A chasing dead-end case report: a fatal lead intoxication following an attempted homicide

Forensic Toxicology - In developed countries, lead intoxication is decreasing in adults as sources of contamination were considerably reduced. Hence, cases of lead encephalopathy have become...     

Exploratory relationships between cognitive improvements and training induced plasticity in hippocampus and cingulum in a rat model of mild traumatic brain injury: a diffusion MRI study

Traumatic brain injury (TBI) is a major cause of long-term cognitive deficits, even in mild TBI patients. Computerized cognitive training can help alleviate complaints and improve daily life functioning of TBI patients. However, the underlying biological mechanisms of cognitive training in TBI are not fully understood. In the present study, we utilised for the first time a touchscreen cognitive training system in a rat model of mild TBI. Moreover, we wanted to examine whether the beneficial effects of a cognitive training are task-dependent and selective in their target. Specifically, we examined the effect of two training tasks, i.e. the Paired Associate Learning (PAL) task targeting spatial memory functioning and 5-Choice Continuous Performance (5-CCP) task loading on attention and inhibition control, on the microstructural organization of the hippocampus and cingulum, respectively, using diffusion tensor imaging (DTI). Our findings revealed that the two training protocols induced similar effects on the diffusion MRI metrics. Further, in the TBI groups who received training microstructural organization in the hippocampus and cingulum improved (as denoted by increases in fractional anisotropy), while a worsening (i.e., increases in mean diffusivity and radial diffusivity) was found in the TBI control group. In addition, these alterations in diffusion MRI metrics coincided with improved performance on the training tasks in the TBI groups who received training. Our findings show the potential of DTI metrics as reliable measure to evaluate cognitive training in TBI patients and to facilitate future research investigating further improvement of cognitive training targeting deficits in spatial memory and attention.

     

Variation in practice: a questionnaire survey of how congruence in attitudes between doctors and patients influences referral decisions.

BACKGROUND: There is a well-known and partly unexplained variation in referral rates among general practitioners (GPs). GPs who are positive toward shared decision making refer less to secondary care, but how congruence in attitudes between doctors and patients influences referral rates has not been investigated. In this study, the authors analyze whether congruence in attitudes between the GP and patients toward shared decision making affects the GP's referral rate. METHODS: Questionnaire survey was distributed by 56 Norwegian GPs, each to 50 consulting patients. The level of congruence in attitudes toward shared decision making of GPs and corresponding patients was measured by the Patient-Practitioner Orientation Scale. The survey also included self-reported referral rates. RESULTS: In total, 1268 patients (45%) returned the questionnaires. Respondents were eliminated if they did not fully answer the questionnaire, resulting in a working sample of 835 patients. The authors found that congruence of attitudes toward shared decision making between the GP and patients had a negative effect on referral rate. CONCLUSION: In this study, congruence of attitudes toward shared decision making between GPs and patients influences referral decisions, indicating that matching attitudes may enhance the effort to solve the medical problem within the GPs' practice (i.e., doctor-patient interaction explains some of the variation in practice). The study supports the policy argument that, if possible, health authorities should enhance the possibilities for patients to choose a GP of matching attitudes.     

Levormeloxifene: safety, pharmacodynamics and pharmacokinetics in healthy postmenopausal women following single and multiple doses of a new selective oestrogen receptor modulator

AIMS: The safety, pharmacodynamics and pharmacokinetics of levormeloxifene, a selective oestrogen receptor modulator (SERM), were investigated in postmenopausal women following single doses and multiple dosing once daily up to 56 days. METHODS: The two randomized, double-blind, placebo controlled studies of six single ascending doses and at four multiple dose levels, respectively, included a total of 104 healthy postmenopausal women. Safety assessments comprised vital signs, ECG, haematology, clinical chemistry and reporting of adverse events. The pharmacodynamic properties were investigated after multiple dosing by assessment of the short-term effects on bone and lipid metabolism and on the hypothalamic-pituitary axis. Blood samples for pharmacokinetic analysis were collected at intervals until 648 h (27 days) after single and multiple dosing. RESULTS: Levormeloxifene was tolerated well after single doses in the range of 2.5--320 mg and multiple once daily dosing in the range of 20--160 mg. Adverse events reported were generally mild or moderate. The most frequent adverse events after multiple dosing were headache, abdominal pain and leukorrhea with the highest frequency reported after the highest daily dose of 160 mg levormeloxifene. Five weeks of treatment with 20--160 mg levormeloxifene and 8 weeks of treatment with 40 or 80 mg levormeloxifene reduced the biochemical marker of bone turnover, the collagen I C-terminal telopeptide (CrossLaps) by 44.4% [95% CI: 11.3, 65.1] and 35.5% [95% CI: 14.0, 51.6], respectively, without any dose-dependent decrease in the studied dose range. The total cholesterol and LDL-cholesterol concentrations were significantly reduced by 19--25% and 28--35%, respectively, when compared with placebo. HDL-cholesterol and triglyceride concentrations were not affected. An oestrogen-like effect on the hypothalamic-pituitary axis was observed with approximately 50% reductions of FSH and LH after 8 weeks of treatment. No clinically significant changes of other safety variables were observed. The pharmacokinetic analysis demonstrated a rapid absorption (mean tmax: 2--3 h), a slow elimination (mean t1/2: 4.8--8.4 days) and dose linearity of Cmax and AUC for doses up to 160 mg. As expected for a drug with slow elimination given frequently, the relative fluctuation around the steady state plasma concentration was small and the drug accumulation considerable (RA: 3--5). CONCLUSIONS: Short-term administration of levormeloxifene in postmenopausal women was well-tolerated at doses that elicited a favourable pharmacodynamic response suggesting oestrogen-like bone preserving and antiatherogenic effects. Little variation of peak-trough plasma concentrations was observed during daily administration due to a plasma half-life of approximately 1 week.     

HLA associated genetic predisposition to autoimmune diseases: Genes involved and possible mechanisms

Autoimmune diseases are the result of an interplay between predisposing genes and triggering environmental factors, leading to loss of self-tolerance and an immune-mediated destruction of autologous cells and/or tissues. Genes in the HLA complex are among the strongest predisposing genetic factors. The HLA complex genes primarily involved are most often those encoding the peptide-presenting HLA class I or II molecules. A probable mechanism is preferential presentation by the disease-associated HLA molecules of peptides from autoantigens to T cells. Recent studies have shown, however, that other genes in the HLA complex also contribute. Taken together, available evidence suggests that the HLA complex harbour both disease predisposing genes which are quite specific for some autoimmune diseases (e.g. HLA-B27 for ankylosing spondylitis) and others which may be more common for several diseases. This will be briefly reviewed in the following.     

Several genes in the extended human MHC contribute to predisposition to autoimmune diseases

Autoimmune diseases, such as type 1 diabetes, rheumatoid arthritis, psoriasis and systemic lupus erythematosus, affect approximately 4% of the population in industrialized countries, and are characterized by an immune-mediated destruction of autologous cells and/or tissues. More knowledge is needed to prevent and treat this large group of diseases. Unravelling the genetic predisposing factors is important in this respect, and large research efforts have been initiated to reach this goal. The human MHC, also called the human leukocyte antigen (HLA) complex, is known to harbour major genetic determinants for autoimmune diseases. For several autoimmune diseases certain classical HLA class II and/or class I genes are strongly associated with disease. As a result of recent systematic screening studies additional genes and regions in the MHC, including the extended MHC, are now known to contribute to the predisposition.     

Lack of association with the CD28/CTLA4/ICOS gene region among Norwegian multiple sclerosis patients

Chromosome region 2q33 encodes several regulators of the immune system, among these the CD28, CTLA4, and ICOS molecules. Involvement of these genes in multiple sclerosis (MS) is not yet clear. We investigated six microsatellites and three SNPs in a relatively large and clinically well characterised Norwegian MS cohort. No associations were observed for any of the markers analysed in 575 MS patients and 551 controls. Associations were neither found when stratifying the material for the HLA-DRB1*1501, DQB1*0602 haplotype, gender, age at onset, disease course nor familial aggregation. In conclusion, this study could not confirm association with the CD28/CTLA4/ICOS gene region.     

Clostridium difficile-associated reactive arthritis in two children

In adults, reactive arthritis (ReA) following Clostridium difficile-enterocolitis has been documented. In children, only one case of C. difficile-associated ReA has been reported. We now describe two other cases of ReA associated with C. difficile in children. The characteristics of ReA due to C. difficile appear to be similar in adults and children. Both children show polyarthritis after an episode of diarrhoea with positive stool cultures for C. difficile. Arthritis is asymmetrical with a self-limiting course. Nonsteroidal antiinflammatory drug (NSAID) therapy is sufficient. One case is remarkable because of its prolonged course of ReA despite NSAID therapy, and its association with the presence of HLA-B27 antigen.