Compliance-Adjusted Estimates of Aspirin Effects Among Older Persons in the ASPREE Randomized Trial.

The Aspirin in Reducing Events in the Elderly (ASPREE) Trial recruited 19,114 participants across Australia and the United States during 2010-2014. Participants were randomized to receive either 100 mg of aspirin daily or matching placebo, with disability-free survival as the primary outcome. During a median 4.7 years of follow-up, 37% of participants in the aspirin group permanently ceased taking their study medication and 10% commenced open-label aspirin use. In the placebo group, 35% and 11% ceased using study medication and commenced open-label aspirin use, respectively. In order to estimate compliance-adjusted effects of aspirin, we applied rank-preserving structural failure time models. The results for disability-free survival and most secondary endpoints were similar in intention-to-treat and compliance-adjusted analyses. For major hemorrhage, cancer mortality, and all-cause mortality, compliance-adjusted effects of aspirin indicated greater risks than were seen in intention-to-treat analyses. These findings were robust in a range of sensitivity analyses. In accordance with the original trial analyses, compliance-adjusted results showed an absence of benefit with aspirin for primary prevention in older people, along with an elevated risk of clinically significant bleeding.

ASPREE-D: Aspirin for the prevention of depression in the elderly.

BACKGROUND: Not only is depression associated with increased inflammation but inflammation is a risk factor for the genesis of depression. Many of the environmental risk factors for depression are transduced through inflammatory signaling. Anti-inflammatory agents show promise for the management of depression in preclinical, epidemiological, and early clinical studies. This opens the door to the potential for anti-inflammatory agents to treat and prevent depression. There are no evidence-based pharmacotherapies for depression prevention. METHOD: ASPREE-D, aspirin in the prevention of depression in the elderly, is a sub study of ASPREE, which explores the potential of aspirin to prevent a range of inflammation related disorders in the elderly. With a sample size of 19,114, and a duration of 5 years, this placebo controlled study will be one of the largest randomized controlled trials in psychiatry and will provide definitive evidence on the ability of aspirin to prevent depression. RESULTS: This paper presents the rationale for the study and presents a summary of the study design. CONCLUSIONS: ASPREE-D may not only define novel therapy but will provide mechanistic proof of concept of the role of inflammation in depression.

Current knowledge of US metal and nonmetal miner health: Current and potential data sources for analysis of miner health status.

Little is known about the current health status of US metal and nonmetal (MNM) miners, in part because no health surveillance systems exist for this population. The National Institute for Occupational Safety and Health (NIOSH) is developing a program to characterize burden of disease among MNM miners. This report discusses current knowledge and potential data sources of MNM miner health. Recent national surveys were analyzed, and literature specific to MNM miner health status was reviewed. No robust estimates of disease prevalence were identified, and national surveys did not provide information specific to MNM miners. Because substantial gaps exist in the understanding of MNM miners' current health status, NIOSH plans to develop a health surveillance program for this population to guide intervention efforts to reduce occupational and personal risks for chronic illness.

Slowing the progression of age-related hearing loss: Rationale and study design of the ASPIRIN in HEARING, retinal vessels imaging and neurocognition in older generations (ASPREE-HEARING) trial.

BACKGROUND: Age-related hearing loss (ARHL) is a leading cause of disability in the elderly. Low-grade inflammation and microvessel pathology may be responsible for initiating or exacerbating some of the hearing loss associated with aging. A growing body of evidence demonstrates an association of hearing loss with cognitive decline. A shared etiological pathway may include a role of inflammation, alongside vascular determinants. The ASPREE-HEARING study aims to determine whether low-dose aspirin decreases the progression of ARHL, and if so, whether this decrease in progression is also associated with retinal microvascular changes and/or greater preservation of cognitive function. DESIGN AND METHODS: A three year double-blind, randomized controlled trial of oral 100mg enteric-coated aspirin or matching placebo, enrolling 1262 Australians aged ≥70years with normal cognitive function and no overt cardiovascular disease. The primary outcome is the change in mean pure tone average hearing threshold (decibels) in the better ear, over a 3-year period. Secondary outcomes consist of changes in retinal microvascular indicators, and changes in cognitive function. Participants are recruited from a larger trial, ASPirin in Reducing Events in the Elderly (ASPREE), which is designed to assess whether daily low dose aspirin will extend disability-free life. DISCUSSION: ASPREE-HEARING will determine whether aspirin slows development or progression of ARHL, and will interrogate the relationship between inflammatory and microvascular mechanisms that may underlie the effects of aspirin on ARHL. This study will improve understanding of the patterns of comorbidity with, and the relationships between, aging and ARHL, alongside modeling the impacts of ARHL.

Psychological status in female carriers of premutation FMR1 allele showing a complex relationship with the size of CGG expansion.

We utilized a sample of 299 adult females aged between 19 and 86 years, carrying fragile X mental retardation (FMR1) alleles with small CCG expansions ranging from 50 to 141 repeats to analyse the relationships between psychological symptoms as assessed by the Symptom Checklist-90-Revised (SCL-90-R) and the size of the CGG repeat in the FMR1 gene. There were highly significant (negative) correlations between the size of the CGG repeat and a great majority of SCL-90-R subscale scores and all the global indices, suggesting that carriers of premutations in the mid-size CGG repeat range may be at greatest risk for the development of psychiatric disorder.

A functional MRI study of motor dysfunction in Friedreich's ataxia.

Friedreich's ataxia (FRDA) is the most common form of hereditary ataxia. In addition to proximal spinal cord and brain stem atrophy, mild to moderate atrophy of the cerebellum has been reported in advanced FRDA. The aim of this study was to examine dysfunction in motor-related areas involved in the execution of finger tapping tasks in individuals with FRDA, and to investigate functional re-organization of cortico-cerebellar, cortico-striatal and parieto-frontal loops as a result of the cerebellar pathology. Thirteen right-handed individuals with FRDA and fourteen right-handed controls participated. Functional MRI images were acquired during four different finger tapping tasks consisting of visually cued regular and irregular single finger tapping tasks, a self-paced regular finger tapping task, and a visually cued multi-finger tapping task. Both groups showed significant activation of the motor-related network including the pre-central cortex and supplementary motor area bilaterally; the left primary motor cortex, somatosensory cortex and putamen; and the right cerebellum. During the visually cued regular finger tapping task, the right hemisphere of the cerebellar cortex, bilateral supplementary motor areas and right inferior parietal cortex showed higher activation in the healthy control group, while in individuals with FRDA the left premotor cortex, left somatosensory cortex and left inferior parietal cortex were more active. In addition, during the visually cued irregular finger tapping task, the right middle temporal gyrus in the control group and the right superior parietal lobule and left superior and middle temporal gyri in the individuals with FRDA showed higher activation. During visually cued multi-finger tapping task, the control group showed higher activation in the bilateral middle frontal gyri, bilateral somatosensory cortices, bilateral inferior parietal lobules, left premotor cortex, left supplementary area, right superior frontal gyrus and right cerebellum, while individuals with FRDA showed increased activity in the left inferior parietal lobule, left primary motor cortex, left middle occipital gyrus, right somatosensory cortex and the left cerebellum. Only the right crus I/II of the cerebellum showed higher activation in individuals with FRDA during the self-paced regular finger tapping task, whereas wide-spread regions including the left superior frontal gyrus, left central opercular cortex, left somatosensory cortex, left putamen, right cerebellum, bilateral primary motor cortices, bilateral inferior parietal lobules and the left insula were more active in the control group. Although the pattern of the BOLD signal from the putamen was different during the self-paced regular finger tapping task to the other tasks in controls, in individuals with FRDA there was no distinction of the signal between the tasks suggesting that primary cerebellar pathology may cause secondary basal ganglia dysregulation. While individuals with FRDA tapped at a slightly lower rate (0.59Hz) compared with controls (0.74Hz) they showed significantly decreased activity of the SMA and the inferior parietal lobule, which may suggest disruption to the fronto-parietal connections. These findings suggest that the motor impairments in individuals with FRDA result from dysfunction extending beyond the spinal cord and cerebellum to include sub-cortical and cortical brain regions.

Decreased functional brain activation in Friedreich ataxia using the Simon effect task.

The present study applied the Simon effect task to examine the pattern of functional brain reorganization in individuals with Friedreich ataxia (FRDA), using functional magnetic resonance imaging (fMRI). Thirteen individuals with FRDA and 14 age and sex matched controls participated, and were required to respond to either congruent or incongruent arrow stimuli, presented either to the left or right of a screen, via laterally-located button press responses. Although the Simon effect (incongruent minus congruent stimuli) showed common regions of activation in both groups, including the superior and middle prefrontal cortices, insulae, superior and inferior parietal lobules (LPs, LPi), occipital cortex and cerebellum, there was reduced functional activation across a range of brain regions (cortical, subcortical and cerebellar) in individuals with FRDA. The greater Simon effect behaviourally in individuals with FRDA, compared with controls, together with concomitant reductions in functional brain activation and reduced functional connectivity between cortical and sub-cortical regions, implies a likely disruption of cortico-cerebellar loops and ineffective engagement of cognitive/attention regions required for response suppression.

Sensory neuropathy as part of the cerebellar ataxia neuropathy vestibular areflexia syndrome.

OBJECTIVE: The syndrome of cerebellar ataxia with bilateral vestibulopathy was delineated in 2004. Sensory neuropathy was mentioned in 3 of the 4 patients described. We aimed to characterize and estimate the frequency of neuropathy in this condition, and determine its typical MRI features. METHODS: Retrospective review of 18 subjects (including 4 from the original description) who met the criteria for bilateral vestibulopathy with cerebellar ataxia. RESULTS: The reported age at onset range was 39-71 years, and symptom duration was 3-38 years. The syndrome was identified in one sibling pair, suggesting that this may be a late-onset recessive disorder, although the other 16 cases were apparently sporadic. All 18 had sensory neuropathy with absent sensory nerve action potentials, although this was not apparent clinically in 2, and the presence of neuropathy was not a selection criterion. In 5, the loss of pinprick sensation was virtually global, mimicking a neuronopathy. However, findings in the other 11 with clinically manifest neuropathy suggested a length-dependent neuropathy. MRI scans showed cerebellar atrophy in 16, involving anterior and dorsal vermis, and hemispheric crus I, while 2 were normal. The inferior vermis and brainstem were spared. CONCLUSIONS: Sensory neuropathy is an integral component of this syndrome. It may result in severe sensory loss, which contributes significantly to the disability. The MRI changes are nonspecific, but, coupled with loss of sensory nerve action potentials, may aid diagnosis. We propose a new name for the condition: cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS).

Impaired inhibition of prepotent motor tendencies in Friedreich ataxia demonstrated by the Simon interference task.

Friedreich ataxia (FRDA) is the most common of the genetically inherited ataxias. We recently demonstrated that people with FRDA have impairment in motor planning - most likely because of pathology affecting the cerebral cortex and/or cerebello-cortical projections. We used the Simon interference task to examine how effective 13 individuals with FRDA were at inhibiting inappropriate automatic responses associated with stimulus-response incompatibility in comparison with control participants. Participants had to respond to arrow targets according to two features which were either congruent or incongruent. We found that individuals with FRDA were differentially affected in reaction time to incongruent, compared with congruent stimuli, when compared with control participants. There was a significant negative correlation between age of onset and the incongruency effect, suggesting an impact of FRDA on the developmental unfolding of motor cognition, independent of the effect of disease duration. Future neuroimaging studies will be required to establish whether this dysfunction is due to cerebellar impairment disrupting cerebro-ponto-cerebello-thalamo-cerebral loops (and thus cortical function), direct primary cortical pathology, or a possible combination of the two.

Occupational distribution of persons with confirmed 2009 H1N1 influenza.

OBJECTIVE: To assess the distribution of illness by industry sector and occupation reflected in early 2009 H1N1 influenza surveillance. METHODS: We analyzed data reported for April to July 2009, for 1361 laboratory-confirmed 2009 H1N1 influenza-infected persons 16 years or older, with work status information from four states. A North American Industry Classification System 2007 code was assigned to each employed person. For a subset, an occupation code was assigned. RESULTS: Of 898 employed individuals, 611 (68.0%) worked in the non-health care sector. The largest proportions worked in public administration, educational services, and accommodation and food services. In Wisconsin health care personnel, 53.6% were paraprofessionals, 33.6% professionals, and 12.7% other workers; 26.9% worked in ambulatory settings, 46.2% in hospitals, and 26.9% in nursing or residential care facilities. CONCLUSIONS: Our findings suggest that industry sectors and occupations should be explored systematically in future influenza surveillance.

Early intervention for mild cognitive impairment: a randomised controlled trial.

BACKGROUND: Positive effects are reported for memory training for healthy older adults, and yet there is limited information about the benefit of cognitive intervention for older adults with increasing memory difficulties-mild cognitive impairment. OBJECTIVE: To investigate the usefulness of an early cognitive intervention for the memory difficulties experienced by people with amnestic mild cognitive impairment. METHODS: Using a randomised control design, 52 participants with amnestic mild cognitive impairment and their family partners were randomly assigned to a cognitive intervention (memory rehabilitation group) or waitlist (control group). Participants were assessed on primary measures of everyday memory (prospective memory) and memory strategies at 2 weeks' and 4 months' follow-up; secondary measures of contentment with memory and the family participants' knowledge of memory strategies were also assessed. RESULTS: Everyday memory, measured by performance on prospective memory tasks, significantly improved following intervention, although self-appraisal of everyday memory did not demonstrate a similar intervention effect. Knowledge and use of memory strategies also significantly increased following intervention. Furthermore, family knowledge of memory strategies increased following intervention. There was a strong trend towards improvement in contentment with memory immediately following intervention, but this effect was not significant. CONCLUSIONS: Early intervention for memory difficulties in amnestic mild cognitive impairment, using cognitive rehabilitation in compensatory strategies, can assist in minimising everyday memory failures as evaluated by performance on prospective memory tasks and knowledge of memory strategies.

A new dominantly inherited pure cerebellar ataxia, SCA 30.

BACKGROUND: The spinocerebellar ataxias (SCAs) are clinically and genetically heterogeneous. Currently, 27 forms are known, with the causative gene identified in 16. Although the majority of dominant pedigrees worldwide have SCAs 1, 2, 3, 6 or 8, new SCAs continue to be delineated. We describe a new disorder: SCA 30. METHODS: An Australian family of Anglo-Celtic ethnicity manifested a relatively pure, slowly evolving ataxia. Six affected and four unaffected members were personally examined in a standardised fashion. MRI and nerve conduction studies were performed in two. An autosomal genome-wide linkage study was undertaken, and an in silico analysis of potential candidate genes in the linkage region was performed. RESULTS: The six affected members had a relatively pure, slowly evolving ataxia developing in mid to late life, with only minor pyramidal signs and no evidence of neuropathy. All had hypermetric saccades with normal vestibulo-ocular reflex gain. Only one displayed (slight) gaze-evoked nystagmus. MRI showed cerebellar atrophy with preservation of nodulus/uvula and brainstem. Linkage analysis excluded currently known SCAs and identified a logarithm (base 10) of odds score of 3.0 at chromosome 4q34.3-q35.1, distinct from all previously reported loci. In silico prioritisation identified the gene ODZ3 as the most likely contender. CONCLUSIONS: SCA 30 is a previously undescribed cause of (relatively) pure adult-onset autosomal dominant cerebellar ataxia. The responsible gene is yet to be determined, but ODZ3 is a plausible candidate.

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. Microsatellite and genealogical analyses of eight separate European kindreds support multiple distinct mutational events at a cytosine-phosphate diester-guanidine dinucleotide mutation hot spot. All of the smaller P102L kindreds were linked to polymorphic human prion protein gene codon 129M and were not connected by genealogy or microsatellite haplotype background to the large kindred or each other. While many present with classical Gerstmann-Sträussler-Scheinker syndrome, a slowly progressive cerebellar ataxia with later onset cognitive impairment, there is remarkable heterogeneity. A subset of patients present with prominent cognitive and psychiatric features and some have met diagnostic criteria for sporadic Creutzfeldt-Jakob disease. We show that polymorphic human prion protein gene codon 129 modifies age at onset: the earliest eight clinical onsets were all MM homozygotes and overall age at onset was 7 years earlier for MM compared with MV heterozygotes (P = 0.02). Unexpectedly, apolipoprotein E4 carriers have a delayed age of onset by 10 years (P = 0.02). We found a preponderance of female patients compared with males (54 females versus 30 males, P = 0.01), which probably relates to ascertainment bias. However, these modifiers had no impact on a semi-quantitative pathological phenotype in 10 autopsied patients. These data allow an appreciation of the range of clinical phenotype, modern imaging and molecular investigation and should inform genetic counselling of at-risk individuals, with the identification of two genetic modifiers.

A low symptomatic form of neurodegeneration in younger carriers of the FMR1 premutation, manifesting typical radiological changes.

Fragile X-associated tremor/ataxia (FXTAS) is a late onset disorder caused by a premutation in the FMR1 gene, in which neurological symptoms are associated with white matter (wm) changes, especially within the middle cerebellar peduncles (MCP sign), seen on magnetic resonance images (MRIs). We report a discrepancy between obvious radiological presentations and minimal clinical involvement in two younger male premutation carriers. These carriers, aged 52 and 39 years, showed distinct MCP sign, but reported no neurological symptoms. If this discrepancy represents the initial stage of FXTAS, our findings suggest the possibility of early diagnosis from MRI scans.

Elaborated spaced-retrieval and prospective memory in mild Alzheimer's disease.

Prospective memory, or the timely remembering of a planned action, is conceptualised as a cognitive process demanding episodic memory and executive attention. Impairments in these skills are characteristic of the cognitive decline in early Alzheimer's disease, providing an expectation of prominent prospective memory difficulties in this population, and yet surprisingly, memory performance in early Alzheimer's disease has rarely been evaluated within a prospective memory framework. In a preliminary study we demonstrated that older adults with early Alzheimer's disease (n=14), as compared to healthy older adults (n=14), were significantly impaired in a simple experimental paradigm of prospective remembering (a text-reading task). In a subsequent intervention study, we investigated the efficacy of spaced-retrieval for improving the prospective remembering performance of older adults with early Alzheimer's disease (n=16) compared to healthy older adults (n=16) under two learning conditions: a spaced-retrieval technique alone or spaced-retrieval combined with elaborated encoding of task. The majority of the Alzheimer's disease group (63%) demonstrated benefit in prospective remembering in the combined condition as compared to spaced-retrieval alone. Participants with Alzheimer's disease who demonstrated better executive attention (Trail Making- set-shifting) and/or better retrospective memory (Hopkins Verbal Learning Test-Revised- recognition) were more successful in the combined learning condition.

Characterization of 'Schizokinen'; a dihydroxamate-type siderophore produced by Rhizobium leguminosarum IARI 917.

The Rhizobia comprise one of the most important groups of beneficial bacteria, which form nodules on the roots (rarely on the stems) of leguminous plants. They live within the nodules and reduce atmospheric nitrogen to ammonia, which is further assimilated by plants into required nitrogenous compounds. The Rhizobia in return obtain nutrition from the plant. Rhizobia are free-living soil bacteria and have to compete with other microorganisms for the limited available iron in the rhizosphere. In order to acquire iron Rhizobia have been shown to express siderophore-mediated iron transport systems. Rhizobium leguminosarum IARI 917 was investigated for its ability to produce siderophore. It was found to produce a dihydroxamate type siderophore under iron restricted conditions. The siderophore was purified and chemically characterized. The ESMS, MS/MS and NMR analysis indicate the dihydroxamate siderophore to be 'schizokinen', a siderophore reported to be produced by Bacillus megaterium that shares a similar structure to 'rhizobactin 1021' produced by Sinorhizobium meliloti 1021. This is the first report of production of schizokinen by a strain of R. leguminosarum, therefore it was carefully investigated to confirm that it is indeed 'schizokinen' and not a degradation product of 'rhizobactin 1021'. Since ferric-siderophore complexes are transported across the outer membrane (OM) into the periplasm via an OM receptor protein, R. leguminosarum IARI 917 was investigated for the presence of an OM receptor for 'ferric-schizokinen'. SDS PAGE analysis of whole cell pellet and extracted OM fractions indicate the presence of a possible iron-repressible OM receptor protein with the molecular weight (MW) of approximately 74 kDa.

Mohs micrographic surgery: a technique for total margin assessment in veterinary cutaneous oncologic surgery.

Mohs micrographic surgery (MMS) is the gold standard for the excision of locally invasive cutaneous malignancies in human dermatological surgery. Using a unique horizontal sectioning technique, MMS enables 100% surgical margin assessment and provides the lowest recurrence rates for locally invasive tumours. The purposes of this preliminary study were to explore the feasibility of application of MMS in the veterinary setting and to establish practical advantages and limitations of its use in a pilot programme. It was hypothesized that MMS technique could provide 100% tumour margin assessment using frozen and/or formalin-fixed horizontal histopathologic sections. Tumour excision and colour-coded mapping were performed, and specimen tissue was fixed using either frozen sections or formalin-fixed sections. Horizontal sections were assessed for quality and presence and location of neoplastic cells based on the mapped orientation. The MMS technique was used in the excision of six squamous cell carcinomas and five mast cell tumours. In all cases, the MMS permitted 100% tumour margins examination.

Spinocerebellar ataxia type 14: study of a family with an exon 5 mutation in the PRKCG gene.

We report our observations in an Australian family with spinocerebellar ataxia type 14 (SCA 14). We describe a novel mutation in exon 5 of the PRKCG gene, altering a highly conserved cysteine to a phenylalanine at codon 150, and record the detailed clinical observations in six affected family members.