Mitochondrial Cardiomyopathy

Mitochondrial diseases are multisystem disorders, resulting from mitochondrial electron transport chain dysfunction and oxidative phosphorylation due to pathogenic variants in mitochondrial or nuclear DNA. The clinical presentations are variable in the age of onset, symptoms, and range and severity of organ involvement. Diagnosis requires a multidisciplinary approach and is based on clinical symptoms, laboratory tests, histopathological findings, and genetic analysis. Due to the multi-organ involvement, the evaluation of mitochondrial diseases should include a systemic screening for all targeted organs, including neuroimaging, ophthalmology, and hearing examinations. Cardiac involvement should be evaluated at the time of diagnosis, as cardiac involvement is an independent predictor of morbidity and early mortality, even in asymptomatic cases. Hypertrophic cardiomyopathy is the most common cardiac manifestation; however, mitochondrial cardiomyopathy might also present as left ventricular non-compaction (LVNC) or as dilated, histiocytoid, or restrictive cardiomyopathy. The precise evaluation of cardiac involvement is of clinical use in predicting future cardiac events and prognosis. Despite advancements in molecular biology, no satisfactory treatments for mitochondrial diseases exist. Treatment remains largely symptomatic and does not significantly alter disease progression

Effect of trinucleotide repeat expansion on the expression of TCF4 mRNA in Fuchs' endothelial corneal dystrophy

Purpose: CTG trinucleotide repeat (TNR) expansion is frequently found in transcription factor 4 (TCF4) in Fuchs' endothelial corneal dystrophy (FECD), though the effect of TNR expansion on FECD pathophysiology remains unclear. The purpose of this study was to evaluate the effect of TNR expansion on TCF4 expression in corneal endothelium of patients with FECD. Methods: Peripheral blood DNA and Descemet membrane with corneal endothelium were obtained from 203 German patients with FECD. The CTG TNR repeat length in TCF4 was determined by short tandem repeat (STR) assays and Southern blotting using genomic DNA. Genotyping of rs613872 in TCF4 was performed by PCR. TCF4 mRNA levels in corneal endothelium were evaluated by quantitative PCR using three different probes. Control corneal endothelial samples were obtained from 35 non-FECD subjects. Results: The STR assay and Southern blotting showed that 162 of the 203 patients with FECD (80%) harbored CTG trinucleotide repeat lengths larger than 50. Quantitative PCR using all three probes demonstrated that TCF4 mRNA is significantly upregulated in the corneal endothelium of patients with FECD, regardless of the presence of TNR expansion. However, the length of the TNR tended to show a positive correlation with TCF4 expression level. No correlation was shown between the genotype of TCF4 SNP, rs613872, and the level of TCF4 expression. Conclusions: Our findings showed that TCF4 mRNA is upregulated in the corneal endothelium of patients with FECD. Further studies on the effects of TCF4 upregulation on corneal endothelial cell function will aid in understanding the pathophysiology of FECD

Oral Administration of Polymer Hyaluronic Acid Alleviates Symptoms of Knee Osteoarthritis: A Double-Blind, Placebo-Controlled Study over a 12-Month Period

This study was conducted to investigate the efficacy of oral hyaluronic acid (HA) administration for osteoarthritis (OA) in knee joints. Sixty osteoarthritic subjects (Kellgren-Lawrence grade 2 or 3) were randomly assigned to the HA or placebo group. The subjects in the HA group were given 200 mg of HA once a day everyday for 12 months, while the subjects in the placebo group were given placebo. The subjects in both groups were requested to conduct quadriceps strengthening exercise everyday as part of the treatment. The subjects’ symptoms were evaluated by the Japanese Knee Osteoarthritis Measure (JKOM) score. The symptoms of the subjects as determined by the JKOM score improved with time in both the HA and placebo groups. This improvement tended to be more obvious with the HA group, and this trend was more obvious with the subjects aged 70 years or less. For these relatively younger subjects, the JKOM score was significantly better than the one for the placebo group at the 2nd and 4th months after the initiation of administration. Oral administration of HA may improve the symptoms of knee OA in patients aged 70 years or younger when combined with the quadriceps strengthening exercise

Hypoxia inhibits TNF-α-induced TSLP expression in keratinocytes.

The expression of thymic stromal lymphopoietin (TSLP), a cytokine which greatly contributes to the induction of type I allergy, is upregulated in chronic inflammation such as atopic dermatitis and psoriasis. As hypoxia in the epidermis is important for maintaining skin homeostasis, we examined the regulation of TSLP expression by hypoxic conditions in normal skin epithelial tissues. TNF-α-induced expression of TSLP in human keratinocyte HaCaT and in mouse keratinocyte PAM212 cell lines were inhibited under hypoxic condition (1% O2), although the mRNA expressions of TNF-α, IL-6, IL-8, MCP-1, and VEGF-A were not inhibited. Hypoxia-mimicking conditions, which include NiCl2, CoCl2, and DMOG, an inhibitor of 2-oxoglutarate-dependent enzymes, also selectively inhibited TNF-α-induced TSLP expression. These results suggested that inactivation of prolyl hydroxylase by hypoxia and hypoxia-mimicking conditions is involved in the repression of TNF-α-induced TSLP expression. Interestingly, the inhibition of TSLP production by hypoxic treatment was significantly reversed by treatment with the HIF-2α antagonist but not with the HIF-1α inhibitor. DMOG-induced inhibition of TSLP promoter activity was dependent on the -71 to +185 bp promoter region, suggesting that the binding of HIF-2 to hypoxia response element (HRE) in this region repressed the TSLP expression. These results indicated that hypoxia and hypoxia-mimicking conditions inhibited TSLP expression via HIF-2 and HRE-dependent mechanisms. Therefore, PHD and HIF-2α could be a new strategy for treatment of atopic dermatitis and psoriasis