Cross-National Burden of Painful Diabetic Peripheral Neuropathy in Asia, Latin America, and the Middle East

The burden of painful diabetic peripheral neuropathy (DPN) is a common complication of diabetes. This study expanded on the human burden of painful DPN by quantifying functional and health status impairments among international patients from a randomized, double-blind, placebo-controlled trial of painful DPN. Evaluated outcomes measures included: Brief Pain Inventory-Short Form (mBPI-sf), EuroQOL 5D, Hospital Anxiety and Depression Scale, and Medical Outcomes Study Sleep Scale. Outcomes were stratified by pain severity using cut-points: 0 to 10 numeric rating scale (NRS) for average pain (0 to 3: none/mild, 4 to 6: moderate, 7 to 10: severe). Study sample is: 401 patients (163 in Asia, 110 in Latin America and 128 in the Middle East), mostly female (61%) (± standard deviation, SD), age of 57 ± 10 years. Participants reported at least moderate levels of pain severity (mean [± SD] scores on a 0 to 10 NRS for average pain of 5.9 ± 1.8 for Asia, 6.7 ± 1.6 for Latin America, and 6.6 ± 1.7 for the Middle East).
Mean (± SD) values on the mBPI-sf Pain Interference Index were 4.7 ± 2.3 for Asia, 5.6 ± 2.1 for Latin America, and 5.5 ± 2.3 for the Middle East. Patients in all 3 regions reported difficulties with functioning, sleep, and overall health status, which increased with higher pain severity levels. Patients in Asia had substantial impairments; however, they reported less serious problems than the other regions. These data are consistent with painful DPN being a burdensome condition worldwide: people with poorly managed neuropathic pain report a substantial burden of disease.     

Block of HERG Potassium Channels by the Antihistamine Astemizole and its Metabolites Desmethylastemizole and Norastemizole

INTRODUCTION: The selective H1-receptor antagonist astemizole (Hismanal) causes acquired long QT syndrome. Astemizole blocks the rapidly activating delayed rectifier K+ current I(Kr) and the human ether-a go-go-related gene (HERG) K+ channels that underlie it. Astemizole also is rapidly metabolized. The principal metabolite is desmethylastemizole, which retains H1-receptor antagonist properties, has a long elimination time of 9 to 13 days, and its steady-state serum concentration exceeds that of astemizole by more than 30-fold. A second metabolite is norastemizole, which appears in serum in low concentrations following astemizole ingestion and has undergone development as a new antihistamine drug. Our objective in the present work was to study the effects of desmethylastemizole, norastemizole, and astemizole on HERG K+ channels. METHODS AND RESULTS: HERG channels were expressed in a mammalian (HEK 293) cell line and studied using the patch clamp technique. Desmethylastemizole and astemizole blocked HERG current with similar concentration dependence (half-maximal block of 1.0 and 0.9 nM, respectively) and block was use dependent. Norastemizole also blocked HERG current; however, block was incomplete and required higher drug concentrations (half-maximal block of 27.7 nM). CONCLUSIONS: Desmethylastemizole and astemizole cause equipotent block of HERG channels, and these are among the most potent HERG channel antagonists yet studied. Because desmethylastemizole becomes the dominant compound in serum, these findings support the postulate that it becomes the principal cause of long QT syndrome observed in patients following astemizole ingestion. Norastemizole block of HERG channels is weaker; thus, the risk of producing ventricular arrhythmias may be lower. These findings underscore the potential roles of some H1-receptor antagonist metabolites as K+ channel antagonists.     

GABRB2 association with schizophrenia: commonalities and differences between ethnic groups and clinical subtypes.

BACKGROUND: Single nucleotide polymorphisms (SNPs) and haplotypes in intron 8 of type A gamma-aminobutyric acid (GABA(A)) receptor beta2 subunit gene (GABRB2) were initially found to be associated with schizophrenia in Chinese. This finding was subjected to cross-validation in this study with Japanese (JP) and German Caucasian (GE) subjects. METHODS: Single nucleotide polymorphisms discovery and genotyping were carried out through resequencing of a 1839 base pair (bp) region in GABRB2. Tagging SNPs (tSNPs) were selected based on linkage disequilibrium (LD), combinations of which were analyzed with Bonferroni correction and permutation for disease association. Random resampling was applied to generate size- and gender-balanced cases and control subjects. RESULTS: Out of the 17 SNPs (9.2/kilobase [kb]) revealed, 6 were population-specific. Population variations in LD were observable, and at least two low LD points were identified in both populations. Although disease association at single SNP level was only shown in GE, strong association was demonstrated in both JP (p = .0002 - .0191) and GE (p = .0033 - .0410) subjects, centering on haplotypes containing rs1816072 and rs1816071. Among different clinical subtypes, the most significant association was exhibited by systematic schizophrenia. CONCLUSIONS: Cross-population validation of GABRB2 association with schizophrenia has been obtained with JP and GE subjects, with the genotype-disease correlations being strongest in systematic schizophrenia, the most severe subtype of the disease.     

Loss of protein kinase C inhibition in the β-T594M variant of the amiloride-sensitive Na+ channel

We previously reported the presence of a novel variant (β-T594M) of the amiloride-sensitive Na⁺ channel (ASSC) in which the threonine residue at position 594 in the β-subunit has been replaced by a methionine residue. Electrophysiological studies of the ASSC on Epstein–Barr virus (EBV)-transformed lymphocytes carrying this variant showed that the 8-(4-chlorophenylthio) adenosine 3′:5′-cyclic monophosphate (8cpt-cAMP)-induced responses were enhanced when compared to wild-type EBV-transformed lymphocytes. Furthermore, in wild-type EBV-transformed cells, the 8cpt-cAMP-induced response was totally blocked by the phorbol ester, phorbol 12-myristate 13-acetate (PMA). This inhibitory effect of PMA was blocked by a protein kinase C inhibitor, chelerythrine. We now have identified individuals who are homozygous for this variant, and showed that PMA had no effect on the 8cpt-cAMP-induced responses in the EBV-transformed lymphocytes from such individuals. Cells heterozygous for this variant showed mixed responses to PMA, with the majority of cells partially inhibited by PMA. Our results demonstrate that an alteration in a single amino acid residue in the β-subunit of the ASSC can lead to a total loss of inhibition to PMA, and establish the β-subunit as having an important role in conferring a regulatory effect on the ASSC of lymphocytes.     

The Association of Fibrinopeptide A with Cardiac Events Following Coronary Angioplasty

Rethrombosis may be a major determinant of poor outcome after angioplasty. Fibrinopeptide A, a marker of thrombin activity, was measured in 79 patients after coronary angioplasty to assess for association with subsequent cardiac events. Fibrinopeptide A levels were drawn postangioplasty on heparin and prior to discharge off heparin. Levels greater than 2.0 ng/mL were considered elevated. During 6-month follow-up, recurrence of stenosis occurred in 14 out of 51 patients (27%) with elevated levels, requiring repeat angioplasty or bypass surgery. One more patient showed angiographic evidence of recurrence (at least 30% increase in stenosis) not severe enough to require revascularization. Fibrinopeptide A was elevated in this patient. There were three late cardiac deaths and one acute myocardial infarction, all in patients with elevated fibrinopeptide A. An additional five patients had an abnormal stress test without subsequent cathe-terization to assess recurrences; four of them had elevated fibrinopeptide A. In total, there were 22 out of 51 patients (43%) with elevated fibrinopeptide A levels with adverse outcomes, as compared with 6 out of 28 (21%) with normal levels (P = 0.05). Thus, an elevated fibrinopeptide A early after angioplasty may be a marker for a group at greater risk for restenosis.     

MORPHOLOGIC OBSERVATIONS ON THE DERMAL NERVES IN VITILIGO: AN ULTRASTRUCTURAL STUDY

Background. Vitiligo is a common idiopathic skin disorder. The etiology is unknown, although various hypotheses have been advanced. These include the neuronal hypothesis, where neuronal factors are thought to play a role in the pathogenesis of this disease. Methods. Skin biopsies were taken from marginal and central parts of four vitiligo patients. Biopsies were also taken from nonvitiliginous skin of each patient and from four normal control subjects. Sections were examined under the electron-microscope. Nerve fibers in the superficial dermis were examined. Results. Subtle ultrastructural changes, including regeneration and degeneration, were consistently found in dermal nerves of vitiligo lesions. The most consistent feature, seen in all four vitiligo patients studied (in both lesional and marginal areas), was an increased thickness of the basement membrane of Schwann cells. This change was found in approximately three-quarters of all dermal nerves in vitiligo biopsies, but in only about one-quarter of dermal nerves in normal control skin. About half the abnormal dermal nerves in vitiligo skin showed minor axonal damage, although indicators of regeneration (increased mitochondria and rough endoplasmic reticulum) predominated. The dermal nerves in vitiligo showed no difference in fiber diameter or fiber density in comparison with controls. Conclusions. In vitiligo both axonal degeneration and nerve regeneration may occur, with the latter possibly being a reactive change to earlier axonal damage. These findings support the hypothesis that there is a neuronal component to this disease.