Estrogens and brain function

Cognitive decline is well recognized during ageing but is often accelerated in women after menopause. Studies have shown that there are significant gender differences in brain ageing with significantly greater changes in brain structure, function and metabolism between females and males. Estrogens exert protective effects on neuronal cells in culture but the exact underlying mechanism for their neuroprotective effect in humans is not completely understood. Estrogens have been shown to affect the nervous system in many different ways: via binding to estrogen receptors (ERs) but also via multiple pathways. The results of small randomized trials and larger observational studies suggest a beneficial effect of estrogen therapy on cognitive function in symptomatic postmenopausal women. However, the results of the Women's Health Initiative Study (WHIMS) do not support this, at least not in women over the age of 65. Alzheimer's disease (AD) is two to three times more common in women than in men. Based on currently available data, routine therapeutic use of estrogens in women with AD is not justified but it may have a role in the prophylaxis of AD. The existing evidence supports the use of HRT only in women with menopausal symptoms for a few years following menopause.     

Pyogenic granuloma of the oral cavity: comparative study of its clinicopathological and immunohistochemical features

There are two histological types of pyogenic granuloma (PG) of the oral cavity: the lobular capillary hemangioma (LCH) and non-LCH type. The aim of the present study was to examine and compare the clinical features, etiological factors, diameter of vascular elements and immunohistochemical features of LCH and non-LCH histological types of PG to determine whether they are two distinct entities. Thirty cases of LCH and 26 cases of non-LCH PG were retrieved and retrospectively studied. Clinically, LCH PG occurred more frequently (66.4%) as sessile lesion whereas non-LCH PG occurred as pedunculated (77%). Non-LCH PG was associated more frequently (86.4%) with etiological factors. The lobular area of the LCH PG contained a greater number of blood vessels with small luminal diameter than did the central area of non-LCH PG. In the central area of non-LCH PG a significantly greater number of vessels with perivascular mesenchymal cells non-reactive for alpha-smooth muscle actin and muscle-specific actin was present than in the lobular area of LCH PG. The differences found in the present study suggest that the two histological types of PG represent distinct entities.     

Structure--activity relationships in the fungistatic activity against Botrytis cinerea of clovanes modified on ring C

The preparation of clovanes 4, 5, 6, 8, and 9, which bear different levels of oxidation on ring C, is described for the first time. The biotransformation of compounds 5, 6, and 9 by the fungus Botrytis cinerea is investigated, yielding compounds 10, 11, and 12, which are described for the first time, together with compounds 4-6, 8, and 9. The evaluation of the fungistatic activity against B. cinerea of compounds 6, 9, 12, 18, 19, 20, and 21 is reported. Comparison of these results with previously published data shows first that the inclusion of hydroxyl groups on ring C leads to a decrease in the biological activity and, second, that the presence of a 9alpha-hydroxyl group and an alkyl chain at C-2 plays an important role in the fungistatic activity against B. cinerea of compounds with a clovane skeleton.     

The ups and downs of addiction: role of metabotropic glutamate receptors

Drug addiction is characterized by drug-induced positive affect, followed by withdrawal-associated negative affect. Such drug-induced positive and negative affective states provide crucial sources of motivation that drive compulsive drug consumption. Metabotropic glutamate (mGlu) receptors, which are responsible for slow glutamate-mediated neurotransmission, are located throughout limbic and cortical brain regions that are implicated in drug addiction. Emerging evidence indicates that mGlu receptors regulate many behavioral actions of addictive drugs. In particular, group I mGlu receptors play an important role in regulating the reinforcing effects of drugs of abuse. Furthermore, group II mGlu receptors have been implicated in the synaptic adaptations that occur in response to chronic drug exposure and contribute to the aversive behavioral syndrome observed during withdrawal. These findings increase our understanding of the pathological processes that are associated with the development of drug addiction, and might ultimately lead to new therapies for the treatment of this disorder.     

The GABAB receptor agonists baclofen and CGP44532 decreased nicotine self-administration in the rat

Rationale Previous work has indicated a potential role for -aminobutyric acid-B (GABA_B) receptor agonists in treating drug addiction in humans. Specifically, GABA_B receptor agonists decreased cocaine, heroin and nicotine self-administration in rats.Objectives The purpose of the present studies was to extend previous findings by assessing the effects of additional GABA_B receptor agonists on nicotine self-administration and food-maintained responding, under both fixed and progressive ratio schedules in rats.Methods Male Wistar rats were exposed to a progressive ratio schedule where various nicotine doses were made available according to a within-subjects Latin Square design. Additional groups of rats were used to test the effects of the GABA_B receptor agonists baclofen and CGP44532 on nicotine self-administration (0.01 and 0.03 mg/kg per infusion) and food-reinforced responding on fixed and progressive ratio (CGP44532 only) schedules.Results Nicotine maintained stable self-administration under a progressive ratio schedule with a linear dose-response function (r=0.61). Both CGP44532 and (–)baclofen dose-dependently reduced nicotine self-administration on the fixed ratio schedule, and also decreased food-maintained responding at higher doses. Further, CGP44532 decreased breakpoints for nicotine and food at identical doses under the progressive ratio schedule.Conclusion The present data demonstrate that administration of GABA_B receptor agonists decreased intravenous nicotine self-administration under both fixed and progressive ratio schedules of reinforcement, possibly reflecting reduced rewarding effects of nicotine. Both baclofen and CGP44532 exhibited specificity for nicotine- versus food-maintained responding on the fixed ratio schedules but not on the progressive ratio schedule (CGP44532 tested only), indicating the potential usefulness of GABA_B receptor agonists as therapeutics for smoking cessation.     

Massive intravascular hemolysis: a fatal complication of clostridium perfringens septicemia in a patient with acute myeloid leukemia

We describe a fatal case of a 74-year old man with acute myeloid leukemia complicated by massive intravascular hemolysis due to Clostridium perfringens sepsis.     

Conditioned facilitation of brain reward function after repeated cocaine administration

Cocaine lowers brain reward thresholds, reflecting increased brain reward function. The authors investigated whether, similar to acute cocaine administration, cocaine-predictive conditioned stimuli would lower intracranial self-stimulation (ICSS) thresholds. Rats received a saline injection for 5 days, a cocaine injection (10 mg/kg) for 20 consecutive days, then saline for 5 additional days. Thresholds were measured immediately before and 10 min after each injection. The initial 5 saline injections had no effect on thresholds, whereas cocaine significantly lowered thresholds for 20 days. There was no tolerance or sensitization to this effect of cocaine over days. During the last 5 days when cocaine administration was substituted with saline, rats demonstrated a conditioned lowering of thresholds during the 2nd daily ICSS session. These data demonstrate that cocaine-predictive conditioned stimuli induce a conditioned facilitation of brain reward function.     

Hypertension superimposed on type II diabetes in Goto Kakizaki rats induces progressive nephropathy

BACKGROUND: Type II diabetes in the Goto Kakizaki (GK) rats (derived from Wistar rats) is not associated with the development of obesity, hyperlipidemia, hypertension, or pronounced renal functional changes. The aim of this study was to investigate the effect of superimposed hypertension on renal function and morphology under conditions of hyper- and normoglycemia. METHODS: The evolution of biochemical and morphologic renal changes was examined in GK and Wistar rats treated with deoxycorticosterone acetate (DOCA) salt over 24 weeks. RESULTS: Blood pressure was increased from 6 weeks on in GK and Wistar rats with no difference in blood pressure levels between both groups (week 24, 183 +/- 14 mm Hg vs. 191 +/- 13 mm Hg, P = NS, vs. 144 +/- 6 mm Hg in normal controls, P < 0.01). A progressive increase in proteinuria was observed in hypertensive GK rats from 12 weeks on (week 24, 168 +/- 62 mg/day vs. 41 +/- 30 mg/day in hypertensive Wistar rats, P = 0.002). Histologic analysis at weeks 15 and 24 showed progressive glomerulosclerosis in hypertensive GK and Wistar rats (week 24, 13 +/- 4% vs. 8 +/- 1%, P = NS) but not in nonhypertensive GK controls. This was associated with evidence of podocyte damage (de novo desmin expression) in hypertensive as compared to nonhypertensive GK rats (week 24, score 1.4 +/- 0.1 vs. 0.8 +/- 0.1, P < 0.001) while no significant increase was observed in hypertensive vs. nonhypertensive Wistar rats. Tubulointerstitial damage was increased in hypertensive GK as compared to hypertensive Wistar rats (week 24, score 1.5 +/- 0.6 vs. 0.6 +/- 0.3, P = 0.01). By immunohistochemistry, this was associated with an up-regulation of tubulointerstitial type IV collagen as well as alpha-smooth muscle actin (alpha-SMA) expression, macrophage infiltration and cell proliferation in hypertensive GK rats. CONCLUSION: Our data demonstrate that long-standing type II diabetes alone is not sufficient to induce progressive nephropathy unless secondary injurious mechanisms such as hypertension are present. The hypertensive GK rat provides a novel model to investigate the mechanisms involved in diabetic nephropathy.     

Assessment of Sertoli cell functional reserve and its relationship to sperm parameters

Sertoli cell functional reserve was assessed in normozoospermic men and oligozoospermic patients and its prognostic potential was evaluated for patient selection and treatment. For the first objective, three groups of normo-follicle-stimulating hormone (FSH)/normozoospermic fertile men (n:12), normo-FSH/oligozoospermic (n:21) and hyper-FSH/oligozoospermic subfertile men participated in the study whereas for the second objective 24 normo-FSH oligozoospermic patients volunteered for a pilot therapeutic trial. For the first part, high purity (hp) FSH (225 i.u., i.m.), human chorionic gonadotropin (hCG) (1500 i.u., i.m.) or their combination was given separately at weekly intervals, with samplings at 0, 3, 24 and 48 h. For the pilot trial, rec-FSH (150 i.u./48 h, i.m.) or placebo were prescribed for 6 months. The main outcome measures for the study were inhibin-B (inh-B), insulin-like growth factor (IGF)-I, testosterone and oestradiol concentrations and the main sperm parameters. Bolus administration of hp-FSH or hp-FSH/hCG combination in normozoospermic men resulted in a significant rise of inh-B in normozoospermic men (mean +/- SD, basal: 183.8+/-24.2 pg/mL in hp-FSH and 175.2+/-23.5 in hp-FSH/hCG treatment; 48 h: 256.1+/-34.2 and 246.3+/-19.0, respectively, p<0.001 for both). In oligozoospermic groups basal inh-B concentration was lower than in normozoospermic men (normo-FSH: 117.4+/-16.5, hyper-FSH: 81.2+/-19.8, p<0.001 for both) with a post-stimulation increase noted only in normo-FSH patients (hp-FSH 24-h: 132.8+/-19.7, p<0.01; hp-FSH/hCG 0 min: 105.7+/-20.1, 24-h: 119.5+/-20.6, p<0.05). Total sperm number and progressive motility showed significant improvements (p<0.05 for both) after 6 months of rec-FSH treatment in the group of patients with a satisfactory response to hp-FSH stimulation. In conclusion, the basal and reserve activity of Sertoli cells, as judged by inh-B secretion, was higher in normozoospermic than in dyspermic men, with a better therapeutic outcome noted in those patients with an adequate response to hp-FSH stimulation.