Decreased efficacy of twice-weekly intravaginal dehydroepiandrosterone on vulvovaginal atrophy.

OBJECTIVE: While daily intravaginal administration of 0.50% (6.5 mg) dehydroepiandrosterone (DHEA, prasterone) for 12 weeks has shown clinically and statistically significant effects on moderate to severe (MS) dyspareunia as the most bothersome symptom (MBS), the present study analyzes the effect of a reduced dosing regimen on MBS vaginal dryness. METHOD: Daily intravaginal 0.50% prasterone for 2 weeks followed by twice weekly for 10 weeks versus placebo. RESULTS: Maximal beneficial changes in vaginal parabasal and superficial cells and pH were observed at 2 weeks as observed for intravaginal 10 µg estradiol (E2). This was followed by a decrease or lack of efficacy improvement after switching to twice-weekly dosing. The decrease in percentage of parabasal cells, increase in percentage of superficial cells and decrease in vaginal pH were all highly significant (p < 0.0001 to 0.0002 over placebo) at 12 weeks. In parallel, the statistical significance over placebo (p value) on MBS vaginal dryness at 6 weeks was 0.09 followed by an increase to 0.198 at 12 weeks. For MBS dyspareunia, the p value of 0.008 at 6 weeks was followed by a p value of 0.077 at 12 weeks, thus illustrating a decrease of efficacy at the lower dosing regimen. The improvements of vaginal secretions, color, epithelial integrity and epithelial surface thickness were observed at a p value < 0.01 or 0.05 over placebo at 2 weeks, with a similar or loss of statistical difference compared to placebo at later time intervals. No significant adverse event was observed. Vaginal discharge related to the melting of Witepsol was reported in 1.8% of subjects. CONCLUSION: The present data show that daily dosing with 0.50% DHEA for 2 weeks followed by twice-weekly dosing is a suboptimal treatment of the symptoms/signs of vulvovaginal atrophy resulting from a substantial loss of the efficacy achieved at daily dosing.

Cardiorespiratory fitness modifies the association between dietary fat intake and plasma fatty acids.

OBJECTIVES: To investigate the relation between (1) cardiorespiratory fitness and plasma saturated, monounsaturated and polyunsaturated fatty acids and (2) the interactions between cardiorespiratory fitness, dietary fat intake and plasma fatty acid composition. DESIGN: Cross-sectional analysis. SETTING AND SUBJECTS: The subjects were randomly selected, 127 middle-aged Finnish men participating in the DNASCO exercise intervention study. INTERVENTIONS: Cardiorespiratory fitness was determined spiroergometrically, dietary intake of macro- and micronutrients by 4-day food records and plasma fatty acids by gas chromatography. The subjects were divided into tertiles of aerobic fitness. RESULTS: Differences between fitness tertiles were not observed for dietary intake of total fat, and saturated, monounsaturated or polyunsaturated fatty acids (percent of total energy). In contrast, plasma saturated fatty acids were significantly lower (P <0.01) and polyunsaturated fatty acids significantly higher (P <0.05) in the highest fitness tertile compared to the lowest tertile. Dietary saturated fat intake was positively associated with plasma saturated fatty acids (r=0.342; P <0.05) and inversely with plasma polyunsaturated fatty acids (r=-0.453; P <0.01) only in the lowest fitness tertile. In addition, a positive correlation between body mass index and plasma saturated fatty acids (r=0.516; P <0.01) as well as a negative correlation between body mass index and plasma polyunsaturated fatty acids (r=-0.516; P <0.01) was observed in the lowest tertile solely. CONCLUSION: Different levels in cardiorespiratory fitness are associated with different levels in plasma saturated and polyunsaturated fatty acids and lead to modifications in the association between dietary and plasma fatty acids. These findings can perhaps be explained by a reduced hepatic fatty acid and lipoprotein synthesis as well as by an enhanced muscular lipid utilization, which are commonly seen in those who are physically active and who exhibit a higher level of fitness.

Delayed-onset expulsive choroidal hemorrhage following traumatic globe rupture.

The authors describe a 59-year-old woman who had a traumatic wound rupture 6 months following penetrating keratoplasty. While she was in the pre-operative holding area awaiting surgical repair, hemorrhagic choroidal detachments developed. Digital pressure was initiated on diagnosis of imminent expulsion of intraocular contents and maintained until repair of the wound rupture could be performed. Four months postoperatively, the patient's vision was 20/80 and her central pachymetry was 585 microns. This case demonstrates that a delayed-onset expulsive choroidal hemorrhage may be successfully managed with simple and rapid intervention based on knowledge of the disease process.

Dietary fat composition and human adiposity.

OBJECTIVES: This study was undertaken to investigate the relation between dietary fat composition and adiposity in adult men. SUBJECTS: A sample of 128 male subjects who participated in Phase 2 of the Québec Family Study. DESIGN: The association between adiposity and total dietary fat intake (TFI), saturated fat intake (SFA), monounsaturated fat intake (MUFA) and polyunsaturated fat intake (PUFA) was analyzed in the overall sample. A comparison of body fatness was also performed between consumers of high (4th quartile) and low amounts (1st quartile) of TFI, SFA, MUFA and PUFA. RESULTS: Significant positive correlations were found between the percentage of dietary energy as total fat and body fatness. Men in the upper quartile of TFI displayed significantly more adiposity than those in the lower quartile. Significant differences were also observed when quartiles were established using SFA and MUFA. However, higher intakes of PUFA had no statistical effects on adiposity. CONCLUSION: These results confirm the notion that high fat diets might lead over time to excess body fat deposition. SFA and MUFA intake also seem to be predictors of actual adiposity markers while high PUFA intake seems to exert no effect on these markers.

[Problems caused by anesthesia of patients with severe burns]. / Problèmes posés par l'anesthésie du brûlé grave.

The treatment of severe burns requires repeated and various surgical procedures under general anaesthesias. Requirements differ according to the evolution phase of the burnt lesion. Three first post-traumatic days are marked by a major oedema and a large haemodynamic instability. Hypovolemia during 12 to 24 hours is followed by an hyperkinetic phase. The secondary period can last several weeks to several months before the cutaneous recovery is complete. Septic risk is then major and dénutrition constant. Problems raised by surgery differ according to the type of surgery: early excision of deep bums, bath therapy, skin graft, dressing. These procedures are often haemorrhagic and painful. Thermal status is constantly threatened. This type of pathology interferes with the pharmacology of anaesthetic drugs. Hypoprotidemia and change of protein-binding modify drug kinetics. Continuous use of opiates and sedatives is source of tolerance and tachyphylaxis. The number of acetylcholine receptors is increased, contraindicating the use of depolarizing muscle relaxants and often induces a resistance to the nondepolarizing muscle relaxants. The knowledge of these alteration leads to discuss indications of anaesthetics, analgesics and muscle relaxants most frequently used in these patients. During anaesthesia the positioning of the patient takes into account the surgical needs. Hypothermia prevention is mandatory. Peroperative resuscitation is dominated by maintenance of haemodynamic balance, compensation of hydroelectrolytic and blood losses, treatment of septic complications. Should be the same who has in change the patient in the intensive care unit.

Modulation of 5-HT release in the guinea-pig brain following long-term administration of antidepressant drugs.

1. The aims of the present study were to determine whether long-term 5-hydroxytryptamine (5-HT) reuptake blockade and inhibition of type-A monoamine oxidase (MAO-A) lead to an enhancement of the electrically evoked release of tritum from guinea-pig brain slices preloaded with [3H]-5-HT, and to assess the sensitivity of the terminal 5-HT1D autoreceptor, the alpha 2-adrenoceptor also located on 5-HT terminals, and the 5-HT3 receptor that modulates 5-HT release following these two types of antidepressant treatments. 2. The electrically evoked release of tritium was significantly enhanced following a 21-day treatment with the 5-HT reuptake blocker, paroxetine and the reversible MAO-A inhibitor, befloxatone, in preloaded slices of the hypothalamus, hippocampus and frontal cortex 48 h after removal of the osmotic minipumps used to deliver the drugs. 3. The inhibitory effect of the terminal 5-HT autoreceptor agonist, 5-methoxytryptamine, on the evoked release of tritium was attenuated in slices of the hypothalamus, hippocampus, but not frontal cortex, following the paroxetine treatment. In the befloxatone group, the effectiveness of 5-methoxytryptamine was unaltered in the same brain structures. 4. The sensitivity of the alpha 2-adrenoceptor on 5-HT terminals, assessed using UK 14.304, was attenuated in hypothalamus, hippocampus, but not frontal cortex slices prepared from befloxatone-treated guinea-pigs and preloaded with [3H]-5-HT. The paroxetine treatment did not alter the sensitivity of this alpha 2-adrenoceptor in the hypothalamus. 5. The sensitivity of the alpha 2-adrenoceptor on noradrenaline terminals, also assessed using UK 14.304, was not altered in hippocampus and hypothalamus slices preloaded with [3H]-noradrenaline following the long-term befloxatone treatment. 6. In frontal cortex slices, [3H]-5-HT uptake was no longer significantly attenuated after a 21-day treatment with paroxetine, whereas it was still markedly inhibited in hypothalamus slices. The enhancing effect of paroxetine on the evoked release of [3H]-5-HT in the superfusion medium was no longer evident in frontal cortex slices of the paroxetine group. These data indicate that long-term 5-HT reuptake blockade desensitized the 5-HT transporter in the frontal cortex. 7. The capacity of the 5-HT3 receptor agonist, 2 methyl-5-HT, to enhance the electrically evoked release of tritium was not altered in hypothalamus, hippocampus, and frontal cortex slices prepared from befloxatone-treated guinea-pigs, but was significantly attenuated in the paroxetine group also treated for 21 days. Following a 2-day paroxetine treatment, the enhancing effect of 2-methyl-5-HT on tritium release was unaltered in frontal cortex slices.

5-HT3 receptors which modulate [3H]5-HT release in the guinea pig hypothalamus are not autoreceptors.

The 5-HT3 agonist 2-methyl-5-HT had previously been shown to enhance the electrically evoked release of [3H]5-HT from preloaded slices of the guinea pig brain. In the present study, 2-methyl-5-HT (1 microM) was also found to increase the K+ evoked release of [3H]5-HT from preloaded slices of the guinea pig hypothalamus and this effect was blocked by the selective 5-HT3 antagonist ondansetron. In the presence of tetrodotoxin, the enhancement of the K(+)-evoked release of [3H]5-HT by 2-methyl-5-HT in hypothalamus slices was blocked, thus suggesting that the 5-HT3 receptors mediating this effect are not located directly on 5-HT terminals. In agreement with this, 2-methyl-5-HT did not alter the K(+)-evoked release of [3H]5-HT in a synaptosomal preparation of the same brain structure, even at a concentration 10-fold greater than that used in the slices. Taken together, these data indicate that these facilitatory 5-HT3 receptors are not located on 5-HT terminals in the guinea pig hypothalamus and therefore are not autoreceptors.

Functional characterization of a 5-HT3 receptor which modulates the release of 5-HT in the guinea-pig brain.

1. The aims of the present study were to confirm the modulation by 5-HT3 receptors of the electrically evoked release of tritium from slices preloaded with [3H]-5-HT of guinea-pig frontal cortex, hippocampus and hypothalamus, and to assess their functional role in 5-HT release. 2. The selective 5-HT3 agonist, 2-methyl-5-HT, introduced 8 min before the electrical stimulation, enhanced in a concentration-dependent manner the evoked release of [3H]-5-HT in the three brain regions studied. The 5-HT3 agonists, phenylbiguanide and m-chlorophenyl-biguanide, did not enhance the release of tritium in frontal cortex and hypothalamus slices. 3. In hypothalamus slices, this response was lost when 2-methyl-5-HT was introduced 20 min before the stimulation, thus indicating that these 5-HT3 receptors desensitize rapidly. When 2-methyl-5-HT was added 20-min before the first stimulation period to desensitize the 5-HT3 receptors, removed for 24 min, and then re-introduced 8 min before the second stimulation period, the enhancing effect of 2-methyl-5-HT was restored, thus indicating that these 5-HT3 receptors can rapidly regain normal sensitivity. 4. The enhancing effect of 2-methyl-5-HT was attenuated by the 5-HT3 receptor antagonists m-chloro-phenylpiperazine = quipazine = ondansetron > or = ICS 205-930 = BRL 24924 > MDL 72222 = zacopride. 5. The 5-HT reuptake blocker, paroxetine, enhanced the electrically evoked release of tritium when introduced 8 min before stimulation; this effect of paroxetine was blocked by ICS 205-930, thus indicating that these 5-HT3 receptors can be activated by endogenous 5-HT. 6. In the absence of electrical stimulation, 2-methyl-5-HT (10 microM) produced a marked enhancement of the basal release of [3H]-5-HT which was calcium-dependent and blocked by S-zacopride but not by paroxetine. 7. The enhancing effect of 2-methyl-5-HT was dependent both on the frequency of stimulation, as indicated by the attenuated effect of 120 stimulations delivered at 1 Hz instead of 5 Hz, and on the duration of the stimulation, as indicated by the more pronounced effect of pulses delivered at 5 Hz for 24 s instead of 72 s or 120 s.

Effect of repeated electroconvulsive shocks on serotonergic neurons.

The hypothermia induced by the serotonin (5-HT)1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was attenuated in rats that had received a course of six electroconvulsive shocks (ECS) over a two-week period. The firing activity of dorsal raphe 5-HT neurons, as well as their responsiveness to microiontophoretic applications of 5-HT and 8-OH-DPAT, was unaltered in ECS-treated rats. The electrically evoked overflow of [3H]5-HT from preloaded slices of guinea pig hypothalamus was unchanged after the same ECS treatment. The concentration-effect curves of the 5-HT autoreceptor agonist 5-carboxyamidotryptamine (0.1-100 nM) were similar in slices prepared from control and ECS-treated guinea pigs. In addition, the reduction in the evoked [3H]5-HT overflow obtained by increasing the stimulation frequency from 1 to 5 Hz, which is due to a greater activation of terminal 5-HT autoreceptors at the higher frequency, was not altered by the ECS treatment. The enhancing effects of the 5-HT autoreceptor antagonist methiothepin (0.1-1 microM) and of the 5-HT3 agonist 2-methyl-5-HT (0.1-1 microM) on the evoked [3H]5-HT overflow were unaltered by the ECS treatment. These results thus indicate that repeated ECS attenuates the 8-OH-DPAT-induced hypothermia in rats, as previously reported, but does not affect the firing activity of 5-HT neurons and the sensitivity of their somatodendritic 5-HT1A autoreceptors in the dorsal raphe. The function of 5-HT terminals in the guinea pig hypothalamus was also unaffected by repeated ECS. In conclusion, repeated ECS does not affect the function of 5-HT neurons at the cell body and nerve terminal.

Surgical treatment for a case of postoperative Pseudallescheria boydii endophthalmitis.

Pseudallescheria boydii (P. boydii) is an uncommon ocular pathogen which previously has been identified in only 10 of 905 fungal isolates identified by the Sid Richardson Microbiology Laboratory at the Cullen Eye Institute of Baylor College of Medicine. Furthermore, only one case of postoperative P. boydii endophthalmitis and four cases of endogenous P. boydii endophthalmitis have been reported. Three of the four patients with endogenous endophthalmitis died within 4 weeks of diagnosis. We describe a second case of postoperative endophthalmitis due to this fungus. The infection was successfully eradicated following vitrectomy, corneoscleral resection, and patch graft, in addition to intraocular, topical, and oral antifungal medication. Although in vitro sensitivities are variable, P. boydii is known to be relatively resistant to amphotericin B. This points to the importance of proper cultures and sensitivities when treating cases of suspected fungal endophthalmitis. Unfortunately, the patient's eye became phthisical 6 months following the initial intervention.