In vivo upregulation of endogenous NGF in the rat brain by the alpha2-adrenoreceptor antagonist dexefaroxan: potential role in the protection of the basalocortical cholinergic system during neurodegeneration.

We have previously reported that the alpha2-adrenoceptor antagonist dexefaroxan protects against the degeneration of nucleus basalis magnocellularis (NbM) cholinergic neurons following cortical devascularization in the adult rat. Since nerve growth factor (NGF) is critical to the survival of NbM cholinergic neurons in the adult brain and its synthesis is known to be regulated by noradrenergic mechanisms, we examined whether the protective effect of dexefaroxan in the devascularization model was associated with regional induction of NGF biosynthesis. Dexefaroxan or vehicle was administered to rats via subcutaneous minipumps for 28 days following devascularization or sham operation procedures. In vehicle-treated devascularized rats, NGF protein levels in the cortex were increased at 5 days but had normalized by 2 weeks postoperation; NGF levels in NbM remained unchanged during this time. In dexefaroxan-treated devascularized rats, increases in NGF protein levels (2-fold) and immunoreactivity were maintained in both the cortex and NbM over the entire 28-day postoperation period; these increases were coincident with changes in functional markers characteristic of NGF's actions, including increases in choline acetyltransferase (ChAT), p75 and TrkA immunoreactivities, and a preservation of NbM cholinergic cell numbers. Dexefaroxan also increased NGF protein levels in sham-operated rats, but without any significant consequence to the otherwise normal NbM cholinergic phenotype in these animals. Results indicate that activation of endogenous NGF systems could contribute to the cholinergic protective effect of dexefaroxan in the cortical devascularization model, and provide further support for a potential therapeutic utility of dexefaroxan in neurodegenerative diseases where central cholinergic function is progressively compromised.

Low peak bone mineral density in healthy Lebanese subjects.

Osteoporosis is a major public health problem in Western countries and is projected to have a similar impact in the Middle East. It has been suggested that peak bone mineral density (BMD), a major determinant of osteoporotic fractures later in life, may be lower in this part of the world compared with the Western world. However, subjects have not been randomly selected or systematically screened to rule out secondary causes of bone loss. The purpose of this study was to determine peak bone mass and lifestyle risk factors for bone loss in a randomly chosen sample of healthy Lebanese subjects from the greater Beirut area. Subjects 25-35 years of age were randomly selected from greater Beirut, which comprises one third of the Lebanese at large, and studied during the Fall of 1999. BMD was measured at the lumbar spine, hip, forearm, and total body. A questionnaire on lifestyle factors was administered to all subjects. Results were compared with the database of subjects from the USA provided by the manufacturer, and to the NHANES database for the total hip. Two hundred thirteen subjects were studied; 45 subjects rotated at all three centers for cross-calibration purposes. Peak BMD in Lebanese subjects was 0.2-0.9 SD below that of peak BMD in American subjects, depending on skeletal site, gender, and densitometer. These differences persisted after attempting to adjust for body size. Osteoporosis and osteopenia were more prevalent than in healthy young Americans. Height, weight, and total body fat were the most significant correlates of BMD/bone mineral content (BMC), accounting for 0.3-0.7 of the variance in bone mass measurement. Lifestyle factors had a very modest but significant contribution to bone mass variance. This is the first population-based study from the Middle East demonstrating that peak BMD is slightly lower in Lebanese subjects compared as with an established database from the USA. Due to the selection of relatively healthier subjects in our study than in the NHANES study, the actual differences between the two populations may be even greater. The impact of our findings on the epidemiology of osteoporotic fractures in Lebanon remains to be determined.

Oxidative and non-oxidative metabolism of 4-iodoanisole by rat liver microsomes.

1. The oxidative metabolism of 4-iodoanisole (1) by liver microsomes from beta-naphthoflavone-treated rats yields 4-iodophenol (2) 2-iodo-5-methoxyphenol (3), 2-methoxy-5-iodophenol (4), 4-methoxyphenol (5), and 3-methoxyphenol (6) in relative yields of 5:2:4:1:1 respectively. 2. [3 5-2H2]-1 was converted to the same five metabolites in the same proportions; formation of 2, 4 and 5 involved no loss of deuterium, but formation of 3 and 6 involved respectively 55 and 28% loss of one deuterium. 3. When metabolism of 1 was carried out in buffers containing D2O or H2(18)O, no incorporation of these isotopes into 2-6 could be detected. Nor was it possible to detect formation of iodinating intermediates derived from 1 by trapping with 2,6-dimethylphenol. 4. The P450-catalysed hydroxylative de-iodination of 1-5 and 6 is suggested to involve C-O bond formation via attack of the ferry moiety on the aromatic ring followed by reductive cleavage of the C-iodine bond, with electrons coming from P450 reductase.

Improvement of spontaneous pregnancy rate after stopping gonadotropin therapy for anovulatory infertility.

In a prospective study, 140 patients with infertility because of ovulatory factors (group A) were followed up for 6 months after failure to achieve pregnancy using human menopausal gonadotropin (hMG) therapy. They included cases of oligomenorrhea, polycystic ovarian disease (PCOD), and hypogonadotropic amenorrhea. They were treated with hMG alone or in combination with clomiphene citrate or gonadotropin-releasing hormone agonist analog. The control group (B) included 83 infertile patients because of similar ovulatory factors. They were followed up for 6 months not preceded by ovulation induction. The overall pregnancy rate (PR) in group A (20.7%) was significantly higher than group B (7.2%). The PR was significantly higher in oligomenorrhea and PCOD patients when compared with the control group. There was no significant difference in the hypogonadotropic group.