Induction of Leydig cell adenomas by ammonium perfluorooctanoate: a possible endocrine-related mechanism.

Ammonium perfluorooctanoate (C8) produced an increased incidence of Leydig cell adenomas in Crl:CD BR (CD) rats fed 300 ppm for 2 years. A hormonal (nongenotoxic) mechanism was examined since C8 was negative in short-term tests for genotoxicity. Adult male CD rats were gavaged with either 0, 1, 10, 25, or 50 mg/kg C8 for 14 days. In addition, a control group was pair-fed to the 50 mg/kg C8 group. A dose-dependent decrease in body and relative accessory sex organ (ASO) weights was seen, with the relative ASO weights of the 50 mg/kg group significantly less than those of the pair-fed control. Serum estradiol levels were elevated in the 10, 25, and 50 mg/kg C8-treated animals. Estradiol levels in the 50 mg/kg C8 group were 2.7-fold greater than those in the pair-fed control. The increase in serum estradiol levels occurred at the same dose levels as the increase in hepatic beta-oxidation activity. A statistically significant downward trend with dose was seen in serum testosterone levels when compared with the ad libitum control. However, when the 50 mg/kg C8-treated rats were compared with their pair-fed control, no significant differences were seen. Challenge experiments, which can identify the presence and location of a lesion in an endocrine axis, were undertaken to clarify the significance of this downward trend in serum testosterone following C8 exposure. In the challenge experiments, adult CD rats were gavaged with either 0 or 50 mg/kg C8 for 14 days. One hour before termination, rats received either a human chorionic gonadotropin (hCG), gonadotropin-releasing hormone (GnRH), or naloxone challenge. Following hCG challenge, serum testosterone levels in the 50 mg/kg C8 were significantly decreased (50%) from those in the ad libitum controls. Similar decreases, although not significant, were seen in serum testosterone following GnRH and naloxone challenge. The challenge experiments suggest that the decrease in serum testosterone following C8 exposure is due to a lesion at the level of the testis. In addition, progesterone, 17 alpha-hydroxyprogesterone, and androstenedione were examined in the 50 mg/kg C8-treated males following hCG challenge. A 60% decrease was observed in androstenedione levels in the C8-treated animals from those in the ad libitum controls; no other differences were seen. These data suggest that the decrease in serum testosterone following hCG challenge may be due to a decrease in the conversion of 17 alpha-hydroxyprogesterone to androstenedione. The observed effects described above can be attributed to the elevated serum estradiol levels.(ABSTRACT TRUNCATED AT 400 WORDS)     

Indomethacin increases the effect of isosorbide dinitrate on cerebral hemodynamic in migraine patients: pathogenetic and therapeutic implications

Intracerebral vascular reactivity induced by the nitric oxide (NO) donor isosorbide dinitrate (IDN, 5 mg sublingually) is more major and longer-lasting in migraine patients who develop delayed headache in response to the drug. The headache is purportedly due to neuronally-mediated vascular mechanisms. Indomethacin inhibits prostaglandin synthesis, which is involved in NO generation. Indomethacin also decreases cerebral blood flow by constricting precapillary resistance vessels. In the present study, the hemodynamic effects of indomethacin were evaluated in migraine patients and healthy controls by means of transcranial Doppler monitoring. Indomethacin caused a significant decrease in mean flow velocity in the middle cerebral artery. This was an additional effect to the mean velocity decrease induced by IDN. The interactions between the two drugs suggest that their effects on cerebral hemodynamics (and pain) may be of relevance both in understanding the role of NO in migraine pathogenesis and in evaluating symptomatic treatments for migraine attacks.     

Combination of ABO blood group incompatibility and glucose-6-phosphate dehydrogenase deficiency: effect on hemolysis and neonatal hyperbilirubinemia

The incidence (%) of hyperbilirubinemia (serum bilirubin ≥257 μmol/l) was similar in neonates with a combination of ABO incompatibility and glucose-6-phosphate dehydrogenase (G-6-PD) deficiency (45%), with ABO incompatibility (54%) or G-6-PD deficiency (37%), alone (ns). Carboxyhemoglobin values, corrected for inspired CO, were similarly elevated in all three groups (0.87 ± 0.32%, 0.82 ± 0.29%, 0.76 ± 0.18%, respectively, ns), but correlated with bilirubin only in those with ABO incompatibility alone. ABO-incompatible/G-6-PD-deficient neonates, compared with those with either condition alone, are not at increased risk for hemolysis or hyperbilirubinemia.     

A critical review of adult health maintenance: Part 4. Prevention of metabolic, behavioral, and miscellaneous conditions

This is the last article in a four-part series that presents an updated protocol for selective longitudinal health maintenance of asymptomatic adults. Nine metabolic, behavioral, and miscellaneous conditions are reviewed with reference to six generally accepted screening criteria. A recommendation is made for each condition and is compared, when appropriate, with the recommendations of the Canadian Task Force on the Periodic Health Examination. The recommendations for all 30 conditions reviewed in this four-part series are combined into a practical health maintenance flow sheet for use by primary care physicians.     

Comparison of the fertilizing capability of spermatozoa from ejaculates, epididymal aspirates and testicular biopsies using intracytoplasmic sperm injection

A prospective study was carried out to compare the fertilizing capability and pregnancy outcome following intracytoplasmic sperm injection (ICSI) using spermatozoa obtained from ejaculates, or surgically from epididymis or seminiferous tubules. A total of 77 ICSI cycles (one per patient) was included. In all, 28 patients had severe oligoasthenoteratozoospermia, 19 patients had obstructive azoospermia and 30 patients had non-obstructive azoospermia. The main outcome measures were fertilization rate per injected metaphase II oocyte and the clinical pregnancy rate per embryo transferred back to the female recipients. In patients with severe oligoasthenoteratozoospermia, the fertilization and pregnancy rates were 79 and 25 %. In patients with obstructive azoospermia, for whom epididymal spermatozoa were used, these were 75 and 28%, and in the non-obstructive group for which testicular spermatozoa were used for injection, they were 69 and 21% respectively. These rates were not significantly different in the three groups (P = 0.85 and P = 0.14 respectively), suggesting that spermatozoa from the ejaculates and epididymal or testicular biopsies are able to fertilize equally by using ICSI. Live birth per embryo transfer was significantly reduced in patients with non-obstructive azoospermia compared to the other two groups. The high abortion rate (50%) in the group in which testicular spermatozoa were used raises doubts about the developmental competence of such embryos.      

Characterization of the human jumonji gene

While constructing a cDNA library of human embryos, we have isolated a clone homologous to jumonji, a mouse gene required for neural tube formation. We have determined the complete coding sequence of the human homologue (JMJ) and deduced the amino acid sequence of the putative protein. We show here that human and mouse jumonji putative proteins are homologous and present 90% identity. During human embryogenesis, JMJ mRNAs are predominantly expressed in neurons and particularly in dorsal root ganglion cells. They are also expressed in neurons of human adult cerebral cortex. In view of these observations, we propose JMJ as a candidate gene for developmental defects of the central nervous system in the human. The human JMJ gene maps at position 6p24-6p23.