Structural Requirements for the Direct and Cytochrome P450-dependent Reaction of Cyclic α,β-Unsaturated Carbonyl Compounds with Glutathione: a Study with Coumarin and Related Compounds

Abstract— The interaction of glutathione (GSH) with coumarin, or one of a series of compounds related to coumarin, was assessed in the absence and presence of liver microsomes (direct reaction and indirect reaction, respectively) to determine the structural requirements for direct and mono-oxygenase-mediated reaction of cyclic α,β-unsaturated carbonyls with GSH. Acrolein was used as a positive control for the direct reaction, and produced complete or nearly complete depletion of GSH under all assay conditions. 5,6-Dihydro-2H-pyran-2-one and 2-cyclohexen-1-one also produced substantial depletion of GSH in the direct reaction, which was not increased by the addition of liver microsomes. Coumarin, 2H-pyran-2-one and precocene I (a substituted pyran lacking the 2-one structure) were not substrates for the direct reaction but did cause depletion of GSH when incubated in the presence of rat or human liver microsomes. These depletions were dependent on a functioning mono-oxygenase system as judged by the effects of omission of cofactors, addition of competitive or inactivating inhibitors of cytochrome P450, and induction. Dihydrocoumarin, ?-valerolactone, cyclohexanone and 4H-pyran-4-one were not substrates for either the direct or indirect reaction. These findings are rationalized on the basis of a direct nucleophilic attack of GSH on the α,β-centre of the α,β-unsaturated carbonyl compounds, which is hindered by benzenoid resonance in coumarin and 2H-pyran-2-one, for which enzyme-mediated reaction with GSH, probably via a 3,4-epoxide, is the favoured mechanism.     

A survey of forensic psychologists’ work with sex offenders in England and Wales

This paper describes the results of a survey of the extent and variety of work with sex offenders by psychologists working in different forensic settings in England and Wales. A postal questionnaire was sent out to all 199 psychologists in the special hospitals, regional forensic psychiatry services, prisons and youth treatment service requesting details about their work with sex offenders during the year June 1991 to July 1992. The results are described under the headings of assessment and treatment; supervision, consultation, teaching and training; research and evaluation. The discussion highlights some of the patterns and trends of the work of forensic psychologists with sex offenders, together with the range of psychological interventions. There are also patterns within services. Results of the survey highlight the links psychologists have with other disciplines in working with sex offenders and raise questions about the most appropriate model of psychology practice, given the limited resources.     

Evaluation of an Australian intervention to encourage breast feeding in primiparous women

Breast feeding has nutritional, immunologic and antiallergicadvantages for the infant. Although it has been widely recommendedthat infants be exclusively breast fed until 4–6 monthsof age, only about half of all Australian babies currently receiveextended breast feeding. The present study evaluated an intensiveprogramme designed to increase the proportion ofprimi-parousmothers who breast fed for 4 months or longer. Women who registeredwith the hospital at least 20 weeks before delivery and whointended to breastfeed were eligible for the study. Two hundredand thirty-five women were allocated to receive either usualcare or an intensive breast feeding programme when they registeredwith the hospital. The intensive programme consisted of writtenmaterials, and group and individual sessions with a lactationcounsellor. It also included a visit from a breastfeeding consultantwhile in hospital after the birth and contact on return home.Women were followed up 6 weeks and 4 months after delivery.There were no significant differences in breastfeeding ratesbetween the control and intervention groups at either follow-uppoint. Breast feeding until 4 months was more likely among womenwhose baby did not receive a bottle feed while still in hospitaland who did not smoke, use the combined oral contraceptive pillor introduce solid food before 4 months. Those mothers who enjoyedand felt satisfied with breastfeeding were more likely to continueto 4 months. It seems likely that programmes designed to increasebreastfeeding will need to address underlying factors such ashospital policy rather than simply providing more health education.     

The Developmental Toxicity of Diethylene Glycol Dimethyl Ether in Mice

The Developmental Toxicity of Diethylene Glycol Dimethyl Etherin Mice. PRICE, C. J., KIMMEL, C. A., GEORGE, J. D., AND MARR,M. C. (1987). Fundam. Appl. Toxicol. 8, 115–126. Diethyleneglycol dimethyl ether (diEGdiME) is structurally related toseveral compounds which produce reproductive and developmentaltoxicity, including teratogenicity in laboratory animals. Inthe present study, diEGdiME (0, 62.5, 125, 250, or 500 mg/kg/day)was administered by gavage in distilled water to timed-pregnantCD-1 mice during major organogenesis [gestational days (gd)6–15]. Clinical status of treated females was monitoreddaily during treatment and on gd 17. At sacrifice (gd 17), pregnancywas confirmed by uterine examination for 20–24 dams pergroup; each live fetus was examined for external, visceral,and skeletal malformations. No maternal deaths, morbidity, ortreatment-related clinical signs were observed. Reduced maternalweight gain during treatment at 250 mg/kg/day was primarilyattributed to compromised pregnancy status resulting in reducedgravid uterine weight. Maternal weight gain during gestationcorrected for gravid uterine weight, and relative liver weight(% body weight) were not affected. Average fetal body weight/litterwas significantly reduced at 125 mg/kg/day. The percentageof postimplantation loss/litter (5, 8, 7, 12, and 50% for controlthrough high dose) and the percentage of malformed live fetuses/litter(0.4, 0, 2, 24, and 96%) were significantly increased at 250mg/kg/day. Developmental defects involved primarily the neuraltube, limbs and digits, craniofacial structures, abdominal wall,cardiovascular system, urogenital organs, and both the axialand appendicular skeleton. In summary, oral administration ofdiEGdiME during major organogenesis did not produce any distinctivesigns of maternal toxicity, but did produce selective and profoundadverse effects upon fetal growth, viability, and morphologicaldevelopment at 125 mg/kg/day.     

GENETIC POLYMORPHISM OF LIVER ALCOHOL DEHYDROGENASE IN SPANTSH SUBJECTS: SIGNIFICANCE OF ALCOHOL CONSUMPTION AND LIVER DISEASE

Class I alcohol dehydrogenase (ADH) phenotypes have been studiedby starch gel electrophoresis and activity analysis in livertissue obtained at necropsy from 61 non-alcoholic subjects withnormal liver (controls), and in biopsies from 60 chronic alcoholicswith liver disease and from 24 subjects with non-alcoholic liverdisease. Twenty-three per cent of controls exhibited the ADH₂^2–1phenotype, which represents the highest frequency for atypicalADH found in a Caucasian population. Both alcoholic and non-alcoholicpatients with liver disease showed a lower frequency of theatypical phenotype (6.6% and 8.8%, respectively). No differencesin the ADH₂ locus were detected among groups of patients withdifferent severity of alcoholic and non-alcoholic liver disease.Theallele frequencies of the ADH₃ locus for the controls (ADH₃¹= 0.63, ADH₃² = 0.37) are common to those of other Caucasianpopulations. Similar ADH₃ allele frequencies were observed inpatients with alcoholic and non-alcoholic liver disease. Discrepanciesbetween the various phenotyping and genotyping studies now knownfor several populations suggest that local differences may existin the distribution of the ADH polymorphism in even geographicallyclose regions, and that the effect of ADH polymorphism on vulnerabilitytowards alcohol may not be identical in different populations.     

Carisoprodol: Reproductive Assessment by Continuous Breeding in Swiss Mice

Carisoprodol (CARI), a commonly prescribed neuromuscular relaxant,was evaluated for reproductive toxicity in Swiss CD-1 mice usingthe Reproductive Assessment by Continuous Breeding (RACB) protocol.Male and female mice were given CARI in corn oil suspensionby daily gavage at doses of 0, 300, 750, and 1200 mg/kg bodywt/day. Clinical signs of general toxicity in Fo animals includedsedation, primarily in the high-dose group during the firstweek of exposure, and reduced body weight in high-dose females.CARI administration for 14 weeks did not affect the abilityof the F₀ animals to produce litters. However, decreases inproportion of pups born alive (4%) and absolute (5%) and adjustedlive pup weight (7%) were observed at 1200 mg/kg CARI when comparedto controls. In a crossover mating trial to determine the affectedsex, there were no significant differences in the measured reproductiveparameters. CARI at the high dose increased the proportion oftime spent in proestrus and estrus, but cycle length was unaffected.At F₀ necropsy (Week 27 of treatment), all sperm parameterswere normal. Right epididymis and liver weights, relative tobody weight, were increased (12 and 23%, respectively) overthe control group for high-dose males. A mating trial to determinethe fertility and reproductive competence of the F₁ generationshowed no effect of CARI on indices of mating, pregnancy, orfertility, the proportion of F₂ pups born alive, the sex ratioof live F₂ pups, live F₂ pup weight, or gestation length. However,decreases in the number of F₂ pups per litter (22%) and adjustedlive F₂ pup weight (8%) were observed in the high-dose group.Indications of generalized toxicity in the F₁ generation includeddecreased survival through Postnatal Day 21 at 750 (5%) and1200 (9%) mg/kg CARI, and transiently decreased body weightsduring postnatal development and as adults for males and femalesat all dose levels. At necropsy, there was no effect of treatmenton the relative weight of any male or female reproductive organs;testicular spermatid concentration was reduced at all levelsof CARI. Relative liver weight was increased for females at300 mg/kg and for males and females at both 750 and 1200 mg/kg.In summary, CARI produced generalized toxicity and moderateeffects on the reproductive processes of F₀ and F₁ generationSwiss mice during chronic exposures of up to 1200 mg/kg/day.     

The Developmental Toxicity of Ethylene Glycol Diethyl Ether in Mice and Rabbits

Timed-pregnant CD-1 outbred Albino Swiss mice and New ZealandWhite rabbits were dosed by gavage with ethylene glycol diethylether (EGdiEE) in distilled water during major organogenesis.Mice were dosed on Gestational Days (gd) 6 through 15 (0, 50,150, 500, or 1000 mg/kg/day) and rabbits on gd 6 through 19(0, 25, 50, or 100 mg/kg/day). Maternal clinical status wasmonitored daily during treatment. At termination (gd 17, mice;gd 30, rabbits), confirmed-pregnant females (22–24 pergroup, mice; 26–32 per group, rabbits) were evaluatedfor clinical status and gestational outcome; each live fetuswas examined for external, visceral, and skeletal malformations.In mice, no maternal mortality was observed, but maternal bodyweight gain during gestation and treatment, and at terminationwas reduced at 1000 mg/kg/day. The reduction of maternal bodyweight gain during gestation was secondary to embryo/fetal toxicity,i.e., reduced gravid uterine weight as a consequence of decreasedlitter size and fetal weight. The no-observed adverse effectlevel (NOAEL) for developmental toxicity was 50 mg/kg/day. At150 mg/kg/day the number of litters of mice with malformed fetuseswas increased. At 500 mg/kg/day fetal body weight was reduced,and malformation incidence was significantly increased. Exencephalyand fused ribs were observed most often. In rabbits, maternalbody weight was unaffected by treatment even though 6% maternalmortality was observed at 100 mg/kg/day. The developmental NOAELwas 25 mg/kg/day. Malformations were increased at 50 mg/kg/day,short tail, small spleen, fused sternebrae, and fused rib cartilagewere observed most often. In summary, oral administration ofEGdiEE to mice and rabbits during organogenesis produced profoundadverse developmental effects even in the absence of significantmaternal toxicity. Developmental effects in rabbits were morevaried.     

Legal Protections in Public Accommodations Settings: A Critical Public Health Issue for Transgender and Gender‐Nonconforming People

Context

Gender minority people who are transgender or gender nonconforming experience widespread discrimination and health inequities. Since 2012, Massachusetts law has provided protections against discrimination on the basis of gender identity in employment, housing, credit, public education, and hate crimes. The law does not, however, protect against discrimination in public accommodations (eg, hospitals, health centers, transportation, nursing homes, supermarkets, retail establishments). For this article, we examined the frequency and health correlates of public accommodations discrimination among gender minority adults in Massachusetts, with attention to discrimination in health care settings.

Methods

In 2013, we recruited a community-based sample (n = 452) both online and in person. The respondents completed a 1-time, electronic survey assessing demographics, health, health care utilization, and discrimination in public accommodations venues in the past 12 months. Using adjusted multivariable logistic regression models, we examined whether experiencing public accommodations discrimination in health care was independently associated with adverse self-reported health, adjusting for discrimination in other public accommodations settings.

Findings

Overall, 65% of respondents reported public accommodations discrimination in the past 12 months. The 5 most prevalent discrimination settings were transportation (36%), retail (28%), restaurants (26%), public gatherings (25%), and health care (24%). Public accommodations discrimination in the past 12 months in health care settings was independently associated with a 31% to 81% increased risk of adverse emotional and physical symptoms and a 2-fold to 3-fold increased risk of postponement of needed care when sick or injured and of preventive or routine health care, adjusting for discrimination in other public accommodations settings (which also conferred an additional 20% to 77% risk per discrimination setting endorsed).

Conclusions

Discrimination in public accommodations is common and is associated with adverse health outcomes among transgender and gender-nonconforming adults in Massachusetts. Discrimination in health care settings creates a unique health risk for gender minority people. The passage and enforcement of transgender rights laws that include protections against discrimination in public accommodations—inclusive of health care—are a public health policy approach critically needed to address transgender health inequities.     

Empowerment, engagement and perceived effectiveness in nursing work environments: does experience matter?

Aims  We examined the impact of empowering work conditions on nurses' work engagement and effectiveness, and compared differences among these relationships in new graduates and experienced nurses.
Background  As many nurses near retirement, every effort is needed to retain nurses and to ensure that work environments are attractive to new nurses. Experience in the profession and generational differences may affect how important work factors interact to affect work behaviours.
Methods  We conducted a secondary analysis of survey data from two studies and compared the pattern of relationships among study variables in two groups: 185 nurses 2 years post-graduation and 294 nurses with more than 2 years of experience.
Results  A multi-group SEM analysis indicated a good fit of the hypothesized model. Work engagement significantly mediated the empowerment/effectiveness relationship in both groups, although the impact of engagement on work effectiveness was significantly stronger for experienced nurses.
Conclusions  Engagement is an important mechanism by which empowerment affects nurses feelings of effectiveness but less important to new graduates' feelings of work effectiveness than empowerment.
Implications for nursing management  Managers must be aware of the role of empowerment in promoting work engagement and effectiveness and differential effects on new graduates and more seasoned nurses.