Targeting Notch signaling in autoimmune and lymphoproliferative disease.
Patients with autoimmune lymphoproliferative syndrome (ALPS) and systemic lupus erythematosis (SLE) have T-cell dysregulation and produce abnormal, activated T lymphocytes and an atypical peripheral T-cell population, termed double negative T cells (DNTs). T-cell functions, including DNT transition in T-cell development and T-cell activation, are critically dependent on Notch signaling. We hypothesized that inhibiting Notch signaling would be effective in ALPS and SLE by reducing the production of abnormal DNTs and by blocking aberrant T-cell activation. We tested this hypothesis using murine models of ALPS and SLE. Mice were randomized to treatment with the notch pathway inhibitor (gamma-secretase inhibitor), N-S-phenyl-glycine-t-butyl ester (DAPT), or vehicle control. Response to treatment was assessed by measurement of DNTs in blood and lymphoid tissue, by monitoring lymph node and spleen size with ultrasound, by quantifying cytokines by bead-array, by ELISA for total IgG and anti-double-stranded DNA (dsDNA) specific antibodies, and by histopathologic assessment for nephritis. We found a profound and statistically significant decrease in all disease parameters, comparing DAPT-treated mice to controls. Using a novel dosing schema, we avoided the reported toxicities of gamma-secretase inhibitors. Inhibiting the Notch signaling pathway may thus present an effective, novel, and well-tolerated treatment for autoimmune and lymphoproliferative diseases.


The modular and integrative functional architecture of the human brain.
Network-based analyses of brain imaging data consistently reveal distinct modules and connector nodes with diverse global connectivity across the modules. How discrete the functions of modules are, how dependent the computational load of each module is to the other modules' processing, and what the precise role of connector nodes is for between-module communication remains underspecified. Here, we use a network model of the brain derived from resting-state functional MRI (rs-fMRI) data and investigate the modular functional architecture of the human brain by analyzing activity at different types of nodes in the network across 9,208 experiments of 77 cognitive tasks in the BrainMap database. Using an author-topic model of cognitive functions, we find a strong spatial correspondence between the cognitive functions and the network's modules, suggesting that each module performs a discrete cognitive function. Crucially, activity at local nodes within the modules does not increase in tasks that require more cognitive functions, demonstrating the autonomy of modules' functions. However, connector nodes do exhibit increased activity when more cognitive functions are engaged in a task. Moreover, connector nodes are located where brain activity is associated with many different cognitive functions. Connector nodes potentially play a role in between-module communication that maintains the modular function of the brain. Together, these findings provide a network account of the brain's modular yet integrated implementation of cognitive functions.


CD4 count remission hypothesis in patients with inflammatory bowel disease and human immunodeficiency virus infection: a systematic review of the literature.
Patients with inflammatory bowel disease (IBD) and human immunodeficiency virus (HIV) infection have shown controversial data concerning the remission hypothesis of IBD due to CD4 count depletion caused by HIV. The aim of our systematic review was to investigate the hypothesis whether low CD4 count due to HIV is related to IBD remission. We systematically searched PubMed for studies reporting on HIV infection in IBD patients. We extracted characteristics of IBD and HIV disease course and CD4 counts. Thirteen papers (2 case-control studies, 2 case series, and 9 case reports) were eligible including 47 patients with IBD and HIV infection (43 male; 27 with Crohn's disease, 19 with ulcerative colitis, and 1 with indeterminate colitis). The IBD diagnosis criteria were heterogeneous among studies. Remission was reported for patients with IBD and HIV infection in 5 studies, including 4 case-control or case series and 1 case report. Four of 5 studies with IBD cases reported remission related to the CD4 count remission hypothesis but only 2 of them explicitly reported the CD4 count cut-off point (500 cells/μL and 200 cells/mm3 respectively). On the contrary, 7 case reports described an active IBD course or relapse even in patients under immunosuppression. Current literature cannot support or reject the CD4 count remission hypothesis in IBD patients with HIV infection. Prospective studies using uniform criteria on IBD and HIV disease course and CD4 counts are needed.


Glucose uptake is limiting in T cell activation and requires CD28-mediated Akt-dependent and independent pathways.
T cell activation potently stimulates cellular metabolism to support the elevated energetic and biosynthetic demands of growth, proliferation, and effector function. We show that glucose uptake is limiting in T cell activation and that CD28 costimulation is required to allow maximal glucose uptake following TCR stimulation by up-regulating expression and promoting the cell surface trafficking of the glucose transporter Glut1. Regulation of T cell glucose uptake and Glut1 was critical, as low glucose prevented appropriate T cell responses. Additionally, transgenic expression of Glut1 augmented T cell activation, and led to accumulation of readily activated memory-phenotype T cells with signs of autoimmunity in aged mice. To further examine the regulation of glucose uptake, we analyzed CD28 activation of Akt, which appeared necessary for maximal glucose uptake of stimulated cells and which we have shown can promote Glut1 cell surface trafficking. Consistent with a role for Akt in Glut1 trafficking, transgenic expression of constitutively active myristoylated Akt increased glucose uptake of resting T cells, but did not alter Glut1 protein levels. Therefore, CD28 appeared to promote Akt-independent up-regulation of Glut1 and Akt-dependent Glut1 cell surface trafficking. In support of this model, coexpression of Glut1 and myristoylated Akt transgenes resulted in a synergistic increase in glucose uptake and accumulation of activated T cells in vivo that were largely independent of CD28. Induction of Glut1 protein and Akt regulation of Glut1 trafficking are therefore separable functions of CD28 costimulation that cooperate to promote glucose metabolism for T cell activation and proliferation.


Public acceptability of nudging and taxing to reduce consumption of alcohol, tobacco, and food: A population-based survey experiment.
There is growing evidence for the effectiveness of choice architecture or 'nudge' interventions to change a range of behaviours including the consumption of alcohol, tobacco and food. Public acceptability is key to implementing these and other interventions. However, few studies have assessed public acceptability of these interventions, including the extent to which acceptability varies with the type of intervention, the target behaviour and with evidence of intervention effectiveness. These were assessed in an online study using a between-participants full factorial design with three factors: Policy (availability vs size vs labelling vs tax) x Behaviour (alcohol consumption vs tobacco use vs high-calorie snack food consumption) x Evidence communication (no message vs assertion of policy effectiveness vs assertion and quantification of policy effectiveness [e.g., a 10% change in behaviour]). Participants (N = 7058) were randomly allocated to one of the 36 groups. The primary outcome was acceptability of the policy. Acceptability differed across policy, behaviour and evidence communication (all ps < .001). Labelling was the most acceptable policy (supported by 78%) and Availability the least (47%). Tobacco use was the most acceptable behaviour to be targeted by policies (73%) compared with policies targeting Alcohol (55%) and Food (54%). Relative to the control group (60%), asserting evidence of effectiveness increased acceptability (63%); adding a quantification to this assertion did not significantly increase this further (65%). Public acceptability for nudges and taxes to improve population health varies with the behaviour targeted and the type of intervention but is generally favourable. Communicating that these policies are effective can increase support by a small but significant amount, suggesting that highlighting effectiveness could contribute to mobilising public demand for policies. While uncertainty remains about the strength of public support needed, this may help overcome political inertia and enable action on behaviours that damage population and planetary health.


Prospective associations between children's depressive symptoms and peer victimization: The role of social helplessness.
Investigating precursors to peer victimization, a particularly damaging form of peer maltreatment, represents an important research objective. This study's purpose was to evaluate the hypothesis that social helplessness is one mechanism underlying the pathway from early depressive symptoms to subsequent peer victimization among preadolescents in the third through fifth grades (N = 230; 126 girls; Mage at recruitment = 9.48; SD = 0.68). We collected self-reports of depressive symptoms and peer victimization and teacher reports of social helplessness in the fall of 2015 or 2016 (T1) and at two subsequent time points (T2 and T3) separated by 6-month lags. Results from a random intercepts cross-lagged panel model provided evidence for our hypothesized model in which T2 social helplessness partially mediated the effect of T1 depressive symptoms on T3 peer victimization. Findings underscore the importance of school-based prevention and youth development programmes that promote social-emotional learning for youth who are symptomatic for depression. Statement of contribution What is already known on the subject? Children's depressive symptoms and interpersonal dysfunction are related in a transactional way. Children who are symptomatic for depression tend to exhibit social-behavioural deficits. Depression-linked, social-behavioural deficits are associated with relationship disturbances. What does this study add? Children's socially helpless behaviour mediated the contribution of depressive symptoms to subsequent peer victimization. Depressive symptoms predicted, and were predicted by, socially helpless behaviour. Socially helpless behaviour increased risk for, but did not result from, peer victimization.


An AAV-CRISPR/Cas9 strategy for gene editing across divergent rodent species: Targeting neural oxytocin receptors as a proof of concept.
A major issue in neuroscience is the poor translatability of research results from preclinical studies in animals to clinical outcomes. Comparative neuroscience can overcome this barrier by studying multiple species to differentiate between species-specific and general mechanisms of neural circuit functioning. Targeted manipulation of neural circuits often depends on genetic dissection, and use of this technique has been restricted to only a few model species, limiting its application in comparative research. However, ongoing advances in genomics make genetic dissection attainable in a growing number of species. To demonstrate the potential of comparative gene editing approaches, we developed a viral-mediated CRISPR/Cas9 strategy that is predicted to target the oxytocin receptor (Oxtr) gene in >80 rodent species. This strategy specifically reduced OXTR levels in all evaluated species (n = 6) without causing gross neuronal toxicity. Thus, we show that CRISPR/Cas9-based tools can function in multiple species simultaneously. Thereby, we hope to encourage comparative gene editing and improve the translatability of neuroscientific research.


Pre-emptive therapy against cytomegalovirus (CMV) disease guided by CMV antigenemia assay after allogeneic hematopoietic stem cell transplantation: a single-center experience in Japan.
From April 1998 to March 2000, a cytomegalovirus (CMV) antigenemia-guided pre-emptive approach for CMV disease was evaluated in 77 adult patients who received allogeneic hematopoietic stem cell transplantation at the National Cancer Center Hospital. A CMV antigenemia assay was performed at least once a week after engraftment. High-level antigenemia was defined as a positive result with 10 or more positive cells per 50 000 cells and low-level antigenemia was defined as less than 10 positive cells. Among the 74 patients with initial engraftment, 51 developed positive antigenemia. Transplantation from alternative donors and the development of grade II-IV GVHD were independent risk factors for positive antigenemia. Ganciclovir was administered as pre-emptive therapy in 39 patients in a risk-adapted manner. None of the nine low-risk patients with low-level antigenemia as their initial positive result developed high-level antigenemia even though ganciclovir was withheld. Only one patient developed early CMV disease (hepatitis) during the study period. CMV antigenemia resolved in all but two cases, in whom ganciclovir was replaced with foscarnet. In eight patients, however, the neutrophil count decreased to 0.5 x 10(9)/l or less after starting ganciclovir, including three with documented infections and two with subsequent secondary graft failure. The total amount of ganciclovir and possibly the duration of high-dose ganciclovir might affect the incidence of neutropenia. We concluded that antigenemia-guided pre-emptive therapy with a decreased dose of ganciclovir and response-oriented dose adjustment might be appropriate to decrease the toxicity of ganciclovir without increasing the risk of CMV disease.


Effects of alcohol on food and energy intake in human subjects: evidence for passive and active over-consumption of energy.
The effects of alcohol on food and energy intake in human subjects have been the subject of a number of controlled studies recently. Unlike the evidence for other macronutrients, there is minimal evidence for any compensatory reduction in food intake in response to energy ingested as alcohol. In contrast, all studies testing intake within 1 h of preload ingestion report a higher intake of food following alcohol relative to energy-matched controls, although this short-term stimulatory effect is not evident if the test meal is delayed beyond 1 h. This time-course suggests that short-term stimulation of appetite may be mediated by the pharmacological action of alcohol on the appetite control system, either through enhanced orosensory reward or impaired satiety. In the long term, energy ingested as alcohol is additive to energy from other sources, suggesting that moderate alcohol consumption results in long-term passive over-consumption alongside short-term active over-consumption of energy through appetite stimulation. Despite the consistency of enhanced energy intake after moderate alcohol, evidence of an association between alcohol in the diet and obesity remains contentious, although the most recent results suggest that alcohol intake correlates with BMI. Future research needs to address this issue and clarify the mechanisms underlying appetite stimulation by alcohol.


PG490-88, a derivative of triptolide, blocks bleomycin-induced lung fibrosis.
In this study we evaluate the antifibrotic properties of PG-490-88, a water-soluble derivative of triptolide. Triptolide is an oxygenated diterpene that is derived from a traditional Chinese herb that has potent immunosuppressive and antitumor activity. We used the intratracheal bleomycin mouse model and found that PG490-88 inhibits fibrosis in the bleomycin group when given the same day or 5 days after bleomycin. PG490-88 also markedly reduced the number of myofibroblasts in the bleomycin treatment group. An enzyme-linked immunosorbent assay of transforming growth factor (TGF)-beta in the bronchoalveolar lavage fluid showed a significant decrease in TGF-beta in the PG490-88-treated groups compared to the bleomycin-treated group. Additionally, triptolide blocked bleomycin-induced increase in TGF-beta mRNA in cultured normal human lung fibroblasts. The efficacy of PG490-88 when administered late after bleomycin installation suggests a potential role in the treatment of idiopathic pulmonary fibrosis.


Vibrio cholerae O139 synonym bengal is closely related to Vibrio cholerae El Tor but has important differences.
Although Vibrio cholerae O139 synonym Bengal strains, from the current epidemics in India and Bangladesh, are closely related to seventh-pandemic strains, as shown by multilocus enzyme electrophoresis, Bengal strains are encapsulated and portions of the O1 antigen biosynthetic complex genes found in O1 strains are altered or lacking. Encapsulated Bengal strains showed resistance to killing by normal human serum. The presence of the capsule suggests the potential for bloodstream invasion in susceptible hosts and has profound implications for vaccine development.


Motor activity during searching and walking movements of cockroach legs.
1. Rhythmic motor activity may be recorded in the legs of cockroaches during the execution of several different types of behaviour that involve leg movements. It was examined in detail during searching and walking. 2. During walking, motor activity always consisted of a series of bursts separated by silent periods. During searching, it was usually continual, but modulated in frequency. 3. Sometimes, the motor pattern recorded from a searching leg was burst-like rather than modulated. In these cases, it could nevertheless be reliably distinguished from the motor pattern recorded during walking by a simple analysis of the burst pattern. 4. An analysis of the motor pattern recorded during righting indicated that this pattern was more like that for walking than that for searching. Therefore, searching is not simply walking that lacks certain periodic sensory input due to leg contact with the ground. 5. It is concluded that walking and searching can be reliably distinguished from one another on the basis of an analysis of a record of motor activity in a single leg muscle only. An ability to distinguish between similar types of behaviour on the basis of the motor pattern may prove useful in a variety of experiments.


Effects of off-pump versus on-pump coronary surgery on reversible and irreversible myocardial injury: a randomized trial using cardiovascular magnetic resonance imaging and biochemical markers.
There is biochemical evidence that off-pump coronary artery bypass grafting (OPCABG) reduces myocardial injury compared with the use of cardiopulmonary bypass (ONCABG), but the functional significance of this is uncertain. We hypothesized that OPCABG surgery would result in reduced postoperative reversible (stunning) and irreversible myocardial injury, as assessed by cardiovascular MRI (CMRI). In a single-center randomized trial, 60 patients undergoing multivessel total arterial revascularization were randomly assigned: 30 to OPCABG and 30 to ONCABG. Patients underwent preoperative and early postoperative cine MRI for assessment of global left ventricular function, and contrast-enhanced CMRI for assessment of irreversible myocardial injury. Serial troponin I measurements were obtained perioperatively and correlated with the CMRI findings. The mean preoperative cardiac index was similar in the 2 surgical groups (2.9+/-0.7 ONCABG; 2.9+/-0.8 OPCABG; P=0.9). After surgery, the cardiac index was significantly higher in the OPCABG group (2.7+/-0.6 ONCABG; 3.2+/-0.8 OPCABG; P=0.04). New irreversible myocardial injury was similar in incidence (36% ONCABG; 44% OPCABG; P=0.8) and magnitude (6.3+/-3.6 g ONCABG; 6.8+/-4.0 g OPCABG; P=0.9) across the 2 groups. The median area-under-the-curve (AUC) troponin I values were significantly larger in the ONCABG group (182 versus 135 microg/L; P=0.02). There was a moderate correlation between the troponin I AUC values and mean mass of new myocardial hyperenhancement (r(2)=0.4; P=0.008). OPCABG results in significantly better left ventricular function early after surgery but does not reduce the incidence or extent of irreversible myocardial injury.


Photothermal treatment of glioma; an in vitro study of macrophage-mediated delivery of gold nanoshells.
One of the major factors that limits the treatment effectiveness for gliomas is the presence of the blood-brain barrier (BBB) which protects infiltrating glioma cells from the effects of anti-cancer agents. Circulating monocytes/macrophages (Ma) have a natural ability to traverse the intact and compromised BBB and loaded with anti cancer agents could be used as vectors to target tumors and surrounding tumor infiltrated tissue. Nanoshells (NS) are composed of a dielectric core (silica) coated with an ultrathin gold layer which converts absorbed near-infrared light (NIR) to heat with an extremely high efficacy and stability. We have investigated the effects of exposure to laser NIR on multicell human glioma spheroids infiltrated with empty (containing no nanoshells) or nanoshell loaded macrophages. Our results demonstrated that; (1) macrophages could efficiently take up bare or coated (PEGylated) gold NS: (2) NS loaded macrophages infiltrated into glioma spheroids to the same or, in some cases, to a greater degree than empty Ma; (3) NIR laser irradiation of spheroids incorporating NS loaded macrophages resulted in complete growth inhibition in an irradiance dependent manner, and (4) spheroids infiltrated with empty macrophages had growth curves identical to untreated control cultures. The results of this study provide proof of concept for the use of macrophages as a delivery vector of NS into gliomas for photothermal ablation and open the possibility of developing such regimens for patient treatment.


A unified framework for cross-modality multi-atlas segmentation of brain MRI.
Multi-atlas label fusion is a powerful image segmentation strategy that is becoming increasingly popular in medical imaging. A standard label fusion algorithm relies on independently computed pairwise registrations between individual atlases and the (target) image to be segmented. These registrations are then used to propagate the atlas labels to the target space and fuse them into a single final segmentation. Such label fusion schemes commonly rely on the similarity between intensity values of the atlases and target scan, which is often problematic in medical imaging - in particular, when the atlases and target images are obtained via different sensor types or imaging protocols. In this paper, we present a generative probabilistic model that yields an algorithm for solving the atlas-to-target registrations and label fusion steps simultaneously. The proposed model does not directly rely on the similarity of image intensities. Instead, it exploits the consistency of voxel intensities within the target scan to drive the registration and label fusion, hence the atlases and target image can be of different modalities. Furthermore, the framework models the joint warp of all the atlases, introducing interdependence between the registrations. We use variational expectation maximization and the Demons registration framework in order to efficiently identify the most probable segmentation and registrations. We use two sets of experiments to illustrate the approach, where proton density (PD) MRI atlases are used to segment T1-weighted brain scans and vice versa. Our results clearly demonstrate the accuracy gain due to exploiting within-target intensity consistency and integrating registration into label fusion.


Increased white matter fibre dispersion and lower IQ scores in adults born preterm.
Preterm birth has been associated with altered microstructural properties of the white matter and lower cognitive ability in childhood and adulthood. Due to methodological limitations of the diffusion tensor model, it is not clear whether alterations in myelination or variation in fibre orientation are driving these differences. Novel models applied to multi-shell diffusion imaging have been used to disentangle these effects, but to date this has not been used to study the preterm brain in adulthood. This study investigated whether novel advanced diffusion MRI metrics such as microscopic anisotropy and orientation dispersion are altered in adults born preterm, and whether this was associated with cognitive performance. Seventy-two preterm born participants (<37 weeks gestational age) were recruited from a 1982-1984 cohort (33 males, mean age 33.5 ± 1.0 years). Seventy-two term born (>37 weeks gestational age) controls (34 males, mean age 30.9 ± 4.0 years) were recruited from the general population. Tensor FA was calculated with FSL, while microscopic FA and orientation dispersion entropy (ODE) were estimated using the Spherical Mean Technique (SMT). Estimated Full Scale IQ (FSIQ), Verbal Comprehension Index (VCI) and Perceptual Reasoning Index (PRI) were obtained from the WASI-II (abbreviated) IQ test. Voxel-wise comparisons using FSL's tract-based spatial statistics were performed to test between-group differences in diffusion MRI metrics as well as within-group associations of diffusion MRI metrics and IQ outcomes. The preterm group had significantly lower FSIQ, VCI and PRI scores. Preterm subjects demonstrated widespread decreases in ODE reflecting increased fibre dispersion, but no differences in microscopic FA. Tensor FA was increased in a small area in the anterior corona radiata. Lower FA values in the preterm population were associated with lower FSIQ and PRI scores. An increase in fibre dispersion in white matter and lower IQ scores after preterm birth exist in adulthood. Advanced diffusion MRI metrics such as the orientation dispersion entropy can be used to monitor white matter alterations across the lifespan in preterm born individuals. Although not significantly different between preterm and term groups, tensor FA values in the preterm group were associated with cognitive outcome.


Durable defense: robust and varied attachment of non-leaching poly"-onium" bactericidal coatings to reactive and inert surfaces.
Developing antimicrobial coatings to eliminate biotic contamination is a critical need for all surfaces, including medical, industrial, and domestic materials. The wide variety of materials used in these fields, from natural polymers to metals, require coatings that not only are antimicrobial, but also contain different surface chemistries for covalent immobilization. Alkyl "-onium" salts are potent biocides that have defied bacterial resistance mechanisms when confined to an interface. In this feature article, we highlight the various methods used to covalently immobilize bactericidal polymers to different surfaces and further examine the mechanistic aspects of biocidal action with these surface bound poly"-onium" salts.


Cat on a Hot Tin Roof: Mechanical Testing of Models of Tourniquets After Environmental Exposure.
The purpose of the present study was to mechanically assess models of emergency tourniquet after 18 months of environmental exposure to weather to better understand risk of component damage. An experiment was designed to test tourniquet performance on a manikin thigh. Three tourniquet models were assessed: Special Operations Forces Tactical Tourniquet Wide, Ratcheting Medical Tourniquet, and Combat Application Tourniquet. Unexposed tourniquets formed a control group stored in a laboratory; exposed tourniquets were placed outdoors on a metal roof for 18 months in San Antonio, Texas. Two users, a military cadet and a scientist, made 300 assessments in total. Assessment included major damage (yes-no), effectiveness (hemorrhage control, yes-no), casualty survival (alive-dead), time to stop bleeding, pressure, and blood loss. Time, pressure, and blood loss were reported in tests with effectiveness. Exposed devices had worse results than unexposed devices for major damage (3% [4/150] versus 0% [0/150]; ρ = .018), effectiveness (89% versus 99%; ρ = .002), and survival of casualties (89% versus 100%; ρ < .001). In tests for effectiveness, exposed devices had worse results than unexposed devices for time to stop bleeding (29 seconds versus 26 seconds; ρ = .01) and pressure (200mmHg versus 204mmHg; ρ = .03, respectively), but blood loss volume did not differ significantly. Compared with unexposed control devices, environmentally exposed tourniquets had worse results in tests of component damage, effectiveness, and casualty survival.


Redundant and opposing functions of two tyrosine kinases, Btk and Lyn, in mast cell activation.
Protein-tyrosine kinases play crucial roles in mast cell activation through the high-affinity IgE receptor (FcepsilonRI). In this study, we have made the following observations on growth properties and FcepsilonRI-mediated signal transduction of primary cultured mast cells from Btk-, Lyn-, and Btk/Lyn-deficient mice. First, Lyn deficiency partially reversed the survival effect of Btk deficiency. Second, FcepsilonRI-induced degranulation and leukotriene release were almost abrogated in Btk/Lyn doubly deficient mast cells while singly deficient cells exhibited normal responses. Tyrosine phosphorylation of cellular proteins including phospholipases C-gamma1 and C-gamma2 was reduced in Btk/Lyn-deficient mast cells. Accordingly, FcepsilonRI-induced elevation of intracellular Ca2+ concentrations and activation of protein kinase Cs were blunted in the doubly deficient cells. Third, in contrast, Btk and Lyn demonstrated opposing roles in cytokine secretion and mitogen-activated protein kinase activation. Lyn-deficient cells exhibited enhanced secretion of TNF-alpha and IL-2 apparently through the prolonged activation of extracellular signal-related kinases and c-Jun N-terminal kinase. Potentially accounting for this phenomenon and robust degranulation in Lyn-deficient cells, the activities of protein kinase Calpha and protein kinase CbetaII, low at basal levels, were enhanced in these cells. Fourth, cytokine secretion was severely reduced and c-Jun N-terminal kinase activation was completely abrogated in Btk/Lyn-deficient mast cells. The data together demonstrate that Btk and Lyn are involved in mast cell signaling pathways in distinctly different ways, emphasizing that multiple signal outcomes must be evaluated to fully understand the functional interactions of individual signaling components.


Physical Activity Characteristics across GOLD Quadrants Depend on the Questionnaire Used.
The GOLD multidimensional classification of COPD severity combines the exacerbation risk with the symptom experience, for which 3 different questionnaires are permitted. This study investigated differences in physical activity (PA) in the different GOLD quadrants and patient's distribution in relation to the questionnaire used. 136 COPD patients (58±21% FEV1 predicted, 34F/102M) completed COPD assessment test (CAT), clinical COPD questionnaire (CCQ) and modified Medical Research Council (mMRC) questionnaire. Exacerbation history, spirometry and 6MWD were collected. PA was objectively measured for 2 periods of 1 week, 6 months apart, in 5 European centres; to minimise seasonal and clinical variation the average of these two periods was used for analysis. GOLD quadrants C+D had reduced PA compared with A+B (3824 [2976] vs. 5508 [4671] steps.d-1, p<0.0001). The choice of questionnaire yielded different patient distributions (agreement mMRC-CAT κ = 0.57; CCQ-mMRC κ = 0.71; CCQ-CAT κ = 0.72) with different clinical characteristics. PA was notably lower in patients with an mMRC score ≥2 (3430 [2537] vs. 5443 [3776] steps.d-1, p <0.001) in both the low and high risk quadrants. Using different questionnaires changes the patient distribution and results in different clinical characteristics. Therefore, standardization of the questionnaire used for classification is critical to allow comparison of different studies using this as an entry criterion. ClinicalTrials.gov NCT01388218.


Weakness of will, akrasia, and the neuropsychiatry of decision making: an interdisciplinary perspective.
This article focuses on both daily forms of weakness of will as discussed in the philosophical debate (usually referred to as akrasia) and psychopathological phenomena as impairments of decision making. We argue that both descriptions of dysfunctional decision making can be organized within a common theoretical framework that divides the decision making process in three different stages: option generation, option selection, and action initiation. We first discuss our theoretical framework (building on existing models of decision-making stages), focusing on option generation as an aspect that has been neglected by previous models. In the main body of this article, we review how both philosophy and neuropsychiatry have provided accounts of dysfunction in each decision-making stage, as well as where these accounts can be integrated. Also, the neural underpinnings of dysfunction in the three different stages are discussed. We conclude by discussing advantages and limitations of our integrative approach.


Low microsatellite instability is associated with poor prognosis in stage C colon cancer.
The significance of low microsatellite instability (MSI-L) in colorectal cancer is poorly understood. No clear biologic distinction has been found between MSI-L and microsatellite stable (MSS) colorectal cancer, and these two phenotypes are usually combined when analyzed against the well-defined high MSI (MSI-H) phenotype. Evidence is emerging that an O(6)-methylguanine DNA methyltransferase (MGMT) gene defect is associated with MSI-L. Therefore, to further define this phenotype, we undertook a detailed analysis of the prognostic significance of MSI-L and loss of MGMT expression in colon cancer. The study cohort was 183 patients with clinicopathologic stage C colon cancer who had not received adjuvant therapy. We analyzed MSI status, MGMT, and mismatch repair protein expression, as well as MGMT and p16 promoter hypermethylation. We showed that MSI-L defines a group of patients with poorer survival (P = .026) than MSS patients, and that MSI-L was an independent prognostic indicator (P = .005) in stage C colon cancer. Loss of MGMT protein expression was associated with the MSI-L phenotype but was not a prognostic factor for overall survival in colon cancer. p16 methylation was significantly less frequent in MSI-L than in MSI-H and MSS tumors and was not associated with survival. MSI-L characterizes a distinct subgroup of stage C colon cancer patients, including the MSI-L subset of proximal colon cancer, who have a poorer outcome. Neither the MGMT defect nor p16 methylation are likely to contribute to the worse prognosis of the MSI-L phenotype.


Phylogenetic variation in the tolerance and uptake of organic contaminants.
An investigation into the phylogenetic variation of plant tolerance and the root and shoot uptake of organic contaminants was undertaken. The aim was to determine if particular families or genera were tolerant of or accumulated organic pollutants. Data were collected from sixty-nine studies. The variation between experiments was accounted for using a residual maximum likelihood analysis to approximate means for individual taxa. A nested ANOVA was subsequently used to determine differences at a number of differing phylogenetic levels. Significant differences were observed at a number of phylogenetic levels for the tolerance to TPH, the root concentration factor and the shoot concentration factor. There was no correlation between the uptake of organic pollutants and that of heavy metals. The data indicate that plant phylogeny is an important influence on both the plant tolerance and uptake of organic pollutants. If this study can be expanded, such information can be used when designing plantings for phytoremediation or risk reduction during the restoration of contaminated sites.


Web-PACS for multicenter clinical trials.
Medical information systems are not designed for clinical trials using clinical imaging. This paper presents a conceptual model for clinical trials based on medical imaging from two complementary points of view: a technical model and a business model. A Web information system (WIS) for supporting multicenter clinical trials has been designed to implement the proposed model. We show that our approach overcomes the actual limitations by facilitating medical image management in the context of clinical trials or cooperative research.


Highly efficient in-line magnetic domain wall injector.
We demonstrate a highly efficient and simple scheme for injecting domain walls into magnetic nanowires. The spin transfer torque from nanosecond long, unipolar, current pulses that cross a 90° magnetization boundary together with the fringing magnetic fields inherently prevalent at the boundary, allow for the injection of single or a continual stream of domain walls. Remarkably, the currents needed for this "in-line" domain wall injection scheme are at least one hundred times smaller than conventional methods.


Protective effects of ibuprofen on testicular torsion/detorsion-induced ischemia/reperfusion injury in rats.
The aim of this study was to investigate the protective effect of ibuprofen on testicular torsion/detorsion-induced ischemia/reperfusion (I/R) injury. A total of 48 prepubertal male Wistar albino rats were divided into two models: early and late orchiectomy. Testicular torsion was created by rotating the right testis 720 degrees in a clockwise direction. The ischemia period was 5 h and orchiectomy was performed after 5 h of detorsion in the early orchiectomy model (EOM). In the late orchiectomy model (LOM), the ischemia period was 5 h and orchiectomy was performed after 7 days of detorsion. In the EOM, ibuprofen (70 mg/kg, po) was administrated only once, 40 min prior to detorsion. In the LOM, ibuprofen (70 mg/kg, po) was administered 40 min before detorsion, once daily for 7 days. Bilateral orchiectomy was performed in all groups to measure the tissue levels of malondialdehyde (MDA) and to microscopically investigate light and electrons. The presence of endothelial nitric oxide synthase (eNOS) activity was shown with immunohistochemical studies. Spermatogenesis and mean seminiferous tubule diameter (MSTD) were significantly decreased in ipsilateral and contralateral testis when both early and late I/R groups were compared to the sham groups. Furthermore, ibuprofen-treated animals showed an improved histological appearance in both models of testicular torsion. Ibuprofen treatment prevented lipid peroxidation resulting in decreased MDA accumulation in the testes of both models. After I/R, eNOS immunoreactivity was increased in the testicular tissues. Ibuprofen treatment decreased eNOS immunoreactivity in the germ cells of the tubules in the contralateral testes, but intense eNOS immunoreactivity was shown in the ipsilateral testes of the LOM. Electron microscopy of the testes of rats demonstrated that ibuprofen pretreatment was particularly effective in preventing the mitochondrial degeneration in both Sertoli and spermatid cells in the LOM. Because of its anti-inflammatory and antioxidant effects, ibuprofen pretreatment may have protective effects in the experimental testicular torsion/detorsion model in rats.


Danazol for unexplained subfertility.
The synthetic androgen Danazol, was developed in the 1970's as a treatment for endometriosis. Its use was soon advocated in women with unexplained subfertility. Two randomised trials were subsequently conducted to assess the effectiveness of danazol in this population. The objective of this review was to assess the effect of danazol on live birth rate in women with unexplained subfertility. We searched the Cochrane Menstrual Disorders and Sub-fertility Group's specialised register of trials (searched November , 2006) the Cochrane Register of Controlled Trials (The Cochrane Library, Issue 4, 2006), MEDLINE (1966-November 2006), EMBASE (1980 - November 2006) and reference lists of articles. Randomised trials of danazol compared with placebo or no treatment in women with unexplained subfertility. Data were extracted by two reviewers EH and GT. Two trials involving seventy-one women were included. There was no statistically significant difference in the live birth/ ongoing pregnancy rate between danazol and placebo at the end of treatment (OR 1.16, 95% CI 0.0 to 8.29; P=0.36) or at the end of follow-up (OR 2.41; 95% CI 0.59, 9.82; P=0.22). There was no significant difference in clinical pregnancies following treatment (OR 0.14, 95% CI 0.01, 2.26; P=0.17), however there were significantly more clinical pregnancies during the follow-up period in the danazol group compared with the placebo group (OR 3.15, 95%CI 0.98, 10.10; P<0.05). Multiple side effects were reported. Available data demonstrate no evidence of the benefit of danazol for unexplained subfertility. Although there is insufficient evidence to be certain of this, the need for contraception during treatment and the adverse effects and costs of danazol, make its use for this problem unwarranted. The increased pregnancy rate in the long term follow-up data may be attributable to additional therapies and did not influence the live birth/ongoing pregnancy data.


A reusable and naked-eye molecular probe with aggregation-induced emission (AIE) characteristics for hydrazine detection.
We report a fluorogenic probe for naked-eye sensing of hydrazine in solution and in the gaseous phase. The probe based on tetraphenylethylene (TPE) with aggregation-induced emission (AIE) characteristics shows OFF-ON fluorescence as observed by thin-layer chromatography (TLC) upon treatment with hydrazine. Specifically, the fluorescence of the probe was quenched due to the attached N[double bond, length as m-dash]N group, which can be reduced to -NH-NH- in the presence of hydrazine to turn on the fluorescence. The reduced intermediate can be easily oxidized in air to regenerate the original probe for recyclable usage. Both fluorometric and colorimetric readings were achieved by TLC with high sensitivity and excellent selectivity. This study thus represents a simple example of a reusable and naked-eye molecular probe for monitoring environmental hazards. Finally, the probe has also been applied to detect hydrazine in live cells.


Superlens in the time domain.
It has been predicted theoretically and demonstrated experimentally that a planar slab supporting surface plasmons or surface phonon polaritons can behave as a super lens. However, the resolution is limited by the losses of the slab. In this Letter, we point out that the resolution limit imposed by losses can be overcome by using time-dependent illumination.


Reliability and accuracy of differentiating pervasive developmental disorder subtypes.
To evaluate the ability of the DSM-IV criteria for the pervasive developmental disorders (PDD) to reliably and accurately differentiate PDD subtypes. The sample consisted of 143 children with various types of developmental disabilities. A diagnosis of PDD and PDD subtype was made by one clinician using information obtained from the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule. The raw data from the Autism Diagnostic Interview-Revised, clinical notes (excluding diagnostic opinion), Autism Diagnostic Observation Schedule, IQ, and other available data were independently assessed by three experienced raters, each of whom then made a separate, blind diagnosis. If there was any disagreement, a consensus best-estimate (CBE) diagnosis was made after discussion. To assess reliability, the agreement between the three raters was calculated using k. Accuracy was assessed by calculating the agreement between the clinician's diagnosis and the CBE and by calculating the error rates associated with the three raters using latent class analysis. The current DSM-IV criteria show good to excellent reliability for the diagnosis of PDD, Asperger's disorder (AsD), and autism, but they show poor reliability for the diagnosis of atypical autism. The clinician (compared to the CBE) had little difficulty differentiating PDD from non-PDD children and autism from AsD but had more difficulty identifying children with atypical autism. The latent class analysis also showed that the average error rates of the three raters for a differentiation of atypical autism from autism were unacceptably high. Although the psychometric properties of the current DSM-IV criteria for autism and AsD appear quite acceptable, there is likely to be a high rate of misclassification of children given a diagnosis of atypical autism.


The Hemostatic Changes in Active Pulmonary Tuberculosis.
Severe pulmonary tuberculosis (PTB) is sometimes complicated with deep venous thrombosis (DVT). We have examined the role of possible hemostat›c disturbance, which are predisposing factors for venous thrombosis in patients with PTB. Coagulation and platelet function tests have been studied in 40 patients with severe PTB and 40 healthy control volunteers before therapy and they were compared with 30th day results and controls. Analysis in patients with active PTB showed anemia, leucocytosis, thrombocytosis, elevation in plasma fibrinogen, factor VIII, plasminogen activator inhibitor 1 (PAI-1) with depressed antithrombin III (ATIII) and protein C (PC) levels. On the 30th day of treatment, anemia, leucocytosis and thrombocytsis were improved. Fibrinogen and factor VIII levels decreased to normal levels, PC and AT III levels increased to normal levels whereas there was no difference in PAI-1 levels. Platelet aggregation studies demonstrated increased platelet activation. Activated protein C resistance was not determined. DVT was not detected in patients during the follow up period. Decreased AT III, PC and elevated plasma fibrinogen levels and increased platelet aggregation appear to induce hypercoagilable state seen in PTB and improves with tretament.


pH-dependent toxicity of high aspect ratio ZnO nanowires in macrophages due to intracellular dissolution.
High-aspect ratio ZnO nanowires have become one of the most promising products in the nanosciences within the past few years with a multitude of applications at the interface of optics and electronics. The interaction of zinc with cells and organisms is complex, with both deficiency and excess causing severe effects. The emerging significance of zinc for many cellular processes makes it imperative to investigate the biological safety of ZnO nanowires in order to guarantee their safe economic exploitation. In this study, ZnO nanowires were found to be toxic to human monocyte macrophages (HMMs) at similar concentrations as ZnCl(2). Confocal microscopy on live cells confirmed a rise in intracellular Zn(2+) concentrations prior to cell death. In vitro, ZnO nanowires dissolved very rapidly in a simulated body fluid of lysosomal pH, whereas they were comparatively stable at extracellular pH. Bright-field transmission electron microscopy (TEM) showed a rapid macrophage uptake of ZnO nanowire aggregates by phagocytosis. Nanowire dissolution occurred within membrane-bound compartments, triggered by the acidic pH of the lysosomes. ZnO nanowire dissolution was confirmed by scanning electron microscopy/energy-dispersive X-ray spectrometry. Deposition of electron-dense material throughout the ZnO nanowire structures observed by TEM could indicate adsorption of cellular components onto the wires or localized zinc-induced protein precipitation. Our study demonstrates that ZnO nanowire toxicity in HMMs is due to pH-triggered, intracellular release of ionic Zn(2+) rather than the high-aspect nature of the wires. Cell death had features of necrosis as well as apoptosis, with mitochondria displaying severe structural changes. The implications of these findings for the application of ZnO nanowires are discussed.


Predictors of Falls and Fractures Leading to Hospitalization in People With Dementia: A Representative Cohort Study.
Investigate predictors of falls and fractures leading to hospitalization in a large cohort of people with dementia. A retrospective cohort study. People with diagnosed dementia between January 2007 and March 2013, aged >65 years, were assembled using data from the Maudsley Biomedical Research Centre Case Register, from 4 boroughs in London serving a population of 1.3 million people. Falls and/or fractures leading to hospitalization were ascertained from linked national records. Demographic data, cognitive test scores, medications, and symptom and functioning scores from Health of the Nation Outcome Scales (HoNOS65+) were modeled in multivariate survival analyses to identify predictors of falls and fractures. Of 8036 people with dementia (63.9% female), 2500 (31.1%, incidence rate 125.5 per 1000 person-years) had a fall during a mean follow-up of 2.5 years and 1437 (17.7%, incidence rate 65.5 per 1000 person-years) had a fracture. In multivariable models, significant predictors of falls were increased age, female gender, physical health problems, previous fall or fracture, vascular dementia vs Alzheimer's disease, higher neighborhood deprivation, noncohabiting status, and problems with living conditions. Ethnic minority status was protective of falls (eg, Caribbean/Asian ethnicity). Medications (including psychotropic and antipsychotics), neuropsychiatric symptoms, cognitive (Mini-Mental State Examination scores), or functional problems did not predict hospitalized falls. Predictors of fractures were similar to those predicting falls. Over an average of 2.5 years, a third of people with dementia had a fall leading to hospitalization, necessitating action in clinical practice. Clinicians should consider that besides established demographic and physical health-related factors, the risk of hospitalization due to a fall or fractures in dementia is largely determined by environmental and socioeconomic factors. Interestingly, our data suggest that neuropsychiatric symptoms, cognitive status, functioning, or pharmacotherapy were not associated with falls/fractures.


Trabecular bone histomorphometry in humans with Type 1 Diabetes Mellitus.
Patients with Type 1 Diabetes Mellitus (DM) have markedly increased risk of fracture, but little is known about abnormalities in bone microarchitecture or remodeling properties that might give insight into the pathogenesis of skeletal fragility in these patients. We report here a case-control study comparing bone histomorphometric and micro-CT results from iliac biopsies in 18 otherwise healthy subjects with Type 1 Diabetes Mellitus with those from healthy age- and sex-matched non-diabetic control subjects. Five of the diabetics had histories of low-trauma fracture. Transilial bone biopsies were obtained after tetracycline labeling. The biopsy specimens were fixed, embedded, and scanned using a desktop μCT at 16 μm resolution. They were then sectioned and quantitative histomorphometry was performed as previously described by Recker et al. [1]. Two sections, >250 μm apart, were read from the central part of each biopsy. Overall there were no significant differences between diabetics and controls in histomorphometric or micro-CT measurements. However, fracturing diabetics had structural and dynamic trends different from nonfracturing diabetics by both methods of analysis. In conclusion, Type 1 Diabetes Mellitus does not result in abnormalities in bone histomorphometric or micro-CT variables in the absence of manifest complications from the diabetes. However, diabetics suffering fractures may have defects in their skeletal microarchitecture that may underlie the presence of excess skeletal fragility.


A Framework for Developing the Structure of Public Health Economic Models.
A conceptual modeling framework is a methodology that assists modelers through the process of developing a model structure. Public health interventions tend to operate in dynamically complex systems. Modeling public health interventions requires broader considerations than clinical ones. Inappropriately simple models may lead to poor validity and credibility, resulting in suboptimal allocation of resources. This article presents the first conceptual modeling framework for public health economic evaluation. The framework presented here was informed by literature reviews of the key challenges in public health economic modeling and existing conceptual modeling frameworks; qualitative research to understand the experiences of modelers when developing public health economic models; and piloting a draft version of the framework. The conceptual modeling framework comprises four key principles of good practice and a proposed methodology. The key principles are that 1) a systems approach to modeling should be taken; 2) a documented understanding of the problem is imperative before and alongside developing and justifying the model structure; 3) strong communication with stakeholders and members of the team throughout model development is essential; and 4) a systematic consideration of the determinants of health is central to identifying the key impacts of public health interventions. The methodology consists of four phases: phase A, aligning the framework with the decision-making process; phase B, identifying relevant stakeholders; phase C, understanding the problem; and phase D, developing and justifying the model structure. Key areas for further research involve evaluation of the framework in diverse case studies and the development of methods for modeling individual and social behavior. This approach could improve the quality of Public Health economic models, supporting efficient allocation of scarce resources.


Fluorinated lamellar phases: structural characterisation and use as templates for highly ordered silica materials.
Highly ordered silica was synthesised by using a lamellar phase comprising the anionic fluorinated surfactant sodium perfluorooctanoate and the partially-fluorinated co-surfactant/oil 1H,1H,2H,2H-perfluorooctan-1-ol in water. The phase behaviour of this system was thoroughly analysed, and it was found that even low levels of the alcohol (<0.5 mol%) were sufficient to induce a phase change from normal micelles to a lamellar phase, rationalised as a result of geometric and electrostatic effects. The properties of these phases were compared to their hydrocarbon analogues, demonstrating the unique and valuable properties exhibited by fluorocarbons, directly related with the observed nanostructure. Small-angle neutron scattering was used to analyse the internal structure of the systems, providing information on the inter-lamellar spacing, bilayer thickness and membrane elasticity. The potential for these phases to act as shear-thinning lubricants was assessed using oscillatory rheology, obtaining shear-dependent viscosity along with storage and loss moduli.


Sex allocation, juvenile mortality and the costs imposed by offspring on parents and siblings.
Generally, sex-specific mortality is not expected to affect optimal patterns of sex allocation. Several authors have, however, made verbal arguments that this is not true if juvenile mortality is sex specific during the period of parental care. Here, we provide formal mathematical models exploring the effect of such mortality on optimal sex allocation. We confirm the prediction that biased production of the sex with higher mortality during care is favoured. Crucially, however, this is only true when juvenile mortality in the period of parental care frees up resources for their current/future siblings (i.e. the saved investment is transferable). Furthermore, we show that although optimal sex allocation is consistent with the theory of equal investment (as asserted by previous authors), thinking in terms of equal investment is not readily feasible in some scenarios. We also show that differences in early mortality overcome biased sex allocation such that the sex ratio at independence is generally, but not always, biased in the opposite direction from that at birth. Our models should prove useful to empiricists investigating the effect of sex-specific juvenile mortality and antagonistic sibling interactions on sex allocation.


Cervicofacial actinomycosis: a long forgotten infectious complication of immunosuppression - report of a case and review of the literature.
Actinomycosis is a rare chronic granulomatous infection caused by Gram-positive, non-acid-fast, anaerobic to microaerophilic bacteria.We report a case of cervicofacial actinomycosis in an 86-year-old woman undergoing immunosuppressive therapy with azathioprine and prednisone for rheumatoid arthritis. She underwent a dental treatment several months earlier. The diagnosis of culture-negative actinomycosis was based on histolopathology findings and the isolation of companion bacteria. The patient was treated with amoxicillin-clavulanic acid for 3 months, which produced complete clearance of her cervicofacial actinomycosis.Our case points out the pitfalls of diagnostic procedures in actinomycosis and the ability of this rare disease to mimic other medical conditions.


Carotid endarterectomy and carotid artery stenting utilization trends over time.
Carotid endarterectomy (CEA) has been the standard in atherosclerotic stroke prevention for over 2 decades. More recently, carotid artery stenting (CAS) has emerged as a less invasive alternative for revascularization. The purpose of this study was to investigate whether an increase in stenting parallels a decrease in endarterectomy, if there are specific patient factors that influence one intervention over the other, and how these factors may have changed over time. Using a nationally representative sample of US hospital discharge records, data on CEA and CAS procedures performed from 1998 to 2008 were obtained. In total, 253,651 cases of CEA and CAS were investigated for trends in utilization over time. The specific data elements of age, gender, payer source, and race were analyzed for change over the study period, and their association with type of intervention was examined by multiple logistic regression analysis. Rates of intervention decreased from 1998 to 2008 (P < 0.0001). Throughout the study period, endarterectomy was the much more widely employed procedure. Its use displayed a significant downward trend (P < 0.0001), with the lowest rates of intervention occurring in 2007. In contrast, carotid artery stenting displayed a significant increase in use over the study period (P < 0.0001), with the highest intervention rates occurring in 2006. Among the specific patient factors analyzed that may have altered utilization of CEA and CAS over time, the proportion of white patients who received intervention decreased significantly (P < 0.0001). In multivariate modeling, increased age, male gender, white race, and earlier in the study period were significant positive predictors of CEA use. Rates of carotid revascularization have decreased over time, although this has been the result of a reduction in CEA despite an overall increase in CAS. Among the specific patient factors analyzed, age, gender, race, and time were significantly associated with the utilization of these two interventions.


Effects of small changes of plasma vasopressin on subcutaneous and skeletal muscle blood flow in man.
The effect of vasopressin (AVP) on subcutaneous blood flow was studied by the 133Xenon wash-out method in 13 healthy subjects during three consecutive infusions of synthetic AVP, using increasing infusion rates. In seven of them, both subcutaneous and skeletal muscle blood flows were measured during the first infusion. The preinfusion, and infusion pAVP levels were 1.6 +/- 0.4, 3.4 +/- 0.4, 4.9 +/- 0.5 and 8.8 +/- 0.7 pg ml-1, respectively (mean +/- SE). The values are within the range normally found during dehydration. During the AVP infusions, the blood flow in subcutaneous tissues decreased 30-40% and the vascular resistance increased 60-80%. Neither heart rate nor blood pressure change significantly during the infusions. Plasma renin activity (PRA) decreased significantly. After cessation of the infusions, blood flow and vascular resistance rapidly returned to preinfusion values, while PRA increased very slowly. Skeletal muscle and subcutaneous tissues blood flows were found to be equally sensitive to small changes in the pAVP level. The present study has demonstrated that even minor increments of pAVP levels, as seen during dehydration, can significantly alter the regional blood flow in subcutaneous and skeletal muscle tissues in man.


Measuring the Contractile Force of Multilayered Human Cardiac Cell Sheets.
Three-dimensional (3D) cardiac tissue reconstruction using tissue engineering technology is a rapidly growing area of regenerative medicine and drug screening development. However, there remains an urgent need for the development of a method capable of accurately measuring the contractile force of physiologically relevant 3D myocardial tissues to facilitate the prediction of human heart tissue drug sensitivity. To this end, our laboratory has developed a novel drug screening model that measures the contractile force of cardiac cell sheets prepared using temperature-responsive culture dishes. To circumvent the difficulties that commonly arise during the stacking of cardiomyocyte sheets, we established a stacking method using centrifugal force, making it possible to measure 3D myocardial tissue. Human induced pluripotent stem cell-derived cardiomyocytes were seeded in a temperature-responsive culture dish and processed into a sheet. The cardiac cell sheets were multilayered to construct 3D cardiac tissue. Measurement of the contractile force and cross-sectional area of the multilayered 3D cardiac tissue were then obtained and used to determine the relationship between the cross-sectional area of the cardiac tissue and its contractile force. The contractile force of the 1-, 3-, and 5-layer tissues increased linearly in proportion to the cross-sectional area. A result of 6.4 mN/mm2, accounting for one-seventh of the contractile force found in adult tissue, was obtained. However, with 7-layer tissues, there was a sudden drop in the contractile force, possibly because of limited oxygen and nutrient supply. In conclusion, we established a method wherein the thickness of the cell sheets was controlled through layering, thus enabling accurate evaluation of the cardiac contractile function. This method may enable comparisons with living heart tissue while providing information applicable to regenerative medicine and drug screening models.


The distribution of eosinophils and lymphocytes in the large and small airways of asthmatics.
Airway inflammation in asthma consists of variably increased numbers of mononuclear and polymorphonuclear cells, and there is a growing body of evidence to suggest a primary role for lymphocytes and eosinophils in the pathogenesis of asthma. The aim of this study was to examine the distribution of lymphocytes and eosinophils in the bronchial tree of cases of mild and severe asthma. In cases of fatal asthma (n = 10), nonfatal asthma (sudden nonrespiratory death with a history of asthma n = 10), and control cases (sudden death with no history of respiratory illness, n = 10), lymphocytes and eosinophils were counted in transverse sections of large and small airways stained with haematoxylin and eosin. Cases of fatal asthma had longstanding severe asthma and nonfatal cases generally had mild asthma. Lymphocytes were increased in all airway size groups both in fatal and nonfatal cases of asthma compared to control cases (p < 0.001). Eosinophils were increased (p < 0.001) in all airway size groups in the cases of fatal asthma compared to the nonfatal asthma and control groups, which were similar. These differences between case groups were of similar magnitude, when only a random single airway section from each case in each size group was examined. The numbers of lymphocytes correlated with the number of eosinophils in the fatal asthma group (r = 0.60; p < 0.0001), and to a lesser extent in the nonfatal (r = 0.34; p = 0.001) and control groups (r = 0.32; p = 0.001). These findings suggest that increased numbers of lymphocytes are uniformly distributed in the large and small airways in cases of asthma, independently of asthma severity, and that eosinophil recruitment may be related to asthma severity. Hence, biopsy specimens of the proximal airways are likely to be representative of the cellular infiltrate in large and small airways in mild and severe asthma.


Diet and lifestyle of the Sami of southern Lapland in the 1930s--1950s and today.
To describe the lifestyle of the Sami of southern Lapland 50 to 70 years ago in relation to the present-day Sami and non-Sami populations and, thereby, to provide a basis for future studies of culturally related determinants of health and illness. A qualitative analysis, and a quantitative comparison of Sami and non-Sami groups. Semi-structured interviews were conducted with 20 elderly Sami concerning their parents' lifestyle and diet 50 to 70 years ago. Questionnaire data from 81 reindeer-herding Sami, 226 non-reindeer-herding Sami and 1,842 sex-, age- and geographically matched non-Sami from the population-based Västerbotten Intervention Project were analysed by non-parametric tests and partial least squares methodology. Surprisingly, fatty fish may have been more important than reindeer meat for the Sami of southern Lapland in the 1930s to 1950s, and it is still consumed more frequently by reindeer-herding Sami than nonreindeer-herding Sami and non-Sami. Other dietary characteristics of the historical Sami and present-day reindeer-herding Sami were higher intakes of fat, blood and boiled coffee, and lower intakes of bread, fibre and cultivated vegetables, compared with present-day non-Sami. Physical activity was also a part of the daily life of the Sami to a greater extent in the 1930s to 1950s than today. Sami men often worked far from home, while the women were responsible for fishing, farming, gardening (which was introduced in the 1930-1950 period), as well as housework and childcare. For studies investigating characteristic lifestyle elements of specific ethnic groups, the elements of greatest acknowledged cultural importance today (in this case reindeer meat) may not be of the most objective importance traditionally.


Phase I Dose-Escalation and -Expansion Study of Telisotuzumab (ABT-700), an Anti-c-Met Antibody, in Patients with Advanced Solid Tumors.
This first-in-human phase I study evaluated the pharmacokinetics, safety, and preliminary efficacy of telisotuzumab, formerly called ABT-700, an antagonistic antibody directed against c-Met. For dose escalation (3+3 design), 3 to 6 patients with advanced solid tumors were enrolled into four dose cohorts (5-25 mg/kg). In the dose-expansion phase, a subset of patients was prospectively selected for MET amplification (FISH screening). Patients received telisotuzumab intravenously on day 1 every 21 days. For dose expansion, 15 mg/kg was chosen as the dose on the basis of safety, pharmacokinetics, and other data from the escalation cohorts. Forty-five patients were enrolled and received at least one dose of telisotuzumab (dose escalation, n = 15; dose expansion, n = 30). Telisotuzumab showed a linear pharmacokinetics profile; peak plasma concentration was proportional to dose level. There were no acute infusion reactions and no dose-limiting toxicities were observed. The most common treatment-related adverse events included hypoalbuminemia (n = 9, 20.0%) and fatigue (n = 5, 11.1%). By Response Evaluation Criteria In Solid Tumors (RECIST), 4 of 10 (40.0%) patients with MET-amplified tumors had confirmed partial response in target lesions (one ovarian, two gastric, and one esophageal), two (20.0%) had stable disease, three (30.0%) had progressive disease; one patient was unable to be evaluated. Among patients with nonamplified tumors (n = 35), no objective responses were observed; however, 11 patients had stable disease per RECIST criteria. In conclusion, telisotuzumab has an acceptable safety profile with clinical activity observed in patients with MET-amplified advanced solid tumors.


Implementation of a tobacco-free workplace program at a local mental health authority.
Tobacco-free workplace policies that incorporate evidence-based practices can increase the reach and effectiveness of tobacco dependence treatment among underserved populations but may be underutilized due to limited knowledge about implementation processes. This paper describes the implementation of a comprehensive tobacco-free workplace program at a behavioral healthcare community center in Texas. The center participated in a tobacco-free workplace program implementation project that provided guidance and resources and allowed center autonomy in implementation. Six employee-based subcommittees guided implementation of program components including consumer and staff surveys, policy development, signage, tobacco use assessments, communication, and nicotine replacement distribution. Timeline development, successes, challenges, lessons learned, and sustainability initiatives are delineated. Concerns about the tobacco-free workplace policy from the center's staff and consumers were gradually replaced by strong support for the initiative. Program success was enabled by consistent support from the center's leadership, publicity of program efforts, and educational campaigns. The center surpassed the program expectations when it adopted a tobacco-free hiring policy, which was not an initial program goal. This center's path to a tobacco-free workplace provides an implementation and sustainability model for other behavioral health community centers and other organizations to become tobacco free.


Larsen syndrome associated with severe congenital hydrocephalus.
Larsen syndrome associated with severe congenital hydrocephalus: Larsen syndrome (LS) is characterized by the association of flattened facies with a prominent forehead, a depressed nasal bridge and hypertelorism, dislocation of hips, elbows and knees, equinovarus or valgus deformities of the feet, long and tapering fingers, normal intelligence. Hydrocephalus has rarely been reported in association with LS. In this article, a newborn infant with the classical features of LS and severe congenital hydrocephalus is presented. Our purpose was to emphasize the importance of congenital hydrocephalus in infants with LS and to highlight the management of cases of LS associated with congenital hydrocephalus.


New highly potent and specific E6 and E7 siRNAs for treatment of HPV16 positive cervical cancer.
Persistent infection by high-risk types of human papillomaviruses (HPV) is a necessary cause of cervical cancer, with HPV16 the most prevalent, accounting for more than 50% of reported cases. The virus encodes the E6 and E7 oncoproteins, whose expression is essential for maintenance of the malignant phenotype. To select efficacious siRNAs applicable to RNAi therapy for patients with HPV16+ cervical cancer, E6 and E7 siRNAs were designed using siDirect computer software, after which 10 compatible with all HPV16 variants were selected, and then extensively examined for RNAi activity and specificity using HPV16+ and HPV16-cells. Three siRNAs with the highest RNAi activities toward E6 and E7 expression, as well as specific and potent growth suppression of HPV16+ cancer cells as low as 1 nM were chosen. Growth suppression was accompanied by accumulation of p53 and p21(WAF1/CIP1), as well as morphological and cytochemical changes characteristic of cellular senescence. Antitumor activity of one of the selected siRNAs was confirmed by retarded tumor growth of HPV16+ cells in NOD/SCID mice when locally injected in a complex with atelocollagen. Our results demonstrate that these E6 and E7 siRNAs are promising therapeutic agents for treatment of virus-related cancer.


Potassium channel regulation.
The sulphonylurea receptor (SUR) is a member of the ATP-binding cassette (ABC) family of membrane proteins. It functions as the regulatory subunit of the ATP-sensitive potassium (KATP) channel, which comprises SUR and Kir6.x proteins. Here, we review data demonstrating functional differences between the two nucleotide binding domains (NBDs) of SUR1. In addition, to explain the structural basis of these functional differences, we have constructed a molecular model of the NBD dimer of human SUR1. We discuss the experimental data in the context of this model, and show how the model can be used to design experiments aimed at elucidating the relationship between the structure and function of the KATP channel.


Empyema thoracis in children: Still a challenge in developing countries.
To evaluate the effectiveness of surgical intervention in managing empyema thoracis in children. A total of 70 patients aged 1-14 years diagnosed to have empyema thoracis and who underwent tube thoracostomy from January 2010 to December 2013 were studied. All patients of which 12 patients needed decortication. The mean age of the study group was 5.44 years and 48.6% were male and 51.4% were female. The most common symptoms at admission were fever (90%), dyspnoea (73%), cough (70%) and chest pain (23%). Pleural fluid cultures were sterile in 60% of patients. The most frequently identified micro-organisms was Staphylococcus aureus (34.2%). Treatment with chest tube drainage was successful in 55 (78.6%) patients. Three patients got expired. Twelve patients had decortications, all of which were successful. The lung re-expansion time was 8.00 ± 1.68 days (range: 5-13 days) in those patients in whom chest tube drainage was successful, whereas it was 7.50 ± 2.623 days (range: 4-14 days) in patients in whom decortication was done. The post-procedure stay was 10.00 ± 1.809 days (range: 7-15 days) in patients with successful chest tube drainage and 9.5 ± 2.902 days (range: 6-17 days) in case of decortication cases. Tube thoracostomy should be done in all cases of empyema thoracis regardless of stage, as this leads to reduction in septic load. Decision of decortication should be taken without any delay.


Anisotropies in the gravitational wave background from preheating.
We investigate the anisotropies in the gravitational wave (GW) background produced at preheating after inflation. Using lattice field theory simulations of a massless preheating model, we show that the GW amplitude depends sensitively on the value of the decay product field χ coupled to the inflaton φ, with the only requisite that χ is light during inflation. We find a strong anisotropy in the amplitude of the GW background on large angular scales, the details of which strongly depend on the reheating dynamics. We expect similar conclusions for a wide class of inflationary models with light scalar fields. If future direct detection GW experiments are capable of detecting the GW produced by preheating, they should also be able to detect this effect. This could eventually provide a powerful way to distinguish between different inflationary and preheating scenarios.


Metabolic consequence of two-week fructose feeding in diabetic subjects.
We studied the metabolic effects of 2-wk fructose feeding as the sweetener in the diet of seven non-insulin-dependent diabetic individuals. The data demonstrated reduced postprandial hyperglycemia to an oral glucose challenge after 14 days without a significant difference in insulin response. There was no change in the markedly blunted glucose response to a fructose challenge but a significantly lower insulin response (area under the 3-h curve) was observed after 14 days of fructose feeding. There was reduced postprandial hyperglycemia after 14 days of fructose feeding with test meals as compared with baseline, without significant differences in insulin response. We also found no significant difference in free fatty acids, cholesterol, high-density lipoprotein (HDL) cholesterol, pyruvate, lactate, or uric acid after fructose feedings. There was a 13% increase in triglyceride levels after 14 days in 5 subjects with initial fasting hypertriglyceridemia (greater than 150 mg/dl). Insulin receptor binding to isolated adipocytes did not change after 14 days of fructose feeding.


Ultracompact CMOS-compatible optical logic using carrier depletion in microdisk resonators.
We present a CMOS-compatible optoelectronic directed logic architecture that achieves high computational throughput (number of operations per second per unit area) by its ultracompact form factor. High speed-to-power performance is also achieved, by the low capacitance and high junction-to-mode overlap of low-radii SOI vertical pn junction microdisk switches. By using wavelength-division multiplexing and two electrical control signals per disk, each switch performs (N)OR, (N)AND, and X(N)OR operations simultaneously. Connecting multiple switches together, we demonstrate higher-order scalability in five fundamental N-bit logic circuits: AND/OR gates, adders, comparators, encoders, and decoders. To the best of our knowledge, these circuits achieve the lowest footprint of silicon-based multigigabit-per-second optical logic devices in literature.


Mild cognitive impairment impacts health outcomes of patients with atrial fibrillation undergoing a disease management intervention.
Mild cognitive impairment (MCI) is prevalent in atrial fibrillation (AF) and has the potential to contribute to poor outcomes. We investigated the influence of MCI on survival and rehospitalisation in patients with chronic forms of AF undergoing a home-based, AF-specific disease management intervention (home-based intervention (HBI)) or standard management (SM). The Montreal Cognitive Assessment tool was administered at baseline (a score of <26/30 indicated MCI) in patients with AF randomised to HBI versus SM. Post hoc analyses of mortality and rehospitalisations during a minimum 24-month follow-up were conducted in the overall cohort and in each study group separately. Of 260 patients (mean age 72±11, 47% female), 65% demonstrated MCI on screening (34% in SM; 31% in HBI). Overall, the number of days spent alive and out-of-hospital during follow-up (P=0.012) and all-cause rehospitalisation were influenced by MCI during follow-up (OR 3.16 (95% CI 1.46 to 6.84)) but MCI did not influence any outcomes in the SM group. However, survival was negatively influenced by MCI in the HBI group (P=0.036); those with MCI in this group were 5.6 times more likely to die during follow-up (OR 5.57 (95% CI 1.10 to 28.1)). Those with MCI in the HBI group also spent less days alive and out-of-hospital than those with no MCI (P=0.022). MCI was also identified as a significant independent correlate of shortest duration of event-free survival (OR 3.48 (95% CI 1.06 to 11.4)), all-cause rehospitalisation (OR 3.30 (95% CI 1.25 to 8.69)) and cardiovascular disease (CVD)-related rehospitalisation (OR 2.35 (95% CI 1.12 to 4.91)) in this group. The effectiveness of home-based, disease management for patients with chronic forms of AF is negatively affected by comorbid MCI. The benefit of adjunctive support for patients with MCI on CVD-related health outcomes requires further investigation.


The impact of childhood epilepsy on quality of life: a qualitative investigation using focus group methods to obtain children's perspectives on living with epilepsy.
As children's perceptions of their quality of life are unique, it is essential to elicit their concerns directly rather than from proxy informants. This study therefore aimed to investigate the impact of childhood epilepsy on quality of life directly from the child's perspective. Focus group techniques and qualitative analysis were utilized. Twenty-two children between 7 years 4 months and 12 years 6 months of age (11 females, 11 males) were stratified by age (7-8, 9-10, 11-12 years) into five focus groups. Data were transcribed and analyzed using grounded theory techniques to generate themes and categories. Themes were presented using the children's language. Two major themes were identified, "things to do with growing up" and "things to do with epilepsy," with five and four subthemes, respectively. No significant age-related differences were found. A conceptual model illustrates these findings, and comparisons are made to previous research with adolescents using similar methodology.


Regenerative medicine for neurological disorders.
The annual meeting of the American Society for Neural Therapy and Repair (ASNTR) has always introduced us to top-notch and up-to-date approaches for regenerative medicine related to neuroscience, ranging from stem cell-based therapy to novel drugs. The 16th ASNTR meeting focused on a variety of different topics, including the unknown pathogenesis or mechanisms of specific neurodegenerative diseases, stem cell biology, and development of novel alternative medicines or devices. Newly developed stem cells, such as amniotic epithelial stem cells and induced pluripotent stem cells, as well as well-known traditional stem cells, such as neural, embryonic, bone marrow mesenchymal, and human umbilical cord blood-derived stem cells, were reported. A number of commercialized stem cells were also covered at this meeting. Fetal neural tissues, such as ventral mesencephalon, striatum, and Schwann cells, were investigated for neurodegenerative diseases or spinal cord injury. A number of studies focused on novel methods for drug monitoring or graft tracking, and combination therapy with stem cells and medicine, such as cytokines or trophic factors. Finally, the National Institutes of Health guidelines for human stem cell research, clinical trials of commercialized stem cells without larger animal testing, and prohibition of medical tourism were big controversial issues that led to heated discussion.


Safety and efficacy of pantoprazole 40 mg daily as relapse prophylaxis in patients with healed reflux oesophagitis-a 2-year follow-up.
Pantoprazole is a benzimidazole derivative which selectively inhibits the proton pump H+, K+-ATPase, necessary for the final step in gastric acid secretion. To assess safety and efficacy of oral pantoprazole (40 mg o.d.) used as a prophylaxis against relapse in patients with healed reflux oesophagitis during an open-label, 2-year study. Outpatients (n=157) with healed stage II or III reflux oesophagitis (Savary-Miller classification) were enrolled into a long-term, multicentre maintenance study. Endoscopy was performed at entry into the study, after 12 and 24 months, or when disease-specific symptoms occurred on more than three consecutive days. Symptoms were assessed at 3-monthly intervals. Endoscopically confirmed relapses (at least stage I) were evaluated as treatment failures. Of the 178 adverse events, experienced by 88 (56%) patients (intention-to-treat population), 12 (7%) were assessed by the investigators as possibly related to the study medication. Median serum gastrin levels increased from a baseline of 46 ng/L to 90 ng/L, reaching a plateau after 9 months. For the intention-to-treat population the endoscopic remission rates after 12 and 24 months were 87% and 76%, respectively (Life-Table survival analysis, Kaplan-Meier). Pantoprazole 40 mg proved to be safe and efficacious during a 2-year prophylaxis treatment in patients with healed reflux oesophagitis.


Microglia in ALS: the good, the bad, and the resting.
Inflammation, including microglial activation and T cell infiltration, is a neuropathological hallmark of amyotrophic lateral sclerosis (ALS), a rapidly progressing neurodegenerative disease. The identification of mutations in the gene for Cu2+/Zn2+ superoxide dismutase (SOD1) from patients with an inherited form of ALS enabled the creation of transgenic mice overexpressing mutant forms of SOD1 (mSOD1) which develop a motoneuron disease that resembles the disease seen in ALS patients. These transgenic mice display similar inflammatory reactions at sites of motoneuron injury as detected in ALS patients, enabling the observation that this inflammation is not simply a late consequence of motoneuron degeneration, but actively contributes to the balance between neuroprotection and neurotoxicity. The microglial and T cell activation states influence the rate of disease progression. Initially, microglia and T cells can slow disease progression, while they may later contribute to the acceleration of disease. Accumulation of intracellular and extracellular misfolded mSOD1 may be key events regulating the transformation from neuroprotective alternatively activated M2 microglia to cytotoxic classically activated M1 microglia. Intracellular and extracellular mSOD1 utilizing different pathways may enhance the production and release of reactive oxygen species (ROS) and augment the inflammatory cytokine cascade from microglia. These ROS and cytokines may increase the susceptibility of motoneurons to glutamate toxicity and inhibit the function and expression of astrocytic glutamate transporters resulting in further neurotoxicity. Thus, the cumulative evidence suggests that inflammation plays a central role in ALS and manipulating these microglial effector functions may potentially modify the outcome of this devastating disease.


Future therapy of hepatitis C.
Currently available therapies for the treatment of chronic hepatitis C are effective in half of patients, but are expensive, often poorly tolerated, and unsuitable for certain patient populations. The ideal therapy would be highly effective, orally bioavailable, have minimal side effects, be cost effective, and suitable for the majority of patients with hepatitis C. Recent advances in understanding the replication cycle of hepatitis C virus (HCV) and structural, crystallographic definitions of components of the viral polyprotein have improved the prospects for development of novel therapies. The lack of a small animal model of HCV infection continues to hamper progress in the preclinical evaluation of new antivirals and vaccines. Strategies to enhance response to current therapies include the development of novel interferons and delivery systems, nucleoside analogues that have reduced hemolysis compared with ribavirin, inosine 5' monophosphate dehydrogenase inhibitors, and other immunomodulators that are being evaluated as adjunctive therapy to interferon-based regimens. Compounds in preclinical or early phase human trials include small molecules that inhibit virus specific enzymes (such as the serine proteases, RNA polymerase and helicase), or those that prevent translation initiation (such as antisense molecules and ribozymes). Antifibrotic agents are also being developed in an attempt to prevent disease progression in patients in whom HCV RNA cannot be eradicated. While the advent of these newer compounds represent an exciting phase in the treatment of HCV, their safety and efficacy need to be established. Most of these newer therapies are unlikely to be available for routine clinical use in the next 3 to 5 years.


Intestinal CD36 and Other Key Proteins of Lipid Utilization: Role in Absorption and Gut Homeostasis.
Several proteins have been implicated in fatty acid (FA) transport by enterocytes including the scavenger receptor CD36 (SR-B2), the scavenger receptor B1 (SR-B1) a member of the CD36 family and the FA transport protein 4 (FATP4). Here, we review the regulation of enterocyte FA uptake and its function in lipid absorption including prechylomicron formation, assembly and transport. Emphasis is given to CD36, which is abundantly expressed along the digestive tract of rodents and humans and has been the most studied. We also address the pleiotropic functions of CD36 that go beyond lipid absorption and metabolism to include recent evidence of its impact on intestinal homeostasis and barrier maintenance. Areas of progress involving contribution of membrane phospholipid remodeling and of cytosolic FA-binding proteins, FABP1 and FABP2 to fat absorption will be covered. © 2018 American Physiological Society. Compr Physiol 8:493-507, 2018.


Child and Family Factors Associated With Child Maltreatment in Vietnam.
This study aims to explore possible risk factors for child maltreatment in Vietnam by investigating the association of child and family factors with different types of child maltreatment (i.e., sexual abuse, physical abuse, emotional abuse, witnessing parental conflict, and neglect) and the occurrence of multiple types of child maltreatment. Cross-sectional data of 1,851 secondary and high school students aged 12 to 17 years (47.3% boys) in four provinces of Northern Vietnam were obtained using self-report questionnaires. Results indicated that the likelihood of emotional abuse, witnessing parental conflict, and experiencing multiple types of child maltreatment during lifetime increased with age. Boys had a higher risk than girls on lifetime sexual abuse, and past year and lifetime physical abuse. Living in a single parent family was the risk factor related to most types of child maltreatment including lifetime sexual abuse, neglect, and multiple types of child maltreatment, and both past year and lifetime witnessing parental conflict. Interestingly, low socioeconomic status (SES) and parental unemployment were associated with a decreased risk on experiencing emotional abuse in the past year and during lifetime, respectively. "Tiger parenting," a parenting style observed frequently in East Asian parents, may be more common in families with high SES and might explain this finding. This study highlights the importance of prioritizing single parent families in parenting programs and implementing child maltreatment interventions early because of the risk on child maltreatment increased with age. More research on emotional abuse and "Tiger parenting" in Vietnam could clarify the association of emotional abuse with high SES and parental employment. Finally, the underlying mechanisms of the risk factors in Vietnam should be studied more to inform interventions.


Wound healing and functional outcomes after infrainguinal bypass with reversed saphenous vein for critical limb ischemia.
To examine wound healing and the functional natural history of patients undergoing infrainguinal bypass with reversed saphenous vein for critical limb ischemia (CLI). Consecutive patients undergoing infrainguinal bypass for CLI were retrospectively entered into a technical and functional outcomes database. The patients were enrolled from the tertiary referral vascular surgery practices at the University of Colorado Health Sciences Center and Southern Illinois University Medical School. Main outcome variables included wound healing, self-assessed degree of ambulation (outdoors, indoors only, or nonambulatory), and living status (community or structured) after a mean follow up of 30 +/- 23 months. These outcome variables were assessed relative to the preoperative clinical characteristics (symptom duration before vascular consultation, lesion severity, and serum albumin level) and graft patency. From August 1997 through December 2004, 334 patients (253 men; median age, 68 years) underwent 409 infrainguinal bypasses (157 popliteal, 235 tibial, and 17 pedal) for CLI (159 Fontaine III and 250 Fontaine IV). Perioperative mortality was 1.2%. At 1 and 3 years, respectively, the primary patency was 63% and 50%, assisted primary patency was 80% and 70%, limb salvage was 85% and 79%, and survival was 89% and 74%. Complete wound healing at 6 and 12 months was 42% and 75%, respectively. Thirty-four patients (10%) died before all wounds were healed. Multivariate analysis indicated that extensive pedal necrosis at presentation independently predicted delayed wound healing (P < or = .01). At baseline (defined as the level of function within 30 days before the onset of CLI), 91% of patients were ambulatory outdoors, and this decreased to 72% at 6 months (P < or = .01). Similarly, 96% of patients lived independently at baseline, and this decreased to 91% at 6 months (P < or = .01) Graft patency was associated with better ambulatory status at 6 months. A longer duration of symptoms before vascular consultation was associated with a worse living status at 6 months. Despite achieving the anticipated graft patency and limb salvage results, 25% of patients did not realize wound healing at 1 year of follow-up, 19% had lost ambulatory function, and 5% had lost independent living status. Prospective natural history studies are needed to further define the functional outcomes and their predictors after infrainguinal bypass for CLI.


Corneal dystrophy-associated R124H mutation disrupts TGFBI interaction with Periostin and causes mislocalization to the lysosome.
The 5q31-linked corneal dystrophies are heterogeneous autosomal-dominant eye disorders pathologically characterized by the progressive accumulation of aggregated proteinaceous deposits in the cornea, which manifests clinically as severe vision impairment. The 5q31-linked corneal dystrophies are commonly caused by mutations in the TGFBI (transforming growth factor-beta-induced) gene. However, despite the identification of the culprit gene, the cellular roles of TGFBI and the molecular mechanisms underlying the pathogenesis of corneal dystrophy remain poorly understood. Here we report the identification of periostin, a molecule that is highly related to TGFBI, as a specific TGFBI-binding partner. The association of TGFBI and periostin is mediated by the amino-terminal cysteine-rich EMI domains of TGFBI and periostin. Our results indicate that the endogenous TGFBI and periostin colocalize within the trans-Golgi network and associate prior to secretion. The corneal dystrophy-associated R124H mutation in TGFBI severely impairs interaction with periostin in vivo. In addition, the R124H mutation causes aberrant redistribution of the mutant TGFBI into lysosomes. We also find that the periostin-TGFBI interaction is disrupted in corneal fibroblasts cultured from granular corneal dystrophy type II patients and that periostin accumulates in TGFBI-positive corneal deposits in granular corneal dystrophy type II (also known as Avellino corneal dystrophy). Together, our findings suggest that TGFBI and periostin may play cooperative cellular roles and that periostin may be involved in the pathogenesis of 5q31-linked corneal dystrophies.


Suburban poverty and the health care safety net.
Although suburban poverty has increased in the past decade, the availability of health care services for low-income and uninsured people in the suburbs has not kept pace. According to a new study by the Center for Studying Health System Change (HSC) of five communities--Boston, Cleveland, Indianapolis, Miami and Seattle--low-income people living in suburban areas face significant challenges accessing care because of inadequate transportation, language barriers and lack of awareness of health care options. Low-income people often rely on suburban hospital emergency departments (EDs) and urban safety net hospitals and health centers. Some urban providers are feeling the strain of caring for increasing numbers of patients from both the city and the suburbs. Both urban and suburban providers are attempting to redirect patients to more appropriate care near where they live by expanding primary care capacity, improving access to specialists, reducing transportation challenges, and generating revenues to support safety net services. Efforts to improve safety net services in suburban areas are hampered by greater geographic dispersion of the suburban poor and jurisdictional issues in funding safety net services. To improve the suburban safety net, policy makers may want to consider flexible and targeted approaches to providing care, regional collaboration to share resources, and geographic pockets of need when allocating resources for community health centers and other safety net services and facilities.


Comparison of the polymerase chain reaction and serology for the detection of canine visceral leishmaniasis.
The polymerase chain reaction (PCR) and serology was evaluated for the diagnosis of canine visceral leishmaniasis in Bahia, Brazil in a study of 125 dogs. The PCR was 100% sensitive in 25 dogs that had Leishmania demonstrated by either culture or hamster inoculation. It was 100% specific for 35 dogs from the northeastern United States, all were PCR negative. However, 22 of 54 Brazilian dogs that were culture-hamster inoculation-negative were positive by PCR. The nature of the PCR product was identified by hybridization with specific Leishmania probes. Whereas the sensitivity of serology in relationship to infection, as determined by hamster or culture assay was more than 80%, sensitivity of serology was only 63% when compared with PCR. These results raise questions about the use of serology to detect Leishmania infection in dogs, and suggest that the PCR might serve as a better gold standard to define Leishmania infection than culture or hamster inoculation.


Diurnal rhythm of agouti-related protein and its relation to corticosterone and food intake.
In the present study we examined the diurnal patterns of agouti-related protein (AGRP) and proopiomelanocortin (POMC) mRNA expression in the arcuate nucleus and their relation to circulating glucocorticoids and food intake. Animals were killed at 4-h intervals throughout the 24-h diurnal cycle, and the expression of AGRP and POMC mRNA was evaluated by semiquantitative in situ hybridization analysis. We observed a significant diurnal rhythm in AGRP mRNA expression, with a marked peak at 2200 h (4 h after lights off) and a trough at 1000 h (4 h after lights on), consistent with the overall day-night rhythm of food intake. In contrast, POMC mRNA levels did not show a significant fluctuation across the diurnal cycle, although there was a tendency for levels to decrease after the onset of the dark cycle. Corticosterone secretion temporally coincided with the rising phase of AGRP mRNA expression. Depletion of corticosterone by adrenalectomy abolished the AGRP diurnal rhythm by suppressing the nighttime expression, but did not alter the feeding rhythm. Exposure of adrenalectomized rats to constant corticosterone replacement (10 or 50 mg continuous release corticosterone pellet) resulted in fixed AGRP mRNA expression throughout the 12-h light, 12-h dark cycle. A relatively high level of corticosterone (50 mg) significantly increased AGRP mRNA expression, with a positive correlation between these two measures. These results indicate that 1) the diurnal expression of AGRP mRNA is regulated by corticosterone independently of the light/dark cue; and 2) a normal endogenous corticosterone rhythm is required for generating the diurnal AGRP rhythm.