N-methyl-D-aspartic acid stimulation of vasopressin release: role in osmotic regulation and modulation by gonadal steroids

Previous experiments demonstrated that excitatory amino acids participate in the osmotic regulation of vasopressin secretion, but the specific involvement of N-methyl-D-aspartic acid (NMDA) receptors was not evaluated. This was demonstrated in the present studies. NMDA stimulated vasopressin release from perifused explants of the hypothalamo-neurohypophyseal system (HNS), and osmotic stimulation of vasopressin release was inhibited by MK-801 (10 microM) and AP5 (100 microM) NMDA receptor antagonists. The effective concentration of NMDA was dependent upon the Mg2+ concentration of the perifusate with stimulation observed at 1 microM NMDA in Mg2+-replete compared with 5 microM in low-Mg2+ medium. Previous experiments also demonstrated that estradiol and dihydrotestosterone (DHT) inhibited osmotically stimulated vasopressin secretion, and a nongenomic mechanism of action was suggested by the ability of steroids conjugated to bovine serum albumin to replicate the effect. Experiments were performed to explore the potential role of NMDA receptors in this mechanism. Estradiol (50 pg/ml) and DHT (3 ng/ml) inhibited NMDA stimulated vasopressin release in perifused HNS explants. These results suggest a role of NMDA receptors in the mediation of vasopressin secretion in osmotically stimulated release. Furthermore, estradiol and DHT may exert their inhibitory effect on osmotically stimulated vasopressin release via the NMDA receptor.     

Pneumococci stimulate the production of the inducible nitric oxide synthase and nitric oxide by murine macrophages

The role of nitric oxide (NO) in the pathophysiology of gram-positive sepsis is uncertain. In inflammatory conditions, high-output NO production is catalyzed by the enzyme inducible nitric oxide synthase (iNOS). The ability of 2 strains of pneumococci, pneumococcal cell wall preparations, and purified pneumococcal capsule (Pnu-Imune 23) to trigger the production of iNOS protein and NO in RAW 264.7 murine macrophages was tested. Live pneumococci, oxacillin-killed pneumococci, and pneumococcal cell wall preparations stimulated the production of iNOS and NO by RAW 264.7 cells in the presence, but not the absence, of low concentrations of recombinant murine interferon-gamma. In contrast, purified pneumococcal capsule induced little or no iNOS or NO production by these cells. Thus, pneumococci stimulate high-output NO production by murine macrophages. The potential role of NO in the pathogenesis of pneumococcal sepsis deserves further study.     

Expenditures for the treatment of major depression

At present, little information is available on specific chromosomal aberrations in malignant melanomas of different subtypes and different growth behaviors. Therefore, we have applied fluorescence in situ hybridization on isolated interphase cells from paraffin sections of 79 primary tumors of malignant melanomas: 47 nodular melanomas and 32 superficial spreading melanomas in various stages. We used centromeric probes for the chromosomes 1, 4, 6, 7, 9, 10, 11, 12, 15, 17, 18, X, and Y and a midisatellite probe localized in 1p36. The number of chromosomal aberrations and the ploidy of the cells rose with the tumor stage in both subtypes, although in superficial spreading melanomas, fewer chromosomal abnormalities were detectable than in nodular melanomas. A deletion in 1p36 could only be found in nodular melanomas (mostly in higher tumor stages), not in superficial spreading melanomas. Our results show that the different histologic subtypes of malignant melanoma of the skin differ also in their chromosomal aberrations. In addition, it seems that there may be a correlation between the growth characteristics and putative tumor suppressor genes on 1p36.     

The alcohol deprivation effect in the alcohol-preferring P rat under free-drinking and operant access conditions

The alcohol-deprivation effect (ADE) was examined under 4-hr operant and 24-hr free-choice alcohol access in the alcohol-preferring (P) rat after deprivation intervals from 2 to 4 weeks. Results indicated that adult male P rats responding for 6 weeks on a concurrent FR-5/FR-1 schedule of reinforcement for alcohol and water, respectively, and then deprived of alcohol for 2 weeks, demonstrated a 40% increase in alcohol responding during the first 60 min of alcohol reinstatement. The alcohol deprivation effect was temporary, however, as responding did not differ from baseline levels on the second day of reinstatement. In a second experiment, weanling male and female P rats received 7 weeks of continuous access to alcohol, beginning at 21 days of age, and were then deprived of alcohol for 4 weeks. On the first day of alcohol reinstatement, P rats exhibited a 40% to 45% increase from baseline alcohol drinking levels, with alcohol intake returning to baseline levels by the 3rd day of reinstatement. Although alcohol intake was higher in females than in males when adjustment was made for body weight, there were no gender differences in the magnitude of the alcohol deprivation effect. Taken together, these results indicate that the ADE is a long-lasting phenomenon that occurs under both operant and continuous access conditions in the P rat, and thus these rats may be useful models for the study of factors involved in relapse of alcohol drinking.     

Decreased response to phototherapy for neonatal jaundice in breast-fed infants

OBJECTIVE: To evaluate the efficacy of phototherapy for nonhemolytic hyperbilirubinemia in breast-fed and formula-fed infants and infants receiving formula and breast milk. DESIGN: Prospective study. SETTING: Nursery for healthy infants. METHOD: Full-term healthy infants with nonhemolytic hyperbilirubinemia (bilirubin concentration, >255 micromol/L [14.9 mg/dL] or 222 micromol/L [13.0 mg/dL] at ages younger than 48 hours) were treated with conventional phototherapy by using daylight fluorescent lamps. Three groups of infants were studied: group 1, formula-fed infants; group 2, breast-fed infants; and group 3, infants receiving formula and breast milk. All patterns of feeding started at birth. Phototherapy was terminated only when bilirubin concentrations had decreased to less than 185 micromol/L (10.8 mg/dL); the minimum exposure period was 24 hours. RESULTS: A total of 163 infants were studied: group 1, 79; group 2, 34; and group 3, 50. The age at the start of exposure was comparable in all groups. The mean+/-SD weight loss as a percentage of birth weight was as follows: group 1, 2.8%+/-5.0%; group 2, 6.1%+/-3.4%; and group 3, 3.2%+/-2.6%. The duration of exposure to phototherapy was as follows: group 1, 54.1+/-20.8 hours; group 2, 64.6+/-25.1 hours; and group 3, 54.9+/-21.5 hours; the 24-hour rate of decrease in the bilirubin concentration was as follows: group 1, 18.6%+/-11.7%; group 2, 17.1%+/-9.6%; and group 3, 22.9%+/-9.4%. The overall rate of decrease in the bilirubin concentration for the duration of exposure to phototherapy was as follows: group 1, 0.8%+/-0.3% per hour; group 2, 0.6%+/-0.3% per hour; and group 3, 0.8%+/-0.3% per hour. Weight loss at the start of phototherapy was significantly greater in group 2 compared with group 1 (P<.001) and group 3 (P<.001), although the hemoglobin and hematocrit values were comparable. The duration of exposure to phototherapy was not significantly different in the 3 groups (P=.06); however, the duration of exposure of group 2 infants was 10 hours more than that of the other 2 groups. The 24-hour rate of decrease in the bilirubin concentration in group 3 was significantly better than that of group 2 (P = .007) and group 3 (P = .02); the rates of decrease for groups 2 and 3 were similar (P = .52). The overall rate of decrease in the bilirubin concentration during the duration of exposure to phototherapy in group 2 was significantly less than that of group 1 (P = .002) and group 3 (P<.001); the rates for groups 1 and 3 were similar (P = .35). The postexposure rebound bilirubin concentrations were comparable in all groups during the first 2 days; however, the duration of moderate jaundice in group 2 was more prolonged. CONCLUSIONS: The response to phototherapy of group 2 infants was significantly slower than that of group 3 and group 1 infants; this response was still of adequate efficacy. The addition of formula to the feedings for totally breast-fed infants, without suspension of breast-feeding, would enhance the efficacy of phototherapy and reduce exposure time.     

Physical abuse among depressed women

BACKGROUND: The evidence-based approach to medical care involves the explicit use of evidence on the magnitude of the effects of interventions to inform diagnostic and treatment decisions. This article critiques current mainstream guidelines on the management of hypertension in the elderly (aged 60 years and over) and presents an alternative evidence-based approach. METHODS: Three major national and international guidelines for the management of hypertension from the United Kingdom (UK), the United States (US) and from a joint World Health Organisation/International Society of Hypertension (WHO/ISH) Working Party were appraised and the evidence on which they were based was reviewed. The relevant evidence was also assessed to determine the likely magnitude of risks and benefits of anti-hypertensive treatment in older people and an alternative approach to making treatment decisions, based on the New Zealand guidelines for the management of hypertension, is described. RESULTS: Hypertension management guidelines from the UK, US and WHO/ISH made similar recommendations about which elderly patients should be treated, although there were some ambiguities in their advice. Treatment recommendations were based primarily on blood pressure levels which were set at about 160 mm Hg systolic and/or 90 mm Hg diastolic. The threshold levels were based mainly on the cut-off blood pressure levels used in randomised trials of anti-hypertensive drug treatment, rather than the estimated magnitude of treatment benefit. Each of the guidelines acknowledged the important effect of associated cardiovascular disease (CVD) risk factors on the likely benefits of treatment, but did not expand on the magnitude of this effect. No patient-specific estimates of the likely absolute benefits of treatment were provided in any of the guidelines. In contrast the New Zealand guidelines for the management of hypertension recommend the use of explicit estimates of absolute CVD risks and benefits to inform treatment decisions. They were designed to provide practitioners with estimates of the likely absolute risk of CVD in patients with different risk factor profiles and with estimates of the absolute benefits of treatment. The New Zealand guidelines recommend that drug treatment be considered in patients with a 5-year risk of CVD of about 10-15% or more; approximately 25 patients with a 10-15% risk would require treatment for 5 years to prevent one CVD event. As elderly patients are generally at higher absolute CVD risk than younger people, the New Zealand recommendation give priority to the treatment of older patients. In order to take account of differences in life expectancy and the medical costs of caring for elderly people, absolute risk-based guidelines can be improved by incorporating potential years of life gained from treatment and the cost-effectiveness of treatment expressed as $/quality adjusted life years gained. Preliminary analyses indicate that the cost-effectiveness of treatment is generally greatest in patients in their 60s and early 70s. Treatment in younger people is not usually very cost-effective because of their low absolute risk of CVD and the cost-effectiveness of treatment in people over about 75 years declines because of the increasing cost of non-CVD morbidity. CONCLUSIONS: The explicit assessment of absolute CVD risks and likely treatment benefits in patients with hypertension can usefully inform treatment decisions and provide a more rational basis for initiating therapy than blood pressure levels alone. This approach highlights the generally greater CVD risk and potential treatment benefits in older compared with younger hypertensive patients. The absolute risk-based approach can be further enhanced by providing decision makers with patient-specific data on the potential life years gained from treatment and its cost-effectiveness. (ABSTRACT TRUNCATED)     

Exploring the potential of problem-based learning in nurse education

Despite the increased attention that problem-based learning has received as an appropriate pedagogical technique for educating adults for professional practice, reports that evaluate the process are rare and usually relate to professions other than nursing. A study was undertaken in order to discover the graduates' own perceptions of a problem-based learning programme and its effectiveness in preparing them for the reality of their chosen profession. Twelve practising graduate nurses who had completed the programme were interviewed according to the ethnographic method. Three categories were identified from the data: 'and all of a sudden...', which describes the transition from PBL student to staff nurse; 'not an unthinking assistant', where the characteristics that the PBL graduates believe make them different from traditionally trained nurses are described; and 'the buck stops here', which describes the sense of personal responsibility that the graduates experience in terms of their learning and actions.     

Protein thermostability above 100 degreesC: a key role for ionic interactions

The discovery of hyperthermophilic microorganisms and the analysis of hyperthermostable enzymes has established the fact that multisubunit enzymes can survive for prolonged periods at temperatures above 100 degreesC. We have carried out homology-based modeling and direct structure comparison on the hexameric glutamate dehydrogenases from the hyperthermophiles Pyrococcus furiosus and Thermococcus litoralis whose optimal growth temperatures are 100 degreesC and 88 degreesC, respectively, to determine key stabilizing features. These enzymes, which are 87% homologous, differ 16-fold in thermal stability at 104 degreesC. We observed that an intersubunit ion-pair network was substantially reduced in the less stable enzyme from T. litoralis, and two residues were then altered to restore these interactions. The single mutations both had adverse effects on the thermostability of the protein. However, with both mutations in place, we observed a fourfold improvement of stability at 104 degreesC over the wild-type enzyme. The catalytic properties of the enzymes were unaffected by the mutations. These results suggest that extensive ion-pair networks may provide a general strategy for manipulating enzyme thermostability of multisubunit enzymes. However, this study emphasizes the importance of the exact local environment of a residue in determining its effects on stability.     

The biology of leptin: a review

Leptin, a 16-kDa protein secreted from white adipocytes, has been implicated in the regulation of food intake, energy expenditure, and whole-body energy balance in rodents and humans. The gene encoding leptin was identified by positional cloning and is the mutation leading to the profound obese phenotype of the ob/ob mouse. Exogenous administration of leptin to ob/ob mice leads to a significant improvement in reproductive and endocrine status as well as reduced food intake and weight loss. The expression and secretion of leptin is highly correlated with body fat mass and adipocyte size. Cortisol and insulin are potent stimulators of leptin expression, and expression is attenuated by beta-adrenergic agonists, cAMP, and thiazolidinediones. The role of other hormones and growth factors in the regulation of leptin expression and secretion is emerging. Leptin circulates specifically bound to proteins in serum, which may regulate its half-life and biological activity. Isoforms of the leptin receptor, members of the interleukin-6 cytokine family of receptors, are found in multiple tissues, including the brain. Many of leptin's effects on food intake and energy expenditure are thought to be mediated centrally via neurotransmitters such as neuropeptide Y. Multiple peripheral effects of leptin have also been recently described, including the regulation of insulin secretion by pancreatic beta cells and regulation of insulin action and energy metabolism in adipocytes and skeletal muscle. Leptin is thought to be a metabolic signal that regulates nutritional status effects on reproductive function. Leptin also plays a major role in hematopoeisis and in the anorexia accompanying an acute cytokine challenge. The profound effects of leptin on regulating body energy balance make it a prime candidate for drug therapies for humans and animals.