Genetic variability of the extraneuronal monoamine transporter EMT (SLC22A3)

The extraneuronal monoamine transporter EMT (HGNC Nomenclature SLC22A3) is the molecular correlate of the classical uptake₂ system responsible for the non-neuronal inactivation of circulating and centrally released catecholamines. Because of its functional profile and expression pattern, EMT is regarded as a candidate gene for diseases related to the sympathetic nervous system and neuropsychiatric disorders. We describe the first investigation of the genetic variability of the EMT gene in human. Six single-nucleotide substitutions and one deletion were detected within the assumed core promoter, the exonic and flanking intronic sequences and the 3'-untranslated region in 100 Caucasian individuals. No amino acid changes were found and Tajima's D was positive (D=2.91; P<0.01). However, the synonymous nucleotide substitution 1233G→A might serve as a cryptic splice acceptor site. Analysis of linkage disequilibrium between polymorphisms yielded 12 possible haplotypes accounting for more than 90% of all haplotypes. Knowledge of the sequence variation and frequency of the underlying polymorphisms in this member of the amphiphilic solute facilitator family of transporters provides the basis for subsequent association studies and candidate gene approaches. Electronic Publication     

Molecular analysis of HLA-D region genes in seropositive rheumatoid arthritis

Analysis of HLA DRB1 and DQB1 Bam HI RFLPs revealed four DRB1 (4.8, 5.2, 6.0 and 7.0 kb) fragments and a 3.2 kb DQB1 fragment to be significantly increased in Caucasians with seropositive RA compared to healthy individuals. The 4.8, 5.2 and 7.0 kb DRB1 fragments were found in 86.5% of RA patients and in 56% of the controls (p = 10(-3), relative risk (RR) = 5.0), while the 6.0 kb fragment was found in 79% of RA patients compared to 32% of controls (p = 2 x 10(-5), RR = 8.0). The 3.2 kb DQB1 fragment was observed in 63.5% of RA patients versus 38.0% of controls (p = 10(-2), RR = 2.8). Analysis of these fragments relative to HLA phenotypes revealed that the 4.8, 5.2 and 7.0 kb DRB1 fragments were strongly correlated with DR4, -7, -9 and -w53 serotypes, the 6.0 kb RFLP with DR4 and the 3.2 kb DQB1 fragment with DR1 and DQw1. Using probes specific for the 5' or 3' regions of the DRB1 gene, the 5.2 and 6.0 kb DRB RFLPs were mapped to the 5' end and the 4.8 and 7.0 kb RFLPs to the 3' end of the DRB1 gene. A probe generated from the second exon of the DRB4 (DRw53) gene recognized only the 5.2 and the 6.0 kb RFLPs corroborating the 5' location of these RFLPs. Family studies further confirmed that these RFLP's segregated with HLA phenotypes.     

Differences in diazepam pharmacokinetics in Chinese and white Caucasians – Relation to body lipid stores

Summary We have compared diazepam pharmacokinetics in 16 Chinese and 18 white Caucasian healthy male volunteers, resident in Hong Kong and have correlated them with physical attributes. Serum concentrations of diazepam and desmethyldiazepam were measured in venous blood by an enzyme-linked immunoassay (0–3 h samples) and HPLC (3–72 h samples). Pharmacokinetic parameters were derived assuming a two compartment model, distribution phase <6 h, and 100% oral systemic availability. Compared with the Chinese the white Caucasians were older, heavier, taller, and fatter, as judged by skin fold thickness (SFT) and total body weight to Ideal body weight (TBW/IBW) ratio; respective mean differences being 16%, 27%, 4%, 26%, and 15% (p<0.05). Mean diazepam apparent volume of distribution (V) and V/IBW were larger in the white Caucasians (52% & 39% respectively, p=0.002). SFT and TBW/IBW ratio yielded the best correlations with V, V/TBW and V/IBW (0.50–0.75, p<0.05). Obesity indices contributed most to the overall regressions (R² up to 0.52), and for V there was a further small effect (2%, partial F test) due to ethnic group, possibly reflecting stature. Mean peak diazepam concentration (C_max) was similar in both ethnic groups. Time to C_max (t_max) was more often prolonged in the Chinese (X ² test, p=0.01). Body fat and stature may thus account for these inter-ethnic differences in the apparent volume of distribution of diazepam, a highly lipid-soluble drug.     

South Asian women with polycystic ovary syndrome exhibit greater sensitivity to gonadotropin stimulation with reduced fertilization and ongoing pregnancy rates than their Caucasian counterparts

Polycystic ovary syndrome (PCOS) is a heterogeneous syndrome. In vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) is required for PCOS cases that are refractory to standard ovulation induction or have co-existing infertility factors in women with PCOS and Tubal factor subfertility. OBJECTIVES: Assess ethnic variations in response to IVF/ICSI treatment. STUDY DESIGN: Observational Comparative study in a University hospital fertility clinic in women with PCOS and Tubal factor subfertility. Women with PCOS (Asians: AP=104; Caucasians: CP=220) and those with tubal factor infertility seeking fertility treatment were assessed (Asians: AC=84; Caucasians: CC=200). Six hundred and eight fresh IVF or ICSI cycles using long protocol of GnRHa suppression and resulting in a fresh embryo transfer were compared. The primary endpoint was to assess the dose of gonadotropins used in the cycles. The secondary outcomes were: total number of oocytes retrieved, fertilization and ongoing clinical pregnancy rates. RESULTS: We found that the South Asian women presented at a younger age for the management of sub-fertility. An extended stimulation phase and Caucasian ethnicity showed an inverse correlation with the number of oocytes retrieved in the PCOS subgroup. Caucasian ethnicity was associated with a higher fertilization rate however increase in body mass index (BMI) and the laboratory technique of IVF appeared to have a negative impact on fertilization rates in the PCOS subgroup. Commencing down regulation on day 1 of the cycles was negatively associated with fertilization rates in the tubal group. In terms of clinical pregnancy rates, the Caucasian PCOS had a 2.5 times (95% CI: 1.25-5) higher chance of an ongoing clinical pregnancy as compared with their Asian counterpart. Also, a unit increase in the basal FSH concentration reduced the odds of pregnancy by 18.6% (95% CI: 1.8-32.6%) in the PCOS group. CONCLUSIONS: The Asian PCOS have a greater sensitivity to gonadotropin stimulation with lower fertilization and ongoing clinical pregnancy rates as compared with their Caucasian counterparts.     

Ethnic Differences in Bone Mineral Density Between Inuit and Caucasians in North Greenland Are Caused by Differences in Body Size

Data on bone mineral density (BMD) in living Inuit are limited and BMD measurements in Arctic Inuit using Dualenergy X-ray Absorptiometry (DXA) are lacking. Ethnicity may be important for bone mass. The aim of this study was to validate DXA in rural Arctic Greenland, to measure BMD in Greenland Inuit and Caucasians, and to estimate the importance of ethnicity for BMD. We measured the BMD in 80 healthy subjects living in Ilulissat and Saqqaq in North Greenland twice in both distal forearms and in both heels using peripheral DXA (pDXA). Participants were stratified by origin (Inuit[settlement])/Caucasians, n = 33 [19]/28), gender (men/women, n = 37/43), and age (30-39/40-49, n = 32/48). Caucasians were bigger than Inuit (men/women, height p < 0.001/p < 0.001; weight p = 0.01/ p = 0.026), but had similar BMI (p = 0.42/0.70). Triplicate pDXA measurements showed individual CV% = 0.16-1.79%; overall CV% = 1.1% (forearm)/1.0% (heel). Data followed the normal distribution (p = 0.65-0.99) with identical variances between Inuit and Caucasians (p = 0.12-0.63). Mean BMD in right forearm/left forearm/right heel/left heel was: Inuit men 0.570/0.568/0.549/0.536 g/cm2; Inuit women 0.484/0.474/0.473/0.464 g/cm2; Caucasian men 0.580/0.570/0.646/0.638 g/cm2; Caucasian women 0.495/0.496/0.552/0.553 g/cm2. An ethnic difference in heel BMD (p < 0.001) disappeared when adjusted for weight (p = 0.30). No difference was found in forearm BMD. In conclusion, pDXA is feasible and reliable in rural Greenland. Ethnic differences in BMD are small and may reflect differences in body size.     

Comparison of primary coronary artery bypass surgery in a British Indo-Asian and white Caucasian population.

AIM: To compare the clinical characteristics, at the time of admission and after coronary revascularization by bypass surgery, among British patients of Indo-Asian and white Caucasian descent. METHOD: One hundred and ninety-four pairs of patients admitted between November 1994 and January 1997 were matched for age (within 3 years), sex and date of admission (within 3 months). Their clinical characteristics at the time of admission for coronary artery bypass grafting surgery, and the incidence of hospital morbidity, hospital mortality and length of stay in the intensive therapy unit or hospital following coronary artery bypass grafting were determined. RESULTS: A higher proportion of Indo-Asian patients underwent coronary revascularization on a non-elective basis (43% vs 32% white Caucasian patients, P =0.018), had a higher prevalence of diabetes (39% vs 12%, P =0.0001), a lower prevalence of smoking (36% vs 80%, P =0.0001) and a lower rate of previous myocardial infarction (47% vs 62%, P =0.012). As regards revascularization, although there was no significant difference in the number of vessels revascularized, there was a lower use of the arterial conduit (internal mammary artery) in the Indo-Asian patients (72% vs 81%, P =0.028) particularly for those undergoing emergency/urgent surgery (59% vs 72%, P =0.001) and with a previous myocardial infarction (65% vs 81%;P =0.01) when compared with their white Caucasian counterparts. Following surgery there were no differences in the types of support required for vital functions. There was no significant difference in the proportion of major post-operative complications, that is, haemorrhage, cerebrovascular accident, renal failure requiring dialysis or respiratory failure. Similarly, there were no differences in the length of intensive therapy unit stay (median stay 1 day vs 1 day, P =0.4) and hospital stay following surgery (median stay 6 days vs 6 days, P =0.5) between the two groups. Although there was a trend towards a higher in-hospital (30 day) mortality (6.7% [95% confidence intervals CI 3.18-10.21] vs 2.6% [CI 0.35-4.9;P =0.0618]), in Indo-Asians compared to white Caucasians this trend disappeared when patients in the two groups undergoing non-elective surgery only were compared (9% vs 7%;P =0.7). CONCLUSIONS: A higher proportion of Indo-Asians underwent non-elective coronary revascularization, with a significantly lower use of the arterial conduit and a relatively higher in-hospital mortality. Following coronary revascularization the medical management, length of stay and hospital morbidity in Indo-Asian patients was no different from that of their white Caucasian counterparts. This is despite a perceived poorer outcome in Indo-Asians compared to white Caucasians.     

Attrition in nursing among Black and White nurses

Fundamental to dealing with the problems associated with attracting and retaining nurses during a tight labour market are issues centreing upon attrition from the field. In the United States, attrition has become such a significant issue that efforts to attract individuals to the field and recruit them to positions in the health care industry are not adequate to offset the flow of individuals from the field, much less bring in the additional nurses who are needed for an ageing population with increasing health care needs. As an example of the seriousness of the problem, it is probably safe to say that of the students who graduate from nursing schools each year and who enter the field of nursing, a significant number will no longer be practicing after 5 years in the profession. In a high attrition environment, even if many individuals were entering nursing, these losses will potentially offset any gains that are made. From the perspective of this study, it is important to know what is leading nurses to leave their careers. Do all nurses face the same challenges in the course of their careers, or is the pattern of turnover somewhat different for different groups of nurses or those in different stages of their careers? In this study, we consider what career differences may exist between the two major groups of nurses in the USA today – Black and White nurses – and ask whether there are differences between the two groups in terms of ‘whether’ and ‘why’ they may be leaving the field. Our primary purpose was to determine if differences in attrition exist between Black and White nurses, and if so, where in the career process are those differences most pronounced. Based on our analysis of data from the National Science Foundation, we do find significant differences in patterns of attrition for the two groups and we suggest what we believe may be their implications for policy.     

Development of an ELISA to study the polymorphism of dextromethorphan oxidation in a french population

Summary Simple, sensitive and selective enzyme immunoassays (ELISA) for monitoring urinary dextromethorphan and its major metabolite, dextrorphan, were developed. Dextromethorphan and dextrorphan hemisuccinates were linked to bovine serum albumin and specific antisera against each immunogen were raised in rabbits. The sensitivity of the ELISA was high (limit of detection 740 and 600 pg·ml^–1 for dextromethorphan and dextrorphan, respectively). Intra- and interassay variation was <10%, and cross-reactivity between the two compounds was <1%.The ELISA was employed to phenotype 216 French subjects. The frequency of poor metabolizers was 5.1%.     

Peripheral arterial disease in relation to glycaemic level in an elderly Caucasian population: the Hoorn Study

Summary We investigated the cross-sectional association between peripheral arterial disease and glycaemic level in an age, sex, and glucose tolerance stratified random sample from a 50–74-year-old Caucasian population. Subjects treated with oral hypoglycaemic agents or insulin were classified as having known diabetes mellitus (KDM) (n = 67). Using two oral glucose tolerance tests, and based on World Health Organisation criteria, all other participants were categorized as having a normal (NGT) (n = 288), an impaired (IGT) (n = 170), or a diabetic (NDM) (n = 106) glucose tolerance. Prevalence rates of ankle-brachial pressure index less than 0.90 were 7.0 %, 9.5 %, 15.1 % and 20.9 % in NGT, IGT, NDM and KDM subjects, respectively (chi-square test for linear trend: p < 0.01). Prevalence rates of any peripheral arterial disease (ankle-brachial pressure index < 0.90, at least one monophasic or absent Doppler flow curve or vascular surgery) were 18.1 %, 22.4 %, 29.2 % and 41.8 % in these categories (chi-square test for linear trend: p < 0.0001). The prevalence of any peripheral arterial disease was higher in KDM and NDM than in NGT (p < 0.03, p < 0.0001, respectively), whereas no statistically significant difference was demonstrated between IGT and NGT. The same applied when using the ankle-brachial pressure index criterion. Logistic regression analyses showed that any arterial disease was significantly associated with HbA_{1 c}, fasting and 2-h post-load plasma glucose after correction for cardiovascular risk factors (odds ratios and 95 % confidence intervals 1.35; 1.10–1.65 per %, 1.20; 1.06–1.36 and 1.06; 1.01–1.12 per mmol/l, respectively), whereas it was not associated with fasting and 2-h post-load specific insulin. Ankle-brachial pressure indices were not associated with either plasma glucose parameters or insulin in univariate or multivariate analyses. In conclusion, parameters of glucose tolerance are independently associated with any peripheral arterial disease, whereas insulin is not. [Diabetologia (1995) 38: 86–96] Received: 11 April 1994 and in revised form: 15 July 1994