Gastrointestinal involvement of primary skin diseases.

Less is known about gastrointestinal (GI) involvement of primary skin diseases due to the difference in embryology, histology, microbiology and physiology between integument and alimentary tract. Oesophagus, following the oropharyngeal mucosa, is the most common GI segment affected by primary skin diseases, especially by eosinophilic oesophagitis, lichen planus and autoimmune bullous dermatoses like pemphigus vulgaris, mucosal membrane pemphigoid and epidermolysis bullosa acquisita. Eosinophilic oesophagitis is an emerging chronic atopic disease with oesophageal dysfunction as the typical presentation, and oesophageal narrowing, rings and stricture as late complications. Oesophageal lichen planus mainly involves the proximal to mid-oesophagus in elderly aged women with long-term oral mucosal lesions. In acute attack of pemphigus vulgaris, oesophageal involvement is not uncommon but often neglected and may cause sloughing oesophagitis (oesophagitis dissecans superficialis) with acute GI bleeding in rare cases. GI manifestation of hereditary bradykininergic angio-oedema with colicky acute abdomen mostly affects small intestine, usually in the absence of pruritus or urticaria, and is more severe and long-lasting than the acquired histaminergic form. Strong evidence supports association between inflammatory bowel disease, especially Crohn disease, and hidradenitis suppurativa/acne inversa. Patients with vitiligo need surveillance of autoimmune liver disease, autoimmune atrophic gastritis or coeliac disease when corresponding symptoms become suspect. Melanoma is the most common primary tumour metastatic to the GI tract, with small intestine predominantly targeted. Gastrointestinal involvement is not uncommon in disseminated mycosis fungoides. Extramammary Paget's disease is an intraepidermal adenocarcinoma of controversial origin, and a high association between the anogenital occurrence and colorectal adenocarcinoma has been reported. As GI tract is the largest organ system with multidimensional functions, dermatologists in daily practice should be aware of the gastrointestinal morbidities related to primary skin diseases for an early diagnosis and treatment.

Horizontal Gene Transfers in Mycoplasmas (Mollicutes).

The class Mollicutes (trivial name "mycoplasma") is composed of wall-less bacteria with reduced genomes whose evolution was long thought to be only driven by gene losses. Recent evidences of massive horizontal gene transfer (HGT) within and across species provided a new frame to understand the successful adaptation of these minimal bacteria to a broad range of hosts. Mobile genetic elements are being identified in a growing number of mycoplasma species, but integrative and conjugative elements (ICEs) are emerging as pivotal in HGT. While sharing common traits with other bacterial ICEs, such as their chromosomal integration and the use of a type IV secretion system to mediate horizontal dissemination, mycoplasma ICEs (MICEs) revealed unique features: their chromosomal integration is totally random and driven by a DDE recombinase related to the Mutator-like superfamily. Mycoplasma conjugation is not restricted to ICE transmission, but also involves the transfer of large chromosomal fragments that generates progenies with mosaic genomes, nearly every position of chromosome being mobile. Mycoplasmas have thus developed efficient ways to gain access to a considerable reservoir of genetic resources distributed among a vast number of species expanding the concept of minimal cell to the broader context of flowing information.

Diets and trophic guilds of small fishes from coastal marine habitats in western Taiwan.

The diets and trophic guilds of small fishes were examined along marine sandy beaches and in estuaries at depths <1·5 m in western Taiwan, Republic of China. Copepods were the most frequently identified item in fish guts, indicating they are key prey for the fish assemblages studied. Piscivore, crustacivore, detritivore, omnivore, zooplanktivore and terrestrial invertivore trophic guilds were identified. The zooplanktivore guild contained the most fish species. Maximum prey size consumption was positively correlated with standard length (LS ) in seven species and at the assemblage level and negatively correlated with LS in a single detritivorous species. The diet data and trophic guild scheme produced by this study contribute to an understanding of coastal marine food webs and can inform ecosystem-based fisheries management.

3-D imaging of islets in obesity: formation of the islet-duct complex and neurovascular remodeling in young hyperphagic mice.

BACKGROUND: Obesity and insulin resistance lead to islet hyperplasia. However, how the islet remodeling influences the pancreatic environment and the associated neurovascular networks is largely unknown. The lack of information is primarily due to the difficulty of global visualization of the hyperplasic islet (>200 µm) and the neurovascular environment with high definition. METHODS: We modulated the pancreatic optical property to achieve 3-dimensional (3-D) whole-islet histology and to integrate transmitted light microscopy (which provides the ground-truth tissue information) with confocal fluorescence imaging. The new optical and imaging conditions were used to globally examine the hyperplastic islets of the young (2 months) obese db/db and ob/ob mice, which otherwise cannot be easily portrayed by the standard microtome-based histology. The voxel-based islet micrographs were digitally processed for stereo projection and qualitative and quantitative analyses of the islet tissue networks. RESULTS: Paired staining and imaging of the pancreatic islets, ducts and neurovascular networks reveal the unexpected formation of the 'neuro-insular-ductal complex' in the young obese mice. The complex consists of the peri- and/or intra-islet ducts and prominent peri-ductal sympathetic nerves; the latter contributes to a marked increase in islet sympathetic innervation. In vascular characterization, we identify a decreased perivascular density of the ob/ob islet pericytes, which adapt to ensheathing the dilated microvessels with hypertrophic processes. CONCLUSIONS: Modulation of pancreatic optical property enables 3-D panoramic examination of islets in the young hyperphagic mice to reveal the formation of the islet-duct complex and neurovascular remodeling. On the basis of the morphological proximity of the remodeled tissue networks, we propose a reactive islet microenvironment consisting of the endocrine cells, ductal epithelium and neurovascular tissues in response to the metabolic challenge that is experienced early in life.

Effects of all-trans retinoid acid and exendin-4 on islet transplantation in NOD mice.

Type 1 diabetes usually develops due to autoimmune destruction of ß-cells in the pancreas. It has been shown that all-trans retinoid acid (ATRA), a potent derivative of vitamin A, hinders the development of autoimmune diabetes by inducing immune tolerance status. In addition, exendin-4, a glucagon-like peptide-1 receptor agonist, stimulates growth and differentiation of ß-cells and exerts anti-apoptotic effect on ß-cells. Thus, we hypothesized that the ATRA and exendin-4 therapy may improve the outcome of islet transplantation in non-obese diabetic (NOD) mice. After the onset of diabetes, each NOD mouse was transplanted with 300 or 600 islets isolated from NOD/severe combined immunodeficient (SCID) mice with or without treatment of ATRA (0.5 mg intraperitoneally every other day) and/or exendin-4 (3 µg/kg subcutaneously twice daily) for 6 weeks. After 300 or 600 NOD/SCID islet transplantation without any other treatment, all NOD recipients remained diabetic. However, the lowest blood glucose level in mice transplanted with 600 but not 300 islets was significantly lower than those without islet transplantation (P < .05), although their survival time was comparable. Among recipients treated with ATRA, exendin-4, ATRA and exendin-4, and without treatment, their lowest blood glucose levels and survival time were not different. However, one recipient treated with ATRA survived for 223 days with intermittent hyperglycemia and the other who was treated with ATRA and exendin-4 achieved normoglycemia. In conclusion, islet transplantation lowered blood glucose levels in diabetic NOD mice. With a few exceptions, treatment with ATRA and exendin-4 alone or in combination in islet recipients could not reverse diabetes or prolong survival.

The facile generation of two-dimensional stiffness maps in durotactic cell platforms through thickness projections of three-dimensional submerged topography.

An innovative platform that aims to facilitate studies of how adherent cells migrate in response to rigidity gradients or durotaxis has been developed. Soft polyacrylamide gel-based cell culture scaffolds are used to fabricate flat surfaces containing elasticity gradients through changes in the underlying patterned features. Moreover, this inert gel surface supports long-term cell viability and offers a tunable stiffness. By manipulating the thickness of the gel substrate through the embedded patterns, this system is also capable of directing collective cell patterning.

Phthalates suppress type I interferon in human plasmacytoid dendritic cells via epigenetic regulation.

BACKGROUND: Exposure to environmental endocrine-disrupting chemicals (EDCs) is associated with allergy, chronic inflammation, and immunodeficiency. Phthalates, the common EDCs used in plastic industry, may act as adjuvants to disrupt immune system and enhance allergy. Plasmacytoid DCs (pDCs) are predominant cells secreting type I interferon (IFN) against infection and are professional antigen-presenting cells in regulating adaptive immunity. However, the effects of phthalates on the function of pDCs are unknown. METHODS: Circulating pDCs were isolated from healthy subjects, were pretreated with diethylhexyl phthalate (DEHP) and butyl benzyl phthalate (BBP), and were stimulated with Toll-like receptor (TLR)-9 agonist CpG. IFN-α/IFN-ß levels, surface markers, and T-cell stimulatory function were investigated using ELISA, flow cytometry, and pDC/T-cell coculture assay. Mechanisms were investigated using receptor antagonists, pathway inhibitors, Western blotting, and chromatin immunoprecipitation. RESULTS: Diethylhexyl phthalate and butyl benzyl phthalate suppressed CpG-induced IFN-α/IFN-ß expression in pDCs, and the effect was reversed by aryl hydrocarbon receptor (AHR) antagonist. Diethylhexyl phthalate suppressed CpG-activated mitogen-activated protein kinase (MAPK)-MEK1/2-ERK-ELK1 and NFκB signaling pathways. Diethylhexyl phthalate suppressed CpG-induced interferon regulatory factor (IRF)-7 expression by suppressing histone H3K4 trimethylation at IRF7 gene promoter region through inhibiting translocation of H3K4-specific trimethyltransferase WDR5 from cytoplasm into nucleus. Butyl benzyl phthalate or diethylhexyl phthalate-treated pDCs suppressed IFN-γ but enhanced IL-13 production by CD4+ T cells. CONCLUSION: Phthalates may interfere with immunity against infection and promote the deviation of Th2 response to increase allergy by acting on human pDCs via suppressing IFN-α/IFN-ß expression and modulating the ability to stimulate T-cell responses.

Effects of exercise training on cardiac apoptosis in obese rats.

BACKGROUND AND AIM: The purpose of this study was to evaluate the effects of exercise training on cardiac apoptotic pathways in obesity. METHODS AND RESULTS: Sixteen lean Zucker rats (LZR) and sixteen obese Zucker rats (OZR) of 5-6 months of age as well as the other sixteen obese rats were subjected to treadmill running exercise for 1 h everyday for 3 months (OZR-EX). After exercise training or sedentary status of the rats, the excised hearts from the three groups were measured by heart weight index, H&E staining, TUNEL assays and Western blotting. Cardiac TUNEL-positive apoptotic cells, the protein levels of TNF alpha, Fas ligand, Fas receptors, Fas-associated death domain (FADD), Bad, Bax, activated caspase 8, activated caspase 9, and activated caspase 3 were higher in OZR than those in LZR. The protein levels of TNF alpha, Fas ligand, Fas receptors, FADD, activated caspase 8, and activated caspase 3 (Fas pathway) and the protein levels of Bad, Bax, Bax-to-Bcl2 ratio, activated caspase 9, and activated caspase 3 (mitochondria pathway) were lower in OZR-EX than those in OZR. CONCLUSION: Cardiac Fas-dependent and mitochondria-dependent apoptotic pathways become more activated in obesity. Exercise training can prevent obesity-activated cardiac Fas-dependent and mitochondria-dependent apoptotic pathways. Our findings demonstrate a new therapeutic effect of exercise training to prevent delirious cardiac Fas-mediated and mitochondria-mediated apoptosis in obesity.

Dynamic character of charge transport parameters in disordered organic semiconductor field-effect transistors.

In this perspective article, we discuss the dynamic instability of charge carrier transport in a range of popular organic semiconductors. We observe that in many cases field-effect mobility, an important parameter used to characterize the performance of organic field-effect transistors (OFETs), strongly depends on the rate of the gate voltage sweep during the measurement. Some molecular systems are so dynamic that their nominal mobility can vary by more than one order of magnitude, depending on how fast the measurements are performed, making an assignment of a single mobility value to devices meaningless. It appears that dispersive transport in OFETs based on disordered semiconductors, those with a high density of localized trap states distributed over a wide energy range, is responsible for the gate voltage sweep rate dependence of nominal mobility. We compare such rate dependence in different materials and across different device architectures, including pristine and trap-dominated single-crystal OFETs, as well as solution-processed polycrystalline thin-film OFETs. The paramount significance given to a single mobility value in the organic electronics community and the practical importance of OFETs for applications thus suggest that such an issue, previously either overlooked or ignored, is in fact a very important point to consider when engaging in fundamental studies of charge carrier mobility in organic semiconductors or designing applied circuits with organic semiconductors.

Time-weighted average sampling of airborne propylene glycol ethers by a solid-phase microextraction device.

A solid-phase microextraction (SPME) device was used as a diffusive sampler for airborne propylene glycol ethers (PGEs), including propylene glycol monomethyl ether (PGME), propylene glycol monomethyl ether acetate (PGMEA), and dipropylene glycol monomethyl ether (DPGME). Carboxen-polydimethylsiloxane (CAR/PDMS) SPME fiber was selected for this study. A polytetrafluoroethylene (PTFE) tubing was used as the holder, and the SPME fiber assembly was inserted into the tubing as a diffusive sampler. The diffusion path length and area of the sampler were 0.3 cm and 0.00086 cm(2), respectively. The theoretical sampling constants at 30°C and 1 atm for PGME, PGMEA, and DPGME were 1.50 × 10(-2), 1.23 × 10(-2) and 1.14 × 10(-2) cm(3) min(-1), respectively. For evaluations, known concentrations of PGEs around the threshold limit values/time-weighted average with specific relative humidities (10% and 80%) were generated both by the air bag method and the dynamic generation system, while 15, 30, 60, 120, and 240 min were selected as the time periods for vapor exposures. Comparisons of the SPME diffusive sampling method to Occupational Safety and Health Administration (OSHA) organic Method 99 were performed side-by-side in an exposure chamber at 30°C for PGME. A gas chromatography/flame ionization detector (GC/FID) was used for sample analysis. The experimental sampling constants of the sampler at 30°C were (6.93 ± 0.12) × 10(-1), (4.72 ± 0.03) × 10(-1), and (3.29 ± 0.20) × 10(-1) cm(3) min(-1) for PGME, PGMEA, and DPGME, respectively. The adsorption of chemicals on the stainless steel needle of the SPME fiber was suspected to be one of the reasons why significant differences between theoretical and experimental sampling rates were observed. Correlations between the results for PGME from both SPME device and OSHA organic Method 99 were linear (r = 0.9984) and consistent (slope = 0.97 ± 0.03). Face velocity (0-0.18 m/s) also proved to have no effects on the sampler. However, the effects of temperature and humidity have been observed. Therefore, adjustments of experimental sampling constants at different environmental conditions will be necessary.

Coculture of hepatocytes with islets.

Bioartificial liver support (BAL) systems are potential new therapeutic approaches for use as liver support to prevent nutrient deficiencies, hypoxia, or ischemia before the acquisition of donated organs. To investigate whether islets are beneficial for hepatocyte function and survival, we cocultured BALB/c mouse islets with C57BL/6J hepatocytes to assess hepatocyte viability, function, and apoptosis. We observe cell viability to decrease progressively by 50% from day 0 to day 3 among isolated hepatocytes (group A) and hepatocytes cocultured with islets (group B). However, group A was prone to necrosis and reduced albumin secretion during culture. In contrast, at day 7 group B maintained albumin secretion (0.3351 ± 0.0581 vs 0.1451 ± 0.0329 µg/h/mL; P < .05). Early apoptosis was observed at day 3 among group A but at day 7 in group B. In addition, quantitative analysis of the apoptotic cells revealed group B to show a delayed phenotype of both early and late apoptosis compared with group A. Our results indicated that islets could retain hepatocyte function and delay apoptosis, suggesting that the coculture system is potentially applicable to develop a high-performance BAL.

Modest effects of Fas-ligand and heme oxygenase-1 double transgenic mouse islets on transplantation outcomes.

Interactions of Fas with its ligand (FasL) play an important role in the maintenance of immunologic homeostasis and peripheral tolerance. Heme oxygenase-1 (HO-1) is a protein capable of cytoprotection via radical scavenging and apoptosis prevention. The aim of this study was to test whether overexpression of FasL and HO-1 in murine islets resulted in cell protection and improved functional performance after transplantation. We first generated FasL and HO-1 double transgenic mice to investigate the protective effect of transgenic islets on transplantation. Islets were isolated from FasL and HO-1 double transgenic and nontransgenic Balb/c mice, for transplantation of 300 islets under the left kidney capsule of each streptozotocin-diabetic Balb/c mouse. During 6 weeks after transplantation, the blood glucose gradually decreased in recipients of double transgenic and nontransgenic islets. However, the decrease in blood glucose was more pronounced in the former (450 ± 16 mg/dL at day 0 to 302 ± 55 mg/dL at day 42; P = .01) than the latter (468 ± 17 mg/dL at day 0 to 379 ± 71 mg/dL at day 42; P = .24). The areas under the curve of intraperitoneal glucose tolerance tests at 2, 4, and 6 weeks were not significantly different between recipients of double transgenic and nontransgenic islets. The body weight increased in recipients of double transgenic islets (21.1 ± 1.4 g at day 0 to 26.2 ± 0.8 g at day 42; P = .0002) and nontransgenic islets (21.0 ± 1.4 g at day 0 to 25.1 ± 0.4 g at day 42; P = .0448). Our data suggested modest beneficial effects of transgenic islets with FasL and HO-1 overexpression for transplantation.

Prospective analysis of KRAS wild-type patients with metastatic colorectal cancer using cetuximab plus FOLFIRI or FOLFOX4 treatment regimens.

Cetuximab, a monoclonal antibody targeting epidermal growth factor receptor, has proven to be efficient in the treatment of metastatic colorectal cancer. We made a prospective study of the efficacy and toxicities of cetuximab-combination first-line (FOLFOX4) versus second/third-line (FOLFIRI) chemotherapy in 98 KRAS wild-type patients who had metastatic colorectal cancer. Wild-type KRAS had been identified by direct sequencing. Associations between clinical response/progression-free survival/overall survival/toxicities and cetuximab-combination chemotherapy timing were evaluated. The overall response rate was significantly higher for first-line treatment than for second/third-line treatment (relative risk = 1.707, 95% confidence interval = 1.121-2.598). Both progression-free survival and overall survival indicated significantly longer survival of first-line treatment than second/third-line treatment patients. This study is a validation of a molecular analysis of KRAS wild-type status for the prediction of response to cetuximab-combination chemotherapy for metastatic colorectal cancer patients; its predictive role was less prominent in the second/third-line than in the first-line treatment patients.

GaN epitaxial layers prepared on nano-patterned Si(001) substrate.

We report the growth of GaN epitaxial layer on Si(001) substrate with nano-patterns prepared by dry etching facility used in integrated circuit (IC) industry. It was found that the GaN epitaxial layer prepared on nano-patterned Si(001) substrate exhibits both cubic and hexagonal phases. It was also found that threading dislocation observed from GaN prepared on nano-patterned Si(001) substrate was significantly smaller than that prepared on conventional unpatterned Si(111) substrate. Furthermore, it was found that we can reduce the tensile stress in GaN epitaxial layer by about 78% using the nano-patterned Si(001) substrate.

Magnetic resonance imaging study of mouse islet allotransplantation.

Although only 10% of islet transplant recipients maintain insulin independence, 80% of them are C-peptide positive at 5 years. To better understand the fate of transplanted islets, a magnetic resonance imaging (MRI) technique has been used to detect superparamagnetic iron oxide (SPIO)-labeled transplanted islets. Recently, we successfully used a novel MRI contrast agent, chitosan-coated SPIO (CSPIO) nanoparticles, to monitor mouse islet isografts for 18 weeks after transplantation. In the present study, we tested whether CSPIO could be applied to monitor islet allografts, which are supposedly rejected without immune interventions. Male C57BL/6 and Balb/c mice were used as donors and recipients of islet transplantation, respectively. After overnight incubation with or without CSPIO (10 µg/mL), 300 C57BL/6 islets were transplanted under the left kidney capsule of each Balb/c mouse. Starting from day 10 after transplantation, 3.0-Tesla MRI of the recipients was performed weekly. Four mice were followed for ≥38 days. At 38 and 45 days, 1 islet graft was removed for insulin and Prussian blue staining, respectively. From days 10 to 45 after transplantation, CSPIO-labeled islet grafts were visualized on MRI scans as sustained distinct hypointense spots homogeneously located at the upper pole of left kidney, the site of transplantation. At days 38 and 45, the histology of CSPIO-labeled islet grafts revealed insulin and iron staining colocalized in the same areas. Our results in a mouse allotransplantation model indicated that CSPIO-labeled islets survived as long as 45 days with positive MRI.

Effects of cyclooxygenase-2 inhibitor and adenosine triphosphate-sensitive potassium channel opener in syngeneic mouse islet transplantation.

In the initial days after transplantation, islet grafts may be attacked by cytokines via cyclooxygenase-2 (COX-2), producing primary nonfunction. In addition, chronic overstimulation of ß-cells may impair insulin secretion. To enhance the function of transplanted islets, the present study investigated the effects of rofecoxib, a COX-2 inhibitor, and NN414 (6-chloro-3-[1-methylcyclopropyl]amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide), an adenosine triphosphate-sensitive potassium channel opener, on islet transplantation. Male inbred C57BL/6 mice were used as donors and recipients. One hundred fifty islets were isolated via collagenase digestion and density gradient, and syngeneically transplanted under the kidney capsule in mice with streptozotocin-induced diabetes. Recipients were treated with or without rofecoxib, 10 mg/kg/d orally, or with or without NN414, 3 mg/kg/d orally, for 4 weeks. After transplantation, recipient body weight, blood glucose concentration, and intraperitoneal glucose tolerance were measured. The grafted kidney was extracted for determination of insulin content at 4 weeks. In the rofecoxib-treated and NN414-treated groups and both control groups, body weight remained stable, and the blood glucose concentration decreased progressively. However, at 4 weeks after transplantation in the groups treated or not treated with rofecoxib or NN414, no significant difference was observed in recipient body weight, blood glucose concentration, and glucose tolerance or in insulin content of the graft. These data indicate that posttransplantation treatment with rofecoxib or NN414 has no beneficial effect on transplantation outcome in diabetic mouse recipients engrafted with a marginal islet mass.

Magnetic resonance imaging of transplanted mouse islets labeled with chitosan-coated superparamagnetic iron oxide nanoparticles.

Although only 10% of islet recipients maintain insulin independence, 80% of them are C-peptide positive at 5 years after transplantation. To better understand the fate of transplanted islets, a magnetic resonance imaging (MRI) technique has been used to detect Feridex-labeled islet grafts in rodents. In this study, we used a novel MRI contrast agent, chitosan-coated superparamagnetic iron oxide (CSPIO) nanoparticles, to monitor mouse islet grafts. Male inbred C57BL/6 mice were used as donors and recipients of islet transplantation. The islet cytotoxicity was evaluated by fluorescein diacetate and propidium iodide staining for RAW cells incubated with CSPIO. After being incubated overnight with and without CSPIO (10 mg/mL), 300 islets were transplanted under the left kidney capsule of each mouse. After transplantation, 3.0-Tesla MRI of the recipients was performed biweekly until 19 weeks. At the end of study, the islet graft was removed for insulin and Prussian blue staining. The cell death rates in RAW cells did not increase with increasing CSPIO concentrations or incubation time. The grafts of CSPIO-labeled islets were visualized on MRI scans as distinct hypointense spots homogeneously located at the upper pole of left kidney. Their MRI signal was 30%-50% that of control islets and was maintained throughout the follow-up period. At 18 weeks, the histology of CSPIO-labeled islet graft revealed the insulin- and iron-stained areas to be almost identical. Our results indicate that isolated mouse islets labeled with CSPIO nanoparticles can be effectively and safely imaged by using MRI as long as 18 weeks after transplantation.