Gestational carrier BMI and reproductive, fetal and neonatal outcomes: are the risks the same with increasing obesity?

OBJECTIVE: Data suggest that female obesity impairs uterine receptivity and increases the risk of fetal and neonatal mortality. We analyzed the reproductive outcomes of gestational carriers (GCs) undergoing donated oocytes and assisted reproductive technology according to body mass index (BMI). DESIGN: A retrospective analysis of 163 GCs undergoing 226 in vitro fertilization (IVF) and embryo transfer cycles. METHODS: GCs undergoing in vitro fertilization and embryo transfer cycles were analyzed and divided according to their BMI (healthy weight: 20-24.9 kg m(-2) (n=77 in 114 cycles); overweight: 25-29.9 kg m(-)(2) (n=55 in 71 cycles); and obese: 30-35 kg m(-)(2) (n=31 in 41 cycles)). All GCs underwent a complete medical evaluation and were cleared for pregnancy before being selected. Overweight and obese GCs also underwent a metabolic screening, including an oral glucose tolerance test and lipid profile. The main outcomes measured were clinical pregnancy and live birth rates, antenatal and neonatal outcomes. RESULTS: Clinical pregnancy and live birth rates were similar despite increasing BMI. There were no statistically significant differences in the implantation rates, clinical pregnancy rates or live birth rates per embryo transfer among patients in the three BMI groups. In the healthy weight, overweight and obese GCs, the clinical pregnancy rates per GC were 72%, 84% and 79%, and per embryo transfer rates were 52%, 49% and 56%, respectively; P=NS. The live birth rates per GC were 70%, 84% and 75%, and per embryo transfer rates were 50%, 49% and 53%, respectively; P=NS. Twin rates were similar between the groups (35%, 31% and 29%, respectively; P=NS). There were no differences in gestational diabetes, preterm admissions or cesarean section rates. Neonatal intensive care unit admissions were similar (11%, 13% and 12%, respectively; P=NS), and no maternal, neonatal or infant mortality occurred. CONCLUSIONS: These data show that increasing obesity does not impair the reproductive outcome in GC cycles. Larger sample size is indicated to verify these findings. Furthermore, this study suggests that the standard metabolic screening used for GCs may lead to selection of healthier patients compared with women of comparable BMI who conceive outside of a fertility clinic setting, indicating the metabolic profile, rather than BMI, may better explain differences in pregnancy outcomes.

The pharmacologic basis for therapeutic interest in bupropion.

Bupropion, a compound chemically dissimilar to tricyclic antidepressants and monoamine oxidase inhibitors, was found to be active in animal models that are predictive of antidepressant activity in man. Bupropion was also found to be pharmacologically and biochemically distinct from tricyclics and monoamine oxidase inhibitors. Furthermore, it lacked anticholinergic activity, was not sympathomimetic, and was at least 10-fold weaker as a cardiac depressant than the tricyclic antidepressants. It was concluded that bupropion would be better tolerated and safer in man than standard therapies and that its pharmacologic and biochemical profile held out the possibility of novel antidepressant actions.

Studies of bupropion's mechanism of antidepressant activity.

The data obtained in these studies show that the antidepressant activity of bupropion cannot be explained by its ability to inhibit MAO present in brain or to increase the release of biogenic amines from nerve endings, since the drug possesses neither of these properties. It is also unlikely that the weak properties of the drug as an inhibitor of dopamine uptake in brain can explain its antidepressant activity. It is clear, however, that dopamine neurons must be present for the CNS properties of bupropion to be manifested in animal models; at antidepressant doses of the drug, dopamine turnover is reduced in brain. Finally, the antidepressant properties of bupropion have been dissociated from down-regulation of postsynaptic beta-receptors. To our knowledge, bupropion is the first clinically effective antidepressant whose mechanism of action cannot be explained on the basis of alterations in either presynaptic events or postsynaptic receptor-mediated events in catecholamine or serotonin pathways. Thus, bupropion is a novel antidepressant whose mechanism of action must still be elucidated.

Effects of a novel antioxidant during resuscitation from severe blunt chest trauma.

Previous work suggests that neutrophils (PMNs) and/or prostaglandins might mediate the progressive respiratory failure after severe pulmonary contusion. Since reactive oxygen metabolites are closely associated with both these factors, we examined the actions of a novel antioxidant after swine received a unilateral injury followed by 25% hemorrhage. An infusion (2mL/kg/h intravenously x 6 h) of either polynitroxylated 5% Dextran + Tempol (PND, n = 9), 5% Dextran (D, n = 6), or lactated Ringers (LR, n = 13) was begun 60 min post-injury to mimic 'pre-hospital resuscitation.' After 15 min, standard resuscitation was initiated (3x shed blood as LR in 30 min) plus further LR for 6 h to maintain hemodynamics. The total LR requirement was lower with PND (1,772+/-267 mL) versus D (3,040+/-689, P = 0.0563) or LR (4145+/-398, P = 0.0005). The ipsilateral bronchoalveolar lavage (BAL) PMN count with PND (8+/-2 x 10(5)/mL), was not different from its baseline (P = 0.131), but the counts with D (16+/-3) and LR (17+/-4) were both higher than their baselines (P = 0.0184 and 0.0431). Similarly, BAL protein with PND (1,560+/-350 mg %) was not elevated from its baseline (P = 0.0721), but the values with D (2,560+/-498) and LR (2,474+/-899) were both higher than their baselines (P = 0.0169 and 0.0325). In the contralateral (uninjured) lung, the effects were similar, but the increases were less for PMNs (8+/-2 versus 10+/-2 or 14+/-4 x 10(5)/mL) and for protein (609 +/-153 versus 1,955+/-671 or 1486+/-357 mg %). Despite these significant BAL changes, there was no obvious improvement in cardiopulmonary dysfunction. Thus oxidants probably have some role in the pathogenic mechanism of progressive secondary injury after thoracic trauma, but further work is needed to determine the therapeutic potential of antioxidants because no clinical improvement was detected.

Comparison of adinazolam pharmacokinetics and effects in healthy and cirrhotic subjects.

The pharmacokinetics and pharmacodynamics of adinazolam were investigated in six patients with cirrhosis and six sex-matched control subjects. These subjects received a single 30-mg oral dose of adinazolam mesylate. Serial blood samples were collected for 24 hours after drug administration. Plasma was assayed for adinazolam and mono-desmethyl-adinazolam (NDMAD) concentrations by a specific HPLC technique. Pharmacokinetic parameters were estimated by noncompartmental methods. Psychomotor effects of adinazolam were assessed using a digit-symbol substitution test (DSST) and aiming test (AIM). Memory effects were assessed by a modification of the Randt memory test (MEM); sedation was assessed using an observer-rated scale. Differences in pharmacokinetics of the parent drug were noted: adinazolam oral clearance was lower in patients with cirrhosis (35.0 +/- 27.9 L/hr) than in normal subjects (73.7 +/- 22.1 L/hr; P = .024); Kel was significantly lower in patients with cirrhosis (.126 +/- .084 vs. .278 +/- .070; P = .007), whereas the mean t1/2 in patients with cirrhosis was 7.70 hours as compared with 2.67 hours in normal subjects. Cmax was higher in the group with cirrhosis (266 +/- 95.5 vs. 153 +/- 29.3 ng/mL; P = .019). For NDMAD, Kel was lower in cirrhotic subjects and resulted in a prolonged t1/2 in cirrhotic subjects compared with normal subjects (6.70 vs. 3.79 hr; P = .0152). NDMAD AUC tended to be higher in cirrhotic subjects (1515 +/- 254 vs. 1162 +/- 254 ng.hr/mL; P = .064). No significant differences were noted in psychomotor performance, memory, or sedation.(ABSTRACT TRUNCATED AT 250 WORDS)

Intra- and inter-individual relationships between central and peripheral serotonergic activity in humans: a serial cerebrospinal fluid sampling study.

Data are lacking concerning the longitudinal covariability and cross-sectional balance between central and peripheral 5-HIAA concentrations in humans and on the possible associations between tobacco smoking or post-traumatic stress disorder (PTSD) and CSF and plasma 5-HIAA concentrations. Using serial cerebrospinal fluid (CSF) and blood sampling, we determined the concentrations of 5-HIAA in CSF and plasma over 6 h, and examined their relationships in healthy volunteers and patients with PTSD-both smokers and nonsmokers. Patients with PTSD and healthy volunteers had very similar CSF 5-HIAA concentrations. Significant and positive correlations between CSF and plasma 5-HIAA levels were observed within individuals, but this CNS-peripheral 5-HIAA relationship was significantly reduced in smokers (nonsmokers: mean r = 0.559 +/- 0.072; smokers: mean r = 0.329 +/- 0.064 p < 0.038). No significant cross-sectional, interindividual correlation of mean CSF and mean plasma 5-HIAA was seen (r = 0.094). These data show that changes in CSF 5-HIAA levels within an individual over time are largely reflected in plasma 5-HIAA, albeit significantly less so in smokers. The present results therefore suggest that clinically, longitudinal determination of plasma 5-HIAA concentrations within an individual patient can be used to make inferences about relative changes in integrated CSF 5-HIAA concentrations. However, plasma 5-HIAA concentrations provide no significant information about absolute levels of the serotonin metabolite in the CSF.

Identification of early predictors for post-traumatic pneumonia.

We demonstrated that the standard clinical criteria of fever, leukocytosis, purulent sputum, and infiltrate on chest radiograph are nonspecific for the diagnosis of post-traumatic pneumonia, and only approximately 50 per cent of patients with these conditions have pneumonia. Quantitative cultures of bronchoalveolar lavage effluent will differentiate pneumonia (requiring antibiotic therapy) from systemic inflammatory response syndrome (not requiring antibiotics). Early identification of patients at risk for pneumonia can target populations for clinical research. Because risk factors for pneumonia when diagnosed by quantitative cultures have not been defined we reviewed our recent experience to identify variables predictive of pneumonia. Patients over a 22-month period who survived > 48 hours were identified from the trauma registry. Pneumonia was defined as growth of > or = 10(5) organisms per milliliter in the bronchoalveolar lavage effluent. Risk factors evaluated included injury severity and severity of shock. There were 7503 patients (75% with blunt and 25% with penetrating injuries). The incidence of pneumonia was 6 per cent (7% of patients with blunt and 2% of patients with penetrating injuries). Logistic regression analysis identified age; Glasgow Coma Scale score; Injury Severity Score; transfusion requirements during resuscitation; spinal cord injury; chest injury severity; and emergent femur fixation, craniotomy, and laparotomy as being independent predictors of pneumonia. We conclude that multiple risk factors, which are all able to be determined early after injury, are predictive of post-traumatic pneumonia. Prompt identification of this high-risk group of patients allows prognostic considerations relative to patient management schemes and targets populations for prophylactic measures or immunomodulation.

Use of health services by men with and without antisocial personality disorder who are alcohol dependent.

In a sample of 104 medically stable male veterans with alcohol dependence, rates of health service utilization were compared for 48 patients with a primary diagnosis of antisocial personality disorder and 56 patients without this diagnosis. Patients were diagnosed using DSM-IV lifetime criteria; previous utilization of health services was based on self-reports. Although a similar proportion of both groups reported previous service use, patients with antisocial personality disorder reported using more substance abuse treatment services than those with a primary diagnosis of alcohol dependence. Between-group multiple regression analysis showed that an earlier age at onset of alcoholism and a history of a comorbid substance-induced mental disorder best predicted higher rates of use of substance abuse treatment.

Cigarette smoking decreases the prolactin response to serotonergic stimulation in subgroups of alcoholics and controls.

BACKGROUND: The prolactin response to serotonergic stimulation has been used as an index of central nervous system serotonin function. We evaluated the prolactin response to d,l-fenfluramine to determine whether subtypes of alcoholics differed in prolactin responsivity compared with nonalcoholics and whether cigarette smoking affected prolactin response. METHODS: One hundred ten healthy, abstinent men across four groups (controls [23% smokers]; alcoholics [72% smokers]; alcoholics with antisocial personality disorder [94% smokers]; nonalcoholic antisocials [88% smokers]) received d,l-fenfluramine (100 mg orally) in a randomized, double-blind, placebo-controlled study. Plasma prolactin levels were obtained at baseline and at half-hour intervals for 5 hr after fenfluramine/placebo administration. Plasma fenfluramine and norfenfluramine levels were obtained hourly. RESULTS: Smokers had a blunted prolactin response to fenfluramine compared with nonsmokers without any alcoholism or antisocial personality effects. Using a cutoff point of delta peak prolactin < 10 ng/ml, more smokers (41/76, 54%) had a dampened response to fenfluramine than did nonsmokers (7/34, 21%) [chi2(1) = 10.6, p < 0.003]. The percentage of low responders was greatest among smokers regardless of whether they were healthy controls, alcoholics, or antisocial. Multiple regression revealed that three variables--(1) number of pack-years of smoking, (2) actual dosage of fenfluramine received, and (3) plasma norfenfluramine level obtained--explained 43% of the variance (R2 = 0.43) in delta prolactin area under the curve. Variables that included alcoholism diagnostic status, antisocial personality diagnostic status, and impulsive aggressive personality, depressive, and suicidal traits failed to explain any additional unique variance. CONCLUSIONS: Cigarette smoking blunted the prolactin response to a pharmacological challenge with d,l-fenfluramine. Pharmacodynamic and pharmacokinetic factors related to smoking both appear to influence fenfluramine-induced prolactin secretion. Phenotypes of alcoholics did not differ in their prolactin response to this serotonergic probe.

Concerning the role of the amine pump of the adrenergic innervation of rabbit aorta in sustaining the neuron blockade produced by bethanindine and bretylium.

Adrenergic neuron blockade produced in rabbit aortic strips by bretylium and bethanidine has been studied. Differences were noted in the characteristics of approximately equal, strong neuron blockade produced by bretylium was readily reversed by washout of the drug from the tissue bath whereas blockade produced by bethanidine was slowly reversed. Desmethylimipramine prevented the onset of blockade from bretylium whereas it only delayed the onset of blockade due to bretylium but only slightly antagonized an established blockade due to bethanidine. It is suggested that the differences observed between these two neuron blocking agents are the result of their differential retention inside the neuron: bretylium is not firmly bound, leaks out of the neuron and goes through a process of recycling across the cell membrane, while bethanidine is more firmly bound inside the neuron than bretylium, only slowly leaks out of the neuron and is not recycled back across the cell membranes.

Behavioral and biochemical effects of the antidepressant bupropion (Wellbutrin): evidence for selective blockade of dopamine uptake in vivo.

Bupropion (BW 323U; Wellbutrin), a novel compound with antidepressant effects in man, was found to reduce immobility in an "experimental helplessness" forced swimming antidepressant test in rats as did imipramine and amitriptyline. Higher doses produced elevated locomotor activity in an automated open field and produced stereotyped sniffing which was contrasted with apomorphine. When bupropion or desmethylimipramine was given before intracisternal injections of 6-hydroxydopamine, bupropion produced a dose-related selective antagonism of the destruction of dopamine neurons, while under the same conditions, desmethylimipramine produced a dose-related selective antagonism of the destruction of noradrenergic neurons. Studies in which the dose of bupropion and the dose of 6-hydroxydopamine were varied revealed that a dose-related selective antagonism of dopamine depletion by 6-hydroxydopamine occurred when doses up to and including 50 mg/kg i.p. to bupropion were administered. Some antagonism of norepinephrine depletion also occurred at 100 mg/kg of bupropion i.p. Bupropion also selectively reversed the dopamine depletion produced by alpha-methyl-m-tyrosine, a finding which is consistent with the view that bupropion is a dopamine uptake inhibitor in vivo. The importance of dopamine systems for the behavioral effects of bupropion were also studied. When the locomotor stimulant effects of bupropion were tested in rats with chronic destruction of dopamine neurons produced by 6-hydroxydopamine, bupropion failed to elevate locomotor activity. Rats treated with procedures using 6-hydroxydopamine to produce relatively selective norepinephrine depletions responded to bupropion with locomotor activity stimulation like controls. Rats with similar depletions of either dopamine or norepinephrine were also tested for the ability of low doses of bupropion to reduce immobility in the "experimental helplessness" forced swim antidepressant test. Prior destruction of dopamine neurons prevented activity of bupropion in this test. Results indicate that bupropion is a selective dopamine uptake inhibitor in vivo and that dopaminergic systems play an important role in its central nervous system pharmacology.

Influence of desipramine on the uptake and efflux of radiolabelled bretylium and bethanidine in the adventitial and media-intimal layers of rabbit aortic strips.

The desipramine-sensitive uptake (neuronal uptake) of 14C-bretylium and 14C-bethanidine into the rabbit aortic adventitial layer from 3 X 10(-6) M solutions increased with time during a 20 min incubation. For both compounds a neuronal uptake of 50 pmol/50 mg wet weight adventitia was associated with 10% block of the contractile response to field stimulation at 16 Hz and 150 pmol/50 mg with 60% block. The concentration of blocking agents inside the neuron at 50% blockade was calculated to be 260 X 10(-6) M, an 87-fold increase over the medium. The bretylium in the neuron decreased by 50% during 20 min washout, and bethanidine by 29%. Desipramine when added to the bath 20 min following the addition of the blocking agents led to a loss of bretylium but not of bethanidine from the adventitia. Desipramine had little or no effect on the uptake, washout or disposition of either blocking agent in the media-intimal layers. The data indicate that bretylium has a greater propensity than bethanidine to be lost from the neurons; however, it appears to be recycled back through the membrane via the amine pump more readily than bethanidine. The fact that conservative calculations indicate that the neuronal membrane slowly established a concentration of the blocking agents within the neuron that is known to produce rapid local anesthesia when topically applied to adrenergic nerve trunks and which approaches a concentration needed to inhibit sensory endings suggests that local anesthesia may play a role in the mechanism of neuron blockade.

A structure-activity study of the transport sites for the hypothalamic and striatal catecholamine uptake systems. Similarities and differences.

A series of eight substrate molecules (substituted phenethylamines, guanethidine, and bretylium) had slightly less affinity for striatal than for hypothalamic synaptosomal uptake receptors as judged by ratios of striatal (s) to hypothalamic (h) IC50 values (s/h average = 3.9; range 2.0--6.0). Catecholamine uptake in striatum was very insensitive to tricyclic antidepressant inhibitors, whereas catecholamine uptake in hypothalamus was very sensitive to these agents (s/h average = 233; range 24--570). By way of contrast with both the substrates and the tricyclic inhibitors, the inhibitors with less rigidly fixed rings or analogous groups (deoxypipradrol, methylphenidate, cocaine) were potent in both brain preparations (s/h average = 1.2; range 0.6--2.3). It is concluded that the rings of nontricyclic inhibitors are able to bind to appropriate hydrophobic binding groups in both receptors, that these receptive groups have different topography in striatum and in hypothalamus, and that the topography in the striatum is incompatible with binding tricyclic systems. The data also indicate that there is great similarity, if not identity, in the receptive area for substrates in striatum and hypothalamus. Although the substrates and inhibitors bind to some groups in common in this substrate receptive area, it is the surrounding hydrophobic molecular environment that is clearly different and permits the phenomenon of selective blockade with drugs.

Electrophysiological effects of antidepressants on mammalian hearts and crayfish giant axon.

Cardiotoxicity is known to occur in patients with or without preexisting cardiac diseases during treatments with the tricyclic antidepressants, amitriptyline and imipramine. The antiarrhythmic action of tricyclics was also demonstrated in clinical studies and in animal experiments. Bupropion, a novel antidepressant, is being studied in man and to date has been found to be effective and devoid of cardiovascular toxicity. This study was intended to show the direct effect of tricyclic antidepressants on excitable membrane and to compare their potential toxicity with bupropion in isolated tissues. In crayfish giant axon, all antidepressants exhibited local anesthetic-like action by reducing the action potential amplitude and maximal rate of upstroke (dv/dt). The tricyclics slowed spontaneous sinus discharges in rat atrium and prolonged the duration of evoked action potential in guinea pig atrium with a concomitant decrease in dv/dt. A quinidine-like action of the tricyclic agents is displayed in the termination of spontaneous depolarization and the suppression of dv/dt of evoked action potential in canine Purkinje fibers. The membrane depressant action of antidepressants resulted in the reduction of dv/dt and increased membrane refractoriness in both atrial and ventricular tissues; excitation is blocked even when resting membrane potential remained fully polarized. The present results confirmed the direct quinidine-like action on cardic tissues, which is probably related to the antiarrhythmic and/or cardiotoxic manifestation in man and animals. On on excitable tissues studied, tricyclic antidepressants are the most potent in blocking membrane excitation, while bupropion is the least toxic on the molar basis.

Resuscitation of severe chest trauma with four different hemoglobin-based oxygen-carrying solutions.

BACKGROUND: The purpose of this study was to test whether polynitroxylation (PN) improved the therapeutic profile of hemoglobin-based oxygen-carrying compounds (HBOCs) that were unpolymerized (alphaalphaHb) or 70% polymerized (polyHb) in a clinically relevant model that combines pulmonary injury and reperfusion. To our knowledge, four different HBOC formulations have never been compared in the same trauma model. METHODS: Anesthetized, ventilated swine (n = 45) received a unilateral lung contusion + 25% hemorrhage. After 60 minutes, 250 mL of either PNalphaalphaHb (n = 5), alphaalphaHb (n = 10), PNpolyHb (n = 6), polyHb (n = 5), or normal saline (NaCl, n = 10) was administered for 20 minutes, followed by standard crystalloid resuscitation for 30 minutes, and supplemental crystalloid as required for 6 hours to maintain heart rate <100 beats/min and mean arterial pressure >70 mm Hg. RESULTS: Nine of 45 deaths occurred before resuscitation. Survival time was 395 minutes with NaCl versus 303 minutes with alphaalphaHb (p = 0.03) or 238 minutes with PNalphaalphaHb (p = 0.04). With both polymerized HBOCs, survival was 480 minutes (polyHb vs. alphaalphaHb, p = 0.005; PNpolyHb vs. PNalphaalphaHb, p = 0.006). All HBOCs were pressors (all p < 0.05) and all reduced the supplemental fluid required to maintain systemic hemodynamics during resuscitation (all p < 0.05). By 90 minutes postresuscitation, cardiac index was 112% of baseline with NaCl (p < 0.02), but was 78% with alphaalphaHb (p = not significant), 63% with PNalphaalphaHb (p < 0.01), 79% with PNpolyHb (p < 0.01), and 67% with polyHb p < 0.02). Relative to NaCI, no HBOC altered trauma-induced neutrophilia, thrombocytopenia, or the trauma-induced increases in bronchoalveolar lavage protein or bronchoalveolar lavage neutrophils. CONCLUSION: After resuscitation from chest trauma, we observed the following: (1) all HBOCs reduced fluid requirements and increased right and left ventricular afterload versus NaCl, which further compromised an already marginal cardiac performance; (2) mortality was less with polyHbs relative to alphaalphaHb, but the pressor action was unchanged; (3) the pressor action was less with polynitroxylated compounds relative to the unmodified HBOC, but this chemical modification had no effect on mortality; and (4) the pressor action of HBOCs must be attenuated by strategies other than polymerization or polynitroxylation for these compounds to be safe, effective resuscitants in humans.