HECTD2, a candidate susceptibility gene for Alzheimer's disease on 10q.

Background: Late onset Alzheimer's disease (LOAD) is a neurodegenerative disorder characterised by the deposition of amyloid plaques and neurofibrillary tangles in the brain and is the major cause of dementia. Multiple genetic loci, including 10q, have been implicated in LOAD but to date, with the exception of APOE, the underlying genes have not been identified. HECTD2 maps to 10q and has been implicated in susceptibility to human prion diseases which are also neurodegenerative conditions associated with accumulation of misfolded host proteins.

Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease.

We undertook a two-stage genome-wide association study (GWAS) of Alzheimer's disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (APOE) locus (most significant SNP, rs2075650, P = 1.8 x 10(-157)) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ) gene (rs11136000, P = 1.

Identification and characterization of serum complement activity in the American crocodile (Crocodylus acutus).

Incubation of unsensitized sheep red blood cells with serum from the American crocodile (Crocodylus acutus) resulted in a concentration-dependent hemolysis. The hemolytic activity was heat-sensitive, and inhibited by EDTA in a concentration-dependent manner. The EDTA-inhibited SRBC hemolysis could be restored by the addition of excess Ca2+ or Mg2+, but not Ba2+ or Cu2+, revealing the specificity of this activity for these two divalent cations.

Progressive logopenic/phonological aphasia: erosion of the language network.

The primary progressive aphasias (PPA) are paradigmatic disorders of language network breakdown associated with focal degeneration of the left cerebral hemisphere. Here we addressed brain correlates of PPA in a detailed neuroanatomical analysis of the third canonical syndrome of PPA, logopenic/phonological aphasia (LPA), in relation to the more widely studied clinico-anatomical syndromes of semantic dementia (SD) and progressive nonfluent aphasia (PNFA). 32 PPA patients (9 SD, 14 PNFA, 9 LPA) and 18 cognitively normal controls had volumetric brain MRI with regional volumetry, cortical thickness, grey and white matter voxel-based morphometry analyses.

No association of PGRN 3'UTR rs5848 in frontotemporal lobar degeneration.

Frontotemporal lobar degeneration (FTLD) is a highly familial neurodegenerative disease. It has been claimed that homozygosity of the SNP rs5848 located in the 3'UTR of progranulin increases risk for FTLD. We have attempted to replicate the association of rs5848 in three independent FTLD cohorts.

A small-scale randomized controlled trial of the revised new forest parenting programme for preschoolers with attention deficit hyperactivity disorder.

The revised new forest parenting programme (NFPP) is an 8-week psychological intervention designed to treat ADHD in preschool children by targeting, amongst other things, both underlying impairments in self-regulation and the quality of mother-child interactions. Forty-one children were randomized to either the revised NFPP or treatment as usual conditions. Outcomes were ADHD and ODD symptoms measured using questionnaires and direct observation, mothers' mental health and the quality of mother-child interactions.

Ubiquitin associated protein 1 is a risk factor for frontotemporal lobar degeneration.

Frontotemporal lobar degeneration (FTLD) is now recognised as a common form of early onset dementia. Up to 40% of patients have a family history of disease demonstrating a large genetic component to its etiology. Linkage to chromosome 9p21 has recently been reported in families with this disorder.

HECTD2 is associated with susceptibility to mouse and human prion disease.

Prion diseases are fatal transmissible neurodegenerative disorders, which include Scrapie, Bovine Spongiform Encephalopathy (BSE), Creutzfeldt-Jakob Disease (CJD), and kuru. They are characterised by a prolonged clinically silent incubation period, variation in which is determined by many factors, including genetic background. We have used a heterogeneous stock of mice to identify Hectd2, an E3 ubiquitin ligase, as a quantitative trait gene for prion disease incubation time in mice.

Genetic risk factors for variant Creutzfeldt-Jakob disease: a genome-wide association study.

Background: Human and animal prion diseases are under genetic control, but apart from PRNP (the gene that encodes the prion protein), we understand little about human susceptibility to bovine spongiform encephalopathy (BSE) prions, the causal agent of variant Creutzfeldt-Jakob disease (vCJD).

Methods: We did a genome-wide association study of the risk of vCJD and tested for replication of our findings in samples from many categories of human prion disease (929 samples) and control samples from the UK and Papua New Guinea (4254 samples), including controls in the UK who were genotyped by the Wellcome Trust Case Control Consortium. We also did follow-up analyses of the genetic control of the clinical phenotype of prion disease and analysed candidate gene expression in a mouse cellular model of prion infection.

DNA polymerase switching: effects on spontaneous mutagenesis in Escherichia coli.

Escherichia coli possesses five known DNA polymerases (pols). Pol III holoenzyme is the cell's main replicase, while pol I is responsible for the maturation of Okazaki fragments and filling gaps generated during nucleotide excision repair. Pols II, IV and V are significantly upregulated as part of the cell's global SOS response to DNA damage and under these conditions, may alter the fidelity of DNA replication by potentially interfering with the ability of pols I and III to complete their cellular functions.

Genetic susceptibility, evolution and the kuru epidemic.

The acquired prion disease kuru was restricted to the Fore and neighbouring linguistic groups of the Papua New Guinea highlands and largely affected children and adult women. Oral history documents the onset of the epidemic in the early twentieth century, followed by a peak in the mid-twentieth century and subsequently a well-documented decline in frequency. In the context of these strong associations (gender, region and time), we have considered the genetic factors associated with susceptibility and resistance to kuru.

A clinical study of kuru patients with long incubation periods at the end of the epidemic in Papua New Guinea.

Kuru is so far the principal human epidemic prion disease. While its incidence has steadily declined since the cessation of its route of transmission, endocannibalism, in Papua New Guinea in the 1950s, the arrival of variant Creutzfeldt-Jakob disease (vCJD), also thought to be transmitted by dietary prion exposure, has given kuru a new global relevance. We investigated all suspected cases of kuru from July 1996 to June 2004 and identified 11 kuru patients.

Association of a null allele of SPRN with variant Creutzfeldt-Jakob disease.

Background: No susceptibility genes have been identified in human prion disase, apart from the prion protein gene (PRNP). The gene SPRN, encodes Shadoo (Sho, shadow of prion protein) which has protein homology and possible functional links with the prion protein.

Methods: A genetic screen was carried out of the open reading frame of SPRN by direct sequencing in 522 patients with prion disease, including 107 with variant Creutzfeldt-Jakob disease (vCJD), and 861 healthy controls.

Phenotypic heterogeneity and genetic modification of P102L inherited prion disease in an international series.

The largest kindred with inherited prion disease P102L, historically Gerstmann-Sträussler-Scheinker syndrome, originates from central England, with émigrés now resident in various parts of the English-speaking world. We have collected data from 84 patients in the large UK kindred and numerous small unrelated pedigrees to investigate phenotypic heterogeneity and modifying factors. This collection represents by far the largest series of P102L patients so far reported.

Age of onset and death in inherited prion disease are heritable.

The common polymorphism at codon 129 of the prion protein gene (PRNP) is known to affect prion disease susceptibility, incubation period and phenotype. Mouse quantitative trait locus (QTL) studies demonstrate multiple modifiers of incubation time unlinked to Prnp, suggesting the existence of homologous human prion disease modifiers, but direct evidence of these has been lacking. We investigated the correlation of age at onset and death, expressed as a composite Z score, between parents and offspring in three large UK inherited prion disease kindreds.

First report of Creutzfeldt-Jakob disease occurring in 2 siblings unexplained by PRNP mutation.

Sibling concurrence of pathologically confirmed prion disease has only been reported in association with pathogenic mutation of the prion protein gene (PRNP). Here, we report 2 siblings with classic neuropathologic features of sporadic Creutzfeldt-Jakob disease unexplained by PRNP mutation or known risk factors for iatrogenic transmission of prion infection. Possible explanations include coincidental occurrence, common exposure to an unidentified environmental source of prions, horizontal transmission of disease, or the presence of unknown shared genetic predisposition.

Mapping the progression of progranulin-associated frontotemporal lobar degeneration.

Background: A 55-year-old woman was followed over a 13-year period as part of a longitudinal study of people at risk for familial dementia. She was a member of a family with an autosomal dominant familial dementia that fulfilled consensus criteria for frontotemporal lobar degeneration. The patient was initially asymptomatic but developed progressive behavioral and cognitive decline characterized by apathy, impaired emotion recognition, mixed aphasia and parietal lobe dysfunction.

Successful amplification of degraded DNA for use with high-throughput SNP genotyping platforms.

Highly accurate and high-throughput SNP genotyping platforms are increasingly popular but the performance of suboptimal DNA samples remains unclear. The aim of our study was to determine the best platform, amplification technique, and loading concentration to maximize genotype accuracy and call rate using degraded samples. We amplified high-molecular weight genomic DNA samples recently extracted from whole blood and degraded DNA samples extracted from 50-year-old patient sera.

Parietal lobe deficits in frontotemporal lobar degeneration caused by a mutation in the progranulin gene.

Objective: To describe the clinical, neuropsychologic, and radiologic features of a family with a C31LfsX35 mutation in the progranulin gene CCDS11483.1).

Design: Case series.

Discovering and differentiating new and emerging clonal populations of Chlamydia trachomatis with a novel shotgun cell culture harvest assay.

Chlamydia trachomatis is the leading cause of preventable blindness and bacterial sexually transmitted diseases worldwide. Plaque assays have been used to clonally segregate laboratory-adapted C. trachomatis strains from mixed infections, but no assays have been reported to segregate clones from recent clinical samples.

Kuru prions and sporadic Creutzfeldt-Jakob disease prions have equivalent transmission properties in transgenic and wild-type mice.

Kuru provides our principal experience of an epidemic human prion disease and primarily affected the Fore linguistic group of the Eastern Highlands of Papua New Guinea. Kuru was transmitted by the practice of consuming dead relatives as a mark of respect and mourning (transumption). To date, detailed information of the prion strain type propagated in kuru has been lacking.

[Crisis and connection.].

Psychiatric interventions for crisis care lie at the center of the conflict between forced treatment and recovery/wellness systems in mental health services. Though crisis can mean completely different things to people who have the experience, the general public has been taught a unilateral fear response based on media representation. More and more this has led to social control but is erroneously still called treatment This does nothing to help the person and in fact further confuses people already trying to make meaning of their experience.

A distinct clinical, neuropsychological and radiological phenotype is associated with progranulin gene mutations in a large UK series.

Mutations in the progranulin gene (GRN) are a major cause of frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions (FTLD-U) but the distinguishing clinical and anatomical features of this subgroup remain unclear. In a large UK cohort we found five different frameshift and premature termination mutations likely to be causative of FTLD in 25 affected family members. A previously described 4-bp insertion mutation in GRN exon 2 comprised the majority of cases in our cohort (20/25), with four novel mutations being identified in the other five affected members.