Comparison of sporadic and familial behavioral variant frontotemporal dementia (FTD) in a North American cohort.

INTRODUCTION: Behavioral variant frontotemporal dementia (bvFTD) may present sporadically or due to an autosomal dominant mutation. Characterization of both forms will improve understanding of the generalizability of assessments and treatments. METHODS: A total of 135 sporadic (s-bvFTD; mean age 63.3 years; 34% female) and 99 familial (f-bvFTD; mean age 59.9; 48% female) bvFTD participants were identified. f-bvFTD cases included 43 with known or presumed chromosome 9 open reading frame 72 (C9orf72) gene expansions, 28 with known or presumed microtubule-associated protein tau (MAPT) mutations, 14 with known progranulin (GRN) mutations, and 14 with a strong family history of FTD but no identified mutation. RESULTS: Participants with f-bvFTD were younger and had earlier age at onset. s-bvFTD had higher total Neuropsychiatric Inventory Questionnaire (NPI-Q) scores due to more frequent endorsement of depression and irritability. DISCUSSION: f-bvFTD and s-bvFTD cases are clinically similar, suggesting the generalizability of novel biomarkers, therapies, and clinical tools developed in either form to the other.

Active lifestyles moderate clinical outcomes in autosomal dominant frontotemporal degeneration.

INTRODUCTION: Leisure activities impact brain aging and may be prevention targets. We characterized how physical and cognitive activities relate to brain health for the first time in autosomal dominant frontotemporal lobar degeneration (FTLD). METHODS: A total of 105 mutation carriers (C9orf72/MAPT/GRN) and 69 non-carriers reported current physical and cognitive activities at baseline, and completed longitudinal neurobehavioral assessments and brain magnetic resonance imaging (MRI) scans. RESULTS: Greater physical and cognitive activities were each associated with an estimated >55% slower clinical decline per year among dominant gene carriers. There was also an interaction between leisure activities and frontotemporal atrophy on cognition in mutation carriers. High-activity carriers with frontotemporal atrophy (-1 standard deviation/year) demonstrated >two-fold better cognitive performances per year compared to their less active peers with comparable atrophy rates. DISCUSSION: Active lifestyles were associated with less functional decline and moderated brain-to-behavior relationships longitudinally. More active carriers "outperformed" brain volume, commensurate with a cognitive reserve hypothesis. Lifestyle may confer clinical resilience, even in autosomal dominant FTLD.

Review: Neuropathology of non-tau frontotemporal lobar degeneration.

Frontotemporal dementia (FTD) is a heterogeneous clinical syndrome associated with frontotemporal lobar degeneration (FTLD) as a relatively consistent neuropathological hallmark feature. However, the discoveries in the past decade of many of the relevant pathological proteins aggregating in human FTD brains in addition to several new FTD causing gene mutations underlined that FTD is a diverse condition on the neuropathological and genetic basis. This resulted in a novel molecular classification of these conditions based on the predominant protein abnormality and allows most cases of FTD to be placed now into one of three broad molecular subgroups; FTLD with tau, TAR DNA-binding protein 43 or FET protein accumulation (FTLD-tau, FTLD-TDP and FTLD-FET respectively). This review will provide an overview of the molecular neuropathology of non-tau FTLD, insights into disease mechanisms gained from the study of human post mortem tissue as well as discussion of current controversies in the field.

Incidence and prevalence of multiple sclerosis in the UK 1990-2010: a descriptive study in the General Practice Research Database.

OBJECTIVES: To estimate the incidence and prevalence of multiple sclerosis (MS) by age and describe secular trends and geographic variations within the UK over the 20-year period between 1990 and 2010 and hence to provide updated information on the impact of MS throughout the UK. DESIGN: A descriptive study. SETTING: The study was carried out in the General Practice Research Database (GPRD), a primary care database representative of the UK population. MAIN OUTCOME MEASURES: Incidence and prevalence of MS per 100 000 population. Secular and geographical trends in incidence and prevalence of MS. RESULTS: The prevalence of MS recorded in GPRD increased by about 2.4% per year (95% CI 2.3% to 2.6%) reaching 285.8 per 100 000 in women (95% CI 278.7 to 293.1) and 113.1 per 100 000 in men (95% CI 108.6 to 117.7) by 2010. There was a consistent downward trend in incidence of MS reaching 11.52 per 100 000/year (95% CI 10.96 to 12.11) in women and 4.84 per 100 000/year (95% CI 4.54 to 5.16) in men by 2010. Peak incidence occurred between ages 40 and 50 years and maximum prevalence between ages 55 and 60 years. Women accounted for 72% of prevalent and 71% of incident cases. Scotland had the highest incidence and prevalence rates in the UK. CONCLUSIONS: We estimate that 126 669 people were living with MS in the UK in 2010 (203.4 per 100 000 population) and that 6003 new cases were diagnosed that year (9.64 per 100 000/year). There is an increasing population living longer with MS, which has important implications for resource allocation for MS in the UK.

Laminar distribution of the pathological changes in sporadic frontotemporal lobar degeneration with transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) proteinopathy: a quantitative study using polynomial curve fitting.

AIMS: Previous data suggest heterogeneity in laminar distribution of the pathology in the molecular disorder frontotemporal lobar degeneration (FTLD) with transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) proteinopathy (FTLD-TDP). To study this heterogeneity, we quantified the changes in density across the cortical laminae of neuronal cytoplasmic inclusions, glial inclusions, neuronal intranuclear inclusions, dystrophic neurites, surviving neurones, abnormally enlarged neurones, and vacuoles in regions of the frontal and temporal lobe. METHODS: Changes in density of histological features across cortical gyri were studied in 10 sporadic cases of FTLD-TDP using quantitative methods and polynomial curve fitting. RESULTS: Our data suggest that laminar neuropathology in sporadic FTLD-TDP is highly variable. Most commonly, neuronal cytoplasmic inclusions, dystrophic neurites and vacuolation were abundant in the upper laminae and glial inclusions, neuronal intranuclear inclusions, abnormally enlarged neurones, and glial cell nuclei in the lower laminae. TDP-43-immunoreactive inclusions affected more of the cortical profile in longer duration cases; their distribution varied with disease subtype, but was unrelated to Braak tangle score. Different TDP-43-immunoreactive inclusions were not spatially correlated. CONCLUSIONS: Laminar distribution of pathological features in 10 sporadic cases of FTLD-TDP is heterogeneous and may be accounted for, in part, by disease subtype and disease duration. In addition, the feedforward and feedback cortico-cortical connections may be compromised in FTLD-TDP.

N-Acetylcysteine inhibits platelet-monocyte conjugation in patients with type 2 diabetes with depleted intraplatelet glutathione: a randomised controlled trial.

AIMS/HYPOTHESIS: The aim of this study was to determine whether oral dosing with N-acetylcysteine (NAC) increases intraplatelet levels of the antioxidant, glutathione (GSH), and reduces platelet-monocyte conjugation in blood from patients with type 2 diabetes. METHODS: In this placebo-controlled randomised crossover study, the effect of oral NAC dosing on platelet-monocyte conjugation and intraplatelet GSH was investigated in patients with type 2 diabetes (eligibility criteria: men or post-menopausal women with well-controlled diabetes (HbA(1c) < 10%), not on aspirin or statins). Patients (n = 14; age range 43-79 years, HbA(1c) = 6.9 ± 0.9% [52.3 ± 10.3 mmol/mol]) visited the Highland Clinical Research Facility, Inverness, UK on day 0 and day 7 for each arm of the study. Blood was sampled before and 2 h after oral administration of placebo or NAC (1,200 mg) on day 0 and day 7. Patients received placebo or NAC capsules for once-daily dosing on the intervening days. The order of administration of NAC and placebo was allocated by a central office and all patients and research staff involved in the study were blinded to the allocation until after the study was complete and the data fully analysed. The primary outcome for the study was platelet-monocyte conjugation. RESULTS: Oral NAC reduced platelet-monocyte conjugation (from 53.1 ± 4.5% to 42.5 ± 3.9%) at 2 h after administration and the effect was maintained after 7 days of dosing. Intraplatelet GSH was raised in individuals with depleted GSH and there was a negative correlation between baseline intraplatelet GSH and platelet-monocyte conjugation. There were no adverse events. CONCLUSIONS/INTERPRETATION: The NAC-induced normalisation of intraplatelet GSH, coupled with a reduction in platelet-monocyte conjugation, suggests that NAC might help to reduce atherothrombotic risk in type 2 diabetes. FUNDING: Chief Scientist Office (CZB/4/622), Scottish Funding Council, Highlands & Islands Enterprise and European Regional Development Fund. TRIAL REGISTRATION: isrctn.org ISRCTN89304265.

Multiple pathologies are common in Alzheimer patients in clinical trials.

OBJECTIVE: To determine the frequency of multiple pathology [Alzheimer Disease (AD) plus Vascular Dementia and/or Dementia with Lewy Bodies] in patients enrolled in clinical trials of AD therapy, and to compare the cognitive and functional assessments between patients with pure AD and AD with multiple pathology. METHODS: We conducted a retrospective analysis of patients with a clinical diagnosis of AD who were enrolled in AD therapy clinical trials and subsequently received an autopsy for confirmation of their diagnosis from 2000 to 2009. Performance on cognitive screening tests, namely Modified Mini Mental state (3MS) exam, Mini Mental state Exam (MMSE) and Functional Rating Scale (FRS) were compared between patients with pure AD and multiple pathology. RESULTS: Autopsy reports were available for 16/47 (34%) of deceased patients. Of these 16 patients, 5 (31%) had pure AD pathology, 10 (63%) had AD with other pathology, and 1 (6%) had non-AD pathology. Compared to patients with pure AD, patients with AD mixed with other pathology had poorer baseline FRS in problem-solving (p<0.01) and community affairs (p<0.02). CONCLUSION: While the strict enrollment criteria for clinical trials identified the presence of AD pathology in the majority of cases (15/16), multiple pathology was more common than pure AD in our series of autopsied patients. Premortem biomarkers that can distinguish between pure AD and AD with multiple pathology will be beneficial in future clinical trials and dementia patient management.

Acupuncture for pain relief during induced labour in nulliparae: a randomised controlled study.

OBJECTIVE: To assess the role of acupuncture for analgesia during labour. DESIGN: Double-blind study of manual, electro and sham acupuncture, and single-blind study comparing acupuncture with a control group for analgesia for labour induction. SETTING: A major obstetric unit in the UK. POPULATION: A cohort of 105 nulliparae undergoing labour induction at term. METHODS: Twenty-three subjects needed to be randomised to each group to have an 80% power of detecting a 50% relative reduction in epidural rate with an alpha value of 0.05. MAIN OUTCOME MEASURES: The primary end point was the rate of intrapartum epidural analgesia, and the secondary end points were parenteral analgesia requirement, labour length, delivery mode, neonatal condition and postpartum haemorrhage. RESULTS: There was no difference in epidural analgesia between acupuncture and sham acupuncture, relative risk 1.18 (95% CI 0.8-1.74), or between acupuncture and control, relative risk 0.88 (95% CI 0.66-1.19). There were no significant differences in the secondary end points between the acupuncture groups and the control group. Side effects or complications of acupuncture were not identified. CONCLUSIONS: Using the protocols studied, there was no analgesic benefit with acupuncture for pain relief during induced labour in nulliparae.

Deafness: malaria as a forgotten cause.

BACKGROUND: Ototoxicity from antimalarials is a well publicised cause of deafness and a great deal of time and resources are spent assessing it in relation to new drugs. The effect of the malaria parasite itself on hearing is, however, poorly documented and most evidence is anecdotal. This paper aims to collate existing evidence of this association. METHODS: Two systematic literature searches were performed on Ovid Medline, first for 'malaria' and 'hearing loss' or 'hearing impairment' or 'deafness', and secondly for 'cerebral malaria' and 'neurologic' or 'neurological' or 'neurocognitive sequelae'. The articles were then individually studied for relevance. RESULTS: Malaria has been implicated as a rare cause of hearing loss in various studies, but recommendations and hypotheses have not been taken seriously or investigated. Searches also returned numerous studies of neurological sequelae after cerebral malaria, a small proportion of which observed hearing impairments on follow-up. However, no attempt was made to distinguish between treatment and disease as the cause. A few antimalarial drug trials which assessed hearing before treatment found unexplained hearing loss which improved with elimination of the parasite. CONCLUSION: Evidence from this review suggests that the falciparum parasite is a potential cause of hearing loss. Malaria is a disease of such high prevalence that even if only a small proportion of survivors develop this impairment the effects on children's education could be detrimental. More attention should be focussed on investigating this association as the clinical and pathophysiological implications are potentially considerable.

The clinical outcome of UK military personnel who received a massive transfusion in Afghanistan during 2009.

OBJECTIVES: The UK Defence Medical Services has developed a Massive Transfusion Protocol (MTP) that forms part of the initial Damage Control Resuscitation process for severely injured combat casualties. The key objectives of this retrospective review of MTP recipients are to document the survival rates, level of critical care support required and the blood components transfused as part of the Massive Transfusion Protocol in Afghanistan during 2009. In addition to providing a measure of our current effectiveness it should also provide a reference point for future reviews as the MTP continues to evolve. METHODS: This was a collaborative project involving the Royal Centre for Defence Medicine and the Critical Care Department, University Hospitals Birmingham. It was limited to UK military personnel who were injured in 2009 and received massive transfusions (defined as the transfusion of 10 or more units of packed red blood cells over a 24-hour period) at Camp Bastion Role 3 Medical Facility, Afghanistan. RESULTS: During the 12-month period, 59 personnel received massive transfusions. 51 (86%) personnel survived to be discharged from hospital in the UK. 48 (92%) personnel required ventilatory support for a median of 3 (2-8) days. The longest period of ventilation was 40 days; 29 (55%) personnel required vasopressor support and eight personnel (15%) required renal replacement therapy. The median total transfusion of blood components was 45 (28.5-62) units. There were seven transfusions of more than 100 units. Five of the personnel in this group (including the recipient of a 237-unit transfusion) survived to be discharged from University Hospitals Birmingham. On average, 1.21 (SD 0.28) units of packed red blood cells were transfused for every unit of fresh frozen plasma. CONCLUSIONS: The use of the current MTP was associated with a high rate of survival. Survivors require a continuity of critical care with a median demand for 3 days. The early use of plasma and platelets can be successfully delivered in the battlefield despite operational and logistic constraints.

Antibodies to intestinal microvillous membranes. I. Characterization and morphologic localization.

Antibodies (AbMVM) were produced in rabbits to microvillous membranes isolated from hamster small bowel. Incubation of frozen sections of hamster small bowel with fluorescein-labeled AbMVM showed specific reaction with brush borders, but not with other intestinal cellular components. Electron microscopy with ferritin-conjugated AbMVM localized the antigens more precisely to the surface mucopolysaccharide coat of the brush borders. AbMVM also reacted with the brush border of colon and of proximal renal tubules of hamsters but not with those of hamster stomach or gall bladder. It also reacted with the brush borders of some rat and human tissues, but not with those of rabbits. In addition, fluorescent-labeled AbMVM combined specifically with cell walls of some yeasts, but not of several bacteria. AbMVM also contained a weak precipitin to a component of hamster serum, which migrated like prealbumin in immunoelectrophoresis.

Antibodies to intestinal microvillous membranes : ii. Inhibition of intrinsic factor-mediated attachment of vitamin b(12)to hamster brush borders.

Microvillous membranes isolated from the distal, but not proximal, half of hamster small bowel induced in rabbits the formation of antisera which inhibited intrinsic factor-mediated uptake of vitamin B(12) by hamster brush borders. The extent of inhibition was directly proportional to the concentration of antiserum, and an excess of IF-bound vitamin B(12) could overcome the inhibitory effect. The inhibitory factor was absorbed from antisera by brush borders isolated from the distal, but not proximal, half of the hamster intestine. Fractionation of antisera by gel filtration and DEAE-cellulose chromatography established that immunoglobulin G contained the inhibitory factor. Antisera capable of completely blocking uptake of IF-bound vitamin B(12) did not react with hamster IF or with the IF-vitamin B(12) complex, did not inhibit brush border disaccharidase activity and did not impair glucose transport by everted sacs of hamster intestine. These results demonstrate that an antibody to distal microvillous membranes competes with the IF-vitamin B(12) complex for a specific binding site or receptor located on the surface of distal hamster intestine.

Antiplatelet drug interactions.

Both laboratory studies in healthy volunteers and clinical studies have suggested adverse interactions between antiplatelet drugs and other commonly used medications. Interactions described include those between aspirin and ibuprofen, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), and the thienopyridine, clopidogrel, and drugs inhibiting CYP2C19, notably the proton pump inhibitors (PPI) omeprazole and esomeprazole. Other interactions between thienopyridines and CYP3A4/5 have also been reported for statins and calcium channel blockers. The ibuprofen/aspirin interaction is thought to be caused by ibuprofen blocking the access of aspirin to platelet cyclo-oxygenase. The thienopyridine interactions are caused by inhibition of microsomal enzymes that metabolize these pro-drugs to their active metabolites. We review the evidence for these interactions, assess their clinical importance and suggest strategies of how to deal with them in clinical practice. We conclude that ibuprofen is likely to interact with aspirin and reduce its anti-platelet action particularly in those patients who take ibuprofen chronically. This interaction is of greater relevance to those patients at high cardiovascular risk. A sensible strategy is to advise users of aspirin to avoid chronic ibuprofen or to ingest aspirin at least 2 h prior to ibuprofen. Clearly the use of NSAIDs that do not interact in this way is preferred. For the clopidogrel CYP2C19 and CYP3A4/5 interactions, there is good evidence that these interactions occur. However, there is less good evidence to support the clinical importance of these interactions. Again, a reasonable strategy is to avoid the chronic use of drugs that inhibit CYP2C19, notably PPIs, in subjects taking clopidogrel and use high dose H2 antagonists instead. Finally, anti-platelet agents probably interact with other drugs that affect platelet function such as selective serotonin reuptake inhibitors, and clinicians should probably judge patients taking such combination therapies as at high risk for bleeding.

Failure and regret after laparoscopic filshie clip sterilization under local anesthetic.

OBJECTIVE: To estimate the failure, regret, and reversal rates 5 or more years after laparoscopic Filshie clip sterilization using local anesthesia. METHODS: A total of 1,101 women underwent Filshie clip sterilization between 1983 and 2002. They completed follow-up questionnaires that were analyzed for the following outcomes: failed sterilization, regret after the operation, and sterilization reversal. RESULTS: Two hundred thirty-three of 968 (24%) eligible women sent the questionnaire had moved from their last known address. Of the remaining 735 women, 573 (78%) completed the questionnaire: 223 (39%) 5-6 years after the operation, 175 (30%) after 7-9 years, and 175 (30%) after 10-15 years. One pregnancy occurred 10 months after surgery, and one woman had the procedure repeated when unilateral tubal patency was identified by hysterosalpingography 3 weeks after surgery. Twenty-four (4%) women regretted having the operation; 7 (1.2%) women had a reversal operation, and all subsequently conceived. CONCLUSION: Failure after tubal sterilization using Filshie clips is less than 1:500 operations. Patient selection and surgeons' experience may have influenced these results. Regret occurred in a small proportion. LEVEL OF EVIDENCE: III.

Why remove all cervical polyps and examine them histologically?

A retrospective analysis of 1366 cervical polyps showed that none had malignant features and 67% were removed from asymptomatic women. A policy removing only cervical polyps from symptomatic women or those with abnormal cervical cytology and limiting histological examination to these polyps would result in significant savings and reduce the small risk of morbidity associated with polypectomy.

Estimation of psychomotor delay from the Fitts' law coefficients.

An intrinsic property of human motor behavior is a trade-off between speed and accuracy. This is classically described by Fitts' law, a model derived by assuming that the human body has a limited capacity to transmit information in organizing motor behavior. However, Fitts' law can also be realized as an emergent property of movements generated by delayed feedback. In this article, we describe the relationship between the Fitts' law coefficients and the physiological parameters of the underlying delayed feedback circuit: the relaxation rate or time constant, and the psychomotor delay of the feedback process. This relationship is then used to estimate the motor circuit delay of several tasks for which Fitts' law data are available in the literature. We consistently estimate the delay to be between 0 and 112 ms. A further consequence of this model is that not all combinations of slope and Y-intercept in Fitts' law are possible when movements are generated by delayed feedback. In fact, it is only possible for an observed speed-accuracy trade-off to be generated by delayed feedback if the Fitts' law coefficients satisfy -0.482 < or = a/b < or = 3.343 [bits] where b represents the slope in bits per second and a represents the Y-intercept in seconds. If we assume human movement is generated by delayed feedback, then the Fitts' law coefficients should always be restricted to this range of values.

Deafness--the neglected and hidden disability.

The problem of deafness or hearing loss is increasing world-wide. In countries rich and poor, people are living longer, and presbyacusis, the deafness of old age, is becoming more frequent. Hearing loss is a chronic and often life-long disability that, depending on the severity and the frequencies affected, can cause profound damage to the development of speech, language, and cognitive skills in children, especially if commencing prelingually. That damage, in turn, affects the child's progress in school and, later, his or her ability to obtain, keep, and perform an occupation. For all ages and for both sexes, hearing loss causes difficulties with interpersonal communication and leads to significant individual social problems, especially isolation and stigmatization. All of these difficulties are much magnified in developing countries, where there are generally limited services for the hard of hearing, few people trained to help those with hearing loss, and little awareness about how to deal with the difficulties associated with such loss. Although deafness and hearing impairment are likely to have huge economic effects in such countries, in most areas these effects remain to be quantified.

Nutritional factors in the pathogenesis of ear disease in children: a systematic review.

BACKGROUND: Ear disease is a major health problem in poorly resourced countries. The role of nutritional deficiencies in its pathogenesis and in relation to chronic suppurative otitis media (CSOM) has not been reviewed previously. METHODS: A systematic review was undertaken using Pubmed, SCOPUS, Cinahl on Ovid, the Cochrane Database and selected medical journals, with no language restriction. Nutritional mechanisms potentially related to ear disease and CSOM risks were reviewed. All studies (observational, case-control, cohort and clinical trials including randomised controlled trials) with nutrition-related information were included. The titles and/or abstracts of all retrieved studies were reviewed and full articles were obtained for relevant studies. Exclusion criteria were multiple publication or studies which did not report nutritional information. RESULTS: Supplementation studies using single micronutrients and vitamins to determine efficacy in reducing acute or chronic otitis media provided some evidence for an association of middle-ear pathology with deficiencies of zinc or vitamin A. Multi-micronutrient supplementation studies provided further support for a beneficial effect, although the number of studies was small and they were heterogeneous and uncontrolled. No human study was identified which specifically examined the association between copper, selenium or vitamin D status and middle-ear disease or infection. CONCLUSION: Particularly in developing countries, research on micronutrient status and vitamin deficiency and their influence on middle-ear disease is required to improve knowledge of the pathogenesis of middle-ear infection and to determine the relevance of nutritional interventions in prevention and treatment.