Characterizing the dynamics of virulence and fungicide resistance of Phytophthora capsici in Michigan vegetable fields reveals loci associated with virulence.
The oomycete, Phytophthora capsici, is a destructive pathogen infecting more than 50 plant species and is one of the most serious threats to cucurbit production. Phytophthora blight can affect all plant stages, fungicides and cultural controls are used to limit losses. Pathogen virulence and fungicide resistance can provide insights into pathogenic mechanisms and inform effective management practices. In this study, we assessed virulence, mefenoxam sensitivity and genetic diversity of nine P. capsici populations collected from Cucurbitaceae, Solanaceae, and Fabaceae host families in Michigan from 2002 to 2016. We developed 992 simple sequence repeats (SSRs) in the P. capsici genome and identified 60 SSRs located within or close to RXLR-class (Arginine-any amino acid-Leucine-Arginine) effectors and 29 SSRs within or close to effector CRN (CRinkling and Necrosis) family protein, which represent 62 RXLR and 34 putative CRNs. Population structure analysis shows that mefenoxam resistance was not associated with the year of collection, host type, or location, but there were significant differences in virulence among the populations. Using the general linear model and mixed linear model-based association analyses with all effector-related SSRs, we identified four SSRs significantly associated with at least one of the virulence-related parameters. Of these SSRs, one (Pce_SC18) was in a predicted CRN effector and had high identity with the putative PhCRN37 effector in a related pathogen Plasmopara halstedii which can be further verified for virulence identification in P. capsici.


Retromalleolar Groove Deepening in Recurrent Peroneal Tendon Dislocation: Technique Tip.
Peroneal tendon dislocations are most prevalent in the active and athletic population, so accurate diagnosis and management are essential for optimal return of function. Although many nonoperative and surgical management options have been described, the optimal treatment method continues to be debated. In this technique article, a modified retromalleolar groove-deepening technique is described for addressing all anatomic variations of the posterior distal fibula and retromalleolar groove without unduly disturbing the important anatomic facets meant for retention in this region. This technique is indicated for chronic dislocated peroneal tendons, recurrent dislocating peroneal tendons, and dislocation of the tendons after acute injury with a shallow fibular peroneal groove. Although it remains unclear what effect a cortically abraded fibular gliding surface or forceful cortical impaction on the fibrocartilage gliding surface might have on peroneal tendon integrity and function long term, it would seem preferable to avoid such techniques if reliable alternatives are available.


HEPATITIS B VACCINATION STATUS AND NEEDLE STICK INJURY EXPOSURE AMONG OPERATING ROOM STAFF IN LAGOS, NIGERIA.
Hepatitis B virus (HBV) is an infective blood-borne pathogen that is a constant threat to operating room staff. The prevalence of Hepatitis B has been reported to range from 4.3% - 68% in Nigeria. The inadequate funding of health care in low income countries impacts negatively on the implementation of effective vaccination programs to protect health care workers including surgical theatre personnel. To determine the Hepatitis B vaccination status and the needle stick injury exposure among operating room staff in Lagos, Nigeria. The multicentre prospective survey was conducted in three public tertiary hospitals and two private hospitals in Lagos utilising a self-administered structured questionnaire that was distributed to operating room staff. We found that 96.7% (265) of respondents agreed that their job had exposed them to the risk of HBV infection. Over half (55.8%) correctly identified three doses of HBV as adequate to confer immunity against infection. It was observed that 58% (159) of the respondents were fully vaccinated, most of whom were doctors (69.8%, p=0.001) while a total of 173 (63.1%) reported exposure to needle-stick injury with blood in the preceding year. The operating room personnel were knowledgeable about the risk of HBV as an occupational hazard but a large number were not fully vaccinated against HBV infection. There was therefore the need to improve the vaccination coverage and educate identified high-risk operating room staff on appropriate post exposure prophylaxis practices.


Theorizing Factors Mediating With the Implementation of a Patient Feedback on Safety Intervention Implemented in the Primary Care Setting.
Developing safety interventions using patient feedback is valuable for creating safer systems of health care. A qualitative process evaluation of a patient feedback on safety intervention was undertaken in six primary care practices. The purpose was to theorize factors mediating with the implementation of the intervention using existing theories. The intervention required practices to obtain patient feedback on safety using a validated tool and respond using quality improvement methods. Multiple methods of qualitative data collection were used, including interviews and overt observation. Abductive reasoning informed the iterative process of analysis that examined theories relevant to the intervention and setting. A theoretical framework was developed, which encompassed mediating factors grouped under three concepts: practice readiness, utilization of problem-solving skills, and agency. Theorizing mediating factors was necessary to understand the complexities of primary care practices, and to identify the essential components for implementation of the intervention on a larger scale.


Chest pain, dyspnoea and elevated D-dimer in a recent air traveller.
A previously asymptomatic 69-year-old lady, who recently travelled on a 4 h flight, presented with acute left-sided pleuritic pain, dyspnoea and calf pain. Blood gases revealed hypoxaemia and D-dimer was significantly elevated. She also had low-grade fever, leukocytosis and a small left-sided pleural effusion on chest x-ray. The working diagnosis was pulmonary embolism and chest infection and she received low molecular weight heparin and antibiotics. A subsequent CT pulmonary angiogram ruled out pulmonary embolism but revealed an abnormal finding in the ascending aorta, suggestive of a penetrating aortic ulcer. Urgent transoesophageal echocardiography was consistent with an intramural haematoma and the patient underwent emergency aortic root replacement with imminent aortic rupture confirmed at surgery. This case highlights the fact that acute aortic syndromes may have atypical presentations and also emphasises the fact that D-dimer levels are elevated in aortic syndromes.


Dual receptor recognizing liposomes containing paclitaxel and hydroxychloroquine for primary and metastatic melanoma treatment via autophagy-dependent and independent pathways.
Autophagy acts as a cytoprotective mechanism for malignant tumors, thus maintaining the survival and promoting proliferation and metastasis of malignant tumors. Recent studies have showed that autophagy inhibitors can enhance the chemotherapeutic efficacy of anti-tumor growth. However, the antimetastasis effects and the possible mechanisms of chemotherapeutics combined with autophagy inhibitors have not been thoroughly explored. Here, we prepared R8-dGR peptide modified paclitaxel (PTX) and hydroxychloroquine (HCQ) co-loaded liposomes (PTX/HCQ-R8-dGR-Lip) for enhanced delivery by recognizing integrin αvβ3 receptors and neuropilin-1 receptors on B16F10 melanoma cells. Our results showed that R8-dGR modified liposomes (R8-dGR-Lip) enhanced tumor-targeting delivery in vitro and in vivo. Besides, PTX/HCQ-R8-dGR-Lip exhibited the optimum inhibitory effects on migration, invasion and anoikis resistance of B16F10 cells in vitro, and showed enhanced efficiency on inhibiting primary tumor growth and reducing lung metastasis in vivo. Meanwhile, the antimetastasis mechanism studies confirmed that the combination of the chemotherapeutic PTX and the autophagy inhibitor HCQ further suppressed the degradation of paxillin, the expression of MMP9 and MMP2. Moreover, HCQ disturbed the CXCR4/CXCL12 axis which could induce invasion and metastasis of malignant melanoma in an autophagy-independent way.


Impacts of terminal modification of [Ru(phen)2dppz](2+) on the luminescence properties: a theoretical study.
[Ru(phen)2dppz](2+) and other closely related ruthenium(II) complexes containing π-extended ligands were found to be non or weakly emissive in water, while exhibiting significant luminescence intensity growth when bound to DNA, however, a satisfactory interpretation has not been provided on this "light switch" mechanism. In the present study, we investigated the vertical transitions and triplet excited states of [Ru(phen)2dppz](2+) (1), [Ru(phen)2dppzi](2+) (2) and [Ru(phen)2dppz-idzo](2+) (3) in the gas phase and aqueous solution, through time dependent-density functional theory (TDDFT). Based on the optimized (3)MLCT and (3)LLCT structures and energies, we found that the (3)MLCT state might be responsible for the emissions of the complexes. Interesting connections between the singlet vertical transitions and the luminescence properties were noticed. Through ZORA-TDDFT calculation with perturbative SOC, we evaluated the intersystem crossing between the lowest singlet excited state, and both (3)MLCT state and (3)LLCT state, which gave a reasonable explanation for the luminescence properties of these complexes.


Formation of recombinant bifunctional fusion protein: A newer approach to combine the activities of two enzymes in a single protein.
The tissue of insects, pests, and fungi has a chitin layer followed by protein in the cell membrane. The complete biodegradation of chitin and protein-present in the waste requires the action of two enzymes, namely chitinase, and protease. Combining chitinase and protease in a single protein/enzyme will serve as a bifunctional enzyme that can efficiently degrade the chitin and protein-rich biomass. The present study was aimed to fuse these two enzymes to produce a single protein and study the kinetics of the recombinant fusion protein. A chitinase and alkaline protease genes were isolated, cloned, and expressed successfully as a fusion product in heterologous host Escherichia coli. The two native genes were successfully fused in E.coli by using flexible glycine-serine (G4S)2 linker (GGGGS, GS linker). The recombinant fusion protein in E.coli showed hydrolyzed chitin and protein on chitin and bovine serum albumin agar plates confirming the successful cloning and expression of chitinase and protease enzymes in a single fusion protein. The common pUC18-T7 mini vector with the ompA signal sequence helps the extracellular expression of fusion protein efficiently. The native gel electrophoresis revealed a molecular mass of purified protein as 92.0 kDa. The fusion protein's maximal chitinase and protease activity occurred at pH 5.0 and 8.0 and 30 0C, respectively resembling the individual enzymes'. In the kinetic studies of the fusion protein, it was observed that the presence of metal ions such as Cu2+, Na2+, and Ca2+; significantly enhanced the enzyme activities while organic solvents oxidants and chemicals have drastically affected the activities of both the enzymes in the fusion protein. No such fusion protein has been produced in a heterologous host yet. The reports on fusion protein with biomass-degrading capacity are also scarce. This is probably the first report of a bifunctional chitinase/protease expressed in E. coli.


[Developments in the treatment of patients with chronic myeloid leukemia].
In the treatment of chronic myelocytic leukaemia (CML) allogeneic bone marrow transplantation (BMT) from a sibling donor is the treatment of choice in patients younger than 50 years; the overall 5-year survival is about 60%. Donor lymphocyte infusion without chemotherapy may serve as an efficacious therapy for recurrence of CML after allogeneic BMT. Application of allogeneic BMT from a matched unrelated donor is increasing, but the outcome is still inferior to that of sibling BMT, largely due to more severe and more frequent complications. Treatment with interferon-alpha has been shown to prolong the overall median survival, but especially in a subgroup of patients (about 15%) who achieve a major cytogenic response. Combination of interferon-alpha and low-dose cytarabine leads to increased survival and a better cytogenic response than interferon-alpha alone. Current investigations are aimed at further improving survival and cytogenic response by using more intensive chemotherapy, such as high-dose cytarabine, followed by interferon-alpha maintenance therapy.


Proton computed tomography reconstruction using a backprojection-then-filtering approach.
A novel approach to proton CT reconstruction using backprojection-then-filtering (BPF) is proposed. A list-mode algorithm is formulated accommodating non-linear proton paths. The analytical form is derived for the deblurring kernel necessary for the filtering step. Further, a finite matrix correction is derived to correct for the limited size of the backprojection matrix. High quantitative accuracy in relative stopping power is demonstrated (⩽0.1%) using Monte Carlo simulations. This accuracy makes the algorithm a promising candidate for future proton CT systems in proton therapy applications. For the purposes of reconstruction, each proton path in the object-of-interest was estimated based on a cubic spline fit to the proton entry and exit vectors. The superior spatial-resolution of the BPF method over the standard filtering-then-backprojection approach is demonstrated. As the BPF algorithm requires only one backprojection and filtering operation on a scan data set, it also offers computational advantages over an iterative reconstruction approach.


Receptor interacting protein kinase 4 promotes cell proliferation, migration, and invasion in ovarian cancer via targeting protein kinase C delta.
Receptor interacting protein kinase 4 (RIPK4) has been reported to function as an oncogenic role in several types of cancers. The aim of this study was to evaluate the role of RIPK4 in ovarian cancer (OC) cells and to elucidate the mechanism behind this effect. In this study, the GEPIA database was used to analyze the RIPK4 expressions in OC tissues and overall survival. qRT-PCR and western blot assay were performed to detect the expressions of RIPK4 and protein kinase C delta (PRKCD) in OC cells. In addition, cell proliferation was assessed by CCK-8 and colony formation assay while cell invasion and migration were evaluated by transwell, wound healing and western blot assay. The interaction of RIPK4 and PRKCD was analyzed by the STRING database and the bioGRID database, and verified with co-immunoprecipitation. Herein, we describe that RIPK4 expression was upregulated in OC tissues and cells and was associated with poor overall survival. RIPK4 silencing repressed the proliferation, migration, and invasion of OC cells. Mechanistically, PRKCD was highly expressed in OC cells and was combined with RIPK4. PRKCD was highly positively associated with RIPK4 in OC and was regulated by RIPK4. Moreover, PRKCD overexpression reversed the inhibitory effects of RIPK4 silencing on OC cell proliferation, migration, and invasion. RIPK4 functions as an oncogene in OC cells via at least partially binding to PRKCD, which might represent a novel therapeutic strategy for improving survival for patients with OC.


Semiclassical transport in nearly symmetric quantum dots. II. Symmetry breaking due to asymmetric leads.
In this work-the second of a pair of articles-we consider transport through spatially symmetric quantum dots with leads whose widths or positions do not obey the spatial symmetry. We use the semiclassical theory of transport to find the symmetry-induced contributions to weak localization corrections and universal conductance fluctuations for dots with left-right, up-down, inversion, and fourfold symmetries. We show that all these contributions are suppressed by asymmetric leads; however, they remain finite whenever leads intersect with their images under the symmetry operation. For an up-down symmetric dot, this means that the contributions can be finite even if one of the leads is completely asymmetric. We find that the suppression of the contributions to universal conductance fluctuations is the square of the suppression of contributions to weak localization. Finally, we develop a random-matrix theory model which enables us to numerically confirm these results.


AP2 adaptor complex-dependent internalization of CD5: differential regulation in T and B cells.
CD5 is a key regulator of Ag receptor-mediated activation, selection, and differentiation in both T and B cells. Accumulating evidence indicates that lymphocyte activation and selection are sensitive to variations in levels of CD5 on the cell surface. We now show that CD5 expression on the surface of B and T cells is regulated posttranslationally by direct interaction with the mu(2) subunit of the AP2 adaptor complex that links transmembrane proteins to clathrin-coated pits. CD5 is rapidly internalized from the cell surface in lymphoid cell lines, mature splenic T and B cells, and peritoneal CD5(+) B cells following monovalent or bivalent ligation of the receptor. We mapped the mu(2) subunit binding site on CD5 to Y(429) and determined that the integrity of this site was necessary for CD5 internalization. Cross-linking of the Ag receptor with intact Abs inhibited CD5 internalization in B cells, but had the opposite effect in T cells. However, if F(ab')(2) Abs were used to stimulate the Ag receptor in B cells, the effect on CD5 internalization was now similar to that observed in T cells, indicating that signals through the Ag receptor and FcR regulate CD5 endocytosis in B cells. This was confirmed using an FcgammaRIIB1-deficient B cell line. The ability to differentially alter posttranslational CD5 expression in T and B cells is likely to be key in regulation of Ag receptor signaling and generation of tolerance in T and B lymphocytes.


History matching through dynamic decision-making.
History matching is the process of modifying the uncertain attributes of a reservoir model to reproduce the real reservoir performance. It is a classical reservoir engineering problem and plays an important role in reservoir management since the resulting models are used to support decisions in other tasks such as economic analysis and production strategy. This work introduces a dynamic decision-making optimization framework for history matching problems in which new models are generated based on, and guided by, the dynamic analysis of the data of available solutions. The optimization framework follows a 'learning-from-data' approach, and includes two optimizer components that use machine learning techniques, such as unsupervised learning and statistical analysis, to uncover patterns of input attributes that lead to good output responses. These patterns are used to support the decision-making process while generating new, and better, history matched solutions. The proposed framework is applied to a benchmark model (UNISIM-I-H) based on the Namorado field in Brazil. Results show the potential the dynamic decision-making optimization framework has for improving the quality of history matching solutions using a substantial smaller number of simulations when compared with a previous work on the same benchmark.


Effects of Field-Relevant Concentrations of Clothianidin on Larval Development of the Butterfly Polyommatus icarus (Lepidoptera, Lycaenidae).
Arable field margins are often sown with wildflowers to encourage pollinators and other beneficial or desirable insects such as bees and butterflies. Concern has been raised that these margins may be contaminated with systemic pesticides such as neonicotinoids used on the adjacent crop, and that this may negatively impact beneficial insects. The use of neonicotinoids has been linked to butterfly declines, and species such as the common blue butterfly ( Polyommatus icarus) that feed upon legumes commonly sown in arable field margins, may be exposed to such toxins. Here, we demonstrate that the larval food plants of P. icarus growing in an arable field margin adjacent to a wheat crop treated with the neonicotinoid clothianidin not only contain the pesticide at concentrations comparable to and sometimes higher than those found in foliage of treated crops (range 0.2-48 ppb) but also remain detectable at these levels for up to 21 months after sowing of the crop. Overall, our study demonstrates that nontarget herbivorous organisms in arable field margins are likely to be chronically exposed to neonicotinoids. Under laboratory conditions, exposure to clothianidin at 15 ppb (a field-realistic dose) or above reduced larval growth for the first 9 days of the experiment. Although there was evidence of clothianidin inducing mortality in larvae, with highest survival in control groups, the dose-response relationship was unclear. Our study suggests that larvae of this butterfly exhibit some deleterious sublethal and sometimes lethal impacts of exposure to clothianidin, but many larvae survive to adulthood even when exposed to high doses.


3D Bioprinting of Developmentally Inspired Templates for Whole Bone Organ Engineering.
The ability to print defined patterns of cells and extracellular-matrix components in three dimensions has enabled the engineering of simple biological tissues; however, bioprinting functional solid organs is beyond the capabilities of current biofabrication technologies. An alternative approach would be to bioprint the developmental precursor to an adult organ, using this engineered rudiment as a template for subsequent organogenesis in vivo. This study demonstrates that developmentally inspired hypertrophic cartilage templates can be engineered in vitro using stem cells within a supporting gamma-irradiated alginate bioink incorporating Arg-Gly-Asp adhesion peptides. Furthermore, these soft tissue templates can be reinforced with a network of printed polycaprolactone fibers, resulting in a ≈350 fold increase in construct compressive modulus providing the necessary stiffness to implant such immature cartilaginous rudiments into load bearing locations. As a proof-of-principal, multiple-tool biofabrication is used to engineer a mechanically reinforced cartilaginous template mimicking the geometry of a vertebral body, which in vivo supported the development of a vascularized bone organ containing trabecular-like endochondral bone with a supporting marrow structure. Such developmental engineering approaches could be applied to the biofabrication of other solid organs by bioprinting precursors that have the capacity to mature into their adult counterparts over time in vivo.


Utility and outcomes of fine-needle aspiration biopsy in Hodgkin's disease.
We present our 10-year experience, including clinical utilization and outcomes, with fine-needle aspiration biopsy (FNAB) in Hodgkin's disease (HD). Eighty-six cases from 68 patients with HD that were evaluated by FNAB were identified over a 10-year period. Medical records of these 68 patients were reviewed. Thirty-seven patients with primary HD underwent 41 aspirates. A diagnosis of HD was yielded in 12 and suggested in 13 cases (sensitivity 86.2%, false-positive 0%). Nine were diagnosed as atypical lymphoid cells, four as hyperplasia/other, and three as unsatisfactory. With these diagnoses, six patients began treatment without tissue exam. Thirty-five patients with suspected recurrent HD underwent 45 FNABs. Recurrent HD was confirmed in 15 and suggested in 12 aspirates (sensitivity 81.3%, false-suspicious 14.3%). With these diagnoses, 22 patients began treatment for recurrence without tissue exam. FNAB is useful both for establishing a primary diagnosis and confirming recurrence in HD and thus has a high utilization at our institution. In many instances, patients can begin therapy, negating the need for formal tissue exam.


Reslizumab in the treatment of inadequately controlled asthma in adults and adolescents with elevated blood eosinophils: clinical trial evidence and future prospects.
Eosinophils have long been implicated as playing a central role in the pathophysiology of asthma in many patients, and eosinophilic asthma is now recognized as an important asthma endotype. Eosinophil differentiation, maturation, migration, and survival are primarily under the control of interleukin-5 (IL-5). Reslizumab is a humanized monoclonal (immunoglobulin G4/κ) antibody that binds with high affinity to circulating human IL-5 and downregulates the IL-5 signaling pathway, potentially disrupting the maturation and survival of eosinophils. In 2016, an intravenous formulation of reslizumab was approved in the USA, Canada, and Europe as add-on maintenance treatment for patients aged ⩾18 years with severe asthma and with an eosinophilic phenotype. The efficacy of reslizumab as add-on intravenous therapy has been reported in several phase III studies in patients with inadequately controlled moderate-to-severe asthma and elevated blood eosinophil counts (⩾400 cells/µl). Compared with placebo, reslizumab was associated with significant improvements in clinical exacerbation rate, forced expiratory volume in 1 s, asthma symptoms and quality of life, and significant reductions in blood eosinophil counts. Reslizumab also demonstrated a favorable tolerability profile similar to that of placebo, with reported adverse events being mostly mild to moderate in severity. Ongoing studies are focusing on the evaluation of a subcutaneous formulation of reslizumab in patients with asthma and elevated eosinophil levels. This review discusses the preclinical and clinical trial data available on reslizumab, potential opportunities for predicting an early response to reslizumab, and future directions in the field of anti-IL-5 antibody therapy.


In silico analysis of high affinity potassium transporter (HKT) isoforms in different plants.
High affinity potassium transporters (HKTs) are located in the plasma membrane of the vessels and have significant influence on salt tolerance in some plants. They exclude Na(+) from the parenchyma cells to reduce Na(+) concentration. Despite many studies, the underlying regulatory mechanisms and the exact functions of HKTs within different genomic backgrounds are relatively unknown. In this study, various bioinformatics techniques, including promoter analysis, identification of HKT-surrounding genes, and construction of gene networks, were applied to investigate the HKT regulatory mechanism. Promoter analysis showed that rice HKTs carry ABA response elements. Additionally, jasmonic acid response elements were detected on promoter region of TmHKT1;5. In silico synteny highlighted several unknown and new loci near rice, Arabidopsis thaliana and Physcomitrella patent HKTs, which may play a significant role in salt stress tolerance in concert with HKTs. Gene network prediction unravelled that crosstalk between jasmonate and ethylene reduces AtHKT1;1 expression. Furthermore, antiporter and transferase proteins were found in AtHKT1;1 gene network. Interestingly, regulatory elements on the promoter region of HKT in wild genotype (TmHKT1;5) were more frequent and variable than the ones in cultivated wheat (TaHKT1;5) which provides the possibility of rapid response and better understanding of environmental conditions for wild genotype. Detecting ABA and jasmonic acid response elements on promoter regions of HKTs provide valuable clues on underlying regulatory mechanisms of HKTs. In silico synteny and pathway discovery indicated several candidates which act in concert with HKTs in stress condition. We highlighted different arrangement of regulatory elements on promoter region of wild wheat (TmHKT1;5) compared to bread wheat (TaHKT1;5) in this study.


Dinuclear Nickel Complexes of Thiolate-Functionalized Carbene Ligands and Their Electrochemical Properties.
Four dimeric nickel(II) complexes [Ni2Cl2(BnC2S)2] [1], [Ni2Cl2(BnC3S)2] [2], [Ni2(PyC2S)2]Br2 [3]Br2, and [Ni2(PyC3S)2]Br2 [4]Br2 of four different thiolate-functionalized N-heterocyclic carbene (NHC) ligands were synthesized, and their structures have been determined by single-crystal X-ray crystallography. The four ligands differ by the alkyl chain length between the thiolate group and the benzimidazole nitrogen (two -C2- or three -C3- carbon atoms) and the second functionality at the NHC being a benzyl (Bn) or a pyridylmethyl (Py) group. The nickel(II) ions are coordinated to the NHC carbon atom and the pendent thiolate group, which bridges to the second nickel(II) ion creating the dinuclear structure. Additionally, in compounds [1] and [2], the fourth coordination position of the square-planar Ni(II) centers is occupied by the halide ions, whereas in [3]2+ and [4]2+, the additional pendant pyridylmethyl groups complete the coordination spheres of the nickel ions. The electrochemical properties of the four complexes were studied using cyclic voltammetry and controlled-potential coulometry methods. The thiolate-functionalized carbene complexes [1] and [2] appear to be poor electrocatalysts for the hydrogen evolution reaction; the complexes [3]Br2 and [4]Br2, bearing an extra pyridylmethyl group, show higher catalytic activity in proton reduction, indicating that the pyridine group plays an important role in the catalytic cycle.


Multilocus analysis of nucleotide variation and speciation in Oryza officinalis and its close relatives.
Nucleotide variation in 10 unlinked nuclear genes was investigated in species-wide samples of Oryza officinalis and its close relatives (Oryza eichingeri and Oryza rhizomatis). Average estimates of nucleotide diversity were the lowest in O. rhizomatis ((sil) = 0.0038) and the highest in O. eichingeri ((sil) = 0.0057) that is disjunctly distributed in Africa and Sri Lanka. These wild rice species appeared to harbor relatively low levels of nucleotide variation relative to other plant species because the diversity level of O. eichingeri is only 23-46% of those in Zea species and 35% of that in Arabidopsis thaliana. The lower nucleotide diversity in these Oryza species could be best explained by their smaller historic effective population sizes. The speciation model test indicated that O. officinalis and its close relatives might have undergone a process of population contraction since divergence from their ancestor. Incongruent topologies among 10 gene trees, particularly regarding the positions of O. eichingeri and O. rhizomatis accessions might be attributed to lineage sorting arising from ancient polymorphism and hybridization/introgression between the Sri Lankan O. eichingeri and O. rhizomatis. However, the null hypothesis of the isolation model was not rejected for any contrast between taxa, which suggested that no subsequent gene flow shaped the present patterns of nucleotide variation since their divergence and that introgression was not pervasive in this group of species. Our molecular dating provides an approximate divergence time of 0.37 Myr between 2 geographical races of O. eichingeri, much more recent compared with the times of other speciation events in this group (0.63-0.68 Myr). A long-distance dispersal from West Africa to Sri Lanka was more likely to play a role in the disjunct distribution of O. eichingeri.


Initial evaluation of the acute and chronic multiple ligament injured knee.
Despite the recent focus on the limited use of urgent arteriograms in the evaluation of acute knee dislocations, physical examination remains the cornerstone of assessment. Several clinical scenarios dictate an orthopedic emergency: vascular disruption, open wound, compartment syndrome, or an irreducible joint/dimple sign. In the acute setting, every attempt should be made to rule out associated injuries and the need for intervention. The multiple ligament knee injury or knee dislocation is a complex dilemma that requires close attention. Concomitant injuries about the knee often arise and must be addressed prior to ligamentous repair, and therefore the orthopedic surgeon must maintain a high index of suspicion for associated injuries in the evaluation of a multiple ligament knee injury.


Nuclear characteristics of the endometrial cytology: liquid-based versus conventional preparation.
The aim of this study was to assess the utility of liquid-based cytologic preparation (LP) compared with conventional preparation (CP) for the assessment of nuclear findings in endometrial glandular and stromal breakdown (EGBD) which may be misdiagnosed as carcinoma in EGBD cases. The material consists of cytologic smears including 20 cases of proliferative endometrium (PE), 20 cases of EGBD, and 20 cases of endometrioid adenocarcinoma grade1 (G1) for which histopathological diagnosis was obtained by endometrial curettage at the JA Suzuka General Hospital. Nuclear findings were examined in PE cells, EGBD-stromal cells, EGBD-metaplastic cells, and G1 cells, respectively. It was examined about the following items; (1) nuclear shape; (2) A long/minor axis ratio in cell nuclei; (3) an area of cell nuclei; (4) overlapping nuclei. Results are as follows: (1) nuclear shape; as for the reniform shape of EGBD-stromal cells and spindle shape of EGBD-metaplastic cells, the ratio of the LP method was a higher value than the CP method. (2) The long axis and area of cell nuclei; LP in all groups was a recognizable tendency for nuclear shrinkage. (3) The long/minor axis ratio in cell nuclei; only EGBD-metaplastic cells recognize a significant difference between CP and LP. (4) Overlapping nuclei; LP was a higher value in comparison with CP in the other groups except PE cells, and the degree of overlapping nuclei was enhanced about three times. Therefore, although a cell of LP has a shrinking tendency, (1) it is excellent that LP preserves a characteristic of nuclear shape than CP; (2) a cellular characteristic becomes clearer, because three-dimensional architecture of LP is preserved of than CP. As for the standard preparation method for endometrial cytology samples, we considered that a concrete introduction of the LP method poses no problems.


Sustained virologic response of 100% in HCV genotype 1b patients with cirrhosis receiving ombitasvir/paritaprevir/r and dasabuvir for 12weeks.
Patients with chronic hepatitis C virus (HCV) infection and cirrhosis have a higher risk for liver-related complications and have historically been more difficult to cure than patients without cirrhosis. We evaluated the safety and efficacy of ombitasvir/paritaprevir/ritonavir and dasabuvir, without ribavirin, for 12weeks in patients with HCV genotype 1b infection and compensated cirrhosis. Treatment-naïve and peginterferon/ribavirin treatment-experienced patients received 12weeks of ombitasvir/paritaprevir/ritonavir (25/150/100mg once daily) and dasabuvir (250mgtwicedaily). Key inclusion criteria were hemoglobin ⩾10g/dl, albumin ⩾2.8g/dl, platelet count ⩾25×10(9)/L, creatinine clearance ⩾30ml/min, and Child-Pugh score ⩽6. Efficacy was assessed by the percentage of patients achieving SVR (HCV RNA <25IU/ml) 12weeks post-treatment (SVR12). Efficacy and safety were assessed in all patients receiving study drug. Sixty patients with HCV genotype 1b infection and cirrhosis received treatment. The study population comprised 62% male, 55% treatment-experienced, 83% with IL28B non-CC genotype, 22% with platelet count <90×10(9)/L, and 17% with albumin <3.5g/dl. All 60 patients completed treatment, and SVR12 was achieved in 100% (95% CI, 94.0-100%) of patients. The most common adverse events were fatigue (22%), diarrhea (20%), and headache (18%). Only one patient (1.7%) experienced a serious adverse event. Laboratory abnormalities were infrequently observed and not clinically significant. The HCV regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir without ribavirin for 12weeks achieved 100% SVR12 and was well tolerated in HCV genotype 1b-infected patients with cirrhosis, suggesting that this 12-week ribavirin-free regimen is sufficient in this population.


Curcumin pretreatment protects against PM2.5‑induced oxidized low‑density lipoprotein‑mediated oxidative stress and inflammation in human microvascular endothelial cells.
A previous study demonstrated that particulate matter (≤2.5 µm in diameter; PM2.5) may promote atherosclerosis. However, the underlying mechanisms of PM2.5 in human microvascular endothelial cells (HMEC‑1) remain to be elucidated. It has been reported that inflammation and oxidative stress can be reduced by curcumin, and in the present study, the aim was to investigate the protective effects of curcumin on PM2.5‑induced oxidative stress and inflammatory response in HMEC‑1. HMEC‑1 were stimulated with curcumin and PM2.5. The HMEC‑1 viability and apoptosis were detected by MTT and annexin V‑fluorescein isothiocyanate/propidium iodide assays. The levels of oxidized low‑density lipoprotein (oxLDL), tumor necrosis factor (TNF)‑α and interleukin (IL)‑8 were detected by ELISA. The intracellular reactive oxygen species formation in HMEC‑1 was detected using flow cytometry and 2',7'‑dichlorofluorescin diacetate. Nuclear factor (NF)‑κB, caspase 3 activity and adhesion molecule expression were also investigated. The results suggested that curcumin reduced PM2.5 (300 µg/ml)‑induced cell apoptosis and intracellular caspase 3 activity in HMEC‑1. ELISA analysis demonstrated that curcumin reduced PM2.5‑induced oxLDL, TNF‑α and IL‑8 levels. Curcumin induced NF‑κB, cell adhesion molecule 1 and vascular cell adhesion protein 1 expression. Thus, curcumin treatment may reduce PM2.5‑induced oxidative stress and inflammation in HMEC‑1. In summary, it was indicated that the effects of PM2.5 are associated with oxLDL via the NF‑κB signaling pathway, thereby inducing PM2.5 mediated oxidative and inflammatory responses. The results also suggested that curcumin may be able to reduce the oxidative and inflammatory effects of PM2.5 in HMEC‑1.


Defects in enzyme regulation versus defects in enzyme synthesis as cause of metabolic disorders.
Based on the consideration that normal metabolic processes depend upon the activity of key enzymes (and membrane carriers) as modulated by regulatory factors (hormones, diet, endogenous compounds, age, physical activity, environmental agents), metabolic disorders might be classified into two groups: (I) defects in enzyme synthesis, leading to enzyme deficiency (classical inborn errors of metabolism) or to qualitative (structural) enzyme alterations (entailing unresponsiveness to regulation), in the presence of normal regulatory factors; (II) defects in enzyme regulation, which include metabolic syndromes such as diabetes mellitus, obesity and hyperlipoproteinemias (other than type I), and are due to changes in enzyme activities caused by alterations in regulatory factor(s) (secondary to various causes), in the presence of normally responsive enzymes.


Pathological diagnosis of antibody-mediated rejection in renal allograft without c4d staining, how much reliable?
C4d as a part of complement activation process is a marker for detecting antibody-mediated rejection (ABMR) and its positivity accompanied by positive donor specific antibody (DSA), and morphologic view of humoral rejection has been suggested to detect ABMR since 2003. 41 specimens of transplanted kidney biopsies gathered from 2006 to 2008 were evaluated for morphological changes on light microscopy, and nephro-pathologist made distinct diagnosis for all of specimens then c4d staining was done for all of them. The association between primary diagnosis without c4d staining and c4d scoring on peritubular capillaries and glomerular capillaries were evaluated to determine whether morphological changes were enough for distinct diagnosis or not. Acute tubular necrosis (ATN) 27%, interstitial fibrosis and tubular atrophy (IF&TA) 17%, and T cell mediated rejection (TCMR) 22% were the commonest diagnosis on light microscopy, and 17% of all biopsies had diffuse positive c4d staining. There was not any report of ABMR in morphological evaluation while c4d positive staining was seen in some specimens (17%). It may result from masking of ABMR by other morphological changes such as TCMR and no specific histologic changes for ABMR on light microscopy. We would like to emphasize that c4d staining should be done for all of renal allograft biopsies, and pathologists all over the world should consider the probability of ABMR masked by other morphological changes on light microscopic evaluation.


MI-Sim: A MATLAB package for the numerical analysis of microbial ecological interactions.
Food-webs and other classes of ecological network motifs, are a means of describing feeding relationships between consumers and producers in an ecosystem. They have application across scales where they differ only in the underlying characteristics of the organisms and substrates describing the system. Mathematical modelling, using mechanistic approaches to describe the dynamic behaviour and properties of the system through sets of ordinary differential equations, has been used extensively in ecology. Models allow simulation of the dynamics of the various motifs and their numerical analysis provides a greater understanding of the interplay between the system components and their intrinsic properties. We have developed the MI-Sim software for use with MATLAB to allow a rigorous and rapid numerical analysis of several common ecological motifs. MI-Sim contains a series of the most commonly used motifs such as cooperation, competition and predation. It does not require detailed knowledge of mathematical analytical techniques and is offered as a single graphical user interface containing all input and output options. The tools available in the current version of MI-Sim include model simulation, steady-state existence and stability analysis, and basin of attraction analysis. The software includes seven ecological interaction motifs and seven growth function models. Unlike other system analysis tools, MI-Sim is designed as a simple and user-friendly tool specific to ecological population type models, allowing for rapid assessment of their dynamical and behavioural properties.


Getting the big picture: the macro-politics of information system development (and failure) in a Canadian hospital.
While recognized that global actors influence health information system design, studies of health informatics have largely focused on micro politics of technology design and implementation. Here a problematic patient care information system (PCIS) is discussed in relation to federal and provincial policies and corporate strategies to demonstrate that our understanding of health informatics can be enhanced by linking micro studies of health informatics to larger macro contexts. Interviews and document study. Although the extent to which federal initiatives influenced (or failed to influence) provincial and hospital initiatives remains debateable, events initiated at one level (the hospital's decision to implement software, initiated at the organizational level) are influenced (perhaps indirectly) by developments in other contexts (federal/macro changes gave an initiative more weight; provincial initiatives such as the Labour Accord altered the industrial relations environment in which system development occurred). Micro-studies of work practice, invaluable in addressing interactions between technologies, users and work practices, often fail to account for the historic reach of global actors, although it is often these historic circumstances that contribute to present-day interactions between user, information system and organization, and that find expression - often indirectly - in daily work practices.


Antibacterial Activity of Boswellia carterii Aqueous Extract and Its Effect on Phagocytosis in vitro.
Boswellia serrate has been traditionally used for the treatment of several inflammatory diseases, and bacterial resistance to antibiotics has recently increased the use of bioproducts. The present study aimed to assess the antibacterial effect and phagocytic ability of the aqueous extract of the Boswellia serrata in bacteria isolated in nosocomial infections. Boswellia carterii plant was collected and prepared from the aqueous extract in different concentrations. A total of 125 samples were collected from various clinical sources, including urine, sputum, wounds, otitis, and blood, from patients of both genders in different age groups. The results demonstrated that out of the 59 infected samples, urine samples had the highest infection (68%), followed by wounds, sputum, and otitis reported as (60%), (44%), and (40%), respectively. On the other hand, blood samples had the lowest percentage of infection (28%). Microscopic diagnostic results, biochemical tests, API Staph System, API 20E System, and Vitek 2 Compact pointed out that the highest infection rates were related to Staphylococcus aureus (32.20%), Pseudomonas aeruginosa (25.33%), and Escherichia coli (22.03%), while the lowest infection rate was detected in Klebsiella pneumonia (20.33%). The results indicated that aqueous extract of Boswellia carterii had an antibacterial activity for all bacterial isolates, 25 mg/ml of extract gave an inhibition zone of 10.8 mm,10.4 mm, 7mm, and 10mm for S. aureus, E. coli, P aeruginosa, and K. pneumonia, respectively, while 200 mg/ml of extract gave 24 mm, 22 mm, 18.4 mm, and 20 mm, respectively. The results pointed to a significant increase in the phagocytosis rate, with the phagocytosis of blood samples treated with Boswellia carterii extract (79.7%), as compared to control samples (57.75%). As evidenced by the results of this study, the aqueous extract of the Boswellia carterii plant showed antibacterial effects and a positive impact on the phagocytic ratio; nonetheless, it is recommended that further studies be conducted to characterize the compounds of this herb.


Genome sequence analysis of the temperate bacteriophage TBP2 of the solvent producer Clostridium saccharoperbutylacetonicum N1-4 (HMT, ATCC 27021).
The genus Clostridium consists of a diverse group of pathogenic and non-pathogenic bacteria. The non-pathogenic clostridia contain several solventogenic members of industrial importance, such as Clostridium acetobutylicum or C. beijerinckii. In the process of acetone-butanol-ethanol (ABE) fermentation, these strains are used in large scale fermentation plants since almost 100 years. Soon after establishment of the first plants, the fermentation processes suffered from different bacteriophage infections worldwide. A limited set of studies addressing bacteriophages in solventogenic clostridia have been conducted since then. In this study, we present the genome sequence of the temperate bacteriophage TBP2 of the solventogenic strain C. saccharoperbutylacetonicum N1-4 (HMT) that is used for ABE fermentation. The phage genome consists of 38 039 bp and includes 48 open reading frames. Sequence analysis indicates that the genome encloses random parts of the bacterial genome in addition to its own DNA. It represents the first fully sequenced genome of a temperate bacteriophage infecting solventogenic clostridia.


The influence of fatalistic beliefs on health beliefs among diabetics in Khartoum, Sudan: a comparison between Coptic Christians and Sunni Muslims.
Although there are many studies assessing the influence of religious beliefs on health they do not agree on whether the impact is positive or negative. More so, there is no consensus in the available literature on the definition of fatalism and what it means to individuals. In this phenomenological study we attempt to define what religious fatalism means to people living with diabetes in Khartoum, and how it affects their health beliefs, and how those beliefs affect their sense of coherence and generalized resistance resources, since salutogenesis is the guiding theory in this study. Three Copts and five Sunnis living with diabetes were interviewed, as well as a Coptic clergyman and a Sunni scholar. The semi-structured interviews were recorded and transcribed verbatim for analysis. Thematic network analysis was used to code salient concepts into basic themes, organizing themes and global themes. The empirical findings are thus structured as the three global themes: (1) fatalism and free will; (2) health responsibility; (3) acceptance and coping. Fatalism was defined as events beyond an individual's control where it is then the individual's free will to seek healthy behavior. Thus health responsibility was stressed upon by the participants in this study as well as the clergyman and scholar. There is also the concept of 'God doesn't give one what one cannot handle' that the participants relate to coping and acceptance. This study finds that the meaning of religious fatalism held by participants and religious clergy is not disempowering. The participants believe that they are responsible for their health. The meaning derived from fatalism is related to how they can accept what is beyond their control and cope with their health condition. Religious fatalism contributed to comprehensibility, manageability and meaningfulness in our participants' response to diabetes.


Clinical radiological aspects of primary endodontic lesions with secondary periodontal involvement.
Damage of pulp tissue usually begins in the coronal pulp. Its mistreatment or its lack of on time detection determines the progressive inclusion of the whole endodontic space in its evolution, opening the way of its expansion in the surrounding tissues of the tooth, and on the marginal apical tissue. Aim. The goal of this study was to highlight that the primary endodontic lesions with secondary periodontal implication healed and bone repair was obtained due to a proper disinfection and an adequate sealing of the endodontic system. In primary endodontic lesion with secondary periodontal involvement, endodontic treatment is required in the first stage followed by specific periodontal treatment. The prognosis is good if an appropriate endodontic approach is chosen, depending on the stage of the periodontal disease and the treatment response. The identification of the etiological factors is the most important to establish the appropriate treatment. In all clinical cases selected in this article, the healing tendency was noticed after an adequate disinfection and sealing of the endodontic system.


Genetic Diversity Relationship Between Grain Quality and Appearance in Rice.
Grain quality is an important breeding objective in rice, and the appearance of the grain also affects its commercial value in the market. The aim of this study was to decode the rice grain qualities and appearances, such as gelatinization temperature (GT), amylose content (AC), grain protein content (GPC), pericarp color (PC), length/width ratio (LWR), and grain volume (GV) at phenotypic and genetic levels, as well as the relationships among them. A genome-wide association study (GWAS) was used to identify the quantitative trait locus (QTLs) associated with the target traits using mixed linear model (MLM) and Bayesian-information and linkage-disequilibrium iteratively nested keyway (BLINK) methods. In general, AC was negatively correlated with GPC and GV, while it was positively correlated with LWR and PC. GPC was positively correlated with LWR. Using the rice diversity panel 1 (RDP1) population, we identified 11, 6, 2, 7, 11, and 6 QTLs associated with GT, AC, GPC, PC, LWR, and GV, respectively. Five germplasm lines, superior in grain qualities and appearances for basic breeding materials or improvement, were identified. Notably, an F-box gene OsFbox394 was located in the linkage disequilibrium (LD) block of qLWR7-2, which specifically expresses in endosperm and seed tissues, suggesting that this gene may regulate the seed development in rice grain. Besides, different haplotypes of OsHyPRP45 showed significant differences in AC, indicating that this gene may be related to AC in rice grain.


Cardiac biopsy in childhood.
Endomyocardial biopsy was attempted in 18 children aged 5 months to 15 years with 82% success. Biopsies obtained from 15 children were examined by light and electron microscope making positive morphological diagnoses in 3 cases. The biopsy findings were actively helpful in 7 other cases, which contrasts with experience in adult biopsy series. This is a low risk procedure which does not add to the hazards of cardiac catheterization in children.


Diabetic patients have an increased risk of vertebral fractures independent of BMD or diabetic complications.
Although patients with type 2 diabetes (T2DM) have an increased risk of hip fracture, risk of vertebral fracture (VF) and its association with BMD are still unclear. We examined Japanese T2DM patients (161 men >50 yr and 137 postmenopausal women) and non-DM controls (76 and 622, respectively) by lateral spine radiography and DXA at the lumbar spine (L), femoral neck (FN), and radius (R). Logistic regression analysis adjusted for age, body mass index, and L-BMD showed that the presence of T2DM was an independent risk factor for prevalent VFs in women (OR = 1.86, p = 0.019) and men (OR = 4.73, p < 0.001). BMD at any site, however, was not significantly associated with the presence of prevalent VFs in T2DM patients, in contrast to the significant association in controls (at least p = 0.010). Comparison of T2DM patients with and without VFs showed no significant differences in BMD values, bone markers, or diabetes status. Receiver operating characteristic analysis showed that the absolute L-, FN-, and R-BMD values for detecting prevalent VFs were higher in T2DM patients than controls, whereas their sensitivity and specificity were lower. T2DM patients may have an increased risk of VFs independent of BMD or diabetic complication status, suggesting that bone quality may define bone fragility in T2DM.


Intravenous iron does not affect the rate of decline of residual renal function in patients on peritoneal dialysis.
The preservation residual renal function (RRF) is important for adequacy of peritoneal dialysis. Oxidative stress from intravenous (IV) iron has been shown to cause renal damage. The effect of IV iron on RRF has not been studied. Here, we report our experience during April 1999-March 2005 of the effect of IV iron on RRF. The study group included 24 patients (9 men, 15 women). The mean age of the group was 61 +/- 17.7 years. Diabetes mellitus and hypertension were the underlying cause of end-stage renal disease in 55% of the patients. We found serum creatinine, creatinine clearance, urea clearance, urine output, hemoglobin, transferrin saturation, and ferritin all to be statistically significantly different before and after administration of IV iron to the patients. However, the rate at which the glomerular filtration rate (GFR) declined over time did not change significantly when calculated for the period before and after the iron infusion, suggesting that the changes we observed after IV iron infusion were the result of the declining RRF--the rate of that decline being unaffected by the IV iron. Furthermore, the rate of GFR decline in this study was similar to that previously reported in our patients.


Dimensional Interpolation for Random Walk.
We employ a simple and accurate dimensional interpolation formula for the shapes of random walks at D = 3 and D = 2 based on the analytically known solutions at both limits D = ∞ and D = 1. The results obtained for the radius of gyration of an arbitrary shaped object have about 2% error compared with accurate numerical results at D = 3 and D = 2. We also calculated the asphericity for a three-dimensional random walk using the dimensional interpolation formula. The results agree very well with the numerically simulated results. The method is general and can be used to estimate other properties of random walks.


Homo- and heteroleptic zinc aminophenolates as initiators for lactide polymerization.
The reaction of ZnEt2 with one or two equivalents of aminophenolate ligand N-[methyl(2-hydroxy-3,5-di-tert-butylphenyl)]-N-methyl-N-cyclohexylamine gives hetero- and homoleptic molecular compounds [(micro,eta2-L2)ZnEt]2 and [Zn(eta2-L2)2]. The later is most probably a mixture of diastereoisomers that in solution shows an interesting dynamic behaviour. Both complexes as well as the BnOH derivative of the latter, [(eta2-L2)Zn(micro-BnO)]2, proved excellent initiators for lactide polymerization.


The relationship between peripheral blood inflammatory markers and diabetic macular edema in patients with severe diabetic retinopathy.
Diabetic macular edema (DME) is a serious complication of diabetic retinopathy (DR). Recent studies have shown that inflammation is closely associated with the development of DME, and peripheral blood inflammatory markers [white blood cell (WBC) count and its subtypes] are relatively simple and easy to detect. Here, we investigated the relationship between peripheral blood inflammatory markers and macular edema in patients with severe DR (including both severe non-proliferative DR and proliferative DR). A total of 42 patients with severe DR were included in this study and divided into two groups: a severe DR with DME group (DME group, n=18) and a severe DR without DME group (non-DME group, n=24). Ophthalmologic findings and hematologic results were retrospectively retrieved from hospitalization records and databases. The neutrophil percentage was significantly higher in the DME group (62.52%±8.21%) than in the non-DME group (57.30%±8.17%) (P<0.05); in contrast, the lymphocyte percentage was significantly lower in the DME group (28.09%±7.45%) than in the non-DME group (33.54%±7.29%) (P<0.05). Logistic regression analysis showed a significant correlation between lymphocyte percentage and DME [odds ratio (OR) =0.654, 95% CI: 0.436-0.851; P=0.011]. Lymphocyte percentage can be used as an inflammatory marker for the development of DME in patients with severe DR.


The herbicide glyphosate inhibits hippocampal long-term potentiation and learning through activation of pro-inflammatory signaling.
Glyphosate, a herbicide marketed as Roundup, is widely used but there are concerns this exposure could impair cognitive function. In the CA1 region of rat hippocampal slices, we investigated whether glyphosate alters synaptic transmission and long-term potentiation (LTP), a cellular model of learning and memory. Our hypothesis is that glyphosate alters neuronal function and impairs LTP induction via activation of pro-inflammatory processes. Roundup depressed excitatory synaptic potentials(EPSPs) in a dose-dependent manner with complete suppression at 2000 mg/L. At concentrations ≤ 20 mg/L Roundup did not affect basal transmission, but 4 mg/L Roundup administered for 30 min inhibited LTP induction. Acute administration of 10-100 μM glyphosate also inhibited LTP induction. Minocycline, an inhibitor of microglial activation, and TAK-242, an inhibitor of toll-like receptor 4 (TLR4), both overcame the inhibitory effects of 100 µM glyphosate. Similarly, lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS), a different TLR4 antagonist, overcame the inhibitory effects. In addition, ISRIB (integrated stress response inhibitor) and quercetin, an inhibitor of endoplasmic reticulum stress, overcame the inhibitory effects. We also observed that in vivo glyphosate injection (16.9 mg/kg i.p.) impaired one-trial inhibitory avoidance learning. This learning deficit was overcome by TAK-242. These observations indicate that glyphosate can impair cognitive function through pro-inflammatory signaling in microglia.


A Case of Antineutrophil Cytoplasmic Antibody Vasculitis-Associated Acute Kidney Injury in a Patient With Asymptomatic COVID-19 Infection.
Vasculitis, or inflammation of blood vessels, is commonly seen with severe acute respiratory syndrome Coronavirus disease 2 (SARS-CoV-2). It is usually triggered by an autoimmune response induced by the virus, infection by the virus itself and trauma to the epithelial vessels caused by the release of cytokines. We present a case of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (pauci-immune crescentic glomerulonephritis [GN]) superimposed on acute kidney injury caused by SARS-CoV-2. Our patient is a 57-year-old Hispanic female who presented with rising creatinine and active urinary sediment in the setting of an asymptomatic COVID-19 infection. A kidney biopsy was done for declining renal function, and positive myeloperoxidase antibodies revealed pauci-immune focal crescentic glomerulonephritis. Normalization of renal function was not achieved with pulse steroids and rituximab. The patient required long-term hemodialysis. Our case here adds to the very few cases of pauci-immune crescentic glomerulonephritis reported in patients with asymptomatic SARS-CoV-2 infection. We recommend keeping this high on the differential in SARS-CoV-2-infected patients presenting with acute kidney injury.


[The remote effects of brain tumors on cerebral blood flow as measured by single photon emission CT].
In order to assess the remote effects of supratentorial brain tumors, the cerebellar blood flow and cerebral blood flow of the symmetrical regions in the contralateral cerebral hemispheres were measured by single photon emission CT. Forty four patients with supratentorial brain tumors, such as gliomas, meningiomas and germ cell tumors etc., were included in this study. Contralateral cerebellar hypoperfusion (CCH) was exhibited in 51%, 18 of 35 unilateral brain tumors. Regarding tumor location, CCH was more correlated with frontoparietal lesions. The mean values of contralateral delta Cerebellar blood flows (delta CBFs) were lower than those of ipsilateral delta CeBFs, and also statistically, bilateral delta CeBFs significantly decreased. The greater the volume of lesions including peritumoral edemas, the lower the delta CeBF became. Among the 9 cases with obstructive hydrocephalus, the preoperative delta CeBFs which had decreased significantly, returned to normal postoperatively. Statistically, it seemed that there was no transcallosal suppression caused by unilateral brain tumors. However the delta rCBF of the mirror foci in postoperative patients decreased significantly. In conclusion, the remote effects on the cerebral blood flow, which are common in strokes cases, were demonstrated in many cases of supratentorial brain tumors and the occurrence of CCH was closely related to the frontoparietal lesion including the tumor and peritumoral edema. Also the mechanism of CCH was discussed with preference for a transneural suppression.


Discovery of (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]- 3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (SCH 503034), a selective, potent, orally bioavailable hepatitis C virus NS3 protease inhibitor: a potential therapeutic agent for the treatment of hepatitis C infection.
Hepatitis C virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, which affects more than 170 million people worldwide. Currently the only therapeutic regimens are subcutaneous interferon-alpha or polyethylene glycol (PEG)-interferon-alpha alone or in combination with oral ribavirin. Although combination therapy is reasonably successful with the majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only about 40% of the patients showing sustained virological response. Herein, the SAR leading to the discovery of 70 (SCH 503034), a novel, potent, selective, orally bioavailable NS3 protease inhibitor that has been advanced to clinical trials in human beings for the treatment of hepatitis C viral infections is described. X-ray structure of inhibitor 70 complexed with the NS3 protease and biological data are also discussed.


Pharmacovigilance of Regenerative Medicine Under the Amended Pharmaceutical Affairs Act in Japan.
Two Japanese regulatory agencies, the Ministry of Health, Labour and Welfare and the Pharmaceuticals and Medical Devices Agency announced the implementation of a new review system called 'Conditional Approval,' specifically for the emerging field of regenerative medicine, in an amendment to the Pharmaceutical Affairs Act in 2014. Regenerative medicine was regulated in the category of 'Medical Devices' prior to the amendment and was not covered by the Relief Service, a system that provides financial aid to people who have experienced an adverse drug reaction and developed serious side effects as a result. Through the amendment, regenerative medicine is defined as a new category and is covered by the Relief Service under the amended Pharmaceutical Affairs Act, called the 'Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics' (PMD Act). This amendment allows the use of Relief Service data for pharmacovigilance activities, making the Relief Service the third adverse drug reaction reporting route in addition to the existing reporting routes from marketing authorization holders and healthcare providers. For optimum incorporation and use of this Relief Service data, earlier access should be allowed even before the reports from the Pharmaceuticals and Medical Devices Agency to the Ministry of Health, Labour and Welfare are finalized, which is mandatory under the current PMD Act.


[Rapidly progressive ANCA-negative glomerulonephritis in the course of pauci immune microscopic vasculitis with hemolytic anemia probable in the course of Wilson's disease].
Pauci-immune glomerulonephritis, i.e., with no evidence of immune deposits in the blood vessel, is the most prevalent form of rapidly progressive glomerulonephritis (RPGN). In the pathogenesis of pauci-immune renal disease inflammation of blood vessels in the presence of circulating anti-neutrophil cytoplasm antibodies (ANCA) takes place. However the lack of ANCA (about 5-30% of patients) does not exclude pauci-immune vasculitis. The patients without circulating ANCA might have fewer extrarenal symptoms than those who are ANCA-positive. We describe a case of a 40-year old women with ANCA-negative renal limited pauci-immune small-vessel vasculitis with rapidly decreasing kidney function. She was ineffectively treated with plasmapheresis combined with a puls of cyclophosphamide (i.v.) and 3 pulses of methyloprednisolone (i.v.). The patient progressed to end-stage renal disease and should be treated with renal replacement therapy. In differential diagnosis we excluded other causes of pauci-immune vasculitis (Churg-Strauss syndrome, Wegener's granulomatosis), vasculitis with immune complexes deposition (systemic lupus erythematosus, Schoenlein-Henoch purpura, post-infection RPGN), Goodpasture disease, haemolytic-uremic syndrome (HUS), disseminated intravascular coagulation (DIC) and Wilson's disease.


Rupture of the bowel due to road trauma: the emergence of the "seat belt syndrome".
Seat belts have proved to be life saving for drivers and passengers involved in motor-car collisions. The number of severe head, face and trunk injuries has been significantly reduced. However, the wearing of belts has been responsible for an increased incidence of bowel rupture, in itself a potentially lethal injury if not diagnosed and treated early. There is still much to be done in improving seat belt design.


Safety and efficacy of endoscopic ultrasound-guided drainage of pancreatic fluid collections with lumen-apposing covered self-expanding metal stents.
Plastic stents, placed via endoscopy to drain pancreatic fluid collections (PFCs), require repeat access. Covered metal stents are larger in diameter and can be inserted in a single step, but can migrate. We evaluated the safety and efficacy of a lumen-apposing, covered, self-expanding metal stent (LACSEMS) for PFC drainage. We performed a prospective study of the outcomes of stent placement in 33 patients (18 men; age, 53 ± 14 y; 28 with chronic pancreatitis) with symptomatic pancreatic pseudocysts and walled-off necrosis (≥ 6 cm with ≥ 70% fluid content). Subjects were enrolled at 7 tertiary care centers (6 in the United States and 1 in Europe) from October 2011 through August 2013. Cystenterostomies were created based on endoscopist preference. Safety outcomes included infection, bleeding, perforation, tissue injury, and stent migration. Efficacy end points included LACSEMS placement, patency, and removal, as well as 50% or more reduction in PFCs. The mean size of the patients' PFCs was 9 ± 3.3 cm. LACSEMSs were placed successfully via endoscopic ultrasound guidance in 30 patients (91%); the remaining 3 patients received 2 double-pigtail stents. One subject could not be evaluated because of a pseudoaneurysm. In the patients receiving LACSEMS, PFCs resolved in 27 of 29 (93%). Overall, PFCs resolved in 30 of 33 patients (91%). Endoscopic debridement through the LACSEMS was conducted in 11 subjects. Complications (15%) included abdominal pain (n = 3), spontaneous stent migration, back pain (n = 1), access-site infection, and stent dislodgement (n = 1). LACSEMS were placed successfully in 91% of subjects with PFCs. Overall, 93% had PFC resolution. Advantages of LACSEMSs over other stents include single-step deployment and the ability to perform endoscopic debridement with minimal stent migration. Clinicaltrials.gov: NCT01419769.


Natural variability in acyl moieties of sugar esters produced by certain tobacco and other Solanaceae species.
A unique feature of glandular trichomes of plants in the botanical family Solanaceae is that they produce sugar esters (SE), chemicals that have been shown to possess insecticidal, antifungal, and antibacterial properties. Sugar esters of tobacco (Nicotiana tabacum) provide pest resistance, and are important flavor precursors in oriental tobacco cultivars. Acyl moieties of SEs in Nicotiana spp., petunia, and tomato are shown to vary with respect to carbon length and isomer structure (2-12 carbon chain length; anteiso-, iso-, and straight-chain). Sugar esters and their acyl groups could serve as a model to explore the basis of phenotypic diversity and adaptation to natural and agricultural environments. However, information on the diversity of acyl composition among species, cultivars, and accessions is lacking. Herein, described is the analysis of SE acyl groups found in 21 accessions of Nicotiana obtusifolia (desert tobacco), six of Nicotiana occidentalis subsp. hesperis, three of Nicotiana alata, two of N. occidentalis, four modern tobacco cultivars, five petunia hybrids, and one accession each of a primitive potato (Solanum berthaultii) and tomato (Solanum pennellii). A total of 20 different acyl groups was observed that were represented differently among cultivars, species, and accessions. In Nicotiana species, acetate and iso- and anteiso-branched acids prevailed. Straight-chain groups (2-8 carbons) were prominent in petunias, while octanoic acid was prominent in N. alata and N. × sanderae. Two unexpected acyl groups, 8-methyl nonanoate and decanoate were found in N. occidentalis subsp. hesperis. Longer chain groups were found in the petunia, tomato, and potato species studied.


Growth and Dark Current Analysis of GaSb- and InP-Based Metamorphic In0.8Ga0.2As Photodetectors.
Short-wavelength infrared photodetectors based on metamorphic InGaAs grown on GaSb substrates and InP substrates are demonstrated. The devices have a pBn structure that employs an AlGaAsSb thin layer as the electron barrier to suppress dark current density. The strain effect on the electrical performance of the devices was specifically studied through the growth of the pBn structure on different substrates, e.g., InP and GaSb, via a specific buffering technique to optimize material properties and minimize dark current. A lower device dark current density, down to 1 × 10-2 A/cm2 at room temperature (295 K), was achieved for the devices grown on the GaSb substrate compared to that of the devices on the InP substrate (8.6 × 10-2 A/cm2). The improved properties of the high-In component InGaAs layer and the AlGaAsSb electron barrier give rise to the low dark current of the photodetector device.


Joint effects of nine antidepressants on Raphidocelis subcapitata and Skeletonema marinoi: A matter of amine functional groups.
Antidepressants are among the most prescribed pharmaceuticals throughout the world. Their presence has already been detected in several aquatic ecosystems worldwide and their effects on non-target organisms justify the growing concern of both the public and regulatory authorities. These emerging pollutants do not occur as isolated compounds but rather as multi-component mixtures, which may lead to increased adverse effects compared to individual compounds. Freshwater and marine algae seem particularly sensitive to pharmaceuticals, including antidepressants. Studies assessing the toxicity of antidepressant mixture to algae focused mainly on binary mixtures of selective serotonin reuptake inhibitors. In the present experiment, the freshwater algae Raphidocelis subcapitata (formerly known as Pseudokirchneriella subcapitata) and the marine diatom Skeletonema marinoi were exposed to equitoxic mixtures of 9 antidepressants (fluvoxamine, fluoxetine, sertraline, duloxetine, venlafaxine, clomipramine, amitriptyline, and citalopram) at different concentrations. The growth inhibition was measured. Results showed that the toxicity of this mixture was higher than the effects of each individual component, highlighting simple additivity or synergistic effects, whereas tested concentrations were below the 10% inhibition concentration (IC10) of each compound. Moreover, the QSAR analysis highlighted that antidepressants would act through narcosis (non-specific mode of action) towards the two species of algae. However, more specific effects can be observed by differentiating compounds with a primary/secondary amine from those with a tertiary amine. These mixture effects on algal species have to be assessed, especially since any impacts on phytoplankton could ultimately impact higher trophic levels (less food, secondary poisoning).


Conjugation and maximal biliary excretion of bilirubin in the rat during pregnancy and lactation and during estroprogestogen treatment.
Hepatic bilirubin conjugation and excretion were investigated during pregnancy and lactation in the rat. Bilirubin uridine diphosphate-glucuronyltransferase activity was decreased by 30% in pregnant rats, both when expressed per milligram of protein or as specific activity and per unit of liver weight. Liver size increased during pregnancy, and, as a consequence, total hepatic glucuronyltransferase activity was unchanged. The biliary bilirubin output was normal in pregnant rats, and when loaded with bilirubin, the maximal output in bile for the whole liver was also normal. In lactating rats, specific glucuronyltransferase activity returned to control values, but the activity per unit of liver weight was still lower, due to the decreased hepatic protein concentration. The liver remained enlarged during lactation, and total hepatic glucuronyltransferase activity was increased, together with the maximal output of bilirubin in bile. Two weeks after delivery, hepatic bilirubin conjugation and excretion in nonlactating mothers were comparable to those of virgin females. Parallel modifications of bilirubin glucuronyltransferase assayed in vitro and of maximal biliary output of the pigment in vivo were observed in all animals studied. The output of bilirubin diconjugates in bile was decreased during pregnancy but no changes of the proportion of the mono-to diconjugates in bile were observed 2 weeks after delivery both in lactating and in nonlactating rats. The modifications observed during pregnancy could not be reproduced by treatment with beta-estradiol and progesterone. This suggests that different hormones or modifications of steroid metabolism are probably involved in the alterations of hepatic bilirubin metabolism in pregnant and lactating rats.


Community structure of the gut microbiota in sympatric species of wild Drosophila.
Many aspects of animal ecology and physiology are influenced by the microbial communities within them. The underlying forces contributing to the assembly and diversity of gut microbiotas include chance events, host-based selection and interactions among microorganisms within these communities. We surveyed 215 wild individuals from four sympatric species of Drosophila that share a common diet of decaying mushrooms. Their microbiotas consistently contained abundant bacteria that were undetectable or at low abundance in their diet. Despite their deep phylogenetic divergence, all species had similar microbiotas, thus failing to support predictions of the phylosymbiosis hypothesis. Communities within flies were not random assemblages drawn from a common pool; instead, many bacterial operational taxonomic units (OTUs) were overrepresented or underrepresented relative to the neutral expectations, and OTUs exhibited checkerboard distributions among flies. These results suggest that selective factors play an important role in shaping the gut community structure of these flies.


High drug payload nanoparticles formed from dexamethasone-peptide conjugates for the treatment of endotoxin-induced uveitis in rabbit.
To develop and demonstrate the effectiveness of a novel dexamethasone (Dex) nanoformulation for treating uveitis. We designed and screened a dexamethasone-peptide conjugate (Dex-SA-FFFE), formed via a biodegradable ester bond linkage, that could spontaneously form high drug payload nanoparticles in aqueous solution for treating uveitis. An in vitro release study indicated that Dex and Dex-SA-FFFE sustainably released from Dex-SA-FFFE nanoparticles over a 48 h study period. Meanwhile, the formed Dex-SA-FFFE nanoparticles hardly caused cytotoxicity in human corneal epithelial cell at drug concentrations up to 1 mM after 24 h of incubation but reduced cell viability after 48 h and 72 h of incubation. An in vitro anti-inflammatory efficacy assay showed that the Dex-SA-FFFE nanoparticles exhibited a comparable anti-inflammatory efficacy to that of Dex in lipopolysaccharide (LPS)-activated RAW264.7 macrophages via significant decreases in the secretion of various pro-inflammatory cytokines (e.g., nitric oxide, tumor necrosis factor-α, interleukin-6). Topical instillation of Dex-SA-FFFE nanoparticles showed good ocular tolerance without causing changes in corneal thickness and intraocular pressure during the entire study period. Furthermore, topical instillation of Dex-SA-FFFE nanoparticles displayed a comparable in vivo therapeutic efficacy to that of dexamethasone sodium phosphate (Dexp) aqueous solutions in an endotoxin-induced uveitis (EIU) rabbit model. Based on these results, it is reasonable to believe that the proposed Dex-SA-FFFE nanoparticles might have great application for the treatment of anterior uveitis.


Stability and aggregation studies of non-sonicated arsonolipid-containing vesicles.
In this study, we investigated non-sonicated arsonolipid-containing liposomes (arsonoliposomes) in terms of the influence of lipid composition on their stability, assessed as membrane integrity and physical stability [size]. Vesicles consisting of plain arsonolipids or mixtures of arsonolipids with cholesterol [Chol] or with distearoyl-phospatidylcholine [DSPC] were studied. Membrane integrity was evaluated by measuring the retention of incorporated 5-(6)carboxyfluorescein [CF] during incubation of the vesicles in Tris buffer, pH 7.4. Photon correlation spectroscopy was used to investigate the time-dependent aggregation of arsonoliposomes in the absence and presence of Ca(2+)ions. Vesicles composed of plain C18 (acyl fatty chain) arsonolipids were found to be unstable, with only 15% of the initially incorporated CF remaining in the vesicles after 24 hours. The addition of Chol to the membrane (1:1 mol/mol) significantly increased the stability of arsonoliposomes, while the addition of DSPC to the lipid bilayer (1:1 mol/mol) increased vesicle stability to a lower extent. The results of particle size analysis showed that non-sonicated arsonoliposomes consisting of plain arsonolipid Ars/Stearic are highly and rapidly aggregated, while calcium-induced aggregation is also significant, but slower. Aggregation could not be always explained on the basis of zeta potential changes, indicating that the process is complex.


Therapeutic effects of metformin and clomiphene in combination with lifestyle intervention on infertility in women with obese polycystic ovary syndrome.
To evaluate the therapeutic effects of metformin and clomiphene in combination with lifestyle adjustment on infertility in women with obese polycystic ovarian syndrome (PCOS). A total of 101 infertile women with obese PCOS admitted to our hospital from July 2013 to July 2015 were randomly divided into an observation group (n=51) and a control group (n=50). The control group was treated with metformin plus clomiphene, based on which the observation group was also subjected to lifestyle adjustment. The body weight, body mass index (BMI) and waist-to-hip ratio (WHR) were measured before and after treatment. The changes of reproductive hormones, ovaries and endometrium were detected, and the rates of menstrual recovery, ovulation and pregnancy were observed. The body weight and BMI of the observation group after treatment were significantly lower than those before treatment and of the control group (P<0.05). There was no significant difference in WHR between the two groups. In the observation group, there were significant differences in LH, T, LH/FSH, FINS and TG levels before and after treatment and from those of the control group after treatment (P<0.05). Both the left and right ovarian volumes of the observation group after treatment were significantly lower than those before treatment and of the control group after treatment (P<0.05). The menstrual recovery, ovulation and pregnancy rates of the observation group were significantly higher than those of the control group (P<0.05). Lifestyle adjustment combined with metformin and clomiphene can improve the reproductive endocrine and lipid metabolism of obese PCOS patients, decrease the volumes of left and right ovaries, and increase the menstrual recovery, ovulation and pregnancy rates.


Magnitude and correlates of bird collisions at glass bus shelters in an urban landscape.
Wildlife residing in urban landscapes face many human-related threats to their survival. For birds, collision with glass on manmade structures has been identified as a major hazard, causing hundreds of millions of avian fatalities in North America every year. Although research has investigated factors associated with bird-glass collision mortality at buildings, no prior studies have focused on bird fatalities at glass-walled bus shelters. Our objectives in this study were to describe the magnitude of bird-bus shelter collisions in the city of Stillwater, Oklahoma and assess potential predictors of collision risk, including characteristics of shelters (glass area) and surrounding land cover (e.g., vegetative features). We surveyed for bird carcasses and indirect collision evidence at 18 bus shelters over a five-month period. Linear regression and model selection results revealed that the amount of glass on shelters and the area of lawn within 50 m of shelters were both positively related to fatal bird collisions; glass area was also positively associated with observations of collision evidence on glass surfaces. After accounting for scavenger removal of carcasses, we estimate that a minimum of 34 birds are killed each year between May and September by collision with the 36 bus shelters in the city of Stillwater. While our study provides an initial look at bird fatalities at bus shelters, additional research is needed to generate a large-scale estimate of collision mortality and to assess species composition of fatalities at a national scale. Designing new bus shelters to include less glass and retrofitting existing shelters to increase visibility of glass to birds will likely reduce fatal bird collisions at bus shelters and thus reduce the cumulative magnitude of anthropogenic impacts to birds in cities.


Intraoperative intravenous administration of rFVIIa and hematoma volume after early surgery for spontaneous intracerebral hemorrhage: a randomized prospective phase II study.
Surgery of spontaneous supratentorial intracerebral hemorrhage (ICH), especially if performed early, can be complicated by rebleeding, a condition that can worsen the outcome. We evaluated the effect of recombinant activated factor VII (rFVIIa) on postoperative rebleeding. In this randomized, open-label, single-blinded study, 21 patients with spontaneous supratentorial ICH diagnosed by computed tomography (CT) scan were treated with intravenous rFVIIa (100 mcg/Kg b.w., N=13) or placebo (N=8). Hematoma volume was assessed using CT scan immediately, 18-30 hours, and 5-7 days after hematoma evacuation. The primary endpoint was a hematoma volume at 18-30 hours after surgery. All CT scans were evaluated at one center by the same investigator who was unaware of the treatment. Hematoma volume was measured using dedicated software. At baseline, the hematoma volume was 59.2±27.4 and 71.5±32.1 mL in the rFVIIa and placebo group, respectively. Hematoma evacuation resulted in significantly smaller ICH volumes that were similar in the rFVIIa and placebo group at 18-30 hours after surgery (15.9±14.2 mL and 18±15.1 mL, respectively; mean difference 2.1 mL, 95% confidence interval -12.1 to 16.2, P=0.76 (0.03 mL after adjustment for baseline value)). The frequencies of deep venous thrombosis, myocardial infarction, troponin I elevation and cerebral ischemia were similar in both groups. In this pilot study, intraoperative, intravenous rFVIIa administration did not modify hematoma volume after early ICH surgery. However, the 95% CI was wide, which indicates considerable uncertainty. Therefore, our results do not disprove the potential benefit of rFVIIa administration, which could be shown in a larger study.


Decreased spinal endomorphin-2 contributes to mechanical allodynia in streptozotocin-induced diabetic rats.
Diabetic neuropathic pain (DNP) plays a major role in decreased life quality of diabetes patients, however, the neural mechanisms underlying DNP remain unclear. Endomorphins are the endogenous ligands for mu-opioid receptor. There is increasing evidence implicating the involvement of spinal endomorphin-2 (EM2) in neuropathic pain. In this study, using a streptozotocin induced diabetic rat model that displayed obvious mechanical allodynia, it was found that the expression of spinal EM2 was significantly decreased in DNP rats. While intrathecal administration of exogenous EM2 attenuated mechanical allodynia in DNP rats, the mu-opioid receptor antagonist β-funaltrexamine facilitated these events. It was found that the reduction in spinal EM2 was mediated by increased activity of dipeptidylpeptidase IV, possibly as a consequence of diabetes-induced oxidative stress. Taken together, our results provide the first evidence that the reduction in the level of an endogenous opioid in primary afferents was significantly associated with DNP. This indicates that the chronic pain associated with DNP might be due to the loss of an inhibitory effect on pain signal transmission.


Peritoneal ultrafiltration for refractory fluid overload and ascites due to pulmonary arterial hypertension.
Pulmonary hypertension is a common finding in patients with advanced liver disease. Similarly, among patients with advanced pulmonary arterial hypertension, right heart failure leads to congestive hepatopathy. Diuretic resistant fluid overload in both advanced pulmonary hypertension and chronic liver disease is a demanding challenge for physicians. Venous congestion and ascites-induced increased intra-abdominal pressure are essential regarding recurrent hospitalization, morbidity and mortality. Due to impaired right-ventricular function, many patients cannot tolerate extracorporeal ultrafiltration. Peritoneal dialysis, a well-established, hemodynamically tolerated treatment for outpatients may be a good alternative to control fluid status. We present a patient with pulmonary arterial hypertension and congestive hepatopathy hospitalized for over 3 months due to ascites induced refractory volume overload treated with peritoneal ultrafiltration. We report the treatment benefits on fluid balance, cardiorenal and pulmonary function, as well as its safety. In conclusion, we report a case in which peritoneal ultrafiltration was an efficient treatment option for refractory ascites in patients with congestive hepatopathy.


Delimitating cryptic species in the Gracilaria domingensis complex (Gracilariaceae, Rhodophyta) using molecular and morphological data.
Species in the genus Gracilaria that display conspicuously flattened vegetative morphologies are a taxonomically challenging group of marine benthic red algae. This is a result of their species richness, morphological similarity, and broad phenotypic plasticity. Within this group, the Gracilaria domingensis complex is one of the most common, conspicuous, and morphologically variable species along the tropical western Atlantic Ocean. Previous research has identified that members of this complex belong to two distantly related clades. However, despite this increased phylogentic resolution, species delimitations within each of these clades remain unclear. Our study assessed the species diversity within this difficult complex using morphological and molecular data from three genetic markers (cox1, UPA, and rbcL). We additionally applied six single-marker species delimitation methods (SDM: ABGD, GMYCs, GMYCm, SPN, bPTP, and PTP) to rbcL, which were largely in agreement regarding species delimitation. These results, combined with our analysis of morphology, indicate that the G. domingensis complex includes seven distinct species, each of which are not all most closely related: G. cervicornis; a ressurected G. ferox; G. apiculata subsp. apiculata; a new species, Gracilaria baiana sp. nov.; G. intermedia subsp. intermedia; G. venezuelensis; and G. domingensis sensu stricto, which includes the later heterotypic synonym, G. yoneshigueana. Our study demonstrates the value of multipronged strategies, including the use of both molecular and morphological approaches, to decipher cryptic species of red algae.


Interleukin-1 inhibits thyrotrophin-induced human thyroglobulin gene expression.
The regulation of thyroglobulin (Tg) and its specific mRNA by interleukin-1 (IL-1) in cultured human thyrocytes was investigated. Specific binding of 125I-labelled IL-1 on thyrocytes was confirmed by solid-phase binding assay. Thyrocytes dispersed from Graves' thyroid tissues were incubated with TSH with or without recombinant human IL-1. TSH stimulated Tg release from cultured human thyrocytes in a dose- and time-dependent manner. Both IL-1 alpha and beta inhibited TSH-induced Tg release at concentrations ranging from 0.01 to 10 U/ml. The suppressive activities of IL-1 alpha and beta were similar. They did not alter the basal level of Tg release. Unstimulated human thyrocytes did not contain any detectable Tg mRNA, but TSH-stimulated thyrocytes expressed a single species of Tg mRNA (8.5 kb). Both IL-1 alpha and beta inhibited TSH-induced Tg mRNA in a dose-responsive manner. IL-1 (10 U/ml) caused maximal suppression of TSH-induced Tg mRNA to nearly basal levels. In contrast, the gamma-actin mRNA hybridization signal was not altered in control or treated cells. Furthermore, IL-1 stimulated [3H]thymidine uptake into thyrocyte DNA. These results demonstrate that IL-1 directly inhibits TSH-induced Tg gene expression and provide further support for a functional role of IL-1 as a local modulator of thyroid hormone synthesis.


Matrix metalloproteinase expression during experimental autoimmune neuritis.
Experimental autoimmune neuritis (EAN) is an animal model of Guillain-Barré syndrome. We have shown recently that BB-1101, a broad-spectrum matrix metalloproteinase (MMP) inhibitor, prevents development of EAN when given from the day of immunization and, more important clinically, reduces disease severity when given from symptom onset. This suggests the involvement of MMP activity in the pathogenesis of EAN. However, the exact function and expression patterns of MMPs in acute inflammation of the PNS have not been investigated. MMP-like enzymes are also involved in the processing of tumour necrosis factor-alpha (TNF-alpha), which has been implicated previously in the pathology associated with EAN. In the present study we investigated the profile of MMP and TNF-alpha expression and their localization in sciatic nerve tissue during EAN, using a semiquantitative competitive reverse transcriptase-coupled polymerase chain reaction and immunohistochemistry. In the normal rat PNS, four of the 10 MMPs studied were constitutively expressed and four MMPs were differentially regulated during EAN. Expression of TNF-alpha was elevated at peak disease severity and localized to Schwann cells, macrophages and endoneurial blood vessels. Expression levels of 92 kDa gelatinase and stromelysin-1 were significantly increased early in the development of EAN and continued to rise, peaking at day 15 coincident with maximum disease severity. Schwann cells and endothelial cells were the main cellular source of these enzymes. Prominent infiltration of inflammatory cells into the sciatic nerve was concordant with a significant increase in the expression levels of matrilysin and macrophage metalloelastase. Both matrilysin and macrophage metalloelastase were detected in invading macrophages, T lymphocytes and resident Schwann cells. The selective upregulation of specific MMPs during EAN and their varied cellular localization suggests that MMPs play a multifactorial role in the aetiology of EAN. Activity of MMPs could participate in the disruption of the blood-nerve barrier, breakdown of the myelin sheath, the release of TNF-alpha, and facilitate leukocyte invasion into the PNS. These observations highlight MMPs as potential targets for therapeutic intervention in acute peripheral neuropathies, such as Guillain-Barré syndrome.


Progress in Molecular Genetic Study of Mitochondrial Cardiomyopathy.
Mitochondria plays a key role in providing ATP for the energy-consuming cardiac tissues. Mitochondrial cardiomyopathy is a myocardial condition characterized by abnormal heart structure and/or function secondary to genetic defects involving the mitochondrial respiratory chain. The typical cardiac manifestations of mitochondrial cardiomyopathy include hypertrophic and dilated cardiomyopathy,while left ventricular myocardial noncompaction is less common. Recent research has suggested that most mitochondrial diseases result from mitochondrial DNA mutation,which can be found in genes that encode ancillary proteins needed for genetic transcription (tRNA),in genes that encode subunits of the electron transport chain complexes,or in genes that control the activities of the mitochondria called D-loop zone. However,the exact physiological mechanisms remain unclear. This review summarizes the recent advances in the molecular mechanism of mitochondrial cardiomyopathy.


Colorimetric Detection of Norovirus in Oyster Samples through DNAzyme as a Signaling Probe.
Worldwide, norovirus is one of the most associated causes of acute gastroenteritis, which leads to nearly 50 000 child deaths every year in developing countries. Therefore, there is great demand to develop a rapid, low-cost, and accurate detection assay for the foodborne norovirus infection to reduce mortality caused by norovirus. Considering the importance of norovirus, we have demonstrated a highly sensitive and specific colorimetric detection method for analysis of human norovirus genogroups I and II (HuNoV GI and GII) in oyster samples. This is the first report to employ colorimetric HRPzyme-integrated polymerase chain reaction (PCR) for direct norovirus detection from the real shellfish samples. We found that the HRPzyme-integrated PCR method is more sensitive than the gel electrophoresis approach and could detect the HuNoV GI and GII genome up to 1 copy/mL. The specificity of the proposed method was successfully demonstrated for HuNoV GI and GII. Further, we performed testing HuNoVs in the spiked oyster samples, and the HRPzyme-integrated PCR method proved to be an ultrasensitive and selective method for detecting HuNoVs in the real samples. By integration of the proposed method with the portable PCR machine, it would be more reliable to improve food safety by detecting HuNoVs in the different types of shellfish, such as oyster and mussel, at the production field.


Laser-Doppler microvascular measurements in the peri-implant areas of different osseointegrated bone conductor implant systems.
The objective of this study was to evaluate the impact of hydroxyapatite coating of newly designed osseointegrated fixtures' abutments on the postoperative complication rates. The integrity of peri-implant microcirculation was used as a marker to compare tissue viability after different surgical techniques. Laser-Doppler Flowmetry (LDF) measures alone, and coupled with heat provocation tests were applied to test the different microcircular patterns. Measures for 17 consecutively implanted patients (8 women, 9 men, ages ranged from 18 to 77 years) were recruited; seven with soft tissue reduction (STR); and 10 with soft tissue preservation (STP).Thirteen non-operated retro-auricular areas were examined as naive controls. In isotherm conditions the baseline blood flow remained stable in all groups. The naive control patients demonstrated significant changes of blood flux in the intact skin. The non-implanted yet previously operated contralateral sides of the patients demonstrated marginally lower (p = 0.09) blood flux index. The STR sides however, showed significantly lower (average 217 %) provoked blood flux compared to controls (p < 0.001). At the STP sides a maladaptation could be observed (average 316 %) compared to the contralateral sides (p = 0.53). STP sides demonstrated a significantly better blood flow improvement compared to the STR sides (p = 0.02). These results suggest a favorable postoperative condition of vascular microcirculation after STP, than after STR surgery. The possibly faster wound healing and lower potential complication rate may widen the inclusion criteria and maybe beneficial for the patient compliance with a better quality-of-life.