Regio entorhinalis in schizophrenia: more evidence for migrational disturbances and suggestions for a new biological hypothesis.

Recently we were able to replicate the original finding of migrational disturbances in the entorhinal cortex (ERC) of schizophrenic patients by measuring the distance of pre-alpha cell clusters to the pial surface. In order to replicate this finding, we performed a detailed analysis of the pre-alpha cell clusters in the ERC in post mortem brains of 22 schizophrenic patients and 15 control subjects. Cluster position relative to gray/white matter boundary were measured and normalized by the widths of the gray matter. In the ERC the pre-alpha cell clusters were situated significantly closer to the gray/white matter junction compared to normal controls (around 30 %, F = 9.52, p = 0.004). No specific effects of sex, age or region of investigation were found. In summary, this is another quantitative replication of pre-alpha cell cluster migrational disturbances in schizophrenia, which are possibly linked to neurobiological abnormalities, e.g. myeloarchitectonic changes. This supports the notion that developmental abnormalities are a core feature of schizophrenia and that the search for candidate genes has to include this aspect, too. However, it is very probable that vulnerability-associated changes - as outlined here - have to be distinguished from disease-related changes.

Lewy body variant of Alzheimer's disease: alpha-synuclein in dystrophic neurites of A beta plaques.

The contribution of alpha-synuclein accumulation in Alzheimer's disease (AD) plaques is currently a matter of scientific debate. In the present study antisera against the N- and C-terminus, the full-length protein and the central so-called non-amyloid component (NAC) domain of the alpha-synuclein protein were used to address this question in brains of cases with typical AD and of cases with the Lewy body (LB) variant of AD. In typical AD cases, none of the antisera revealed evidence for co-accumulation of alpha-synuclein with extracellular A beta peptides in plaques or in dystrophic neurites decorating the plaque core. Interestingly, cases with mixed pathology of the LB variant of AD revealed accumulation of alpha-synuclein in LBs and in dystrophic neurites of A beta plaques.

Evidence for activation of microglia in patients with psychiatric illnesses.

Activation of microglia/macrophages is a key event in response to pathological changes in the CNS. HLA-DR is a valuable immunohistochemical marker that specifically reacts with activated microglia cells. In order to elucidate a potential role of microgliosis in severe psychiatric illnesses, post-mortem frontal cortex and hippocampus of patients with schizophrenia (n = 14) and affective disorder (n = 6) and control specimens (n = 13) were studied. Additionally Alzheimer's disease cases (n = 8) were included as a human model system with typical neurodegenerative alterations and microglia activation. All patient groups revealed subjects with abundant microglia immunostaining (schizophrenia, three patients; affective disorder, one patient; Alzheimer's disease, four patients) in both gray and white matter. This finding provides evidence for distinct neuropathological changes in brains of patients with schizophrenia and affective disorder. The activation of microglia cells, which represent a major part of the brain immune response, may help to unravel the pathophysiological processes in severe psychiatric illnesses.

Alpha-synuclein accumulates in Lewy bodies in Parkinson's disease and dementia with Lewy bodies but not in Alzheimer's disease beta-amyloid plaque cores.

A growing body of evidence suggests that the non-Abeta component of Alzheimer's disease amyloid precursor protein (NACP) or alpha-synuclein contributes to the neurodegenerative processes in Alzheimer's disease (AD), Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In the present study antisera to the N terminus and the NAC domain of the alpha-synuclein protein were employed to elucidate the expression pattern in brains of patients with AD, PD, DLB and control specimen. Alpha-synuclein exhibited an overall punctuate expression profile compatible with a synaptic function. Interestingly, while Lewy bodies were strongly immunoreactive, none of the alpha-synuclein antisera revealed staining in mature beta-amyloid plaques in AD. These observations suggest that alpha-synuclein does not contribute to late neurodegenerative processes in AD brains.

HLA-Dr expression by tumor cells compared with survival in high grade astrocytomas.

Frozen samples from 78 high grade astrocytomas were reacted with a monoclonal antibody directed against HLA-Dr invariant chain. Survival data was obtained for all 78 cases. HLA-Dr was expressed by a proportion of tumor cells in 65/78 (83%). Comparison of the survival of positive and negative cases showed that the difference was not statistically significant (p = 0.4). The relevance of the finding is discussed in the context of the immunoreaction to brain tumors.

Mononuclear cell infiltrate and HLA-Dr expression in intra- and extradural secondary carcinomas.

Frozen sections from 30 secondary carcinomas (22 intra- and 8 extradural) were reacted with a panel of monoclonal antibodies to macrophages, lymphocytes, NK cells and HLA-Dr invariant chain. A moderate number of macrophages was demonstrated in 91% of tumours. CD 8 and CD 4 lymphocytes were detected in smaller numbers in 68% and 28% of tumours respectively. B lymphocytes were present in only one tumour and NK cells were absent. There was no significant difference between the mononuclear cell infiltrate in the intra- and extradural tumours and in respect to the histological tumour type. HLA-Dr antigen was expressed by macrophages in most cases and by tumour cells in 5/22 (22%) (4 adeno and 1 anaplastic carcinoma; of which one adenocarcinoma was extradural and the remaining intradural). The results may represent evidence for a degree of cellular immune response to secondary carcinomas which is independent of the intra- or extradural location of the tumour.

Mononuclear cell infiltrate and HLA-Dr expression in 28 pituitary adenomas.

Frozen sections from 28 pituitary adenomas were reached with a panel of monoclonal antibodies to macrophages, lymphocytes and HLA-Dr invariant chain. A low number of macrophages were demonstrated in all tumors, mainly perivascular. CD8 and CD4 lymphocytes were detected in even smaller numbers in 80% and 14% of tumors respectively. B lymphocytes were present in only 1 case. An occasional NK cell was present in 1/13 cases studied. HLA-Dr antigen was expressed by macrophages in all cases and by tumor cells in 2 growth hormone-producing adenomas/19 adenomas. These findings may represent evidence for a low degree of cellular immune response to pituitary adenomas.

Mononuclear cell infiltrate, HLA-Dr expression and proliferation in 37 acoustic schwannomas.

Frozen sections from 37 schwannomas of the VIII nerve were reacted with a panel of monoclonal antibodies to macrophage, lymphocyte, HLA-Dr invariant chain and nuclear proliferation antigens. A moderate number of macrophages was demonstrated in 96% of tumours. CD8- and CD4-lymphocytes were detected in slightly smaller numbers in up to 87% and 23% of tumours respectively. B-lymphocytes were present in only 2/32 cases and NK-cells were absent from all 16 cases tested. HLA-Dr antigen was expressed by macrophages in most cases and by tumour cells in 13/24 tumours. These findings may represent evidence for a degree of cellular immune response. Occasional cells featuring nuclear proliferation were detected in 15/27 cases.

Intranasal interferon (rIFN-alpha A, Ro 22-8181) for contact prophylaxis against common cold: a randomized, double-blind and placebo-controlled field study.

The prophylactic efficacy of low-dose intranasal recombinant leucocyte interferon alpha (rIFN-alpha A, Ro 22-8181) was investigated under field conditions in 147 families (n = 587 participants), randomized to receive placebo or rIFN-alpha A intranasally in daily doses of 1.5 or 0.3 X 10(6) IU. Treatment was started within 2 days after the appearance of an index case in the household and was continued for 5 days. Clinical data of the index case and of all members of the household were recorded for 10 days. In index cases and all ill contact persons nasal washes were collected for rhinovirus isolation and immunochemical detection of other respiratory viruses. The local tolerance of the intranasal rIFN-alpha A was excellent. Both doses of rIFN-alpha A failed to exert therapeutic effects on established common cold or to prevent the spread of common cold within families. Prophylactic treatment with 1.5 X 10(6) IU did however shorten the duration of the cold (median of 2 days vs. 4 in the placebo group, P = 0.01) and reduced the severity of any ensuing common cold (median total score of 10.5 vs. 30, P less than 0.001). No correlation was found between viral etiology (55% rhinoviruses vs. 13% other respiratory viruses, n = 122 nasal washes) and prophylactic efficacy or clinical severity.

Autoradiographic evidence for penetration of 3H-ceftriaxone (Rocephin) into cells of spleen, liver and kidney of mice.

Ceftriaxone (Rocephin), a broad-spectrum parenteral cephalosporin with an exceptionally long elimination half-life, has a marked activity against both Salmonella typhimurium infections in mice and typhoid fever in man. This study investigates autoradiographically the penetration of ceftriaxone into murine cells of liver, spleen and kidney, with emphasis on the cells of the reticuloendothelial system (RES). The RES is an important site of localization of the pathogenic agent of typhoid fever. An incorporation of ceftriaxone was found in several cell types of the three investigated organs, in particular the cells of the RES and in precursors, e.g. monocytes of the blood stream, Kupffer cells or reticular cells. Besides long biological half-life, satisfactory penetration into phagocytes and other tissue cells has been shown, which is essential to the good in vivo activity of ceftriaxone against systemic Salmonella infections.

One-dose treatment of acute uncomplicated gonorrhoea of male patients with ceftriaxone Ro 13-9904, a new parenteral cephalosporin. A dose-range finding pilot study using doses of 500, 250, 125 and 50 mg respectively, in descending order.

54 adult male patients suffering from acute uncomplicated gonococcal urethritis entered a dose-range trial with a new parenteral cephalosporin, ceftriaxone Ro 13-9904. In order to evaluate the lowest effective dose of a single intramuscular injection of Ro 13-9904, the patients received different doses in descending order: 500 mg for the first group of 10 patients, 250 mg for the second group of 13 patients, 125 mg for the third group of 11 patients and 50 mg for the fourth group of 20 patients. All 34 patients of the first three trial groups were cured clinically and bacteriologically. In the group receiving 50 mg of the cephalosporin, 1 patient was bacteriologically a failure and a second was considered to be a reinfection. 7 further patients of this trial group showed clinical symptoms of urethritis after therapy, but gonococci were eradicated. The systemic and local tolerance of the drug was satisfactory. On the basis of this trial, the lowest effective dose for the eradication of Neisseria gonorrhoeae in male patients with uncomplicated gonorrhoea seems to be a single injection of between 50 and 125 mg of Ro 13-9904.

Phosphonopeptides as antibacterial agents: metabolism and pharmacokinetics of alafosfalin in animals and humans.

The metabolism and pharmacokinetics of a synthetic antibacterial phosphonodipeptide, alafosfalin, have been studied in rats, baboons, and human volunteers. The compound was rapidly absorbed from the injection site after subcutaneous and intramuscular administration and gave peak plasma concentrations at 15 to 20 min after dosing. Distribution studies showed that high drug concentrations were produced in inflammatory exudates and most tissues except brain. Alafosfalin was rapidly cleared from the general circulation, mainly by the kidney. Plasma half-lives were 20 min in rats and approximately 1 h in baboons and humans. Alafosfalin was well absorbed after oral administration, but was extensively hydrolyzed to alanine and L-1-aminoethylphosphonic acid before it reached the general circulation. This first-pass metabolism was less marked in humans than in animals. Administration of 200-mg intramuscular and 500-mg oral doses produced concentrations of intact phosphonodipeptide in human plasma and urine which were in excess of the in vitro minimal inhibitory concentrations for many pathogenic organisms. The rate of absorption and elimination of alafosfalin in humans were also very similar to published data on beta-lactam antibiotics. This suggests that the pharmacokinetics can be matched to provide synergistic combinations for clinical use.