Glucose-induced alterations in nerve metabolism: current perspective on the pathogenesis of diabetic neuropathy and future directions for research and therapy

Recent animal and in vitro studies have identified several interrelated metabolic abnormalities in diabetic nerve that are attributable to elevated ambient glucose concentrations. In combination, these metabolic changes may induce a variety of biochemical and biophysical alterations in peripheral nerve that are highly relevant to the pathogenesis of diabetic neuropathy. This article reviews the current status of several of these metabolic defects and describes ways in which their interaction could lead to pathogenetically important changes in nerve metabolism, function, and structure. Areas of related future research are also discussed.     

In vivo and in vitro binding of C4 molecules on red cells: a correlation of numbers of molecules and agglutination

The fourth component of human complement (C4) is one that is essential to the antibody-mediated classical activation pathway. C4d, present on all normal and most patient red cells (RBCs), may be detected by the human antisera anti-Rodgers (Rg) and -Chido (Ch). A study has been made of the Rg/Ch antigens on normal and patient RBCs in an attempt to understand the mechanism by which C4 is bound to normal RBCs in the absence of RBC antibodies (Abs). Because RBCs from C1q-deficient patients express Rg/Ch, it seems that C1q is not essential for C4 binding. Treatment of normal RBCs with proteolytic enzymes, including trypsin, eliminated positive reactions with anti-Rg/Ch even though the C4d fragment is considered to be resistant to cleavage by trypsin. By correlating agglutination reactions with numbers of bound C4d and C3d molecules, it is evident that both C4d and C3d were affected by trypsin treatment and that anti-Rg/Ch were not capable of agglutinating RBCs with less than 50 molecules of bound C4d. It is concluded that trypsin-sensitive and -insensitive RBC membrane structures may both act as acceptors for C4. RBCs with null phenotypes of the major blood group systems all expressed Rg/Ch antigens, so none of the structures that carry these antigens act preferentially as acceptors for C4.     

Transcutaneous implantation of an internal cardioverter defibrillator in a small infant with recurrent myocardial ischemia and cardiac arrest simulating sudden infant death syndrome

This report describes the implantation of a transcutaneous ICD system using a small patch electrode in the subscapular position, and an active-can device in a 5.3-kg infant. The indication for ICD implantation was recurrent cardiac arrest in the presence of normal coronary anatomy. Metabolic evaluation suggested a defect in fatty acid oxidation.     

Co-internalization of the p55 and p70 subunits of the high-affinity human interleukin 2 receptor. Evidence for a stable ternary receptor complex

The high-affinity IL-2-R complex is composed of at least two distinct IL-2-binding subunits, including p55 (Tac, IL-2-R alpha) and p70 (IL-2-R beta). Using a radiolabeled mAb specific for the p55 receptor subunit and cells expressing a homogeneous population of high-affinity binding sites, we demonstrate that p55 is co-internalized with p70 after IL-2 binding to the receptor complex. Endocytosis of p55 depends upon the presence of IL-2 in a form capable of effectively interacting with the p70 subunit. Whether IL-2 is required for high-affinity receptor assembly or triggering of the internalization of preassembled receptors remains unresolved. Together, these findings support the existence of a stable, high-affinity human IL-2-R membrane complex composed of at least the p55 and p70 receptor subunits and IL-2.     

Identification and characterization of teicoplanin-intermediate Staphylococcus aureus blood culture isolates in NE Scotland

The study objective was to screen both methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) isolates from blood cultures for reduced susceptibility to vancomycin and teicoplanin. A total of 72 MRSA and 143 MSSA isolates were screened on brain-heart infusion agar containing either 4 mg/L vancomycin or 8 mg/L teicoplanin, using an inoculum of approximately 10(6) organisms. MICs were determined by Etest, broth microdilution and agar incorporation. Isolates were characterized by PFGE, mecA and nuc PCR, transmission electron microscopy (TEM) and analysis of cell proteins (proteomics). Based on British Society for Antimicrobial Chemotherapy (BSAC) breakpoints, seven MRSAs and seven MSSAs were teicoplanin resistant, with MICs of up to 16 and 24 mg/L respectively, but were vancomycin sensitive. Based on higher NCCLS breakpoints, five MRSAs and six MSSAs were teicoplanin intermediate, vancomycin sensitive. All the MRSAs belonged to the EMRSA-16 clone and subdivided into two groups. The MSSAs belonged to five different clones. TEM showed the resistant variants to have slightly thicker cell walls than sensitive variants. Most notably, the resistant variants possessed characteristic dark, granular material concentrated in the middle of the cells, believed to be chromosome. Proteomics showed the resistant variants to overexpress phosphoglycerate kinase. Both MRSA and MSSA with reduced teicoplanin susceptibility may remain vancomycin sensitive by NCCLS and BSAC criteria and it is important to screen clinical isolates of MRSA and MSSA for reduced susceptibility to both agents.     

Functional and phenotypic comparison of human T cell leukemia/lymphoma virus positive adult T cell leukemia with human T cell leukemia/lymphoma virus negative Sézary leukemia, and their distinction using anti-Tac. Monoclonal antibody identifying the human receptor for T cell growth factor.

Adult T cell leukemia (ATL) and Sézary leukemia are malignant proliferations of T lymphocytes that share similar cell morphology and clinical features. ATL is associated with HTLV (human T cell leukemia/lymphoma virus), a unique human type C retrovirus, whereas most patients with the Sézary syndrome do not have antibodies to this virus. Leukemic cells of both groups were of the T3, T4-positive, T8-negative phenotype. Despite the similar phenotype, HTLV-negative Sézary leukemic cells frequently functioned as helper cells, whereas some HTLV-positive ATL and HTLV-positive Sézary cells appeared to function as suppressors of immunoglobulin synthesis. One can distinguish the HTLV-positive from the HTLV-negative leukemias using a monoclonal antibody (anti-Tac) that appears to identify the human receptor for T cell growth factor (TCGF). Resting normal T cells and most HTLV-negative Sézary cells were Tac-negative, whereas all ATL cell populations were Tac-positive. The observation that ATL cells manifest TCGF receptors suggests the possibility that an abnormality of the TCGF-TCGF receptor system may partially explain the uncontrolled growth of these cells.     

Prognostic value of surfactant proteins A and D in patients with acute lung injury

OBJECTIVE: The primary objective of this study was to test the hypothesis that in patients intubated for acute lung injury, lower concentrations of surfactant proteins A and D in the pulmonary edema fluid and higher concentrations in the plasma are associated with more severe lung injury and worse clinical outcomes. DESIGN: Observational study. SETTING: Intensive care unit patients in a tertiary university hospital and a university-affiliated city hospital. PATIENTS: Thirty-eight intubated, mechanically ventilated intensive care unit patients with acute lung injury or acute respiratory distress syndrome as defined by the North American European Consensus Conference. INTERVENTIONS: Undiluted pulmonary edema fluid and plasma samples were collected within 24 hrs of endotracheal intubation in all patients. MEASUREMENTS AND MAIN RESULTS: The concentrations of surfactant proteins A and D were measured in pulmonary edema fluid and in plasma. Plasma surfactant protein A, but not surfactant protein D, was higher in patients with fewer days of unassisted ventilation (p = .03) and in patients with an absence of intact alveolar fluid clearance (p =.03). In contrast, pulmonary edema fluid surfactant protein D, but not surfactant protein A, was lower in patients with worse oxygenation, as measured by the alveolar-arterial oxygen difference (p = .01) and was lower in the patients who died (2646 ng/mL) compared with those who survived (5503 ng/mL; p = .02). CONCLUSIONS: These results demonstrate that reduced pulmonary edema fluid surfactant protein D and elevated plasma surfactant protein A concentrations at the onset of acute lung injury may be associated with more severe disease and worse clinical outcome and may serve as valuable biochemical markers of prognosis.     

Primary preventive and secondary interventionary effects of acetyl-L-carnitine on diabetic neuropathy in the bio-breeding Worcester rat.

The abnormalities underlying diabetic neuropathy appear to be multiple and involve metabolic neuronal and vasomediated defects. The accumulation of long-chain fatty acids and impaired beta-oxidation due to deficiencies in carnitine and/or its esterified derivatives, such as acetyl-L-carnitine, may have deleterious effects. In the present study, we examined, in the diabetic bio-breeding Worcester rat, the short- and long-term effects of acetyl-L-carnitine administration on peripheral nerve polyols, myoinositol, Na+/K+ -ATPase, vasoactive prostaglandins, nerve conduction velocity, and pathologic changes. Short-term prevention (4 mo) with acetyl-L-carnitine had no effects on nerve polyols, but corrected the Na+/K+ -ATPase defect and was associated with 63% prevention of the nerve conduction defect and complete prevention of structural changes. Long-term prevention (8 mo) and intervention (from 4 to 8 mo) with acetyl-L-carnitine treatment normalized nerve PGE(1) whereas 6-keto PGF(1-alpha) and PGE(2) were unaffected. In the prevention study, the conduction defect was 73% prevented and structural abnormalities attenuated. Intervention with acetyl-L-carnitine resulted in 76% recovery of the conduction defect and corrected neuropathologic changes characteristic of 4-mo diabetic rats. Acetyl-L-carnitine treatment promoted nerve fiber regeneration, which was increased two-fold compared to nontreated diabetic rats. These results demonstrate that acetyl-L-carnitine has a preventive effect on the acute Na+/- K+_ATPase defect and a preventive and corrective effect on PGE1 in chronically diabetic nerve associated with improvements of nerve conduction velocity and pathologic changes.     

In vitro pharmacology of ICI 198,615: a novel, potent and selective peptide leukotriene antagonist

ICI 198,615 is a representative compound from a new class of peptide leukotriene (LT) receptor antagonists. In isolated guinea pig trachea and parenchymal lung strips, ICI 198,615 demonstrated competitive antagonism of the contractile activity of LTD4 and LTE4 with pA2 values of 10.1 to 9.5, respectively. The compound also appeared to antagonize the contractile activity of LTC4 in guinea pig trachea; however, in the presence of an inhibitor of the metabolism of LTC4 to LTD4, ICI 198, 615 provided a pKB value of 5.3, indicating weak antagonism at the LTC4 receptor. ICI 198,615 was also a potent antagonist of LTC4 and LTD4 in isolated human bronchi and pulmonary veins with pKa values of 9.75 +/- 0.32 to 9.20 +/- 0.24, respectively. When evaluated for activity on a broad variety of non-LT receptors, the compound displayed a minimal selectivity of 6310 and a maximal selectivity of greater than 125,000 for the LTE4 receptor. These in vitro studies indicate that ICI 198,615 is the most potent and selective peptide LT receptor antagonist described to date.