Endocrine effects of dehydroepiandrosterone and its fluorinated analog,fluasterone, in rats

Cancer chemoprevention is the use of pharmacologic agents to inhibit the development of cancer. The adrenal steroid dehydroepiandrosterone (DHEA) has demonstrated chemopreventive efficacy in animal models of tumorigenesis. However, due to DHEA's undesirable hormonal actions, the fluorinated analog fluasterone (fl‐DHEA), which also has chemopreventive characteristics, was synthesized as a potential alternate agent. It is not known whether fl‐DHEA has hormonal actions. The endocrinologic effects of DHEA and fl‐DHEA in adult male and female Fischer 344 rats were examined following 28 days of daily oral treatment. Initial doses tested were 30 and 300 mg/kg/day for each drug (n=12/sex/group), which are equivalent to 104 and 1,042 µmoles/kg/day DHEA, and 103 and 1,034 µmoles/kg/day fl‐DHEA. However, due to weight loss at the high dose, doses were lowered to 150 mg/kg/day for each drug (521 and 517 µmoles/kg/day DHEA and fl‐DHEA, respectively). Administration of DHEA resulted in dose‐dependent increases in plasma DHEA and DHEA‐S 1 h after dosing in week 4. DHEA produced an estrogenic effect in female rats expressed as decreased plasma FSH and LH, inhibition of ovulation, prolonged estrus, and increased uterine estrogen receptors. DHEA also increased plasma levels of androstenedione in males and females. Administration of fl‐DHEA increased the estrus cycle length due to a prolonged diestrus II phase and decreased the weights of the uterus, prostate, seminal vesicles, and testes. In addition, fl‐DHEA decreased plasma FSH, LH, and tissue estradiol, and increased plasma dihydrotestosterone levels in both sexes. These results indicate that fl‐DHEA is hormonally active and additional studies are warranted to further describe its endocrinologic effects. Drug Dev. Res. 58:169–178, 2003. © 2003 Wiley‐Liss, Inc.     

Effects of a high-selenium yeast supplement on celecoxib plasma levels: a randomized phase II trial.

A combination of celecoxib and selenium was used in a randomized double-blind Phase II trial as a preliminary study to a multicenter Phase III colorectal cancer chemoprevention trial using these two agents together. The purpose of this trial was to determine whether high-selenium baker's yeast [(Saccharomyces cerevisiae) 200 microg once daily] in combination with celecoxib (400 mg once daily) altered the steady-state plasma concentration of celecoxib or produced clinically significant toxicities. Seventy-three healthy subjects (ages 40-75 years) were recruited to the 6-week study from the general local population and were randomized to either the celecoxib plus selenized baker's yeast group or the celecoxib plus placebo group after a 2-week run in period of celecoxib only. Blood samples were taken at baseline (to document that there was no evidence of celecoxib intake), after the 2-week run-in period on celecoxib to verify steady-state blood levels of this agent, and at end of study (4 weeks postrandomization). Toxicities were monitored at 2 weeks after initiation of celecoxib, at 4 weeks after initiation, and at the end of the study. Blood level concentrations of celecoxib did not differ between the two groups as determined by high-performance liquid chromatography analysis nor were there significant differences in blood chemistry values between the two groups. Subjects' self-report of general physical toxicities was uncommon and limited to National Cancer Institute toxicity grade 2 or less; however, 2 female participants (3%) were removed from the study medications because of grade 2 edema and significant weight gain after 2 and 2.5 weeks of celecoxib administration. In conclusion, high-selenium yeast and celecoxib can be taken at the described doses with minimum short-term negative effects. In future Phase III chemoprevention trials of celecoxib, weight gain should be carefully monitored, and participants should be made aware of this potential side effect before study entry.     

Use and need for post-acute services following paediatric head injury

This paper aims to document the types of inpatient and outpatient post-acute services children receive after discharge from an acute care hospital for head injury and to better understand the extent to which children fail to receive services and the reasons for not receiving needed services. A follow-up was conducted on 95 children (aged 5-15) 1 year after they were hospitalized for head injury. Parents were interviewed by phone concerning their child's use of and need for medical, rehabilitation, and social services since the injury. Questions were also asked regarding the child's current health status and behaviour. Inpatient records were reviewed to obtain information on the characteristics of the injury. Overall use of outpatient rehabilitation and social services was low during the year following injury, ranging from 0-18% of the study sample. Although need for and use of services was positively correlated with head injury severity, it appears that unmet need was highest for children with the least severe head injuries. Finally, need for physical or occupational therapy and mental health services was unrecognized for one third of children with physical limitations and 40% of children with at least 14 identified behaviour problems. These findings underscore the need for physicians and other health care professionals to thoroughly evaluate children during follow-up visits as well as during the initial hospitalization for head injury-related deficits. Identification of functional deficits or behavioural problems should be followed-up by evaluation and treatment by qualified rehabilitation professionals.     

Formal retrospective case review and sudden infant death

A review of 24 consecutive sudden infant deaths was undertaken to evaluate the importance of the various stages in the postmortem assessment of such cases. Death in three cases was caused by obvious trauma. Of the remainder, 16 were attributed to sudden infant death syndrome (SIDS), 4 to accidental asphyxia (identified by death scene examination and/or formal case review) and 1 to a lingual thyroglossal duct cyst. Three (14%) of 21 deaths thought to be SIDS after postmortem examination were attributed to asphyxia following subsequent formal case review.     

Recombinant human relaxin as a cervical ripening agent

Objective The aim of this study was to investigate the efficacy and safety of recombinant human relaxin (rhRIx) as a cervical ripening agent in women with an unfavourable cervix before induction of labour at term.
Design A multi-centre, double-blind, placebo-controlled trial performed in Edinburgh, Glasgow and Oxford. Women were treated with 0, 1, 2 or 4 mg of rhRIx in a gel vehicle administered intravaginally. Analysis of variance tests were performed on all continuous variables, and Cochran Mantel-Haenszel tests employed for all discrete variables.
Participants Ninety-six women at 37 to 42 weeks of gestation with a singleton pregnancy and a modified Bishop score of 4 were recruited.
Results There was no significant difference in the change in modified Bishop score between the four treatment groups. The lengths of the first and second stages of labour were similar in all 4 groups. PGE₂ and oxytocin requirements were similar in all groups, as was the mode of delivery. There was no evidence that relaxin was absorbed systemically when given in this way.
Conclusion Recombinant human relaxin 1 to 4 mg, administered as an intravaginal gel, has no effect as a cervical ripening agent before induction of labour at term.     

Alcohol intake is associated with altered pulmonary function.

Little is known about the effect of moderate alcohol intake on lung function in the general population. Because moderate alcohol intake appears to reduce cardiovascular disease risk, we hypothesized that moderate alcohol intake is associated with better pulmonary function. To test this hypothesis, we examined the association between alcohol intake and pulmonary function, measured by spirometry, in a representative sample of U.S. adults who participated in the Third National Health and Nutrition Examination Survey. A stratified multistage clustered probability design was used to select a population-based sample. Data analyzed included alcohol intake, smoking status, education, body mass, sex, age, race, diabetes status, and CHF status. The Third National Health and Nutrition Examination Survey was conducted from 1988 to 1994 by the National Center for Health Statistics of the Centers for Disease Control and Prevention, Atlanta, GA. We analyzed data from 15,294 study participants who completed extensive questionnaires in the household and a comprehensive physical examination, including pulmonary function testing, either in the household or at a specially equipped mobile examination center. Low-to-moderate alcohol intake was not associated with reduced odds of obstructive lung function. In fact, increased odds for obstructive lung pattern were observed only in former heavy drinkers. In contrast, low-to-moderate alcohol intake was associated with better forced vital capacity and forced exhaled volume in 1s in the absence of obstruction, consistent with reduced odds for lung restriction. Using a logistic regression model, we found that individuals reporting alcohol consumption had a lower risk of lung restriction both before and after adjusting for confounding factors including smoking (P< or =.001). Alcohol intake-related reduced risk for restriction was associated with lower risk of CHF, diabetes, obesity, and lower markers of inflammation (white blood cell, fibrinogen, and C-reactive protein) consistent with less lung congestion, external restriction, and/or lung inflammation. Our analyses indicate that alcohol consumption, even at very modest intake levels, is associated with less lung restriction.     

Determinants of disability after lower extremity fracture

BACKGROUND: Factors influencing the progression of physical impairment to patient-perceived disability are not well known. We sought to better understand this relationship in the setting of injury. METHODS: We followed a cohort of 302 patients with lower extremity fractures over a 1-year period. Physical impairment was assessed by range of motion, strength, and pain. Range of motion and strength were assessed together as a proportion of normal function of the extremity (impairment score). Pain was assessed using a Visual Analogue Scale (VAS) pain score. Disability was assessed using the Sickness Impact Profile (SIP), a widely used measure of patient-perceived limitations of everyday activities attributable to illness. The SIP was administered during hospitalization to assess preinjury baseline. Impairment assessment and readministration of the SIP were performed at 12 months after injury. RESULTS: Impairment in leg function (range of motion and strength) was highly correlated (p < 0.001) with overall SIP score at 12 months, but accounted for only 23% of the variance in overall SIP scores. Likewise, VAS pain score was highly correlated (p < 0.001) with overall SIP score at 12 months, but accounted for only 29% of the variance in overall SIP scores. In a multivariate linear regression analysis, variables that were independently associated with overall SIP score included impairment score, VAS pain score, preinjury SIP, poverty status, education status, social support, having hired a lawyer, and involvement with workers' compensation. These variables accounted for 52% of the variance in overall SIP scores at 12 months. CONCLUSION: The degree of physical impairment accounts for only a small amount of the variance in disability from lower extremity fracture. Identifiable patient characteristics including age, socioeconomic status, preinjury health, and social support together with impairment account for over half of the variance in long-term disability. Further research is needed to increase understanding of other factors that influence the progression of impairment to disability, especially those factors that may be amenable to intervention.