μ‐Opioid receptor desensitization: homologous or heterologous?

There is considerable controversy over whether μ‐opioid receptor (MOPr) desensitization is homologous or heterologous and over the mechanisms underlying such desensitization. In different cell types MOPr desensitization has been reported to involve receptor phosphorylation by various kinases, including G‐protein‐coupled receptor kinases (GRKs), second messenger and other kinases as well as perturbation of the MOPr effector pathway by GRK sequestration of G protein βγ subunits or ion channel modulation. Here we report that in brainstem locus coeruleus (LC) neurons prepared from relatively mature rats (5–8 weeks old) rapid MOPr desensitization induced by the high‐efficacy opioid peptides methionine enkephalin and DAMGO was homologous and not heterologous to α₂‐adrenoceptors and somatostatin SST₂ receptors. Given that these receptors all couple through G proteins to the same set of G‐protein inwardly rectifying (GIRK) channels it is unlikely therefore that in mature neurons MOPr desensitization involves G protein βγ subunit sequestration or ion channel modulation. In contrast, in slices from immature animals (less than postnatal day 20), MOPr desensitization was observed to be heterologous and could be downstream of the receptor. Heterologous MOPr desensitization was not dependent on protein kinase C or c‐Jun N‐terminal kinase activity, but the change from heterologous to homologous desensitization with age was correlated with a decrease in the expression levels of GRK2 in the LC and other brain regions. The observation that the mechanisms underlying MOPr desensitization change with neuronal development is important when extrapolating to the mature brain results obtained from experiments on expression systems, cell lines and immature neuronal preparations.     

Handedness Scale: How Many and Which Items?

A stepwise analysis of the Cronbach Alpha Coefficient (CAC) was performed on five large samples of adults and young children, in order to choose the “minimum” set of items of a handedness scale which gives the maximum reliability. In adults, a handedness scale with 12 items has nearly the same or even a better CAC than other scales with more items; so, a choice of 10 to 12 items seems to be adequate. For children, a scale with eight items seems to be quite reliable but it is not impossible that a scale including more items would lead to a slight increase of CAC. The controversial usefulness of a precise assessment of the “general handedness factor” (the first principal component) generated by handedness questionnaires and its J-shaped distribution in the general population are discussed.     

The response scale for the intellectual disability module of the WHOQOL: 5‐point or 3‐point?

Objective To deal with the question of whether a 5‐point response Likert scale should be changed to a 3‐point scale when used in the field testing of people with intellectual disabilities (IDs), which was raised after the pilot study of World Health Organization Quality of Life (WHOQOL)‐DIS, a module being developed with the World Health Organization measure of quality of life for disabilities. Methods Three possible ways were used to generate hypothetical data by merging a 5‐point scale into a 3‐point scale. The analyses were based on both item response theory and classical measurement theory. The partial credit model for polytomous response was performed for item evaluation; the confirmatory factor analysis was used to check construct validity, the Cronbach's alpha for domain reliability, and correlation analyses for the relationship between the 5‐point scale and the generated 3‐point scale. Results Most items with a 5‐point response scale had disordered response options and/or unequal‐length intervals between successive response options; these deficiencies were removed or improved without decline of validity and reliability in the hypothetical data of 3‐point scales. Conclusion Instead of the 5‐point scale, a 3‐point scale could be used for IDs in the field test of developing the module WHOQOL‐DIS.     

HMGB‐1, TLR4, IL‐1R1, TNF‐α, and IL‐1β: novel epilepsy markers?

Aim: The purpose of this study was to compare HMGB‐1, TLR4, IL‐1β, IL‐1R1, and TNF‐α levels in patients with mild and severe epilepsy with those in a healthy control group. Methods: Children aged 4–17 years, diagnosed with epilepsy for at least three years and with no progressive neurological disease, metabolic disease or infection, were selected for the study. The severe epilepsy group consisted of 28 children with at least one episode a week despite receiving three or more antiepileptic drugs. The mild epilepsy group consisted of 29 children with no seizures in the previous year, receiving only one antiepileptic drug, while 27 healthy children were selected as the control group. HMGB‐1, TLR4, IL‐1R1, TNF‐α and IL‐1β levels were investigated in these three groups. The MRI findings and clinical characteristics of the patients in the epilepsy group were also compared with these markers. Results: HMGB‐1, TLR4, TNF‐α, and IL‐1β levels in the severe epilepsy group were higher than in the control group and the mild epilepsy group (p<0.05), and were higher in the mild epilepsy group than in the control group (p<0.05). IL‐1R1 was also higher in the severe epilepsy group than in the control group (p<0.05). Conclusion: In this first report to identity a possible correlation between HMGB‐1, TLR4, IL‐1β, IL‐1R1, and TNF‐α levels and severity of epilepsy, our data demonstrates that the serum level of these cytokines is higher in cases of drug‐refractory epilepsy.     

How many dementia cases in France and Europe? Alternative projections and scenarios 2010–2050

Background and purpose: The objective of this study is to estimate the number of dementia cases expected to occur in France and Europe over the next few decades until 2050. Methods: Our estimates are based on a model using the European incidence data for dementia by age and sex, the relative mortality risks related to dementia stratified by age classes, and the projections of mortality coefficients in the French and European general population. Results: In France, in 2010, the number of dementia cases should reach 754000, i.e., 1.2% of the general population or 2.8% of the active population. By 2050 this number should be multiplied by 2.4, i.e., 1813000 cases, which will be 2.6% of the total population and 6.2% of the active population. In Europe this number could reach more than 6 millions in 2010 and 14 millions in 2050. The sensitivity analysis performed on French data showed that our projections were robust to the use of alternative data for incidence and relative mortality risk (variation of 5.5% and 6.5%), but very sensitive to hypotheses of evolution of mortality (variation of ?22% to 29%). Conclusions: The approach used in our study, integrating both the dementia incidence and the mortality in the calculations, allowed us to refine the projections and stress the great sensitivity of the demographic hypotheses forecasts on the evolution of life expectancy. The likely increase is particularly important and confirms that French and European health systems must take this into account when making future plans.     

How does stroke restrict participation in long‐term post‐stroke survivors?

OBJECTIVE: To explore the factors determining 'restricted participation' in a selected population of long-term post-stroke survivors. MATERIALS AND METHODS: Seventy-three consecutive post-stroke inpatients were scored for mood and restriction in participation by means of self-administered questionnaires, respectively the Hospital Anxiety and Depression Scale (HADS/A; HADS/D) and London Handicap Scale (LHS). Neurological impairment and functional disability were evaluated with the Unified Neurological Stroke Scale (UNSS) and Functional Independence Measure (FIM). RESULTS: Physical independence and occupation were the most severely affected domains on the LHS. UNSS, FIM, HADS/A, HADS/D scores were significant determinants of restriction in participation at univariate analysis performed with each LHS domain. FIM score and emotional status finally emerged as the independent determinants of restricted participation for the LHS domains most related to body function (mobility, physical independence, occupation). Depression was the determinant factor for orientation and social integration. CONCLUSION: Functional disability and mood disorders may independently contribute to the restricted participation of post-stroke patients. Most of the LHS domains remain stable over time.     

Multifaceted roles of sphingosine‐1‐phosphate: How does this bioactive sphingolipid fit with acute neurological injury?

Sphingosine-1-phosphate (Sph-1-P) is an essential bioactive sphingolipid metabolite that has currently become the focus of intense interest. Sph-1-P is generated by the enzyme sphingosine kinase (SphK) in response to diverse stimuli, including growth factors, cytokines, and G-protein-coupled receptor (GPCR) agonists. Its precursor, sphingosine (Sph), is produced from the precursor ceramide (Cer) via a ceramidase (CDase) that is released from membrane sphingomyelin (SPM) by sphingomyelinases (SMase). Accumulating evidence indicates that Sph-1-P is the key regulatory lipid involved in the metabolism of sphingolipids and is involved in the control of numerous aspects of cell physiology, including mitogenesis, differentiation, migration, and apoptosis. These actions of Sph-1-P are mediated by a family of high-affinity S1P receptors, named S1P1-5, which are coupled differentially via G(i), G(q), G(12/13), and Rho to multiple effector systems, including adenylate cyclase, phospholipases C (PLC) and D (PLD), extracellular-signal-regulated kinase, c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, and nonreceptor tyrosine kinases. In this Review, we accumulate available evidence implying that sphingolipid signaling may represent a novel neuroprotective target to counteract the pathophysiology of acute brain and spinal cord injury in regard to apoptotic cell death mechanisms, mitochondrial dysfunction, lipid hydrolysis, and oxidative damage mechanisms. Furthermore, we discuss how Sph-1-P agonist approaches might be expected to increase the resistance of the central nervous system to injury by promoting neurotrophic activity, neurogenesis, and angiogenesis. On the other hand, antagonists of certain Sph-1-P-related activity might possess proregenerative effects via promotion of neurite growth and inhibition of astrogliotic scarring.