Pentacoordinate silicon(IV): cationic, anionic and neutral complexes derived from the reaction of NHC→SiCl4 with highly Lewis acidic (C2F5)2SiH2.

Addition of NHC→SiCl4 to the highly Lewis acidic bis(pentafluoroethyl)silane ((C2F5)2SiH2) afforded the salt [(NHC)2SiCl2H][(C2F5)2SiCl3] with pentacoordinate silicon in the cation and the anion. The anion represents the first example of a chlorosilicate structurally characterized in the solid state. In this reaction, the long sought pentacoordinate NHC-adduct of silicochloroform was identified as an intermediate and its crystal structure is presented.

Frequency of Fabry disease in patients with small-fibre neuropathy of unknown aetiology: a pilot study.

BACKGROUND: Early occurrence of small-fibre neuropathy (SFN) is a common feature of Fabry disease (FD) - an X-linked storage disorder caused by reduced activity of the α-galactosidase A (α-GAL). Although SFN may result from different disorders, the cause is often unclear. Therefore, we investigated the frequency of FD in patients with SFN of unknown aetiology. METHODS: Patients with idiopathic SFN, established by sensory quantitative testing and/or skin biopsy, were examined for mutations in the α-GAL gene. Where mutations in the α-GAL gene were identified, levels of globotriaosylceramide (Gb(3)) were measured in urine and blood and the α-GAL activity was evaluated. When new mutations were detected, a diagnostic work-up was performed as well as a Gb(3) accumulation in the skin, lyso-Gb(3) in blood and Gb(3)_24 in urine were proved. RESULTS: Twenty-four of 29 eligible patients were enrolled in the study. Mutations in the α-GAL gene were observed in five patients. A typical mutation for FD (c.424T>C, [C142R]) was detected in one patient. In four patients, a complex intronic haplotype within the α-GAL gene (IVS0-10C>T [rs2071225], IVS4-16A>G [rs2071397], IVS6-22C>T [rs2071228]) was identified. The relevance of this haplotype in the pathogenesis of FD remains unclear until now. However, these patients showed increased concentrations of Gb(3) and/or lyso-Gb(3), while no further manifestations for FD could be proved. CONCLUSIONS: Fabry disease should be considered in patients with SFN of unknown aetiology, and screening for FD should be included in the diagnostic guidelines for SFN. The significance of the intronic haplotype regarding SFN needs further evaluation.

[Pathophysiology of neuronal injury in bacterial meningitis and experimental adjunctive therapeutic approaches]. / Pathophysiologie des neuronalen Schadens bei bakterieller Meningitis und experimentelle adjuvante Therapieansätze.

In bacterial meningitis, death and long-term neurological sequelae are caused jointly by several factors. Despite highly qualified intensive care and effective antibacterial therapy mortality rates remain high. Beta-lactam antibiotics, currently used for initial therapy of bacterial meningitis, lead to a rapid lysis of bacteria with a consecutive profound release of proinflammatory bacterial cell wall components, causing a substantial burst of meningeal inflammation. The only approved adjunctive therapy so far is corticosteroids. The use of nonbacteriolytic, protein-synthesis inhibiting antibiotics in experimental models of pneumococcal meningitis appeared to be a promising therapeutic approach towards neuroprotection by diminishing the inflammatory process.

[A case of autochthonous early summer meningoencephalitis in Mecklenberg-Western Pomerania]. / Ein Fall einer autochthonen Frühsommermeningoenzephalitis (FSME) in Mecklenburg-Vorpommern.

HISTORY: A 61-year-old man was bitten by a tick at Lake Woblitz, near the town of Neustrelitz in former East Germany. Nine days later he saw his general practitioner because of fever and headache. Three weeks after the tick bite he was hospitalized with fever (39.2 degrees C) and mental confusion. Because he had taken a Nile cruise six months earlier, malaria was considered and he was transferred to the department of tropical medicine and infectious diseases of the University of Rostock. INVESTIGATIONS: The patient was somnolent, his speech was slurred, and he had amnesic aphasia, as well as impaired fine motor control, but no meningism, focal signs, pyramidal tract or sensory impairment. Cerebrospinal fluid (CSF) showed mild lymphocytosis (9,400 leukocytes per microL; 89% lymphocytes) and elevated protein concentration (1322 mg/L) with blood brain barrier impairment and intrathecal IgM synthesis. Anti-tick-bite encephalitis (TBE) antibodies (ELISA: IgG and IgM) were present in serum and CSF, and serum immunofluorescence showed an eight-fold titer increase within two weeks. These findings confirm the diagnosis of TBE. Other infections (including those with cross-reacting flaviviruses) were excluded by appropriate antibody testing. THERAPY AND CLINICAL COURSE: There is no specific antiviral treatment for TBE, but on symptomatic therapy the patient recovered fully within four weeks. CONCLUSION: The site of the patient's infection is located 10 km to the west of an old TBE focus, but no TBE virus had been detected there after 1975. The case demonstrates that TBE should be included in the differential diagnosis of meningoencephalitis, even if the patient has not been in an acknowledged TBE endemic area.

Regional differences in glutamine synthetase inhibition by L-methionine sulfoximine: a microdialysis study in the rabbit brain.

Elevated levels of glutamate, an endogenous excitatory amino acid, contribute to the development of neuronal injury in various cerebral diseases. Using a microdialysis approach, the response of extracellular levels of amino acids and metabolic parameters to glutamine synthetase inhibition by l-methionine sulfoximine was monitored simultaneously in the hippocampal formation and in the frontal cortex of the rabbit brain. In the hippocampal formation the decrease of glutamine levels during l-methionine sulfoximine treatment was more pronounced than in the frontal cortex, and was accompanied by a delayed decline of extracellular glutamate concentrations. Furthermore, l-methionine sulfoximine diminished the increase of lactate and pyruvate concentrations in the hippocampal formation, but not in the frontal cortex. Neither l-methionine sulfoximine treatment nor microdialysis probe insertion caused neuronal apoptosis, as measured by in situ tailing. An impaired function of hippocampal astrocyte glutamate uptake mechanisms or a higher functional capacity of the cortical glutamine synthetase may be possible explanations for the differences demonstrated. The present data are in accordance with regional differences in glutamine synthetase activation during bacterial meningitis and may explain, in part, the higher susceptibility of certain areas of the hippocampal formation (i.e., the dentate gyrus) to neuronal injury.

Gene expression profiling of the nervous system in murine experimental autoimmune encephalomyelitis.

Multiple sclerosis is thought to be a polygenic disease driven by dysregulation of the immune system leading to an autoimmune response against one or several antigens of cerebral white matter tissue. Experimental autoimmune encephalomyelitis (EAE) is a mouse model that is used to study the aetiology and pathogenesis of multiple sclerosis and new therapeutic approaches. We used oligonucleotide microarrays to determine gene expression profiles of the inflamed spinal cords of EAE mice at the onset and at the peak of the disease. Of the approximately 11 000 genes studied, 213 were regulated differentially and 100 showed consistent differential regulation throughout the disease. Inflammation resulted in a profile of increased gene expression of immune-related molecules, extracellular matrix and cell adhesion molecules and molecules involved in cell division and transcription, and differential regulation of molecules involved in signal transduction, protein synthesis and metabolism. Of the 104 genes with defined chromosomal locations, 51 mapped to known EAE-linked quantitative trait loci and as such are putative candidate genes for susceptibility to EAE.

Rifampin reduces production of reactive oxygen species of cerebrospinal fluid phagocytes and hippocampal neuronal apoptosis in experimental Streptococcus pneumoniae meningitis.

Bacterial compounds induce the production of reactive oxygen species (ROS) in meningitis. Rifampin releases smaller quantities of proinflammatory compounds from Streptococcus pneumoniae than do beta-lactam antibiotics. Therefore, rabbits infected intracisternally with S. pneumoniae were treated intravenously either with rifampin 5 mg/kg/h or ceftriaxone 10 mg/kg/h (n=9 each). Before initiation of antibiotic treatment, a strong positive correlation between ROS production of cerebrospinal fluid (CSF) phagocyte populations and bacterial CSF titers was observed (granulocytes: rs=.90, P<.0001; monocytes: rs=.81, P<.0001). CSF leukocytes from rifampin-treated rabbits produced less ROS (monocytes at 2 h after initiation of treatment: P=.045; at 5 h: P=.014; granulocytes at 5 h: P=.036) than did leukocytes from animals receiving ceftriaxone. The CSF malondialdehyde concentrations and the density of apoptotic neurons in the dentate gyrus were lower in rifampin- than in ceftriaxone-treated animals (P=.002 and.005). The use of rifampin to reduce the release of ROS and to decrease secondary brain injury appears promising.

Granulocytes in the subarachnoid space of humans and rabbits with bacterial meningitis undergo apoptosis and are eliminated by macrophages.

The contribution of leukocyte apoptosis to the resolution of meningeal inflammation in bacterial meningitis was studied in the cerebrospinal fluid (CSF) and in meningeal infiltrates of humans and rabbits by in situ tailing, flow cytometry, agarose gel electrophoresis, and electron microscopy. In humans, the rate of apoptotic granulocytes was 21.0+/-20.8% (n=11) in cytocentrifuge preparations and 3.3+/-3.4 (n=14) in putrid infiltrates of autopsy cases (P=0.02). In rabbits, CSF pleocytosis peaked 8 h after the initiation of antibiotic treatment (5311+/-3122/microl). At this time, the rate of apoptotic granulocytes was 15.2+/-7.3% in CSF and 1.8+/-1.4% in the meningeal infiltrates (each group n=6, P=0.007). Thereafter, the rate of apoptotic granulocytes in CSF declined below 10%. In humans and rabbits, bands representing internucleosomal fragments of approximately 180 base pairs and multiples thereof were documented on agarose gels. Phagocytosis of apoptotic granulocytes by macrophages was visualized by light and electron microscopy. In conclusion, during resolution of subarachnoid space inflammation in bacterial meningitis, a substantial fraction of granulocytes undergoes apoptosis. These granulocytes are removed by phagocytosis by macrophages. Apoptosis is more frequent in granulocytes floating in the CSF than in adherent cells.