR2 mutations and describe four novel cases identified through whole-exome sequencing (WES). The four unrelated families harbor novel homozygous mutations in MTMR2 (NM_016156, Family 1: c.1490dupC; p.Phe498IlefsTer2; Family 2: c.1479+1G>A; Family 3: c.1090C>T; p.Arg364Ter; Family 4: c.883C>T; p.Arg295Ter) and present with CMT4B1-related severe early-onset motor and sensory neuropathy, generalized muscle atrophy, facial and bulbar weakness, and pes cavus deformity. The clinical description of the new mutations reported here overlap with previously reported CMT4B1 phenotypes caused by mutations in the phosphatase domain of MTMR2, suggesting that nonsense MTMR2 mutations, which are predicted to result in loss or disruption of the phosphatase domain, are associated with a severe phenotype and loss of independent ambulation by the early twenties. Whereas the few reported missense mutations and also those truncating mutations occurring at the C-terminus after the phosphatase domain cause a rather mild phenotype and patients were still ambulatory above the age 30 years. Charcot-Marie-Tooth neuropathy and Centronuclear Myopathy causing mutations have been shown to occur in proteins involved in membrane remodeling and trafficking pathway mediated by phosphoinositides. Earlier studies have showing the rescue of MTM1 myopathy by MTMR2 overexpression, emphasize the importance of maintaining the phosphoinositides equilibrium and highlight a potential compensatory mechanism amongst members of this pathway. This proved that the regulation of expression of these proteins involved in the membrane remodeling pathway may compensate each other's loss- or gain-of-function mutations by restoring the phosphoinositides equilibrium. This provides a potential therapeutic strategy for neuromuscular diseases resulting from mutations in the membrane remodeling pathway

Unlocking the Mysteries of Diastolic Function Deciphering the Rosetta Stone 10 Years Later

It has now been a quarter of a century since the first description by Kitabatake and his associates of the use of echo-Doppler to characterize the transmitral flow velocity curves in various disease states. A decade ago we described the role of echocardiography in the “Evaluation of Diastolic Filling of Left Ventricle in Health and Disease: Doppler Echocardiography Is the Clinician’s Rosetta Stone.” Over the ensuing decade, advances in echo-Doppler have helped to further decipher the morphologic and physiological expression of cardiovascular disease and unlock additional mysteries of diastology. The purpose of this review is to highlight the developments in echo-Doppler and refinements in our knowledge that have occurred over the past decade that enhance our understanding of diastology

Evaluation of a chemoresponse assay as a predictive marker in the treatment of recurrent ovarian cancer: Further analysis of a prospective study

BACKGROUND: Recently, a prospective study reported improved clinical outcomes for recurrent ovarian cancer patients treated with chemotherapies indicated to be sensitive by a chemoresponse assay, compared with those patients treated with non-sensitive therapies, thereby demonstrating the assay's prognostic properties. Due to cross-drug response over different treatments and possible association of in vitro chemosensitivity of a tumour with its inherent biology, further analysis is required to ascertain whether the assay performs as a predictive marker as well. METHODS: Women with persistent or recurrent epithelial ovarian cancer (n=262) were empirically treated with one of 15 therapies, blinded to assay results. Each patient's tumour was assayed for responsiveness to the 15 therapies. The assay's ability to predict progression-free survival (PFS) was assessed by comparing the association when the assayed therapy matches the administered therapy (match) with the association when the assayed therapy is randomly selected, not necessarily matching the administered therapy (mismatch). RESULTS: Patients treated with assay-sensitive therapies had improved PFS vs patients treated with non-sensitive therapies, with the assay result for match significantly associated with PFS (hazard ratio (HR)=0.67, 95% confidence interval (CI)=0.50–0.91, P=0.009). On the basis of 3000 simulations, the mean HR for mismatch was 0.81 (95% range=0.66–0.99), with 3.4% of HRs less than 0.67, indicating that HR for match is lower than for mismatch. While 47% of tumours were non-sensitive to all assayed therapies and 9% were sensitive to all, 44% displayed heterogeneity in assay results. Improved outcome was associated with the administration of an assay-sensitive therapy, regardless of homogeneous or heterogeneous assay responses across all of the assayed therapies. CONCLUSIONS: These analyses provide supportive evidence that this chemoresponse assay is a predictive marker, demonstrating its ability to discern specific therapies that are likely to be more effective among multiple alternatives

Exercise and nutritional interventions on sarcopenia and frailty in heart failure: a narrative review of systematic reviews and meta-analyses

The purpose of this review is to describe the present evidence for exercise and nutritional interventions as potential contributors in the treatment of sarcopenia and frailty (i.e. muscle mass and physical function decline) and the risk of cardiorenal metabolic comorbidity in people with heart failure (HF). Evidence primarily from cross-sectional studies suggests that the prevalence of sarcopenia in people with HF is 37% for men and 33% for women, which contributes to cardiac cachexia, frailty, lower quality of life, and increased mortality rate. We explored the impact of resistance and aerobic exercise, and nutrition on measures of sarcopenia and frailty, and quality of life following the assessment of 35 systematic reviews and meta-analyses. The majority of clinical trials have focused on resistance, aerobic, and concurrent exercise to counteract the progressive loss of muscle mass and strength in people with HF, while promising effects have also been shown via utilization of vitamin D and iron supplementation by reducing tumour necrosis factor-alpha (TNF-a), c-reactive protein (CRP), and interleukin-6 (11-6) levels. Experimental studies combining the concomitant effect of exercise and nutrition on measures of sarcopenia and frailty in people with HF are scarce. There is a pressing need for further research and well-designed clinical trials incorporating the anabolic and anti-catabolic effects of concurrent exercise and nutrition strategies in people with HF

Electron phonon coupling in ultrathin Pb films on Si(111): Where the heck is the energy?

In this work, we study the heat transfer from electron to phonon system within a five monolayer thin epitaxial Pb film on Si(111) upon fs-laser excitation. The response of the electron system is determined using time-resolved photoelectron spectroscopy while the lattice excitation is measured by means of the Debye-Waller effect in time-resolved reflection high-energy electron diffraction. The electrons lose their heat within 0.5 ps while the lattice temperature rises slowly in 3.5 to 8 ps, leaving a gap of 3-7 ps. We propose that the hidden energy is transiently stored in high-frequency phonon modes for which diffraction is insensitive and which are excited in 0.5 ps. Within a three-temperature model we use three heat baths, namely electrons, high-frequency and low-frequency phonon modes to simulate the observations. The excitation of low-frequency acoustic phonons, i.e., thermalization of the lattice is facilitated through anharmonic phonon-phonon interaction

KIR2DS3 is associated with protection against acute myeloid leukemia

Background: Interaction between killer cell immunoglobulin-like receptors (KIR) and human leukocyte antigen (HLA) class I molecules is important for regulation of natural killer (NK) cell function. Objective: The aim of this study was to investigate the impact of compound KIR-HLA genotype on susceptibility to acute leukemia. Methods: Cohorts of Iranian patients with acute myeloid leukemia (AML; n=40) and acute lymphoid leukemia (ALL; n=38) were genotyped for seventeen KIR genes and their three major HLA class I ligand groups (C1, C2, Bw4) by a combined polymerase chain reaction-sequence-specific primers (PCR-SSP) assay. The results were compared with those of 200 healthy control individuals. Results: We found a significantly decreased frequency of KIR2DS3 in AML patients compared to control group (12.5 vs. 38, odds ratio=0.23, p=0.0018). Also, the KIR3DS1 was less common in AML group than controls (27.5 vs. 44.5, p=0.0465, not significant after correction). Other analyses including KIR genotypes, distribution and balance of inhibitory and activating KIR+HLA combinations, and coinheritance of activating KIR genes with inhibitory KIR+HLA pairs were not significantly different between leukemia patients and the control group. However, in AML patients a trend toward less activating and more inhibitory KIR-HLA state was observed. Interestingly, this situation was not found in ALL patients and inhibition enhancement through increase of HLA ligands and inhibitory combinations was the main feature in this group. Conclusion: Our findings may suggest a mechanism for escape of leukemic cells from NK cell immunity

Inhibitory killer cell immunoglobulin-like receptor KIR3DL1 in combination with HLA-B Bw4iso protect against Ankylosing spondylitis

Background: The HLA class I molecules serve as ligands for both T cell receptors and killer cell immunoglobulin-like receptors (KIRs). Objective: We investigated the HLA- C and HLA-Bw4 alleles as well as KIRs expression on CD56 positive lymphocytes to evaluate whether these genes and molecules could influence Ankylosing spondylitis (AS) susceptibility, alone or in combination. Methods: We typed 40 AS patients and 40 normal controls for HLA-C asn80 (group 1) and HLA-C lys80 (group 2), HLA-B Bw4thero, HLA-B Bw4iso and HLA-A Bw4 alleles by PCR-SSP method. We also as- sessed the expression of KIR2DL1/2DS1, KIR2DL2/2DL3, KIR3DL1 and KIR2DS4 by flow cytometry. The Pearson chi-square or Fisher exact test was performed for statisti- cal analysis. Results: The frequency of HLA-B Bw4iso but not HLA-B Bw4thero and HLA-A Bw4, ligand for the inhibitory KIR3DL1, was significantly reduced in AS pa- tients as compared with controls (p<0.01). No significant differences were observed in gene carrier frequencies of HLA-C group 1 and 2 between AS and controls. Although no differences were found in the expression of KIR receptors between AS and normal subjects, we found that expression of KIR3DL1 in the presence of HLA Bw4-Biso gene was reduced in patients with AS compared to healthy controls (p<0.009). Conclusion: We conclude that HLA-B Bw4iso, the ligand of inhibitory KIR3DL1, with and without the expression of KIR3DL1 might be involved in protection against AS. Our results suggest that besides the HLA and KIR genotype, expression levels of KIRs may be in- volved in the pathogenesis of AS disease

Violation of Boltzmann Equipartition Theorem in Angular Phonon Phase Space Slows down Nanoscale Heat Transfer in Ultrathin Heterofilms

Heat transfer through heterointerfaces is intrinsically hampered by a thermal boundary resistance originating from the discontinuity of the elastic properties. Here, we show that with shrinking dimensions the heat flow from an ultrathin epitaxial film through atomically flat interfaces into a single crystalline substrate is significantly reduced due to violation of Boltzmann equipartition theorem in the angular phonon phase space. For films thinner than the phonons mean free path, we find phonons trapped in the film by total internal reflection, thus suppressing heat transfer. Repopulation of those phonon states, which can escape the film through the interface by transmission and refraction, becomes the bottleneck for cooling. The resulting nonequipartition in the angular phonon phase space slows down the cooling by more than a factor of 2 compared to films governed by phonons diffuse scattering. These allow tailoring of the thermal interface conductance via manipulation of the interface

Genetic Variants of Cytochrome b-245, Alpha Polypeptide Gene and Premature Acute Myocardial Infarction Risk in An Iranian Population

Background: Oxidative stress induced by superoxide anion plays critical roles in the pathogenesis of coronary artery disease (CAD) and hence acute myocardial infarction (AMI). The major source of superoxide production in vascular smooth muscle and endothelial cells is the NADPH oxidase complex. An essential component of this complex is p22phox, that is encoded by the cytochrome b-245, alpha polypeptide (CYBA) gene. The aim of this study was to investigate the association of CYBA variants (rs1049255 and rs4673) and premature acute myocardial infarction risk in an Iranian population. Methods: The study population consisted of 158 patients under the age of 50 years, with a diagnosis of premature AMI, and 168 age-matched controls with normal coronary angiograms. Genotyping of the polymorphisms was performed by the polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Results: There was no association between the genotypes and allele frequencies of rs4673 polymorphism and premature acute myocardial infarction (P>0.05). A significant statistical association was observed between the genotypes distribution of rs1049255 polymorphism and AMI risk (P=0.037). Furthermore, the distribution of AA+AG/GG genotypes was found to be statistically significant between the two groups (P=0.011). Conclusions: Our findings indicated that rs1049255 but not rs4673 polymorphism is associated with premature AMI

Isolation and proliferation of spermatogonial cells from ghezel sheep

Background: Sheep industry has taken steps toward transforming itself into a more efficient and competitive field. There are many varieties of sheep breeds in the world that each of them serves a useful purpose in the economies of different civilizations. Ghezel sheep is one of the Iranian important breeds that are raised for meat, milk and wool. Field of spermatogonial cell technologies provides tools for genetic improvement of sheep herd and multiple opportunities for research. Spermatogonial cells are the only stem cells capable of transmitting genetic information to future generations. Methods: This study was designed to extend the technique of isolation and in vitro proliferation of spermatogonial cells in Ghezel sheep. Results: Isolated cells were characterized further by using specific markers for type A spermatogonia, including PLZF. Also, sertoli cells were characterized by vimentin which is a specific marker for sertoli cells. After 10 days of co-culture, viability rates of the cells was above 94.7, but after the freezing process the viability rates were 74 percent. Conclusion: In this study, a standard method for isolation and in vitro proliferation of spermatogonial stem cells in Ghezel sheep was developed. © 2018, Avicenna Journal of Medical Biotechnology. All rights reserved