Intestinal parasitic infestation among children in a semi-urban Indian population.
Survey on the prevalence of various intestinal parasitic infestations in different geographic regions is a prerequisite to obtain an accurate understanding of the burden and cause of intestinal parasitic infestations in a particular area. The aim of the present study was to determine the intestinal parasitic infestation among children in a semi-urban area. A total of 335 stool samples were collected, processed, and microscopically examined for intestinal parasites. One hundred twenty-eight (38%) stool samples showed presence of ova/cysts. Multiple parasites were seen in 42 (32.8%) samples. Among the protozoans, Entamoeba histolytica (55.3%) was the most common followed by Giardia lamblia (40.4%). Ascaris lumbricoides and Hymenolepis nana (24.2%) were the most common helminths detected. In most of the cases, intestinal parasitic infestation spreads due to low standards of personal hygiene, poor sanitation, non-usage of toilets and an illiterate population, thus suggesting regular surveys to help in devising optimum methods of control.


[Efficacy of lamivudine on acute-on-chronic liver failure in patients with chronic hepatitis B].
To observe the therapeutic effects of lamivudine treatment in patients with early- to mid-stage hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). Clinical data of 73 hospitalized patients with HBV-ACLF were retrospectively analyzed. Prothrombin time (PT, active coagulation), HBV DNA, and model for end-stage liver disease (MELD) score data from treatment weeks 4, 8, 24, and 48 were collected and analyzed using the statistical t-test. During the treatment duration, the complete virologic response rates were 57.5% (42/73) at 4 weeks, 71.0% (44/62) at 8 weeks, 83.1% (49/59) at 24 weeks, and 86.5% (45/52) at 48 weeks. The partial virologic response rates were 30.1% (22/73) at 4 weeks, 25.8% (16/62) at 8 weeks, 17.0% (10/59) at 24 weeks, and 13.5% (7/52) at 48 weeks. At week 48, the survival rate was 71.2% (52/73) and the probability of survival was higher in the complete virological response rate (VRR) group than in the partial VRR group [45/73 (61.6%) vs. 7/73 (30.1%), respectively; P = 0.000]. In addition, there were significant improvements in the serum normalization rate of HBV DNA, alanine aminotransferase, aspartate aminotransferase, albumin, total bilirubin, PT and MELD score in surviving patients compared to baseline (P less than 0.05) and in the complete VRR group compared to the partial VRR group (P less than 0.05). Antiviral therapy using lamivudine may be an effective therapeutic option for patients with HBV-ACLF.


Genetically low vitamin D concentrations and myopic refractive error: a Mendelian randomization study.
Myopia prevalence has increased in the past 20 years, with many studies linking the increase to reduced time spent outdoors. A number of recent observational studies have shown an inverse association between vitamin D [25(OH)D] serum levels and myopia. However, in such studies it is difficult to separate the effects of time outdoors and vitamin D levels. In this work we use Mendelian randomization (MR) to assess if genetically determined 25(OH)D levels contribute to the degree of myopia. We performed MR using results from a meta-analysis of refractive error (RE) genome-wide association study (GWAS) that included 37 382 and 8 376 adult participants of European and Asian ancestry, respectively, published by the Consortium for Refractive Error And Myopia (CREAM). We used single nucleotide polymorphisms (SNPs) in the DHCR7, CYP2R1, GC and CYP24A1 genes with known effects on 25(OH)D concentration as instrumental variables (IV). We estimated the effect of 25(OH)D on myopia level using a Wald-type ratio estimator based on the effect estimates from the CREAM GWAS. Using the combined effect attributed to the four SNPs, the estimate for the effect of 25(OH)D on refractive error was -0.02 [95% confidence interval (CI) -0.09, 0.04] dioptres (D) per 10 nmol/l increase in 25(OH)D concentration in Caucasians and 0.01 (95% CI -0.17, 0.19) D per 10 nmol/l increase in Asians. The tight confidence intervals on our estimates suggest the true contribution of vitamin D levels to degree of myopia is very small and indistinguishable from zero. Previous findings from observational studies linking vitamin D levels to myopia were likely attributable to the effects of confounding by time spent outdoors.


Squamous cell carcinoma in rudd Scardinius erythrophthalmus: histopathology, ultrastructure, and transmission.
The histopathology and ultrastructure of a skin neoplasm in rudd Scardinius erythrophthalmus (L.) are described and the neoplasm is diagnosed as squamous cell carcinoma. In the early stage, tumour cells appear singly or in clusters close to the epidermis; then tumour cells are seen in the dermis as epithelial pearls/nests, cords or sheets with central keratin; and with further development of the neoplasm, tumour cells appear as large sheets and masses, enclosing extensive keratinous formations and foci of necrotic cells, infiltrating deeper into the dermis and penetrating the muscle layers. Increasing vascularity and inflammation are associated with all stages of progression. In some cases metastases are observed in the viscera. Electron microscopic examination shows that the neoplastic cells are joined by desmosomes; the cytoplasm contains abundant mitochondria and rough endoplasmic reticulum. The neoplasm was successfully transmitted experimentally to healthy rudd when tumour cells were inoculated subcutaneously. Eight of 19 surviving test fish developed tumour growth at the site of tumour cell injection and/or in a corresponding site on the opposite of the body. One of these 8 fish, which developed a neoplasm, also showed a microscopic internal tumour in the viscera. One of the 19 test fish showed a microscopic tumour in the spleen, even though no skin tumour was visible in this fish. No tumours were found in control fish. In contrast, intraperitoneal injection of tumour cells into healthy rudd did not result in transmission of the neoplasm.


Correlation between Slug transcription factor and miR-221 in MDA-MB-231 breast cancer cells.
Breast cancer and its metastatic progression is mainly directed by epithelial to mesenchymal transition (EMT), a phenomenon supported by specific transcription factors and miRNAs. In order to investigate a possible correlation between Slug transcription factor and miR-221, we performed Slug gene silencing in MDA-MB-231 breast cancer cells and evaluated the expression of genes involved in supporting the breast cancer phenotype, using qRT-PCR and Western blot analysis. Chromatin immunoprecipitation and wound healing assays were employed to determine a functional link between these two molecules. We showed that Slug silencing significantly decreased the level of miR-221 and vimentin, reactivated Estrogen Receptor α and increased E-cadherin and TRPS1 expression. We demonstrated that miR-221 is a Slug target gene, and identified a specific region of miR-221 promoter that is transcriptionally active and binds the transcription factor Slug "in vivo". In addition, we showed that in Slug-silenced cells, wich retained residual miR-221 (about 38%), cell migration was strongly inhibited. Cell migration was inhibited, but to a less degree, following complete knockdown of miR-221 expression by transfection with antagomiR-221. We report for the first time evidence of a correlation between Slug transcription factor and miR-221 in breast cancer cells. These studies suggest that miR-221 expression is, in part, dependent on Slug in breast cancer cells, and that Slug plays a more important role than miR-221 in cell migration and invasion.


Surface plasmon interferometric microscopy for three-dimensional imaging of dynamic processes.
A method, which we named surface plasmon interferometric microscopy, for real-time displaying of the dynamic evolution of the refractive index (RI) of a sample in three-dimensions is demonstrated experimentally. The Fourier fringe analysis technique is employed to get the phase variations of the samples by demodulating the interference patterns captured by a CCD camera, and the 3D RI distribution can be obtained through numerical interpolation from the relation between the phase and the RI of the samples. Our method may provide an interesting way to monitor fast dynamics of physical, biological, and chemical processes in real time.


Suicide in Illinois, 2005-2010: A reflection of patterns and risks by age groups and opportunities for targeted prevention.
Suicide accounts for two thirds of all deaths from intentional or violence-related injury and is a leading cause of death in the United States. Patterns of suicide have been well described among high-risk groups, but few studies have compared the circumstances related to suicides across all age groups. We sought to understand the epidemiology of suicide cases in Illinois and to characterize the risks and patterns for suicide among different age groups. We used suicide data collected from the Illinois Violent Death Reporting System to assess demographics, method of suicide, circumstances, and mental health status among different age groups. Between 2005 and 2010, 3,016 suicides were reported; 692 (23%) were female, and the median age (n = 3,013) was 45 years (range, 10-98 years). The most common method/weapon types were hanging/strangulation (33%), firearm (32%) and poisoning (21%). Hanging was more common (74%) among young people aged 10 to 19 years, while firearm use was more common among elderly persons age 65 years and older (55%). The percentage of victims within an age group experiencing a crisis within two weeks before committing suicide was highest among 10- to 14-year-olds, while the risk factor of having a family member or friend die in the past 5 years was highest among older victims. The final analysis demonstrated age-related trends in suicide in Illinois, suggesting prevention programs should tailor services by age. Epidemiologic study, level IV.


Hemolysis-associated phosphatidylserine exposure promotes polyclonal plasmablast differentiation.
Antimalarial antibody responses are essential for mediating the clearance of Plasmodium parasite-infected RBCs from infected hosts. However, the rapid appearance of large numbers of plasmablasts in Plasmodium-infected hosts can suppress the development and function of durable humoral immunity. Here, we identify that the formation of plasmablast populations in Plasmodium-infected mice is mechanistically linked to both hemolysis-induced exposure of phosphatidylserine on damaged RBCs and inflammatory cues. We also show that virus and Trypanosoma infections known to trigger hemolytic anemia and high-grade inflammation also induce exuberant plasmablast responses. The induction of hemolysis or administration of RBC membrane ghosts increases plasmablast differentiation. The phosphatidylserine receptor Axl is critical for optimal plasmablast formation, and blocking phosphatidylserine limits plasmablast expansions and reduces Plasmodium parasite burden in vivo. Our findings support that strategies aimed at modulating polyclonal B cell activation and phosphatidylserine exposure may improve immune responses against Plasmodium parasites and potentially other infectious diseases that are associated with anemia.


Pulse steroid therapy.
Intravenous supra-pharmacological doses of corticosteroids are used in various inflammatory and autoimmune conditions because they are cumulatively less toxic than sustained steroid treatment at lower quantitative dosage. Their action is supposed to be mediated through non-genomic actions within the cell. Common indications for use in children include steroid resistant and steroid dependent nephrotic syndrome, rapidly progressive glomerulonephritis, systemic vasculitis, systemic lupus erythematosus, acute renal allograft rejection, juvenile rheumatoid arthritis, juvenile dermatomyositis, pemphigus, optic neuritis, multiple sclerosis and acute disseminated encephalomyelitis. Methylprednisolone and dexamethasone show similar efficacy in most conditions. Therapy is associated with significant side effects including worsening of hypertension, infections, dyselectrolytemia and behavioral effects. Adequate monitoring is essential during usage.


Market integration and soil-transmitted helminth infection among the Shuar of Amazonian Ecuador.
Soil-transmitted helminth (STH) infections have many negative health outcomes (e.g., diarrhea, nutritional deficiencies) that can also exacerbate poverty. These infections are generally highest among low-income populations, many of which are also undergoing market integration (MI; increased participation in a market-based economy). Yet the direct impact of MI-related social and environmental changes on STH infection patterns is poorly understood, making it unclear which lifestyle factors should be targeted to better control disease spread. This cross-sectional study examines if household infrastructure associated with greater MI is associated with lower STH burdens among Indigenous Ecuadorian Shuar. Kato-Katz fecal smears were used to determine STH infection status and intensity (n = 620 participants; 308 females, 312 males, aged 6 months-86 years); Ascaris lumbricoides (ascarid) and Trichuris trichiura (whipworm) were the primary infection types detected. Structured interviews assessing lifestyle patterns (e.g., measures of household infrastructure) measured participant MI. Multilevel regression analyses and zero-inflated negative binomial regression models tested associations between MI measures and STH infection status or intensity, controlling for individual and community characteristics. Participants residing in more market-integrated households exhibited lower infection rates and intensities than those in less market integrated households. Parasite infection status and T. trichiura infection intensity were lower among participants living in houses with wood floors than those with dirt floors, while individuals using well or piped water from a spring exhibited lower A. lumbricoides infection intensities compared to those using river or stream water. Unexpectedly, latrine type was not significantly related to STH infection status or intensity. These results suggest that sources of exposure differ between the two helminth species. This study documents associations between household measures and STH infection among an Indigenous population undergoing rapid MI. These findings can help healthcare programs better target interventions and reduce STH exposure among at-risk populations.


Microtensile bond strength of total-etch and self-etch adhesives to the enamel walls of Class V cavities.
To determine the difference in microtensile bond strengths (MTBS) of resin-based composite bonded to the enamel of cavity preparations using a conventional or a self-etching adhesive. Buccal and lingual Class V cavities were prepared in each of 12 caries-free human molars. Six teeth were randomly selected to be restored with Spectrum TPH resin-based composite and Prime & Bond NT adhesive. The remaining six teeth were restored with the same composite and Prompt L-Pop self-etching adhesive. Enamel/composite sticks were cut from each specimen and subjected to microtensile bond testing. Each debonded specimen was evaluated by SEM to determine the mode of failure. The mean MTBS for Prime & Bond NT specimens was 15.2+/-13.1 MPa. The mean MTBS for Prompt L-Pop self-etching adhesive samples was 18.2+/-14.3 MPa. ANOVA demonstrated no statistically significant difference between the mean MTBS associated with the two adhesives (P> 0.05). The results of SEM analysis revealed that the bonding failures occurred primarily at the interface between the adhesive and the enamel, suggesting a primarily adhesive failure.


Frequency of B cells committed to the production of antibodies to insulin in newly diagnosed patients with insulin-dependent diabetes mellitus and generation of high affinity human monoclonal IgG to insulin.
Circulating autoantibodies to insulin can be detected in patients with insulin-dependent (type I) diabetes mellitus (IDDM) at the onset of the clinical disease. To characterize the autoantibody response in IDDM patients, we determined the frequency of circulating B cells committed to the production of IgM, IgG, and IgA to insulin in 12 newly diagnosed IDDM patients and, for comparison, in 9 healthy subjects and 17 insulin-treated IDDM patients. We found that B cells committed to the production of anti-insulin IgG, but not IgM, autoantibodies are present at much higher frequency in the circulation of newly diagnosed IDDM patients before insulin treatment (0.209 +/- 0.142%, mean value +/- SD of total IgG-producing cell precursors) as compared with age-matched healthy controls (0.032 +/- 0.030% of total IgG-producing cell precursors). In IDDM patients who had been treated with insulin, cells producing IgG antibody to insulin were 0.177 +/- 0.139% of total IgG-producing cell precursors. Generation of IgG mAb from B cells of IDDM patients revealed that they were monoreactive, i.e., they bound to insulin, but to none of the other Ag tested, and displayed a high affinity for insulin (Kd approximately 10(-7) moles/liter). In contrast, the IgG mAb derived from healthy subjects were polyreactive, i.e., they bound to all Ag tested, and displayed a low to moderate affinity for insulin (Kd approximately 10(-5) to 10(-6) moles/liter). These findings show that lymphocytes committed to the production of high affinity IgG autoantibodies to insulin are common in the B cell repertoire at the onset of IDDM.


Effect of Microsphaeropsis sp. on the Production of Perithecia and Ascospores of Gibberella zeae.
The potential of Microsphaeropsis sp. (isolate P130A) as an antagonist of Gibberella zeae was tested under in vitro and field conditions. Firstly, an in vitro method of ascospore production was developed on wheat and corn residues. The plant type (corn or wheat), residue type (straw/stalk or grain), and incubation conditions (closed or open) had a significant effect on ascospore production. Perithecia were more abundant on wheat and corn grain incubated under open conditions. On these two substrates, the application of Microsphaeropsis sp. significantly reduced ascospore production. On wheat, the antagonist had a significant effect when applied 2 weeks before (-2), at the same time (0), and 4 weeks after (+4) inoculation with G. zeae, with 1.73, 0.31, 1.11, and 1.36 log ascospores per cm2 for the control, -2, 0, and +4 weeks treatments, respectively. On corn, Microsphaeropsis sp. had a significant effect when applied 2 weeks before, at the same time, 4 weeks after, and 6 weeks after inoculation with G. zeae with 3.02, 0.23, 1.29, 2.35, and 2.22 log ascospores per cm2 for the control, -2, 0, +4, and +6 weeks treatments, respectively. When applied to crop residues in the field as postharvest or preplanting applications, Microsphaeropsis sp. had no effect on the pattern of perithecia maturation, but significantly reduced the number of perithecia produced on two sampling dates, May 1998 and July 1999. There is a potential to biologically reduce the initial inoculum of G. zeae; however, more work is needed to optimize the efficacy of the biocontrol agent.


Occurrence of Toxigenic Bacillus cereus and Bacillus thuringiensis in Doenjang, a Korean Fermented Soybean Paste.
This study determined the prevalence and toxin profile of Bacillus cereus and Bacillus thuringiensis in doenjang, a fermented soybean food, made using both traditional and commercial methods. The 51 doenjang samples tested were broadly contaminated with B. cereus; in contrast, only one sample was positive for B. thuringiensis. All B. cereus isolates from doenjang were positive for diarrheal toxin genes. The frequencies of nheABC and hblACD in traditional samples were 22.7 and 0%, respectively, whereas 5.1 and 5.1% of B. cereus isolates from commercial samples possessed nheABC and hblACD, respectively. The detection rate of ces gene was 10.8%. The predominant toxin profile among isolates from enterotoxigenic B. cereus in doenjang was profile 4 (entFM-bceT-cytK). The major enterotoxin genes in emetic B. cereus were cytK, entFM, and nheA genes. The B. thuringiensis isolate was of the diarrheagenic type. These results provide a better understanding of the epidemiology of the enterotoxigenic and emetic B. cereus groups in Korean fermented soybean products.


Combined microwave thermal ablation and liver resection for single step treatment of otherwise unresectable colorectal liver metastases; a monoistitutional experiences.
Over half of colorectal cancer patients will develop liver metastases. Thermal ablation with or without associated liver resection for colorectal hepatic metastasis has been suggested as an alternative method to improve survival if radical surgical resection is not achievable. A retrospective case series of patients treated with microwave ablation(MWA) associated with hepatic resection in one step procedure, was reviewed to analyze the clinical outcome. In a group of 40 patients surgically cured for liver tumors in our Department, 5 patients with technically unresectable disease underwent combined treatment LR-MWA. Four patients were treated with multiple segmentectomies and MWA and one patient received a left lobectomy (S2-S3) and MWA. Only 1 patient (20%) developed post surgical complication which was a liver abscess (grade II of Dindo classification). Hepatic resection combined with MWA expanded indications for operative treatment of multiple bilobar liver metastasis. This procedure promise to have good long-term outcomes.


The amino-terminal domains of Epstein-Barr virus nuclear proteins 3A, 3B, and 3C interact with RBPJ(kappa).
The ability of Epstein-Barr virus (EBV) latent infection nuclear protein EBNA3C to activate transcription of two EBNA2-responsive genes and to inhibit EBNA2 activation of transcription in transient-transfection assays appears to be due to its ability to interact with RBPJkappa, a cell protein that links EBNA2 to its response elements. We now show that EBNA3A and EBNA3B expressed in non-EBV-infected Burkitt tumor lymphoblasts are similar to EBNA3C in binding to glutathione S-transferase-RBPJkappa in vitro and in coimmunoprecipitating from cell lysates with antibody to RBPJkappa. EBNA3A and EBNA3B can also inhibit the interaction of RBPJkappa with cognate DNA in vitro. Although EBNA3 open reading frames are each close to 1,000 codons long, EBNA3A amino acids 1 to 138, EBNA3B amino acids 1 to 311, and EBNA3C amino acids 1 to 183 are sufficient for RBPJkappa interaction, while EBNA3B amino acids I to 109 have less or no binding. The RBPJkappa interacting domains overlap with the most highly conserved domain (amino acids 90 to 320) among the EBNA3 proteins. Thus, the EBNA3 gene family appears to have evolved to differentially regulate promoters with RBPJkappa binding sites. EBNA2, EBNA3A, and EBNA3C are important in EBV transformation of primary human B lymphocytes. Their interaction with RBPJkappa links EBV transformation to the notch signaling pathway and the effects of activated notch in T-cell leukemogenesis.


Hit-to-lead optimization of a benzene sulfonamide series for potential antileishmanial agents.
A series of benzene sulphonamides with good potency and selectivity against Leishmania spp. intracellular amastigotes was identified by high-throughput screening. Approximately 200 compounds were synthesized as part of a hit-to-lead optimization program. The potency of the series appears to be strongly dependent on lipophilicity, making the identification of suitable orally available candidates challenging due to poor pharmacokinetics. Despite not identifying a clinical candidate, a likely solvent exposed area was found, best exemplified in compound 29. Ongoing detailed mode-of-action studies may provide an opportunity to use target-based medicinal chemistry to overcome the issues with the current series.


Hospital admissions due to alcohol related disorders among young adult refugees who arrived in Sweden as teenagers - a national cohort study.
Psychological distress and lack of family support may explain the mental health problems that are consistently found in young unaccompanied refugees in Western countries. Given the strong relationship between poor mental health and alcohol misuse, this study investigated hospital admissions due to alcohol related disorders among accompanied and unaccompanied young refugees who settled in Sweden as teenagers. The dataset used in this study was derived from a combination of different registers. Cox regression models were used to estimate the risks of hospital care due to alcohol related disorders in 15,834 accompanied and 4376 unaccompanied young refugees (2005-2012), aged 13 to 19 years old when settling in Sweden and 19 to 32 years old in December 2004. These young refugees were divided into regions with largely similar attitudes toward alcohol: the former Yugoslavian republics, Somalia, and the Middle East. The findings were compared with one million peers in the native Swedish population. Compared to native Swedes, hospital admissions due to alcohol related disorders were less common in young refugees, with a hazard ratio (HR) of 0.65 and 95% confidence interval (CI) between 0.56 and 0.77. These risks were particularly lower among young female refugees. However, there were some differences across the refugee population. For example, the risks were higher in unaccompanied (male) refugees than accompanied ones (HR = 1.49, 95% CI = 1.00-2.19), also when adjusted for age, domicile and income. While the risks were lower in young refugees from Former Yugoslavia and the Middle East relative to native Swedes, independent of their length of residence in Sweden, refugees from Somalia who had lived in Sweden for more than ten years showed increased risks (HR = 2.54, 95% CI = 1.71-3.76), after adjustments of age and domicile. These risks decreased considerably when income was adjusted for. Young refugees have lower risks of alcohol disorders compared with native Swedes. The risks were higher in unaccompanied young (male) refugees compared to the accompanied ones. Moreover, Somalian refugees who had lived in Sweden for more than ten years seems to be particularly vulnerable to alcohol related disorders.


Ultrawideband radiation and pentylenetetrazol-induced convulsions in rats.
New non-ionizing pulsed systems using ultrawideband (UWB) require safety assessment before they can be used by either military or civilian communities. The development of directed energy weaponry intended for use against electronically vulnerable targets, as well as ground-probing radar systems, have used fast-rise-time high-peak-power electromagnetic pulses characteristic of UWB emitters. It has been postulated that these ultrashort pulses might produce electromagnetic transients resulting in tissue damage. Several challenges to this notion have been posed, however. One report found that rats exposed to UWB after receiving a convulsant drug tended toward longer latency to the onset of convulsions than the no-exposure group. Although not statistically significant, the presence of this trend prompted the present study. An ED99 dose of the convulsant pentylenetetrazol (PTZ) or saline was given just before UWB or sham exposure and resultant seizure activity was recorded. The data from the current study show no effect of UWB exposure on PTZ-induced seizure activity, thereby not supporting the tissue damage concerns, at least for the exposure parameters used here.


Formation and alteration of airborne particles in the subway environment.
Most particles in the rail subway environment are sub-micron sized ferruginous flakes and splinters generated mechanically by frictional wear of brake pads, wheels and rails. To better understand the mechanisms of formation and the alteration processes affecting inhalable particles in subways, PM samples (1-2.5 μm and 2.5-10 μm) were collected in the Barcelona Metro and then studied under a scanning electron microscope. Most particles in these samples are hematitic (up to 88%), with relatively minor amounts of mineral matter (up to 9%) and sulphates (up to 5%). Detailed microscopy (using back scattered and TEM-DRX imaging) reveals how many of the metallic particles comprise the metallic Fe nucleus surrounded by hematite (Fe2O3) and a coating of sulphate and chloride salts mixed with mineral matter (including Ca-carbonates, clay minerals and quartz). These observations record the emission of fine to ultrafine FePM by frictional wear at elevated temperatures that promote rapid partial (or complete) oxidation of the native metal. Water condensing on the PM surface during cooling leads to the adsorption of inorganic mineral particles that coat the iron oxide. The distinctively layered polymineralic structure that results from these processes is peculiar to particles generated in the subway environment and very different from PM typically inhaled outdoors.


Results of combined stereotactic radiosurgery and transarterial embolization for dural arteriovenous fistulas of the transverse and sigmoid sinuses.
Most dural arteriovenous fistulas (DAVFs) of the transverse and sigmoid sinuses do not have angiographically demonstrated features associated with intracranial hemorrhage and, therefore, may be treated nonsurgically. The authors report their experience using a staged combination of radiosurgery and transarterial embolization for treating DAVFs involving the transverse and sigmoid sinuses. Between 1991 and 1998, 25 patients with DAVFs of the transverse and/or sigmoid sinuses were treated using stereotactic radiosurgery; 22 of these patients also underwent transarterial embolization. Two patients were lost to follow-up review. Clinical data, angiographic findings, and follow-up records for the remaining 23 patients were collected prospectively. The mean duration of clinical follow up after radiosurgery was 50 months (range 20-99 months). The 18 women and five men included in this series had a mean age of 57 years (range 33-79 years). Twenty-two (96%) of 23 patients presented with pulsatile tinnitus as the primary symptom; two patients had experienced an earlier intracerebral hemorrhage (ICH). Cognard classifications of the DAVFs included the following: I in 12 patients (52%), IIa in seven patients (30%), and III in four patients (17%). After treatment, symptoms resolved (20 patients) or improved significantly (two patients) in 96% of patients. One patient was clinically unchanged. No patient sustained an ICH or irradiation-related complication during the follow-up period. Seventeen patients underwent follow-up angiographic studies at a mean of 21 months after radiosurgery (range 11-38 months). Total or near-total obliteration (> 90%) was seen in 11 patients (65%), and more than a 50% reduction in six patients (35%). Two patients experienced recurrent tinnitus and underwent repeated radiosurgery and embolization at 21 and 38 months, respectively, after the first procedure. A staged combination of radiosurgery and transarterial embolization provides excellent symptom relief and a good angiographically verified cure rate for patients harboring low-risk DAVFs of the transverse and sigmoid sinuses. This combined approach is a safe and effective treatment strategy for patients without angiographically determined risk factors for hemorrhage and for elderly patients with significant comorbidities.


A Task-Centric Cooperative Sensing Scheme for Mobile Crowdsourcing Systems.
In a densely distributed mobile crowdsourcing system, data collected by neighboring participants often exhibit strong spatial correlations. By exploiting this property, one may employ a portion of the users as active participants and set the other users as idling ones without compromising the quality of sensing or the connectivity of the network. In this work, two participant selection questions are considered: (a) how to recruit an optimal number of users as active participants to guarantee that the overall sensing data integrity is kept above a preset threshold; and (b) how to recruit an optimal number of participants with some inaccurate data so that the fairness of selection and resource conservation can be achieved while maintaining sufficient sensing data integrity. For question (a), we propose a novel task-centric approach to explicitly exploit data correlation among participants. This subset selection problem is regarded as a constrained optimization problem and we propose an efficient polynomial time algorithm to solve it. For question (b), we formulate this set partitioning problem as a constrained min-max optimization problem. A solution using an improved version of the polynomial time algorithm is proposed based on (a). We validate these algorithms using a publicly available Intel-Berkeley lab sensing dataset and satisfactory performance is achieved.


Multimodal MRI reveals structural connectivity differences in 22q11 deletion syndrome related to impaired spatial working memory.
Impaired spatial working memory is a core cognitive deficit observed in people with 22q11 Deletion syndrome (22q11DS) and has been suggested as a candidate endophenotype for schizophrenia. However, to date, the neuroanatomical mechanisms describing its structural and functional underpinnings in 22q11DS remain unclear. We quantitatively investigate the cognitive processes and associated neuroanatomy of spatial working memory in people with 22q11DS compared to matched controls. We examine whether there are significant between-group differences in spatial working memory using task related fMRI, Voxel based morphometry and white matter fiber tractography. Multimodal magnetic resonance imaging employing functional, diffusion and volumetric techniques were used to quantitatively assess the cognitive and neuroanatomical features of spatial working memory processes in 22q11DS. Twenty-six participants with genetically confirmed 22q11DS aged between 9 and 52 years and 26 controls aged between 8 and 46 years, matched for age, gender, and handedness were recruited. People with 22q11DS have significant differences in spatial working memory functioning accompanied by a gray matter volume reduction in the right precuneus. Gray matter volume was significantly correlated with task performance scores in these areas. Tractography revealed extensive differences along fibers between task-related cortical activations with pronounced differences localized to interhemispheric commissural fibers within the parietal section of the corpus callosum. Abnormal spatial working memory in 22q11DS is associated with aberrant functional activity in conjunction with gray and white matter structural abnormalities. These anomalies in discrete brain regions may increase susceptibility to the development of psychiatric disorders such as schizophrenia. Hum Brain Mapp 37:4689-4705, 2016. © 2016 Wiley Periodicals, Inc.


Design of a transdermal formulation containing raloxifene nanoparticles for osteoporosis treatment.
In the clinical setting, raloxifene, a second-generation selective estrogen receptor modulator, is administered orally; however, the bioavailability (BA) is only 2% because of its poor solubility in aqueous fluids and its extensive first-pass metabolism. Therefore, it is expected that the development of a transdermally delivered formulation may reduce the necessary dose without compromising its therapeutic efficacy. In this study, we designed transdermal formulations containing raloxifene nanoparticles and evaluated their usefulness for osteoporosis therapy. Raloxifene was crushed with methylcellulose by the bead mill method, and the milled raloxifene was gelled with or without menthol (a permeation enhancer) by Carbopol® 934 (without menthol, Ral-NPs; with menthol, mRal-NPs). The drug release and transdermal penetration were measured using a Franz diffusion cell, and the therapeutic evaluation of osteoporosis was determined in an ovariectomized rat model. The mean particle size of raloxifene in the transdermal formulation (Ral-NPs) was 173.7 nm. Although the raloxifene released from Ral-NPs remained in the nanoparticle state, the skin penetration of raloxifene nanoparticles was prevented by the stratum corneum in rat. On the other hand, inclusion of menthol in the formulation attenuated the barrier function of the stratum corneum and permitted the penetration of raloxifene nanoparticles through the skin. Moreover, macropinocytosis relates to the skin penetration of the formulation including menthol (mRal-NPs), since penetration was inhibited by treatment with 2 µM rottlerin, a macropinocytosis inhibitor. In addition, the application of 0.3% mRal-NPs (once a day) attenuated the decreases in calcium level and stiffness of the bones of ovariectomized rat. We prepared raloxifene solid nanoparticles by a bead mill method and designed a novel transdermal formulation containing nanoparticles and permeation enhancers. These trans-dermal formulations overcome the barrier properties of the skin and show high drug penetration through the transdermal route (BA 8.5%). In addition, we found that raloxifene transdermal formulations are useful for the treatment of osteoporosis in ovariectomized rat.


Microneutralization assay titres correlate with protection against seasonal influenza H1N1 and H3N2 in children.
Although the microneutralization (MN) assay has been shown to be more sensitive than the hemagglutination inhibition (HAI) assay for the measurement of humoral immunity against influenza viruses, further evidence relating MN titres to protective efficacy against infection is needed. Serum antibodies against seasonal H1N1 and H3N2 influenza were measured in children and adolescents (n = 656) by MN and hemagglutination inhibition (HAI) assays. Compared to HAI, the MN assay is more sensitive in detecting serum antibodies and estimates of protective effectiveness against PCR-confirmed infection were higher for both subtypes. Given our findings, the MN assay warrants further consideration as a formal tool for the routine evaluation of vaccine-induced antibody responses.


MCM - 2 and Ki - 67 as proliferation markers in renal cell carcinoma: A quantitative and semi - quantitative analysis.
Fuhrman nuclear grade is the most important histological parameter to predict prognosis in a patient of renal cell carcinoma (RCC). However, it suffers from inter-observer and intra-observer variation giving rise to need of a parameter that not only correlates with nuclear grade but is also objective and reproducible. Proliferation is the measure of aggressiveness of a tumour and it is strongly correlated with Fuhrman nuclear grade, clinical survival and recurrence in RCC. Ki-67 is conventionally used to assess proliferation. Mini-chromosome maintenance 2 (MCM-2) is a lesser known marker of proliferation and identifies a greater proliferation faction. This study was designed to assess the prognostic significance of MCM-2 by comparing it with Fuhrman nuclear grade and Ki-67. n=50 cases of various ages, stages, histological subtypes and grades of RCC were selected for this study. Immunohistochemical staining using Ki-67(MIB-1, Mouse monoclonal antibody, Dako) and MCM-2 (Mouse monoclonal antibody, Thermo) was performed on the paraffin embedded blocks in the department of Morbid anatomy and Histopathology, University of Health Sciences, Lahore. Labeling indices (LI) were determined by two pathologists independently using quantitative and semi-quantitative analysis. Statistical analysis was carried out using SPSS 20.0. Kruskall-Wallis test was used to determine a correlation of proliferation markers with grade, and Pearson's correlate was used to determine correlation between the two proliferation markers. Labeling index of MCM-2 (median=24.29%) was found to be much higher than Ki-67(median=13.05%). Both markers were significantly related with grade (p=0.00; Kruskall-Wallis test). LI of MCM-2 was found to correlate significantly with LI of Ki-67(r=0.0934;p=0.01 with Pearson's correlate). Results of semi-quantitative analysis correlated well with quantitative analysis. Both Ki-67 and MCM-2 are markers of proliferation which are closely linked to grade. Therefore, they can act as surrogate markers for grade in a manner that is more objective and reproducible.


Emergency department utilization by noninstitutionalized elders.
To the best of the authors' knowledge, no nationally representative, population-based study has characterized the proportion of elders using the emergency department (ED) and factors associated with ED use by elders. This article describes the proportion of elder Medicare beneficiaries using the ED and identifies attributes associated with elder ED users as compared with nonusers. The 1993 Medicare Current Beneficiary Survey was used, a national, population-based, cross-sectional survey of Medicare beneficiaries linked with Medicare claims data. The study population was limited to 9,784 noninstitutionalized individuals aged 66 years or older. The Andersen model of health service utilization was used, which explains variation in ED use through a combination of predisposing (demographic and social), enabling (access to care), and need (comorbidity and health status) characteristics. Eighteen percent of the sample used the ED at least once during 1993. Univariate analysis showed ED users were older; were less educated and lived alone; had lower income and higher Charlson Comorbidity Index scores; and were less satisfied with their ability to access care than nonusers (p < 0.01, chi-square). Logistic regression identified older age, less education, living alone, higher comorbidity scores, worse reported health, and increased difficulties with activities of daily living as factors associated with ED use (p < 0.05). Need characteristics predicted ED use with the greatest accuracy. The proportion of elder ED users is slightly higher than previously reported among Medicare beneficiaries. Need (comorbidity and health status) characteristics predict ED utilization with the greatest accuracy.


Long-read assembly of the Chinese rhesus macaque genome and identification of ape-specific structural variants.
We present a high-quality de novo genome assembly (rheMacS) of the Chinese rhesus macaque (Macaca mulatta) using long-read sequencing and multiplatform scaffolding approaches. Compared to the current Indian rhesus macaque reference genome (rheMac8), rheMacS increases sequence contiguity 75-fold, closing 21,940 of the remaining assembly gaps (60.8 Mbp). We improve gene annotation by generating more than two million full-length transcripts from ten different tissues by long-read RNA sequencing. We sequence resolve 53,916 structural variants (96% novel) and identify 17,000 ape-specific structural variants (ASSVs) based on comparison to ape genomes. Many ASSVs map within ChIP-seq predicted enhancer regions where apes and macaque show diverged enhancer activity and gene expression. We further characterize a subset that may contribute to ape- or great-ape-specific phenotypic traits, including taillessness, brain volume expansion, improved manual dexterity, and large body size. The rheMacS genome assembly serves as an ideal reference for future biomedical and evolutionary studies.


N-methyl-D-aspartate receptor antibody-associated movement disorder without encephalopathy.
N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis is a well-recognized clinico-immunological syndrome that presents with a movement disorder, cognitive decline, psychiatric symptoms, and epileptic seizures. A pure monosymptomatic presentation is rare; however, some patients present predominantly with a movement disorder in the absence of encephalopathy. Here, we describe three paediatric patients with an NMDAR antibody-mediated movement disorder: a 5-year-old female with acute onset hemichorea, a 10-year-old female with generalized chorea, and a 12-year-old male with abdominal myoclonus. These patients did not develop the characteristic encephalopathy syndrome seen in NMDAR encephalitis, but all three had other associated subtle cognitive deficits. The patients demonstrated good responses to immunotherapy.


Electrostatic balance between global repulsion and local attraction in reentrant polymerization of actin.
Actin polymerization depends on the salt concentration, exhibiting a reentrant behavior: the polymerization is promoted by increasing KCl concentration up to 100 mM, and then depressed by further increase above 100 mM. We here investigated the physical mechanism of this reentrant behavior by calculating the polymerization energy, defined by the electrostatic energy change upon binding of an actin subunit to a filament, using an implicit solvent model based on the Poisson-Boltzmann (PB) equation. We found that the polymerization energy as a function of the salt concentration shows a non-monotonic reentrant-like behavior, with the minimum at about 100 mM (1:1 salt). By separately examining the salt concentration effect on the global electrostatic repulsion between the like-charged subunits and that on the local electrostatic attraction between the inter-subunit ionic-bond-forming residues in the filament, we clarified that the reentrant behavior is caused by the change in the balance between the two opposing electrostatic interactions. Our study showed that the non-specific nature of counterions, as described in the mean-field theory, plays an important role in the actin polymerization. We also discussed the endothermic nature of the actin polymerization and mentioned the effect of ATP hydrolysis on the G-F transformation, indicating that the electrostatic interaction is widely and intricately involved in the actin dynamics.


Curcuma longa inhibits TNF-alpha induced expression of adhesion molecules on human umbilical vein endothelial cells.
Identification of non-steroidal anti-inflammatory small molecules is very important for the development of anti-inflammatory drugs. We demonstrate here that out of three compounds, viz diferuloylmethane, p-coumaroylferuloylmethane and di-p-coumaroylmethane, present in the ethyl acetate extract of Curcuma longa, diferuloylmethane is most potent in inhibiting TNF-alpha induced expression of ICAM-1, VCAM-1 and E-selectin on human umbilical vein endothelial cells. The inhibition by diferuloylmethane is time dependent and is reversible. By using RT-PCR, we demonstrate that it inhibits the induction of steady state transcript levels of ICAM-1, VCAM-1 and E-selectin, and therefore it may interfere with the transcription of their genes. As diferuloylmethane significantly blocks the cytokine induced transcript levels for the leukocyte adhesion molecules, it may be interfering at an early stage of signalling event induced by TNF-alpha.


Emergency assistance provided abroad to insured travellers from Australia following the Bali bombing.
Background. On 12 October 2002, terrorist bombs detonated in the Kuta entertainment district of Bali, Indonesia, a popular tourist destination for Australian travellers. This study was designed to investigate travel insurance claims reported by travellers from Australia requiring emergency assistance and/or aeromedical evacuation, as well as to examine the role of travel insurance and emergency assistance companies, following the Bali bombing. Methods. In 2003, all claims reported, following the Bali bombing attack on 12 October 2002, to a major Australian travel insurance company were examined for those claims that described the use of the insurer's emergency assistance contractor by travellers in Bali following the bombing. Results. Thirteen insured travellers used the emergency assistance service following the Bali bombing. Six travellers cancelled their trip to Bali. Five travellers, who were already abroad cancelled their trip to Bali and one was given evacuation assistance. One traveller required aeromedical evacuation by scheduled aircraft with glass injuries resulting from the bomb blast, and there was also assistance provided to significant others following the death of one insured traveller as a direct consequence of the bombing. Two travellers sought only claiming and policy advice and no claim was made. The mean refund, where a travel insurance claim was made, was AUD1185.09 (SD=AUD3047.31). Conclusions. This study highlights the importance of travellers taking out appropriate travel insurance, which provides for emergency assistance. Travel insurance agencies do play some role after emergencies such as the Bali bombing. This assistance involves predominantly dealing with cancellation of travellers' intended visits to the affected area, but does also involve some assistance to travellers evacuating from the crisis, including some who require aeromedical evacuation. Travellers should be advised to seek travel health advice well before departure overseas and to ensure that they are aware of travel advisories for their destination.


StrBioLib: a Java library for development of custom computational structural biology applications.
StrBioLib is a library of Java classes useful for developing software for computational structural biology research. StrBioLib contains classes to represent and manipulate protein structures, biopolymer sequences, sets of biopolymer sequences, and alignments between biopolymers based on either sequence or structure. Interfaces are provided to interact with commonly used bioinformatics applications, including (psi)-blast, modeller, muscle and Primer3, and tools are provided to read and write many file formats used to represent bioinformatic data. The library includes a general-purpose neural network object with multiple training algorithms, the Hooke and Jeeves non-linear optimization algorithm, and tools for efficient C-style string parsing and formatting. StrBioLib is the basis for the Pred2ary secondary structure prediction program, is used to build the astral compendium for sequence and structure analysis, and has been extensively tested through use in many smaller projects. Examples and documentation are available at the site below. StrBioLib may be obtained under the terms of the GNU LGPL license from http://strbio.sourceforge.net/


What Factors Are Associated With Failure of Compressive Osseointegration Fixation?
Compressive osseointegration is as an alternative to traditional intramedullary fixation. Two- to 10-year survivorship and modes of failure have been reported; however, as a result of relatively small numbers, these studies are limited in their ability to identify risk factors for failure. (1) What is survivorship free from aseptic mechanical and survivorship free from overall failure of compressive osseointegration fixation? (2) What patient factors (age, sex, body mass index [BMI], anatomic location of reconstruction, indication for reconstruction, radiation, chemotherapy) are associated with increased risk of failure? Between 2006 and 2014, surgeons at one center treated 116 patients with 137 Compress® implants for lower extremity oncologic reconstructions, revision arthroplasty, and fracture nonunion or malunion. One hundred sixteen implants were available for review with a minimum of 2-year followup (mean, 4 years; range, 2-9 years). Kaplan-Meier survival plots were produced to examine survivorship and Cox regression modeling was used to generate hazard ratios (HRs) for potential risk factors for failure. Patient factors (age, sex, BMI, anatomic location of reconstruction, indication for reconstruction, radiation, chemotherapy) were obtained from chart review and an institutional database. Survivorship free from aseptic mechanical failure was 95% (95% confidence interval [CI], 91%-99%) at 18 months and 93% (95% CI, 86%-99%) at 4 years. Survivorship free from overall failure was 82% (95% CI, 75%-89%) at 18 months and 75% (95% CI, 66%-84%) at 4 years. Risk of overall failure was increased with reconstruction of the proximal tibia (HR, 4.42; 95% CI 0.98-19.9) and distal femur (HR, 1.74; 95% CI, 0.50-6.09) compared to the proximal femur (HR, 1; referent; p = 0.049). Risk of aseptic mechanical failure was increased with reconstruction of the proximal tibia (HR, 1; referent) and distal femur (HR, 0.37; 95% CI, 0.08-1.77) compared with the proximal femur (HR, 0, p = 0.048). Radiation was associated with increased risk of overall failure (HR, 3.85; 95% CI, 1.84-8.02; p < 0.003), but not aseptic mechanical failure. Age, sex, BMI, chemotherapy, and surgical indication were not associated with increased risk of aseptic or overall failure. This study questions the use of age as a contraindication for the use of this technology and suggests this technology may be considered in proximal femoral reconstruction and for patients with indications other than primary oncologic reconstructions. Future research should establish long-term survivorship data to compare this approach with conventional intramedullary stems and to evaluate the potential benefits of preventing stress shielding and preserving bone stock in revision situations. Level III, therapeutic study.


Antecedents of Exercise Dependence in Ultra-Endurance Sports: Reduced Basic Need Satisfaction and Avoidance-Motivated Self-Control.
Initiating and maintaining sports and exercise behavior are usually discussed in terms of strategies for promoting health. In the present study, we analyzed a sample of extreme endurance sport athletes and set out to predict exercise addiction, which is a facet of a sport-related health risk. We therefore draw on self-determination theory (Deci and Ryan, 1985, 2000), according to which low basic psychological need satisfaction can lead to excessive compensatory behavior. We aim to disentangle the effects of need satisfaction in the activity itself (exercising) and outside the activity (work/leisure) on exercise addiction. Furthermore, we propose anxious self-motivation as a mediator and tested whether it links low basic need satisfaction with exercise dependence. A correlational study with 323 multi-triathlon athletes confirmed our hypothesis that need satisfaction in work/leisure (but not in sports) is negatively related to exercise addiction. Furthermore, only need for competence in both domains (sport, work/leisure) is associated with anxious self-motivation. Mediation models showed that low competence satisfaction leads to anxious self-motivation that in turn predicts exercise addiction. The results are discussed critically in terms of their practical and theoretical implications for promoting health through sport and exercise.


TG13 guidelines for diagnosis and severity grading of acute cholangitis (with videos).
Since the publication of the Tokyo Guidelines for the management of acute cholangitis and cholecystitis (TG07), diagnostic criteria and severity assessment criteria for acute cholangitis have been presented and extensively used as the primary standard all over the world. However, it has been found that there are crucial limitations in these criteria. The diagnostic criteria of TG07 do not have enough sensitivity and specificity, and its severity assessment criteria are unsuitable for clinical use. A working team for the revision of TG07 was organized in June, 2010, and these criteria have been updated through clinical implementation and its assessment by means of multi-center analysis. The diagnostic criteria of acute cholangitis have been revised as criteria to establish the diagnosis where cholestasis and inflammation demonstrated by clinical signs or blood test in addition to biliary manifestations demonstrated by imaging are present. The diagnostic criteria of the updated Tokyo Guidelines (TG13) have high sensitivity (87.6 %) and high specificity (77.7 %). TG13 has better diagnostic capacity than TG07. Severity assessment is classified as follows: Grade III: associated with organ failure; Grade II: early biliary drainage should be conducted; Grade1: others. As for the severity assessment criteria of TG07, separating Grade II and Grade I at the time of diagnosis was impossible, so they were unsuitable for clinical practice. Therefore, the severity assessment criteria of TG13 have been revised so as not to lose the timing of biliary drainage or treatment for etiology. Based on evidence, five predictive factors for poor prognosis in acute cholangitis--hyperbilirubinemia, high fever, leukocytosis, elderly patient and hypoalbuminemia--have been extracted. Grade II can be diagnosed if two of these five factors are present. Free full-text articles and a mobile application of TG13 are available via http://www.jshbps.jp/en/guideline/tg13.html.


A cohort study of traffic-related air pollution and mortality in Toronto, Ontario, Canada.
Chronic exposure to traffic-related air pollution (TRAP) may contribute to premature mortality, but few studies to date have addressed this topic. In this study we assessed the association between TRAP and mortality in Toronto, Ontario, Canada. We collected nitrogen dioxide samples over two seasons using duplicate two-sided Ogawa passive diffusion samplers at 143 locations across Toronto. We calibrated land use regressions to predict NO2 exposure on a fine scale within Toronto. We used interpolations to predict levels of particulate matter with aerodynamic diameter < or = 2.5 microm (PM(2.5)) and ozone levels. We assigned predicted pollution exposures to 2,360 subjects from a respiratory clinic, and abstracted health data on these subjects from medical billings, lung function tests, and diagnoses by pulmonologists. We tracked mortality between 1992 and 2002. We used standard and multilevel Cox proportional hazard models to test associations between air pollution and mortality. After controlling for age, sex, lung function, obesity, smoking, and neighborhood deprivation, we observed a 17% increase in all-cause mortality and a 40% increase in circulatory mortality from an exposure contrast across the interquartile range of 4 ppb NO2. We observed no significant associations with other pollutants. Exposure to TRAP was significantly associated with increased all-cause and circulatory mortality in this cohort. A high prevalence of cardiopulmonary disease in the cohort probably limits inference of the findings to populations with a substantial proportion of susceptible individuals.


Development Review of the BACE1 Inhibitor Lanabecestat (AZD3293/LY3314814).
Several ongoing clinical development programs are investigating potential disease-modifying treatments for Alzheimer's disease (AD), including lanabecestat (AZD3293/LY3314814). Lanabecestat is a brain-permeable oral inhibitor of human beta-site amyloid (Aβ) precursor protein-cleaving enzyme 1 (BACE1) that reduces Aβ production. As a potent BACE1 inhibitor, lanabecestat significantly reduced soluble Aβ species and soluble amyloid precursor proteins (sAPPβ) in mouse, guinea pig, and dog in a time- and dose-dependent manner. Significant reductions in plasma and cerebrospinal fluid (CSF) Aβ1-40 and Aβ1-42 were observed in Phase 1 studies of healthy subjects and AD patients treated with lanabecestat. Three lanabecestat trials are ongoing and intended to support registration in Early AD: (1) Phase 2/3 study in patients with mild cognitive impairment (MCI) due to AD and mild AD dementia (AMARANTH, NCT02245737); (2) Delayed-start extension study (AMARANTH-EXTENSION, NCT02972658) for patients who have completed treatment in the AMARANTH Study; and (3) Phase 3 study in mild AD dementia (DAYBREAK-ALZ, NCT02783573). This review will discuss the development of lanabecestat, results from the completed nonclinical and clinical studies, as well as describe the ongoing Phase 3 clinical trials.


Hexabromocyclododecane inhibits depolarization-induced increase in intracellular calcium levels and neurotransmitter release in PC12 cells.
Environmental levels of the brominated flame retardant (BFR) hexabromocyclododecane (HBCD) have been increasing. HBCD has been shown to cause adverse effects on learning and behavior in mice, as well as on dopamine uptake in rat synaptosomes and synaptic vesicles. For other BFRs, alterations in the intracellular Ca(2+) homeostasis have been observed. Therefore, the aim of this study was to investigate whether the technical HBCD mixture and individual stereoisomers affect the intracellular Ca(2+) concentration ([Ca(2+)](i)) in a neuroendocrine in vitro model (PC12 cells). [Ca(2+)](i) and vesicular catecholamine release were measured using respectively single-cell Fura-2 imaging and amperometry. Exposure of PC12 cells to the technical HBCD mixture or individual stereoisomers did neither affect basal [Ca(2+)](i), nor the frequency of basal neurotransmitter release. However, exposure to HBCD (0-20 microM) did cause a dose-dependent reduction of a subsequent depolarization-evoked increase in [Ca(2+)](i). This effect was apparent only when HBCD was applied at least 5 min before depolarization (maximum effect after 20 min exposure). The effects of alpha- and beta-HBCD were comparable to that of the technical mixture, whereas the inhibitory effect of gamma-HBCD was larger. Using specific blockers of L-, N- or P/Q-type voltage-gated Ca(2+) channels (VGCCs) it was shown that the inhibitory effect of HBCD is not VGCC-specific. Additionally, the number of cells showing depolarization-evoked neurotransmitter release was markedly reduced following HBCD exposure. Summarizing, HBCD inhibits depolarization-evoked [Ca(2+)](i) and neurotransmitter release. As increasing HBCD levels should be anticipated, these findings justify additional efforts to establish an adequate exposure, hazard and risk assessment.


Kinetic analysis of the heparin-enhanced plasmin--antithrombin III reaction. Apparent catalytic role of heparin.
Inactivation of plasmin by a 3-4-fold molar excess of antithrombin III follows pseudo-first-order kinetics and the apparent rate constants are proportional to the concentration of the inhibitor. Heparin accelerates the inactivation reaction without changing its pseudo-first-order character, and the apparent rate constants are also proportional to the concentration of the polysaccharide. Heparin results in a minimum 20-fold rate enhancement of the reaction between plasmin and antithrombin III when the concentrations of heparin and plasmin are approx. 0.5mum and 1mum respectively. Heparin at a molar concentration well below that of plasmin still accelerates the reaction: one molecule of the polysaccharide is able to facilitate the inactivation of about 100 molecules of plasmin. Heparin must bind to plasmin to accelerate the plasmin-antithrombin III reaction, since the modification of four to five lysine residues of the enzyme inhibits the rate-enhancement effect of heparin and the dissociation of heparin-plasmin complex decreases the inactivation rate of plasmin. Increasing the concentration of antithrombin III, at a constant amount of heparin, results in increase of the inactivation rate. By contrast, the effect of increasing the amount of plasmin in the presence of constant amount of heparin and antithrombin III is such that higher plasmin-to-heparin ratios are associated with lower rates of inactivation. It seems, therefore, that to obtain ;optimal' conditions for fast enzyme inactivation, the amount of heparin should be matched to plasmin rather than to antithrombin III. Arrhenius plots of the plasmin-antithrombin III reaction are linear both in the absence and presence of heparin, at concentrations of 1 or 2mug/ml, over a range of 26K. Under these experimental conditions, heparin increases activation entropy. The findings show that heparin seems to fulfil some criteria that are characteristic for biological catalysis: binding, reaction-rate enhancement (increasing activation entropy), recycling of heparin (effectiveness of non-stoichiometric amounts of the polysaccharide) and specificity.


Small LDL-cholesterol is superior to LDL-cholesterol for determining severe coronary atherosclerosis.
Recent evidence suggests that small dense low-density lipoprotein (sd-LDL) particles are more atherogenic than large-LDL in spite of their lower cholesterol content. This study aimed to determine whether sd-LDL-cholesterol (sd-LDL-C) is superior to LDL-C as a biomarker of coronary heart disease (CHD). LDL particle size determined by gradient gel electrophoresis and sd-LDL-C concentrations quantified by heparin-magnesium precipitation were compared between 482 stable CHD patients and 389 non-diabetic subjects without CHD who were not receiving any lipid-lowering drugs. Both male and female CHD patients had significantly smaller LDL particles and lower large-LDL-C concentrations (estimated by subtracting the sd-LDL-C concentration from the LDL-C concentration), and significantly higher sd-LDL-C concentrations than the control subjects. LDL-C concentrations were modestly higher and sd-LDL-C concentrations were significantly higher in 258 patients with angiographically documented severe CHD than in the patients with mild CHD irrespective of treatment by LDL-lowering drugs and history of myocardial infarction and/or coronary revascularization. Large-LDL-C concentrations, in contrast, were similar between the two groups. Multivariate logistic regression analysis revealed that sd-LDL-C levels were significantly associated with severe CHD independently of LDL-C. sd-LDL-C levels are more powerful than LDL-C levels for the determination of severe stable CHD.


Abdo-Man: a 3D-printed anthropomorphic phantom for validating quantitative SIRT.
The use of selective internal radiation therapy (SIRT) is rapidly increasing, and the need for quantification and dosimetry is becoming more widespread to facilitate treatment planning and verification. The aim of this project was to develop an anthropomorphic phantom that can be used as a validation tool for post-SIRT imaging and its application to dosimetry. The phantom design was based on anatomical data obtained from a T1-weighted volume-interpolated breath-hold examination (VIBE) on a Siemens Aera 1.5 T MRI scanner. The liver, lungs and abdominal trunk were segmented using the Hermes image processing workstation. Organ volumes were then uploaded to the Delft Visualization and Image processing Development Environment for smoothing and surface rendering. Triangular meshes defining the iso-surfaces were saved as stereo lithography (STL) files and imported into the Autodesk® Meshmixer software. Organ volumes were subtracted from the abdomen and a removable base designed to allow access to the liver cavity. Connection points for placing lesion inserts and filling holes were also included. The phantom was manufactured using a Stratasys Connex3 PolyJet 3D printer. The printer uses stereolithography technology combined with ink jet printing. Print material is a solid acrylic plastic, with similar properties to polymethylmethacrylate (PMMA). Measured Hounsfield units and calculated attenuation coefficients of the material were shown to also be similar to PMMA. Total print time for the phantom was approximately 5 days. Initial scans of the phantom have been performed with Y-90 bremsstrahlung SPECT/CT, Y-90 PET/CT and Tc-99m SPECT/CT. The CT component of these images compared well with the original anatomical reference, and measurements of volume agreed to within 9 %. Quantitative analysis of the phantom was performed using all three imaging techniques. Lesion and normal liver absorbed doses were calculated from the quantitative images in three dimensions using the local deposition method. 3D printing is a flexible and cost-efficient technology for manufacture of anthropomorphic phantom. Application of such phantoms will enable quantitative imaging and dosimetry methodologies to be evaluated, which with optimisation could help improve outcome for patients.


The susceptibility of the giant freshwater prawn Macrobrachium rosenbergii to Lactococcus garvieae and its resistance under copper sulfate stress.
Addition of copper sulfate (0.1 to 0.4 mg l(-1)) to tryptic soy broth (TSB) had no effect on growth rate of the bacterial pathogen Lactococcus garvieae. Giant freshwater prawns Macrobrachium rosenbergii were injected with L. garvieae (4 x 10(6) colony-forming units [cfu] prawn(-1)) grown in TSB or TSB containing copper sulfate at 0.1, 0.2, 0.3 or 0.4 mg l(-1). After 48 h, the cumulative mortality was significantly (p < 0.05) higher for prawns exposed to L. garvieae grown in 0.4 mg l(-1) copper sulfate than at the lower concentrations examined. In other experiments, prawns were injected with TSB-grown L. garvieae (4 x 10(6) and 2 x 10(5) cfu prawn(-1)), then held in water containing copper sulfate. After 8 h the mortality of L. garvieae-exposed prawns held in water containing 0.4 mg l(-1) copper sulfate was significantly higher than prawns held in water containing 0.2 and 0.3 mg l(-1) copper sulfate. At the lower L. garvieae density, cumulative mortality of prawns increased directly with ambient copper sulfate concentrations in the range of 0.2 to 0.4 mg l(-1). All prawns survived a 168 h exposure to 0.1 mg l(-1) copper sulfate. Prawns exposed to different concentrations of copper sulfate were examined for hemocyte density, phenoloxidase activity and respiratory burst. No significant differences in hemocyte density were observed among treatments. In prawns following a 48 h exposure to 0.1 mg l(-1) copper sulfate, phenoloxidase activity was decreased, but respiratory burst was increased. In conclusion, copper sulfate increased the virulence of L. garvieae to M. rosenbergii and modulated its immune system. Copper sulfate at 0.1 mg l(-1) decreased susceptibility of M. rosenbergii to L garvieae infection, whereas at 0.2 mg l(-1) the susceptibility was increased. The generation of superoxide anion by M. rosenbergii exposed to copper sulfate at a concentration higher than 0.2 mg l(-1) was considered to be cytoxic.


An exploration of the perceptions of caring held by students entering nursing programmes in the United Kingdom: A longitudinal qualitative study phase 1.
In a climate of intense international scrutiny of healthcare and nursing in particular, there is an urgent need to identify, foster and support a caring disposition in student nurses worldwide. Yet relatively little is known about how core nursing values are shaped during education programmes and this warrants further investigation. This longitudinal study commencing in February 2013 examines the impact of an innovative nursing curriculum based on a humanising framework (Todres et al. 2009) and seeks to establish to what extent professional and core values are shaped over the duration of a three year nursing programme. This paper reports on Phase One which explores student nurses' personal values and beliefs around caring and nursing at the start of their programme. Undergraduate pre-registration nursing students from two discrete programmes (Advanced Diploma and BSc (Honours) Nursing with professional registration) were recruited to this study. Utilising individual semi-structured interviews, data collection commenced with February 2013 cohort (n = 12) and was repeated with February 2014 (n = 24) cohort. Findings from Phase One show that neophyte student nurses are enthusiastic about wanting to care and aspire to making a difference to patients and their families. This research promises to offer contributions to the debate around what caring means and in particular how it is understood by student nurses. Findings will benefit educators and students which will ultimately impact positively on those in receipt of healthcare.


Functional Analysis of the Hsp93/ClpC Chaperone at the Chloroplast Envelope.
The Hsp100-type chaperone Hsp93/ClpC has crucial roles in chloroplast biogenesis. In addition to its role in proteolysis in the stroma, biochemical and genetic evidence led to the hypothesis that this chaperone collaborates with the inner envelope TIC complex to power preprotein import. Recently, it was suggested that Hsp93, working together with the Clp proteolytic core, can confer a protein quality control mechanism at the envelope. Thus, the role of envelope-localized Hsp93, and the mechanism by which it participates in protein import, remain unclear. To analyze the function of Hsp93 in protein import independently of its ClpP association, we created a mutant of Hsp93 affecting its ClpP-binding motif (PBM) (Hsp93[P-]), which is essential for the chaperone's interaction with the Clp proteolytic core. The Hsp93[P-] construct was ineffective at complementing the pale-yellow phenotype of hsp93 Arabidopsis (Arabidopsis thaliana) mutants, indicating that the PBM is essential for Hsp93 function. As expected, the PBM mutation negatively affected the degradation activity of the stromal Clp protease. The mutation also disrupted association of Hsp93 with the Clp proteolytic core at the envelope, without affecting the envelope localization of Hsp93 itself or its association with the TIC machinery, which we demonstrate to be mediated by a direct interaction with Tic110. Nonetheless, Hsp93[P-] expression did not detectably improve the protein import efficiency of hsp93 mutant chloroplasts. Thus, our results do not support the proposed function of Hsp93 in protein import propulsion, but are more consistent with the notion of Hsp93 performing a quality control role at the point of import.


Exploring the Process of Implementing Healthy Workplace Initiatives: Mapping to Kotter's Leading Change Model.
The aim of this study was to use Kotter's leading change model to explore the implementation of workplace health and wellbeing initiatives. Qualitative interviews were conducted with 31 workplace representatives with a healthy workplace initiative. None of the workplaces used a formal change management model when implementing their healthy workplace initiatives. Not all of the steps in Kotter model were considered necessary and the order of the steps was challenged. For example, interviewees perceived that communicating the vision, developing the vision, and creating a guiding coalition were integral parts of the process, although there was less emphasis on the importance of creating a sense of urgency and consolidating change. Although none of the workplaces reported using a formal organizational change model when implementing their healthy workplace initiatives, there did appear to be perceived merit in using the steps in Kotter's model.


Brain network connectivity-behavioral relationships exhibit trait-like properties: Evidence from hippocampal connectivity and memory.
Despite a growing number of studies showing relationships between behavior and resting-state functional MRI measures of large-scale brain network connectivity, no study to our knowledge has sought to investigate whether intrinsic connectivity-behavioral relationships are stable over time. In this study, we investigated the stability of such brain-behavior relationships at two timepoints, approximately 1 week apart. We focused on the relationship between the strength of hippocampal connectivity to posterior cingulate cortex and episodic memory performance. Our results showed that this relationship is stable across samples of a different age and reliable over two points in time. These findings provide the first evidence that the relationship between large-scale intrinsic network connectivity and episodic memory performance is a stable characteristic that varies between individuals.


The p53 cofactor Strap exhibits an unexpected TPR motif and oligonucleotide-binding (OB)-fold structure.
Activation of p53 target genes for tumor suppression depends on the stress-specific regulation of transcriptional coactivator complexes. Strap (stress-responsive activator of p300) is activated upon DNA damage by ataxia telangiectasia mutated (ATM) and Chk2 kinases and is a key regulator of the p53 response. In addition to antagonizing Mdm2, Strap facilitates the recruitment of p53 coactivators, including JMY and p300. Strap is a predicted TPR-repeat protein, but shows only limited sequence identity with any protein of known structure. To address this and to elucidate the molecular mechanism of Strap activity we determined the crystal structure of the full-length protein at 2.05 Å resolution. The structure of Strap reveals an atypical six tetratricopeptide repeat (TPR) protein that also contains an unexpected oligonucleotide/oligosaccharide-binding (OB)-fold domain. This previously unseen domain organization provides an extended superhelical scaffold allowing for protein-protein as well as protein-DNA interaction. We show that both of the TPR and OB-fold domains localize to the chromatin of p53 target genes and exhibit intrinsic regulatory activity necessary for the Strap-dependent p53 response.


Highly purified lipopolysaccharides from Burkholderia cepacia complex clinical isolates induce inflammatory cytokine responses via TLR4-mediated MAPK signalling pathways and activation of NFkappaB.
In cystic fibrosis (CF), bacteria of the Burkholderia cepacia complex (Bcc) can induce a fulminant inflammation with pneumonitis and sepsis. Lipopolysaccharide (LPS) may be an important virulence factor associated with this decline but little is known about the molecular pathogenesis of Bcc LPS. In this study we have investigated the inflammatory response to highly purified LPS from different Bcc clinical isolates and the cellular signalling pathways employed. The inflammatory response (TNFalpha, IL-6) was measured in human MonoMac 6 monocytes and inhibition experiments were used to investigate the Toll-like receptors and associated adaptor molecules and pathways utilized. LPS from all clinical Bcc isolates induced significant pro-inflammatory cytokines and utilized TLR4 and CD14 to mediate activation of mitogen-activated protein kinase pathways, IkappaB-alpha degradation and NFkappaB activation. However, LPS from different clinical isolates of the same clonal strain of Burkholderia cenocepacia were found to induce a varied inflammatory response. LPS from clinical isolates of Burkholderia multivorans was found to activate the inflammatory response via MyD88-independent pathways. This study suggests that LPS alone from clinical isolates of Bcc is an important virulence factor in CF and utilizes TLR4-mediated signalling pathways to induce a significant inflammatory response.


Calculation of the positron annihilation rate in PsH with the positronic extension of the explicitly correlated nuclear-electronic orbital method.
The nuclear-electronic orbital explicitly correlated Hartree-Fock (NEO-XCHF) method is modified and extended to study electron-positron quantum systems. The NEO-XCHF method is more computationally efficient than the explicitly correlated methods previously applied to positron systems because only the electron-positron dynamical correlation is treated explicitly in NEO-XCHF. As a result, the form of the wave function is much simpler with fewer parameters, and the variational optimization of the molecular orbital parameters is performed through an iterative scheme rather than a stochastic optimization. The NEO-XCHF approach is used to calculate the positron annihilation rate for positronium hydride (PsH). The resulting annihilation rate for PsH is within 20% of the most accurate values available and is calculated at a fraction of the computational cost. These results suggest that qualitatively accurate positron annihilation rates can be calculated treating only electron-positron correlation explicitly, leading to significant computational savings by neglecting electron-electron dynamical correlation. Thus, the NEO-XCHF approach could potentially enable the calculation of qualitatively accurate positron annihilation rates for larger positron systems.


The joint effects of efficacy and compliance: a study of household water treatment effectiveness against childhood diarrhea.
The effectiveness of household water treatment (HWT) at reducing diarrheal disease is related to the efficacy of the HWT method at removing pathogens, how people comply with HWT, and the relative contributions of other pathogen exposure routes. We define compliance with HWT as the proportion of drinking water treated by a community. Although many HWT methods are efficacious at removing or inactivating pathogens, their effectiveness within actual communities is decreased by imperfect compliance. However, the quantitative relationship between compliance and effectiveness is poorly understood. To assess the effectiveness of HWT on childhood diarrhea incidence via drinking water for three pathogen types (bacterial, viral, and protozoan), we developed a quantitative microbial risk assessment (QMRA) model. We examined the relationship between log(10) removal values (LRVs) and compliance with HWT for scenarios varying by: baseline incidence of diarrhea; etiologic fraction of diarrhea by pathogen type; pattern of compliance within a community; and size of contamination spikes in source water. Benefits from increasing LRVs strongly depend on compliance. For perfect compliance, diarrheal incidence decreases as LRVs increase. However, if compliance is incomplete, there are diminishing returns from increasing LRVs in most of the scenarios we considered. Higher LRVs are more beneficial if: contamination spikes are large; contamination levels are generally high; or some people comply perfectly. The effectiveness of HWT interventions at the community level may be limited by imperfect compliance, such that the benefits of high LRVs are not realized. Compliance with HWT should be carefully measured during HWT field studies and HWT dissemination programs. Studies of pathogen concentrations in a variety of developing-country source waters are also needed. Guidelines are needed for measuring and promoting compliance with HWT.


Realizable differential matrices for depolarizing media.
The evolution of a Stokes vector through depolarizing media is considered. A general form for the differential matrix is found that is appropriate in the presence of depolarization and it is parameterized in a manner that ensures that it yields, upon integration, a valid Mueller matrix for any choice of parameters. The form expands the more limited form for a nondepolarizing matrix given by Azzam [J. Opt. Soc. Am. 68, 1756 (1978)] and which was extended recently by others to include depolarization. A Mueller matrix decomposition is proposed that is based upon the new parameterization.


Adult attention-deficit/hyperactivity disorder, risky substance use and substance use disorders: a follow-up study among young men.
We investigated whether adult attention-deficit/hyperactivity disorder (ADHD) predicts risky substance use and substance use disorders (SUDs), and its impact on the course of these problematic substance use patterns. Our sample included 4975 Swiss men (mean age 20 ± 1.2 years) who participated in the baseline and 15-month follow-up assessments of the Cohort Study on Substance Use Risk Factors. We examined: (1) the contribution of ADHD, as assessed at baseline, on the risky use of alcohol, nicotine and cannabis, and their corresponding use disorders (AUD, NUD, CUD) at follow-up; and (2) the association between ADHD and the course of outcomes (i.e., absence, initiation, maturing out, persistence) over 15 months. All analyses were adjusted for socio-demographics and co-morbidity. Men with ADHD were more likely to exhibit persistent risky alcohol and nicotine use, and to mature out of risky cannabis use. ADHD at baseline was positively linked to AUD and negatively to CUD at follow-up, but not to NUD. For all SUDs, ADHD had a positive association with use persistence and maturing out. Comparing these two trajectories revealed that early age of alcohol use initiation distinguished between persistence and maturing out of AUD, while the course of NUD and CUD was related to ADHD symptoms and SUD severity at baseline. Already in their early twenties, men with ADHD are especially likely to exhibit persistent problematic substance use patterns. Substance-specific prevention strategies, particularly implemented before early adulthood, may be crucial to reducing the development and persistence of pathological patterns in such individuals.


Omega-3 polyunsaturated fatty acids promote amyloid-β clearance from the brain through mediating the function of the glymphatic system.
Impairment of amyloid-β (Aβ) clearance leads to Aβ accumulation in the brain during the development of Alzheimer's disease (AD). Strategies that can restore or improve the clearance function hold great promise in delaying or preventing the onset of AD. Here, we show that n-3 polyunsaturated fatty acids (PUFAs), by use of fat-1 transgenic mice and oral administration of fish oil, significantly promote interstitial Aβ clearance from the brain and resist Aβ injury. Such beneficial effects were abolished in Aqp4-knockout mice, suggesting that the AQP4-dependent glymphatic system is actively involved in the promoting the effects of n-3 PUFAs on the clearance of extracellular Aβ. Imaging on clarified brain tissues clearly displayed that n-3 PUFAs markedly inhibit the activation of astrocytes and protect the AQP4 polarization in the affected brain region after Aβ injection. The results of the present study prove a novel mechanism by which n-3 PUFAs exert protective roles in reducing Aβ accumulation via mediating the glymphatic system function.-Ren, H., Luo, C., Feng, Y., Yao, X., Shi, Z., Liang, F., Kang, J. X., Wan, J.-B., Pei, Z., Su, H. Omega-3 polyunsaturated fatty acids promote amyloid-β clearance from the brain through mediating the function of the glymphatic system.


Contribution of familiarity and recollection to associative recognition memory: insights from event-related potentials.
Within the dual-process perspective of recognition memory, it has been claimed that familiarity is sufficient to support recognition of single items, but recollection is necessary for associative recognition of item pairs. However, there are some reports suggesting that familiarity might support associative recognition judgments when the items form an easy to access bound representation. In contrast, recollection seems to be required for the recognition of bindings that might be flexibly rearranged in novel situations. We investigated whether both forms of binding are mediated by different mechanisms as reflected by a qualitatively different spatiotemporal eventrelated potential (ERP) pattern. In a recognition memory experiment, subjects gave old/new judgments to words learned by focusing either on interitem associations or on size relation of word triplets. Results revealed higher hit rates in the relational condition as compared to the associative condition. In addition, the proportion of triplets from which all three items were remembered was significantly larger in the relational condition suggesting that memory retrieval in this condition relies primarily on bound representations of word triplets. The ERP revealed a late parietal old/new effect for both conditions, with relational processing resulting in a greater effect. In contrast, an early frontal old/new effect was solely present in the associative condition. Taken together, these data provide evidence that familiarity might support associative recognition if the associated components are coherently encoded into a bound representation. Recollection might foster the recognition of relational bindings among items. This indicates that the contribution of familiarity and recollection to associative recognition depends on the kind of binding operations performed on the items rather than on the single versus multiple item distinction.


Newly qualified nurses' experiences of a preceptorship.
What was the experience of preceptorship like for newly qualified registered nurses in a healthcare trust? A qualitative approach was used with data collected using semi-structured one-to-one interviews with eight participants who had recently completed their preceptorship period. The data was analysed using Newell and Burnard's (2011) Pragmatic Approach to Qualitative Data Analysis, which involved a six-stage analysis process. Two main categories emerged from the data. These were Support Requirements and Expectations of Preceptorship. Support was further broken down into two themes: time and build confidence. Expectations of preceptorship was further broken down into two themes; understanding the process and understanding the preceptor's role. The participants felt that preceptorship offered support and helped them in developing their confidence in the transition to registrant. It would appear that consistency of provision of preceptorship is a key issue that would warrant further study.


The safety of dental extractions in patients with hematologic malignancies.
Dental disorders have been recognized as major sources of infection in patients with hematologic malignancies (HM). Management of severe dental infections usually includes dental extractions (DE), but the safety of extractions in patients with HM who are at risk for bleeding, sepsis, and poor wound healing has not been well established. In conjunction with an aggressive program of dental care, 142 DE were performed in 26 patients with acute leukemia, myelodysplastic syndromes, and myeloproliferative disorders. Granulocytopenia (less than 1,000 granulocytes/microL) was present during or within ten days following surgery in 14 patients. In these 14 patients (101 DE), the mean granulocyte count was less than 450/microL, with a median duration of granulocytopenia following surgery of 32 days (range, four to 169 days). Thrombocytopenia (less than 100,000 platelets/microL) occurred during or within two days following surgery in 13 patients (80 DE), with a mean platelet count of 63,500/microL. Transfusions were given for platelet counts less than 50,000/microL. All DE were performed without significant complications. Bleeding was minor to moderate and easily controlled with local measures; no patient required transfusion due to hemorrhage. Average maximum temperature 24 hours after DE was 37.7 degrees C. No episodes of bacteremia were documented within ten days of DE. Minor delay in wound healing was observed in two patients. We conclude that DE can be safely performed in patients with HM in combination with aggressive supportive care.


Analysis of Prevalence and Clinical Features of Ameloblastoma and its Histopathological Subtypes in Southeast Myanmar and Lower Northern Thailand Populations: A 13-Year Retrospective Study.
Prevalence of ameloblastomas has been established worldwide but collective data of ameloblastoma in Southeast Asian countries has not been well analyzed. Aim of this study was to report analysis and comparison of the prevalence and demographic data of clinical features of ameloblastoma and its histopathological variants in Southeast Myanmar and lower Northern Thailand populations. A retrospective study on ameloblastoma was performed based on the availability of oral biopsy specimens in Faculty of Dentistry, Naresuan University, Phitsanulok, Thailand, between January 2002 and August 2015. The collected data were subjected to descriptive statistical analyses with the SPSS version 17.0 statistical software package (SPSS Inc., Chicago, USA). Pearson's chi square (χ2) test and t-test were employed. The critical level of significance was set at p<0.05. Total of 616 cases were reviewed, 30 cases (5%) were diagnosed as ameloblastoma with male:female ratio of 1.14:1. The mean age of the patients was 31.3±15.6 years. The predominance anatomical distribution was observed in the mandible (86.7%). Posterior body-ramus-angle region was the most common site. Almost all cases were asyptomatic and most common clinical manifestation was swelling of affected region. Multilocular radiolucency was observed in 70% of cases, whereas 30% were unilocular. Three subtypes of ameloblastomas were diagnosed: unicystic ameloblastoma (20%), conventional solid/multicystic ameloblastoma (70%), and desmoplastic ameloblastoma (10%). The most common histologic pattern was the plexiform type (57.2%) followed by follicular type (23.8%). Prevalence of ameloblastoma in Southeast Myanmar and lower Northern Thailand populations correspond with data from other geographic areas of Thailand and other Asian countries. However, some demographic and histopathological profiles are different, with plexiform ameloblastoma being the most common subtype in this study.


Regulation of angiogenesis by ETS transcription factors.
Transcription factors of the ETS family are important regulators of endothelial gene expression. Here, we review the evidence that ETS factors regulate angiogenesis and briefly discuss the target genes and pathways involved. Finally, we discuss novel evidence that shows how these transcription factors act in a combinatorial fashion with others, through composite sites that may be crucial in determining endothelial specificity in gene transcription.


PDGF receptor-α does not promote HCMV entry into epithelial and endothelial cells but increased quantities stimulate entry by an abnormal pathway.
Epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor-α (PDGFRα) were reported to mediate entry of HCMV, including HCMV lab strain AD169. AD169 cannot assemble gH/gL/UL128-131, a glycoprotein complex that is essential for HCMV entry into biologically important epithelial cells, endothelial cells, and monocyte-macrophages. Given this, it appeared incongruous that EGFR and PDGFRα play widespread roles in HCMV entry. Thus, we investigated whether PDGFRα and EGFR could promote entry of wild type HCMV strain TR. EGFR did not promote HCMV entry into any cell type. PDGFRα-transduction of epithelial and endothelial cells and several non-permissive cells markedly enhanced HCMV TR entry and surprisingly, promoted entry of HCMV mutants lacking gH/gL/UL128-131 into epithelial and endothelial cells. Entry of HCMV was not blocked by a panel of PDGFRα antibodies or the PDGFR ligand in fibroblasts, epithelial, or endothelial cells or by shRNA silencing of PDGFRα in epithelial cells. Moreover, HCMV glycoprotein induced cell-cell fusion was not increased when PDGFRα was expressed in cells. Together these results suggested that HCMV does not interact directly with PDGFRα. Instead, the enhanced entry produced by PDGFRα resulted from a novel entry pathway involving clathrin-independent, dynamin-dependent endocytosis of HCMV followed by low pH-independent fusion. When PDGFRα was expressed in cells, an HCMV lab strain escaped endosomes and tegument proteins reached the nucleus, but without PDGFRα virions were degraded. By contrast, wild type HCMV uses another pathway to enter epithelial cells involving macropinocytosis and low pH-dependent fusion, a pathway that lab strains (lacking gH/gL/UL128-131) cannot follow. Thus, PDGFRα does not act as a receptor for HCMV but increased PDGFRα alters cells, facilitating virus entry by an abnormal pathway. Given that PDGFRα increased infection of some cells to 90%, PDGFRα may be very useful in overcoming inefficient HCMV entry (even of lab strains) into the many difficult-to-infect cell types.


Are larvae of demersal fishes plankton or nekton?
A pelagic larval stage is found in nearly all demersal marine teleost fishes, and it is during this pelagic stage that the geographic scale of dispersal is determined. Marine biologists have long made a simplifying assumption that behaviour of larvae--with the possible exception of vertical distribution--has negligible influence on larval dispersal. Because advection by currents can take place over huge scales during a pelagic larval stage that typically lasts for several days to several weeks, this simplifying assumption leads to the conclusion that populations of marine demersal fishes operate over, and are connected over, similar huge scales. This conclusion has major implications for our perception of how marine fish populations operate and for our management of them. Recent (and some older) behavioural research-reviewed here-reveals that for a substantial portion of the pelagic larval stage of perciform fishes, the simplifying assumption is invalid. Near settlement, and for a considerable portion of the pelagic stage prior to that, larvae of many fish species are capable of swimming at speeds faster than mean ambient currents over long periods, travelling tens of kilometres. Only the smallest larvae of perciform fishes swim in an energetically costly viscous hydrodynamic environment (i.e., low Reynolds number). Vertical distribution is under strong behavioural control from the time of hatching, if not before, and can have a decisive, if indirect, influence on dispersal trajectories. Larvae of some species avoid currents by occupying the epibenthic boundary layer. Larvae are able to swim directionally in the pelagic environment, with some species apparently orientating relative to the sun and others to settlement sites. These abilities develop relatively early, and ontogenetic changes in orientation are seemingly common. Larvae of some species can use sound to navigate, and others can use odour to find settlement habitat, at least over small scales. Other senses may also be important to orientation. Larvae are highly aware of their environment and of potential predators, and some school during the pelagic larval stage. Larvae are selective about where they settle at both meso and micro scales, and settlement is strongly influenced by interactions with resident fishes. Most of these behaviours are flexible; for example, swimming speeds and depth may vary among locations, and speed may vary with swimming direction. In direct tests, these behaviours result in dispersal different from that predicted by currents alone. Work with both tropical and temperate species shows that these behaviours begin to be significant relatively early in larval development, but much more needs to be learned about the ontogeny of behaviour and sensory abilities in larvae of marine fishes. As a preliminary rule of thumb, behaviour must be taken into account in considerations of dispersal after the preflexion stage, and vertical distribution behaviour can influence dispersal from hatching. Larvae of perciform fishes are close to being planktonic at the start of the pelagic period and are clearly nektonic at its end, and for a substantial period prior to that. All these things differ among species. Larvae of clupeiform, gadiform and pleuronectiform fishes may be less capable behaviourally than perciform fishes, but this remains to be confirmed. Clearly, these behaviours, along with hydrography, must be included in modelling dispersal and retention and may provide explanations for recent demonstrations of self-recruitment in marine fish populations. Current work is directed at understanding the ontogeny of the gradual transition from planktonic to nektonic behaviour. Although it is clear that larvae of perciform fishes have the ability to strongly influence their dispersal trajectories, it is less clear whether or how these abilities are applied.