Increased frequency of HLA A2/DR4 and A2/DR8 haplotypes in young saskatchewan aboriginal people with diabetic end-stage renal disease

AIMS: To determine the association of HLA with diabetic end-stage renal disease (DESRD) in Saskatchewan aboriginal people. METHODS: This was a retrospective study of HLA profiles in four groups of Saskatchewan residents with ESRD diagnosed from 1980 to 1998: aboriginal people with and without DESRD, and non-aboriginal people with and without DESRD. The aboriginal DESRD group was also subdivided into those 50 years of age. Frequencies of individual and combinations of HLA antigens were compared between groups and subgroups. RESULTS: HLA data were available for 634 subjects. Young aboriginal people with DESRD had a higher frequency of HLA-A2 than older AB DESRD subjects (69 vs. 36%; p = 0.03), and of HLA-DR4 and/or DR8 compared to older AB DESRD subjects (91 vs. 68%; p = 0.07) and AB non-DESRD subjects (91 vs. 67%; p = 0.03). Over 65% of young AB DESRD subjects had either an A2/DR4 or A2/DR8 haplotype (odds ratio 5.09 [confidence intervals 1.35, 20.15] versus older AB DESRD subjects; odds ratio 3.32 [confidence intervals 1.20, 9.3] versus AB non-DESRD subjects). Forty percent of young AB DESRD subjects were homozygous for at least one of A2, DR4 or DR8. CONCLUSIONS: Our findings suggest that DESRD in young AB subjects with T2DM has a genetic basis related to HLA.     

Referral paths, patient profiles and treatment adherence of older alcoholic men

We sought factors affecting completion by older men of 1-year outpatient treatment for alcohol dependence. We retrospectively studied clinical datasets of 110 men, age > or =55 years, consecutively admitted over 4 years, examining the association of 18 referral, treatment and patient variables with completion of treatment. We found that referral source was the most significant correlate of completion. Legal and self/family referrals were far more likely to complete treatment than patients referred by health or social services. Referral groups had distinctive profiles. Legal referrals were the healthiest. Self/family referrals were most likely to be married, to have had prior alcoholism treatment (a factor also associated with treatment completion), and to suffer currently from depression. Health/social services referrals showed the highest levels of psychosocial and physical dysfunction. Referral pathways deserve special consideration by programs treating older alcoholics. Special strategies for engaging dysfunctional older patients in alcoholism treatment are discussed.     

EEG abnormalities associated with antipsychotics: a comparison of quetiapine, olanzapine, haloperidol and healthy subjects

In this study the effects of the atypical antipsychotics quetiapine and olanzapine, and the typical antipsychotic haloperidol on EEG patterns were retrospectively investigated in 81 patients under stable monotherapy with either drug (quetiapine: n=22, olanzapine: n=37, haloperidol: n=22). These three subgroups were compared with a control group of healthy subjects (n=30) which were matched regarding sex and age. Diagnoses of patients were schizophrenia (DSM-IV 295.xx, n=61), brief psychotic disorder (DSM-IV 298.8, n=9), schizoaffective disorder (DSM-IV 295.70, n=8) and delusional disorder (DSM-IV 297.1, n=3). There were no statistically significant differences regarding demographic characteristics between the groups. Digital EEG recordings were retrieved from a database and visually assessed by two independent investigators, and one blinded regarding medication. One patient from the quetiapine group (5%), 13 olanzapine patients (35%), five of the haloperidol patients (23%) and two subjects of the control group (7%) had an abnormal EEG. Epileptiform activity was observed in four patients (11%) of the olanzapine group, and none in the others. EEG abnormalities were statistically significantly increased with dose in the olanzapine group, in contrast to patients treated with haloperidol, quetiapine or healthy subjects. In conclusion, EEG abnormalities seem to occur rarely in patients treated with quetiapine comparable to the control group, but significantly more often with haloperidol and olanzapine, possibly due to different receptor profiles of these substances. To our knowledge, this is the first electrophysiological investigation comparing the new atypical antipsychotics quetiapine, haloperidol, olanzapine with healthy subjects.     

Magnetic drug targeting--biodistribution of the magnetic carrier and the chemotherapeutic agent mitoxantrone after locoregional cancer treatment

Magnetic Drug Targeting means the specific delivery of chemotherapeutic agents to their desired targets, e.g. tumors, by using magnetic nanoparticles (ferrofluids) bound to these agents and an external magnetic field which is focused on the tumor. This type of target directed drug injection attempts to concentrate a pharmacologic agent by enhancing its efficacy while simultaneously minimizing deleterious side effects. In previous studies, we have been able to demonstrate the efficacy of this type of localized intraarterial chemotherapy in VX2 squamous cell carcinoma among rabbits [Alexiou, C., Arnold, W., Klein, R.J., Parak, F.G., Hulin, P., Bergemann, C., Erhardt, W., Wagenpfeil, S. and Lübbe, A.S. "Locoregional cancer treatment with Magnetic Drug Targeting", Cancer Res. 60 (2000) 6641-6648]. In the present investigation, we have studied the biodistribution of ferrofluids and chemotherapeutic agent by measuring the amount in the tumor, peritumoral area, various organs and body fluids (e.g. blood and urine), with and without Magnetic Drug Targeting. We compared results to that of administering a chemotherapeutic agent soley. An external magnetic field was directed toward the tumor for 60 min. Biodistribution of ferrofluids in the tumor was investigated using histological cross sections and measured semi-quantitatively using 123I-labeled nanoparticles and quantitatively by the use of radioactive 59Fe-ferrofluids. Mitoxantrone was quantitatively measured using HPLC-analysis. The strength of the external magnetic field was 0.6 Tesla (permanent magnet) in the 123iodine study and 1.7 Tesla (electromagnet) in the 59Fe-study and HPLC-analysis. The concentration of the ferrofluids (FFs) in the tumor region i.e. the tumor tissue and the surrounding area, which was under the influence of an external magnetic field, was found to be much higher than in the absence of one. In contrast to systemic chemotherapy, a much higher concentration of mitoxantrone in the tumor and the peritumoral area (region surrounding the tumor < or = 1 cm), by using only 50% and 20% of the normal dose was seen. Thus, the higher concentration of mitoxantrone could explain the therapeutic efficacy of Magnetic Drug Targeting in treatment of VX2 squamous cell carcinoma in rabbits in our previous studies with the advantage of no adverse clinical side effects.     

Structure-based design of thrombin inhibitors

Despite tremendous efforts by the pharmaceutical industry during the last decade, the prevention of thromboembolic events--the major cause of death in industrialized countries--by efficient anticoagulatory therapy has still not been achieved. One therapeutic strategy focuses on competitive small-molecule thrombin inhibitors, which may block undesirable excessive thrombin activity (conversion of fibrinogen to fibrin and activation of platelet aggregation) and inactivate thrombin in preformed clots. The design of potent tailor-made thrombin inhibitors has been carried out based on structural data; however, the requirements for a target inhibitor, i.e., good pharmacokinetic and physicochemical profiles, still need to be addressed. This constitutes the main challenge in the current quest for a marketable drug, and is the major focus of the developments described in this review.     

What is next in pharmacogenomics? Translating it to clinical practice

Pharmacogenomics (PG) holds promise for transforming medical therapeutics but the details of how the promise will become reality are still vague. In this article, we focus on the role that laboratory medicine, as a discipline, might play in transitioning the application of pharmacogenomics into the healthcare system and begin to frame a perspective on how PG may be viewed in this context. Development of clinical diagnostic tests usually evolves as a continuum of information starting with the discovery of a potential biological marker through to its routine use in clinical practice. This process has traditionally been rooted in the practice of laboratory medicine and, importantly, includes the development of testing strategies to optimize the predictive value of single or a combination of biological markers. In this context, we also discuss a perspective on some future strategies that may prove useful in advancing the application of PG, including the need for an evidenced-based approach and the potential role of proteomics as a means to drive more comprehensive strategies.     

Review of ibandronate in the treatment of osteoporosis

Several antiresorptive treatments that reduce the risk of osteoporotic fracture are now available, including bisphosphonates. Ibandronate is a new potent bisphosphonate, currently under development, with unique features. In several animal models of human osteoporosis, it has been shown to inhibit bone resorption and improve bone mechanical properties. Ibandronate is more potent than most current bisphosphonates. Several dosages and schedules have been tested in humans. With the oral daily dose of 2.5 mg, a reduction of 62% in the incidence of vertebral fracture has been demonstrated in a randomised, placebo-controlled trial. In the same trial, a reduction of 50% has been observed - for the first time using a bisphosphonate - with an intermittent regimen (20 mg every other day for the first 24 days, followed by 9 weeks without the treatment). In contrast, another randomised, placebo-controlled trial failed to find a significant reduction in vertebral fracture risk using an dose of 1 mg i.v. every 3 months. Thus, ibandronate can be considered as a promising new option for the treatment of postmenopausal osteoporotic women.     

Paying doctors by salary: a controlled study of general practitioner behaviour in England

The study aim was to evaluate the impact of the experimental introduction of salaried contracts in England on general practitioner (GP) behaviour and the quality of care. A controlled before-and-after design was implemented involving ten practices of standard contract GPs, paid largely by capitation and fee-for-service, and ten salaried GP practices. Diaries and routinely available data were used to assess GP workload, and patient assessments of the quality of care were obtained by postal questionnaire. GPs in salaried practices spent less time on practice administration but more working out-of-hours and in direct patient care, allowing more patients to be seen. Total list sizes were smaller in salaried compared with standard contract practices, but lists per GP were higher because of staffing policies. Salaried GPs tended to provide shorter consultations compared with standard contract GPs, prescribe in fewer consultations, but referral rates were similar. Quality was rated as higher for seven out of thirteen aspects of care examined in salaried practices and two in standard contract practices. However, none of these differences were statistically significant. To conclude, salaried contracts did not adversely affect GP productivity and had little impact on other aspects of GP behaviour or the quality of care provided.     

GPs working in solo practice: obstacles and motivations for working in a group? A qualitative study

OBJECTIVE: Our aim was to analyse the obstacles and eventual motivations of solo GPs for working in group practice. METHODS: A qualitative study using 12 focus groups was carried out in primary care in French-speaking Belgium. The subjects comprised four samples of GPs: 20 GP trainers, 18 GP trainees, 25 women GPs and 25 other GPs. The focus groups were taped and transcribed. Two independent researchers carried out the analysis using the QSR NUD.IST software. RESULTS: The participants (88 GPs) did not share a common definition of group practice-in particular multidisciplinary working-the need for a common pool of patients and shared premises. Their main sources of motivation for eventually setting up a group practice were better quality of life, continuity of care and sharing professional knowledge. The main obstacles were a required agreement between colleagues, the loss of a personal patient-GP relationship, budgetary constraints, and divergent views on group practice and GPs' profession (especially true for the association of GPs from different age groups). CONCLUSION: The current study shows that GPs working solo have divergent views of group practice. However, they clearly perceive advantages to this type of association (e.g. better quality of life and continuity of care). This study also confirms the high level of stress and tiredness felt by GPs and especially senior practitioners.