Misdiagnosis of narcolepsy

BACKGROUND: Narcolepsy is a chronic primary sleep disorder, characterized by excessive daytime sleepiness and sleep dysfunction with or without cataplexy. Narcolepsy is uncommon, with a low prevalence rate which makes it difficult to diagnose definitively without a complex series of tests and a detailed history. The aim of this study was to review patients referred to a tertiary sleep centre who had been labelled with a diagnosis of narcolepsy prior to referral in order to assess if the diagnosis was accurate, and if not, to determine the cause of diagnostic misattribution. METHODS: All patients seen at a sleep centre from 2007–2013 (n = 551) who underwent detailed objective testing including an MSLT PSG, as well as wearing an actigraphy watch and completing a sleep diary for 2 weeks, were assessed for a pre-referral and final diagnosis of narcolepsy. RESULTS: Of the 41 directly referred patients with a diagnostic label of narcolepsy, 19 (46 %) were subsequently confirmed to have narcolepsy on objective testing and assessment by a sleep physician using ICSD-2 criteria. CONCLUSIONS: The diagnosis of narcolepsy was incorrectly attributed to almost 50 % of patients labelled with a diagnosis of narcolepsy who were referred for further opinion by a variety of specialists and generalists. Accurate diagnosis of narcolepsy is critical for many reasons, such as the impact it has on quality of life, driving, employment, insurance and pregnancy in women as well as medication management

Thumb reconstruction by grafting skeletonized amputated phalanges and soft tissue cover – A new technique: A case series

This study reports five cases of crush-avulsion injury to the thumb at different levels presented at our plastic and hand surgery unit between 2005 and 2007. All of the patients were male labors with machine injuries to the thumb with non-replantable amputations. Distal phalanx or proximal phalanx, or both, were used as a free cortical bone graft. The amputated part was skeletonized keeping the periosteum attached to the cortical bone of the phalanx fixing it to the stump and covering it by either local flap like dorsal metacarpal flap or regional flaps like the distally based pedicled radial forearm flap and neurovascular island sensate flap or groin flap. The results were functionally and cosmetically good and follow up X rays showed no osteoporotic resorption after one year

Spin polarization versus lifetime effects at point contacts between superconducting niobium and normal metals

Point-contact Andreev reflection spectroscopy is used to measure the spin polarization of metals but analysis of the spectra has encountered a number of serious challenges, one of which is the difficulty to distinguish the effects of spin polarization from those of the finite lifetime of Cooper pairs. We have recently confirmed the polarization-lifetime ambiguity for Nb-Co and Nb-Cu contacts and suggested to use Fermi surface mismatch, the normal reflection due to the difference of Fermi wave vectors of the two electrodes, to solve this dilemma. Here we present further experiments on contacts between superconducting Nb and the ferromagnets Fe and Ni as well as the noble metals Ag and Pt that support our previous results. Our data indicate that the Nb - normal metal interfaces have a transparency of up to about 80 per cent and a small, if not negligible, spin polarization.Comment: 7 pages, 2 figures, submitted to Proceedings of the 26th Conference on Low Temperature Physic

A retrospective population based cohort study of access to specialist palliative care in the last year of life: who is still missing out a decade on?

Background: Historically, specialist palliative care has been accessed by a greater proportion of people dying with cancer compared to people with other life-limiting conditions. More recently, a variety of measures to improve access to palliative care for people dying from non-cancer conditions have been implemented. There are few rigorous population-based studies that document changes in palliative care service delivery relative to the number of patients who could benefit from such services. Method: A retrospective cohort study of the last year of life of persons with an underlying cause of death in 2009-10 from cancer, heart failure, renal failure, liver failure, chronic obstructive pulmonary disease, Alzheimer's disease, motor neurone disease, Parkinson's disease, Huntington's disease and/or HIV/AIDS. The proportion of decedents receiving specialist palliative care was compared to a 2000-02 cohort. Logistic regression models were used identify social and demographic factors associated with accessing specialist palliative care. Results: There were 12,817 deaths included into the cohort; 7166 (56 %) from cancer, 527 (4 %) from both cancer and non-cancer conditions and 5124 (40 %) from non-cancer conditions. Overall, 46.3 % of decedents received community and/or hospital based specialist palliative care; a 3.5 % (95 % CI 2.3-4.7) increase on specialist palliative care access reported ten years earlier. The majority (69 %; n?=?4928) of decedents with cancer accessed palliative care during the last year of life. Only 14 % (n?=?729) of decedents with non-cancer conditions accessed specialist palliative care, however, this represented a 6.1 % (95 % CI 4.9-7.3) increase on the specialist palliative care access reported for the same decedent group ten years earlier. Compared to decedents with heart failure, increased odds of palliative care access was observed for decedents with cancer (OR 10.5; 95 % CI 9.1-12.2), renal failure (OR 1.5; 95 % CI 1.3-1.9), liver failure (OR 2.3; 95 % CI 1.7-3.3) or motor neurone disease (OR 4.5; 95 % CI 3.1-6.6). Living in major cities, being female, having a partner and living in a private residence was associated with increased odds of access to specialist palliative care. CONCLUSION: There is small but significant increase in access to specialist palliative care services in Western Australia, specifically in patients dying with non-cancer conditions

Cholesterol and the risk of grade-specific prostate cancer incidence: evidence from two large prospective cohort studies with up to 37 years' follow up

<b>Background</b> High cholesterol may be a modifiable risk factor for prostate cancer but results have been inconsistent and subject to potential "reverse causality" where undetected disease modifies cholesterol prior to diagnosis.<p></p> <b>Methods</b> We conducted a prospective cohort study of 12,926 men who were enrolled in the Midspan studies between 1970 and 1976 and followed up to 31st December 2007. We used Cox-Proportional Hazards Models to evaluate the association between baseline plasma cholesterol and Gleason grade-specific prostate cancer incidence. We excluded cancers detected within at least 5 years of cholesterol assay.<p></p> <b>Results</b> 650 men developed prostate cancer in up to 37 years' follow-up. Baseline plasma cholesterol was positively associated with hazard of high grade (Gleason score[greater than or equal to]8) prostate cancer incidence (n=119). The association was greatest among men in the 4th highest quintile for cholesterol, 6.1 to <6.69 mmol/l, Hazard Ratio 2.28, 95% CI 1.27 to 4.10, compared with the baseline of <5.05 mmol/l. This association remained significant after adjustment for body mass index, smoking and socioeconomic status.<p></p> <b>Conclusions</b> Men with higher cholesterol are at greater risk of developing high-grade prostate cancer but not overall risk of prostate cancer. Interventions to minimise metabolic risk factors may have a role in reducing incidence of aggressive prostate cancer

Suv4-20h Histone Methyltransferases Promote Neuroectodermal Differentiation by Silencing the Pluripotency-Associated Oct-25 Gene

Post-translational modifications (PTMs) of histones exert fundamental roles in regulating gene expression. During development, groups of PTMs are constrained by unknown mechanisms into combinatorial patterns, which facilitate transitions from uncommitted embryonic cells into differentiated somatic cell lineages. Repressive histone modifications such as H3K9me3 or H3K27me3 have been investigated in detail, but the role of H4K20me3 in development is currently unknown. Here we show that Xenopus laevis Suv4-20h1 and h2 histone methyltransferases (HMTases) are essential for induction and differentiation of the neuroectoderm. Morpholino-mediated knockdown of the two HMTases leads to a selective and specific downregulation of genes controlling neural induction, thereby effectively blocking differentiation of the neuroectoderm. Global transcriptome analysis supports the notion that these effects arise from the transcriptional deregulation of specific genes rather than widespread, pleiotropic effects. Interestingly, morphant embryos fail to repress the Oct4-related Xenopus gene Oct-25. We validate Oct-25 as a direct target of xSu4-20h enzyme mediated gene repression, showing by chromatin immunoprecipitaton that it is decorated with the H4K20me3 mark downstream of the promoter in normal, but not in double-morphant, embryos. Since knockdown of Oct-25 protein significantly rescues the neural differentiation defect in xSuv4-20h double-morphant embryos, we conclude that the epistatic relationship between Suv4-20h enzymes and Oct-25 controls the transit from pluripotent to differentiation-competent neural cells. Consistent with these results in Xenopus, murine Suv4-20h1/h2 double-knockout embryonic stem (DKO ES) cells exhibit increased Oct4 protein levels before and during EB formation, and reveal a compromised and biased capacity for in vitro differentiation, when compared to normal ES cells. Together, these results suggest a regulatory mechanism, conserved between amphibians and mammals, in which H4K20me3-dependent restriction of specific POU-V genes directs cell fate decisions, when embryonic cells exit the pluripotent state

Methods in Molecular Biology

Developmental processes are inherently dynamic and understanding them requires quantitative measurements of gene and protein expression levels in space and time. While live imaging is a powerful approach for obtaining such data, it is still a challenge to apply it over long periods of time to large tissues, such as the embryonic spinal cord in mouse and chick. Nevertheless, dynamics of gene expression and signaling activity patterns in this organ can be studied by collecting tissue sections at different developmental stages. In combination with immunohistochemistry, this allows for measuring the levels of multiple developmental regulators in a quantitative manner with high spatiotemporal resolution. The mean protein expression levels over time, as well as embryo-to-embryo variability can be analyzed. A key aspect of the approach is the ability to compare protein levels across different samples. This requires a number of considerations in sample preparation, imaging and data analysis. Here we present a protocol for obtaining time course data of dorsoventral expression patterns from mouse and chick neural tube in the first 3 days of neural tube development. The described workflow starts from embryo dissection and ends with a processed dataset. Software scripts for data analysis are included. The protocol is adaptable and instructions that allow the user to modify different steps are provided. Thus, the procedure can be altered for analysis of time-lapse images and applied to systems other than the neural tube

Differences in HIV Natural History among African and Non-African Seroconverters in Europe and Seroconverters in Sub-Saharan Africa

Introduction It is unknown whether HIV treatment guidelines, based on resource-rich country cohorts, are applicable to African populations. Methods We estimated CD4 cell loss in ART-naïve, AIDS-free individuals using mixed models allowing for random intercept and slope, and time from seroconversion to clinical AIDS, death and antiretroviral therapy (ART) initiation by survival methods. Using CASCADE data from 20 European and 3 sub-Saharan African (SSA) cohorts of heterosexually-infected individuals, aged ≥15 years, infected ≥2000, we compared estimates between non-African Europeans, Africans in Europe, and Africans in SSA. Results Of 1,959 (913 non-Africans, 302 Europeans - African origin, 744 SSA), two-thirds were female; median age at seroconversion was 31 years. Individuals in SSA progressed faster to clinical AIDS but not to death or non-TB AIDS. They also initiated ART later than Europeans and at lower CD4 cell counts. In adjusted models, Africans (especially from Europe) had lower CD4 counts at seroconversion and slower CD4 decline than non-African Europeans. Median (95% CI) CD4 count at seroconversion for a 15–29 year old woman was 607 (588–627) (non-African European), 469 (442–497) (European - African origin) and 570 (551–589) (SSA) cells/µL with respective CD4 decline during the first 4 years of 259 (228–289), 155 (110–200), and 199 (174–224) cells/µL (p<0.01). Discussion Despite differences in CD4 cell count evolution, death and non-TB AIDS rates were similar across study groups. It is therefore prudent to apply current ART guidelines from resource-rich countries to African populations

Post-mortem brain analyses of the Lothian Birth Cohort 1936:Extending lifetime cognitive and brain phenotyping to the level of the synapse

INTRODUCTION: Non-pathological, age-related cognitive decline varies markedly between individuals andplaces significant financial and emotional strain on people, their families and society as a whole.Understanding the differential age-related decline in brain function is critical not only for the development oftherapeutics to prolong cognitive health into old age, but also to gain insight into pathological ageing suchas Alzheimer’s disease. The Lothian Birth Cohort of 1936 (LBC1936) comprises a rare group of people forwhom there are childhood cognitive test scores and longitudinal cognitive data during older age, detailedstructural brain MRI, genome-wide genotyping, and a multitude of other biological, psycho-social, andepidemiological data. Synaptic integrity is a strong indicator of cognitive health in the human brain;however, until recently, it was prohibitively difficult to perform detailed analyses of synaptic and axonalstructure in human tissue sections. We have adapted a novel method of tissue preparation at autopsy toallow the study of human synapses from the LBC1936 cohort in unprecedented morphological andmolecular detail, using the high-resolution imaging techniques of array tomography and electronmicroscopy. This allows us to analyze the brain at sub-micron resolution to assess density, proteincomposition and health of synapses. Here we present data from the first donated LBC1936 brain andcompare our findings to Alzheimer’s diseased tissue to highlight the differences between healthy andpathological brain ageing. RESULTS: Our data indicates that compared to an Alzheimer’s disease patient, the cognitively normalLBC1936 participant had a remarkable degree of preservation of synaptic structures. However,morphological and molecular markers of degeneration in areas of the brain associated with cognition(prefrontal cortex, anterior cingulate cortex, and superior temporal gyrus) were observed. CONCLUSIONS: Our novel post-mortem protocol facilitates high-resolution neuropathological analysis of the well-characterized LBC1936 cohort, extending phenotyping beyond cognition and in vivo imaging to nowinclude neuropathological changes, at the level of single synapses. This approach offers an unprecedentedopportunity to study synaptic and axonal integrity during ageing and how it contributes to differences in agerelatedcognitive change. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40478-015-0232-0) contains supplementary material, which is available to authorized users