Elevation of hypothalamic neuropeptide Y-neurons in adult offspring of diabetic mother rats

We recently reported on an elevation of neurons expressing the main orexigenic peptide neuropeptide Y (NPY) in the arcuate hypothalamic nucleus (ARC) of neonatally hyperinsulinaemic offspring of gestational diabetic mother rats (GD) at weaning. To investigate possible consequences, the long-term outcome of those animals was examined. At adult age, GD offspring showed hyperphagia (p < 0.001), basal hyperinsulinaemia (p < 0.05) and impaired glucose tolerance (p < 0.05), and were overweight (p < 0.01). This was accompanied by an elevated number of NPY neurons (p < 0.001) and galanin neurons (p < 0.001) in the ARC in adult GD offspring under basal conditions. These findings support our hypothesis on perinatally acquired, persisting malformation and/or malprogramming of peptidergic hypothalamic neurons in the offspring of GD mothers, possibly promoting the development of overweight and diabetogenic disturbances during life.     

Expression of BCL-2 oncoprotein on tumor cells and tumor-infiltrating lymphocytes (TIL) in meningiomas

The Expression of the antiapoptotic oncoprotein BCL-2 and its correlation to tumor grade in 62 meningiomas (48 classic, 9 atypical, and 5 anaplastic) using single and double immunohistochemistry was investigated. BCL-2 expression was found in two different cell populations identified as lymphocytes (BCL-2+CD3+) and tumor cells (BCL+/CD3–). Tumor-infiltrating lymphocytes (TIL) (CD3+) were found within classic (9.5% of cells), atypical (2.4% of cells), and anaplastic (1.8% of cells) meningiomas. In classic meningiomas, 66.5% of TIL were BCL-2-positive, in atypical meningiomas 79.2%, and in anaplastic meningiomas 37.9%. In 33 (68.8%) of the classic meningiomas, medium to high counts of BCL-2+ tumor cells were detected. Atypical meningiomas showed nearly equal percentages of high (two patients), medium (five patients), and low (two patients) BCL-2+ tumor cell counts, whereas anaplastic meningiomas showed only medium (two patients) and low (three patients) BCL-2 tumor cell counts or were BCL-2-negative (one patient). In summary, a significant inverse correlation between the number of BCL-2-positive tumor cells and tumor grade in meningiomas was found. These findings support the hypothesis of cell survival prolongation by the antiapoptotic ability of BCL-2 proto- oncogenes and demonstrate the prognostic relevance of BCL-2 immunoreactivity in meningiomas. Received: 10 June 1998 / Accepted: 23 February 1999     

Nitric oxide-independent inhibitory effects of L-arginine analog NG-monomethy-L-arginine on the generation of interleukin-2 activated cytotoxic activity in humans

Nitric oxide (NO) derived intracellularly from L-arginine (Arg) is indispensable for optimalgeneration of lymphokine-activated killer (LAK) cell activity in rodents. Still unclear, however, is its role in humans. To address this question human peripheral blood mononuclear cells (PBMC) from healthy donors were cultured in L-arginine free medium supplemented with recombinant interleukin-2 (rIL-2) and in the presence of exogenous L-arginine analog NG-monomethyl-L-arginine (NMMA), a specific inhibitor of the NO synthetic pathway. Cultured PBMC were tested for cytotoxic activity, proliferative capacity, and expression of phenotypic and activation markers (CD3, CD4, CD8, CD16, CD56 and CD25). Culture supernatants were assayed for nitrite (NO2-) and tumor necrosis factor-alpha (TNF-alpha) production. We found that NMMA inhibits the generation of optimal LAK cell activity when no exogenous Arg is supplied. Similar effects were also observed on proliferation, expression of IL-2 receptor induced upon rIL-2 stimulation and on TNF-alpha production. Sodium nitroprusside (SNP), used as a source of exogenous NO could not overcome this effect of NMMA on LAK cell activity. NO2- production was virtually undetectable in culture supernatants. Thus, NMMA affects in an NO-independent manner rlL-2 induced LAK activity in human PBMC.     

Evidence for preferential repair of 3-carbethoxypsoralen plus UVA induced DNA lesions in the active MAT{alpha} locus in Saccharomyces cerevisiae using the UvrABC assay

The occurrence of preferential repair in Saccharomyces cerevisiaeof the active MAT locus compared with the inactive HML locuswas confirmed after 254 nm UV irradiation. Experiments carriedout using the UvrABC excinuclease assay with the monofunctionalfurocoumarin 3-carbethoxypsoralen (3-CPs) plus UVA radiationwhich induce mainly monoadducts in DNA demonstrated preferentialrepair of the active MAT locus compared with the inactive HMLlocus in a SIR⁺ strain. However, as after 254 nm UV irradiation,no difference in the rate of removal of 3-CPs plus UVA inducedlesions was observed between the two loci in the sir-3 mutantin which both loci are active. Thus, it appears that 3-CPs plusUVA induced monoadducts as well as pyrimidine dinners a e subjectto preferential repair. ³To whom correspondence should be addressed     

A case of phenobarbital exacerbation of a preexisting maladaptive behavior partially suppressed by chlorpromazine and misinterpreted as chlorpromazine efficacy.

An adult female with developmental disability was prescribed chlorpromazine for the target behaviors of aggression and self-injurious behavior (SIB), and she was prescribed phenobarbital for seizures. Upon a chlorpromazine minimal effective dose reduction, target behaviors increased and dosage was returned to prior levels with the conclusion that chlorpromazine was controlling the target behaviors. Upon subsequent reduction and discontinuation of phenobarbital, however, chlorpromazine was able to be reduced with no increase in target behaviors. Ten years of behavioral data are presented to support the hypothesis that phenobarbital was exacerbating maladaptive behaviors. Given tardive dyskinesia (TD), clinicians and interdisciplinary teams should remain alert to the following client profile: (1) prescribed phenobarbital (or primidone), (2) prescribed neuroleptics, especially at high dosages, to control maladaptive behaviors, (3) failure of neuroleptic gradual minimal effective dose attempts, and (4) possible presence of behavioral procedures, especially intrusive procedures, to control maladaptive behaviors. This profile should trigger a "red flag" as to the possibility of phenobarbital behavioral side effects or exacerbation of preexisting maladaptive behaviors.     

The pharmacokinetics of high-dose medroxyprogesterone acetate (MPA) in the therapy of advanced breast cancer

Summary Oral MPA 1.5 g/day leads to plasma concentrations between 1 and 12 g/ml, with a broad intra-and interindividual variance. The plateau state is reached in between 4 and 16 days. Plasma concentrations in the plateau state are very sensitive to dose modifications. After cessation of administration, the decline in plasma levels seems to proceed in two phases, with half-times of about 20 h and 4 days. Extraction procedures reveal no benefit in discriminating between MPA and its metabolites.     

Combined endovascular therapy of ruptured aneurysms and cerebral vasospasm

We describe two patients with subarachnoid haemorrhage due to a ruptured intracranial aneurysm and severe symptomatic vasospasm. The aneurysm was occluded with detachable coils followed by intra-arterial infusion of papaverine to treat vasospasm as an one-stage procedure. There was significant resolution of the vasospasm. The long-term clinical outcome in one patient was excellent, the other still has minor deficits. Combined endovascular aneurysm therapy followed by intra-arterial spasmolysis with papaverine is a technically feasable therapeutic alternative in patients with symptomatic vasospasm. Received: 5 November 1999/Accepted: 12 July 2000