Inducing humoral and cellular responses to multiple sporozoite and liver-stage malaria antigens using exogenous plasmid DNA.

A vaccine candidate that elicits humoral and cellular responses to multiple sporozoite and liver-stage antigens may be able to confer protection against Plasmodium falciparum malaria; however, a technology for formulating and delivering such a vaccine has remained elusive. Here, we report the preclinical assessment of an optimized DNA vaccine approach that targets four P. falciparum antigens: circumsporozoite protein (CSP), liver stage antigen 1 (LSA1), thrombospondin-related anonymous protein (TRAP), and cell-traversal protein for ookinetes and sporozoites (CelTOS). Synthetic DNA sequences were designed for each antigen with modifications to improve expression and were delivered using in vivo electroporation (EP). Immunogenicity was evaluated in mice and nonhuman primates (NHPs) and assessed by enzyme-linked immunosorbent assay (ELISA), gamma interferon (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) assay, and flow cytometry. In mice, DNA with EP delivery induced antigen-specific IFN-γ production, as measured by ELISpot assay and IgG seroconversion against all antigens. Sustained production of IFN-γ, interleukin-2, and tumor necrosis factor alpha was elicited in both the CD4(+) and CD8(+) T cell compartments. Furthermore, hepatic CD8(+) lymphocytes produced LSA1-specific IFN-γ. The immune responses conferred to mice by this approach translated to the NHP model, which showed cellular responses by ELISpot assay and intracellular cytokine staining. Notably, antigen-specific CD8(+) granzyme B(+) T cells were observed in NHPs. Collectively, the data demonstrate that delivery of gene sequences by DNA/EP encoding malaria parasite antigens is immunogenic in animal models and can harness both the humoral and cellular arms of the immune system.

Benefits of oat beta-glucan on respiratory infection following exercise stress: role of lung macrophages.

Exercise stress is associated with an increased risk for upper respiratory tract infection (URTI). We have shown that consumption of the soluble oat fiber beta-glucan (ObetaG) can offset the increased risk for infection and decreased macrophage antiviral resistance following stressful exercise; however, the direct role of macrophages is unknown. This study examined the effect of macrophage depletion on the benefits of orally administered ObetaG on susceptibility to infection (morbidity, symptom severity, and mortality) following exercise stress. CL(2)MDP (Ex- H(2)O-CL(2)MDP, Ex-ObetaG-CL(2)MDP, Con-H(2)O-CL(2)MDP, Con-ObetaG-CL(2)MDP)-encapsulated liposomes were administered intranasally to deplete macrophages, and PBS (Ex-H(2)O-PBS, Ex-ObetaG-PBS, Con-H(2)O-PBS, Con-ObetaG-PBS)-encapsulated liposomes were given to macrophage-intact groups. Ex mice ran to volitional fatigue on a treadmill for 3 consecutive days, and ObetaG mice were fed a solution of 50% ObetaG in their drinking water for 10 consecutive days before infection. Fifteen minutes following the final bout of Ex or rest, mice were intranasally inoculated with 50 microl of a standardized dose of herpes simplex virus-1. Ex increased morbidity (P < 0.001) and symptom severity (P < 0.05) but not mortality (P = 0.09). The increase in morbidity and symptom severity was blocked by ObetaG consumption for 10 consecutive days before exercise and infection [morbidity (P < 0.001) and symptom severity (P < 0.05)]. Depletion of macrophages negated the beneficial effects of ObetaG on reducing susceptibility to infection following exercise stress, as evidenced by an increase in morbidity (P < 0.01) and symptom severity (P < 0.05). Results indicate that lung macrophages are at least partially responsible for mediating the beneficial effects of ObetaG on susceptibility to respiratory infection following exercise stress.

Susceptibility to HSV-1 infection and exercise stress in female mice: role of estrogen.

Exhaustive exercise has been associated with an increased risk for upper respiratory tract infections in mice and humans. We have previously shown (Brown AS, Davis JM, Murphy AE, Carmichael MD, Ghaffer A, Mayer EP. Med Sci Sports Exerc 36: 1290-1295, 2004) that female mice are better protected from the lethal effects of herpes simplex virus type 1 (HSV-1) infection, both at rest and following exercise stress, but little is known about possible mechanisms. This study tested the effects of estrogen on HSV-1 infection and macrophage antiviral resistance following repeated exhaustive exercise. Female mice were assigned to either exercise (Ex) or control (C): intact female (I-C or I-Ex), ovariectomized female (O-C or O-Ex), or ovariectomized estrogen-supplemented female (E-C or E-Ex). Exercise consisted of treadmill running to volitional fatigue ( approximately 125 min) for 3 consecutive days. Intact female mice had a later time to death than O and E (P < 0.05) and fewer deaths than both O and E (P < 0.05). Exercise stress was associated with increased time to sickness (P < 0.05) and symptom severity at days 6 and 12-21 postinfection (P < 0.05) and decreased macrophage antiviral resistance (P < 0.001) in all groups. E had increased symptom severity at days 6 and 13-21 postinfection (P < 0.05). Results indicate that intact female mice are better protected from the lethal effects of HSV-1 infection and that exercise stress had a similar negative impact in all groups. This protective effect was lost in ovariectomized mice, but it was not reinstated by 17beta-estradiol replacement. This indicates that other ovarian factors, alone or in combination with estrogen, are responsible for the protective effects in females.

Value of transoesophageal echocardiography for diagnosis of intraoperative tumour embolization.

Malignant neoplasms such as renal cell carcinoma may invade the inferior vena cava leading to a risk of pulmonary tumour embolization during surgical excision. Although massive pulmonary tumour embolism occurs relatively rarely, it can have catastrophic consequences. We report the case of an acute intraoperative pulmonary tumour embolism during resection of a renal cell carcinoma. The use of transoesophageal echocardiography allowed the immediate diagnosis and appropriate management of the underlying cause of acute haemodynamic instability. The role of transoesophageal echocardiography in the diagnosis of pulmonary embolism is discussed.

Effects of moderate exercise and oat beta-glucan on lung tumor metastases and macrophage antitumor cytotoxicity.

Both moderate exercise and the soluble fiber beta-glucan can have beneficial effects on the initiation and growth of tumors, but the data are limited, and there is no information on their combined effects. This study tested the independent and combined effects of short-term moderate-exercise training and the soluble oat fiber beta-glucan (ObetaG) on the metatastic spread of injected tumor cells and macrophage antitumor cytotoxicity. Male C57BL/6 mice were assigned to one of four groups: exercise (Ex)-H2O, Ex-ObetaG, control (Con)-H2O, or Con-ObetaG. ObetaG was fed in the drinking water for 10 days before tumor administration and death. Exercise consisted of treadmill running (1 h/day) for 6 days. After rest or exercise on the last day of training, syngeneic B16 melanoma cells (2 x 10(5)) were administered via intravenous injection (n = 8-11 per group). Lungs were removed 14 days later, and tumor foci were counted. Additional mice (n = 8 per group) were killed, and peritoneal macrophages were assayed for cytotoxicity against the same mouse tumor cell line at various effector-to-target ratios. Both moderate exercise and ObetaG decreased lung tumor foci and increased macrophage cytotoxicity. However, there were no differences in lung tumor foci and macrophage cytotoxicity between Ex-ObetaG and either Ex-H2O or Con-ObetaG. These data suggest that, although not additive in their effects, both short-term moderate-exercise training and consumption of the soluble ObetaG can decrease the metatastic spread of injected B16 melanoma cells, and these effects may be mediated in part by an increase in macrophage cytotoxicity to B16 melanoma.

Effects of moderate exercise and oat beta-glucan on innate immune function and susceptibility to respiratory infection.

Both moderate exercise and the soluble oat fiber beta-glucan can increase immune function and decrease risk of infection, but no information exists on their possible combined effects. This study tested the effects of moderate exercise and oat beta-glucan on respiratory infection, macrophage antiviral resistance, and natural killer (NK) cell cytotoxicity. Mice were assigned to four groups: exercise and water, exercise and oat beta-glucan, control water, or control oat beta-glucan. Oat beta-glucan was fed in the drinking water for 10 days before intranasal inoculation of herpes simplex virus type 1 (HSV-1) or euthanasia. Exercise consisted of treadmill running (1 h/day) for 6 days. Macrophage resistance to HSV-1 was increased with both exercise and oat beta-glucan, whereas NK cell cytotoxicity was only increased with exercise. Exercise was also associated with a 45 and 38% decrease in morbidity and mortality, respectively. Mortality was also decreased with oat beta-glucan, but this effect did not reach statistical significance. No additive effects of exercise and oat beta-glucan were found. These data confirm a positive effect of both moderate exercise and oat beta-glucan on immune function, but only moderate exercise was associated with a significant reduction in the risk of upper respiratory tract infection in this model.

Acute rise of circulating vascular endothelial growth factor-A in patients with coronary artery disease following cardiothoracic surgery.

AIMS: Vascular endothelial growth factor-A (VEGF-A) is an angiogenic and vasoprotective molecule whose expression is modulated by hypoxia and inflammatory mediators. Here we have tested the hypothesis that plasma levels of VEGF-A are influenced by pre-existing coronary artery disease and by changes in circulating interleukin-6 (IL-6). METHODS AND RESULTS: Plasma VEGF-A and IL-6 were measured prior to and at various time intervals following surgery in individuals with angiographically normal coronary arteries requiring cardiac valve replacement (N group) and in patients with coronary artery disease and stable angina undergoing coronary artery bypass grafting (CAD group). Baseline VEGF-A levels were not significantly different in CAD (22.3+/-2.6 pg x ml(-1)) compared to the N group (14.9+/-2.9 pg x ml(-1)). Following cardiac surgery there was a significant rise of VEGF-A in CAD (P<0.0005 vs baseline), but not in the N group, reaching a maximum (approximately 2 fold increase) after 24 h. Surgery caused a rapid increase of plasma IL-6 in both groups, but the rise was significantly larger in CAD patients (P<0.0005 vs N) where it preceded the increase in VEGF-A. Furthermore, in patients with CAD there was a significant correlation between the change in VEGF-A and the change in IL-6 (P<0.04). CONCLUSION: These findings demonstrate that in patients with coronary artery disease cardiothoracic surgery leads to an acute rise in VEGF-A. We suggest that this rise may result from an interaction between the pre-existing atheromatous process and a systemic increase of inflammatory mediators.

Maternal prepregnant body mass and risk of schizophrenia in adult offspring.

This study examined the relation between maternal prepregnant body mass index (BMI) and development of schizophrenia and schizophrenia spectrum disorders in adult offspring from the Prenatal Determinants of Schizophrenia Study. The study drew on a previously studied cohort of births occurring between 1959 and 1967 to women enrolled in a prepaid health plan. Computerized treatment registries were used to identify possible cases of schizophrenia and spectrum disorders in adult offspring belonging to the health plan from 1981 to 1997. Diagnostic interviews and medical record reviews resulted in diagnosis of 63 cases of schizophrenia and spectrum disorders; these cases and 6,570 unrelated and unaffected cohort members whose mothers also had prepregnancy measures of BMI comprised the sample for analyses. High (> or = 30.0), compared with average (20.0-26.9), maternal prepregnant BMI (kg/m2) was significantly associated with schizophrenia and spectrum disorders in the adult offspring (relative risk [RR] = 2.9; 95% confidence interval [CI] 1.3-6.6), independently of maternal age, parity, race, education, or cigarette smoking during pregnancy. Low (< or = 19.9) maternal BMI was not associated with schizophrenia and spectrum disorders (RR = 1.2; 95% CI 0.64-2.2). Future studies of this cohort will examine factors that may help explain the relationship of high maternal prepregnant BMI with schizophrenia, including nutritional and metabolic factors, toxic exposures, and obstetrical complications.

Maternal exposure to respiratory infections and adult schizophrenia spectrum disorders: a prospective birth cohort study.

We sought to examine the relationship between maternal exposure to adult respiratory infections and schizophrenia spectrum disorder (SSD) in the Prenatal Determinants of Schizophrenia (PDS) Study, a large birth cohort investigation. Previous work suggests that second trimester exposure to respiratory infection may be a risk factor for SSD. We therefore examined whether this class of infection was associated with adult SSD. For this purpose, we capitalized on several design advantages of the PDS Study, including a comprehensive, prospective data base on physician-diagnosed infections and a continuous followup in which diagnoses of SSD were made, in the majority, by face-to-face interview. Second trimester exposure to respiratory infections was associated with a significantly increased risk of SSD, adjusting for maternal smoking, education, and race (rate ratio [RR] = 2.13 [1.05-4.35], chi2 = 4.36, df= 1,p = 0.04); no associations were shown for first trimester and third trimester exposure to these respiratory infections. These findings support-and extend-previous studies suggesting that second trimester respiratory infections are risk factors for SSD. This study therefore has implications toward uncovering the etiology of schizophrenia and developing preventive strategies.

Palatoplasty: Furlow's double reversing Z-plasty versus intravelar veloplasty.

OBJECTIVE: To evaluate the efficacy of Furlow's double reversing z-plasty (Furlow) versus intravelar veloplasty with longitudinal closure including palatal muscle reorientation (IVV). DESIGN: Retrospective, single-institution, single-surgeon comparison. PATIENTS: One hundred nineteen consecutive cleft palate patients were enrolled; 34 syndromic and 9 language-impaired patients were removed from speech and reoperation analysis. Furlow and IVV groups were similar with respect to sex and mean age at primary repair. INTERVENTIONS: One surgeon performed all surgery and one of two speech pathologists conducted language and speech evaluations at 3 years of age without prior knowledge of the surgical technique utilized. OUTCOME MEASURES: Outcome measures included frequency of palatal fistulae, speech abnormalities, and need for secondary pharyngoplasty procedures. RESULTS: Patients who had undergone IVV demonstrated a 34% higher incidence of hoarseness, nasal escape, and hypernasality at 3 years of age than did Furlow patients. These same patients likewise required significantly more secondary pharyngoplasty procedures. No significant difference was noted between fistulae frequencies. CONCLUSIONS: These findings suggest that Furlow palatoplasty may provide a better clinical outcome than intravelar veloplasty.

A naturalistic study of home detoxification from opiates using lofexidine.

The study describes the outcome of home detoxification from opiates using lofexidine, a centrally-acting alpha2-adrenergic agonist, in a consecutive series of 28 unselected individuals. Eleven detoxifications (39%) were successful and 17 (61%) unsuccessful. No major medical or psychological problems were reported. Successful outcome was associated with not using heroin, good compliance with a methadone programme and prediction of success by the key worker. Home detoxification using lofexidine appears to be a useful treatment for some opiate-dependent individuals, and is most likely to be successful in those individuals whose drug use is already well-controlled.

Prenatal counseling for cleft lip and palate.

Prenatal diagnoses of cleft lip and palate can occur during both routine screening obstetrical ultrasound and high resolution obstetrical ultrasound done for other reasons. The affected family or obstetrician may request prenatal consultation with the plastic surgeon. To define this population, a survey was done of all families who were referred to our cleft program with a prenatal diagnosis of cleft between 1990 and 1994. Of 80 newborn referrals, 13 had a prenatal diagnosis of cleft. These children had a higher incidence of bilateral cleft than our average population (53.8 percent versus 28.7 percent, p < 0.03, chi square test). No isolated cleft palates were identified. Nine families were available for follow-up. Only one-third of the families felt that they had been given adequate information about clefts from their obstetrician or ultrasonographer. All who had prenatal contact with the cleft team felt it was valuable. A review of prenatal diagnosis of cleft is given including limitations. Specific counseling information is discussed.

Megakaryocyte ploidy and platelet changes in human diabetes and atherosclerosis.

Altered platelet morphology and function have been reported in patients with diabetes. They are likely to be associated with the pathological processes and increased risk of vascular disease seen in these patients. Mean platelet volume (MPV), platelet count, and megakaryocyte (MK) ploidy (DNA content) were measured in (1) nondiabetics with normal coronary arteries, (2) nondiabetics with coronary artery atherosclerosis, (3) diabetics without evidence of vascular complications, and (4) diabetics with vascular disease. The platelet count (+/- SD) was increased in all groups but only significantly in the diabetics with vascular disease (236 +/- 65 versus 250 +/- 54 versus 257 +/- 64 versus 295 +/- 90 [P < or = .05] x 10(9)/L, for groups, I, II, II, and IV, respectively). The MPV was significantly increased in patients with atherosclerosis (7.0 +/- 0.4 versus 8.0 +/- 1.2 [P < or = .05] versus 7.2 +/- 0.9 versus 8.1 +/- 0.9 [P < or = .05] IL). Geometric mean MK ploidy was significantly increased in all groups compared with controls (16 +/- 1.5 versus 18.7 +/- 1.8 [P < or = .05] versus 19.8 +/- 1.6 [P < or = .05] versus 20.1 +/- 2.7 [P < or = .05]). Furthermore, some patients with vascular disease and/or diabetes had a modal ploidy shift from 16 (the normal mammalian modal ploidy) to 32, with a concomitant reduction of MKs in the 8 and 16 ploidy classes. This shift was seen particularly in the diabetics with vascular disease (P = .007). Interleukin-6 (IL-6) levels were measured and were elevated in patients with atherosclerosis; the highest levels were found in the diabetic patients (0.7 +/- 0.9 versus 5.3 +/- 5.5 [P < or = .05] versus 2.5 +/- 2.8 versus 6.7 +/- 5.5 [P < or = .05] ng/L). In the diabetic patients with atherosclerosis, fibrinogen levels were also increased (2.85 +/- 0.76 versus 3.34 +/- 1.32 versus 2.43 +/- 1.50 versus 5.59 +/- 1.72 [P < or = .05] g/L). Furthermore, IL-6 levels correlated with MK ploidy (r = .45, P = .009) and fibrinogen levels (r = .5, P = .0001). This study demonstrates that patients with vascular disease, particularly diabetics, have an altered MK ploidy distribution, showing a shift toward higher ploidy in association with an increased platelet mass (count x volume). Changes in platelets in diabetes probably reflect MK changes, which themselves are a response to systemic change.

Peripheral benzodiazepine receptor in cholesterol transport and steroidogenesis.

Steroidogenesis begins with the metabolism of cholesterol to pregnenolone by the inner mitochondrial membrane cytochrome P450 side-chain cleavage (P450scc) enzyme. The rate of steroid formation, however, depends on the rate of cholesterol transport from intracellular stores to the inner mitochondrial membrane and loading of P450scc with cholesterol. In previous in vitro studies, we demonstrated that a key element in the regulation of cholesterol transport is the mitochondrial peripheral-type benzodiazepine receptor (PBR). We also showed that the polypeptide diazepam binding inhibitor (DBI), an endogenous PBR ligand, stimulates cholesterol transport and promotes loading of cholesterol to P450scc in vitro, and that its presence is vital for hCG-induced steroidogenesis by Leydig cells. Based on these data and the observations that i) the mitochondrial PBR binding and topography are regulated by hormones; ii) the 18-kDa PBR protein is functionally coupled to the mitochondrial contact site voltage-dependent anion channel protein; iii) the 18-kDa PBR protein is a channel for cholesterol, as shown by molecular modeling and in vitro reconstitution studies; iv) targeted disruption of the PBR gene in steroidogenic cells dramatically reduces the ability of the cells to transport cholesterol in the mitochondria and produce steroids; v) endocrine disruptors, with known anisteroidogenic effect, inhibit PBR ligand binding; and vi) in vivo reduction of adrenal PBR expression results in reduced circulating glucocorticoid levels, we conclude that PBR is an indispensable element of the steroidogenic machinery.

Sex differences in prevalence of congenital neural defects after periconceptional famine exposure.

The purpose of this investigation was to examine the sex distribution of deaths from spina bifida in birth cohorts exposed and unexposed to severe periconceptional famine. For this purpose, we compared the risk of deaths from spina bifida between birth cohorts exposed and unexposed to the Dutch Hunger Winter of 1944-1946. In males, the relative risk of death from spina bifida was 2.62 [95% confidence interval (CI) = 1.14-6.01]. In females, the relative risk for spina bifida was 0.59 (95% CI = 0.14-2.37). The sex ratio (male:female) for deaths from spina bifida in the exposed birth cohort was 2.74; a female predominance was not seen in any other birth cohort. Deaths from anencephaly and other central nervous system disorders did not exhibit this male predominance in the exposed birth cohort. These findings indicate that severe periconceptional nutrient deficiency may have a greater effect on the occurrence of spina bifida in males vs females. Other potential explanations include sex-specific effects of prenatal famine on prenatal or postnatal survival rates of cases.

The effects of S-nitrosoglutathione on platelet activation, hypertension, and uterine and fetal Doppler in severe preeclampsia.

OBJECTIVE: To determine the effects of the platelet-specific nitric oxide donor S-nitrosoglutathione on women with severe preeclampsia. METHODS: Ten women with severe preeclampsia or preeclampsia with severe fetal compromise at 21-33 weeks' gestation each received a 60-90-minute intravenous infusion of 50-250 micrograms/minute of S-nitrosoglutathione. Each was hypertensive, despite conventional oral antihypertensive therapy in eight. Maternal blood pressure, heart rate, platelet activation, uterine artery, and fetal Doppler indices were measured during the infusion. RESULTS: A dose-dependent reduction in mean arterial pressure from 125 mmHg (95% confidence interval [CI] 117-133) to 103.5 (95% CI 97-111) (P < .005) and an increase in pulse rate from 73.7 beats per minute (95% CI 64.3-84.5) to 89.1 (95% CI 81.2-97.8) (P < .02) was observed during the infusion. Mean uterine artery resistance index fell from 0.76 (95% CI 0.73-0.81) to 0.70 (95% CI 0.65-0.75) (P < .009). Platelet activation measured by P-selectin expression was reduced from 3.02% (95% CI 2.09-4.36) to 1.22% (95% CI 0.94-1.58) (P < .01). Fetal Doppler indices (umbilical artery, middle cerebral artery, and thoracic aorta) showed no significant changes during the infusion. CONCLUSION: S-nitrosoglutathione infusion reduced material mean arterial pressure, platelet activation, and uterine artery resistance without further compromising fetal Doppler indices. This study suggests that platelet-specific nitric oxide donors may prove beneficial in the management of severe preeclampsia.

Assessing third-year medical students' knowledge of and exposure to cleft palate before and after plastic surgery rotation.

The purpose of this study was to evaluate third-year medical students' knowledge of and exposure to cleft palate before and after a rotation in plastic surgery. A 26-item questionnaire was administered to 37 students before and after their 12-week rotation that included the evaluation and management of patients with cleft palate. The questions addressed various aspects of the disorder, including identification of the members of a cleft palate team. Students were also asked about their clinical and academic exposure to cleft palate. When the students' responses to the 19 basic information items about cleft palate and associated problems were compared before and after the rotation, positive changes were documented for 14 of the 19 questions, minimal negative changes for 4, and no change for 1 question. The overall percentage of students indicating any type of clinical or academic exposure to cleft palate increased significantly after the rotation. Findings from this study suggest that an undergraduate clinical rotation in plastic surgery can increase the knowledge of and exposure to cleft palate. It was clear that supplemental learning can occur in other settings outside the classroom through interactions between faculty and students without additional curricular time.

Schizophrenia after prenatal famine. Further evidence.

BACKGROUND: Suggestive findings of an earlier study that prenatal nutritional deficiency was a determinant of schizophrenia prompted us to undertake a second test of the hypothesis using more precise data on both exposure and outcome. METHODS: Among persons born in the cities of western Netherlands during 1944 through 1946, we compared the risk for schizophrenia in those exposed and unexposed during early gestation to the Dutch Hunger Winter of 1944/1945. The frequency of hospitalized patients with schizophrenia at age 24 to 48 years in the exposed and unexposed birth cohorts was ascertained from a national psychiatric registry. RESULTS: The most exposed birth cohort, conceived at the height of the famine, showed a twofold and statistically significant increase in the risk for schizophrenia (relative risk [RR] = 2.0; 95% confidence interval [CI] = 1.2 to 3.4; P < .01) in both men (RR = 1.9; 95% CI = 1.0 to 3.7; P = .05) and women (RR = 2.2; 95% CI = 1.0 to 4.7; P = .04). Among all birth cohorts of 1944 through 1946, the risk for schizophrenia clearly peaked in this exposed cohort. CONCLUSION: Prenatal nutritional deficiency may play a role in the origin of some cases of schizophrenia.

Ranitidine increases the bioavailability of postprandial ethanol by the reduction of first pass metabolism.

Blood ethanol concentrations after separate oral dosing and intravenous infusion of ethanol (0.15 g/kg) were measured in 16 control subjects and 13 subjects treated with ranitidine. All subjects underwent routine upper gastrointestinal endoscopy. Peak blood ethanol concentrations, and area under the blood ethanol/time curve, were significantly higher in the ranitidine group after oral, but not intravenous, ethanol administration. The first pass metabolism, as calculated by the difference between the area under the curves, was significantly lower in the ranitidine group. In addition, all subjects withdrawn from ranitidine (n = 6) had a significant reduction in peak blood ethanol concentration and area under the curve after repeat dosing with oral ethanol. Both groups were well matched for age, sex, indications for endoscopy, findings at endoscopy, and gastric histology. These findings show that ranitidine increases the bioavailability of low dose ethanol and has possible short term forensic, and longterm physical implications for moderate drinkers who are taking the drug.

The gonadal axis in men with schizophrenia.

The typical onset of schizophrenia during late adolescence and early adulthood has stimulated interest in the potential contribution of hypothalamo-pituitary-gonadal (HPG) axis abnormalities to this disorder. Previous investigations of reproductive hormone function in men with schizophrenia suggest diminished activity of the HPG axis. These studies have been hampered, however, by methodologic limitations. We have attempted to address these limitations by rigorous determination of gonadotropin and gonadal hormone levels, and attention to demographic and diagnostic variables. In contrast to prior studies, our results indicate that schizophrenic patients do not show statistically significant differences from healthy volunteers with respect to luteinizing hormone pulsatility, response to gonadotropin-releasing hormone challenge, and testosterone secretion. Due to the small number of subjects, however, these findings must be regarded as preliminary and warrant further study.