Velocity recovery cycles of human muscle action potentials in chronic renal failure

To test the hypothesis that muscle fibers are depolarized in patients with chronic renal failure, by measuring velocity recovery cycles of muscle action potentials as indicators of muscle membrane potential.

Excitability properties of mouse motor axons in the mutant SOD1(G93A) model of amyotrophic lateral sclerosis

Non-invasive excitability studies of motor axons in patients with amyotrophic lateral sclerosis (ALS) have revealed a changing pattern of abnormal membrane properties with disease progression, but the heterogeneity of the changes has made it difficult to relate them to pathophysiology. The SOD1(G93A) mouse model of ALS displays more synchronous motoneuron pathology. Multiple excitability measures of caudal and sciatic nerves in mutant and wild-type mice were compared before onset of signs and during disease progression (4-19 weeks), and they were related to changes in muscle fiber histochemistry. Excitability differences indicated a modest membrane depolarization in SOD1(G93A) axons at about the time of symptom onset (8 weeks), possibly due to deficient energy supply. Previously described excitability changes in ALS patients, suggesting altered sodium and potassium conductances, were not seen in the mice. This suggests that those changes relate to features of the human disease that are not well represented in the animal model.

Monospecific high-affinity and complement activating anti-GM1 antibodies are determinants in experimental axonal neuropathy

It has been difficult to replicate consistently the experimental model of axonal Guillain-Barré syndrome (GBS). We immunized rabbits with two lipo-oligosaccharides (LOS1 and LOS2) derived from the same C. jejuni strain and purified in a slightly different way. LOS1 did not contain proteins whereas several proteins were present in LOS2. In spite of a robust anti-GM1 antibody response in all animals the neuropathy developed only in rabbits immunized with LOS1. To explain this discrepancy we investigated fine specificity, affinity and ability to activate the complement of anti-GM1 antibodies. Only rabbits immunized with LOS1 showed monospecific high-affinity antibodies which activated more effectively the complement. Although it is not well understood how monospecific high-affinity antibodies are induced these are crucial for the induction of experimental axonal neuropathy. Only a strict adherence to the protocols demonstrated to be successful may guarantee the reproducibility and increase the confidence in the animal model as a reliable tool for the study of the human axonal GBS.

Improved detection of pulmonary nodules on energy-subtracted chest radiographs with a commercial computer-aided diagnosis software: comparison with human observers

To retrospectively analyze the performance of a commercial computer-aided diagnosis (CAD) software in the detection of pulmonary nodules in original and energy-subtracted (ES) chest radiographs.

Favourable long-term outcome after immediate treatment of neonatal hyperammonemia due to N-acetylglutamate synthase deficiency

INTRODUCTION: N-Acetylglutamate synthase (NAGS) deficiency is a rare urea cycle disorder, which may present in the neonatal period with severe hyperammonemia and marked neurological impairment. CASE REPORT: We report on a Turkish family with a patient who died due to hyperammonemia in the neonatal period. Reduced activity of NAGS and carbamyl phosphate synthetase were found at autopsy. A second child who developed hyperammonemia on the second day of life was immediately treated with arginine hydrochloride, sodium benzoate and protein restriction. After NAGS deficiency was suspected by enzyme analysis, sodium benzoate was replaced by N-carbamylglutamate (NCG). A third child who developed slight hyperammonemia on the third day of life was treated with NCG before enzyme analysis confirmed reduced NAGS activity. Neither of the patients developed hyperammonemia in the following years. After the human NAGS gene was identified, mutation analysis revealed that the older sibling on NCG therapy was homozygous for a 971G>A (W324X) mutation. The parents and the younger sibling were heterozygous. Therapy was continued in the older sibling until now without any adverse effects and favourable neurodevelopment outcome. In the younger sibling, therapy was stopped without any deterioration of urea cycle function. CONCLUSION: NAGS deficiency can be successfully treated with NCG and arginine hydrochloride with favourable outcome. Molecular diagnostic rather than enzyme analysis should be used in patients with suspected NAGS deficiency.

Adult-onset ornithine transcarbamylase (OTC) deficiency unmasked by the Atkins' diet

Late-onset symptoms of urea-cycle disorder may lead to a life-threatening disease which is often undetected. We report the clinical and metabolic manifestations of acute hyperammonemic encephalopathy in a 47-year-old asymptomatic man with ornithine transcarbamylase (OTC) deficiency. The hyperammonemic encephalopathy was unmasked by a high-protein Atkins diet.

Ubiquitylation and SUMOylation of Cardiac Ion Channels

Cardiac ion channels play an essential role in the generation of the action potential of cardiomyocytes. Over the past 15 years, a new field of research called channelopathies has emerged; it regroups all diseases caused by ion channel dysfunction. Investigators have largely determined the physiological roles of cardiac ion channels, but little is known about the molecular determinants of their regulation. Two post-translational mechanisms that are crucial in determining the fate of proteins are ubiquitylation and the SUMOylation pathways, which lead to the degradation and/or regulation of modified proteins. Recently, several groups have investigated the physiological impacts of these mechanisms on the regulation of different classes of cardiac ion channels. The objective of this review is to summarize and briefly discuss these results.

Variable Na(v)1.5 protein expression from the wild-type allele correlates with the penetrance of cardiac conduction disease in the Scn5a(+/-) mouse model

BACKGROUND: Loss-of-function mutations in SCN5A, the gene encoding Na(v)1.5 Na+ channel, are associated with inherited cardiac conduction defects and Brugada syndrome, which both exhibit variable phenotypic penetrance of conduction defects. We investigated the mechanisms of this heterogeneity in a mouse model with heterozygous targeted disruption of Scn5a (Scn5a(+/-) mice) and compared our results to those obtained in patients with loss-of-function mutations in SCN5A. METHODOLOGY/PRINCIPAL FINDINGS: Based on ECG, 10-week-old Scn5a(+/-) mice were divided into 2 subgroups, one displaying severe ventricular conduction defects (QRS interval>18 ms) and one a mild phenotype (QRS< or = 18 ms; QRS in wild-type littermates: 10-18 ms). Phenotypic difference persisted with aging. At 10 weeks, the Na+ channel blocker ajmaline prolonged QRS interval similarly in both groups of Scn5a(+/-) mice. In contrast, in old mice (>53 weeks), ajmaline effect was larger in the severely affected subgroup. These data matched the clinical observations on patients with SCN5A loss-of-function mutations with either severe or mild conduction defects. Ventricular tachycardia developed in 5/10 old severely affected Scn5a(+/-) mice but not in mildly affected ones. Correspondingly, symptomatic SCN5A-mutated Brugada patients had more severe conduction defects than asymptomatic patients. Old severely affected Scn5a(+/-) mice but not mildly affected ones showed extensive cardiac fibrosis. Mildly affected Scn5a(+/-) mice had similar Na(v)1.5 mRNA but higher Na(v)1.5 protein expression, and moderately larger I(Na) current than severely affected Scn5a(+/-) mice. As a consequence, action potential upstroke velocity was more decreased in severely affected Scn5a(+/-) mice than in mildly affected ones. CONCLUSIONS: Scn5a(+/-) mice show similar phenotypic heterogeneity as SCN5A-mutated patients. In Scn5a(+/-) mice, phenotype severity correlates with wild-type Na(v)1.5 protein expression.

Cardiac sodium channel Na(v)1.5 and interacting proteins: Physiology and pathophysiology

The cardiac voltage-gated Na(+) channel Na(v)1.5 generates the cardiac Na(+) current (INa). Mutations in SCN5A, the gene encoding Na(v)1.5, have been linked to many cardiac phenotypes, including the congenital and acquired long QT syndrome, Brugada syndrome, conduction slowing, sick sinus syndrome, atrial fibrillation, and dilated cardiomyopathy. The mutations in SCN5A define a sub-group of Na(v)1.5/SCN5A-related phenotypes among cardiac genetic channelopathies. Several research groups have proposed that Na(v)1.5 may be part of multi-protein complexes composed of Na(v)1.5-interacting proteins which regulate channel expression and function. The genes encoding these regulatory proteins have also been found to be mutated in patients with inherited forms of cardiac arrhythmias. The proteins that associate with Na(v)1.5 may be classified as (1) anchoring/adaptor proteins, (2) enzymes interacting with and modifying the channel, and (3) proteins modulating the biophysical properties of Na(v)1.5 upon binding. The aim of this article is to review these Na(v)1.5 partner proteins and to discuss how they may regulate the channel's biology and function. These recent investigations have revealed that the expression level, cellular localization, and activity of Na(v)1.5 are finely regulated by complex molecular and cellular mechanisms that we are only beginning to understand.

Long-term cell-mediated protein release from calcium phosphate ceramics

Efficient delivery of growth factors from carrier biomaterials depends critically on the release kinetics of the proteins that constitute the carrier. Immobilizing growth factors to calcium phosphate ceramics has been attempted by direct adsorption and usually resulted in a rapid and passive release of the superficially adherent proteins. The insufficient retention of growth factors limited their bioavailability and their efficacy in the treatment of bone regeneration. In this study, a coprecipitation technique of proteins and calcium phosphate was employed to modify the delivery of proteins from biphasic calcium phosphate (BCP) ceramics. To this end, tritium-labeled bovine serum albumin ([(3)H]BSA) was utilized as a model protein to analyze the coprecipitation efficacy and the release kinetics of the protein from the carrier material. Conventional adsorption of [(3)H]BSA resulted in a rapid and passive release of the protein from BCP ceramics, whereas the coprecipitation technique effectively prevented the burst release of [(3)H]BSA. Further analysis of the in vitro kinetics demonstrated a sustained, cell-mediated release of coprecipitated [(3)H]BSA from BCP ceramics induced by resorbing osteoclasts. The coprecipitation technique described herein, achieved a physiologic-like protein release, by incorporating [(3)H]BSA into its respective carriers, rendering it a promising tool in growth factor delivery for bone healing.

Usefulness of a clinical diagnosis of ICU-acquired paresis to predict outcome in patients with SIRS and acute respiratory failure

Neuromuscular abnormalities are common in ICU patients. We aimed to assess the incidence of clinically diagnosed ICU-acquired paresis (ICUAP) and its impact on outcome.

Acute subdural hematoma from ruptured cerebral aneurysm

The combination of ruptured aneurysms with acute subdural hematomas (aSDHs) is a rare presentation. Patients with aSDH associated with aneurysmal bleeding represent a subgroup within the spectrum of aneurysmatic hemorrhage. We summarize the clinical characteristics, diagnostic evaluation, and management of a series of cases presenting with aSDH associated with aneurysmal subarachnoid hemorrhage (SAH).

Intraocular pressure during a very high altitude climb

Reports on intraocular pressure (IOP) changes at high altitudes have provided inconsistent and even conflicting

Effects of combination therapy with verteporfin photodynamic therapy and ranibizumab in patients with age-related macular degeneration

This open-label, prospective, small-scale study investigated the benefits of same-day verteporfin and intravitreal ranibizumab in patients with predominantly classic, minimally classic or occult subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration.