Negative superhelicity promotes ATP-dependent binding of yeast RAD3 protein to ultraviolet-damaged DNA.
The RAD3 gene of Saccharomyces cerevisiae is required for excision repair of UV-damaged DNA and is essential for cell viability. Remarkable homology exists between RAD3 and the human excision repair gene XPD, whose mutational inactivation underlies the cancer-prone disorder in xeroderma pigmentosum group D patients. Our previous work demonstrated that RAD3-encoded protein contains a DNA helicase activity. Here, we show that RAD3 binds preferentially to UV-damaged DNA over nondamaged DNA. Removal of pyrimidine dimers from damaged DNA by enzymatic photoreactivation does not affect binding, suggesting an affinity of RAD3 for pyrimidine (6-4) pyrimidone photoproducts. Damage-specific binding by RAD3 is strongly dependent on ATP and on the degree of negative superhelicity in DNA. The requirement of superhelicity in damage binding may target RAD3 to regions of DNA undergoing transcription, resulting in the preferential repair of these regions. The rad3 Arg-48 mutant protein, which lacks the DNA helicase activity, also binds UV-damaged DNA preferentially, indicating that DNA helicase and damage binding are two distinct and separable functional entities in RAD3.


Lymphedematous fibroepithelial polyps of the glans penis and prepuce: a clinicopathologic study of 7 cases demonstrating a strong association with chronic condom catheter use.
This report describes an underrecognized entity of the penis that is associated with chronic condom catheter use and phimosis. Our study group consisted of 7 patients who presented with polypoid or cauliflower-like masses that involved the glans penis or prepuce and that ranged in size from 2 to 7.5 cm in greatest dimension (median size, 2.5 cm). The majority of lesions affected the ventral surface of the glans, near the urethral meatus. The patients ranged in age from 25 to 58 years (median age, 40 years) at the time of initial surgical resection. The preoperative duration of the lesions ranged from 6 months to 10 years. Five patients had a history of long-term condom catheter use (duration: 5 to 21 years), and 1 patient had paraphimosis. The background history for 1 patient is unknown. Histologically, all specimens had a polypoid configuration and a keratinizing squamous epithelial surface. The underlying stroma was notably edematous, and there was vascular dilation of preexisting vessels, and in many instances, a focal mild small vessel proliferation. The stroma had mildly to moderately increased cellularity with mononucleated and multinucleated mesenchymal cells. A mild inflammatory infiltrate was often present. Two cases were examined with immunohistochemistry, and the stromal cells had limited immunoreactivity for muscle-specific actin, alpha-smooth muscle actin, and desmin and had no reactivity for S100 protein or CD34. Surgical intervention was local in all instances. Follow-up information was available for 5 of the 7 patients (71%), with a mean follow-up interval of 11 years 4 months. Two patients developed a local recurrence of the process at intervals of less than 1 years and 3 years 7 months. Both recurrent lesions were also managed by local excision.


[Isolation of enteropathogenic Escherichia coli O157:H16 identified in a diarrhea case in a child and his household contacts in La Pampa Province, Argentina].
Enteropathogenic Escherichia coli (EPEC) is a major causative agent of acute diarrhea in children in developing countries. This pathotype is divided into typical EPEC (tEPEC) and atypical EPEC (aEPEC), based on the presence of the bfp virulence factor associated with adhesion, encoded in the pEAF plasmid. In the present study, the isolation of aEPEC O157:H16 from a bloody diarrhea case in a child and his household contacts (mother, father and sister) is described. The strain was characterized as E. coli O157:H16 eae-ɛ-positive, sorbitol fermenter with β-glucuronidase activity, susceptible to all antimicrobials tested, and negative for virulence factors stx1, stx2, ehxA and bfp. XbaI-PFGE performed on all isolates showed the AREXHX01.1040 macrorestriction pattern, with 100% similarity. These results highlight the importance of epidemiological surveillance of E. coli O157-associated diarrhea cases identified in children and their family contacts, as well as the incorporation of molecular techniques that allow the detection of the different E. coli pathotypes.


Sonoporation enables high-throughput loading of trehalose into red blood cells.
Despite recent advances in biostabilization, clinical blood supplies still experience shortages and storage limitations for red blood cells (RBCs) have not yet been sufficiently addressed. Storing RBCs in a frozen or dried state is an appealing solution to address storage limitations, but many promising cryoprotectants, including the non-reducing sugar trehalose, are impermeant to mammalian cell membranes and cannot be utilized effectively using currently available compound-loading methods. We found that transient pore formation induced by ultrasound and microbubbles (sonoporation) offers an effective means of loading trehalose into RBCs to facilitate long-term storage in a frozen or desiccated state. The protective potential of trehalose loading was demonstrated by freezing processed RBCs at -1 °C/min to -80 °C, then either storing the cells at -80 °C or lyophilizing them. RBCs were either thawed or rehydrated after 42 days of storage and evaluated for membrane integrity and esterase activity to estimate recovery and cell viability. The intracellular concentration of trehalose reached 40 mM after sonoporation and over 95% of treated RBCs were recovered after loading. Loading of trehalose was sufficient to maintain RBC morphology and esterase activity in most cells during freezing (>90% RBC recovery) and to a lower degree after lyophilization and rehydration (>20% recovery). Combining sonoporation with an integrated fluidics device allowed for rapid loading of up to 70 mM trehalose into RBCs. These results demonstrate the potential of sonoporation-mediated trehalose loading to increase recovery of viable RBCs, which could lead to effective methods for long-term stabilization of RBCs.


Decrease in blood coagulation factors II (prothrombin), VII, IX and X in the rat after a single oral dose of butylated hydroxytoluene.
Male Sprague-Dawley rats were given butylated hydroxytoluene (BHT) in a dose of 800 mg/kg body weight orally, and 0.5-72 hr later plasma concentrations of factors II, VII, IX and X and hepatic levels of BHT and BHT quinone methide (2,6-di-tert-butyl-4-methylene-2,5-cyclohexadienone) were determined. Levels of factors II, VII, X and IX were reduced 36-60 hr after BHT treatment, but by 72 hr, those most affected (VII and IX) showed some recovery and X had returned to normal. Hepatic levels of BHT reached a maximum 3 hr (a major peak) and 24 hr after BHT dosing and BHT quinone methide reached a maximum at 6 and 24 hr (a major peak). In rats given BHT orally in doses of 200, 400 and 800 mg/kg, factors II, VII and X decreased after 48 hr only in rats given the highest dosage, but factor IX was more susceptible to BHT and showed a dose-dependent decrease. Phylloquinone (1 mg/rat) injected ip 24 hr after the administration of 800 mg BHT/kg maintained normal levels of factors VII and X and an almost normal level of factor IX, but had little effect on the level of factor II. In studies of the effects of drug-metabolizing-enzyme modifiers, neither ip pretreatment with 75 mg phenobarbital sodium/kg for 3 days nor the feeding of 1% cysteine in the diet throughout the experiment prevented the decrease in vitamin-K-dependent factors by 800 mg BHT/kg, but 2-day ip pretreatment with 60 mg cobaltous chloride/kg/day maintained normal levels of factors II and VII and reduced the BHT effect on factors IX and X. SKF 525A (50 mg/kg) injected ip either 30 min before or 12 hr after BHT treatment partially prevented the decrease in factors II, VII and X, or in all four factors, respectively. Thus the decrease in vitamin K-dependent factors may be the same with a single oral dose of BHT as with dietary BHT, and the anticoagulant effect may require the metabolic activation of BHT.


Balanophorin B inhibited glycolysis with the involvement of HIF-1α.
Cancer cells exhibit a metabolic change called aerobic glycolysis compared with normal cells. Balanophorin B is a terpenoid ingredient reported from the genus Balanophora. In this research, we studied the effect of balanophorin B on glycolysis of HepG2 cells and Huh-7 cells under hypoxia. The Warburg effect was monitored by assessing glucose uptake, oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Key enzymes in the glycolytic pathway and HIF-1α protein expression and degradation were analyzed by real-time PCR and western blotting. The anti-cancer effect of balanophorin B in vivo was also investigated. Balanophorin B inhibited the proliferation, glucose uptake, and ECAR in both HepG2 cells and Huh-7 cells. In addition, balanophorin B inhibited the protein level of HIF-1α and its downstream targets LDHA and HKII under hypoxia, whereas HIF-1α mRNA level did not change after balanophorin B treatment. The HIF-1α plasmid reversed the inhibition of balanophorin B on glycolysis, and the proteasome inhibitor MG132 attenuated the effect of balanophorin B on HIF-1α protein expression, suggesting that balanophorin B might post-transcriptionally affect HIF-1α. Moreover, balanophorin B increased the expression of VHL and PHD2. HIF-1α siRNA also greatly attenuated the inhibitory effect of balanophorin B on HepG2 cells glucose uptake. Balanophorin B significantly inhibited tumor growth in vivo, without causing obvious toxicity to mice. These data suggest that balanophorin B inhibits glycolysis probably via an HIF-1α-dependent pathway, and the ubiquitin-proteasome pathway was greatly involved in the induction of balanophorin B on HIF-1α degradation.


Evaluation and Isolation of Cancer Stem Cells Using ALDH Activity Assay.
The aldehyde dehydrogenase (ALDH) is a polymorphic enzyme responsible for the oxidation of aldehydes to carboxylic acids. In this chapter, it is described the role of ALDH in the identification of cancer stem cells (CSCs), having been shown that stem cells express high levels of ALDH. Here, we present a method called ALDEFLUOR assay used for the identification, evaluation, and isolation of normal, cancer stem and progenitor cells.


Australian Lamb Meat - The Response to Societal and Ethnic Influences.
Lamb has long been considered a traditional meal within Australia; however as consumer preferences have changed since the 1950's, consumption of lamb has decreased from the 1980's. This is the result of changing societal roles, particularly for females, decreasing household sizes and increasing awareness of the impact of food choices on human health. Since the 1980's improvement of farm practices and increases in genetic gains has addressed part of this decline by increasing the amount of lean meat and decreasing fat in lamb retail cuts. Yet, this has created a challenge for the industry to utilise the larger carcases now being produced. Thus, a whole value chain approach to increasing consumption has been undertaken through several research programs to create cuts which suit the modern consumer, examine nutritional and eating quality and increase adoption of value added cuts. Therefore, this paper outlines this history of changing consumer patterns and the consequent research to address these changes.


Overexpression of RING box protein-1 (RBX1) associated with poor prognosis of non-muscle-invasive bladder transitional cell carcinoma.
RING box protein-1 (RBX1) is a key subunit of the ubiquitin E3 ligase Skp1/Cullin1/Rbx1/F-box protein complex. Altered expression RBX1 is shown to associate with tumorigenesis and tumor progression. This study detected RBX1 expression for association with clinical significance (such as clinicopathological data and survival of the patients) in non-muscle-invasive bladder transitional cell carcinoma (NMIBC). A total of 70 primary NMIBC tissue specimens and 24 normal tissue specimens were recruited and analyzed immunohistochemically for expression of RBX1 protein and associated with clinicopathological data and survival of the patients. RBX1 was highly expressed in NMIBC, but was lowly expressed in the normal tissue. RBX1 expression was associated with high tumor grade and advanced clinical stage (P < 0.01 and P < 0.05, respectively). Moreover, patients with high RBX1 expression had shorter recurrence-free survival and progression-free survival rates (P < 0.001 and P < 0.01, respectively). Multivariate analysis demonstrated that RBX1 expression is an independent prognostic factor for tumor recurrence and progression of NMIBC (P < 0.05). Overexpression of RBX1 protein contributes to tumor progression and poor prognosis of NMIBC.


Analysis of defect layers' insertion effect on optical transmission properties of multilayer structures based on one-dimensional photonic crystals.
In this paper, we are interested in the analysis of the transmission spectrum of several multilayer structures based on one-dimensional photonic crystals (1D PCs) infiltrated with different kinds of defect materials, such as bismuth oxide (Bi2O3), lithium niobate (LiNbO3), and E7 liquid crystal (LC). A 1D PC acting as a multichannel filter is constructed by inserting multiple Bi2O3 defect layers, while a localized mode is moved by applying various electric fields on a LiNbO3 defect layer inserted in the middle of a 1D PC structure used as a tunable device. A localized mode is also tuned by applying different magnetic fields on an E7 LC phase shifter inserted between SiO2/TiO2 alternative layers.


[New possibilities screening of refractive errors among children].
To establish early detection of refractive errors among children in Slovakia. Different screening methods have been evaluated and compared in this work. we have been working on a prospective study. Pre-school children in kindergardens in Central Slovakia were checked up between years 2009-2011. Effectiveness of various screening methods was compared within 2 groups, using test-type and Plusoptix Vision Screener. Parentęs of children positive to refractive errors were recommended to consult a paediatrician ophthalmologist. 3982 children were examined. As a result, 13-14.1% of children who have not been examinated by the specialist, were positive. 53.3% of them went to see the doctor afterwards. establishment of early refractive errors screening is an important method how to prevent strabismus and amblyopia. It is very important to improve parentęs knowledge about the risk of refractive errors and also to improve screening methods with collaboration with kindergarten teachers.


Left ventricular function in subacute and chronic mitral regurgitation. Effect on function early postoperatively.
Quantitative analysis of biplane ventriculograms, including calculation of the end-systolic pressure/volume ratio, was used to define left ventricular systolic performance in 10 normal subjects, 10 patients with symptomatic subacute (less than 6 months' duration) mitral regurgitation, and 18 patients with symptomatic chronic mitral regurgitation. Left ventricular volume, mass, and systolic function were similar for patients with subacute and with chronic mitral regurgitation, suggesting that some patients with recent-onset nonischemic mitral regurgitation have partial adaptation to chronic valve insufficiency prior to their symptomatic event. Rate of development of left ventricular wall stress in early systole was increased in subacute mitral regurgitation compared with chronic mitral regurgitation and normal subjects. Duration of symptoms did not correlate with degree of ventricular adaptation to mitral regurgitation, and end-systolic indices of left ventricular performance did not predict early postoperative clinical response to valve replacement or repair.


Measuring violence perpetration: Stability of teachers' self-reports before and after an anti-violence training in Cote d'Ivoire.
Epidemiological studies of interpersonal violence commonly use self-reported violence perpetration as an outcome measure, but few studies have investigated the stability of and influences on self-reports. To assess changes in teachers' self-reported use of physical violence against students before and after a one-day violence prevention training, and factors associated with changed reports in Cote d'Ivoire. Before and after the training, 157 teachers completed surveys containing 32 questions adapted from the ICAST-CI. Changes in physical violence usage were summarized over lifetime, past school term, and past-week timeframes, and the consistency in responses assessed via intraclass correlation coefficients (3,k), percent agreement, and kappa statistics. Factors associated with changed reports were assessed using robust multiple linear regression with 1,000 bootstrapped replications. Although reports before and after the training should have remained constant, the proportion of teachers reporting 1+ act of violence dropped substantially (lifetime: 73% to 47%). Most teachers (73%) changed 1+ response. Kappa for individual items showed ranging disagreement (lifetime: 0.275-0.795). Variables significantly associated with greater numbers of changed reports included: greater mental health distress (lifetime: beta = 1.061, 95% CI = 0.229, 2.404), older age (past school term: beta = 0.067, 95% CI = 0.018, 0.113); and variables targeted during training, including increasing awareness of consequences of violence (past week: beta = 0.241, 95% CI = 0.046, 0.435) and decreasing acceptance of physical discipline practices in schools (past school term: beta= -0.169, 95% CI= -0.338, -0.045). Interpreting self-reports of violence perpetration requires caution. Formal investigations into reliability and validity of self-reported violence perpetration and victimization are needed.


ras-induced c-fos expression and proliferation in living rat fibroblasts involves C-kinase activation and the serum response element pathway.
We have examined the early events involved in the proliferative activation of quiescent rat embryo fibroblasts by microinjection of oncogenic ras protein. Cells injected with ras show a transient expression of c-fos after 30-60 min visualized by immunofluorescence in the nucleus. This c-fos expression can be specifically suppressed by coinjection of a double-stranded oligonucleotide which corresponds to the serum response element (SRE) present in the c-fos promoter, implying that ras utilizes a pathway which activates the binding of serum response factor(s) (SRF) to SRE to induce c-fos transcription. Inhibition of this pathway also abolished ras-induced DNA synthesis indicating that the proliferative induction by ras requires expression of SRE-regulated genes. Both c-fos induction and DNA synthesis were prevented when ras oncoprotein was injected into quiescent cells together with either antibodies against calcium phospholipid-dependent protein kinase (C-kinase) or a synthetic peptide that specifically inhibits C-kinase. These data demonstrate the involvement of both functional C-kinase and the SRE pathway in the activation of quiescent cells by ras and suggest a potential relationship in their mechanism of action.


Node negative colorectal cancer patients: assesment of high-risk features on recurrence.
The introduction of population-based screening programs for colorectal cancer (CRC) results in less patients with advanced disease. There is an increase in the amount of node negative CRC, which makes adequate risk stratification for this particular group of patients necessary. The addition of more risk factors to the conventional histological high-risk factors is investigated in this retrospective study. A cohort of 227 node negative (stage I and II) CRC patients who were not treated with adjuvant chemotherapy were selected from two previously conducted cohort studies. Detailed histopathological examination was performed by two independent observers and molecular background (BRAF/RAS mutations, microsatellite status (MSI)) was studied. Univariate analyses were used to analyse differences in histological and mutational characteristics between patients with and without recurrence. P-values below 0.05 were considered statistically significant. Poorly differentiated histology (p:0.002), BRAF mutation (p:0.002) and MSI status (p:0.006) were found significant relevant risk factors that were related to recurrent disease. Poorly differentiated histology was associated with intermediate/high tumor budding (TB) (p:0.001), a BRAF mutation (p:0.001) and MSI status (p:0.001). A combination of all three features (poorly differentiated histology, BRAF and MSI) was more often present in the recurrence group. Recurrence in node negative CRC patients could be better predicted when molecular features such as, BRAF mutation and MSI status are incorporated into a model with poorly differentiated CRC. Therefore, these features might help in the selection of patients who possibly will benefit from adjuvant treatment.


Isolation to homogeneity and partial characterization of a histo-blood group A defined Fuc alpha 1----2Gal alpha 1----3-N-acetylgalactosaminyltransferase from human lung tissue.
The soluble histo-blood group A glycosyltransferase (Fuc alpha 1----Gal alpha 1----3-N-acetylgalactosaminyltransferase) was purified approximately 600,000-fold to homogeneity from human lung tissue. The enzyme was solubilized in 1% Triton X-100, partially purified by affinity chromatography on Sepharose 4B, and eluted with UDP. Final purification was obtained by twice repeated fast protein liquid chromatography ion exchange (Mono STM) with NaCl gradient elution and reverse-phase chromatography (proRPC) with acetonitrile gradient elution. Identity of the purified protein was established by (i) demonstration of the putative A transferase protein only in affinity-purified extracts of A but not O individuals, and (ii) specific immunoprecipitation of enzyme activity and putative protein with monoclonal antibodies. Sodium dodecyl sulfate electrophoresis revealed a single protein band with apparent Mr of approximately 40,000 under both reducing and nonreducing conditions. Digestion with N-glycanase yielded a reduction in Mr of approximately 6,000 (estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis), suggesting that the A transferase is a glycoprotein with N-linked carbohydrate chains. Amino acid composition and N-terminal amino acid sequence of the intact transferase, as well as of peptides released by endolysyl peptidase digest or cyanogen bromide cleavage, are presented.


The role of legume peptides released during different digestion stages in modulating the bioaccessibility of exogenous iron and zinc: An in-vitro study.
The effects of legume protein fractions on Fe and Zn bioaccessibility remain equivocal to date, largely due to the protein's structure and the presence of anti-nutritional compounds. We administered Fe and Zn salts with legume concentrates consisting mainly of albumin or globulin from lupin, pea and faba to in vitro gastrointestinal digestion. Under the fasted intestinal state, faba globulins were found to enhance Fe2+ and Zn solubility compared to control salts without legume proteins. Meanwhile, other fractions had no effect or significantly lowered Fe and Zn solubility. Under the fed intestinal state, the presence globulins enhanced Fe solubility versus the control, where protein solubilization due to high bile concentration likely played a role in circumventing precipitation. The lupin albumin fraction significantly enhanced Fe2+ and Zn solubility, whilst other fractions generally reduced Zn solubility under fed state. Our results highlight the complex role of legume proteins towards Fe and Zn solubility.


Nucleotide sequence of the middle dsRNA segment of bacteriophage phi 6: placement of the genes of membrane-associated proteins.
The genome of the lipid-containing bacteriophage phi 6 contains three segments of double-stranded RNA. We have determined the nucleotide sequence of cDNA derived from the middle-size RNA segment. The coding sequences of three proteins on this segment were identified on the basis of size and the correlation of predicted N-terminal amino acid sequences with those found through the analysis of isolated proteins. In contrast to our results with the small phi 6 dsRNA segment, the open reading frames are not tightly clustered. The homologous terminal noncoding regions between the middle and small dsRNA segments are found to be more extensive than RNA sequencing had previously indicated.


alpha1beta1-integrin engagement to distinct laminin-1 domains orchestrates spreading, migration and survival of neural crest cells through independent signaling pathways.
Integrin engagement regulates cell adhesion, shape, migration, growth, and differentiation, but molecular mechanisms coordinating these functions in cells remain unclear. Because of their migratory and differentiation potential, neural crest cells constitute a powerful paradigm to address this question. Here, we describe that laminin-1, a major component of their migration routes, promotes crest cell spreading, migration and survival through two distinct integrin-binding domains that are situated on both sides of its alpha1 subunit and can be separated in the LN-1 elastase proteolytic fragments E1' and E8. Interaction with either domain was mediated by the same integrin alpha1beta1 but produced distinct, complementary responses through specific signaling cascades. FAK activation upon E8 binding induced spreading, formation of actin bundles and focal adhesions, stimulated oriented migration, but failed to support survival. Conversely, Erk activation upon E1' binding promoted long-term survival and random migration without actin reorganization. Consistent with this, interaction with laminin-5 or laminin-10/11, which do not harbor integrin-binding domains in the N-terminal side of their alpha chains, failed to support survival. Thus, the signaling activity and function of integrins might depend on binding domains in their ligands, thereby revealing ligand control of integrin function as a possible mechanism for the modulation and coordination of cell response to adhesive signals.


Fever and pulmonary thromboembolism.
Fever patterns associated with pulmonary thromboembolism have not been well characterized. Upon review of 35 consecutive patients with angiographically documented pulmonary emboli, fever was present in 24 patients; and in 20, it was attributed solely to pulmonary thromboembolism. Analysis of these cases indicates that high fever (temperature greater than 39 degrees C) due to pulmonary thromboembolism may occur early, and low-grade fever may continue for a week or more. Fever persisting beyond six days, however, especially with temperatures over 38.5 degrees C, should not be ascribed to pulmonary thromboembolism unless other causes have been carefully excluded. If the clinical setting and patient's findings are consistent with pulmonary thromboembolism, one should not be deterred from presumptively making this diagnosis and initiating therapy because of the presence of high fever.


Erratum: Local Deterministic Model of Singlet State Correlations Based on Relaxing Measurement Independence [Phys. Rev. Lett. 105, 250404 (2010)].
This corrects the article DOI: 10.1103/PhysRevLett.105.250404.


Ketamine Increases Permeability and Alters Epithelial Phenotype of Renal Distal Tubular Cells via a GSK-3β-Dependent Mechanism.
Ketamine, a dissociative anesthetic, is misused and abused worldwide as an illegal recreational drug. In addition to its neuropathic toxicity, ketamine abuse has numerous effects, including renal failure; however, the underlying mechanism is poorly understood. The process called epithelial phenotypic changes (EPCs) causes the loss of cell-cell adhesion and cell polarity in renal diseases, as well as the acquisition of migratory and invasive properties. Madin-Darby canine kidney cells, an in vitro cell model, were subjected to experimental manipulation to investigate whether ketamine could promote EPCs. Our data showed that ketamine dramatically decreased transepithelial electrical resistance and increased paracellular permeability and junction disruption, which were coupled to decreased levels of apical junctional proteins (ZO-1, occludin, and E-cadherin). Consistent with the downregulation of epithelial markers, the mesenchymal markers N-cadherin, fibronectin, and vimentin were markedly upregulated following ketamine stimulation. Of the E-cadherin repressor complexes tested, the mRNA levels of Snail, Slug, Twist, and ZEB1 were elevated. Moreover, ketamine significantly enhanced migration and invasion. Ketamine-mediated changes were at least partly caused by the inhibition of GSK-3β activity through Ser-9 phosphorylation by the PI3K/Akt pathway. Inhibiting PI3K/Akt with LY294002 reactivated GSK-3β and suppressed ketamine-enhanced permeability, EPCs, and motility. These findings were recapitulated by the inactivation of GSK-3β using the inhibitor 3F8. Taken together, these results provide evidence that ketamine induces renal distal tubular EPCs through the downregulation of several junction proteins, the upregulation of mesenchymal markers, the activation of Akt, and the inactivation of GSK-3β.


Metal Oxide/Nitrogen-Doped Carbon Nanosheet Heteronanostructures as Highly Efficient Electromagnetic Wave Absorbing Materials.
In this paper, we will discuss the excellent broadband microwave absorption behaviors of Cu/CuO/carbon nanosheet composites: traces of copper and oxide embedded in a carbon nano-sheet not only cut down the high permittivity of adsorbs but also induce more interfacial polarization centers. The results showed that at a cracking temperature of 900 °C, the fabricated material has a unique ripple-like structure, which promotes the hierarchical interfacial polarization. The prepared material has a maximum absorption bandwidth of 4.48 GHz at an exceedingly thin thickness of 1.7 mm and a maximum reflection loss of -25.3 dB at a thickness of 2 mm. It is a relatively ideal material for electromagnetic wave absorption.


Open-label feasibility study of pazopanib, carboplatin, and paclitaxel in women with newly diagnosed, untreated, gynaecologic tumours: a phase I/II trial of the AGO study group.
Although most patients with advanced gynaecologic malignancies respond to first-line treatment with platinum-taxane doublets, a significant proportion of patients relapse. Combining targeted agents that have non-overlapping mechanisms of action with chemotherapy may potentially increase the disease-free interval. Accordingly, this study evaluated the feasibility of combining pazopanib, an oral angiogenesis inhibitor, with paclitaxel and carboplatin. This open-label, phase I/II study planned to evaluate the safety and efficacy of paclitaxel 175 mg m(-2) plus carboplatin (AUC5 (Arm A) or AUC6 (Arm B)) once in every 3 weeks for up to six cycles with either 800 or 400 mg per day pazopanib. Dose-limiting toxicities (DLTs) were observed in two of the first six patients enrolled at pazopanib 800 mg plus paclitaxel 175 mg m(-2) plus carboplatin AUC5. Of the six patients enrolled in the next and lowest dosing level planned in the study, pazopanib 400 mg plus paclitaxel 175 mg m(-2) plus carboplatin AUC5, two patients also experienced DLTs and the study was terminated. Two of the 4 DLTs observed overall were gastrointestinal perforations. Severe myelotoxicity was reported in 6 of 12 patients. Combining either 800 or 400 mg per day pazopanib with standard carboplatin/paclitaxel chemotherapy is not a feasible treatment option.


Early and Long-Term Outcomes after Direct Bridge-to-Transplantation with Extracorporeal Membrane Oxygenation.
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) as direct bridge-to-transplantation (dBTT) remains controversial. We compared the short- and long-term outcomes of adult patients undergoing urgent heart transplantation (HT) with (dBTT) and without (non-BTT) VA-ECMO support at the time of HT. Adults who underwent urgent HT in two institutions were assessed (N = 133; dBTT: N = 34 and non-BTT: N = 99). Patient characteristics, donor characteristics, in-hospital outcomes, and overall survival were compared. Mean follow up was 77±38 months and was 100% complete. Mortality predictors were identified using univariate and multivariate analyses. Before HT, patients with dBTT had higher rates of ischemic cardiomyopathy, acute kidney injury, liver failure, respiratory failure, and longer graft ischemia times. More patients in the dBTT group had complications, such as requiring VA-ECMO postoperatively (dBTT=50% vs. non-BTT=20%, P < 0.01). Hospital deaths (dBTT=23% vs. non-BTT=19%, P = 0.58), one-year (74% vs. 80%) and five-year survival (62% vs. 75%, P = 0.74 for overall survival) were not significantly different. The MELD-XI score and previous cardiac surgery were independent predictors of hospital mortality. Direct bridge-to-transplantation in patients on VA-ECMO support was not associated with worse long-term outcomes compared with non-VA-ECMO urgent HT, especially in recipients without any associated organ failure and a low MELD-XI score before HT.


Saccharide-Containing Dynamic Proteoids.
Dynamic proteoids are dynamic covalent analogues of proteins, which can be used as new adaptive biomaterials. We designed and synthesized a range of sugar-containing dynamic proteoid biodynamers based on the polycondensation of different types of amino acid and dipeptide hydrazides with a biological aliphatic dialdehyde and a nonbiological aromatic dialdehyde. By using the saccharide-based dialdehyde, the biocompatibility of biodynamers should be enhanced compared to previously reported biodynamers.


Poststroke depression: prevalence, diagnosis, treatment, and disease progression.
In recent years, poststroke depression has attracted worldwide interest. This review focuses on the major research themes that have emerged. Pooled data from studies conducted throughout the world have found prevalence rates for major depression of 19.3% among hospitalized patients and 23.3% among outpatient samples. The diagnosis of poststroke depression is most appropriately based on a structured mental state exam and DSM-IV criteria for depression due to stroke with major depressive-like episode or depressive features. Rarely, poststroke patients may also develop bipolar mood disorder. The treatment of poststroke depression has been examined in several placebo-controlled randomized clinical trials with both nortriptyline and citalopram showing efficacy. The progression of recovery following stroke can be altered by treating depression, which has been shown to improve recovery in activities of daily living and cognitive impairment and to decrease mortality. In addition, two studies have demonstrated that poststroke depression can be prevented using antidepressant medication, which also decreases the frequency of associated physical illness. Furthermore, two studies have shown that premorbid depression can significantly increase the risk of stroke over the subsequent 10-15 years. The mechanisms underlying the association of cerebrovascular diseases and mood disorder are important areas for future investigation.


Thrombolysis in antiphospholipid syndrome: current hematologic perspectives.
Antiphospholipid antibodies (aPL) can cause thromboembolic events, but the reason for the thrombogenesis has not been fully elucidated. Studies show that the true pathogenic targets of aPL are plasma proteins involved in hemostasis (eg, beta(2)-glycoprotein I and prothrombin). These plasma proteins in turn bind to phospholipids, leading to the misclassification as "antiphospholipid" antibodies. The hemostatic system has abundant checks and balances to avoid excess hemorrhage and thrombosis. Thus, thrombosis requires more than interrupting one protein in the complex system. This review examines host genetic factors important in predisposition to thrombosis associated with aPL and concentrates on how antibodies in antiphospholipid syndrome interact with our natural anticoagulants and lead to thrombosis.


Ontogeny of limb force distribution in squirrel monkeys (Saimiri boliviensis): insights into the mechanical bases of primate hind limb dominance.
The distribution of peak vertical forces between the forelimbs and the hind limbs is one of the key traits distinguishing primate quadrupedal locomotion from that of other mammals. Whereas most mammals generate greater peak vertical forelimb forces, primates generate greater peak vertical hind limb forces. At the ultimate level, hind limb dominance in limb force distribution is typically interpreted as an adaptation to facilitate fine-branch arboreality. However, the proximate biomechanical bases for primate limb force distribution remain controversial. Three models have been previously proposed. The Center of Mass (COM) Position model attributes primates' unique mode of limb loading to differences in the position of the whole-body COM relative to the hands and feet. The Active Weight Shift model asserts that primates actively redistribute body weight to their hind limbs by pitching the trunk up via the activation of hind limb retractor muscles. Finally, the Limb Compliance model argues that primates selectively mitigate forelimb forces by maintaining a compliant forelimb and a flat shoulder trajectory. Here, a detailed dataset of ontogenetic changes in morphology and locomotor mechanics in Bolivian squirrel monkeys (Saimiri boliviensis) was employed as a model system to evaluate each of these proposed models in turn. Over the first 10 months of life, squirrel monkeys transitioned from forelimb dominant infants to hind limb dominant juveniles, a change that was precipitated by decreases in peak vertical forelimb forces and increases in peak vertical hind limb forces. Results provided some support for all three of the models, although the COM Position and Active Weight Shift models were most strongly supported by the data. Overall, this study suggests that primates may use a variety of biomechanical strategies to achieve hind limb dominance in limb force distribution.


Cerebroplacental versus Umbilicocerebral Ratio-Analyzing the Predictive Value Regarding Adverse Perinatal Outcomes in Low- and High-Risk Fetuses at Term.
Background and Objectives: The aim of this study was to investigate the prediction of adverse perinatal outcomes using the cerebroplacental (CPR) and umbilicocerebral (UCR) ratios in different cohorts of singleton pregnancies. Materials and Methods: In this retrospective cohort study, we established our own Multiple of Median (MoM) for CPR and UCR. The predictive value for both ratios was studied in the following outcome parameters: emergency cesarean delivery, operative intervention (OI), OI due to fetal distress, 5-min Apgar < 7, admission to neonatal intensive care unit, and composite adverse perinatal outcome. The performance of the ratios was assessed in the following cohorts: total cohort (delivery ≥ 37 + 0 weeks gestation, all birth weight centiles), low-risk cohort (delivery ≥ 37 + 0 weeks gestation, birth weight ≥ 10. centile), prolonged pregnancy cohort (delivery ≥ 41 + 0 weeks gestation, birth weight ≥ 10. centile) and small-for-gestational-age fetuses (delivery ≥ 37 + 0 weeks gestation, birth weight < 10. centile). The underlying reference values for MoM were estimated using quantile regression depending on gestational age. Prediction performance was evaluated using logistic regression models assessing the corresponding Brier score, combining discriminatory power and calibration. Results: Overall, 3326 cases were included. Across all cohorts, in the case of a significant association between a studied outcome parameter and CPR, there was an association with UCR, respectively. The Brier score showed only minimal differences for both ratios. Conclusions: Our study provides further evidence regarding predictive values of CPR and UCR. The results of our study suggest that reversal of CPR to UCR does not improve the prediction of adverse perinatal outcomes.


Micronutrient content of certain tropical conventional and unconventional feed resources of Southern India.
The ash, silica and certain important micronutrients were estimated in conventional and unconventional feed and fodder resources available in Southern India. Commonly used dry roughages, such as paddy straw, ragi straw, maize kadbi/stalk, jowar kadbi/stalk, bajra stalk and wheat straw, were high in ash (9.9% +/- 0.77%) and silica (6.4% +/- 0.65%) and low in most of the other micronutrients, except iron, with paddy straw containing most silica (>9%). Cultivated non-leguminous (maize, jowar) and improved green crops (hybrid napier, guinea, green panic, NB-21, CO-1) were also high in ash (10.5% +/- 0.60% and 12.5% +/- 0.51%) but were moderate sources of P, Mg and Cu and good sources of Zn (98 +/- 13.8 ppm and 55 +/- 6.7 ppm). Leguminous green fodders (stylosanthus, lucerne, cow pea, soyabean) were excellent sources of Ca (1.9% +/- 0.16%), Mg (0.40% +/- 0.05%), Cu (30 +/- 5.2 ppm), Zn (121 +/- 14.7 ppm) and Fe (1234 +/- 166 ppm) and moderate sources of P. Mixed local grasses and weeds were high in silica (6.9% +/- 1.00%) but were good sources of Cu, Zn and Fe. Cereal grains (maize, wheat, rice, ragi) were low in ash (2.9% +/- 0.33%) and were relatively poor sources of Ca (0.22% +/- 0.03%), Mg (0.19% +/- 0.03%) and Cu (13 +/- 3.1 ppm). Pulses were low to medium sources of most minerals and good sources of Fe (1230 +/- 293 ppm). Oil seed cake/extractions (groundnut cake, cotton seed cake, soyabean meal, sunflower cake, safflower cake) and cereal by-products (rice polish, rice bran, wheat bran) were excellent sources of P (1.1% +/- 0.47% and 2.3% +/- 0.19%) and good sources of Zn (65 +/- 3.9 ppm and 66 +/- 10.7 ppm) and Fe (938 +/- 130 ppm and 662 +/- 126 ppm). Among the unconventional feeds screened, orange peel, sunflower heads, meat meal, rubber seed cake, spirulina algae and sea weeds contained plentiful Ca, Zn and Fe: tree leaves/top feeds (mulberry, erythrina, glyricidia, banana, subabul, groundnut haulms) were excellent sources of Ca (1.5% +/- 0.13%), Zn (120 +/- 22.9 ppm) and Fe (1033 +/- 133 ppm) but relatively poor sources of P. Soyabean husk, cocoa seed husk, rubber seed cake and meat meal were moderate to good sources of P (1.0% and 0.33%). The high Zn and Fe values of most feeds/fodders were probably due to soil contamination. This account of the micronutrient content of feed/fodder resources should help in strategic supplementation intended to alleviate local deficiencies.


Lasiodiplodia theobromae keratitis: a case report and review of literature.
A case report and review of literature is reported of a rare case of fungal keratitis from eastern India. A 32-year-old woman with a history of vegetative trauma presented with keratitis in left eye. Microbiological examination of corneal scraping showed refractile hyphae with aseptate branching filaments and black pigmented colonies on multiple solid agar medium. Organism was identified from culture using D1/D2 region of LSU (Large Sub Unit: 28S rDNA)-based molecular technique. PCR amplified a band with a sequence that was 100 % homologous with Lasiodiplodia theobromae. The organism was susceptible to amphotericin B and voriconazole and demonstrated resistance to itraconazole and fluconazole. A therapeutic keratoplasty was performed following non-responsiveness to initial topical voriconazole (2 %) therapy. Recurrence in graft was controlled with topical voriconazole and intracameral amphotericin B. However, the graft failed at the end of 3 months. L. theobromae is a rare cause of fungal keratitis. Management of these cases is difficult, often involving surgical procedures.


Temporal change in the location of egg-laying by a bud-galling sawfly, Euura mucronata, on growing shoots of Salix cinerea.
Temporal change in the egg-laying behaviour of Euura mucronata was studied on growing shoots of Salix cinerea. Many new shoots arise from each previous year's shoot of S. cinerea; they grow very rapidly at the beginning of the oviposition period of E. mucronata, but their growth pattern changes dramatically during the 3 weeks of oviposition. When oviposition commences, all new shoots are equally long, and E. mucronata females lay eggs on them randomly; but toward the end of oviposition, eggs are laid on the longest of the new shoots, which originate on the distal part of the previous year's shoot. By the end of oviposition, the mean proportion of ovipositor borings that had resulted in egg-laying was 65.8% on distal shoots and declined linearly to 25% on shoots arising from the base of the previous year's shoot. The proportion of attacked buds from which larvae emerged declined non-linearly from 13.8% on the distal shoot to 3.5% on the basal shoots. The position of the shoot accounted for 67% and 73% of the variance in success of egg-laying and larval development, respectively.


The impact of diabetes status on total and site-specific cancer risk in the elderly population: A nationwide cohort study.
We aimed to evaluate the association of prediabetes, diabetes, and diabetes duration with risk of total and site-specific cancer in the Korean population aged 65 years and above. This study included 1,232,173 subjects aged ≥ 65 years who underwent a general health screening program. Diabetes status was categorized as normal glucose tolerance, impaired fasting glucose, new-onset diabetes, diabetes duration of < 5 years, and diabetes duration of ≥ 5 years. Cox proportional hazards models were used to investigate the association of diabetes status with cancer risk. The risk of total cancer increased as diabetes status worsened, as did the risks of liver, biliary, and pancreatic cancer. Risks of liver, biliary, and pancreatic cancer were significantly higher in subjects aged 65-74 years than in those aged ≥ 75 years. The relationship of diabetes status with overall cancer incidence was found to significantly interact with sex. Among subjects with diabetes, the risks of liver and lung cancer were significantly higher in men than in women regardless of diabetes duration. Diabetes status is associated with increased risk of cancer in the elderly. There are age and sex differences in the risk of total and site-specific cancers, including liver, biliary, and pancreatic cancer. This study highlights the importance of cancer screening for elderly subjects with diabetes.


Purification of human plasma fibrinogen by chromatography on protamine-agarose.
A study was performed to investigate if protamine covalently attached to CNBr-activated agarose is a useful tool for the purification of fibrinogen from human plasma samples. One chromatography step yielded a preparation with a clottability greater than 90% from platelet-poor plasma with a yield of 65-80% of fibrinogen applied. The preparation is free of plasminogen, immunoglobulins, fibronectin, albumin, antithrombin III, alpha 2-macroglobulin, and alpha 1-antitrypsin, as determined by immunological and functional methods. 6.5 mg of fibrinogen were adsorbed to 1.0 ml of protamine-agarose. Protamine-agarose chromatography can be applied to plasma samples as small as 200 microliters.


Association of genital mycoplasma colonization with low birth weight.
This study was conducted to document the prevalence of maternal genital tract colonization by Ureaplasma urealyticum and Mycoplasma hominis, and to assess its association with low birth weight (LBW) and prematurity. The high vaginal swabs of pregnant women in spontaneous labor after 26 weeks of gestation were cultured for U. urealyticum and M. hominis. Clinical details and perinatal outcomes including birth weight and gestation were documented. Of a total of 303 women enrolled, 148 (48.8%) had positive vaginal cultures for U. urealyticum, while only five (1.6%) grew M. hominis. The mean birth weight and the incidences of LBW and preterm neonates among ureaplasma positive and ureaplasma negative mothers were statistically comparable. U. urealyticum emerged as a common inhabitant of the lower genital tract of women in labor, being present in nearly half of them. Its presence was not a risk factor of LBW or prematurity. Maternal colonization with M. hominis was uncommon.


Vermiculite as a potential functional additive for water treatment bioreactors inhibiting toxic action of heavy metal cations upsetting the microbial balance.
A new adsorbent that combines mineral vermiculite with the yeast Saccharomyces cerevisiae, was used for Cd2+ removal. The influence of vermiculite presence on the toxic effects of Cd2+ to Saccharomyces cerevisiae yeast was evaluated as a function of the microorganisms' respiratory activity (CO2 production). The Cd2+ toxicity increased with prolonged exposure time reaching the LC50 value of 857 and 489 mg L-1 after 30 and 120 min, respectively. The yeast managed to bioaccumulate 25.0 ± 0.6 mg g-1 of Cd2+ at the initial Cd2+ concentration of 741.9 mg L-1; the maximum Cd2+ adsorption capacity of vermiculite reached 25 ± 5 mg g-1. The addition of the mineral decreased the cations toxic effect; the LC20 value in vermiculite absence attained approximately 200 mg L-1 after 30 min and decreased to 80 mg L-1 after 2 h, while in the bio-mineral system it was at the level of 435 ± 50 mg L-1 without a significant change in time. The mineral provided a superior living environment for the yeast by removing part of the cations, releasing essential microelements and providing a protective, clay hutch-like habitat for the cells.


Interaction between nerve growth factor and GM1 monosialoganglioside in preventing cortical choline acetyltransferase and high affinity choline uptake decrease after lesion of the nucleus basalis.
Monosialoganglioside GM1 and nerve growth factor (NGF) were administered alone or concomitantly to adult male rats with a unilateral ibotenic acid lesion of the nucleus basalis magnocellularis (NBM). High-affinity choline uptake (HACU) rate and choline acetyltransferase (ChAT) activity were measured, 4 and 21 days after surgery, respectively, in the frontal and parietal cortices of both hemispheres. A 33-34% decrease in HACU rate and a 43-39% decrease in ChAT activity was found in the ipsilateral cortices 4 and 21 days, respectively, after the lesion. If the lesioned rats received NGF (10 micrograms i.c.v.) twice a week or daily administrations of GM1 (30 mg/kg, i.p.), beginning immediately after surgery the decrease in HACU rate and ChAT activity was smaller. If NGF and GM1 were given concomitantly no decrease in HACU rate and ChAT activity was detected in the lesioned hemisphere and a slight increase occurred in the contralateral hemisphere. However, after the concurrent administration of NGF (10 micrograms i.c.v.) and the inactive dose of GM1 10 mg/kg i.p. no decrease in HACU and ChAT activity was also found in the lesioned rats. The latter finding indicates a potentiation by GM1 of NGF effects on the cholinergic neurons of the NBM. The two drugs may either antagonize the neurotoxic effects of ibotenic acid or stimulate a compensatory activity in the remaining neurons.


Comparison of the Morphology of the Foveal Pit Between African and Caucasian Populations.
The purpose of this study was to characterize foveal pit morphology in an African (Ghanaian) population, to compare it to that of a Caucasian group and to determine if it varied with age in the two populations. The depth, diameter, slope, and volume of the foveal pit were interpolated from optical coherence tomography volume scans recorded in 84 Ghanaian and 37 Caucasian individuals. Their association with age, sex, and ethnicity was investigated using multilevel regression models. The foveal pit differed significantly in width, slope, and volume between Ghanaian men and women (P < 0.001), but only in width and volume between Caucasian men and women (P < 0.01). In Ghanaians, age was associated with a narrowing of the foveal depression and a reduction of its volume. Overall, these changes were more pronounced in women as compared to men and were largely absent from the Caucasian group. When controlled for age, the foveal pit of Ghanaians was significantly wider and larger in volume as compared to the Caucasian group (P < 0.001). The morphology of the foveal pit differs between African and Caucasian individuals. These anatomic differences should be considered when examining differences in prevalence and clinical features of vitreoretinal disorders involving the fovea between the two populations. Differences in retinal anatomy may partly explain variations in the prevalence and clinical features of retinal diseases between Africans and Caucasians. Such differences should be adequately considered in diagnoses and monitoring of ocular diseases in patients with African ancestry.


Tourette syndrome: a follow-up study.
We describe a long-term follow-up study (1-15 years) of 33 patients with Tourette syndrome who were treated with pimozide (2-18 mg), haloperidol (2-15 mg), or no drugs. Both drugs produced comparable relief of symptoms at follow up; however, significantly more patients on haloperidol (eight of 17), compared with those on pimozide (one of 13), discontinued treatment (p less than or equal to 0.05). Haloperidol produced significantly more acute dyskinesias/dystonias than pimozide (p less than or equal to 0.03); otherwise, the adverse effect profile was similar for the two drugs. In particular, we found no increased incidence of ECG abnormalities in patients treated with pimozide. A prospective, randomized, double-blind crossover trial is required to determine whether there are significant differences in efficacy between pimozide and haloperidol in treatment of Tourette's disorder.


Molecular dynamics of histone H1.
The H1 or linker histones bind dynamically to chromatin in living cells via a process that involves transient association with the nucleosome near the DNA entry/exit site followed by dissociation, translocation to a new location, and rebinding. The mean residency time of H1 on any given nucleosome is about a minute, which is much shorter than that of most core histones but considerably longer than that of most other chromatin-binding proteins, including transcription factors. Here we review recent advances in understanding the kinetic pathway of H1 binding and how it relates to linker histone structure and function. We also describe potential mechanisms by which the dynamic binding of H1 might contribute directly to the regulation of gene expression and discuss several situations for which there is experimental evidence to support these mechanisms. Finally, we review the evidence for the participation of linker histone chaperones in mediating H1 exchange.


Incidence, recurrence and management of electrical storm in Brugada syndrome.
Brugada syndrome (BrS) is associated with ventricular tachyarrhythmias. However, the presence of electrical strom (ES) and its management still debated. We present the outcome and management of 44 BrS patients suffering from ES. A systematic literature review and pooled analysis Through database review including PubMed, Web of Science, Cochrane Libary and Cinahl studies were analyzed. Evidence from 7 reports of 808 BrS patients was identified. The mean age of patients suffering from ES was 34 ± 9.5 months (94.7% males, 65.8% spontaneous BrS type I). Using electrophysiological study ventricular tachycardia/ventricular fibrillation were inducible in 12/23 (52.2%). Recurrence of ES was documented in 6.1%. Death from ES was 8.2% after a follow-up of 83.5 ± 53.4. In up to 27 ES resolved without treatment. External shock was required in 35.6%, internal ICD shock in 13.3%, Overdrive pacing, left cardiac sympathetic block and atropin in 2.2%. Short-term antiarrhythmic management was as the following: Isopreterenol or Isopreterenol in combination with quinidine 35.5%, orciprenaline in 2.2%, quinidine 2.2%, disopyramide 2.2% or denopamide 2.2%. However, lidocaine, magensium sulfate, mexiletine and propanolol failed to control ES. Although ES is rare in BrS, this entity challenges physicians. Despite its high mortality rate, spontaneous termination is possible. Short-term management using Isoproterenol and/or quinidine might be safe. Prospective studies on management of ES are warranted.


Impact of cis-acting elements' frequency in transcription activity in dicot and monocot plants.
The production of new cultivars via recombinant DNA technology is important in applied agriculture. Promoters play fundamental roles in successful transformation and gene expression. Fragments of the upstream regulatory region of the movement protein gene of the Tomato yellow leaf curl virus (TYLCV; two fragments) and Watermelon chlorotic stunt virus (WmCSV, two fragments) and one fragment of the coat protein putative promoter of TYLCV (CPTY-pro) were isolated to assess their abilities to drive expression in monocot and dicot plants. We used bioinformatic analyses to identify tentative motifs in the fragments. The five promoter fragments were isolated, fused with the GUS reporter gene, and transformed into tomato, watermelon, and rice plantlets via Agrobacterium infiltration. GUS expression driven by each putative promoter was analysed using histochemical and fluorometric analyses. In both dicots and the monocots, the highest level of GUS expression was obtained using a truncated regulatory region from TYLCV (MMPTY-pro) followed by a truncated regulatory region from WmCSV (MMPWm-pro). However, the corresponding full-length fragments from TYLCV and WmCSV showed essentially equivalent expression levels in the fluorometric GUS assay compared with the enhanced Cauliflower mosaic virus e35S-pro. In addition, CPTY-pro showed no expression in either the dicots or the monocot. This study demonstrated that MMPTY-pro and MMPWm-pro may be useful as plant promoters.


CREB-binding protein is a nuclear integrator of nuclear factor-kappaB and p53 signaling.
Transcriptional coactivators may function as nuclear integrators by coordinating diverse signaling events. Here we show that the p65 (RelA) component of nuclear factor-kappaB (NF-kappaB) and p53 mutually repress each other's ability to activate transcription. Additionally, tumor necrosis factor-activated NF-kappaB is inhibited by UV light-induced p53. Both p65 and p53 depend upon the coactivator CREB-binding protein (CBP) for maximal activity. Increased levels of the coactivator relieve p53-mediated repression of NF-kappaB activity and p65-mediated repression of p53-dependent gene expression. Nuclear competition for limiting amounts of CBP provides a novel mechanism for altering the balance between the expression of NF-kappaB-dependent proliferation or survival genes and p53-dependent genes involved in cell cycle arrest and apoptosis.


Peritalar dislocation: a follow-up report of 21 cases.
A total of 21 patients with peritalar dislocation, treated during the last 15 years in our hospital are reviewed. Of these, 18 had medial and 3 lateral dislocations. At follow-up, 10 patients with medial dislocation experienced either occasional pain due to the limitation of subtalar movements, or chronic pain due to severe osteoporosis of the hindfoot. All these patients with lateral dislocation had severe chronic pain, which was alleviated by subtalar arthrodesis in two of them. It is concluded that peritalar dislocation produces varying degrees of disability in the majority of patients with medial dislocation and serious disability in all patients with lateral dislocation. This is due to the severity of the soft tissue damage and the prolonged immobilization of the foot without bearing weight. It is essential to mobilize the foot as soon as possible after the injury.


Dose-dependent beneficial and detrimental effects of ROCK inhibitor Y27632 on axonal sprouting and functional recovery after rat spinal cord injury.
Axonal regeneration within the injured central nervous system (CNS) is hampered by multiple inhibitory molecules in the glial scar and the surrounding disrupted myelin. Many of these inhibitors stimulate, either directly or indirectly, the Rho intracellular signaling pathway, providing a strong rationale to target it following spinal cord injuries. In this study, we infused either control (PBS) or a ROCK inhibitor, Y27632 (2 mM or 20 mM, 12 microl/day for 14 days) into the intrathecal space of adult rats starting immediately after a cervical 4/5 dorsal column transection. Histological analysis revealed that high dose-treated animals displayed significantly more axon sprouts in the grey matter distal to injury compared to low dose-treated rats. Only the high dose regimen stimulated sprouting of the dorsal ascending axons along the walls of the lesion cavity. Footprint analysis revealed that the increased base of support normalized significantly faster in control and high dose-treated animals compared to low dose animals. Forepaw rotation angle, and the number of footslips on a horizontal ladder improved significantly more by 6 weeks in high dose animals compared to the other two groups. In a food pellet reaching test, high dose animals performed significantly better than low dose animals, which failed to recover. There was no evidence of mechanical allodynia in any treatment group; however, the slightly shortened heat withdrawal times normalized only with the high dose treatment. Collectively, our data support beneficial effects of high dose Y27632 treatment but indicate that low doses might be detrimental.


Fine structure of corpora allata of castes with different rates of juvenile hormone production in the termite Reticulitermes flavipes.
The aim of this work is to describe corpora allata (CA) of several castes of the termite Reticulitermes flavipes that have different rates of juvenile hormone (JH) synthesis, with respect to differences in fine structure, volume, and intensity of allatostatin immunoreactivity in their innervation. The castes chosen are workers and their potential derivatives, apterous secondary reproductives and pre-soldiers (the precursors of soldiers). These castes, at the stages chosen, produce JH at low, high and intermediate rates respectively. Hormone production is positively correlated with volume and negatively correlated with intensity of allatostatin immunoreactivity in axons within the glands. Characteristics of fine structure that correlate with increased activity are increase in abundance and width of mitochondria, decrease in ability to fix and visualize smooth endoplasmic reticulum. These features have previously been described for CA of cockroaches and other insects. Glycogen in the CA of all of the castes studied, especially the large amounts in highly active glands of physogastric apterous reproductive females, is the most striking difference between the CA cells of R. flavipes and previously described CA of cockroaches, in which glycogen is absent throughout the reproductive cycles. This suggests that glycogen is an important source of energy for hormone production by termite CA.


HSC Fate Is Tethered to Mitochondria.
Mitochondria play important roles in homeostasis of hematopoietic stem cells (HSCs), which exhibit clonal heterogeneity in their lymphoid and myeloid production. Recently in Nature, Luchsinger et al. (2016) showed that mitochondria-ER tethering maintains lymphoid-biased HSCs through calcium-dependent NFAT signaling, providing molecular insights into the basis of HSC heterogeneity.


Combination of estrogen and dioxin is involved in the pathogenesis of endometriosis by promoting chemokine secretion and invasion of endometrial stromal cells.
The CC chemokines, regulated on activation, normal T-cell expressed and secreted (RANTES) and macrophage-inflammatory protein-1alpha (MIP-1alpha), have been identified as potential contributors to the pathogenesis and the progression of endometriosis. Dioxin, an air pollutant, and estrogen also appear to be involved in endometriosis. The aim of this study was to probe into the effect of dioxin and estrogen on expression of the chemokines in endometriosis-associated cells, and to explore the pathogenesis of endometriosis. Co-culture models were established to evaluate the secretion of human RANTES and MIP-1alpha. The effects of a dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) and estrogen on the invasion of endometrial stromal cells (ESC) were also examined by using an invasion assay, and the translation and proteolytic activity of matrix metalloproteinase (MMP)-9 and MMP-2 in ESC were determined by western blot and zymography, respectively. Our results showed that the combination of 17beta-estradiol and TCDD increased the secretion of RANTES and MIP-1alpha, promoted the invasiveness of ESC and increased the expression of MMP-2 and MMP-9 in ESC. Anti-RANTES, anti-MIP-1alpha neutralizing antibody or antibody against their receptors could effectively inhibit the invasiveness of ESC and the expression of MMP-2 and MMP-9. The combination of 17beta-estradiol with TCDD may facilitate the onset of endometriosis and contribute to its development by increasing the invasion of ESC mediated by CC-motif chemokines.


Heart Failure Hospitalizations and Risk Factors among the Multi-Ethnic Population from a Middle Income Country: The Suriname Heart Failure Studies.
Heart failure (HF) is an emerging epidemic with poor disease outcomes and differences in its prevalence, etiology and management between and within world regions. Hypertension (HT) and ischemic heart disease (IHD) are the leading causes of HF. In Suriname, South-America, data on HF burden are lacking. The aim of this Suriname Heart Failure I (SUHF-I) study, is to assess baseline characteristics of HF admitted patients in order to set up the prospective interventional SUHF-II study to longitudinally determine the effectiveness of a comprehensive HF management program in HF patients. A cross-sectional analysis was conducted of Thorax Center Paramaribo (TCP) discharge data from January 2013-December 2015. The analysis included all admissions with primary or secondary discharge of HF ICD-10 codes I50-I50.9 and I11.0 and the following variables: patient demographics (age, sex, and ethnicity), # of readmissions, risk factors (RF) for HF: HT, diabetes mellitus (DM), smoking, and left ventricle (LV) function. T-tests were used to analyze continuous variables and Chi-square test for categorical variables. Differences were considered statistically significant when a p-value <0.05 is obtained. 895 patients (1:1 sex ratio) with either a primary (80%) or secondary HF diagnosis were admitted. Female patients were significantly older (66.2 ± 14.8 years, p < 0.01) at first admission compared to male patients (63.5 ± 13.7 years) and the majority of admissions were of Hindustani and Creole descent. HT, DM and smoking were highly prevalent respectively 62.6%, 38.9 and 17.3%. There were 379 readmissions (29.1%) and 7% of all admissions were readmissions within 30 days and 16% were readmissions for 31-365 day. IHD is more prevalent in patients from Asian descendant (52.2%) compared to African descendant (11.7%). Whereas, HT (39.3%) is more prevalent in African descendants compared to Asian descendants (12.7%). There were no statistically significant differences in age, sex, ethnicity, LV function and RFs between single admitted and readmitted patients. RF prevalence, ethnic differences and readmission rates in Surinamese HF patients are in line with reports from other Caribbean and Latin American countries. These results are the basis for the SUHF-II study which will aid in identifying the country specific and clinical factors for the successful development of a multidisciplinary HF management program.


[Nephrectomy for infantile hypernephroma. 30 years cure (author's transl)].
The study involves the treatment of infantile hypernephroma. It shows that, as in the adult, 30 years cures may be obtained.


[Restoration of hand grip ability by combined tissue transfer].
The coordination of such classical methods as skin grafts, bone grafts or pedicled flaps with microsurgical techniques opens new areas in the field of hand surgery. The combination resulted in useful function of three mutilated hands. A clear concept and good postoperative physiotherapy are important to achieve good results in these cases.


Effects of soy milk consumption on gut microbiota, inflammatory markers, and disease severity in patients with ulcerative colitis: a study protocol for a randomized clinical trial.
Several strategies are recommended to alleviate clinical symptoms of ulcerative colitis (UC). Soy milk may affect UC through its anti-inflammatory properties. However, no study has examined the effects of soy milk consumption on gut microbiota and inflammatory biomarkers in patients with UC. The current study will be done to examine the effects of soy milk consumption on UC symptoms, inflammation, and gut microbiota in patients with UC. This study is a randomized clinical trial, in which thirty patients with mild to moderate severity of UC will be randomly allocated to receive either 250 mL/day soy milk plus routine treatments (n = 15) or only routine treatments (n = 15) for 4 weeks. Assessment of anthropometric measures and biochemical indicators including serum concentrations of high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interferon gamma (IFN-γ) will be done at the study baseline and end of trial. In addition, the quantity of butyrate-producing bacteria including Clostridium cluster IV, Faecalibacterium prausnitzii, and Roseburia spp.; prebiotic bacteria including Lactobacillus spp. and Bifidobacteria spp.; and mucus-degrading bacteria including Akkermansia muciniphila, Bacteroides fragilis, and Ruminococcus spp., as well as calprotectin and lactoferrin levels, will be explored in fecal samples. Also, the Firmicutes to Bacteroidetes ratio which is of significant relevance in human gut microbiota composition will be assessed. Altered gut microbiota has been reported as an important contributing factor to inflammation in patients with inflammatory bowel disease (IBD). Soy milk contains several components such as phytoestrogens with potential anti-inflammatory properties. This product might affect gut microbiota through its protein and fiber content. Therefore, soy milk might beneficially affect systemic inflammation, gut microbiota, and then clinical symptoms in patients with UC. Iranian Registry of Clinical Trials (www.irct.ir) IRCT20181205041859N1. Registered on 27 January 2019.


Circadian and circannual rhythms of allergic rhinitis: an epidemiologic study involving chronobiologic methods.
Seven hundred sixty-five patients, living in France and suffering from allergic rhinitis (eg, with positive skin tests to various antigens), agreed to self-rate (visual analog scales), four times daily, symptoms such as sneezing, stuffy or blocked nose, runny nose, itchy nose, itchy eyes, wheeze, or cough. Despite acute symptoms, patients did not take medications of any kind by any route during 36 hours. Several statistical methods (eg, Student's t test, analysis of variance, cosinor, chi-square, etc.) were used to validate both circadian and circannual rhythms of these symptoms in the group as a whole, as well as in subgroups related to age, sex, etc. Large-amplitude circadian rhythms with early morning peak times (eg, approximately 6 AM) were validated for sneezing, stuffy nose, and runny nose (with p less than 0.0001) but not for wheeze or cough. Such time-dependent changes were related neither to age (from 10 to 80 years) nor to sex. However, small differences were observed in subgroups sorted with regard to duration of disease (old versus new cases), smoking habits, and geographic location (north versus south France). Reanalysis of data taking into account interindividual differences revealed that the respective peak times of the three major symptoms occurred in the early morning in about 60% to 70% of the patients. Annual changes were validated as well with the annual peak time being January to April. The proposed interpretation of both circadian and circannual rhythms suggests taking into account endogenous component rhythms (eg, involving metabolic, immunologic, and endocrine systems), since they contribute to time-dependent changes in the human susceptibility to antigens. In addition, the elevated severity of symptoms in the morning experienced by 60% to 70% of patients should serve as a guide to individually optimize dosing time(s) of medications, such as antihistamines.


A blind trial of silicone chamber fluid in nerve regeneration in the rat.
The nerve growth-promoting effects of the fluid accumulating in vivo from 1 to 28 days within silicone chambers were tested on the sciatic nerves of rats. We measured the elongation of sensory axons following nerve transection repaired by means of fibrin sealant allowing local application of the fluid. We found no difference between transections treated with chamber fluid and controls.


Sleep-Disordered Breathing and Prevalent Hypertension in Men With and Without HIV.
Sleep-disordered breathing (SDB) is a known risk factor for hypertension. Despite the well-established link between HIV infection and hypertension, it remains to be determined whether HIV infection modifies the association between SDB and hypertension. The Multicenter AIDS Cohort Study. SDB was assessed using in-home polysomnography in 779 men (436 with and 343 without HIV). The apnea-hypopnea index (AHI) based on oxyhemoglobin desaturation threshold of ≥3% or arousal (AHI 3a ) and ≥4% (AHI 4 ) along with oxygen desaturation index (ODI) were used to quantify SDB severity. Hypertension was defined as a blood pressure ≥140/90 mm Hg, use of antihypertensive medication, or self-report of a clinical diagnosis. The associations between HIV, SDB, and hypertension were characterized using multivariable logistic regression. The prevalence of hypertension and SDB (AHI 3a ≥ 5 events/hr) was high, with estimates of 53.8% and 82.8%, respectively. Among men without SDB, HIV was independently associated with hypertension, with an adjusted odds ratio (OR) of 3.05 [95% confidence interval (CI): 1.33 to 7.01]. In men without HIV, SDB was associated with hypertension (OR: 2.93; 95% CI: 1.46 to 5.86). No significant increase in the odds of hypertension was noted in men with both HIV and SDB compared with men with either factor alone, with an OR of 3.24 (95% CI: 1.62 to 6.47). These results were consistent across different measures used to define SDB (AHI 3a , AHI 4 , ODI 3 , and ODI 4 ). Predictors of hypertension differed by HIV status. SDB was associated with hypertension in men without HIV, but not in men with HIV. Among men with HIV, SDB did not affect the odds of hypertension.


Morphine produces release of substance P-like immunoreactivity from guinea-pig central nervous system.
Recent evidence suggests that opioids might have excitatory as well as inhibitory actions on neurones. Since substance P (SP) has been implicated in opioid withdrawal, the present experiment was conducted to determine whether SP was released by morphine or morphine withdrawal. Sagittal brain slices and a 2 cm piece of ileum from 5 guinea-pigs were placed in Krebs solution. Morphine 1 microM, produced significant release of SP-like immunoreactivity (SP-LI) within 2 min from brain slices but release from ileum preparations was variable. Naloxone 1 microM, added 5 min after morphine, did not produce significantly greater increase in concentration of SP-LI. It is concluded that morphine releases SP from guinea-pig brain slices.


Review of Marine Cyanobacteria and the Aspects Related to Their Roles: Chemical, Biological Properties, Nitrogen Fixation and Climate Change.
Marine cyanobacteria are an ancient group of photosynthetic microbes dating back to 3.5 million years ago. They are prolific producers of bioactive secondary metabolites. Over millions of years, natural selection has optimized their metabolites to possess activities impacting various biological targets. This paper discusses the historical and existential records of cyanobacteria, and their role in understanding the evolution of marine cyanobacteria through the ages. Recent advancements have focused on isolating and screening bioactive compounds and their respective medicinal properties, and we also discuss chemical property space and clinical trials, where compounds with potential pharmacological effects, such as cytotoxicity, anticancer, and antiparasitic properties, are highlighted. The data have shown that about 43% of the compounds investigated have cytotoxic effects, and around 8% have anti-trypanosome activity. We discussed the role of different marine cyanobacteria groups in fixing nitrogen percentages on Earth and their outcomes in fish productivity by entering food webs and enhancing productivity in different agricultural and ecological fields. The role of marine cyanobacteria in the carbon cycle and their outcomes in improving the efficiency of photosynthetic CO2 fixation in the chloroplasts of crop plants, thus enhancing the crop plant's yield, was highlighted. Ultimately, climate changes have a significant impact on marine cyanobacteria where the temperature rises, and CO2 improves the cyanobacterial nitrogen fixation.


Challenges for the Dentist in Managing Orofacial Pain.
This presentation describes a patient's extensive and expensive search for relief of pain in the orofacial area. The journey includes many diagnostic errors and failed and likely unnecessary treatments. A systematic approach to problem definition and rule-out reasoning for the differential diagnoses based on the International Classification of Orofacial Pain is described. Conservative treatment was implemented with satisfactory results. Common pitfalls in the management and treatment of complex pain patients are discussed.


Platelet-derived growth factor-BB-mediated activation of Akt suppresses smooth muscle-specific gene expression through inhibition of mitogen-activated protein kinase and redistribution of serum response factor.
Platelet-derived growth factor (PDGF) inhibits expression of smooth muscle (SM) genes in vascular smooth muscle cells and blocks induction by arginine vasopressin (AVP). We have previously demonstrated that suppression of SM-alpha-actin by PDGF-BB is mediated in part through a Ras-dependent pathway. This study examined the role of phosphatidylinositol 3-kinase (PI3K)y and its downstream effector, Akt, in regulating SM gene expression. PDGF caused a rapid sustained activation of Akt, whereas AVP caused only a small transient increase. PDGF selectively caused a sustained stimulation of p85/p110 alpha PI3K. In contrast, p85/110 beta PI3K activity was not altered by either PDGF or AVP, whereas both agents caused a delayed activation of Class IB p101/110 gamma PI3K. Expression of a gain-of-function PI3K or myristoylated Akt (myr-Akt) mimicked the inhibitory effect of PDGF on SM-alpha-actin and SM22 alpha expression. Pretreatment with LY 294002 reversed the inhibitory effect of PDGF. Expression of myr-Akt selectively inhibited AVP-induced activation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinases, which we have shown are critical for induction of these genes. Nuclear extracts from PDGF-stimulated or myr-Akt expressing cells showed reduced serum response factor binding to SM-specific CArG elements. This was associated with appearance of serum response factor in the cytoplasm. These data indicate that activation of p85/p110 alpha/Akt mediates suppression of SM gene expression by PDGF.


Why psychiatry needs an honest dose of gentle medicine.
The pharmaceutical industry's influence on psychiatric research and practice has been profound and has resulted in exaggerated claims of the effectiveness of psychotropic medications and an under-reporting of harms. After the regulatory approval of fluoxetine, the pharmaceutical industry began promoting (and continues to promote) a chemical imbalance theory of emotional distress. In the last decade, there has been an increased awareness about the limits of this theory and the risks of psychotropic medications. Nonetheless, the medicalization of distress, the sedimented belief in "magic bullets," and the push to "scale up" mental health treatment have contributed to the meteoric rise in the prescription of psychiatric drugs and of polypharmacy. A major premise of this paper is that the conceptual framework of medical nihilism can help researchers and clinicians understand and address the harms incurred by inflated claims of the efficacy of psychotropic medications. We propose that psychiatry, and the mental health field more generally, adopt a model of 'gentle medicine' with regard to both the diagnosis of and treatment for mental health conditions and focus greater attention on the upstream causes of distress.


Neuroactive pharmaceuticals in estuaries: Occurrence and tissue-specific bioaccumulation in multiple fish species.
Contamination of surface waters by pharmaceuticals is an emerging problem globally. This is because the increased access and use of pharmaceuticals by a growing world population lead to environmental contamination, threatening non-target species in their natural environment. Of particular concern are neuroactive pharmaceuticals, which are known to bioaccumulate in fish and impact a variety of individual processes such as fish reproduction or behaviour, which can have ecological impacts and compromise fish populations. In this work, we investigate the occurrence and bioaccumulation of 33 neuroactive pharmaceuticals in brain, muscle and liver tissues of multiple fish species collected in four different estuaries (Douro, Tejo, Sado and Mira). In total, 28 neuroactive pharmaceuticals were detected in water and 13 in fish tissues, with individual pharmaceuticals reaching maximum concentrations of 1590 ng/L and 207 ng/g ww, respectively. The neuroactive pharmaceuticals with the highest levels and highest frequency of detection in the water samples were psychostimulants, antidepressants, opioids and anxiolytics, whereas in fish tissues, antiepileptics, psychostimulants, anxiolytics and antidepressants showed highest concentrations. Bioaccumulation was ubiquitous, occurring in all seven estuarine and marine fish species. Notably, neuroactive compounds were detected in every water and fish brain samples, and in 95% of fish liver and muscle tissues. Despite variations in pharmaceutical occurrence among estuaries, bioaccumulation patterns were consistent among estuarine systems, with generally higher bioaccumulation in fish brain followed by liver and muscle. Moreover, no link between bioaccumulation and compounds' lipophilicity, species habitat use patterns or trophic levels was observed. Overall, this work highlights the occurrence of a highly diverse suite of neuroactive pharmaceuticals and their pervasiveness in waters and fish from estuarine systems with contrasting hydromorphology and urban development and emphasizes the urgent need for toxicity assessment of these compounds in natural ecosystems, linked to internalized body concentration in non-target species.


Physical frailty and its associated factors among elderly nursing home residents in China.
Evidence is scarce on the trend in prevalence of physical frailty in China; the primary purpose of this study was to identify the prevalence and correlates of physical frailty among older nursing home residents in China. Cross-sectional study in 20 nursing homes in Changsha, China. Physical frailty was defined based on the frailty phenotype including weight loss, low grip strength, exhaustion, slow gait speed, and low physical activity. Participants with at least three affected criteria were defined as being frail. Participants with one or two affected criteria were considered as pre-frail, and those with no affected criteria were considered as robust. A total of 1004 nursing home residents aged 60 and over were included in this study. A multinomial logistic regression model was used to analyze the associations of physical frailty with its potential risk factors, including age, sex, education levels, marital status, type of institution, living status, current drinking, current smoking, regular exercise, and self-reported health. The overall prevalence of physical frailty and prefrailty was 55.6, and 38.5%, respectively. The rate of physical frailty substantially increased with age, and was higher in women than in men (69.5% vs. 30.5%). The multinomial logistic regression analysis showed that older age, being women, living in a private institution, living alone or with unknown person, having no regular exercise (≤ 2 times/week), and poor self-reported health were significantly associated with increased odds of being physically frail. We demonstrated physical frailty is highly prevalent among older residents in nursing homes in China, especially in women. The potential role of those associated factors of physical frailty warrant further investigations to explore their clinical application among elderly nursing home residents.


Prevalence of BRCA mutations and founder effect in high-risk Hispanic families.
Approximately 12% of the U.S. population is Hispanic, with the majority residing in urban centers such as Los Angeles. The prevalence of BRCA mutations among high-risk Hispanic families is unknown. One hundred and ten unrelated probands of Hispanic origin, with a personal or family history of breast and/or ovarian cancer, presented for genetic cancer risk assessment, were enrolled in an Institutional Review Board-approved registry and underwent BRCA testing. Haplotype analyses were done if BRCA mutations were observed in two or more unrelated probands. Mean age at diagnosis was 37 years (range = 23-59) for the 89 (81%) probands with invasive breast cancer. Overall, 34 (30.9%) had deleterious mutations (25 in BRCA1, 9 in BRCA2), 25 (22.7%) had one or more unclassified variants, and 51 (46.4%) had negative results. The mean pretest mutation probability using the Couch model, Myriad model, and BRCAPro was 19.6% (range = 4-77%). The combined average mutation probability was 32.8% for carriers, 15.5% for noncarriers, and 12.9% for variant carriers (P < 0.0001). The most common deleterious mutation was 185delAG (4 of 34, 11.8%). The Hispanic 185delAG carrier families share the same haplotype from D17s1320 through BRCA1, as do two reference Ashkenazi Jewish families. Haplotype analyses of additional recurrent BRCA1 mutations [IVS5+1G>A (n=2),S955X (n = 3), R1443X (n = 3), and 2552delC (n = 2)] also suggest founder effects, with four of six mutations seen almost exclusively in families with Latin American/Caribbean or Spanish ancestry. This is the largest study to date of high-risk Hispanic families in the United States. Six recurrent mutations accounted for 47% (16 of 34) of the deleterious mutations in this cohort. The BRCA1185delAG mutation was prevalent (3.6%) in this clinic-based cohort of predominantly Mexican descent, and shared the Ashkenazi Jewish founder haplotype.


Professional participation in organizational decision making: physicians in HMOs.
Although it has been suggested that participation by physicians in administrative and policy decisions is linked to outcomes in health care organizations, there is little research on this subject. Using Shortell's framework this paper considers relationships between perceived participation and three intermediate organizational outcomes: physician work satisfaction, perceived staff consensus about day-to-day activities, and attitudes toward patients. Also considered are situational, professional, and personal characteristics which may be related to participation. Data were collected from four staff model health maintenance organizations (HMOs) in 1978 and 1979 through physician questionnaires, administrator interviews, and documents. Physicians who reported greater participation were more satisfied with work, perceived greater staff consensus, and had more favorable attitudes toward patients. Greater participation was associated with full-time employment status and more years in the HMO (but not with the physicians' professional or personal characteristics). Implications of these findings are discussed, and it is proposed that the findings suggest mechanisms by which participation in organizational decision making may affect ultimate outcomes of the organization.


Congenital asplenia due to a tlx1 mutation reduces resistance to Aeromonas hydrophila infection in zebrafish.
It is documented that tlx1, an orphan homeobox gene, plays critical roles in the regulation of early spleen developmental in mammalian species. However, there is no direct evidence supporting the functions of tlx1 in non-mammalian species, especially in fish. In this study, we demonstrated that tlx1 is expressed in the splenic primordia as early as 52 hours post-fertilization (hpf) in zebrafish. A tlx1-/- homozygous mutant line was generated via CRISPR/Cas9 to elucidate the roles of tlx1 in spleen development in zebrafish. In the tlx1-/- background, tlx1-/- cells persisted in the splenic primordia until 52 hpf but were no longer detectable after 53 hpf, suggesting perturbation of early spleen development. The zebrafish also exhibited congenital asplenia caused by the tlx1 mutation. Asplenic zebrafish can survive and breed normally under standard laboratory conditions, but the survival rate of animals infected with Aeromonas hydrophila was significantly lower than that of wild-type (WT) zebrafish. In asplenic zebrafish, the mononuclear phagocyte system was partially impaired, as demonstrated by retarded b7r expression and reduced ccr2 expression after injection with an inactivated A. hydrophila vaccine. Furthermore, the expression of MHCII/IgM was significantly reduced in the congenitally asplenic fish compared with that of the WT zebrafish. Taken together, our data suggest that tlx1 is a crucial regulator of spleen development in fish, as it is in mammals. We have also provided a new perspective for studying the role of the spleen during pathogen challenge in fish.


Extracellular enzyme activity in grass litter varies with grazing history, environment and plant species in temperate grasslands.
Long-term livestock grazing (here after 'grazing') affects carbon (C) and nutrient cycling in grassland ecosystems, in part by altering the quantity and quality of litter inputs. Despite their spatial extent and size of carbon and nutrient stocks, the effect of grazing on grassland biogeochemical cycling through the mediation of microbial activity remains poorly understood. To better understand the relationship between grazing and C and nutrient cycling in litter, we conducted an 18-month long study in paired grasslands previously grazed and nongrazed by cattle for 25 years, measuring extracellular enzyme activity (EEA) in various plant litter samples. Litter sources, including seven grass species dominant in one or more subregions and possessing divergent responses to grazing, as well as a community mix of litter sourced from each site, were tested at 15 sites spanning three grassland subregions in Alberta, Canada. We quantified EEAs associated with C cycling (β-glucosidase, β-Cellobiosidase and β-xylosidase), nitrogen (N) cycling (N-acetyl-glucosaminidase) and phosphorus (P) cycling (phosphatase). In general, litter in grasslands exposed to grazing had greater activity of C-liberating and P-liberating enzyme (β-xylosidase and phosphatase) in the mesic grasslands of the Foothills Fescue subregion (P ≤ 0.10). Observed EEAs were strongly mediated by litter type, with greater EEAs in litter of grass species known to increase in abundance under long-term grazing, including Poa pratensis in the Foothills Fescue subregion, and Bouteloua gracilis in arid grasslands of the Mixedgrass Prairie. In contrast, Pascopyrum smithii litter had the lowest enzyme activities in all subregions. We also found that EEAs changed through time (0-18 months) with consistently high levels detected at 1 (June 2014), 6 (October 2014) and 18 months (October 2015) after placement. Overall, these findings indicate grazing enhances EEA, and thus C and N-cycling, in northern temperate grasslands.


Synthesis and evaluation of thiophene based small molecules as potent inhibitors of Mycobacterium tuberculosis.
Herein, we report the synthesis and anti-tubercular studies of novel molecules based on thiophene scaffold. We identified two novel small molecules 4a and 4b, which demonstrated 2-fold higher in vitro activity (MIC99: 0.195 μM) compared to first line TB drug, isoniazid (0.39 μM). The identified leads demonstrated additive effect with front line TB drugs (isoniazid, rifampicin and levofloxacin) and synergistic effect with a recently FDA-approved drug, bedaquiline. Mechanistic studies (i) negated the role of Pks13 and (ii) suggested the involvement of KatG in the anti-tubercular activity of these identified leads.


Microsurgical anatomy of membranous layers of the pituitary gland and the expression of extracellular matrix collagenous proteins.
There are several reports about the microanatomical and histological features of sellar and parasellar membranous structures and clinical studies about MMP proteinase as a predictive factor. However, studies on collagen contents of sellar and parasellar membranous structures are limited. We demonstrated the membranous structures surrounding the pituitary gland and defined extracellular matrix (ECM) collagenous proteins, collagen I-IV expression patterns of sellar and parasellar connective tissues. The study was carried out on ten fresh postmortem human bodies at the Forensic Medicine Institution. Cavernous sinuses were resected with sellar structures and were stored at -80°C liquid nitrogen tanks. Medial wall of the cavernous sinus, pituitary capsule and pituitary tissue samples were obtained for RT-PCR. Opposite side specimens were used for histological and immune staining studies. Collagens I-IV were studied by immunohistochemical and reverse transcription polymerase chain reaction (RT-PCR) methods. The pituitary capsule and medial wall were identified as two different structures. The fibrous membrane, as the third membrane, was identified as staying whole in eight of ten specimens. Increased type IV collagen was determined in the pituitary gland, medial wall and pituitary capsule, respectively, in both RT-PCR and immunhistochemical studies. Immunhistochemical studies revealed that collagen I was strongly expressed in both the medial wall and pituitary gland. Increased type IV collagen was detected especially in pituitary tissue, the medial wall and the pituitary capsule by immune staining and RT-PCR. Type IV collagen was considered to be an important factor in the progression of adenoma and invasion.


Impacts of extreme flooding on riverbank filtration water quality.
Riverbank filtration schemes form a significant component of public water treatment processes on a global level. Understanding the resilience and water quality recovery of these systems following severe flooding is critical for effective water resources management under potential future climate change. This paper assesses the impact of floodplain inundation on the water quality of a shallow aquifer riverbank filtration system and how water quality recovers following an extreme (1 in 17 year, duration >70 days, 7 day inundation) flood event. During the inundation event, riverbank filtrate water quality is dominated by rapid direct recharge and floodwater infiltration (high fraction of surface water, dissolved organic carbon (DOC) >140% baseline values, >1 log increase in micro-organic contaminants, microbial detects and turbidity, low specific electrical conductivity (SEC) <90% baseline, high dissolved oxygen (DO) >400% baseline). A rapid recovery is observed in water quality with most floodwater impacts only observed for 2-3 weeks after the flooding event and a return to normal groundwater conditions within 6 weeks (lower fraction of surface water, higher SEC, lower DOC, organic and microbial detects, DO). Recovery rates are constrained by the hydrogeological site setting, the abstraction regime and the water quality trends at site boundary conditions. In this case, increased abstraction rates and a high transmissivity aquifer facilitate rapid water quality recoveries, with longer term trends controlled by background river and groundwater qualities. Temporary reductions in abstraction rates appear to slow water quality recoveries. Flexible operating regimes such as the one implemented at this study site are likely to be required if shallow aquifer riverbank filtration systems are to be resilient to future inundation events. Development of a conceptual understanding of hydrochemical boundaries and site hydrogeology through monitoring is required to assess the suitability of a prospective riverbank filtration site.


Titanium decorated iron oxide (Ti@Fe2O3) regulates the proliferation of bovine muscle satellite cells through oxidative stress.
In the present study, the titanium decorated iron oxide (Ti@Fe2O3) nanocomposites are synthesized using the chemical method. The as-prepared nanocomposite was characterized for successful formulation and the elemental spectra showed the composition of Fe (44%), Ti (0.71%) and O (55%) is confirmed the homogenous distribution. Crystallographic spectra depict the strong peaks corresponding to the of TiO2 and Fe2O3 nanoparticles planes with minor shift variation due to the formulation of Ti on the surface of Fe2O3 nanoparticles and it is also confirmed with SAED analysis. The X-ray photoelectron spectroscopy (XPS) analysis of Ti@Fe2O3) nanocomposite confirms the existence of elements such as Fe, O and Ti. Further, the morphology of the composite showed the well-defined encapsulation and aggregation of TiO2 nanoparticles on the surface of Fe2O3 nanoparticles. Further, the TiO2 nanoparticles showed less cytotoxic activity against bovine satellite cells, as well the nanocomposite increased the growth of bovine satellite cells comparing with control cells. Further, the morphological analysis showed the significant changes in TiO2 nanoparticles treated cells and the nanocomposite induces the myotube formation due to the increased ROS level in bovine satellite cells. Moreover, the nanocomposite regulates the expression of genes IGF-1, TGF-β, MSTN, CASP3, CASP2 and proteins such as CALP1, CALP2, MyoD, MyoG which are responsible for the growth, proliferation, and differentiation of satellite cells. Together, the prepared Ti@Fe2O3 nanocomposites afford additional support for the applications of nanomaterials in skeletal muscle repair and tissue regeneration engineering.