Dose-ranging kinetics and behavioral pharmacology of naltrexone and acamprosate,both alone and combined,in alcohol-dependent subjects

We examined kinetic and dynamic factors to determine the pharmacological and behavioral safety and tolerability of low versus high doses of an opiate antagonist, naltrexone (50 mg/day vs. 100 mg/day), and acamprosate (2 g/day vs. 3 g/day), a functional N-methyl-D-aspartate receptor antagonist, both independently and combined, among non-treatment-seeking, alcohol-dependent individuals. This double-blind, double-dummy, placebo-controlled, randomized, 23-day, four-way crossover study involved 23 subjects assigned to one of four groups. Placebo washout (phase I) preceded phase II, where subjects received low-dose or high-dose naltrexone or acamprosate. In phases III and IV, the alternative medication type at its lower and higher doses, respectively, was administered with continuation of the phase II medication. Predetermined behavioral, performance, and pharmacological criteria determined significant pathological change from baseline (phase I). Case records were reviewed. Criterion-significant increases in symptoms from baseline with monotherapy included nervousness and fatigue with 3 g acamprosate and somnolence and headache with 50 mg and 100 mg naltrexone, respectively. Combined treatment at various doses evinced anger, depression, somnolence, nervousness, diarrhea, and headache. Notably, for all but one subject who dropped out, increased symptoms did not produce any remarkable clinical deterioration. Naltrexone administration significantly increased plasma acetylhomotaurine (i.e., acamprosate) levels, presumably by prolonging gastric emptying. The level of neither plasma acetylhomotaurine nor plasma 6-beta naltrexol (i.e., naltrexone's metabolite) predicted adverse-event frequency. Naltrexone and acamprosate, both alone and in combination at the tested doses, were behaviorally and pharmacologically safe. Adverse events were infrequent, were of moderate intensity, and resolved with reassurance and symptomatic treatment. More side effects were noted with the combination of medications than with either medication alone. Naltrexone administration significantly increased plasma acamprosate levels.     

Low-grade systemic inflammation and the development of type 2 diabetes: the atherosclerosis risk in communities study

To examine the association of low-grade systemic inflammation with diabetes, as well as its heterogeneity across subgroups, we designed a case-cohort study representing the approximately 9-year experience of 10,275 Atherosclerosis Risk in Communities Study participants. Analytes were measured on stored plasma of 581 incident cases of diabetes and 572 noncases. Statistically significant hazard ratios of developing diabetes for those in the fourth (versus first) quartile of inflammation markers, adjusted for age, sex, ethnicity, study center, parental history of diabetes, and hypertension, ranged from 1.9 to 2.8 for sialic acid, orosomucoid, interleukin-6, and C-reactive protein. After additional adjustment for BMI, waist-to-hip ratio, and fasting glucose and insulin, only the interleukin-6 association remained statistically significant (HR = 1.6, 1.01-2.7). Exclusion of GAD antibody-positive individuals changed associations minimally. An overall inflammation score based on these four markers plus white cell count and fibrinogen predicted diabetes in whites but not African Americans (interaction P = 0.005) and in nonsmokers but not smokers (interaction P = 0.13). The fully adjusted hazard ratio comparing white nonsmokers with score extremes was 3.7 (P for linear trend = 0.008). In conclusion, a low-grade inflammation predicts incident type 2 diabetes. The association is absent in smokers and African-Americans.     

Synthetic bedding and wheeze in childhood

BACKGROUND: The reasons for the increase in childhood asthma over time are unclear. The indoor environment is of particular concern. An adverse role for synthetic bedding on asthma development in childhood has been suggested by cross-sectional studies that have found an association between synthetic pillow use and childhood wheeze. Prospective data on infant bedding have not been available. METHODS: Bedding data at 1 month of age were available from an infant survey for children who were participating in a 1995 follow-up study (N = 863; 78% traced). The 1995 follow-up was embedded in a larger cross-sectional survey involving 6,378 seven year olds in Tasmania (N = 92% of eligible). Outcome measures included respiratory symptoms as defined in the International Study of Asthma and Allergies in Childhood protocol. Frequent wheeze was defined as more than 12 wheeze episodes over the past year compared with no wheeze. RESULTS: Synthetic pillow use at 1 month of age was associated with frequent wheeze at age 7 (adjusted relative risk [aRR] = 2.5; 95% confidence interval [CI] = 1.2-5.5) independent of childhood exposure. Current synthetic pillow and quilt use was strongly associated with frequent wheeze (aRR = 5.2; CI = 1.3-20.6). Substantial trends were evident for an association of increasing number of synthetic bedding items with frequent wheeze and with increasing wheeze frequency. Among children with asthma, the age of onset of asthma occurred earlier if synthetic bedding was used in infancy. CONCLUSIONS: In this cohort, synthetic bedding was strongly and consistently associated with frequent childhood wheeze. The association did not appear to be attributable to bedding choice as part of an asthma management strategy.     

Rural hospital focus: staffing

Rural and Remote Health is committed to the task of providing a freely accessible, international, peer-reviewed evidence base for rural and remote health practice. Inherent in this aim is a recognition of the universal nature of rural health issues that transcends both regional interests and local culture. While RRH is already publishing peer-reviewed material, the Editorial Board believes many articles of potential worth are largely inaccessible due to their primary publication in small-circulation, paper-based journals whose readership is geographically limited. In order to augment our already comprehensive, international evidence base, the RRH Editorial Board has decided to republish, with permission, selected articles from such journals. This will also give worthwhile small-circulation articles the wide audience only a web-based journal can offer. The RRH editorial team encourages journal users to nominate similar, suitable articles from their own world region. First, then, in what RRH hopes will become a regular feature, is a series of articles from the prominent South African rural doctor, Professor Ian Couper. This article first appeared in South African Family Practice 2000; 22 (5), and is reproduced here in its original form, with kind permission of both publisher and author. This article introduced a regular column feature in SAFP, 'Rural hospital focus', and was entitled 'Staffing'.     

Rural hospital focus: no transport, no primary health care

Rural and Remote Health is committed to the task of providing a freely accessible, international, peer-reviewed evidence base for rural and remote health practice. Inherent in this aim is a recognition of the universal nature of rural health issues that transcends local culture and regional interests. While RRH is already publishing such peer-reviewed material, the Editorial Board believes many articles of potential worth are largely inaccessible due to their primary publication in small-circulation, paper-based journals whose readership is geographically limited. In order to generate and make available a comprehensive, international evidence base, the RRH Editorial Board has decided to republish, with permission, selected articles from such journals. This will also give worthwhile small-circulation articles the wide audience only a web-based journal can offer. The RRH RRH editorial team encourages journal users to nominate similar, suitable articles from their own world region. This article 'Rural hospital focus: No transport, no primary health care', is second in our series. It first appeared in South African Family Practice 2000; 22 (6), and is reproduced here in its original form, with kind permission of both publisher and author, prominent South African rural doctor, Professor Ian Couper. 'Rural hospital focus' was the title of the SAFP column which presented this article.     

Indomethacin treatment of infantile cortical periostosis in twins

Twin girls presented with infantile cortical periostosis (Caffey's disease) at 2 and 3 weeks of age, respectively. This disorder initially involved their upper and lower limbs and resulted in fever, irritability and tenderness. X-rays showed extensive periosteal new bone formation. Multiple relapses occurred in the first year of life and during some of these relapses mandibular and clavicular involvement was noted. Prednisolone, 1 mg/kg per day, was used to treat relapses until 9 months of age. Indomethacin therapy at this age at a dose of 3 mg/kg per day allowed the cessation of prednisolone therapy and disease flares were thereafter infrequent and responsive to indomethacin.     

Cloning of rat betacellulin and characterization of its expression in the gastrointestinal tract

Betacellulin (BTC) is relatively a more recently discovered member of the EGF family of growth factors. As a prelude to its expression and functional studies in rat models of gut damage/repair, we have cloned rat BTC and examined its expression in the gastrointestinal tract. Rat BTC was found to be nearly identical to mouse betacellulin. A single 3 kb mRNA species was detected by Northern blotting, and ribonuclease protection analysis showed that its expression was ubiquitous but low in abundance throughout the gut. BTC mRNA and protein were found expressed in the gastric surface and upper pit epithelium as well as in some cells of gastric glands. In the jejunum, BTC mRNA and protein were localised to the crypt epithelium and in villous goblet cells. In the colon, BTC mRNA and protein were found produced in crypt and surface epithelium as well as in goblet cells. Taken together, the wide spread expression in the gut epithelium and in mucous cells in particular suggests an important and unique role for BTC in the gastrointestinal tract.     

Changes in body temperature and urinary cortisol after routine immunization in babies with intrauterine growth retardation

Aim : To investigate whether infants with intrauterine growth retardation (IUGR) experience different changes in temperature and cortisol excretion after routine immunization compared with normal healthy infants. Methods : Overnight deep body temperature and urinary cortisol to creatinine ratios were measured on the night after immunization and a control night in normal and IUGR infants. Results : In 60 normal infants, first vaccination at about 10 wk of age led to a significant increase in minumum overnight temperature compared to the control night, mean rise 0.25°C (95% CI, 0.12 to 0.38). In 35 IUGR infants the mean rise in temperature between immunization night and control night was 0.35°C (95% CI, 0.15 to 0.55). The increases in minimum temperature did not differ significantly between the normal and IUGR infants ( p = 0.11). Cortisol to creatinine ratios measured from overnight urine samples showed that 23 IUGR infants had consistently higher levels than 39 normal infants; control night medians 34 and 15 ( p = 0.01) and immunization night medians 56 and 26 ( p= 0.02), respectively. However, the percentage increase did not differ significantly between the IUGR infants and the normal infants. A smaller number of second immunizations were studied, but no significant differences were found.

Conclusion : These results suggest that although the impact of immunization is the same for IUGR and normal infants, because IUGR infants are less mature and at greater stress before immunization, the absolute levels that they experience after immunization are higher than those for normal infants.