Outer mitochondrial membrane E3 Ub ligase MARCH5 controls de novo peroxisome biogenesis.

We report that the outer mitochondrial membrane (OMM)-associated E3 Ub ligase MARCH5 is vital for generating mitochondria-derived pre-peroxisomes. In human immortalized cells, MARCH5 knockout leads to the accumulation of immature peroxisomes, reduced fatty-acid-induced peroxisomal biogenesis, and abnormal peroxisome biogenesis in MARCH5/Pex14 and MARCH5/Pex3 dko cells. Upon fatty-acid-induced peroxisomal biogenesis, MARCH5 redistributes to peroxisomes, and ubiquitination activity-deficient mutants of MARCH5 accumulate on peroxisomes containing high levels of the OMM protein Tom20 (mitochondria-derived pre-peroxisomes).

Outer mitochondrial membrane E3 Ub ligase MARCH5 controls mitochondrial steps in peroxisome biogenesis.

Unlabelled: Peroxisome biogenesis requires yet unidentified mitochondrial proteins. We report that the outer mitochondrial membrane (OMM)-associated E3 Ub ligase MARCH5 is vital for generating mitochondria-derived pre-peroxisomes. MARCH5 knockout results in accumulation of immature peroxisomes and lower expression of various peroxisomal proteins.

Na /K ATPase-Ca 1.2 nanodomain differentially regulates intracellular [Na ], [Ca ] and local adrenergic signaling in cardiac myocytes.

Background: The intracellular Na concentration ([Na ] ) is a crucial but understudied regulator of cardiac myocyte function. The Na /K ATPase (NKA) controls the steady-state [Na ] and thereby determines the set-point for intracellular Ca . Here, we investigate the nanoscopic organization and local adrenergic regulation of the NKA macromolecular complex and how it differentially regulates the intracellular Na and Ca homeostases in atrial and ventricular myocytes.

Calcium and bicarbonate signaling pathways have pivotal, resonating roles in matching ATP production to demand.

Mitochondrial ATP production in ventricular cardiomyocytes must be continually adjusted to rapidly replenish the ATP consumed by the working heart. Two systems are known to be critical in this regulation: mitochondrial matrix Ca ([Ca]) and blood flow that is tuned by local cardiomyocyte metabolic signaling. However, these two regulatory systems do not fully account for the physiological range of ATP consumption observed.

Mitochondrial proteotoxicity: implications and ubiquitin-dependent quality control mechanisms.

Through their role in energy generation and regulation of several vital pathways, including apoptosis and inflammation, mitochondria are critical for the life of eukaryotic organisms. Mitochondrial dysfunction is a major problem implicated in the etiology of many pathologies, including neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), diabetes, cardiovascular diseases, and many others. Proteotoxic stress, here defined as a reduction in bioenergetic activity induced by the accumulation of aberrant proteins in the mitochondria, is likely to be implicated in disease-linked mitochondrial and cellular decline.

The OMM-severed and IMM-ubiquitinated mitochondria are intermediates of mitochondrial proteotoxicity-induced autophagy in PRKN/parkin-deficient cells.

Among other mechanisms, mitochondrial membrane dynamics including mitochondrial fission and fusion, and the activity of the ubiquitin (Ub)-proteasome system (UPS) both are critical for maintaining mitochondrial function. To advance our knowledge of the role of mitochondrial fission, the UPS, and how they coordinatively affect mitochondrial response to proteotoxicity, we analyzed mitochondrial ubiquitination and mitochondria-specific autophagy (mitophagy) in E3 Ub ligase PRKN/parkin-expressing and -deficient cells. Through imaging, biochemical, and genetic analyses, we found that in a model of acute reduction of mitochondrial translation fidelity (MTF) some population of mitochondria within a single cell are enriched, while some showed reduced levels of CYCS (cytochrome c, somatic) and CPOX (coproporphyrinogen oxidase) proteins, both located in the intermembrane space (IMS); henceforth called "mosaic distribution".

Parkin-independent mitophagy via Drp1-mediated outer membrane severing and inner membrane ubiquitination.

Here, we report that acute reduction in mitochondrial translation fidelity (MTF) causes ubiquitination of the inner mitochondrial membrane (IMM) proteins, including TRAP1 and CPOX, which occurs selectively in mitochondria with a severed outer mitochondrial membrane (OMM). Ubiquitinated IMM recruits the autophagy machinery. Inhibiting autophagy leads to increased accumulation of mitochondria with severed OMM and ubiquitinated IMM.

Increased AMP deaminase activity decreases ATP content and slows protein degradation in cultured skeletal muscle.

Background: Protein degradation is an energy-dependent process, requiring ATP at multiple steps. However, reports conflict as to the relationship between intracellular energetics and the rate of proteasome-mediated protein degradation.

Methods: To determine whether the concentration of the adenine nucleotide pool (ATP + ADP + AMP) affects protein degradation in muscle cells, we overexpressed an AMP degrading enzyme, AMP deaminase 3 (AMPD3), via adenovirus in C2C12 myotubes.

Salvage revision arthroplasty after failed TMC joint prosthesis.

The purpose of this retrospective study was to describe our experience with failed TMC joint prostheses and to report the results of 7 cases that were treated by a salvage revision arthroplasty. We only performed this salvage arthroplasty when partial (cup replacement) or total replacement of TMC prosthesis was not possible. We performed a resection arthroplasty with (partial) trapezial excision and spacer insertion to prevent scaphometacarpal collaps.

Lysine-Restricted Diet as Adjunct Therapy for Pyridoxine-Dependent Epilepsy: The PDE Consortium Consensus Recommendations.

Background: Seventy-five percent of patients with pyridoxine-dependent epilepsy (PDE) due to Antiquitin (ATQ) deficiency suffer from developmental delay and/or intellectual disability (IQ < 70) despite seizure control. An observational study showed that adjunct treatment with a lysine-restricted diet is safe, results in partial normalization of lysine intermediates in body fluids, and may have beneficial effects on seizure control and psychomotor development.

Methods: In analogy to the NICE guideline process, the international PDE Consortium, an open platform uniting scientists and clinicians working in the field of this metabolic epilepsy, during four workshops (2010-2013) developed a recommendation for a lysine-restricted diet in PDE, with the aim of standardizing its implementation and monitoring of patients.

Focal fibrocartilaginous dysplasia in the upper limb: case report and review of the literature.

Focal fibrocartilaginous dysplasia (FFCD) is an uncommon, benign bone lesion that causes angular deformities of the long bones in young children. Most deformities were seen around the knee. Diagnostic criteria are based on clinical and radiological signs: unilateral angular deformity in a long bone of a young child, associated with on X-ray a typical lucent bony defect with surrounding sclerosis at the concavity of the deformity with a cortical defect.

Intra-articular versus serum C-reactive protein analysis in suspected periprosthetic knee joint infection.

The purpose of this study was to investigate the comparative diagnostic strength of C-reactive protein (CRP) values in synovial fluid and serum in patients with presumed periprosthetic joint infection. We collected 44 synovial fluid samples and 24 serum samples from 43 patients. Patients were judged to be uninfected or infected based on standardized criteria.

Midfoot arthritis: diagnosis and treatment.

Background: Midfoot arthritis is a challenging problem causing chronic foot pain and impeding daily activity. There is not much written about this subject in literature and is often not well known by orthopaedic surgeons. The primary aim of treatment is to afford pain relief by enhancing midfoot stability and modifying loads sustained at the inflamed joints.

Identification of genes that contribute to the pathogenesis of invasive pneumococcal disease by in vivo transcriptomic analysis.

Streptococcus pneumoniae (the pneumococcus) continues to be responsible for a high level of global morbidity and mortality resulting from pneumonia, bacteremia, meningitis, and otitis media. Here we have used a novel technique involving niche-specific, genome-wide in vivo transcriptomic analyses to identify genes upregulated in distinct niches during pathogenesis after intranasal infection of mice with serotype 4 or 6A pneumococci. The analyses yielded 28 common, significantly upregulated genes in the lungs relative to those in the nasopharynx and 25 significantly upregulated genes in the blood relative to those in the lungs in both strains, some of which were previously unrecognized.

A common variant in ERBB4 regulates GABA concentrations in human cerebrospinal fluid.

The neuregulin 1 (NRG1) receptor ErbB4 is involved in the development of cortical inhibitory GABAergic circuits and NRG1-ErbB4 signaling has been implicated in schizophrenia (SCZ). A magnetic resonance spectroscopy ((1)H-MRS) study has demonstrated that a single-nucleotide polymorphism in ERBB4, rs7598440, influences human cortical GABA concentrations. Other work has highlighted the significant impact of this genetic variant on expression of ERBB4 in the hippocampus and dorsolateral prefrontal cortex in human post mortem tissue.

Formation of a new crystalline form of anhydrous β-maltose by ethanol-mediated crystal transformation.

β-Maltose monohydrate was transformed into an anhydrous form by ethanol-mediated method under several temperatures with agitation. A new stable anhydrous form of β-maltose (Mβ(s)) was obtained, as substantiated by the X-ray diffraction patterns. Mβ(s) obtained by this method presented a fine porous structure, resulting in greater specific surface area compared to those of β-maltose monohydrate and anhydrous β-maltose obtained by vacuum drying (Mβ(h)).

Metabolic profiles in children during fasting.

Background: Hypoglycemia is one of the most common metabolic derangements in childhood. To establish the cause of hypoglycemia, fasting tolerance tests can be used. Currently available reference values for fasting tolerance tests have limitations in their use in daily practice.

Is there still a place for arthrodesis in the surgical treatment of basal joint osteoarthritis of the thumb?

Despite the obvious success of arthroplasty trapeziectomy with or without interposition and prosthesis--in the treatment for trapeziometacarpal osteoarthritis, one may question the value of an arthrodesis in particular situations. In most reported series the outcome is reasonably successful, but when comparing the results of arthrodesis with arthroplasty, there is convincing evidence that the latter gives better outcomes. Considering the overall complication rate, and more specifically the incidence of nonunion after trapeziometacarpal fusion, it can be reasonably concluded that the latter should be reserved for specific indications.

Reduced brain choline in homocystinuria due to remethylation defects.

Objective: To investigate whether secondary impairment of the transmethylation pathway is a mechanism underlying the neurologic involvement in homocystinuria due to remethylation defects.

Methods: Twelve patients with neurologic disease due to remethylation defects were examined by brain magnetic resonance spectroscopic imaging ((1)H MRSI). Brain N-acetylaspartate, choline-containing compounds (Cho), and creatine (Cr) were quantified and compared to with controls.

High-pressure injection injury of the hand: an often underestimated trauma: case report with study of the literature.

The real extent of damage in high-pressure injection injuries (grease gun injuries, paint gun injuries, pressure gun in juries) is hidden behind a small and frequently painless punctiform skin lesion on the finger or the hand. These kinds of injuries require prompt surgical intervention with surgical debridement of all ischemic tissue. Possibility of a general intoxication by the fluid must always be ruled out.

Detection of transaldolase deficiency by quantification of novel seven-carbon chain carbohydrate biomarkers in urine.

Transaldolase deficiency, a recently discovered disorder of carbohydrate metabolism with multisystem involvement, has been diagnosed in 6 patients. Affected patients have abnormal concentrations of polyols in body fluids and in all patients we have previously found increased amounts of a seven-carbon chain carbohydrate which we suspected of being sedoheptulose. We report development of a liquid chromatography-tandem mass spectrometry method for quantitation of the seven-carbon carbohydrates sedoheptulose and mannoheptulose in urine.

L-2-hydroxyglutaric aciduria: characterisation of the molecular defect in a spontaneous canine model.

l-2-hydroxyglutaric aciduria (l-2-HGA) is a neurometabolic disorder that produces a variety of clinical neurological deficits, including psychomotor retardation, seizures and ataxia. The biochemical hallmark of l-2-HGA is the accumulation of l-2-hydroxyglutaric acid (l-2-HG) in cerebrospinal fluid, plasma and urine. Mutations within the gene L2HGDH (Entrez Gene ID 79944) on chromosome 14q22 encoding L-2-hydroxyglutaric acid dehydrogenase have recently been shown to cause l-2-HGA in humans.

Global developmental delay in guanidionacetate methyltransferase deficiency: differences in formal testing and clinical observation.

Guanidinoacetate N-methyltransferase (GAMT) deficiency is a defect in the biosynthesis of creatine (Cr). So far, reports have not focused on the description of developmental abilities in this disorder. Here, we present the result of formal testing of developmental abilities in a GAMT-deficient patient.

Guanidinoacetate methyltransferase deficiency masquerading as a mitochondrial encephalopathy.

Guanidinoacetate methyltransferase (GAMT) deficiency is a rare disorder of creatine synthesis. We report a patient who presented at 10 months of age with hypotonia and global developmental delay. Subsequently, she developed seizures and choreoathetosis.