We are preventing some dementias now-But how? The Potamkin lecture.

Most dementias are untreatable and their prevalence is increasing around the world. However, the incidence of dementia is declining in some countries. We need to find out urgently why and how and apply the lessons promptly and widely.

The apathy, gait impairment, and executive dysfunction (AGED) triad vascular variant.

Apathy, gait disturbances, and executive dysfunction (AGED) often occur together. Although they can arise independently, the presence of one might portend another. This recognition suggests the possible etiology.

Infliximab for Crohn's Disease: More Than 13 Years of Real-world Experience.

Background: The purpose of this study was to compare the long-term safety of infliximab and nonbiologic agents as Crohn's disease (CD) therapy.

Methods: Patients with CD were prospectively evaluated in this large, observational registry.

Results: Patients (n = 6273) participated in this observational registry from July 1999 through March 2012; 3440 (54.

Autosomal-Recessive Intellectual Disability with Cerebellar Atrophy Syndrome Caused by Mutation of the Manganese and Zinc Transporter Gene SLC39A8.

Manganese (Mn) and zinc (Zn) are essential divalent cations used by cells as protein cofactors; various human studies and animal models have demonstrated the importance of Mn and Zn for development. Here we describe an autosomal-recessive disorder in six individuals from the Hutterite community and in an unrelated Egyptian sibpair; the disorder is characterized by intellectual disability, developmental delay, hypotonia, strabismus, cerebellar atrophy, and variable short stature. Exome sequencing in one affected Hutterite individual and the Egyptian family identified the same homozygous variant, c.

The lipid-lowering effects of lomitapide are unaffected by adjunctive apheresis in patients with homozygous familial hypercholesterolaemia - a post-hoc analysis of a Phase 3, single-arm, open-label trial.

Objective: Lomitapide (a microsomal triglyceride transfer protein inhibitor) is an adjunctive treatment for homozygous familial hypercholesterolaemia (HoFH), a rare genetic condition characterised by elevated low-density lipoprotein-cholesterol (LDL-C), and premature, severe, accelerated atherosclerosis. Standard of care for HoFH includes lipid-lowering drugs and lipoprotein apheresis. We conducted a post-hoc analysis using data from a Phase 3 study to assess whether concomitant apheresis affected the lipid-lowering efficacy of lomitapide.

Repeated exposure to high-frequency low-amplitude vibration induces degeneration of murine intervertebral discs and knee joints.

Objective: High-frequency, low-amplitude whole-body vibration (WBV) is being used to treat a range of musculoskeletal disorders; however, there is surprisingly limited knowledge regarding its effect(s) on joint tissues. This study was undertaken to examine the effects of repeated exposure to WBV on bone and joint tissues in an in vivo mouse model.

Methods: Ten-week-old male mice were exposed to vertical sinusoidal vibration under conditions that mimic those used clinically in humans (30 minutes per day, 5 days per week, at 45 Hz with peak acceleration at 0.

Four-year maintenance treatment with adalimumab in patients with moderately to severely active ulcerative colitis: Data from ULTRA 1, 2, and 3.

Objectives: The safety and efficacy of adalimumab for patients with moderately to severely active ulcerative colitis (UC) has been reported up to week 52 from the placebo-controlled trials ULTRA (Ulcerative Colitis Long-Term Remission and Maintenance with Adalimumab) 1 and 2. Up to 4 years of data for adalimumab-treated patients from ULTRA 1, 2, and the open-label extension ULTRA 3 are presented.

Methods: Remission per partial Mayo score, remission per Inflammatory Bowel Disease Questionnaire (IBDQ) score, and mucosal healing rates were assessed in adalimumab-randomized patients from ULTRA 1 and 2 up to week 208.

Carnitine therapy for the treatment of metabolic syndrome and cardiovascular disease: evidence and controversies.

As the incidence of metabolic syndrome increases, there is also a growing interest in finding safe and inexpensive treatments to help lower associated risk factors. L-carntine, a natural dietary supplement with the potential to ameliorate atherosclerosis, has been the subject of recent investigation and controversy. A majority of studies have shown benefit of L-C supplementation in the metabolic syndrome or cardiovascular risk factors.

Uncloaking the genetic determinants of metabolic syndrome.

The metabolic syndrome (MetS) is a commonly encountered cluster of clinical phenotypes, including central obesity, hypertension, hyperglycemia, and dyslipidemia. Identifying genetic determinants of MetS will lead to better understanding of its progression and pathogenesis. To further the knowledge of MetS it is important to not only study the candidate genes for each individual component but to also investigate patients with rare monogenic disorders who express a cluster of the phenotypes commonly observed in MetS, however defined.

Automatic target and trajectory identification for deep brain stimulation (DBS) procedures.

This paper presents an automatic surgical target and trajectory identification technique for planning deep brain stimulation (DBS) procedures. The probabilistic functional maps, constructed from population-based actual stimulating field information and intra-operative electrophysiological activities, were integrated into a neurosurgical visualization and navigation system to facilitate the surgical planning and guidance. In our preliminary studies, we compared the actual surgical target locations and trajectories established by an experienced stereotactic neurosurgeon with those automatically planned using our probabilistic functional maps on 10 subthalamic nucleus (STN) DBS procedures.

Development and application of functional databases for planning deep-brain neurosurgical procedures.

This work presents the development and application of a visualization and navigation system for planning deep-brain neurosurgeries. This system, which incorporates a digitized and segmented brain atlas, an electrophysiological database, and collections of final surgical targets of previous patients, provides assistance for non-rigid registration, navigation, and reconstruction of clinical image data. The fusion of standardized anatomical and functional data, once registered to individual patient images, facilitates the delineation of surgical targets.

Clinical and genetic associations with hypertriglyceridemic waist in a Canadian aboriginal population.

Objectives: To determine the prevalence of 'hypertriglyceridemic waist' (HTGW) in Oji-Cree, to examine its interaction with hepatic nuclear factor-1alpha (HNF1A) in association with type 2 diabetes, and to characterize its putative genetic determinants.

Method: The presence or absence of HTGW was determined in 522 Oji-Cree subjects (223 males, 299 females), >or=18 years of age, in whom physical measurements and fasting plasma analyte concentrations were gathered, and a 75-g oral glucose tolerance test was administered, as part of a cross-sectional study. Subjects were genotyped for HNF1A codon 319, angiotensinogen (AGT) codons 174 and 235, G-protein beta3-subunit (GNB3) nucleotide 825, fatty acid-binding protein (FABP2) codon 54, nucleotides -455 and -482 of the apolipoprotein (apo) C-III (APOC3) promoter, and a 5-bp insertion/deletion polymorphism within the 3'-untranslated region of protein phosphatase 1 regulatory subunit 3 (PPP1R3).

Synergism between mutant HNF1A and the metabolic syndrome in Oji-Cree Type 2 diabetes.

Aims: To determine the prevalence of the metabolic syndrome in the Sandy Lake Oji-Cree and to examine its interaction with HNF1A in association with impaired glucose tolerance and Type 2 diabetes.

Methods: Using data collected from the Sandy Lake Health and Diabetes Project (1993-1995), the presence or absence of the metabolic syndrome was determined in 515 Oji-Cree subjects, > or = 18 years of age. In the original study, fasting plasma analytes were measured, a 75-g oral glucose tolerance test was administered, and subjects were genotyped for HNF1A G319S.

LMNA mutation position predicts organ system involvement in laminopathies.

The underlying disease mechanisms likely include mutation effects on the nuclear envelope and on interactions between lamins and transcription factors. At the same time, can a simple genomic attribute -- for instance, mutation position within the LMNA sequence -- predict the complex phenotypic effects? In order to assess this, hierarchical cluster analysis (HCA) was used for assembling 16 laminopathies into two classes based on organ system involvement. Ninety-one reported causative LMNA mutations in these laminopathies were then classified according to their position upstream or downstream of the nuclear localization signal sequence (NLS).

Novel mutation in DGUOK in hepatocerebral mitochondrial DNA depletion syndrome associated with cystathioninuria.

Mitochondrial depletion syndrome (MDS) refers to a heterogeneous group of mitochondrial disorders characterized by a reduction of the mtDNA copy number in affected tissues. Mutations in DGUOK encoding deoxyguanosine kinase (MIM 601465) cause the hepatocerebral form of MDS (MIM 251880). Cystathioninuria (MIM 219500) can result from mutations in CTH encoding cystathionine gamma lyase (MIM 607657) or can be a secondary finding in several diverse clinical conditions.

Phenotypic heterogeneity of sitosterolemia.

Sitosterolemia is a rare autosomal recessive disorder of lipoprotein metabolism characterized by xanthomas and increased plasma concentrations of plant sterols, such as sitosterol. Causative mutations occur in either the ABCG5 or ABCG8 gene, each of which encodes a sterol half-transporter expressed in the intestine. We report five Canadian subjects with nonsense mutations in these half-transporters: four related Caucasian subjects were homozygous for the ABCG8 S107X mutation, and one unrelated Japanese-Canadian subject was homozygous for a complex insertion/deletion (I/D) mutation in ABCG5 exon 3.

Optimizing RNA extraction yield from whole blood for microarray gene expression analysis.

Objectives: Microarray analysis of gene expression profiles of blood leukocytes has many potential clinical and research applications.

Design And Methods: We used the PAXgene Blood RNA System to prepare RNA from the whole blood of normal volunteers using two incubation times followed by gene expression profiling using the Affymetrix HU133A GeneChip.

Conclusions: Longer incubation gave a significantly higher RNA yield and samples that were satisfactory for microarray analysis, with excellent pairwise correlations between replicates.

Laminopathies and atherosclerosis.

Laminopathies are genetic diseases that encompass a wide spectrum of phenotypes with diverse tissue pathologies and result mainly from mutations in the LMNA gene encoding nuclear lamin A/C. Some laminopathies affect the cardiovascular system, and a few (namely, Dunnigan-type familial partial lipodystrophy [FPLD2] and Hutchinson-Gilford progeria syndrome [HGPS]) feature atherosclerosis as a key component. The premature atherosclerosis of FPLD2 is probably related to characteristic proatherogenic metabolic disturbances such as dyslipidemia, hyperinsulinemia, hypertension, and diabetes.

Carotid plaque area: a tool for targeting and evaluating vascular preventive therapy.

Background And Purpose: Carotid plaque area measured by ultrasound (cross-sectional area of longitudinal views of all plaques seen) was studied as a way of identifying patients at increased risk of stroke, myocardial infarction, and vascular death.

Methods: Patients from an atherosclerosis prevention clinic were followed up annually for up to 5 years (mean, 2.5+/-1.