R47H TREM2 variant increases risk of typical early-onset Alzheimer's disease but not of prion or frontotemporal dementia.

BACKGROUND: Rare TREM2 variants are significant risk factors for Alzheimer's disease (AD). METHODS: We used next generation sequencing of the whole gene (n = 700), exon 2 Sanger sequencing (n = 2634), p.R47H genotyping (n = 3518), and genome wide association study imputation (n = 13,048) to determine whether TREM2 variants are risk factors or phenotypic modifiers in patients with AD (n = 1002), frontotemporal dementia (n = 358), sporadic (n = 2500), and variant (n = 115) Creutzfeldt-Jakob disease (CJD). RESULTS: We confirm only p.R47H as a risk factor for AD (odds ratio or OR = 2.19; 95% confidence interval or CI = 1.04-4.51; P = .03). p.R47H does not significantly alter risk for frontotemporal dementia (OR = 0.81), variant or sporadic CJD (OR = 1.06 95%CI = 0.66-1.69) in our cohorts. Individuals with p.R47H associated AD (n = 12) had significantly earlier symptom onset than individuals with no TREM2 variants (n = 551) (55.2 years vs. 61.7 years, P = .02). We note that heterozygous p.R47H AD is memory led and otherwise indistinguishable from "typical" sporadic AD. CONCLUSION: We find p.R47H is a risk factor for AD, but not frontotemporal dementia or prion disease.

Randomized trial of nicotine replacement therapy (NRT), bupropion and NRT plus bupropion for smoking cessation: effectiveness in clinical practice.

BACKGROUND AND AIMS: Bupropion was introduced for smoking cessation following a pivotal trial showing that it gave improved efficacy over the nicotine patch and also suggesting combination treatment was beneficial. We tested in clinical practice for an effectiveness difference between bupropion and nicotine replacement therapy (NRT), whether the combination improves effectiveness and whether either treatment might be more beneficial for certain subgroups of smokers. DESIGN: Open-label randomized controlled trial with 6-month follow-up. SETTING: Four UK National Health Service (NHS) smoking cessation clinics. PARTICIPANTS: Smokers (n = 1071) received seven weekly behavioural support sessions and were randomized to an NRT product of their choice (n = 418), bupropion (n = 409) or NRT plus bupropion (n = 244). MEASURES: The primary outcome was self-reported cessation over 6 months, with biochemical verification at 1 and 6 months. Also measured were baseline demographics, health history, smoking characteristics and unwanted events during treatment. FINDINGS: Abstinence rates for bupropion (27.9%) and NRT (24.2%) were not significantly different (odds ratio = 1.21, 95% confidence interval = 0.883-1.67), and the combination rate (24.2%) was similar to that for either treatment alone. There was some evidence that the relative effectiveness of bupropion and NRT differed according to depression (χ(2) = 2.86, P = 0.091), with bupropion appearing more beneficial than NRT in those with a history of depression (29.8 versus 18.5%). Several unwanted symptoms were more common with bupropion. CONCLUSION: There is no difference in smoking cessation effectiveness among bupropion, nicotine replacement therapy and their combination when used with behavioural support in clinical practice. There is some evidence that bupropion is more beneficial than nicotine replacement therapy for smokers with a history of depression.

Radiographic evaluation of marginal bone levels around dental implants with different designs after 1 year.

OBJECTIVE: The aim of this study was to use intra-oral radiographs to evaluate changes in marginal bone levels around three different implant designs after 1 year. MATERIALS AND METHODS: Three implant designs; two with a straight and one with a conical design, were placed adjacent to each other in the partially edentulous areas of 25 patients. The patients received 46 implants with a straight design (All fit SSO and SPI-element) and 29 implants with a conical design (SPI-contact). Two-way repeated analysis of variance (ANOVA) was used to evaluate the marginal bone changes in each group at 12 months follow-up (p < 0.05). RESULTS: None of the implants had failed by the end of this study. After 12 months, significant differences were noted in the amount of alveolar bone loss recorded between the All fit SSO and SPI implants (p < 0.05). Mean crestal bone loss was 0.88 ± 0.43 mm for the All fit, 0.61 ± 0.34 mm for the SPI contact and 0.54 ± 0.27 mm for the SPI element implants. CONCLUSIONS: The results of this study demonstrate that straight (cylindrical) implants with shorter high polish surface displayed less bone resorption.

Championing of dementia in England.

Dementia is starting to attract attention following decades of comparative neglect relative to other disease areas. England has been at the forefront of this sea change as one of the first countries in the world to develop a National Dementia Strategy (in 2009). Events leading up to the publication of this strategy and since will be examined here together with a glimpse at the international landscape.

Pharmacokinetic behavior and appraisal of intravenous busulfan dosing in infants and older children: the results of a population pharmacokinetic study from a large pediatric cohort undergoing hematopoietic stem-cell transplantation.

BACKGROUND: Intravenous (IV) busulfan (Bu) dosing approved in Europe based on 5 body weight (BW) strata has been validated for targeting Bu exposures in children undergoing hematopoietic stem-cell transplantation and with mostly malignant diseases. The authors conducted an observational study aiming to investigate the behavior and ontogeny of IV Bu pharmacokinetic (PK) disposition, and to reevaluate the consistency of the BW-based dosing in very young children with rare diseases. METHODS: The observational study comprised 115 patients, mostly infants with immunodeficiencies and metabolic inherited disorders and with altered liver function and/or iron overload. Additional data (90 children, mostly malignant diseases) were pooled with the first data set. The overall data (205 children aged from 10 days to 15 years) were analyzed using population PK modeling. RESULTS: The BW remained the main determinant of IV Bu PK, and no further covariate effect was identified. Bu clearance (CL) variability was best described by BW allometric functions. Increase of drug CL with the child's growth was faster in younger children. This pattern is likely related to the maturation of GSTA1 enzymes during infancy and was accounted for in the model by estimating a higher BW allometric exponent in children <9 kg compared with that in children ≥9 kg. IV Bu PK was not modified in children with altered liver function and/or iron overload, and no disease specific difference was observed. Bu dosing either adjusted according to the final model or with the approved EU labeling yields similar targeting performances. For both dosing strategies, the percent of patients achieving the therapeutic area under the curve window (900-1500 µmole·min/L were 60% and 70%-90% in children <9 and ≥9 kg, respectively. CONCLUSIONS: A population PK model accounting for the highest Bu CL in the youngest patients was validated on training and evaluation data sets. The BW-based dosing strategy recommended in Europe proved to be consistent on a large paediatric cohort representative of the population heterogeneity observed in hematopoietic stem-cell transplantation.

Hepatectomy for hepatocellular carcinoma complicated by vasculitis flare.

BACKGROUND: The hepatitis C virus is a major cause of hepatocellular carcinoma. Extrahepatic manifestations of hepatitis C include mixed cryoglobulinemia which can result in ischemic damage to multiple organs. The management of these sequelae in posthepatectomy patients is unclear. CASE REPORT: A 49-year-old male with hepatitis C was found to have a 4 cm hepatocellular carcinoma on surveillance imaging. He underwent portal vein embolization followed by hepatectomy. His postoperative course was complicated by the development of splenic infarcts, small bowel ischemia, skin lesions, and liver damage. Findings of elevated cryocrit and elevated rheumatoid factor suggested the diagnosis of cryoglobulin-related vasculitis. The patient improved on supportive care. CONCLUSION: Cryoglobulinemia is associated with hepatitis C and may complicate the care of this patient population. The treatment of cryoglobulinemia posthepatectomy patients is complicated by concerns over how medications may affect the regenerating liver. Steroids should be used with caution in this setting. SUMMARY: Brief report of hepatectomy complicated by vasculitis in the context of hepatocellular carcinoma secondary to hepatitis C addresses the management of mixed cryoglobulinemia in post-hepatectomy patients.

Social cognition and its neural correlates in schizophrenia and autism.

The study of social cognition in psychiatric disorders has become increasingly popular in recent years. This is due to the its proposed link to social functioning and the inability of general neurocognitive skills to explain the spectrum of impairments observed in patients. This article reviews research into two of the processes thought to underlie social cognition (emotion perception and theory of mind) in schizophrenia and autism. This is followed by a look at neuroimaging studies and their efforts to localize the neural correlates of emotion perception and theory of mind in the two disorders. We concluded that while a specific impairment in emotion perception and theory of mind skills cannot be generalized to all individuals with autism and schizophrenia, there are subpopulations that have lingering deficits of social cognition tasks. Neuroimaging work consistently points to the involvement of the fusiform gyrus and amygdala in emotion processing, while the medial prefrontal and frontal cortex are implicated in tasks invoking theory of mind. We propose that deficits of social cognition may benefit from cognitive remediation therapy and pharmacological cognitive enhancers.