Utility of assessing nerve morphology in central cornea versus whorl area for diagnosing diabetic peripheral neuropathy

Purpose To compare small nerve fiber damage in the central cornea and whorl area in participants with diabetic peripheral neuropathy (DPN) and to examine the accuracy of evaluating these 2 anatomical sites for the diagnosis of DPN. Methods A cohort of 187 participants (107 with type 1 diabetes and 80 controls) was enrolled. The neuropathy disability score (NDS) was used for the identification of DPN. The corneal nerve fiber length at the central cornea (CNFLcenter) and whorl (CNFLwhorl) was quantified using corneal confocal microscopy and a fully automated morphometric technique and compared according to the DPN status. Receiver operating characteristic analyses were used to compare the accuracy of the 2 corneal locations for the diagnosis of DPN. Results CNFLcenter and CNFLwhorl were able to differentiate all 3 groups (diabetic participants with and without DPN and controls) (P < 0.001). There was a weak but significant linear relationship for CNFLcenter and CNFLwhorl versus NDS (P < 0.001); however, the corneal location x NDS interaction was not statistically significant (P = 0.17). The area under the receiver operating characteristic curve was similar for CNFLcenter and CNFLwhorl (0.76 and 0.77, respectively, P = 0.98). The sensitivity and specificity of the cutoff points were 0.9 and 0.5 for CNFLcenter and 0.8 and 0.6 for CNFLwhorl. Conclusions Small nerve fiber pathology is comparable at the central and whorl anatomical sites of the cornea. Quantification of CNFL from the corneal center is as accurate as CNFL quantification of the whorl area for the diagnosis of DPN.

A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: A systematic analysis for the Global Burden of Disease Study 2010

BACKGROUND Quantification of the disease burden caused by different risks informs prevention by providing an account of health loss different to that provided by a disease-by-disease analysis. No complete revision of global disease burden caused by risk factors has been done since a comparative risk assessment in 2000, and no previous analysis has assessed changes in burden attributable to risk factors over time. METHODS We estimated deaths and disability-adjusted life years (DALYs; sum of years lived with disability [YLD] and years of life lost [YLL]) attributable to the independent effects of 67 risk factors and clusters of risk factors for 21 regions in 1990 and 2010. We estimated exposure distributions for each year, region, sex, and age group, and relative risks per unit of exposure by systematically reviewing and synthesising published and unpublished data. We used these estimates, together with estimates of cause-specific deaths and DALYs from the Global Burden of Disease Study 2010, to calculate the burden attributable to each risk factor exposure compared with the theoretical-minimum-risk exposure. We incorporated uncertainty in disease burden, relative risks, and exposures into our estimates of attributable burden. FINDINGS In 2010, the three leading risk factors for global disease burden were high blood pressure (7·0% [95% uncertainty interval 6·2-7·7] of global DALYs), tobacco smoking including second-hand smoke (6·3% [5·5-7·0]), and alcohol use (5·5% [5·0-5·9]). In 1990, the leading risks were childhood underweight (7·9% [6·8-9·4]), household air pollution from solid fuels (HAP; 7·0% [5·6-8·3]), and tobacco smoking including second-hand smoke (6·1% [5·4-6·8]). Dietary risk factors and physical inactivity collectively accounted for 10·0% (95% UI 9·2-10·8) of global DALYs in 2010, with the most prominent dietary risks being diets low in fruits and those high in sodium. Several risks that primarily affect childhood communicable diseases, including unimproved water and sanitation and childhood micronutrient deficiencies, fell in rank between 1990 and 2010, with unimproved water and sanitation accounting for 0·9% (0·4-1·6) of global DALYs in 2010. However, in most of sub-Saharan Africa childhood underweight, HAP, and non-exclusive and discontinued breastfeeding were the leading risks in 2010, while HAP was the leading risk in south Asia. The leading risk factor in Eastern Europe, most of Latin America, and southern sub-Saharan Africa in 2010 was alcohol use; in most of Asia, North Africa and Middle East, and central Europe it was high blood pressure. Despite declines, tobacco smoking including second-hand smoke remained the leading risk in high-income north America and western Europe. High body-mass index has increased globally and it is the leading risk in Australasia and southern Latin America, and also ranks high in other high-income regions, North Africa and Middle East, and Oceania. INTERPRETATION Worldwide, the contribution of different risk factors to disease burden has changed substantially, with a shift away from risks for communicable diseases in children towards those for non-communicable diseases in adults. These changes are related to the ageing population, decreased mortality among children younger than 5 years, changes in cause-of-death composition, and changes in risk factor exposures. New evidence has led to changes in the magnitude of key risks including unimproved water and sanitation, vitamin A and zinc deficiencies, and ambient particulate matter pollution. The extent to which the epidemiological shift has occurred and what the leading risks currently are varies greatly across regions. In much of sub-Saharan Africa, the leading risks are still those associated with poverty and those that affect children.

Leaf micromorphology and anatomy of Myrceugenia rufa (Myrtaceae): An endemic coastal shrub of north-central Chile

Species of fleshy-fruited Myrtaceae are generally associated with humid environments and their vegetative anatomy is mainly mesophytic. Myrceugenia rufa is an endemic and rare species from arid zones of the coast of central Chile and there are no anatomical studies regarding its leaf anatomy and environmental adaptations. Here we describe the leaf micromorphology and anatomy of the species using standard protocols for light and scanning electron microscopy. The leaf anatomy of M. rufa matches that of other Myrtaceae, such as presence of druses, schizogenous secretory ducts and internal phloem. Leaves of M. rufa exhibit a double epidermis, thick cuticle, abundant unicellular hairs, large substomatal chambers covered by trichomes and a dense palisade parenchyma. Leaf characters of M. rufa confirm an anatomical adaptation to xerophytic environments.

High-temperature, low-H₂O silicic magmas of the Yellowstone Hotspot: an experimental study of Rhyolite from the Bruneau-Jarbidge eruptive center, Central Snake River Plain, USA

The phase relations have been investigated experimentally at 200 and 500 MPa as a function of water activity for one of the least evolved (Indian Batt Rhyolite) and of a more evolved rhyolite composition (Cougar Point Tuff XV) from the 12·8-8·1 Ma Bruneau-Jarbidge eruptive center of the Yellowstone hotspot. Particular priority was given to accurate determination of the water content of the quenched glasses using infrared spectroscopic techniques. Comparison of the composition of natural and experimentally synthesized phases confirms that high temperatures (>900°C) and extremely low melt water contents (<1·5 wt % H₂O) are required to reproduce the natural mineral assemblages. In melts containing 0·5-1·5 wt % H₂O, the liquidus phase is clinopyroxene (excluding Fe-Ti oxides, which are strongly dependent on fO₂), and the liquidus temperature of the more evolved Cougar Point Tuff sample (BJR; 940-1000°C) is at least 30°C lower than that of the Indian Batt Rhyolite lava sample (IBR2; 970-1030°C). For the composition BJR, the comparison of the compositions of the natural and experimental glasses indicates a pre-eruptive temperature of at least 900°C. The composition of clinopyroxene and pigeonite pairs can be reproduced only for water contents below 1·5 wt % H₂O at 900°C, or lower water contents if the temperature is higher. For the composition IBR2, a minimum temperature of 920°C is necessary to reproduce the main phases at 200 and 500 MPa. At 200 MPa, the pre-eruptive water content of the melt is constrained in the range 0·7-1·3 wt % at 950°C and 0·3-1·0 wt % at 1000°C. At 500 MPa, the pre-eruptive temperatures are slightly higher (by 30-50°C) for the same ranges of water concentration. The experimental results are used to explore possible proxies to constrain the depth of magma storage. The crystallization sequence of tectosilicates is strongly dependent on pressure between 200 and 500 MPa. In addition, the normative Qtz-Ab-Or contents of glasses quenched from melts coexisting with quartz, sanidine and plagioclase depend on pressure and melt water content, assuming that the normative Qtz and Ab/Or content of such melts is mainly dependent on pressure and water activity, respectively. The combination of results from the phase equilibria and from the composition of glasses indicates that the depth of magma storage for the IBR2 and BJR compositions may be in the range 300-400 MPa (13 km) and 200-300 MPa (10 km), respectively.

Brain structure in healthy adults is related to serum transferrin and the H63D polymorphism in the HFE gene

Control of iron homeostasis is essential for healthy central nervous system function: iron deficiency is associated with cognitive impairment, yet iron overload is thought to promote neurodegenerative diseases. Specific genetic markers have been previously identified that influence levels of transferrin, the protein that transports iron throughout the body, in the blood and brain. Here, we discovered that transferrin levels are related to detectable differences in the macro- and microstructure of the living brain. We collected brain MRI scans from 615 healthy young adult twins and siblings, of whom 574 were also scanned with diffusion tensor imaging at 4 Tesla. Fiber integrity was assessed by using the diffusion tensor imaging-based measure of fractional anisotropy. In bivariate genetic models based on monozygotic and dizygotic twins, we discovered that partially overlapping additive genetic factors influenced transferrin levels and brain microstructure. We also examined common variants in genes associated with transferrin levels, TF and HFE, and found that a commonly carried polymorphism (H63D at rs1799945) in the hemochromatotic HFE gene was associated with white matter fiber integrity. This gene has a well documented association with iron overload. Our statistical maps reveal previously unknown influences of the same gene on brain microstructure and transferrin levels. This discovery may shed light on the neural mechanisms by which iron affects cognition, neurodevelopment, and neurodegeneration.

Genetics of path lengths in brain connectivity networks: HARDI-based maps in 457 adults

Brain connectivity analyses are increasingly popular for investigating organization. Many connectivity measures including path lengths are generally defined as the number of nodes traversed to connect a node in a graph to the others. Despite its name, path length is purely topological, and does not take into account the physical length of the connections. The distance of the trajectory may also be highly relevant, but is typically overlooked in connectivity analyses. Here we combined genotyping, anatomical MRI and HARDI to understand how our genes influence the cortical connections, using whole-brain tractography. We defined a new measure, based on Dijkstra's algorithm, to compute path lengths for tracts connecting pairs of cortical regions. We compiled these measures into matrices where elements represent the physical distance traveled along tracts. We then analyzed a large cohort of healthy twins and show that our path length measure is reliable, heritable, and influenced even in young adults by the Alzheimer's risk gene, CLU.

Scalar connectivity measures from fast-marching tractography reveal heritability of white matter architecture

Recent advances in diffusion-weighted MRI (DWI) have enabled studies of complex white matter tissue architecture in vivo. To date, the underlying influence of genetic and environmental factors in determining central nervous system connectivity has not been widely studied. In this work, we introduce new scalar connectivity measures based on a computationally-efficient fast-marching algorithm for quantitative tractography. We then calculate connectivity maps for a DTI dataset from 92 healthy adult twins and decompose the genetic and environmental contributions to the variance in these metrics using structural equation models. By combining these techniques, we generate the first maps to directly examine genetic and environmental contributions to brain connectivity in humans. Our approach is capable of extracting statistically significant measures of genetic and environmental contributions to neural connectivity.

Pyroxene thermometry of rhyolite lavas of the Bruneau–Jarbidge eruptive center, Central Snake River Plain

The Bruneau–Jarbidge eruptive center of the central Snake River Plain in southern Idaho, USA produced multiple rhyolite lava flows with volumes of <10 km³ to 200 km³ each from ~11.2 to 8.1 Ma, most of which follow its climactic phase of large-volume explosive volcanism, represented by the Cougar Point Tuff, from 12.7 to 10.5 Ma. These lavas represent the waning stages of silicic volcanism at a major eruptive center of the Yellowstone hotspot track. Here we provide pyroxene compositions and thermometry results from several lavas that demonstrate that the demise of the silicic volcanic system was characterized by sustained, high pre-eruptive magma temperatures (mostly ≥950 °C) prior to the onset of exclusively basaltic volcanism at the eruptive center. Pyroxenes display a variety of textures in single samples, including solitary euhedral crystals as well as glomerocrysts, crystal clots and annealed microgranular inclusions of pyroxene ±magnetite± plagioclase. Pigeonite and augite crystals are unzoned, and there are no detectable differences in major and minor element compositions according to textural variety — mineral compositions in the microgranular inclusions and crystal clots are identical to those of phenocrysts in the host lavas. In contrast to members of the preceding Cougar Point Tuff that host polymodal glass and mineral populations, pyroxene compositions in each of the lavas are characterized by single rather than multiple discrete compositional modes. Collectively, the lavas reproduce and extend the range of Fe–Mg pyroxene compositional modes observed in the Cougar Point Tuff to more Mg-rich varieties. The compositionally homogeneous populations of pyroxene in each of the lavas, as well as the lack of core-to-rim zonation in individual crystals suggest that individual eruptions each were fed by compositionally homogeneous magma reservoirs, and similarities with the Cougar Point Tuff suggest consanguinity of such reservoirs to those that supplied the polymodal Cougar Point Tuff. Pyroxene thermometry results obtained using QUILF equilibria yield pre-eruptive magma temperatures of 905 to 980 °C, and individual modes consistently record higher Ca content and higher temperatures than pyroxenes with equivalent Fe–Mg ratios in the preceding Cougar Point Tuff. As is the case with the Cougar Point Tuff, evidence for up-temperature zonation within single crystals that would be consistent with recycling of sub- or near-solidus material from antecedent magma reservoirs by rapid reheating is extremely rare. Also, the absence of intra-crystal zonation, particularly at crystal rims, is not easily reconciled with cannibalization of caldera fill that subsided into pre-eruptive reservoirs. The textural, compositional and thermometric results rather are consistent with minor re-equilibration to higher temperatures of the unerupted crystalline residue from the explosive phase of volcanism, or perhaps with newly generated magmas from source materials very similar to those for the Cougar Point Tuff. Collectively, the data suggest that most of the pyroxene compositional diversity that is represented by the tuffs and lavas was produced early in the history of the eruptive center and that compositions across this range were preserved or duplicated through much of its lifetime. Mineral compositions and thermometry of the multiple lavas suggest that unerupted magmas residual to the explosive phase of volcanism may have been stored at sustained, high temperatures subsequent to the explosive phase of volcanism. If so, such persistent high temperatures and large eruptive magma volumes likewise require an abundant and persistent supply of basalt magmas to the lower and/or mid-crust, consistent with the tectonic setting of a continental hotspot.

Genome-wide association study for radiographic vertebral fractures: A potential role for the 16q24 BMD locus

Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fractures applying a genome-wide association study (GWAS) approach. The GWAS discovery was based on the Rotterdam Study, a population-based study of elderly Dutch individuals aged >55years; and comprising 329 cases and 2666 controls with radiographic scoring (McCloskey-Kanis) and genetic data. Replication of one top-associated SNP was pursued by de-novo genotyping of 15 independent studies across Europe, the United States, and Australia and one Asian study. Radiographic vertebral fracture assessment was performed using McCloskey-Kanis or Genant semi-quantitative definitions. SNPs were analyzed in relation to vertebral fracture using logistic regression models corrected for age and sex. Fixed effects inverse variance and Han-Eskin alternative random effects meta-analyses were applied. Genome-wide significance was set at p<5×10-8. In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p=4.6×10-8. However, the association was not significant across 5720 cases and 21,791 controls from 14 studies. Fixed-effects meta-analysis summary estimate was 1.06 (95% CI: 0.98-1.14; p=0.17), displaying high degree of heterogeneity (I2=57%; Qhet p=0.0006). Under Han-Eskin alternative random effects model the summary effect was significant (p=0.0005). The SNP maps to a region previously found associated with lumbar spine bone mineral density (LS-BMD) in two large meta-analyses from the GEFOS consortium. A false positive association in the GWAS discovery cannot be excluded, yet, the low-powered setting of the discovery and replication settings (appropriate to identify risk effect size >1.25) may still be consistent with an effect size <1.10, more of the type expected in complex traits. Larger effort in studies with standardized phenotype definitions is needed to confirm or reject the involvement of this locus on the risk for vertebral fractures.

Pathogens penetrating the central nervous system: Infection pathways and the cellular and molecular mechanisms of invasion

The brain is well protected against microbial invasion by cellular barriers, such as the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB). In addition, cells within the central nervous system (CNS) are capable of producing an immune response against invading pathogens. Nonetheless, a range of pathogenic microbes make their way to the CNS, and the resulting infections can cause significant morbidity and mortality. Bacteria, amoebae, fungi, and viruses are capable of CNS invasion, with the latter using axonal transport as a common route of infection. In this review, we compare the mechanisms by which bacterial pathogens reach the CNS and infect the brain. In particular, we focus on recent data regarding mechanisms of bacterial translocation from the nasal mucosa to the brain, which represents a little explored pathway of bacterial invasion but has been proposed as being particularly important in explaining how infection with Burkholderia pseudomallei can result in melioidosis encephalomyelitis.

The role of environmental factors in the spatial distribution of Japanese encephalitis in mainland China

Japanese encephalitis (JE) is the most common cause of viral encephalitis and an important public health concern in the Asia-Pacific region, particularly in China where 50% of global cases are notified. To explore the association between environmental factors and human JE cases and identify the high risk areas for JE transmission in China, we used annual notified data on JE cases at the center of administrative township and environmental variables with a pixel resolution of 1 km×1 km from 2005 to 2011 to construct models using ecological niche modeling (ENM) approaches based on maximum entropy. These models were then validated by overlaying reported human JE case localities from 2006 to 2012 onto each prediction map. ENMs had good discriminatory ability with the area under the curve (AUC) of the receiver operating curve (ROC) of 0.82-0.91, and low extrinsic omission rate of 5.44-7.42%. Resulting maps showed JE being presented extensively throughout southwestern and central China, with local spatial variations in probability influenced by minimum temperatures, human population density, mean temperatures, and elevation, with contribution of 17.94%-38.37%, 15.47%-21.82%, 3.86%-21.22%, and 12.05%-16.02%, respectively. Approximately 60% of JE cases occurred in predicted high risk areas, which covered less than 6% of areas in mainland China. Our findings will help inform optimal geographical allocation of the limited resources available for JE prevention and control in China, find hidden high-risk areas, and increase the effectiveness of public health interventions against JE transmission.

Molecular and pathological insights into Chlamydia pecorum-associated sporadic bovine encephalomyelitis (SBE) in Western Australia

Background Despite its global recognition as a ruminant pathogen, cases of Chlamydia pecorum infection in Australian livestock are poorly documented. In this report, a C. pecorum specific Multi Locus Sequence Analysis scheme was used to characterise the C. pecorum strains implicated in two cases of sporadic bovine encephalomyelitis confirmed by necropsy, histopathology and immunohistochemistry. This report provides the first molecular evidence for the presence of mixed infections of C. pecorum strains in Australian cattle. Case presentation Affected animals were two markedly depressed, dehydrated and blind calves, 12 and 16 weeks old. The calves were euthanized and necropsied. In one calf, a severe fibrinous polyserositis was noted with excess joint fluid in all joints whereas in the other, no significant lesions were seen. No gross abnormalities were noted in the brain of either calf. Histopathological lesions seen in both calves included: multifocal, severe, subacute meningoencephalitis with vasculitis, fibrinocellular thrombosis and malacia; diffuse, mild, acute interstitial pneumonia; and diffuse, subacute epicarditis, severe in the calf with gross serositis. Immunohistochemical labelling of chlamydial antigen in brain, spleen and lung from the two affected calves and brain from two archived cases, localised the antigen to the cytoplasm of endothelium, mesothelium and macrophages. C. pecorum specific qPCR, showed dissemination of the pathogen to multiple organs. Phylogenetic comparisons with other C. pecorum bovine strains from Australia, Europe and the USA revealed the presence of two genetically distinct sequence types (ST). The predominant ST detected in the brain, heart, lung and liver of both calves was identical to the C. pecorum ST previously described in cases of SBE. A second ST detected in an ileal tissue sample from one of the calves, clustered with previously typed faecal bovine isolates. Conclusion This report provides the first data to suggest that identical C. pecorum STs may be associated with SBE in geographically separated countries and that these may be distinct from those found in the gastrointestinal tract. This report provides a platform for further investigations into SBE and for understanding the genetic relationships that exist between C. pecorum strains detected in association with other infectious diseases in livestock.

Postnatal depressive symptoms amongst women in Central Vietnam: A cross-sectional study investigating prevalence and associations with social, cultural and infant factors

Background This study investigated the prevalence and socio-cultural correlates of postnatal mood disturbance amongst women 18–45 years old in Central Vietnam. Son preference and traditional confinement practices were explored as well as factors such as poverty, parity, family and intimate partner relationships and infant health. Methods A cross-sectional study was conducted in twelve randomly selected Commune Health Centres from urban and rural districts of Thua Thien Hue Province, Vietnam. Mother-infant dyads one to six months postpartum were invited to participate. Questionnaires from 431 mothers (urban n = 216; rural n = 215) assessed demographic and family characteristics, traditional confinement practices, son preference, infant health and social capital. The Edinburgh Postnatal Depression Scale (EPDS) and WHO5 Wellbeing Index indicated depressive symptoms and emotional wellbeing. Data were analysed using general linear models. Results Using an EPDS cut-off of 12/13, 18.1 % (n = 78, 95 % CI 14.6 - 22.1) of women had depressive symptoms (20.4 % urban; 15.8 % rural). Contrary to predictions, infant gender and traditional confinement were unrelated to depressive symptoms. Poverty, food insecurity, being frightened of family members, and intimate partner violence increased both depressive symptoms and lowered wellbeing. The first model accounted for 30.2 % of the variance in EPDS score and found being frightened of one’s husband, husband’s unemployment, breastfeeding difficulties, infant diarrhoea, and cognitive social capital were associated with higher EPDS scores. The second model had accounted for 22 % of the variance in WHO5 score. Living in Hue city, low education, poor maternal competence and a negative family response to the baby lowered maternal wellbeing. Conclusions Traditional confinement practices and son preference were not linked to depressive symptoms among mothers, but were correlates of family relationships and wellbeing. Poverty, food insecurity, violence, infant ill health, and discordant intimate and family relationships were linked with depressive symptoms in Central Vietnam.

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis. © 2011 Macmillan Publishers Limited. All rights reserved.

Characteristics of on-road driving by persons with central vision loss: Learning to drive with a bioptic telescope

There is limited research on the driving performance and safety of bioptic drivers and even less regarding the driving skills that are most challenging for those learning to drive with bioptic telescopes. This research consisted of case studies of five trainee bioptic drivers whose driving skills were compared with those of a group of licensed bioptic drivers (n = 23) while they drove along city, suburban, and controlled-access highways in an instrumented dual-brake vehicle. A certified driver rehabilitation specialist was positioned in the front passenger seat to monitor safety and two backseat evaluators independently rated driving using a standardized scoring system. Other aspects of performance were assessed through vehicle instrumentation and video recordings. Results demonstrate that while sign recognition, lane keeping, steering steadiness, gap judgments and speed choices were significantly worse in trainees, some driving behaviors and skills, including pedestrian detection and traffic light recognition were not significantly different to those of the licensed drivers. These data provide useful insights into the skill challenges encountered by a small sample of trainee bioptic drivers which, while not generalizable because of the small sample size, provide valuable insights beyond that of previous studies and can be used as a basis to guide training strategies.