A hybrid discrete–continuum approach for modelling microcirculatory blood flow

In recent years, biological imaging techniques have advanced significantly and it is now possible to digitally reconstruct microvascular network structures in detail, identifying the smallest capillaries at sub-micron resolution and generating large 3D structural data sets of size >106 vessel segments. However, this relies on ex vivo imaging; corresponding in vivo measures of microvascular structure and flow are limited to larger branching vessels and are not achievable in three dimensions for the smallest vessels. This suggests the use of computational modelling to combine in vivo measures of branching vessel architecture and flows with ex vivo data on complete microvascular structures to predict effective flow and pressures distributions. In this paper, a hybrid discrete–continuum model to predict microcirculatory blood flow based on structural information is developed and compared with existing models for flow and pressure in individual vessels. A continuum-based Darcy model for transport in the capillary bed is coupled via point sources of flux to flows in individual arteriolar vessels, which are described explicitly using Poiseuille’s law. The venular drainage is represented as a spatially uniform flow sink. The resulting discrete–continuum framework is parameterized using structural data from the capillary network and compared with a fully discrete flow and pressure solution in three networks derived from observations of the rat mesentery. The discrete–continuum approach is feasible and effective, providing a promising tool for extracting functional transport properties in situations where vascular branching structures are well defined

Systematically missing confounders in individual participant data meta-analysis of observational cohort studies.

One difficulty in performing meta-analyses of observational cohort studies is that the availability of confounders may vary between cohorts, so that some cohorts provide fully adjusted analyses while others only provide partially adjusted analyses. Commonly, analyses of the association between an exposure and disease either are restricted to cohorts with full confounder information, or use all cohorts but do not fully adjust for confounding. We propose using a bivariate random-effects meta-analysis model to use information from all available cohorts while still adjusting for all the potential confounders. Our method uses both the fully adjusted and the partially adjusted estimated effects in the cohorts with full confounder information, together with an estimate of their within-cohort correlation. The method is applied to estimate the association between fibrinogen level and coronary heart disease incidence using data from 154,012 participants in 31 cohort

Interoception in anxiety and depression

We review the literature on interoception as it relates to depression and anxiety, with a focus on belief, and alliesthesia. The connection between increased but noisy afferent interoceptive input, self-referential and belief-based states, and top-down modulation of poorly predictive signals is integrated into a neuroanatomical and processing model for depression and anxiety. The advantage of this conceptualization is the ability to specifically examine the interface between basic interoception, self-referential belief-based states, and enhanced top-down modulation to attenuate poor predictability. We conclude that depression and anxiety are not simply interoceptive disorders but are altered interoceptive states as a consequence of noisily amplified self-referential interoceptive predictive belief states

De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures.

Next-generation sequencing has been invaluable in the elucidation of the genetic etiology of many subtypes of intellectual disability in recent years. Here, using exome sequencing and whole-genome sequencing, we identified three de novo truncating mutations in WAS protein family member 1 (WASF1) in five unrelated individuals with moderate to profound intellectual disability with autistic features and seizures. WASF1, also known as WAVE1, is part of the WAVE complex and acts as a mediator between Rac-GTPase and actin to induce actin polymerization. The three mutations connected by Matchmaker Exchange were c.1516C>T (p.Arg506Ter), which occurs in three unrelated individuals, c.1558C>T (p.Gln520Ter), and c.1482delinsGCCAGG (p.Ile494MetfsTer23). All three variants are predicted to partially or fully disrupt the C-terminal actin-binding WCA domain. Functional studies using fibroblast cells from two affected individuals with the c.1516C>T mutation showed a truncated WASF1 and a defect in actin remodeling. This study provides evidence that de novo heterozygous mutations in WASF1 cause a rare form of intellectual disability

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Reactions of pulmonary emphysema patients before and after VRS - Forcusing on the rehabilitation, activity, surgery -

今まで内科的治療が主体であった肺気腫に対して,近年外科的治療(Volume Reduction Surgery 以後VRSと略す)が行われるようになった｡VRSを受ける患者の看護では,手術前後において, リハビリテーション(以後リハビリと略す)や機能回復に向けてのケアが必要不可欠とされる。そこで,本研究は肺気腫患者の適切な看護援助を検討するために,手術前後に示す肺気腫患者のリハビリや活動に対する反応を明らかにすることを目的とした｡対象者は当病棟に入院している肺気腫患者8名(VRS手術前8名,手術後はそのうちの6名である)で, リハビリ, 日常生活活動,呼吸,手術などについて,面接ならびに観察による調査を行った｡分析の結果,手術前においてリハビリでは≪義務感≫,頑張って行えば呼吸が楽になるという≪期待感≫,≪サポート≫,≪不安≫が,活動では≪活動の制限≫,手術では呼吸が楽になるのではという≪期待感≫,≪おまかせ≫,≪いちかばちかの賭け≫,≪不安≫,≪回復に向けての欲求の高まり≫が明らかになった｡手術後においてリハビリでは≪呼吸が楽になるための手段≫が, 日常生活活動では≪今の状態よりは良くなると いう期待感≫が,手術では≪達成感≫ と≪身体的苦痛≫が,将来については≪ささやかな欲求≫が明らかになった｡Pulmonary emphysema has been mainly treated with medicine, but recently VRS(volume reduction surgery) has been receiving much attention. In nursing care for VRS patients, it is important to help the patient improve his/her daily activities and recover physical function smoothly after surgery. The purpose of this study is to clarify the reactions of pulmonary emphysema patients before and after VRS for appropriate nursing. The subjects were eight pulmonary emphysema patients at a ward in Okayama University Hospital, but six of them completed both before and after VRS data collection. The data were collected by interview and observation, and from medical and nursing records. Contents of the interview included rehabilitation, daily activities, respiratory symptoms, operative stress, and so on. The results were as follows : , , , and on rehabilitation, on activity, , , , , and on surgery were extracted as pre-operative patients's reactions. on rehabilitation, on activity, and on surgery, on future were extracted as post-operative patients's reactions

Genetic contributions to variation in general cognitive function:a meta-analysis of genome-wide association studies in the CHARGE consortium (<i>N</i>=53 949)

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10−9, MIR2113; rs17522122, P=2.55 × 10−8, AKAP6; rs10119, P=5.67 × 10−9, APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10−6). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10−17). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer’s disease: TOMM40, APOE, ABCG1 and MEF2C

Biallelic Mutation of ARHGEF18, Involved in the Determination of Epithelial Apicobasal Polarity, Causes Adult-Onset Retinal Degeneration

Mutations in more than 250 genes are implicated in inherited retinal dystrophy; the encoded proteins are involved in a broad spectrum of pathways. The presence of unsolved families after highly parallel sequencing strategies suggests that further genes remain to be identified. Whole-exome and -genome sequencing studies employed here in large cohorts of affected individuals revealed biallelic mutations in ARHGEF18 in three such individuals. ARHGEF18 encodes ARHGEF18, a guanine nucleotide exchange factor that activates RHOA, a small GTPase protein that is a key component of tight junctions and adherens junctions. This biological pathway is known to be important for retinal development and function, as mutation of CRB1, encoding another component, causes retinal dystrophy. The retinal structure in individuals with ARHGEF18 mutations resembled that seen in subjects with CRB1 mutations. Five mutations were found on six alleles in the three individuals: c.808A>G (p.Thr270Ala), c.1617+5G>A (p.Asp540Glyfs∗63), c.1996C>T (p.Arg666∗), c.2632G>T (p.Glu878∗), and c.2738_2761del (p.Arg913_Glu920del). Functional tests suggest that each disease genotype might retain some ARHGEF18 activity, such that the phenotype described here is not the consequence of nullizygosity. In particular, the p.Thr270Ala missense variant affects a highly conserved residue in the DBL homology domain, which is required for the interaction and activation of RHOA. Previously, knock-out of Arhgef18 in the medaka fish has been shown to cause larval lethality which is preceded by retinal defects that resemble those seen in zebrafish Crumbs complex knock-outs. The findings described here emphasize the peculiar sensitivity of the retina to perturbations of this pathway, which is highlighted as a target for potential therapeutic strategies