Inherited neuropathies: Charcot-Marie-Tooth disease and related disorders

Collectively, the inherited disorders of peripheral nerves represent a common group of neurological diseases and are frequently encountered in the clinical setting. Recent advances in molecular genetics have not only provided improved diagnosis and counselling, but may ultimately lead to specific, rational therapies for the various forms of inherited neuropathy. Charcot-Marie-Tooth neuropathy type 1 (CMT1) is a genetically heterogeneous group of chronic demyelinating polyneuropathies with loci mapping to chromosome 17p (CMT1A), chromosome 1q (CMT1B), the X chromosome (CMTX) and to another unknown autosome (CMT1C). CMT1A is most often associated with a tandem 1.5-megabase (Mb) duplication in chromosome 17p11.2-12, or may occasionally result from a point mutation in the peripheral myelin protein 22 (PMP22) gene. CMT1B is associated with point mutations in the myelin protein zero (P0) gene. The molecular defect in CMT1C is unknown. CMTX is associated with defects in the connexin 32 gene. Charcot-Marie-Tooth neuropathy type 2 (CMT2) is an axonal neuropathy, also of undetermined cause. One locus for CMT2 has been assigned for chromosome 1p (CMT2A). Dejerine-Sottas disease is a severe, infantile-onset, demyelinating polyneuropathy which may be associated with point mutations in the P0 or PMP22 genes. Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder that results in a recurrent, episodic demyelinating neuropathy. HNPP is associated with a 1.5-Mb deletion in chromosome 17p11.2-12 and may result from reduced expression of the PMP22 gene. CMT1A and HNPP are apparent reciprocal duplication/deletion syndromes originating from unequal cross-over during germ-cell meiosis.     

The in vivo pharmacological profile of the novel glycoprotein IIb/IIIa antagonist, SK&F 106760

The in vivo pharmacological profile of SK&F 106760 [N alpha-acetyl-cyclo(S,S)-cysteinyl-N alpha-methylarginyl-glycyl-aspartyl-penicillamine-amide], a novel, potent glycoprotein IIb/IIIa (GPIIb/IIIa) antagonist has been investigated. In conscious dogs, SK&F 106760 (0.3-3 mg/kg i.v.) produced a dose-related inhibition of ex vivo whole blood platelet aggregation induced by collagen (5 micrograms/ml) with complete inhibition being produced for 5, 90 and 165 min after administration of 0.3, 1 and 3 mg/kg i.v., respectively. Plasma levels of SK&F 106760 were measured by high-performance liquid chromatography after i.v. bolus administration of 1 mg/kg. An initial alpha-disposition phase with a T1/2 of 11 +/- 6 min was followed by a longer terminal beta-elimination phase with a T1/2 of 66 +/- 12 min, which accounted for 79 +/- 9% of the total area under the plasma concentration-time curve. The apparent steady-state volume of distribution was 259 +/- 26 ml/kg and the plasma clearance was 3.4 +/- 0.8 ml/min/kg. The plasma concentration of SK&F 106760 at which collagen-induced ex vivo whole blood aggregation was inhibited by 50% was estimated to be 593 +/- 52 nM. After intraduodenal and intrajejunal administration of 3 mg/kg, SK&F 106760 had a bioavailability of 3 to 6% and produced a peak inhibition of ex vivo platelet aggregation of 40 to 50%. In anesthetized dogs, SK&F 106760 (0.3-3.0 mg/kg i.v.) produced a complete inhibition of platelet-dependent coronary artery thrombosis, with a dose-related duration of action.(ABSTRACT TRUNCATED AT 250 WORDS)     

Report of the Second Equine Leucocyte Antigen Workshop, Squaw valley, California, July 1995

The final assignment of antibody clusters for leucocyte antigens and immunoglobulins, as described in detail in Sections 3 and 4, is summarized in Table 4. Together with other mAbs developed outside of ELAW II (Table 9) this pool of reagents represent a powerful array of tools for the study of equine immunity. The Second Equine Leucocyte Antigen Workshop made considerable advances in pursuing the objectives of establishing the specificities of mAbs and achieving consensus on the nomenclature for equine leucocyte and immunoglobulin molecules. Of equal importance, several productive collaborations were fostered among the participating laboratories and observers. Overall, enormous advances have been made in the past decade since mAbs specific for equine leucocyte antigens and immunoglobulins were first reported. There remains enormous scope and need for further studies of equine leucocyte antigens and immunoglobulins, both for the purposes of comparative immunology and for the good of the horse. In the future novel techniques will be required to develop reagents for specific target antigens such as the orthologues of the CD25 or CD45 isoforms. In studies of equine immunoglobulins the functional role of the IgG isotypes must be better established, reagents for IgE must be developed, and cloning of the immunoglobulin heavy chain genes will be essential if the complexities of the IgG sub-isotypes are to be elucidated. The tasks still facing the currently small group of equine immunologists throughout the world remain formidable, and will only be tackled successfully in a spirit of collaboration.     

Treatment of hyperhomocysteinemia in renal transplant recipients. A randomized, placebo-controlled trial

BACKGROUND: Stable renal transplant recipients have an excess prevalence of hyperhomocysteinemia, which is a risk factor for arteriosclerosis. OBJECTIVE: To determine the effect of treatment with 1) vitamin B6 or 2) folic acid plus vitamin B12 on fasting and post-methionine-loading plasma total homocysteine levels in renal transplant recipients. DESIGN: Block-randomized, placebo-controlled, 2 x 2 factorial study. SETTING: University-affiliated transplantation program. PATIENTS: 29 clinically stable renal transplant recipients. INTERVENTION: Patients were randomly assigned to one of four regimens: placebo (n = 8); vitamin B6, 50 mg/d (n = 7); folic acid, 5 mg/d, and vitamin B12, 0.4 mg/d (n = 7); or vitamin B6, 50 mg/d, folic acid, 5 mg/d, and vitamin B12, 0.4 mg/d (n = 7). MEASUREMENTS: Fasting and 2-hour post-methionine-loading plasma total homocysteine levels. RESULTS: Vitamin B6 treatment resulted in a 22.1% reduction in geometric-mean post-methionine-loading increases in plasma total homocysteine levels (P = 0.042), and folic acid plus vitamin B12 treatment caused a 26.2% reduction in geometric-mean fasting plasma total homocysteine levels (P = 0.027). These results occurred after adjustment for age; sex; and pretreatment levels of total homocysteine, B vitamins, and creatinine. CONCLUSIONS: Vitamin B6 should be added to the combination of folic acid and vitamin B12 for effective reduction of both post-methionine-loading and fasting plasma total homocysteine levels in renal transplant recipients.     

Tenidap inhibits 5-lipoxygenase product formation in vitro, but this activity is not observed in three animal models

OBJECTIVE AND DESIGN: The effect of tenidap on the metabolism of arachidonic acid via the 5-lipoxygenase (5-LO) pathway was investigated in vitro and in vivo. MATERIALS AND TREATMENT: In vitro (cells). Arachidonic acid (AA) stimulated rat basophilic leukemia, (RBL) cells; A23817 activated neutrophils (human rat, and rabbit), macrophages (rat), and blood (human). In vitro (enzyme activity). RBL-cell homogenate; purified human recombinant 5-LO. In vivo: Rat (Sprague-Dawley) models in which peritoneal leukotriene products were measured after challenge with zymosan (3 animals per group), A23187 (11 animals per group), and immune complexes (3-5 animals per group), respectively. METHODS: 5-Hydroxyeicosatetraenoic acid (5-HETE) and dihydroxyeicosatetraenoic acids (diHETEs, including LTB4) were measured as radiolabeled products (derived from [14C]-AA) or by absorbance at 235 or 280 nm, respectively, after separation by HPLC. Radiolabeled 5-HPETE was measured by a radio-TLC analyser after separation by thin layer chromatography (TLC). Deacylation of membrane bound [14C]-AA was determined by measuring radiolabel released into the extracellular medium. 5-LO translocation from cytosol to membrane was assessed by western analysis. Rat peritoneal fluid was assayed for PGE, 6-keto-PGF1 alpha, LTE4 or LTB4 content by EIA and for TXB2 by RIA. RESULTS: Tenidap suppressed 5-LO mediated product production in cultured rat basophilic leukemia (RBL-1) cells from exogenously supplied AA, and in human and rat neutrophils, and rat peritoneal macrophages stimulated with A23187 (IC50, 5-15 microM). In addition, tenidap was less potent in inhibiting the release of radiolabeled AA from RBL-1 cells (IC50, 180 microM), suggesting that the decrease in 5-LO derived products could not be explained by an effect on cellular mobilization of AA (i.e., phospholipase). Tenidap blocked 5-hydroxyeicosatetraenoic acid (5-HETE) production by dissociated RBL-1 cell preparations (IC50, 7 microM), as well as by a 100000 x g supernatant of 5-LO/hydroperoxidase activity, suggesting a direct effect on the 5-LO enzyme itself. In addition, tenidap impaired 5-LO translocation from cytosol to its membrane-bound docking protein (FLAP) which occurs when human neutrophils are stimulated with calcium ionophore, indicating a second mechanism for inhibiting the 5-LO pathway. Surprisingly, tenidap did not block the binding of radiolabeled MK-0591, an indole ligand of FLAP, to neutrophil membranes. Although its ability to inhibit the cyclooxygenase pathway was readily observed in whole blood and in vivo, tenidap's 5-LO blockade could not be demonstrated by ionophore stimulated human blood, nor after oral dosing in rat models in which peritoneal leukotriene products were measured after challenge with three different stimuli. The presence of extracellular proteins greatly reduced the potency of tenidap as a 5-LO inhibitor in vitro, suggesting that protein binding is responsible for loss of activity in animal models. CONCLUSIONS: Tenidap inhibits 5-lipoxygenase activity in vitro both directly and indirectly by interfering with its translocation from cytosol to the membrane compartment in neutrophils. A potential mechanism for the latter effect is discussed with reference to tenidap's ability to lower intracellular pH. Tenidap did not inhibit 5-LO pathway activity in three animal models.     

Petaops and Exaops: supercomputing on the Web

There are large-scale computation problems that could benefit from the power of the Web. The authors have chosen the year 2007 to set a hardware scenario where petaflops performance could be obtained by a variety of architectures, including an ATM-connected corporate intranet. They classify the kinds of parallelism found in different applications, arguing that the Web has advantages in the expression of general forms of parallelism that make it suitable as the software environment of choice for these applications on all hardware platforms. They conclude by analyzing Web software approaches in some detail, taking an inevitably nearer term perspective. Their purpose is to show how the Web and MPP can be advanced synergistically to solve different problems     

Electron microscopy of surface structures of Blastocystis sp. from different hosts

Samples of Blastocystis sp. obtained from humans, monkeys, pigs and chickens were examined by scanning electron microscopy and transmission electron microscopy to compare surface structures. The surface coat of Blastocystis sp. cells from each host species showed some morphological variations, but these were not sufficiently different to allow judgement to be made on speciation. The surface structure morphology appeared similar for samples of Blastocystis sp. from the same host species. The surface coat of the cultured human isolate of B. hominis was much thinner than that of cells from fresh human faecal material, and the cell surface appeared to be smoother and without the small projections seen in the fresh forms. Bacteria were frequently found in association with the surface coat of Blastocystis sp. from all fresh faecal material. Possible functions of the surface coat, especially in relation to protection against osmotic shock, are discussed.     

1.9-W quasi-CW from a near-diffraction-limited 1.55-μmInGaAsP-InP tapered laser

1.9-W quasi-CW output power with about 80% of the power in the central lobe is obtained from a 1.55-μm wavelength InGaAsP-InP MQW tapered unstable resonator laser. This power is found to be emitted in a near-diffraction-limited beam