Evidence against a role for rare ADAM10 mutations in sporadic Alzheimer Disease

The Alzheimer amyloid protein precursor (APP) is subject to proteolysis by ADAM10 and ADAM17, precluding the formation of Aβ. Recently, coding variations in ADAM10 resulting in altered function have been reported in familial Alzheimer disease (AD). The authors carried out a large-scale (n = 576: Controls, 271; AD, 305) resequencing study of ADAM10 in sporadic AD. The results do not support a significant role for ADAM10 mutations in AD. The results also make it clear that the careful examination of ancestry required in any case-control comparison is especially true with rare variations, where even a very small number of variations might form the basis of scientific conclusions.     

Prolonged-release melatonin improves sleep quality and morning alertness in insomnia patients aged 55 years and older and has no withdrawal effects

Melatonin, secreted nocturnally by the pineal gland, is an endogenous sleep regulator. Impaired melatonin production and complaints on poor quality of sleep are common among the elderly. Non-restorative sleep (perceived poor quality of sleep) and subsequently poor daytime functioning are increasingly recognized as a leading syndrome in the diagnostic and therapeutic process of insomnia complaints. The effects of 3-weeks prolonged-release melatonin 2 mg (PR-melatonin) versus placebo treatment were assessed in a multi-center randomized placebo-controlled study in 170 primary insomnia outpatients aged > or =55 years. Improvements in quality of sleep (QOS) the night before and morning alertness (BFW) were assessed using the Leeds Sleep Evaluation Questionnaire and changes in sleep quality (QON) reported on five categorical unit scales. Rebound insomnia and withdrawal effects following discontinuation were also evaluated. PR-melatonin significantly improved QOS (-22.5 versus -16.5 mm, P = 0.047), QON (0.89 versus 0.46 units; P = 0.003) and BFW (-15.7 versus -6.8 mm; P = 0.002) compared with placebo. The improvements in QOS and BFW were strongly correlated (Rval = 0.77, P < 0.001) suggesting a beneficial treatment effect on the restorative value of sleep. These results were confirmed in a subgroup of patients with a greater symptom severity. There was no evidence of rebound insomnia or withdrawal effects following treatment discontinuation. The incidence of adverse events was low and most side-effects were judged to be of minor severity. PR-melatonin is the first drug shown to significantly improve quality of sleep and morning alertness in primary insomnia patients aged 55 years and older-suggesting more restorative sleep, and without withdrawal symptoms upon discontinuation.     

<Emphasis Type="Italic">IL6</Emphasis> (-174) and <Emphasis Type="Italic">TNFA</Emphasis> (-308) promoter polymorphisms are associated with systemic creatine kinase response to eccentric exercise

Exertional rhabdomyolysis is a complex and poorly understood entity. The inflammatory system has an important role in muscle injury and repair. Serum creatine kinase (CK) is often used as systemic biomarker representing muscle damage. Considerable variation exists in CK response between different subjects. Genetic elements may act as predisposition factors for exertional srhabdomyolysis. Based on their biological activity, we hypothesized that in healthy subjects IL6 G-174C and TNFA G-308A promoter polymorphisms would be associated with CK response to exercise. We determined serum CK activity pre- and post-maximal eccentric contractions of the elbow flexor muscles. IL6 G-174C and TNFA G-308A genotypes were analyzed for possible relationship with changes in serum CK activity. IL6 G-174C genotype was associated with CK activity in a Dose-Dependent fashion. Subjects with one or more of the -174C allele had a greater increase and higher peak CK values than subjects homozygous for the G allele (mean +/- SE U/L: GG, 2,604 +/- 821; GC, 7,592 +/- 1,111; CC, 8,403 +/- 3,849, ANOVA P = 0.0003 for GG + GC genotypes versus CC genotype, P = 0.0005 for linear trend). IL6-174CC genotype was associated with a greater than threefold increased risk of massive CK response (adjusted odds ratio 3.29, 95% confidence interval 1.27-7.85, P = 0.009). A milder association (P = 0.06) was noted between TNFA G-308A genotype and CK activity. In conclusion, we found a strong association of the IL6 G-174C genotype with systemic CK response to strenuous exercise. Data suggest that homozygosity for the IL6-174C allele is a clinically important risk factor for exercise-induced muscle injury, further supporting the central role of cytokines in the reactive inflammatory process of muscle damage and repair.     

Pulmonary Eosinophilia

Eosinophils may infiltrate the lung tissue, thus impairing gas exchange and causing several symptoms as dyspnea, fever, and cough. This process may be secondary to several factors, including drugs or parasite migration, or primary (idiopathic). Acute eosinophilic pneumonia is life-threatening and presents frequently in young smokers as an acute hypoxemic respiratory failure of generally less than a week with bilateral lung infiltrates, frequently misdiagnosed as severe community-acquired pneumonia. This patients present without peripheral eosinophilia but usually have more than 25% eosinophils on bronchoalveolar fluid. Chronic eosinophilic pneumonia is a protracted disease of usually more than a month before presentation, with a predilection for middle aged asthmatic patients. Hypoxemia is mild-moderate, and there are usually more than 1,000 eosinophils/mm3 of peripheral blood. Bronchoalveolar fluid has high eosinophil levels (usually more than 25%). Migratory peripheral infiltrates are seen in the chest x-ray film. Both acute and chronic eosinophilic pneumonia are treated by glucocorticoids and respiratory support as well as avoidance of any recognized trigger.     

Neurologic abnormalities in children presenting with diskitis

BACKGROUND: Neurologic impairment is not considered a clinical manifestation of diskitis in children and has seldom been associated with it in the medical literature. OBJECTIVE: To describe neurologic findings and their implications in children with diskitis. STUDY DESIGN: Retrospective medical records review of children discharged with a diagnosis of diskitis between January 1992 and December 2000. The study included children in whom the diagnosis was based on the presence of clinical findings, laboratory evidence of an inflammatory process, and findings on imaging studies compatible with diskitis. RESULTS: Neurologic findings of decreased muscle strength or hyporeflexia in the lower extremities were found in 7 (41%) of 17 children who met the diagnostic criteria for diskitis. Five of the 7 underwent magnetic resonance imaging, 2 of whom demonstrated intraspinal inflammatory involvement. CONCLUSIONS: Neurologic impairment does not exclude the diagnosis of diskitis and may be a common manifestation of the disease in children. Nevertheless, when neurologic findings are present, advanced imaging studies are needed to exclude intraspinal involvement.     

Comparison of positive allergy skin tests among asthmatic children from rural and urban areas living within small geographic area.

BACKGROUND: Evidence of increased asthma and allergic response among urban versus rural residents has been reported. OBJECTIVE: To evaluate the prevalence of allergic response among asthmatic children from urban and rural areas living within close proximity. METHODS: In all, 448 asthmatic children from urban (363) and rural (85) areas were studied. The study group consisted of 234 9-year-olds and 214 12-year-olds. A health questionnaire was completed on each child who subsequently underwent allergic skin prick tests (SPTs). RESULTS: There was significantly more positive SPT response to house-dust mite, mold, cat, and cypress among asthmatic children from urban areas compared with children living in rural areas: 58.3% versus 37.6%, 46.1% versus 31.8%, 17.45 versus 5.9%, and 26.2% versus 15.3%, respectively. Positive SPT for indoor allergens were significantly greater among asthmatic urban residents than asthmatic rural residents: 63.3% versus 45.5%, respectively (P < 0.02). Positive SPT response to all the allergens checked was higher among the 12-year-old age group when compared with the 9-year-olds, 34.6% versus 22.7%, respectively (P = 0.05). CONCLUSIONS: Allergic response measured by SPT is significantly more common among asthmatic children from urban areas as opposed to rural, even though both areas are within small distance of one another. Further, asthmatic children living in urban areas demonstrated more allergic response to both indoor and outdoor allergens. The allergic response tends to increase with increased age in both urban and rural asthmatic children.     

NK cells are primed by ANRS MVAHIV‐infected DCs,via a mechanism involving NKG2D and membrane‐bound IL‐15, to control HIV‐1 infection in CD4+ T cells

Natural killer (NK) cells are the major antiviral effector cell population of the innate immune system. It has been demonstrated that NK‐cell activity can be modulated by the interaction with dendritic cells (DCs). The HIV‐1 vaccine candidate Modified Vaccinia Ankara encoding an HIV polypeptide (MVA_HIV), developed by the French National Agency for Research on AIDS (ANRS), has the ability to prime NK cells to control HIV‐1 infection in DCs. However, whether or not MVA_HIV‐primed NK cells are able to better control HIV‐1 infection in CD4⁺ T cells, and the mechanism underlying the specific priming, remain undetermined. In this study, we show that MVA_HIV‐primed NK cells display a greater capacity to control HIV‐1 infection in autologous CD4⁺ T cells. We also highlight the importance of NKG2D engagement on NK cells and DC‐produced IL‐15 to achieve the anti‐HIV‐1 specific priming, as blockade of either NKG2D or IL‐15 during MVA_HIV‐priming lead to a subsequent decreased control of HIV‐1 infection in autologous CD4⁺ T cells. Furthermore, we show that the decreased control of HIV‐1 infection in CD4⁺ T cells might be due, at least in part, to the decreased expression of membrane‐bound IL‐15 (mbIL‐15) on DCs when NKG2D is blocked during MVA_HIV‐priming of NK cells.