Lifecourse socioeconomic predictors of midlife drinking patterns, problems and abstention: findings from the 1958 British Birth Cohort Study.

BACKGROUND: Research suggests that outcomes associated with drinking may differ depending upon patterns of consumption, drinking related symptoms and social problems. This paper investigated socioeconomic predictors (measuring multiple indices, period and consistency of disadvantage) of midlife drinking patterns. METHODS: Socioeconomic information from the 1958 British Birth Cohort Study (n=9146) included: manual socioeconomic position and owner/buyer residential tenure (7, 11, 16, 33 and 42 y), and educational attainment (33 y). At 45 y, the overlap between drinking patterns was explored using the Alcohol Use Disorders Identification Test. Patterns included: 'Moderate-binge' (binge drinkers with low-problem scores, consuming within UK sensible drinking weekly guidelines); Low-Problem Heavy (LPH) drinkers (regardless of binge); 'Problem' (and heavy or binge) and 'Non-/occasional' (< or =monthly) drinkers. These categories were compared to 'Low-risk' drinkers. RESULTS: Socioeconomic disadvantage was consistently associated with moderate-binge, non-/occasional and problem but not LPH drinking. The highest risk was associated with multiple and persistent disadvantage across childhood and adulthood; this risk was partially accounted for education. Non-/occasional and moderate-binge drinking was predicted by disadvantage during childhood alone. The socioeconomic disadvantage of non-/occasional drinkers was not explained by past problem or heavy drinking. CONCLUSIONS: Socioeconomic disadvantage across the lifecourse was consistently linked to specific drinking patterns. Furthermore, associations linking socioeconomic disadvantage with drinking patterns will typically be underestimated if multiple and persistent disadvantage is not investigated. The role of persistent socioeconomic disadvantage in the poor health of non-drinkers and moderate-binge drinkers needs investigation. The findings support current initiatives targeting the reduction of social and individual costs associated with specific drinking patterns.

Drinking histories of self-identified lifetime abstainers and occasional drinkers: findings from the 1958 British Birth Cohort Study.

AIMS: To investigate the validity of retrospective items used to distinguish people who have rarely or never consumed alcohol. METHODS: The 1958 British Birth Cohort Study has followed 9377 individuals until age 45. Previous drinking (at 16, 23, 33 and 42 years) was investigated for two groups of 45-year-old non-drinkers, those reporting never having consumed alcohol ('never drinkers', n = 143, 1.5%), and having only consumed very infrequently ('occasional-only drinkers', n = 1149, 12.3%). RESULTS: 67% of never drinkers previously reported drinking, 25% were past weekly/daily drinkers; 56% of occasional-only drinkers reported weekly/daily consumption. The validity of the retrospective items was progressively questionable when presumed to cover longer time periods. CONCLUSIONS: Substantial measurement error was evident when identifying 'occasional-only' and 'never' drinkers using retrospective items covering the lifecourse. Researchers investigating potential health benefits associated with moderate drinking need to incorporate more sophisticated methods when identifying sub-groups of non-drinkers.

General practice encounters for psychological problems in rural, remote and metropolitan areas in Australia.

OBJECTIVE: Previous Australian research suggests there is very little difference in the prevalence of mental health disorders across rural, remote and metropolitan areas. However, mental health specialists are particularly scarce in rural and remote areas and some researchers have argued that non-metropolitan residents rely heavily on general practitioners (GPs) for mental health care. This article investigated rates of GP services for psychological problems across rural, remote and metropolitan areas. METHOD: The Bettering the Evaluation and Care of Health (BEACH) program, Medicare and Pharmaceutical Benefits Scheme data were used in this report. Data included all psychological, depression and anxiety problems reported as managed by GPs and prescriptions for mental health medications (written and filled). Problem and medication rates are given per 100 patient encounters and per 1000 population. RESULTS: Only a few regional differences were evident in the rate of psychological problems and prescriptions for mental health medications per 100 GP-patient encounters. However, rural and remote residents visited GPs less frequently than their metropolitan counterparts. Lower rates of GP encounters for psychological problems were evident for residents of most non-metropolitan areas (per 1000 population). Additionally, GPs prescribed mental health medications at half the rate for residents of remote areas than capital cities. CONCLUSIONS: General practitioners provide fewer mental health services per capita in non-metropolitan areas. This difference could represent completely untreated psychological problems or fewer follow-up consultations. While non-metropolitan residents have limited access to specialists, rates of GP encounters for psychological problems are also very low.

Patterns of association between alcohol consumption and symptoms of depression and anxiety in young adults.

AIMS: Recent epidemiological findings indicate that non-drinkers as well as hazardous/harmful drinkers experience higher levels of distress than moderate drinkers. Little is known about the age at which this develops. This paper examines levels of affect, depression and anxiety over the full range of alcohol consumption in young adults. DESIGN: Cross-sectional findings from the first wave of a prospective, longitudinal study are presented. PARTICIPANTS: The general population sample comprised of 2404 young adults (aged 20-24 years). living in the Canberra region. Measures included: the Goldberg Depression and Anxiety scales, the Positive and Negative Affect Schedule, and the Alcohol Use Disorders Identification Test. FINDINGS: For men, both non/occasional and hazardous/harmful consumption were associated with lower levels of positive affect and higher levels of anxiety and depression. The higher levels of distress evident for male abstainers were related to being less extroverted and less healthy and not to past hazardous/harmful alcohol consumption, current tobacco or marijuana use. For women, only hazardous/harmful drinkers were found to have higher levels of depression and negative affect. Hazardous/harmful consumption was related to using marijuana, tobacco and recent stressful events in both men and women. CONCLUSIONS: Higher levels of distress are already evident in male non-drinkers in early adulthood. The findings counter theories that distress in non-drinkers is due to past hazardous/harmful alcohol consumption, marijuana or tobacco use, or characteristics in common with hazardous/harmful drinkers. Alcohol use disorders and mental health problems are pertinent issues for young adults. However, more understanding is needed of the experiences of non-drinkers in an alcohol consuming culture.

Synthesis and evaluation of 4-fluoro-8-substituted-2,3,4,5-tetrahydro-1H-2-benzazapines as selective inhibitors of phenylethanolamine N-methyltransferase versus the alpha(2)-adrenoceptor.

A small series of 4-fluoro-8-substituted-2,3,4,5-tetrahydro-1H-2-benzazapines (4-fluoro-THBAs; 12-15) were synthesized and evaluated as inhibitors of phenylethanolamine N-methyltransferase (PNMT; EC 2.1.1.28) and as inhibitors of the binding of clonidine at the alpha(2)-adrenoceptor. 4-Fluoro-THBAs 13-15 displayed selectivity ratios (alpha(2) K(i)/PNMT K(i)) greater than 75 and 4-fluoro-8-nitro-THBA (13) was found to be one of the most selective inhibitors of PNMT known, with a selectivity ratio of greater than 900. These compounds are also quite lipophilic and according to previous results from this laboratory should be able to penetrate the blood-brain barrier. These 4-fluoro-THBAs represent important leads in the development of new, more selective, CNS-active inhibitors of PNMT.

Mental health nurses' beliefs about likely outcomes for people with schizophrenia or depression: a comparison with the public and other healthcare professionals.

This paper explores mental health nurses' beliefs about prognosis, long-term outcomes and discrimination in response to vignettes describing a person with either schizophrenia or depression. Mental health nurses were added to previous research describing the beliefs of professionals (psychiatrists, general practitioners and clinical psychologists) and the public. This study used a self- completion, postal survey procedure. Mental health nurses tended to be more negative than the community but more positive than the other professional groups (particularly the medical professions) about long-term outcomes and prognosis. Nurses were similar to the medical professional groups in believing that considerable discrimination occurs within the community. Given the potential impact on consumers and the public, all practitioners need to be aware of their own beliefs and those of their professional colleagues.

Can costs be measured and predicted by modeling within a cooperative clinical trials group? Economic methodologic pilot studies of the radiation therapy oncology group (RTOG) studies 90-03 and 91-04.

PURPOSE: To (1) measure radiation therapy costs for patients in randomized controlled clinical trials, (2) compare measured costs to modeling predictions, (3) examine cost distributions, and (4) assess feasibility of collecting economic data within a cooperative group. METHODS: The Radiation Therapy Oncology Group conducted economic pilot studies for two Phase III studies that compared fractionation patterns. Expected quantities of Current Procedural Terminology (CPT) codes and relative value units (RVU) were modeled. Institutions retrospectively provided procedure codes, quantities, and components, which were converted to RVUs used for Medicare payments. Cases were included if the radiation therapy quality control review judged them to have been treated per protocol or with minor variation. Cases were excluded if economic quality review found incomplete economic data. RESULTS: The median and mean RVUs were within the range predicted by the model for all arms of one study and above the predicted range for the other study. CONCLUSION: The model predicted resource use well for patients who completed treatment per protocol. Actual economic data can be collected for critical cost items. Some institutions experienced difficulty collecting retrospective data, and prospective collection of data is likely to allow wider participation in future Radiation Therapy Oncology Group economic studies.

Mental health nurses' beliefs about interventions for schizophrenia and depression: a comparison with psychiatrists and the public.

OBJECTIVE: The main objective of this paper was to investigate and compare mental health nurses' beliefs about interventions for schizophrenia and depression with those of psychiatrists and the public. Factors affecting nurses' beliefs were also investigated. METHOD: This research used methods employed in previous surveys of professional and public beliefs. A postal survey of 673 Australian mental health nurses was carried out. The survey was comprised of a vignette describing a person with either depression or schizophrenia. Participants rated whether particular medical, psychological and lifestyle interventions were helpful, harmful or neither. Factors examined included: nurses' age, sex, degree of contact with similar problems, work setting, level of highest qualification and whether their education was hospital-based or completed within the tertiary sector. RESULTS: The nurses agreed with psychiatrists (but not the public) about the interventions most likely to be helpful, such as antidepressants for depression and antipsychotic medication for schizophrenia. However, there were many differences between nurses, psychiatrists and the public. Nurses were more likely than psychiatrists to believe that certain non-standard interventions such as vitamins, minerals and visiting a naturopath would be helpful. Nurses' beliefs tended to form a bridge between the attitudes of psychiatrists and the public for some of these non-standard interventions. Age, work setting and qualifications were related to nurses' intervention beliefs. CONCLUSIONS: Mental health practitioners need to be aware of a range of beliefs within mental health services. The acknowledgement of differing belief systems is important for high quality, integrated care.

Enantiospecific synthesis of 3-fluoromethyl-, 3-hydroxymethyl-, and 3-chloromethyl-1,2,3,4-tetrahydroisoquinolines as selective inhibitors of phenylethanolamine N-methyltransferase versus the alpha(2)-adrenoceptor.

An enantiospecific method was developed for the synthesis of 3-fluoromethyl-, 3-hydroxymethyl-, and 3-chloromethyl-7-substituted-1,2,3,4-tetrahydroisoquinolines (THIQs) from phenylalanine. Biochemical evaluation of the enantiomers of these compounds at both PNMT and the alpha(2)-adrenoceptor indicates that both sites display similar stereoselectivity. Overall the R-enantiomer was usually the more potent enantiomer at both PNMT and the alpha(2)-adrenoceptor for these 3-fluoromethyl-, 3-hydroxymethyl-, and 3-chloromethyl-THIQs. The one exception is 3-hydroxymethyl-7-nitro-THIQ (9), which was found to display the opposite stereoselectivity at the alpha(2)-adrenoceptor. A comparison of the PNMT inhibitory potency of the enantiomers of these 3-fluoromethyl-, 3-hydroxymethyl-, and 3-chloromethyl-THIQs indicates that all of the 3-substituted-THIQs displayed similar inhibitory potency for PNMT. However, the nature of the 3-substituent was found to have a major effect on the alpha(2)-adrenoceptor affinity of these compounds with the 3-hydroxymethyl- and 3-fluoromethyl-THIQs having the highest affinity and THIQs containing the 3-chloromethyl moiety the least. Compounds R-3-fluoromethyl-7-cyano-THIQ (R-12) and R-3-fluoromethyl-7-N-(4-chlorophenyl)aminosulfonyl-THIQ (R-13) and both enantiomers of 3-chloromethyl-7-nitro-THIQ (R- and S-30) are the most selective inhibitors in this study and display selectivities (alpha(2)-adrenoceptor K(i)/PNMT K(i)) greater than 200. These compounds give important insight into the steric and stereochemical preferences of both PNMT and the alpha(2)-adrenoceptor, which should assist in the development of new PNMT inhibitors.

Synthesis and biochemical evaluation of 3-fluoromethyl-1,2,3, 4-tetrahydroisoquinolines as selective inhibitors of phenylethanolamine N-methyltransferase versus the alpha(2)-adrenoceptor.

A series of 3-fluoromethyl-1,2,3,4-tetrahydroisoquinolines (3-fluoromethyl-THIQs) was proposed, and their phenylethanolamine N-methyltransferase (PNMT) and alpha(2)-adrenoceptor affinities were predicted through the use of comparative molecular field analysis (CoMFA) models. These compounds were synthesized and evaluated for affinity at PNMT and the alpha(2)-adrenoceptor. It was discovered that these compounds are some of the most selective inhibitors of PNMT versus the alpha(2)-adrenoceptor known. To determine the ability of these compounds to penetrate the blood-brain barrier (BBB), a series of THIQs possessing a variety of calculated partition coefficients (Clog P) were assayed using an in vitro BBB model. This study found a good correlation between lipophilicity (Clog P) and BBB permeability, which indicated that THIQs possessing Clog P values of at least 0.13-0.57 should have some penetration into the brain. Two compounds [3-fluoromethyl-7-N-(4-chlorophenyl)aminosulfonyl-THIQ (18) and 3-fluoromethyl-7-cyano-THIQ (20)] possess calculated partition coefficients greater than 0.57 and display selectivities (alpha(2)-adrenoceptor K(i)/PNMT K(i)) greater than 200 and thus represent promising leads in the development of highly selective inhibitors of PNMT with the ability to penetrate the BBB.

Synthesis and evaluation of 3-trifluoromethyl-7-substituted-1,2,3, 4-tetrahydroisoquinolines as selective inhibitors of phenylethanolamine N-methyltransferase versus the alpha(2)-adrenoceptor.

A series of 3-trifluoromethyl-1,2,3,4-tetrahydroisoquinolines was synthesized and evaluated as inhibitors of phenylethanolamine N-methyltransferase (PNMT) and as inhibitors of the binding of clonidine at the alpha(2)-adrenoceptor. These compounds were found to be selective inhibitors of PNMT due to their decreased affinity for the alpha(2)-adrenoceptor, which was attributed to steric bulk intolerance around the 3-position of 1,2,3,4-tetrahydroisoquinoline (THIQ) at the alpha(2)-adrenoceptor and to the decreased pK(a) of the THIQ amine due to the 3-trifluoromethyl moiety. Overall, these compounds displayed less affinity for PNMT compared to previously studied THIQ-type inhibitors, except for 16 which was found to have good affinity for PNMT (PNMT K(i) = 0.52 microM). Compounds 14 and 16 proved to be the most selective inhibitors in this small series of compounds and are some of the most selective inhibitors of PNMT known (14, selectivity alpha(2) K(i)/PNMT K(i) = 700; 16, selectivity alpha(2) K(i)/PNMT K(i) > 1900). Compounds 14 and 16 are also quite lipophilic due to the 3-trifluoromethyl moiety and represent promising new leads for the development of new highly selective inhibitors of PNMT, which should be sufficiently lipophilic to penetrate the blood-brain barrier.

1,3-Dimethyl-7-substituted-1,2,3,4-tetrahydroisoquinolines as probes for the binding orientation of tetrahydroisoquinoline at the active site of phenylethanolamine N-methyltransferase.

In order to determine the function of epinephrine (Epi) in the central nervous system, we have targeted the enzyme that catalyzes the final step in the biosynthesis of Epi, phenylethanolamine N-methyltransferase (PNMT; EC 2.1.1.28). 1,2,3,4-Tetrahydroisoquinolines (THIQs) are inhibitors of this enzyme, but also display affinity for the alpha2-adrenoceptor. To gain further understanding about how THIQs bind at the PNMT active site and in an attempt to further increase the selectivity of THIQ-type inhibitors versus the alpha2-adrenoceptor, a series of cis- and trans-1,3-dimethyl-7-substituted-THIQs were synthesized. Evaluation of these compounds suggests that THIQs bind in two different orientations at the PNMT active site, based on the lipophilicity of the 7-substituent. However, no significant increases in selectivity versus the alpha2-adrenoceptor were observed for these compounds.

Comparative molecular field analysis (CoMFA) models of phenylethanolamine N-methyltransferase (PNMT) and the alpha2-adrenoceptor: the development of new, highly selective inhibitors of PNMT.

As a guide to the development of new and more selective inhibitors of phenylethanolamine N-methyltransferase (PNMT) vs the alpha2-adrenoceptor, we have performed a comparative molecular field analysis (CoMFA) on a series of 80 benzylamine analogues. Using the models obtained, we have proposed a series of 3-trifluoromethyl-1,2,3,4-tetrahydroisoquinolines and predicted the activity of other analogues.

Systolic and diastolic cardiac function time intervals and exercise capacity in women.

PURPOSE: To determine the relationship between exercise capacity and resting cardiac function time intervals in women. METHODS: The noninvasive method of seismocardiography was used to measure resting cardiac intervals in 12 female subjects. On the basis of maximal treadmill time (Bruce protocol), two groups were studied and categorized as long duration runners (LDR; N = 6) or short duration runners (SDR, N = 6). The following resting atrial and left ventricular (LV) cardiac function time intervals were determined: atrial systole, LV systole, LV diastole, LV isovolumetric contraction, LV isovolumetric relaxation, LV ejection, LV preejection, LV filling, LV rapid filling, and Tei index. RESULTS: Heart rate (HR) (65+/-3 vs 61+/-4 b x min(-1) for LDR and SDR, respectively; P = NS) and atrial systolic time (75+/-6 vs 81+/-5 ms for LDR and SDR, respectively; P = NS) were similar between groups. LV systole (348+/-15 vs 302+/-8 ms for LDR and SDR, respectively; P < 0.05) and LV ejection (297+/-13 vs 247+/-7 ms for LDR and SDR, respectively; P < 0.01) were longer in LDR, despite a similar LV isovolumetric contraction time. There was a general trend for a shortened LV diastole in LDR with a significantly shortened LV isovolumetric time in LDR (80+/-8 vs 107+/-8 ms for LDR and SDR, respectively; P < 0.05). LV preejection was shorter in LDR versus SDR (LDR; 114+/-6 vs SDR; 130+/-3 ms, P < 0.05), and the Tei index was less in LDR versus SDR. CONCLUSIONS: Independent of HR, increased treadmill time in young women is associated with greater resting systolic time intervals and decreased diastolic cardiac function time intervals.

Examination of the role of the acidic hydrogen in imparting selectivity of 7-(aminosulfonyl)-1,2,3,4-tetrahydroisoquinoline (SK&F 29661) toward inhibition of phenylethanolamine N-methyltransferase vs the alpha 2-adrenoceptor.

7-(Aminosulfonyl)-1,2,3,4-tetrahydroisoquinoline (SK&F 29661, 1) is a potent inhibitor of the enzyme phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28). In contrast to other inhibitors of PNMT, it is also highly selective toward PNMT in comparison with its affinity toward the alpha 2-adrenoceptor (PNMT Ki = 0.55 microM, alpha 2 Ki = 100 microM, selectivity [alpha 2 Ki/PNMT Ki] = 180). A diverse set of compounds was synthesized and evaluated to probe the role of the acidic hydrogen of the aminosulfonyl group of 1 in imparting this selectivity. Compounds were designed to investigate the effect on selectivity of the acidity of the NH group [the 7-N-methyl (compound 5) and 7-N-(p-chlorophenyl) (compound 4) derivatives of 1], the relative spatial position of the acidic hydrogen [7-(N-(methylsulfonyl)amino)-1,2,3,4-tetrahydroisoquinoline (6) and 7-((N-(methylsulfonyl)amino)methyl)-1,2,3,4-tetrahydroisoquinoline (8)], or the effect of the substitution of an acidic phenolic group for the aminosulfonyl moiety [1-(aminomethyl)-6-hydroxynaphthalene (23) and 8-hydroxy-1,2,3,4-tetrahydrobenz[h]isoquinoline (9)]. All of the compounds studied displayed lower affinity for PNMT than 1, and nine of the eleven compounds studied showed increased, rather than the desired decreased, affinity for the alpha 2-adrenoceptor. Specifically, compound 4, in which the aminosulfonyl NH group is more acidic than that in 1, showed greatly reduced selectivity on account of increased alpha 2-adrenoceptor affinity as compared to 1 (PNMT Ki = 2.6 microM, alpha 2 Ki = 6.3 microM, selectivity = 2.4). Compound 8, in which the acidic NH group is in the same region of space as that in 1, although the aminosulfonyl group is reversed with respect to the aromatic ring, showed poor PNMT affinity and modest alpha 2-adrenoceptor affinity (PNMT Ki = 330 microM, alpha 2 Ki = 18 microM, selectivity = 0.055). Compound 9, in which a phenolic group is in the same region of space as the acidic NH of 1, exhibited the best alpha 2-adrenoceptor affinity of any of the compounds studied (PNMT Ki = 0.98 microM, alpha 2 Ki = 0.078 microM, selectivity = 0.080). Results from this study suggest that the selectivity of 1 is not solely due to the presence of an acidic hydrogen on the 7-aminosulfonyl group of 1 but is likely also dependent on some other property (e.g. electron-withdrawing character) of the aminosulfonyl group.

Growth of the young heart: influence of nutrition and stress.

Newborn rat pups reared in litters of 4 and 16 inhaled up to 500 ppm carbon monoxide for 14 days, while others in litters of equal size remained in room air. Body weight, combined ventricle weight, hemoglobin concentration, hematocrit, and myocardial DNA content were measured. Differences in hemoglobin concentration and hematocrit between the four groups of pups were small. Cardiomegaly resulting from CO-stress was intensified in pups from small, as opposed to large litters. Relative combined ventricle weight was unaltered by change in litter size in the absence of CO-stress, although combined ventricle weight and body weight were increased with small litter size. Ventricular DNA content, indicative of cellularity, was increased in small litters and with CO-stress. Exacerbated postnatal anemia is not responsible for the differential effects of litter size and stress on the heart.

Malignant melanoma of the skin. I. The association of tumor depth and type, and patient sex, age, and site with survival.

The occurrence and behavior of cutaneous melanomas in a group of 1123 patients studied prospectively, is described in terms of histologic type, tumor thickness and levels of invasion, the patients' sex and age, and the anatomic location of the primary tumors. Associations amongst these attributes, and with survival, are also examined. The characteristics of the patients in this study (who on average are somewhat younger, and have better prognoses and survivals than those reported by most other groups) are compared with data obtained (primarily over the past decade) in other geographical areas, and with different patient populations. Evidence is presented that sex, tumor location, and age (in the case of males) are also predictive of survival.

Judging prognosis in malignant melanoma of the skin. A problem of inference over small data sets.

Data was generated for 828 clinical stage 1 melanoma patients, divided into groups according to sex, tumor location, and tumor level for each of the 56 groups. Summary data, including the number of patients, number of patients dying as a result of melanoma, range of tumor thickness, mean and median tumor thickness, and mean length of follow-up of the surviving patients, are shown. Patients with melanoma of the palms and soles, subungual melanomas, and mucosal melanomas were excluded. A physician with a new melanoma patient could select the appropriate group for his or her patient, matched with respect to sex, location, and level, and then make a judgment regarding the prognosis, based on the survival experience of the group. In a few groups, the small numbers of patients provides only a rough impression of survival, but with many groups, a fair estimate can be made. The effectiveness of elective lymph node dissection was examined by creating 111 pairs of patients, matched by sex, level, location, and tumor thickness (to within +/- 12%), in which one member of the pair had an elective node dissection (ELND) and the other did not. There was no statistically significant difference between the survival of the two groups.

Immediate hypersensitivity to seminal fluid and atopic dermatitis.

A woman with atopic dermatitis experienced anaphylactic episodes following intercourse with her husband, with subsequent exacerbations of her atopic dermatitis. Skin testing and an in vitro leukocyte histamine release assay established the diagnosis of immediate hypersensitivity to her husband's seminal fluid; delayed hypersensitivity to seminal fluid could not be demonstrated. Antigen was found in the seminal fluid of nonrelated men. Radioallergosorbent testing detected the presence of circulating IgE antibodies specific for seminal plasma protein. Immunotherapy with seminal plasma may have limited the severity of a subsequent reaction. Serum from the husband and nonrelated men also contained antigen that provoked histamine release from the patient's leukocytes in vitro. The antigen in serum was associated with the globulin fraction and had a temporal relationship to ejaculation, appearing within 12 hours of ejaculation and disappearing within four days.