Sexual dimorphism in renal ischemia-reperfusion injury in rats: possible role of endothelin

BACKGROUND: Postischemic organ dysfunction is influenced by gender and sexual steroids. METHODS: To compare the susceptibility of the kidney to postischemic failure between sexes, the left vascular pedicle was clamped for 50 minutes in anesthetized male and female Wistar rats. Survival rate, renal and systemic hemodynamics and renal prepro-endothelin (pp-ET) mRNA expression were measured. RESULTS: Eight percent of males as compared to 75% of females survived for more than 7 days. Previous orchidectomy of mature rats or sexual immaturity improved the rate of 7 day survival to 67% and 58%, respectively, as compared to intact males (P < 0.05). Estradiol treatment of mature male animals also resulted in a significantly better survival. Ovariectomy, sexual immaturity or testosterone treatment had no impact on the course of renal failure in females. The early postischemic recovery of renal blood flow was delayed due to a dramatic increase in renal vascular resistance in male versus female rats. The expression of pp-ET gene in the kidneys was increased at 5 minutes following reperfusion and was significantly higher 2 hours after ischemia in males, but not in females. Pretreatment with the endothelin A receptor antagonist LU 135252 provided indistinguishable survival rates in intact male and female rats after warm renal ischemia. CONCLUSION: Female rats enjoy relative protection against postischemic renal failure. Furthermore, in intact males the effects of androgens upon ischemic kidney damage seem to be mediated by endothelin-induced vascular changes.     

Detection of minimal residual diseases in B-cell tumors using PCR specific for the immunoglobulin heavy chain gene

In B-cell non-Hodgkin's lymphomas (NHL), clonal rearrangement of the immunoglobulin heavy chain (IgH) gene provides a useful marker for the detection of minimal residual disease (MRD) after treatment. To explore clinical usefulness of polymerase chain reaction (PCR) analysis of clonal IgH gene rearrangement in the detection of MRD a follow up study of 10 patients with B-cell NHL have been performed. At the time of diagnosis, tumor DNAs were PCR-amplified using sense primer specific for the heavy chain variable region (VH) and antisense primer specific for the heavy chain joining region (JH) of the IgH gene. The clonal rearrangement of IgH gene detected by PCR was used as clonal marker to determine MRD after treatment. In three cases, where clinical remission was not achieved, clonal IgH gene rearrangement was detected after the treatment. In seven cases, clinical remission was achieved after induction therapy but the PCR analysis revealed clonal IgH gene rearrangement in three of the cases. In all of the three cases, where MRD was detected by PCR, clinical relapse developed after 7-28 months of the therapy. In all cases that have relapsed, the IgH gene rearrangement was identical at the time of initial diagnosis and at the relapse. This study demonstrates that PCR analysis of clonal IgH gene rearrangement is a useful method to monitor and detect MRD before clinical relapse.     

Lipid and apolipoprotein levels and enteral nutrition in very low-birth-weight preterm infants

Lipid, lipoprotein cholesterol and apolipoprotein A-I, A-II and B levels were determined in 10 very low-birth-weight (birth weight 1279 ±144 g; gestational age 29.2±1.2 weeks, mean ± SD) preterm infants on postnatal days 3, 10 and 21. Feeding with pooled human milk began on day 3 ± 1 and by day 10 all infants were exclusively enterally fed. Both triglyceride and total cholesterol levels increased significantly from day 3 to day 10 (0.84 ± 0.28 versus 1.53 ± 0.72 and 2.42 ± 0.47 versus 3.24 ± 0.80, mmol/l, respectively) ( p <0.01); thereafter no further increase was observed. The increase in total cholesterol level was primarily due to a significant enhancement of very low-density lipoprotein and low-density lipoprotein cholesterol (1.52±.34 versus 2.29 ± 0.73 mmol/l, p <0.01). Apo A-I, A-II and B levels did not change between day 3 and day 10. From day 10 to day 21, however, a significant increase in apo A-I concentration was noted (0.57±.20 versus 0.87 ± 0.17 g/l, p <0.01), whereas apo A-II levels increased significantly from day 3 to 21 (0.15 ± 0.03 versus 0.27 ± 0.08 g/l, p<0.01). No change in apo B level was seen.     

Acid sphingomyelinase deficiency in Beckwith-Wiedemann syndrome

We report the association of Beckwith-Wiedemann syndrome (BWS) and a residual acid sphingomyelinase (ASM) activity of about 35% in a 23 months old Hungarian boy. Besides the classical triad of exomphalos, macroglossia and gigantism some other BWS-related features: polyhydramnios (known from the praenatal history), hemihypertrophy, craniofacial dysmorphy, a mild mental retardation, bilaterally undescended testes, cardiac anomalies and a terminally developed, fatal embryonal rhabdomyosarcoma were present in the patient. The decreased activity of the ASM was measured in the patient s skin fibroblasts. This result, with hepatomegaly, mental retardation, feeding problems, a failure to thrive and muscle-hypotony, partially resembled the ASM-deficient forms of Niemann-Pick disease (NPD). Morphological analysis of the bone-marrow cells gave normal results. There was no chromosomal alteration found by conventional karyotyping of the patient s lymphocytes.BWS-associated genes as well as the human ASM gene (SMPD1) are all located at 11p15. DNA-studies by region specific markers as well as mutational analysis for the most common NPD-mutations are planned in the future. This is the first report on the simultaneous occurrence of BWS and ASM-deficiency.     

Activation of dihydropyridine-sensitive parotid salivary gland calcium channels by epidermal growth factor.

The calcium channel complex of the parotid was isolated from solubilized acinar-cell membranes by affinity chromatography on wheatgerm agglutinin. The channel, after labelling the calcium antagonist-receptor site with [3H]-PN200-100, was reconstituted into phosphatidylcholine vesicles that exhibited active 45Ca2+ uptake. This uptake was independent of sodium and potassium gradients, indicating its electroneutrality. The channels responded in a dose-dependent manner to the dihydropyridine calcium antagonist, PN200-110, which at 0.4 microM exerted a maximal inhibitory effect of 75% on 45Ca2+ uptake; a 46% enhancement in 45Ca2+ uptake occurred with a specific calcium-channel activator, BAY K8644. On epidermal growth-factor (EGF) binding in the presence of ATP, there was an increase in tyrosine phosphorylation of 55 and 170 kDa calcium-channel proteins. Such phosphorylated channels, after reconstitution into vesicles, displayed a 61% greater 45Ca2+ uptake, indicating the involvement of tyrosine kinase in EGF-dependent activation of the calcium channel. The results point towards the importance of EGF in the regulation of calcium homeostasis in salivary gland.     

EGYT-2509 a novel neuroleptic agent without extrapyramidal and endocrine side effects

The dibenzodioxazocine derivative EGYT-2509 was effective in neuropsychopharmacological tests characteristic for neuroleptics and antiparkinsonian drugs. It interacted with dopaminergic compounds similarly to chlorpromazine and haloperidol, but in certain tests it showed different activity. Similarly to chlorpromazine and haloperidol it inhibited the lethal effect of amphetamine in grouped mice. The apomorphine-induced stereotypy was potentiated by lower, and antagonized by higher doses of EGYT-2509. The compound did not show cataleptogenic activity and even antagonized the catalepsy evoked by bulbocapnine. The in vitro potency of EGYT-2509 to block dopamine-mediated inhibition of prolactin release was weaker by three orders of magnitude than that of haloperidol. In preliminary human studies it did not affect the plasma prolactin level. It is concluded that EGYT-2509 is a new potential antipsychotic agent with minimal risk of extrapyramidal and endocrine side effects.