Sympathoadrenal response of postmenopausal women prior and during prolonged administration of estradiol

Objective: Cardiovascular disease seems to increase after the menopause and is thought to be reduced by estrogen replacement therapy. Among the many studies which have tried to define the multifactorial mechanisms of estrogens cardiovascular prevention, very few have focused on their possible modulation of adrenergic activity. In the present study we investigated whether prolonged estradiol replacement via transdermal patches is able to modulate cardiovascular and adrenergic responses to stimuli. Methods: Baseline and responses to a cold stimulus and to the upright position of catecholamines (epinephrine and norepinephrine), heart rate, systolic and diastolic blood pressure were investigated in 15 healthy volunteer postmenopausal women both prior to and after 2 months of treatment with patches rated to deliver 50 μg/day of estradiol. Results: Basal norepinephrine levels (P<0.005), as well as their integrated responses to the cold stimulus (P<0.02) were lower during estradiol. By contrast, responses of norepinephrine to the upright test, as well as basal and responses to stimuli of epinephrine and circulatory parameters were not different before and during estradiol. Conclusions: Estradiol replacement at low doses significantly decreases overall sympathetic output, both in basal conditions and under specific stimuli. These effects whether maintained or magnified in the long term may play a role in the prevention of the postmenopausal cardiovascular risk.     

Sexually stimulating signals of canary (Serinus canaria) songs: evidence for a female-specific auditory representation in the HVc nucleus during the breeding season

During the breeding season under long-day conditions, male canaries sing sexually attractive songs and females respond behaviorally to such songs. This study assessed whether auditory response properties of neurons in nucleus HVc of female and male canaries are tuned to sexually salient song features: special song phrases and canary song segmentation. In sexually receptive female canaries, neurons responded to special song phrases with a decreased spike rate and were sensitive to canary song segmentation. The nonreceptive females showed no clear response to special song phrases. In females on short days, neurons responded to song phrases with an increase in activity. In males on long days, they exhibited phasic responses after the phrase onset, whatever the song phrase and song segmentation. This study demonstrates both a plasticity in relation to females' sexual responsiveness and a sexual dimorphism in the auditory processing performed in the HVc.     

Serum progesterone, estradiol-17beta and testosterone at the time of relapse in patients with epithelial ovarian cancer

Raised levels of steroid hormones may be detected in women with ovarian cancer at the time of diagnosis. The goal of this study was to investigate the levels of progesterone, testosterone and estradiol-17beta in patients with relapsed epithelial ovarian cancer. We studied 52 patients with a histologic diagnosis of ovarian cancer; 46 of 52 patients were affected by epithelial tumors, two patients had sexcord-stromal tumors, one patient had a germ cell tumor and three patients had a metastatic cancer from the bowel. Of 34 patients with disease relapse, none had elevated serum testosterone levels (>1 ng/ml), one patient (2.9%) had an elevated serum progesterone level (>1.24 ng/ml) and two patients (5.9%) had elevated estradiol-17beta levels (>28 pg/ml). The relationship between the three hormone levels at the time of initial treatment and at relapse was tested using the Students's t-test. At the time of initial treatment venous concentrations of progesterone, estradiol-17beta and testosterone were higher and statistically different (p<0.05) from samples obtained at the time of relapse in the same patients. No significant differences were found between patients studied at the time of relapse and the control group. Measurement of progesterone, estradiol-17beta and testosterone is not helpful in detecting disease relapse in patients with epithelial ovarian cancer.     

Variability of 5-HT2C receptor cys23ser polymorphism among European populations and vulnerability to affective disorder

Substantial evidence supports a role for dysfunction of brain serotonergic (5-HT) systems in the pathogenesis of major affective disorder, both unipolar (recurrent major depression) and bipolar.(1) Modification of serotonergic neurotransmission is pivotally implicated in the mechanism of action of antidepressant drugs(2) and also in the action of mood stabilizing agents, particularly lithium carbonate.(3) Accordingly, genes that code for the multiple subtypes of serotonin receptors that have been cloned and are expressed in brain,(4) are strong candidates for a role in the genetic etiology of affective illness. We examined a structural variant of the serotonin 2C (5-HT2C) receptor gene (HTR2C) that gives rise to a cysteine to serine substitution in the N terminal extracellular domain of the receptor protein (cys23ser),(5) in 513 patients with recurrent major depression (MDD-R), 649 patients with bipolar (BP) affective disorder and 901 normal controls. The subjects were drawn from nine European countries participating in the European Collaborative Project on Affective Disorders. There was significant variation in the frequency of the HT2CR ser23 allele among the 10 population groups included in the sample (from 24.6% in Greek control subjects to 9.2% in Scots, chi(2) = 20.9, df 9, P = 0.01). Logistic regression analysis demonstrated that over and above this inter-population variability, there was a significant excess of HT2CR ser23 allele carriers in patients compared to normal controls that was demonstrable for both the MDD (chi(2) = 7.34, df 1, P = 0.006) and BP (chi(2) = 5.45, df 1, P = 0.02) patients. These findings support a possible role for genetically based structural variation in 5-HT2C receptors in the pathogenesis of major affective disorder.     

Acute effect of 3-(4-acetamido)-butyrril-lorazepam (DDS2700) on brain function assessed by PET at rest and during attentive tasks

The aim of this study was to assess, by positron emission tomography (PET), the effect on cerebral functional activity of a new lorazepam-gamma-aminobutyric acid (GABA) conjugate [3-(4-acetamido)-butyrril lorazepam (DDS2700)]. Ten healthy volunteers were studied by PET and [18F]fluoro-deoxy-D-glucose ([18F]FDG) under baseline conditions and following the administration of DDS2700. Regional cerebral blood flow (rCBF) was measured by PET and 15O-water in three additional participants while they performed attentive tasks, before and after drug administration. DDS2700 induced a decrease in the regional cerebral metabolic rate of glucose (rCMRglu) in the thalamus (-17%), cerebellum (-11%) and caudate nucleus (-8%). The observed effects on glucose metabolism were probably related to the subjective sedation and tiredness reported by the participants. During the attentive tasks, rCBF increased in frontal and temporal regions associated with attentional processing of auditory material. These circuits were no longer active after DDS2700 administration, while rCBF increased in cingulate cortex, occipitoparietal regions, pons and cerebellum. These drug-induced activations might be directly related to intervening sleepiness and to the consequent effort in keeping attention focused on the tasks. The effects of DDS2700 on glucose metabolism at rest, and on rCBF during activation conditions, indicate a drug action on cerebral networks involved in alertness, vigilance and attention maintenance. PET assessment by [18F]FDG and water may provide complementary information in pharmacodynamic studies.     

Effect of ring liner and casting ring temperature on the dimension of cast posts

STATEMENT OF PROBLEM: If a post does not fit passively, binding with the radicular tooth structure occurs, possibly increasing the risk for root fracture. Therefore, it is necessary to fabricate slightly undersized cast posts to allow for passive fit and cement placement. Shrinkage of the mold cavity may be a desired effect during the casting of posts. PURPOSE: This study evaluated the influence of: (1) a cellulose ring liner, and (2) a lower casting temperature of the metal ring, on the dimensions of a cast post. MATERIAL AND METHODS: Eighty plastic posts were divided in 4 equal groups (group 1, 815 degrees C, liner; group 2, 815 degrees C, no liner; group 3, 600 degrees C, liner; and group 4, 600 degrees C, no liner), invested in phosphate-bonded investment and cast with a noble alloy. Posts were measured at 2 locations, the tip and base, before and after casting. RESULTS: Investing in a lined metal ring and using a casting ring temperature of 815 degrees C (group 1) resulted in markedly oversized posts (tip: +25.8 microm; base: +20.3 microm). The absence of the cellulose liner in the casting ring (group 2) decreased the expansion of the investment producing slightly oversized castings (tip: +9.75 microm; base: +4.52 microm). Lined rings that were heated to a final temperature of 600 degrees C (group 3) produced posts that were oversized (tip: +16.65 microm; base: +11.05 microm). Final casting ring temperature of 600 degrees C and the absence of a cellulose liner (group 4) resulted in posts slightly undersized (tip: -4.1 microm; base: -2.2 microm). CONCLUSION: The use of 2 casting ring temperatures (815 degrees C or 600 degrees C) and the influence of a ring liner were investigated. Decreasing the casting ring temperature from 815 degrees C to 600 degrees C and the absence of a ring liner significantly decreased the dimensions of a cast post.     

Maternal pulse oximetry perfusion index as a predictor of early adverse respiratory neonatal outcome after elective cesarean delivery.

OBJECTIVE: Evidence suggests increased morbidity, in particular early neonatal respiratory complications, in newborns from elective cesarean section compared with those from vaginal delivery. No reliable maternal predictors of adverse neonatal outcome at elective cesarean section are known. Here, we prospectively tested the hypothesis that a low maternal perfusion index at the baseline phase (i.e., preanesthesia) of the elective cesarean section is a predictor of early adverse neonatal respiratory outcome. DESIGN: Prospective cohort study. SETTING: Operating and delivery rooms of a public health hospital with a tertiary-level neonatal intensive care unit. PATIENTS: Forty-four healthy pregnant women with no known risk factors undergoing elective cesarean section at term gestation. INTERVENTIONS: Elective cesarean section was divided into nine phases. Analysis of pulse oximetry-derived signals (perfusion index, pulse rate, and oximetry) and systolic, diastolic, and differential blood pressure were recorded. Maternal arterial and venous newborn cord blood gas analyses and placental histology were evaluated. MEASUREMENTS AND MAIN RESULTS: Early respiratory complications (transient tachypnea of the newborn, n = 5; respiratory distress syndrome, n = 1) were observed in 13.6% (6 of 44) of the newborns. A maternal perfusion index < or = 1.9 (lower quartile) during the preanesthesia phase of the elective cesarean section was an independent predictor of early adverse neonatal respiratory outcome (odds ratio 68.0, 95% confidence interval 6.02-767.72; p < .0001). CONCLUSIONS: A decreased perfusion index value in the preanesthesia phase of elective cesarean section is a maternal predictor of increased neonatal morbidity and is significantly related to subclinical placental inflammatory disease. These observations suggest the feasibility of a noninvasive pulse oximeter prenatal screening of the high-risk fetus/newborn in elective cesarean section.     

Relationship between 5-fluorouracil disposition, toxicity and dihydropyrimidine dehydrogenase activity in cancer patients

Background:Previous work demonstrated that 5-fluorouracil(5-FU) metabolism is a critical factor for treatment tolerability. Inorder to study the predictivity of pharmacokinetics with respect to theoccurrence of 5-FU toxicity, this study investigates the relationshipbetween the pharmacokinetics of 5-FU and its metabolite5-fluoro-5,6-dihydrouracil (5-FDHU), dihydropyrimidine dehydrogenase(DPD) activity in peripheral blood mononuclear cells (PBMNC) andtreatment tolerability. Patients and methods:Pharmacokinetics and metabolismof 5-FU and activity of DPD in PBMNC were examined in110 colorectal cancer patients given adjuvant 5-FU 370mg/m² plus L-folinic acid 100 mg/m² for five daysevery four weeks. Drug levels were examined by HPLC, while toxicitieswere graded according to WHO criteria. Results:DPD activity in patients with mild toxicities (WHOgrade 1) was 197.22 ± 11.34 pmol of 5-FDHU/min/mg of protein,while in five patients with grade 3–4 gastrointestinal toxicity,DPD ranged from low to normal values (range 31.12–182.37pmol/min/mg of protein). In these patients, 5-FU clearance (CL) waslower (range 14.12–25.17 l/h/m²), and the area underthe curve (AUC) was higher (range 14.70–26.20 h×µg/ml)than those observed in 84 patients with mild toxicities (CL, 56.30± 3.60 l/h/m²; AUC, 7.91 ± 0.44h×µg/ml). The severity of adverse events was associated withincreased 5-FU/5-FDHU AUC ratio and reduced 5-FU CL, while 5-FU and5-FDHU pharmacokinetics were not related to DPD activity. Conclusion:This study shows that DPD activity in PBMNC isunrelated to 5-FU/5-FDHU disposition and patients with severe toxicitydisplay marked pharmacokinetic alterations while a reduction of DPDactivity may not occur.