Numerical simulation of blood flow and pressure drop in the pulmonary arterial and venous circulation

A novel multiscale mathematical and computational model of the pulmonary circulation is presented and used to analyse both arterial and venous pressure and flow. This work is a major advance over previous studies by Olufsen et al. (Ann Biomed Eng 28:1281–1299, 2012) which only considered the arterial circulation. For the first three generations of vessels within the pulmonary circulation, geometry is specified from patient-specific measurements obtained using magnetic resonance imaging (MRI). Blood flow and pressure in the larger arteries and veins are predicted using a nonlinear, cross-sectional-area-averaged system of equations for a Newtonian fluid in an elastic tube. Inflow into the main pulmonary artery is obtained from MRI measurements, while pressure entering the left atrium from the main pulmonary vein is kept constant at the normal mean value of 2 mmHg. Each terminal vessel in the network of ‘large’ arteries is connected to its corresponding terminal vein via a network of vessels representing the vascular bed of smaller arteries and veins. We develop and implement an algorithm to calculate the admittance of each vascular bed, using bifurcating structured trees and recursion. The structured-tree models take into account the geometry and material properties of the ‘smaller’ arteries and veins of radii ≥ 50 μ m. We study the effects on flow and pressure associated with three classes of pulmonary hypertension expressed via stiffening of larger and smaller vessels, and vascular rarefaction. The results of simulating these pathological conditions are in agreement with clinical observations, showing that the model has potential for assisting with diagnosis and treatment for circulatory diseases within the lung

Suicidality and hostility following involuntary hospital treatment

Background Psychiatric patients showing risk to themselves or others can be involuntarily hospitalised. No data is available on whether following hospitalisation there is a reduction in psychopathological indicators of risk such as suicidality and hostility. This study aimed to assess changes in suicidality and hostility levels following involuntary admission and their patient-level predictors. Methods A pooled analysis of studies on involuntary treatment, including 11 countries and 2790 patients was carried out. Suicidality and hostility were measured by the Brief Psychiatric Rating Scale. Results 2790 patients were included; 2129 followed-up after one month and 1864 after three months. 387 (13.9%) patients showed at least moderate suicidality when involuntarily admitted, 107 (5.0%) after one month and 97 (5.2%) after three months. Moderate or higher hostility was found in 1287 (46.1%) patients after admission, 307 (14.5%) after one month, and 172 (9.2%) after three months. Twenty-three (1.2%) patients showed suicidality, and 53 (2.8%) patients hostility at all time-points. Predictors of suicidality three months after admission were: suicidality at baseline, not having a diagnosis of psychotic disorder and being unemployed. Predictors of hostility were: hostility at baseline, not having a psychotic disorder, living alone, and having been hospitalized previously. Conclusions After involuntary hospital admission, the number of patients with significant levels of suicidality and hostility decreases substantially over time, and very few patients show consistently moderate or higher levels of these symptoms. In patients with psychotic disorders these symptoms are more likely to improve. Social factors such as unemployment and isolation could hamper suicidality and hostility reduction and may be targeted in interventions to reduce risk in involuntarily admitted patients

Current and future diagnostic and treatment strategies for patients with invasive lobular breast cancer.

BACKGROUND: Invasive lobular breast cancer (ILC) is the second most common type of breast cancer after invasive breast cancer of no special type (NST), representing up to 15% of all breast cancers. DESIGN: Latest data on ILC are presented, focusing on diagnosis, molecular make-up according to the European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets (ESCAT) guidelines, treatment in the early and metastatic setting and ILC-focused clinical trials. RESULTS: At the imaging level, magnetic resonance imaging-based and novel positron emission tomography/computed tomography-based techniques can overcome the limitations of currently used imaging techniques for diagnosing ILC. At the pathology level, E-cadherin immunohistochemistry could help improving inter-pathologist agreement. The majority of patients with ILC do not seem to benefit as much from (neo-)adjuvant chemotherapy as patients with NST, although chemotherapy might be required in a subset of high-risk patients. No differences in treatment efficacy are seen for anti-human epidermal growth factor receptor 2 (HER2) therapies in the adjuvant setting and cyclin-dependent kinases 4 and 6 inhibitors in the metastatic setting. The clinical utility of the commercially available prognostic gene expression-based tests is unclear for patients with ILC. Several ESCAT alterations differ in frequency between ILC and NST. Germline BRCA1 and PALB2 alterations are less frequent in patients with ILC, while germline CDH1 (gene coding for E-cadherin) alterations are more frequent in patients with ILC. Somatic HER2 mutations are more frequent in ILC, especially in metastases (15% ILC versus 5% NST). A high tumour mutational burden, relevant for immune checkpoint inhibition, is more frequent in ILC metastases (16%) than in NST metastases (5%). Tumours with somatic inactivating CDH1 mutations may be vulnerable for treatment with ROS1 inhibitors, a concept currently investigated in early and metastatic ILC. CONCLUSION: ILC is a unique malignancy based on its pathological and biological features leading to differences in diagnosis as well as in treatment response, resistance and targets as compared to NST

Increasing incidence of skin disorders in children? A comparison between 1987 and 2001

BACKGROUND: The increasing proportion of skin diseases encountered in general practice represents a substantial part of morbidity in children. Only limited information is available about the frequency of specific skin diseases. We aimed to compare incidence rates of skin diseases in children in general practice between 1987 and 2001. METHODS: We used data on all children aged 0–17 years derived from two consecutive surveys performed in Dutch general practice in 1987 and 2001. Both surveys concerned a longitudinal registration of GP consultations over 12 months. Each disease episode was coded according to the International Classification of Primary Care. Incidence rates of separate skin diseases were calculated by dividing all new episodes for each distinct ICPC code by the average study population at risk. Data were stratified for socio-demographic characteristics. RESULTS: The incidence rate of all skin diseases combined in general practice decreased between 1987 and 2001. Among infants the incidence rate increased. Girls presented more skin diseases to the GP. In the southern part of the Netherlands children consulted their GP more often for skin diseases compared to the northern part. Children of non-Western immigrants presented relatively more skin diseases to the GP. In general practice incidence rates of specific skin diseases such as impetigo, dermatophytosis and atopic dermatitis increased in 2001, whereas warts, contact dermatitis and skin injuries decreased. CONCLUSION: The overall incidence rate of all skin diseases combined in general practice decreased whereas the incidence rates of bacterial, mycotic and atopic skin diseases increased

Protein network analysis reveals selectively vulnerable regions and biological processes in FTD

Objective: The neuroanatomical profile of behavioral variant frontotemporal dementia (bvFTD) suggests a common biological etiology of disease despite disparate pathologic causes; we investigated the genetic underpinnings of this selective regional vulnerability to identify new risk factors for bvFTD. Methods: We used recently developed analytical techniques designed to address the limitations of genome-wide association studies to generate a protein interaction network of 63 bvFTD risk genes. We characterized this network using gene expression data from healthy and diseased human brain tissue, evaluating regional network expression patterns across the lifespan as well as the cell types and biological processes most affected in bvFTD. Results: We found that bvFTD network genes show enriched expression across the human lifespan in vulnerable neuronal populations, are implicated in cell signaling, cell cycle, immune function, and development, and are differentially expressed in pathologically confirmed frontotemporal lobar degeneration cases. Five of the genes highlighted by our differential expression analyses, BAIAP2, ERBB3, POU2F2, SMARCA2, and CDC37, appear to be novel bvFTD risk loci. Conclusions: Our findings suggest that the cumulative burden of common genetic variation in an interacting protein network expressed in specific brain regions across the lifespan may influence susceptibility to bvFTD

Genetic variation across RNA metabolism and cell death gene networks is implicated in the semantic variant of primary progressive aphasia

The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by neurodegeneration and progressive loss of semantic knowledge. Unlike many other forms of frontotemporal lobar degeneration (FTLD), svPPA has a highly consistent underlying pathology composed of TDP-43 (a regulator of RNA and DNA transcription metabolism). Previous genetic studies of svPPA are limited by small sample sizes and a paucity of common risk variants. Despite this, svPPA's relatively homogenous clinicopathologic phenotype makes it an ideal investigative model to examine genetic processes that may drive neurodegenerative disease. In this study, we used GWAS metadata, tissue samples from pathologically confirmed frontotemporal lobar degeneration, and in silico techniques to identify and characterize protein interaction networks associated with svPPA risk. We identified 64 svPPA risk genes that interact at the protein level. The protein pathways represented in this svPPA gene network are critical regulators of RNA metabolism and cell death, such as SMAD proteins and NOTCH1. Many of the genes in this network are involved in TDP-43 metabolism. Contrary to the conventional notion that svPPA is a clinical syndrome with few genetic risk factors, our analyses show that svPPA risk is complex and polygenic in nature. Risk for svPPA is likely driven by multiple common variants in genes interacting with TDP-43, along with cell death,x` working in combination to promote neurodegeneration

Metallothionein expression correlates with metastatic and proliferative potential in squamous cell carcinoma of the oesophagus

The goal of this study is to clarify whether the expression of metallothionein (MT) could affect the prognosis and the metastatic potential of squamous cell carcinoma (SCC) of the oesophagus. In paraffin-embedded specimens resected from 57 patients, MT mRNA and protein expressions were detected by in situ hybridization and immunohistochemistry respectively. The expression of MT was evaluated in respect of clinicopathologic variables and patients' survival. MT mRNA expression was significantly associated with the proportion of lymph node metastasis (71% in MT mRNA-positive tumours vs 42% in MT mRNA-negative tumours; P = 0.0343) and that of distant metastasis (29% in MT mRNA-positive tumours vs 5% in MT mRNA-negative tumours; P = 0.0452). In respect of MT protein expression, the frequency of distant metastasis was more common in MT-positive tumours than in MT-negative tumours (30% in MT-positive tumours vs 8% in MT-negative tumours; P = 0.0446). The survival rate of the patients with MT protein-negative tumours was significantly better than that of the patients with MT protein-positive tumours (P = 0.0340). There was a positive correlation between the expression of MT protein and that of proliferating cell nuclear antigen (P = 0.0018). Therefore, we conclude that MT expression, both at the mRNA and protein levels, may be a potential marker predicting metastatic and proliferative activities of oesophageal SCC. © 1999 Cancer Research Campaig

Astrocytes grown in Alvetex® 3 dimensional scaffolds retain a non-reactive phenotype

yesProtocols which permit the extraction of primary astrocytes from either embryonic or postnatal mice are well established however astrocytes in culture are different to those in the mature CNS. Three dimensional (3D) cultures, using a variety of scaffolds may enable better phenotypic properties to be developed in culture. We present data from embryonic (E15) and postnatal (P4) murine primary cortical astrocytes grown on coated coverslips or a 3D polystyrene scaffold, Alvetex. Growth of both embryonic and postnatal primary astrocytes in the 3D scaffold changed astrocyte morphology to a mature, protoplasmic phenotype. Embryonic-derived astrocytes in 3D expressed markers of mature astrocytes, namely the glutamate transporter GLT-1 with low levels of the chondroitin sulphate proteoglycans, NG2 and SMC3. Embroynic astrocytes derived in 3D show lower levels of markers of reactive astrocytes, namely GFAP and mRNA levels of LCN2, PTX3, Serpina3n and Cx43. Postnatal-derived astrocytes show few protein changes between 2D and 3D conditions. Our data shows that Alvetex is a suitable scaffold for growth of astrocytes, and with appropriate choice of cells allows the maintenance of astrocytes with the properties of mature cells and a non-reactive phenotype.BBSR

The contribution of office work to sedentary behaviour associated risk

Background: Sedentary time has been found to be independently associated with poor health and mortality. Further, a greater proportion of the workforce is now employed in low activity occupations such as office work. To date, there is no research that specifically examines the contribution of sedentary work to overall sedentary exposure and thus risk. The purpose of the study was to determine the total exposure and exposure pattern for sedentary time, light activity and moderate/vigorous physical activity (MVPA) of office workers during work and non-work time.Methods: 50 office workers from Perth, Australia wore an Actical (Phillips, Respironics) accelerometer during waking hours for 7 days (in 2008–2009). Participants recorded wear time, waking hours, work hours and daily activities in an activity diary. Time in activity levels (as percentage of wear time) during work and non-work time were analysed using paired t-tests and Pearson’s correlations.Results: Sedentary time accounted for 81.8% of work hours (light activity 15.3% and MVPA 2.9%), which was significantly greater than sedentary time during non-work time (68.9% p 30 minutes) and significantly less brief duration (0–10 minutes) light intensity activity during work hours compared to non-work time (p < 0.001). Further, office workers had fewer breaks in sedentary time during work hours compared to non-work time (p < 0.001).Conclusions: Office work is characterised by sustained sedentary time and contributes significantly to overall sedentary exposure of office workers