MELAS phenotype associated with m.3302A>G mutation in mitochondrial tRNA gene

The m.3302A>G mutation in the mitochondrial tRNA^Leu(UUR) gene has been identified in only 12 patients from 6 families, all manifesting adult-onset slowly progressive myopathy with minor central nervous system involvement. An 11-year-old boy presented with progressive proximal-dominant muscle weakness from age 7 years. At age 10, he developed recurrent stroke-like episodes. Mitochondrial myopathy, encephalopathy, lactic acidosis, plus stroke-like episodes (MELAS) was diagnosed by clinical symptoms and muscle biopsy findings. Mitochondrial gene analysis revealed a heteroplasmic m.3302A>G mutation. Histological examination showed strongly SDH reactive blood vessels (SSVs), not present in previous cases with myopathies due to the m.3302A>G mutation. These findings broaden the phenotypic spectrum of this mutation.     

Persistent verbal and behavioral deficits after resection of the left supplementary motor area in epilepsy surgery

An 8-year-old boy underwent a resection for focal cortical dysplasia at the left supplementary motor area (SMA) for the treatment of intractable epilepsy. The manifestations of SMA syndrome, such as transient mutism and right hemiparesis, resolved within a few weeks. Verbal disfluency and impaired executive function, accompanied by impulsivity and distractibility, persisted for more than 12 months. The verbal and behavioral problems caused serious difficulties in the school life of the patient, until they became less evident at 18 months after surgery. Tractography performed 18 months after surgery revealed a defect in the subportion of fronto-parietal association fibers within the left superior longitudinal fascicles. Verbal influency can persist with unusually long duration after resection of SMA during childhood. Although not discernible on the routine neuroimaging, white matter damage beneath the SMA region could result in serious disabilities in executive function. These complications should be recognized for the prediction and assessment of deficits in children after surgical intervention involving this region.     

Significance of combined cyclosporine−prednisolone therapy and cyclosporine blood concentration monitoring for idiopathic membranous nephropathy with steroid-resistant nephrotic syndrome: a randomized controlled multicenter trial

Background

Combined treatment with cyclosporine microemulsion preconcentrate (CyA MEPC) and steroids has been widely used for idiopathic membranous nephropathy (IMN) associated with steroid-resistant nephrotic syndrome (SRNS). Recent studies have shown that once-a-day and preprandial administration of CyA MEPC is more advantageous than the conventional twice-a-day administration in achieving the target blood CyA concentration at 2 h post dose (C2). We designed a randomized trial to compare these administrations.

Methods

IMN patients with SRNS (age 16–75 years) were divided prospectively and randomly into 2 groups. In group 1 (n = 23), 2–3 mg/kg body weight (BW) CyA MEPC was given orally once a day before breakfast. In group 2 (n = 25), 1.5 mg/kg BW CyA MEPC was given twice a day before meals. CyA + prednisolone was continued for 48 weeks.

Results

Group 1 showed a significantly higher cumulative complete remission (CR) rate (p = 0.0282), but not when incomplete remission 1 (ICR1; urine protein 0.3–1.0 g/day) was added (p = 0.314). Because a C2 of 600 ng/mL was determined as the best cut-off point, groups 1 and 2 were further divided into subgroups A (C2 ≥600 ng/mL) and B (C2 <600 ng/mL). Groups 1A and 2A revealed significantly higher cumulative remission (CR + ICR1) (p = 0.0069) and CR-alone (p = 0.0028) rates. On the other hand, 3 patients with high CyA levels (C2 >900 ng/mL) in Group 1A were withdrawn from the study because of complications.

Conclusion

CyA + prednisolone treatment is effective for IMN with associated SRNS at a C2 of ≥600 ng/mL. To achieve remission, preprandial once-a-day administration of CyA at 2–3 mg/kg BW may be the most appropriate option. However, we should adjust the dosage of CyA by therapeutic drug monitoring to avoid complications.     

Diabetes,Collagen, and Bone Quality

Diabetes increases risk of fracture, although type 2 diabetes is characterized by normal or high bone mineral density (BMD) compared with the patients without diabetes. The fracture risk of type 1 diabetes as well as type 2 diabetes increases beyond an explained by a decrease of BMD. Thus, diabetes may reduce bone strength without change in BMD. Whole bone strength is determined by bone density, structure, and quality, which encompass the micro-structural and tissue material properties. Recent literature showed that diabetes reduces bone material properties rather than BMD. Collagen intermolecular cross-linking plays an important role in the expression of bone strength. Collagen cross-links can be divided into beneficial enzymatic immature divalent and mature trivalent cross-links and disadvantageous nonenzymatic cross-links (Advanced glycation end products: AGEs) induced by glycation and oxidation. The formation pathway and biological function are quite different. Not only hyperglycemia, but also oxidative stress induces the reduction in enzymatic cross-links and the formation of AGEs. In this review, we describe the mechanism of low bone quality in diabetes and the usefulness of the measurement of plasma or urinary level of AGEs for estimation of fracture risk.