Epidemiological, clinical and laboratory characteristics of 19 serologically confirmed rickettsial disease in Singapore.

AIM: To identify epidemiological, clinical and laboratory features of serologically-proven typhus in the local setting. METHOD & RESULTS: Retrospective study looking at rickettsial serologies done over a six-month period and collection of the epidemological, clinical, laboratory and treatment response data from the case notes of the patients with an ordered rickettsial serology. Twenty of the 35 cases had a positive serology. Of these 20 patients, 18 were already clinically diagnosed as having murine typhus. All except one were males and all were migrant workers. Majority of the patients were construction workers staying in containers where rats abound. The most consistent clinical features were high fever (100%) for a median period of seven days, headache (94%) and cough (47%). The white cell count was usually normal (74%) but thrombocytopenia was common (68%). Transaminitis was also common (90%) with the AST component higher than the ALT in half of the cases. Response to doxycycline therapy was rapid and most (88%) were afebrile by 72 hours. CONCLUSION: Typhus (notably murine type) can be confidently diagnosed from consistent clinical features supported by epidemiological and laboratory clues. Early recognition with the prompt treatment response will result in shorter hospital stay with decreased cost. Serological testing may only prove useful in difficult situations when the clinical diagnosis is less clear

Enhancing the Efficiency of Organic Photovoltaics by a Photoactive Molecular Mediator

High boiling-point solvent additives, such as 1,8-diiodooctane, have been widely used to tune nanoscale phase morphology for increased efficiency in bulk heterojunction organic solar cells. However, liquid-state solvent additives remain in the active films for extended times and later migrate or evaporate from the films, leading to unstable device performance. Here, a solid-state photoactive molecular mediator, namely N(BAI)3, is reported that could be employed to replace the commonly used solvent additives to tune the morphology of bulk heterojunction films for improved device performance. The N(BAI)3 mediator not only resides in the active films locally to fine tune the phase morphology, but also contributes to the additional absorption of the active films, leading to ∼11% enhancement of power conversion efficiency of P3HT:PC60BM devices. Comparative studies are carried out to probe the nanoscale morphologies using grazing incidence wide-angle X-ray scattering and complementary neutron reflectometry. The use of 1 wt% N(BAI)3 is found to effectively tune the packing of P3HT, presumably through balanced π-interactions endowed by its large conjugated π surface, and to promote the formation of a PC60BM-rich top interfacial layer. These findings open up a new way to effectively tailor the phase morphology by photoactive molecular mediators in organic photovoltaics

ALIX binds a YPX(3)L motif of the GPCR PAR1 and mediates ubiquitin-independent ESCRT-III/MVB sorting.

The sorting of signaling receptors to lysosomes is an essential regulatory process in mammalian cells. During degradation, receptors are modified with ubiquitin and sorted by endosomal sorting complex required for transport (ESCRT)-0, -I, -II, and -III complexes into intraluminal vesicles (ILVs) of multivesicular bodies (MVBs). However, it remains unclear whether a single universal mechanism mediates MVB sorting of all receptors. We previously showed that protease-activated receptor 1 (PAR1), a G protein-coupled receptor (GPCR) for thrombin, is internalized after activation and sorted to lysosomes independent of ubiquitination and the ubiquitin-binding ESCRT components hepatocyte growth factor-regulated tyrosine kinase substrate and Tsg101. In this paper, we report that PAR1 sorted to ILVs of MVBs through an ESCRT-III-dependent pathway independent of ubiquitination. We further demonstrate that ALIX, a charged MVB protein 4-ESCRT-III interacting protein, bound to a YPX(3)L motif of PAR1 via its central V domain to mediate lysosomal degradation. This study reveals a novel MVB/lysosomal sorting pathway for signaling receptors that bypasses the requirement for ubiquitination and ubiquitin-binding ESCRTs and may be applicable to a subset of GPCRs containing YPX(n)L motifs

Modeling the functional genomics of autism using human neurons.

Human neural progenitors from a variety of sources present new opportunities to model aspects of human neuropsychiatric disease in vitro. Such in vitro models provide the advantages of a human genetic background combined with rapid and easy manipulation, making them highly useful adjuncts to animal models. Here, we examined whether a human neuronal culture system could be utilized to assess the transcriptional program involved in human neural differentiation and to model some of the molecular features of a neurodevelopmental disorder, such as autism. Primary normal human neuronal progenitors (NHNPs) were differentiated into a post-mitotic neuronal state through addition of specific growth factors and whole-genome gene expression was examined throughout a time course of neuronal differentiation. After 4 weeks of differentiation, a significant number of genes associated with autism spectrum disorders (ASDs) are either induced or repressed. This includes the ASD susceptibility gene neurexin 1, which showed a distinct pattern from neurexin 3 in vitro, and which we validated in vivo in fetal human brain. Using weighted gene co-expression network analysis, we visualized the network structure of transcriptional regulation, demonstrating via this unbiased analysis that a significant number of ASD candidate genes are coordinately regulated during the differentiation process. As NHNPs are genetically tractable and manipulable, they can be used to study both the effects of mutations in multiple ASD candidate genes on neuronal differentiation and gene expression in combination with the effects of potential therapeutic molecules. These data also provide a step towards better understanding of the signaling pathways disrupted in ASD

Ferritin immobilization on patterned poly(2-hydroxyethyl methacrylate) brushes on silicon surfaces from colloid system

In this paper, we describe a graft polymerization/solvent immersion method for generating poly(2-hydroxyethyl methacrylate) (PHEMA) brushes in various patterns. We used a novel fabrication process, involving very-large-scale integration and oxygen plasma treatment, to generate well-defined patterns of polymerized PHEMA on patterned Si(100) surfaces. We observed brush- and mushroom-like regions for the PHEMA brushes, with various pattern resolutions, after immersing wafers presenting lines of these polymers in MeOH and n-hexane, respectively. The interaction between PHEMA and ferritin protein sheaths in MeOH and n-hexane (good and poor solvent for PHEMA, respectively) was used to capture and release ferritins from fluidic system. The “tentacles” behaver for PHEMA brushes was found through various solvents in fluidic system. Using high-resolution scanning electron microscopy, we observed patterned ferritin Fe cores on the Si surface after pyrolysis of the patterned PHEMA brushes and ferritin protein sheaths, which verify the “tentacles” behaver for PHEMA brushes

Platinum binding preferences dominate the binding of novel polyamide amidine anthraquinone platinum(II) complexes to DNA

Complexes incorporating a threading anthraquinone intercalator with pyrrole lexitropsin and platinum(II) moieties attached were developed with the goal of generating novel DNA binding modes, including the targeting of AT-rich regions in order to have high cytotoxicities. The binding of the complexes to DNA has been investigated and profiles surprisingly similar to that for cisplatin were observed; the profiles were different to those for a complex lacking the pyrrole lexitropsin component. The lack of selective binding to AT-rich regions suggests the platinum binding was dominating the sequence selectivity, and is consistent with the pyrrole lexitropsin slowing intercalation. The DNA unwinding profiles following platinum binding were evaluated by gel electrophoresis and suggested that intercalation and platinum binding were both occurring

An EPTAS for Scheduling on Unrelated Machines of Few Different Types

In the classical problem of scheduling on unrelated parallel machines, a set of jobs has to be assigned to a set of machines. The jobs have a processing time depending on the machine and the goal is to minimize the makespan, that is the maximum machine load. It is well known that this problem is NP-hard and does not allow polynomial time approximation algorithms with approximation guarantees smaller than $1.5$ unless P$=$NP. We consider the case that there are only a constant number $K$ of machine types. Two machines have the same type if all jobs have the same processing time for them. This variant of the problem is strongly NP-hard already for $K=1$. We present an efficient polynomial time approximation scheme (EPTAS) for the problem, that is, for any $\varepsilon > 0$ an assignment with makespan of length at most $(1+\varepsilon)$ times the optimum can be found in polynomial time in the input length and the exponent is independent of $1/\varepsilon$. In particular we achieve a running time of $2^{\mathcal{O}(K\log(K) \frac{1}{\varepsilon}\log^4 \frac{1}{\varepsilon})}+\mathrm{poly}(|I|)$, where $|I|$ denotes the input length. Furthermore, we study three other problem variants and present an EPTAS for each of them: The Santa Claus problem, where the minimum machine load has to be maximized; the case of scheduling on unrelated parallel machines with a constant number of uniform types, where machines of the same type behave like uniformly related machines; and the multidimensional vector scheduling variant of the problem where both the dimension and the number of machine types are constant. For the Santa Claus problem we achieve the same running time. The results are achieved, using mixed integer linear programming and rounding techniques

Differential Regulation of Extracellular Matrix and Soluble Fibulin-1 Levels by TGF-β<inf>1</inf> in Airway Smooth Muscle Cells

Fibulin-1 (FBLN-1) is a secreted glycoprotein that is associated with extracellular matrix (ECM) formation and rebuilding. Abnormal and exaggerated deposition of ECM proteins is a hallmark of many fibrotic diseases, such as chronic obstructive pulmonary disease (COPD) where small airway fibrosis occurs. The aim of this study was to investigate the regulation of FBLN-1 by transforming growth factor beta 1 (TGF-β1) (a pro-fibrotic stimulus) in primary human airway smooth muscle (ASM) cells from volunteers with and without COPD. Human ASM cells were seeded at a density of 1×104 cells/cm2, and stimulated with or without TGF-β1 (10 ng/ml) for 72 hours before FBLN-1 deposition and soluble FBLN-1 were measured. Fold change in FBLN-1 mRNA was measured at 4, 8, 24, 48, 72 hours. In some experiments, cycloheximide (0.5 μg/ml) was used to assess the regulation of FBLN-1 production. TGF-β1 decreased the amount of soluble FBLN-1 both from COPD and non-COPD ASM cells. In contrast, the deposition of FBLN-1 into the ECM was increased in ASM cells obtained from both groups. TGF-β1 did not increase FBLN-1 gene expression at any of the time points. There were no differences in the TGF-β1 induced FBLN-1 levels between cells from people with or without COPD. Cycloheximide treatment, which inhibits protein synthesis, decreased both the constitutive release of soluble FBLN-1, and TGF-β1 induced ECM FBLN-1 deposition. Furthermore, in cycloheximide treated cells addition of soluble FBLN-1 resulted in incorporation of FBLN-1 into the ECM. Therefore the increased deposition of FBLN-1 by ASM cells into the ECM following treatment with TGF-β1 is likely due to incorporation of soluble FBLN-1 rather than de-novo synthesis. © 2013 Chen et al

Impact of participation in the Adalimumab (Humira) patient support program on rheumatoid arthritis treatment course : results from the PASSION study

Introduction: Patients with rheumatoid arthritis (RA) who are treated with adalimumab (ADA) are offered a proprietary patient support program (PSP, AbbVie Care (R)). The main objective of this study was to examine the effectiveness of ADA on RA treatment course over time in the context of PSP utilization. Methods: PASSION was a 78-week post-marketing observational study of RA patients with an insufficient response to >= 1 DMARD newly initiating ADA in routine clinical care that was conducted in Europe, Israel, Mexico, Puerto Rico, and Australia. One prior biologic DMARD was allowed. The primary endpoint was percentage of patients achieving the minimal clinically important difference (MCID; improvement of >= 0.22 compared to baseline) in Health Assessment Questionnaire (HAQ) Disability Index (HAQ-DI) at week 78. Additionally, multiple clinical and patient-reported outcomes (PROs) were evaluated over time. Patients were categorized based on their participation in the PSP: ever (PSP users) vs. never (PSP non-users). Safety events were monitored throughout the study. Results: Overall, 42.8% of PSP users achieved the MCID in HAQ-DI at week 78 (improvement of at least 0.22 compared to baseline). From 1025 enrolled, 48.7% of patients were PSP users while treated with ADA. The percentage of patients achieving MCID in the HAQ-DI was higher in PSP users vs. PSP non-users (48.1 vs. 37.8%) at week 78 (p < 0.001, NRI). Most of the studied clinical outcomes and PROs showed significant improvements (p < 0.05) from baseline to week 78 favoring PSP users over PSP non-users. Conclusions: In patients with moderate-to-severe RA who initiated ADA, improvements in clinical, functional, and PROs were achieved in real-world settings with significantly greater improvements among PSP users in comparison with PSP non-users

Metabonomics and Intensive Care

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency medicine 2016. Other selected articles can be found online at http://www.biomedcentral.com/collections/annualupdate2016. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901