Protein C concentrate prevents peripartum thrombosis.

A protein C deficient woman, with a past history of recurrent thrombosis and purpura fulminans, was successfully treated with protein C concentrate in the peripartum period. © 1992 Wiley-Liss, Inc.     

A rare polymorphism affects a mitogen-activated protein kinase site in synapsin III: possible relationship to schizophrenia.

BACKGROUND: Synapsin III plays a role in neuronal plasticity and maps to chromosome 22q12-13, a region suggested to be linked to schizophrenia. To determine if synapsin III plays a role in this disease, we searched for polymorphisms in this gene in patients with schizophrenia and controls. METHODS: The synapsin III gene was initially sequenced from 10 individuals with schizophrenia to identify polymorphisms. Association analysis was then performed using 118 individuals with schizophrenia and 330 population controls. Synapsin III expression was studied by immunoblot analyses, and phosphorylation sites were mapped by sequencing trypsin-digested synapsin III fragments phosphorylated with phosphorus-32. RESULTS: A rare, missense polymorphism, S470N, was identified in the synapsin III gene and appeared more frequently in individuals with schizophrenia than in controls (p =.0048). The site affected by the polymorphism, Ser470, was determined to be a substrate for mitogen-activated protein kinase, a downstream effector of neurotrophin action. Phosphorylation at Ser470 was increased during neonatal development and in response to neurotrophin-3 in cultured hippocampal neurons. CONCLUSIONS: Our observations suggest an association of a rare polymorphism in synapsin III with schizophrenia, but further studies will be required to clarify its role in this disease.     

PRKCG mutation (SCA-14) causing a Ramsay Hunt phenotype.

Progressive myoclonic ataxia, also referred to as Ramsay Hunt syndrome, is characterized by a combination of myoclonus and cerebellar ataxia, infrequently accompanied by tonic-clonic seizures. Its differential diagnosis overlaps with progressive myoclonic epilepsy, a syndrome with myoclonus, tonic-clonic seizures, progressive ataxia and dementia. In patients with progressive myoclonic epilepsy, specific diseases can frequently be recognized, but the diagnostic yield in progressive myoclonic ataxia is much lower. We describe a patient who presented with multifocal myoclonus in his thirties and who later developed cerebellar ataxia and focal dystonia. His father was similarly affected. Genetic studies revealed a mutation in the protein kinase C gamma (PRKCG) gene, known to cause spinocerebellar ataxia type 14 (SCA-14). This case illustrates that both myoclonus and dystonia are part of the clinical spectrum in SCA-14 and that myoclonus can even be the presenting symptom. We suggest that SCA-14 should be considered in the differential diagnosis of progressive myoclonic ataxia.     

Pharmacokinetics of orally administered hexobarbital in plasma and saliva of healthy subjects

Hexobarbital (HB) concentrations were determined in plasma and saliva of 8 healthy subjects, following oral administration of 500 mg HB-Na. Mean plasma half-lives were 3.2 +/- 0.1 h, and salivary half-lives 3.3 +/- 0.2 h. Mean plasma clearance was 22.9 +/- 2.3 1 h-1. There was a linear relationship between HB concentrations in saliva and plasma (r = 0.92). Mean salivary levels were 34 per cent of plasma levels. Salivary pH was constant throughout the experiment, 7.06 +/- 0.09. There was an inconsistent tendency of the saliva over plasma ratios to increase as a function of time. The percentage of protein binding calculated from saliva over plasma ratios was in reasonable agreement with in vitro data of equilibrium dialysis, 64.1 +/- 2.6 per cent and 65.9 +/- 0.8 per cent, respectively. The experiment was repeated in 4 subjects, and considerable intraindividual differences were shown to exist in saliva over plasma ratio, half-lives, and protein binding. It was concluded that HB elimination half-lives can relatively accurately be determined from salivary concentrations. Oral plasma clearance can only be estimated if the individual saliva over plasma ratios are known; this would require the taking of at least one blood sample during the experiment. When employing HB as a model substrate for drug metabolizing enzyme activity in vivo, the determination of its pharmacokinetic parameters, particularly oral plasma clearance as a reflection of cytochrome P-450 activity, cannot be achieved by taking saliva samples only.     

Plasma protein binding of furosemide in the elderly

Summary The protein binding of furosemide was investigated in plasma from 22 old and 11 young subjects by equilibrium dialysis. The unbound fraction of furosemide was 3.16% in plasma from the elderly and 1.71% in plasma from the young. A significant correlation was found between the unbound fraction of furosemide and the plasma concentration of albumin. The average number of binding sites was 3.8 (elderly) and 2.7 (young) 10^–6 mol/g albumin. The average association constant (K) was 4.3 (elderly) and 4.2 (young) 10⁵ M^–1. By increasing the concentration of furosemide up to 200 µg/ml buffer the unbound fraction of the drug rose to 5.2% (elderly) and 3.5% (young).     

Neurogenous hyperplasia leading to appendiceal obliteration: an immunohistochemical study of 237 cases

A series of 237 appendices was studied immunohistochemically for neurogenous hyperplasia. This was observed in 195 cases. It was possible to trace a continuum from appendices with intact lumens, featuring intramucosal neurogenous hyperplasia often with co-existent submucosal and muscular nerve growth, to obliterated specimens whose axial portions were composed of varying proportions of nerve tangles and fibrous tissue. Predominantly fibrotic specimens were considered as end-stages of this process. Stromal, argyrophilic cells lying amidst the nerve elements were prominent in the early, non-obliterated cases; their number decreased in the obliterated nerve rich specimens and such cells became inapparent in the late fibrotic stage. Repeated minimal subclinical attacks of inflammation are thought to trigger this lesion.     

Light microscopy of GTP-binding protein (Go) immunoreactivity within the retina of different vertebrates

To examine species differences in the distribution pattern of guanosine triphosphate (GTP)-binding protein (Go) within the vertebrate retina, paraffin-embedded retinae from a number of vertebrate species, including the goldfish, frog, turtle, chicken, monkey, and human, were immunohistochemically stained with affinity-purified antibody against the alpha-subunit of Go. Go-immunoreactive products were found to be located in the neuropil, but not in the cell bodies of neurons, in the retina of all these species. However, some species differences were observed. In the frog, monkey and human, the inner plexiform layer (IPL) was homogeneously stained with this antibody, but in the goldfish, turtle and chicken, the IPL was heterogeneously stained. In the frog, chicken, turtle and human, the outer plexiform layer (OPL) was densely stained with this antibody, but in the goldfish and monkey, the OPL was rather faintly immunoreactive to the antibody. In the goldfish, monkey and human, the outer nuclear layer (ONL) was not immunoreactive to the Go-antibody, whereas in the frog, turtle and chicken, the ONL was immunoreactive to it. The implications of these species differences in Go localization in the vertebrate retina are discussed.     

Coronavirus induced primary demyelination: indications for the involvement of a humoral immune response

Coronavirus MHV-JHM infection of rodents can result in demyelinating encephalomyelitis. We analysed histological changes induced by coronavirus MHV-JHM infection in Lewis rats. Besides an acute disease (AE), chronic panencephalitis (CPE) and subacute demyelinating encephalomyelitis (SDE) were induced. These disease types were differentiated by the incubation period, the localization of lesions, the type of tissue damage and distribution of virus antigen. In AE and CPE, virus antigen was detected in neurons, astrocytes and oligodendrocytes, whereas in SDE neurons lacked virus antigen. Viral nucleocapsid protein (N) was present in the cytoplasm and the spike protein (S) was displayed on the surface of infected neural cells. However, expression of S protein relative to N protein was severely impaired in SDE lesions. Quantitative analysis of infiltrating inflammatory cells revealed that the number of macrophages and T cells were similar in lesions of AE, CPE and SDE. In contrast to that, SDE lesions contained a significantly higher number of IgG + B cells and plasma cells. In addition active demyelinating SDE lesions displayed an enhanced IgG content and deposits of complement C9. These results indicate that virus induced primary demyelination could be a consequence of antibody mediated cytotoxicity. Furthermore, a reduction in the number of cells producing spike protein in the chronic forms of the disease indicates down-regulation of this protein, possibly mediated by anti-S antibodies.     

Competitive dissociation of encephalitogenic complexes between antigen presenting cells and myelin basic protein

Splenic T cells from myelin basic protein (MBP)-immunised Lewis rats were activated to transfer experimental autoimmune encephalomyelitis (EAE) by co-culture with MBP-pulsed lymphoid dendritic cells (DC). MBP-pulsed DC could be kept for at least 24 h at 37 degrees C in antigen-free medium without affecting their ability subsequently to activate encephalitogenic T cells. However, MBP-pulsed DC were rendered much less stimulatory after a 6 h, but not 2 h, secondary incubation with ovalbumin. Thus, although encephalitogenic complexes between MBP and DC appear very stable in the absence of competing antigens, in their presence, antigen exchange can take place over a period of a few hours; this has positive implications for therapy of EAE by antigen competition.