An assessment of mosquito breeding and control in four surface flow wetlands in tropical-subtropical Australia.
In Queensland, Australia, the tropical-subtropical climate is ideal to promote macrophyte growth in surface flow wetlands; however, there have been concerns that constructed wetlands are potential breeding sites for disease-bearing mosquitoes. The aim of this study was to assess whether mosquitoes were breeding in these constructed wetlands, and if so, where they breed, and what parameters might influence breeding: e.g. water quality, vegetation, or macroinvertebrate communities. A study of four surface flow constructed wetlands located in different climatic regions was undertaken. Mosquito larvae were sampled using 240 ml dippers and macroinvertebrates using dip nets. The wetland with the greatest biodiversity of macrophytes and macroinvertebrates had the least number of mosquito larvae (< 1% of all dips). Samples with most mosquito larvae occurred amongst dense mats of Paspalum grass or dead Typha. Despite the presence of larvae in some parts of these wetlands very few late instars or pupae were found i.e. completion of the mosquito life cycle to adult mosquitoes was unsuccessful. This study has shown that the presence of mosquito larvae can be minimised by increasing macroinvertebrate biodiversity, by planting a variety of macrophyte types and species, excluding aggressive plant species, and maintaining at least 30% open water. Macroinvertebrates are probably a crucial factor in the control of mosquito larvae ensuring that predation of the early instars prevents or limits the development of pupae and the emergence of adults.


Introducing micrometer-sized artificial objects into live cells: a method for cell-giant unilamellar vesicle electrofusion.
Here, we report a method for introducing large objects of up to a micrometer in diameter into cultured mammalian cells by electrofusion of giant unilamellar vesicles. We prepared GUVs containing various artificial objects using a water-in-oil (w/o) emulsion centrifugation method. GUVs and dispersed HeLa cells were exposed to an alternating current (AC) field to induce a linear cell-GUV alignment, and then a direct current (DC) pulse was applied to facilitate transient electrofusion. With uniformly sized fluorescent beads as size indexes, we successfully and efficiently introduced beads of 1 µm in diameter into living cells along with a plasmid mammalian expression vector. Our electrofusion did not affect cell viability. After the electrofusion, cells proliferated normally until confluence was reached, and the introduced fluorescent beads were inherited during cell division. Analysis by both confocal microscopy and flow cytometry supported these findings. As an alternative approach, we also introduced a designed nanostructure (DNA origami) into live cells. The results we report here represent a milestone for designing artificial symbiosis of functionally active objects (such as micro-machines) in living cells. Moreover, our technique can be used for drug delivery, tissue engineering, and cell manipulation.


The interaction of eye movements and retinal signals during the perception of 3-D motion direction.
When an object is tracked with the eyes, veridical perception of the motion of that object and other objects requires the brain to take account of and compensate for the eye movement. Here, I explore the effects of version and vergence eye movements on three-dimensional (3-D) motion perception. After demonstrating that eye movement compensation can be poor for detecting small objects moving in depth, I develop two models for how eye movement and visual signals may interact during the perception of 3-D motion direction. The first model assumes that the visual system is aiming to form an explicit representation of 3-D motion. From the results of a second experiment, on 3-D motion direction judgements, I show that this model could only hold with almost perfect 3-D motion compensation, contradicting the results from the first experiment. A second model assumes a much simpler strategy for estimating 3-D motion direction, based on recent experimental work. It predicts that compensation for vergence is not required because the Z-component of 3-D motion is not needed for direction judgements, consistent with the experimental results. This suggests that, for 3-D motion direction discrimination and angle judgements, extraretinal signals from vergence are not used.


The appropriateness of more intensive colonoscopy screening than recommended in Medicare beneficiaries: a modeling study.
Many Medicare beneficiaries undergo more intensive colonoscopy screening than recommended. Whether this is favorable for beneficiaries and efficient from a societal perspective is uncertain. To determine whether more intensive colonoscopy screening than recommended is favorable for Medicare beneficiaries (ie, whether it results in a net health benefit) and whether it is efficient from a societal perspective (ie, whether the net health benefit justifies the additional resources required). Microsimulation modeling study of 65-year-old Medicare beneficiaries at average risk for colorectal cancer (CRC) and with an average life expectancy who underwent a screening colonoscopy at 55 years with negative results. Colonoscopy screening as recommended by guidelines (ie, at 65 and 75 years) vs scenarios with a shorter screening interval (5 or 3 instead of 10 years) or in which screening was continued to 85 or 95 years. Quality-adjusted life-years (QALYs) gained (measure of net health benefit); additional colonoscopies required per additional QALY gained and additional costs per additional QALY gained (measures of efficiency). Screening previously screened Medicare beneficiaries more intensively than recommended resulted in only small increases in CRC deaths prevented and life-years gained. In comparison, the increases in colonoscopies performed and colonoscopy-related complications experienced were large. As a result, all scenarios of more intensive screening than recommended resulted in a loss of QALYs, rather than a gain (ie, a net harm). The only exception was shortening the screening interval from 10 to 5 years, which resulted in 0.7 QALYs gained per 1000 beneficiaries. However, this scenario was inefficient because it required no less than 909 additional colonoscopies and an additional $711 000 per additional QALY gained. Results in previously unscreened beneficiaries were slightly less unfavorable, but conclusions were identical. Screening Medicare beneficiaries more intensively than recommended is not only inefficient from a societal perspective; often it is also unfavorable for those being screened. This study provides evidence and a clear rationale for clinicians and policy makers to actively discourage this practice.


Transfers of N metabolites across the ovine liver in response to short-term infusions of an amino acid mixture into the mesenteric vein.
The effect of acute (4.5 h) infusions into the mesenteric vein of an amino acid (AA) mixture, which simulated the composition of rumen microbial protein, on net transfers of NH3, urea and total AA across the portal-drained viscera (PDV) and liver in the ovine has been examined. Four wether sheep were surgically prepared with vascular catheters across the PDV and liver (Lobley et al. 1995) and were offered a basal diet of 1000 g grass pellets/d (approximately 1.4 x energy maintenance). Each animal was infused at weekly intervals with one of four dilutions of the AA mixture. These dilutions provided 0.44, 0.88, 1.32 and 1.84 mmol AA-N/min infused, the lowest of which approximately doubled the net absorption of AA-N from the basal diet. Animals were treated with heparin to allow continuous collection of blood by peristaltic pump for 2 h preceding, and between 0.5-2.5 and 2.5-4.5 h after, the start of the AA infusions. Blood flow in the hepatic artery increased (100 v. 208 g/min; P = 0.002) in response to AA infusion, while hepatic portal venous flow decreased (2090 v. 1854 g/min; P = 0.006). The AA infusion also stimulated O2 uptake by the PDV (P < 0.001) and liver (P = 0.016). Absorption across the PDV and hepatic removal of NH3 were unchanged between basal and amino acid infusion conditions. Urea-N removal across the PDV was unaltered, but hepatic production increased (P < 0.001) with level of AA infusion. During infusions, net appearance of AA across the PDV was below the theoretical level. This may have been due to inhibition of AA uptake from the small intestine, and/or increased removal by the digestive tract of AA from the systemic circulation associated with greater arterial concentrations. Hepatic extraction of AA increased with level of infusion, both for total AA and those included in the infusate. Total hepatic urea-N production tended towards a maximum (estimated as 2 mumol N/g liver wet weight per min). The AA removed by the liver and not used for ureagenesis remained similar (170 mumol AA-N/min) between basal and AA infusions. This was presumed available for anabolic purposes (mainly synthesis of export proteins). The proportion of net AA-N appearance (absorption plus infused) across the PDV removed by the liver declined from 0.71 to 0.53 between basal and AA infusions. In contrast to findings from cattle (Wray-Cahen et al. 1997), increased AA infusion did not alter the net removal of glutamine across the liver. This may reflect differences between the studies in NH3: AA-N absorbed. Further differences between the cattle study and the current findings may relate to the different physiological state (pregnancy v. growth), which may alter the partition of AA between anabolic and catabolic fates.


TRIP-1 via AKT modulation drives lung fibroblast/myofibroblast trans-differentiation.
Myofibroblasts are the critical effector cells in the pathogenesis of pulmonary fibrosis which carries a high degree of morbidity and mortality. We have previously identified Type II TGFβ receptor interacting protein 1 (TRIP-1), through proteomic analysis, as a key regulator of collagen contraction in primary human lung fibroblasts--a functional characteristic of myofibroblasts, and the last, but critical step in the process of fibrosis. However, whether or not TRIP-1 modulates fibroblast trans-differentiation to myofibroblasts is not known. TRIP-1 expression was altered in primary human lung fibroblasts by siRNA and plasmid transfection. Transfected fibroblasts were then analyzed for myofibroblast features and function such as α-SMA expression, collagen contraction ability, and resistance to apoptosis. The down-regulation of TRIP-1 expression in primary human lung fibroblasts induces α-SMA expression and enhances resistance to apoptosis and collagen contraction ability. In contrast, TRIP-1 over-expression inhibits α-SMA expression. Remarkably, the effects of the loss of TRIP-1 are not abrogated by blockage of TGFβ ligand activation of the Smad3 pathway or by Smad3 knockdown. Rather, a TRIP-1 mediated enhancement of AKT phosphorylation is the implicated pathway. In TRIP-1 knockdown fibroblasts, AKT inhibition prevents α-SMA induction, and transfection with a constitutively active AKT construct drives collagen contraction and decreases apoptosis. TRIP-1 regulates fibroblast acquisition of phenotype and function associated with myofibroblasts. The importance of this finding is it suggests TRIP-1 expression could be a potential target in therapeutic strategy aimed against pathological fibrosis.


Childhood determinants of suicidality: comparing males in military and civilian employed populations.
To better understand the associations of childhood trauma and childhood disorder with past-year suicidality (thoughts, plans or attempts), we compared male military and civilian populations aged 18-60 years old. Data derived from the 2010 Australian Defence Force (ADF) Mental Health Prevalence and Wellbeing Study and the 2007 Australian Bureau of Statistics Australian National Survey of Mental Health and Wellbeing were compared using logistic regression and Generalized Structural Equation Modelling (GSEM). A greater proportion of the ADF experienced suicidality than civilians. Those who experienced childhood trauma that was not interpersonal in nature were not at increased odds of suicidality, in either population. A higher proportion of the ADF experienced three or more types of trauma in childhood and first experienced three or more types of trauma in adulthood. Both were associated with suicidality in the ADF and civilians. Childhood anxiety had a strong and independent association with suicidality in the ADF (controlling for demographics and childhood trauma, adult trauma and adult onset disorder). Childhood anxiety fully mediated the relationship between childhood trauma and suicidality in the ADF, but not in civilians. These data highlight the need to take a whole life approach to understanding suicidality, and the importance of categorizing the nature of childhood trauma exposure. Importantly, childhood anxiety was not only associated with suicidality, it fully mediated the relationship between childhood trauma and suicidality in the more trauma exposed (military) population only. These findings have the potential to inform the development of strategies for suicide prevention.


Mosaic maternal ancestry in the Great Lakes region of East Africa.
The Great Lakes lie within a region of East Africa with very high human genetic diversity, home of many ethno-linguistic groups usually assumed to be the product of a small number of major dispersals. However, our knowledge of these dispersals relies primarily on the inferences of historical, linguistics and oral traditions, with attempts to match up the archaeological evidence where possible. This is an obvious area to which archaeogenetics can contribute, yet Uganda, at the heart of these developments, has not been studied for mitochondrial DNA (mtDNA) variation. Here, we compare mtDNA lineages at this putative genetic crossroads across 409 representatives of the major language groups: Bantu speakers and Eastern and Western Nilotic speakers. We show that Uganda harbours one of the highest mtDNA diversities within and between linguistic groups, with the various groups significantly differentiated from each other. Despite an inferred linguistic origin in South Sudan, the data from the two Nilotic-speaking groups point to a much more complex history, involving not only possible dispersals from Sudan and the Horn but also large-scale assimilation of autochthonous lineages within East Africa and even Uganda itself. The Eastern Nilotic group also carries signals characteristic of West-Central Africa, primarily due to Bantu influence, whereas a much stronger signal in the Western Nilotic group suggests direct West-Central African ancestry. Bantu speakers share lineages with both Nilotic groups, and also harbour East African lineages not found in Western Nilotic speakers, likely due to assimilating indigenous populations since arriving in the region ~3000 years ago.


Tumor suppressor PNRC1 blocks rRNA maturation by recruiting the decapping complex to the nucleolus.
Focal deletions occur frequently in the cancer genome. However, the putative tumor-suppressive genes residing within these regions have been difficult to pinpoint. To robustly identify these genes, we implemented a computational approach based on non-negative matrix factorization, NMF, and interrogated the TCGA dataset. This analysis revealed a metagene signature including a small subset of genes showing pervasive hemizygous deletions, reduced expression in cancer patient samples, and nucleolar function. Amid the genes belonging to this signature, we have identified PNRC1, a nuclear receptor coactivator. We found that PNRC1 interacts with the cytoplasmic DCP1α/DCP2 decapping machinery and hauls it inside the nucleolus. PNRC1-dependent nucleolar translocation of the decapping complex is associated with a decrease in the 5'-capped U3 and U8 snoRNA fractions, hampering ribosomal RNA maturation. As a result, PNRC1 ablates the enhanced proliferation triggered by established oncogenes such as RAS and MYC These observations uncover a previously undescribed mechanism of tumor suppression, whereby the cytoplasmic decapping machinery is hauled within nucleoli, tightly regulating ribosomal RNA maturation.


Human protection of telomeres 1 (POT1) is a negative regulator of telomerase activity in vitro.
The telomeric single-strand DNA binding protein protection of telomeres 1 (POT1) protects telomeres from rapid degradation in Schizosaccharomyces pombe and has been implicated in positive and negative telomere length regulation in humans. Human POT1 appears to interact with telomeres both through direct binding to the 3' overhanging G-strand DNA and through interaction with the TRF1 duplex telomere DNA binding complex. The influence of POT1 on telomerase activity has not been studied at the molecular level. We show here that POT1 negatively effects telomerase activity in vitro. We find that the DNA binding activity of POT1 is required for telomerase inhibition. Furthermore, POT1 is incapable of inhibiting telomeric repeat addition to substrate primers that are defective for POT1 binding, suggesting that in vivo, POT1 likely affects substrate access to telomerase.


A cyclophilin function in Hsp90-dependent signal transduction.
Cpr6 and Cpr7, the Saccharomyces cerevisiae homologs of cyclophilin-40 (CyP-40), were shown to form complexes with Hsp90, a protein chaperone that functions in several signal transduction pathways. Deletion of CPR7 caused severe growth defects when combined with mutations that decrease the amount of Hsp90 or Sti1, another component of the Hsp90 chaperone machinery. The activities of two heterologous Hsp90-dependent signal transducers expressed in yeast, glucocorticoid receptor and pp60(v-src) kinase, were adversely affected by cpr7 null mutations. These results suggest that CyP-40 cyclophilins play a general role in Hsp90-dependent signal transduction pathways under normal growth conditions.


Catastrophic Caustic Ingestion: A Case Report.
The majority of oral ingestion of caustic material by adults is intentional, and the aftermath varies widely with potentially fatal results. Injuries range from superficial burns of facial and oropharyngeal structures to extensive necrosis of the gastrointestinal tract. Management focuses on the identification of the ingested substance and prompt treatment and supportive care of the multiple complications stemming from the ingestion. Complications following caustic ingestion include both immediate and long term. A fifty-seven-year-old man presented following intentional ingestion of drain cleaner. The patient was intubated and underwent emergent esophagogastroduodenoscopy [EGD], which revealed extensive damage to his oesophagus and stomach. He survived his initial injury but had a prolonged hospital course and ultimately died after developing tracheoesophageal and bronchooesophageal fistulas which were too extensive for surgical repair. The sequelae of caustic ingestion can be minor or severe, both immediate and delayed. Despite appropriate prompt management and supportive care, patients may die as a result of the initial injury or subsequent complications.


Multiple drug resistance in osteogenic sarcoma: INT0133 from the Children's Oncology Group.
Multiple drug resistance due to P-glycoprotein (P-gp) expression has been reported to be a cause of disease recurrence in osteosarcoma. Tumor specimens derived from children and young adults with osteosarcoma enrolled onto a national Intergroup trial (INT0133) were analyzed prospectively to determine the role of multiple drug resistance in osteosarcoma. From October 15, 1992, to November 25, 1997, 685 patients with localized, high-grade osteosarcoma were enrolled onto INT0133. Paraffin-embedded diagnostic tumor specimens were assayed for P-gp using monoclonal antibodies C-494 (139 patients) and JSB-1 (133 patients). Percent necrosis at the time of definitive surgery (NEC), event-free survival (EFS), and overall survival (OS) were evaluated as outcome measures for patients with P-gp-positive disease and were compared with patients with P-gp-negative disease. P-gp expression in the biopsy specimen did not significantly increase the risk for adverse outcomes as measured by EFS, OS, or NEC. EFS for those patients with C-494-positive tumors was 59% at 4 years versus 61% at 4 years for patients with C-494-negative tumors (P = .79), or 58% at 4 years versus 61% at 4 years for patients with JSB-1-positive versus JSB-1-negative tumors (P = .65). OS for patients with C-494-positive tumors was 82% at 4 years versus 82% at 4 years for patients with C-494-negative tumors (P = .61). Prospective analysis of the role of multiple drug resistance in localized osteosarcoma did not find that immunohistochemical analysis of P-gp expression predicted outcome for patients treated on INT0133.


Development of renovascular hypertension after central serotonin depletion.
The participation of the central serotonergic system in the development of two-kidney, two clip (2K2C) Goldblatt renovascular hypertension in the rat has been examined. Half of the rats were treated with desmethylimipramine intraperitoneally and 5,7-dihydroxytryptamine intracisternally; the other half received only desmethylimipramine and the 5,7-dihydroxytryptamine vehicle. Two days later, a silver clip was placed in both renal arteries in half of the rats of each group. A sham operation was performed in the remaining rats. Blood pressure was recorded during the 5 weeks after treatment. At the end of the experiment, blood and cerebrospinal fluid samples were obtained. The brain was dissected into several areas and kept frozen. Norepinephrine, serotonin, angiotensinogen, and renin-like concentration were evaluated in the brain areas. Plasma renin activity and angiotensinogen concentration in the plasma and cerebrospinal fluid were estimated. In the sham-operated groups, blood pressure was lower in the treated than in the control rats. The curve of blood pressure increase, as well as the final blood pressure, was similar in the treated and control 2K2C rats. Serotonin was significantly depleted by the 5,7-dihydroxytryptamine treatment in all brain areas. Treatment did not induce any changes in central norepinephrine concentration. Plasma renin activity was diminished in the treated sham-operated rats. These data indicate that the central serotonin depletion does not prevent the development of hypertension and confirm the role of the amine in normal blood pressure regulation. On the other hand, the peripheral renin-angiotensin system might participate in the development of high blood pressure in serotonin-depleted animals.


A novel automatic detection system for ECG arrhythmias using maximum margin clustering with immune evolutionary algorithm.
This paper presents a novel maximum margin clustering method with immune evolution (IEMMC) for automatic diagnosis of electrocardiogram (ECG) arrhythmias. This diagnostic system consists of signal processing, feature extraction, and the IEMMC algorithm for clustering of ECG arrhythmias. First, raw ECG signal is processed by an adaptive ECG filter based on wavelet transforms, and waveform of the ECG signal is detected; then, features are extracted from ECG signal to cluster different types of arrhythmias by the IEMMC algorithm. Three types of performance evaluation indicators are used to assess the effect of the IEMMC method for ECG arrhythmias, such as sensitivity, specificity, and accuracy. Compared with K-means and iterSVR algorithms, the IEMMC algorithm reflects better performance not only in clustering result but also in terms of global search ability and convergence ability, which proves its effectiveness for the detection of ECG arrhythmias.


Students being and becoming scientists: measured success in a novel science education partnership.
The primary and secondary learning years shape development of scientific interest and skills required for science literacy, presenting a critical timeline target for science education intervention. Although many initiatives exist to target this timeframe, the modern classroom belies easy scientific investigation. Numerous initiatives often run simultaneously in a given classroom, creating limited capacity for variable control. Consequently, there is a dearth of high-quality and meaningful data in education sciences that exacerbates the general segregation of education research from practice. Many science reform programmes go unmeasured. The limited number that is researched often report strictly qualitative results or stop short of statistically significant quantitative investigation. Lack of high-resolution data restricts the ability to make informed policy changes and precludes attainment of "evidence-based education". Here, we demonstrate 5-year efficacy of a novel, inquiry-based primary and secondary science reform programme Integrated Science Education Outreach (InSciEd Out). Five years of data over three cohorts of matched students from US grades 5-8 show maintained gains in science fair and honours biology election, as well as improved performance on Minnesota state standardized science testing. Detailed value-added analyses further reveal InSciEd Out-correlated gains in partnership-focused areas of life sciences, and history and nature of science. These analyses provide evidence that scientifically rigorous evaluation demonstrating relevant programme efficacy is indeed achievable in education science. Our results support the premise that the InSciEd Out programme is a scalable intervention capable of primary and secondary science education reform. The programme substantively builds upon prior efforts in the field. Although InSciEd Out deploys novel approaches and tools, the broad lessons learned from this programme are readily translatable to other contemporary efforts cultivating science literacy for all.


A cluster randomized-controlled trial of a community mobilization intervention to change gender norms and reduce HIV risk in rural South Africa: study design and intervention.
Community mobilization (CM) interventions show promise in changing gender norms and preventing HIV, but few have been based on a defined mobilization model or rigorously evaluated. The purpose of this paper is to describe the intervention design and implementation and present baseline findings of a Cluster Randomized Controlled Trial (RCT) of a two-year, theory-based CM intervention that aimed to change gender norms and reduce HIV risk in rural Mpumalanga province, South Africa. Community Mobilizers and volunteer Community Action Teams (CATs) implemented two-day workshops, a range of outreach activities, and leadership engagement meetings. All activities were mapped onto six theorized mobilization domains. The intervention is being evaluated by a randomized design in 22 communities (11 receive intervention). Cross-sectional, population-based surveys were conducted with approximately 1,200 adults ages 18-35 years at baseline and endline about two years later. This is among the first community RCTs to evaluate a gender transformative intervention to change norms and HIV risk using a theory-based, defined mobilization model, which should increase the potential for impact on desired outcomes and be useful for future scale-up if proven effective. ClinicalTrials.gov NCT02129530.


Adolescent psychopathy, heart rate, and skin conductance.
Researchers have advocated for a greater focus on measuring neurobiological underpinnings of serious psychological conditions such as psychopathy. This has become particularly important to investigate early in the life span, when intervention efforts for psychopathy-related behavior like conduct disorder (CD) are more successful. Given that psychopathy is a complex syndrome, it is also important to investigate physiological processes at a dimensional level. Using a sample of 56 adolescent male offenders (Mage = 15.92; SD = 1.31), this study explored the relationship between the Psychopathy Checklist-Youth Version (Forth, Kosson, & Hare, 2003), heart rate (HR), and skin conductance (SC). A white noise countdown task was used to measure autonomic activity across a baseline, anticipatory (prenoise), and reactivity (postnoise) period. Findings revealed no significant associations between psychopathy and HR activity across the time intervals. However, results revealed a positive association between grandiose-manipulative traits and SC activity and a negative association between callous-unemotional traits and SC activity. The results indicate that autonomic processes may contribute to distinct psychopathic traits in different ways, implicating slightly differential brain functioning. The findings suggest that, in order to better understand and treat youth with CD, future research should continue to examine the biological correlates of psychopathy at the broader construct level but perhaps especially at the component level.


Moringa Oleifera Alleviates Homocysteine-Induced Alzheimer's Disease-Like Pathology and Cognitive Impairments.
Alzheimer's disease (AD) is multifactorial with unclear etiopathology. Due to the complexity of AD, many attempted single therapy treatments, like Aβ immunization, have generally failed. Therefore, there is a need for drugs with multiple benefits. Naturally occurring phytochemicals with neuroprotective, anti-amyloidogenic, antioxidative, and anti-inflammatory properties could be a possible way out. In this study, the effect of Moringa oleifera (MO), a naturally occurring plant with high antioxidative, anti-inflammatory, and neuroprotective effects, was evaluated on hyperhomocysteinemia (HHcy) induced AD-like pathology in rats. Homocysteine (Hcy) injection for 14 days was used to induce AD-like pathology. Simultaneous MO extract gavage followed the injection as a preventive treatment or, after injection completion, MO gavage was performed for another 14 days as a curative treatment. MO was found to not only prevent but also rescue the oxidative stress and cognitive impairments induced by Hcy treatment. Moreover, MO recovered the decreased synaptic proteins PSD93, PSD95, Synapsin 1 and Synaptophysin, and improved neurodegeneration. Interestingly, MO decreased the Hyc-induced tau hyperphosphorylation at different sites including S-199, T-231, S-396, and S-404, and at the same time decreased Aβ production through downregulation of BACE1. These effects in HHcy rats were accompanied by a decrease in calpain activity under MO treatment, supporting that calpain activation might be involved in AD pathogenesis in HHcy rats. Taken together, our data, for the first time, provided evidence that MO alleviates tau hyperphosphorylation and Aβ pathology in a HHcy AD rat model. This and previous other studies support MO as a good candidate for, and could provide new insights into, the treatment of AD and other tauopathies.


Osteogenic and antimicrobial nanoparticulate calcium phosphate and poly-(D,L-lactide-co-glycolide) powders for the treatment of osteomyelitis.
Development of a material for simultaneous sustained and localized delivery of antibiotics and induction of spontaneous regeneration of hard tissues affected by osteomyelitis stands for an important clinical need. In this work, a comparative analysis of the bacterial and osteoblastic cell response to two different nanoparticulate carriers of clindamycin, an antibiotic commonly prescribed in the treatment of bone infection, one composed of calcium phosphate and the other comprising poly-(D,L-lactide-co-glycolide)-coated calcium phosphate, was carried out. Three different non-cytotoxic phases of calcium phosphate, exhibiting dissolution and drug release profiles in the range of one week to two months to one year, respectively, were included in the analysis: monetite, amorphous calcium phosphate and hydroxyapatite. Spherical morphologies and narrow size distribution of both types of nanopowders were confirmed in transmission and scanning electron microscopic analyses. The antibiotic-containing powders exhibited sustained drug release contingent upon the degradation rate of the carrier. Assessment of the antibacterial performance of the antibiotic-encapsulated powders against Staphylococcus aureus, the most common pathogen isolated from infected bone, yielded satisfactory results both in broths and on blood agar plates for all the analyzed powders. In contrast, no cytotoxic behavior was detected upon the incubation of the antibiotic powders with the osteoblastic MC3T3-E1 cell line for up to three weeks. The cells were shown to engage in a close contact with the antibiotic-containing particles, irrespective of their internal or surface phase composition, polymeric or mineral. At the same time, both types of particles upregulated the expression of osteogenic markers osteocalcin, osteopontin, Runx2 and protocollagen type I, suggesting their ability to promote osteogenesis and enhance remineralization of the infected site in addition to eliminating the bacterial source of infection.


DNA methylation-based measures of biological age: meta-analysis predicting time to death.
Estimates of biological age based on DNA methylation patterns, often referred to as "epigenetic age", "DNAm age", have been shown to be robust biomarkers of age in humans. We previously demonstrated that independent of chronological age, epigenetic age assessed in blood predicted all-cause mortality in four human cohorts. Here, we expanded our original observation to 13 different cohorts for a total sample size of 13,089 individuals, including three racial/ethnic groups. In addition, we examined whether incorporating information on blood cell composition into the epigenetic age metrics improves their predictive power for mortality. All considered measures of epigenetic age acceleration were predictive of mortality (p≤8.2x10-9), independent of chronological age, even after adjusting for additional risk factors (p<5.4x10-4), and within the racial/ethnic groups that we examined (non-Hispanic whites, Hispanics, African Americans). Epigenetic age estimates that incorporated information on blood cell composition led to the smallest p-values for time to death (p=7.5x10-43). Overall, this study a) strengthens the evidence that epigenetic age predicts all-cause mortality above and beyond chronological age and traditional risk factors, and b) demonstrates that epigenetic age estimates that incorporate information on blood cell counts lead to highly significant associations with all-cause mortality.


Genome and physiology of the ascomycete filamentous fungus Xeromyces bisporus, the most xerophilic organism isolated to date.
Xeromyces bisporus can grow on sugary substrates down to 0.61, an extremely low water activity. Its genome size is approximately 22 Mb. Gene clusters encoding for secondary metabolites were conspicuously absent; secondary metabolites were not detected experimentally. Thus, in its 'dry' but nutrient-rich environment, X. bisporus appears to have relinquished abilities for combative interactions. Elements to sense/signal osmotic stress, e.g. HogA pathway, were present in X. bisporus. However, transcriptomes at optimal (∼ 0.89) versus low aw (0.68) revealed differential expression of only a few stress-related genes; among these, certain (not all) steps for glycerol synthesis were upregulated. Xeromyces bisporus increased glycerol production during hypo- and hyper-osmotic stress, and much of its wet weight comprised water and rinsable solutes; leaked solutes may form a protective slime. Xeromyces bisporus and other food-borne moulds increased membrane fatty acid saturation as water activity decreased. Such modifications did not appear to be transcriptionally regulated in X. bisporus; however, genes modulating sterols, phospholipids and the cell wall were differentially expressed. Xeromyces bisporus was previously proposed to be a 'chaophile', preferring solutes that disorder biomolecular structures. Both X. bisporus and the closely related xerophile, Xerochrysium xerophilum, with low membrane unsaturation indices, could represent a phylogenetic cluster of 'chaophiles'.


Extreme-Ultraviolet Excited Scintillation of Methylammonium Lead Bromide Perovskites.
Inorganic-Organic lead halide materials have been recognized as potential high-energy X-ray detectors because of their high quantum efficiencies and radiation hardness. Surprisingly little is known about whether the same is true for extreme-ultraviolet (XUV) radiation, despite applications in nuclear fusion research and astrophysics. We used a table-top high-harmonic generation setup in the XUV range between 20 and 45 eV to photoexcite methylammonium lead bromide (MAPbBr3) and measure its scintillation properties. The strong absorbance combined with multiple carriers being excited per photon yield a very high carrier density at the surface, triggering photobleaching reactions that rapidly reduce the emission intensity. Concurrent to and in spite of this photobleaching, a recovery of the emission intensity as a function of dose was observed. X-ray photoelectron spectroscopy and X-ray diffraction measurements of XUV-exposed and unexposed areas show that this recovery is caused by XUV-induced oxidation of MAPbBr3, which removes trap states that normally quench emission, thus counteracting the rapid photobleaching caused by the extremely high carrier densities. Furthermore, it was found that preoxidizing the sample with ozone was able to prolong and improve this intensity recovery, highlighting the impact of surface passivation on the scintillation properties of perovskite materials in the XUV range.


Isolation of sophorose during sophorolipid production and studies of its stability in aqueous alkali: epimerisation of sophorose to 2-O-β-D-glucopyranosyl-D-mannose.
NMR and anion exchange chromatography analysis of the waste streams generated during the commercial production of sophorolipids by the yeast Candida bombicola identified the presence of small but significant quantities (1% w/v) of free sophorose. Sophorose, a valuable disaccharide, was isolated from the aqueous wastes using a simple extraction procedure and was purified by chromatography on a carbon celite column providing easy access to large quantities of the disaccharide. Experiments were undertaken to identify the origin of sophorose and it is likely that acetylated sophorose derivatives were produced by an enzyme catalysed hydrolysis of the glucosyl-lipid bond of sophorolipids; the acetylated sophorose derivatives then undergo hydrolysis to release the parent disaccharide. Treatment of sophorose with aqueous alkali at elevated temperatures (0.1M NaOH at 50 °C) resulted in C2-epimerisation of the terminal reducing sugar and its conversion to the corresponding 2-O-β-D-glucopyranosyl-D-mannose which was isolated and characterised. In aqueous alkaline solution β-(1,2)-linked glycosidic bonds do not undergo either hydrolysis or peeling reactions.


Gene-Centric Analysis of Preeclampsia Identifies Maternal Association at PLEKHG1.
The genetic susceptibility to preeclampsia, a pregnancy-specific complication with significant maternal and fetal morbidity, has been poorly characterized. To identify maternal genes associated with preeclampsia risk, we assembled 498 cases and 1864 controls of European ancestry from preeclampsia case-control collections in 5 different US sites (with additional matched population controls), genotyped samples on a cardiovascular gene-centric array composed of variants from ≈2000 genes selected based on prior genetic studies of cardiovascular and metabolic diseases and performed case-control genetic association analysis on 27 429 variants passing quality control. In silico replication testing of 9 lead signals with P<10-4 was performed in independent European samples from the SOPHIA (Study of Pregnancy Hypertension in Iowa) and Inova cohorts (212 cases, 456 controls). Multiethnic assessment of lead signals was then performed in samples of black (26 cases, 136 controls), Hispanic (132 cases, 468 controls), and East Asian (9 cases, 80 controls) ancestry. Multiethnic meta-analysis (877 cases, 3004 controls) revealed a study-wide statistically significant association of the rs9478812 variant in the pleiotropic PLEKHG1 gene (odds ratio, 1.40 [1.23-1.60]; Pmeta=5.90×10-7). The rs9478812 effect was even stronger in the subset of European cases with known early-onset preeclampsia (236 cases diagnosed <37 weeks, 1864 controls; odds ratio, 1.59 [1.27-1.98]; P=4.01×10-5). PLEKHG1 variants have previously been implicated in genome-wide association studies of blood pressure, body weight, and neurological disorders. Although larger studies are required to further define maternal preeclampsia heritability, this study identifies a novel maternal risk locus for further investigation.


Proinflammatory cytokine profiling of tears from dry eye patients by means of antibody microarrays.
In the pathogenesis of keratoconjunctivitis sicca, immune processes are thought to play an important role. However, the exact details of the pathomechanisms are still unknown. In this study, the expression patterns of proinflammatory cytokines in the tears of patients with different subtypes of dry eye were analyzed. One hundred forty-three subjects subdivided into healthy controls (CTRL, n = 38), patients with aqueous-deficient dry eye (DRYaq, n = 35), patients with changes of the lipid layer (DRYlip, n = 36), and patients with a combination of both (DRYaplip, n = 34) were examined. Expression patterns of proteins (e.g., IL-1β, IL-6, ITNF-α, and IFN-γ) were examined using an advanced antibody microarray approach. Several highly significant differences in the cytokine levels of dry eye patients compared with healthy controls were detected. Patients with DRYaq or those with DRYaplip showed elevated levels for most of the tested proteins. For example, IL-1β was found to be elevated 2.4-fold in DRYaq patients and 2.75-fold in DRYaqlip patients (both P < 8.00E-6). The detected amounts of protein in DRYlip patients and in healthy controls showed only minimal differences (fold increase/decrease for all proteins >1.2; P > 5.00E-1). The similarity between the profiles of healthy controls and DRYlip patients justifies the assumption that the pathomechanism of this dry eye subtype is based on mechanisms other than inflammation, whereas it seems to be the case for DRYaq patients.


Motion correction and attenuation correction for respiratory gated PET images.
Positron emission tomography (PET) is a molecular imaging technique which provides important functional information about the human body. However, thoracic PET images are often substantially degraded by respiratory motion, which adversely impacts on subsequent diagnosis. In this paper, a motion correction and attenuation correction method is proposed to correct for motion in respiratory gated PET images and to yield an accurate distribution of the radioactivity concentration. Experimental results show that this method can effectively correct for motion and improve PET image quality. The method is able to provide improved diagnostic information without increasing the acquisition time or the radiation burden.


beta-Adrenergic and endothelin receptor interaction in dilated human cardiomyopathic myocardium.
Although end-stage dilated cardiomyopathy (DCM) is characterized by defects in beta-adrenergic receptor (beta-AR) activity and increased endothelin-1 (ET-1), possible interactions between these 2 systems remain to be defined. Accordingly, the goal of this study was to determine the effects of ET receptor activation on beta-AR signaling through measurement of cyclic adenosine monophosphate (cAMP) in normal and DCM myocardium. Myocardial sarcolemmal preparations were prepared from normal human (n = 6), dilated cardiomyopathic (n = 10), and ischemic cardiomyopathic (ICM, n = 10) tissue. Basal cAMP production was measured in the presence of ET-1 alone (10(-6) to 0(-9) mol/L) as well as after (-)isoproterenol (10(-6) to 10(-2) mol/L) or forskolin (0.05 to 30.0 micromol/L) stimulation. beta-AR and ET receptor profiles were determined by radiolabeled ligand assays. ET-1 inhibited basal cAMP production in all preparations in a concentration-dependent manner. However, beta-AR-stimulated cAMP production by either isoproterenol or forskolin was not significantly affected by ET-1. beta-AR receptor density was reduced, and a selective reduction of the ET(B) receptor occurred in both forms of DCM. Under basal conditions, ET receptor stimulation reduced cAMP levels, which may influence contractility, particularly with DCM.


Distinct Roles and Synergistic Function of FruM Isoforms in Drosophila Olfactory Receptor Neurons.
Sexual dimorphism in Drosophila courtship circuits requires the male-specific transcription factor fruM, which is alternatively spliced to encode the FruMA, FruMB, and FruMC isoforms. Most fruM-positive neurons express multiple variants; however, the functional significance of their co-expression remains undetermined. Do co-expressed isoforms each play unique roles to jointly regulate dimorphism? By focusing on fruM-positive olfactory receptor neurons (ORNs), here, we show that FruMB and FruMC are both required for males' age-dependent sensitization to aphrodisiac olfactory cues in a cell-autonomous manner. Interestingly, FruMB expression is upregulated with age in Or47b and Ir84a ORNs, and its overexpression mimics the effect of age in elevating olfactory responses. Mechanistically, FruMB and FruMC synergistically mediate response sensitization through cooperation of their respective downstream effectors, namely, PPK25 and PPK23, which are both required for forming a functional amplification channel in ORNs. Together, these results provide critical mechanistic insight into how co-expressed FruM isoforms jointly coordinate dimorphic neurophysiology.


Causes and consequences of apoptosis in spermatozoa; contributions to infertility and impacts on development.
During early development, apoptosis plays a major role in the ontogeny of the germ line as a means of regulating the germ cell:Sertoli cell ratio. In the adult, apoptosis fulfils another function in removing damaged germ cells from the seminiferous epithelium in response to a wide range of physiological and environmental triggers. These include various forms of electromagnetic radiation, chemotherapeutic agents and commonly encountered toxicants such as phthalate esters, bisphenol A and cadmium. This form of apoptosis can lead to spermatogenic arrest and is predominantly mediated by the Fas/FasL system. In addition, senescent mature spermatozoa can undergo a truncated form of apoptosis in order to ensure their efficient phagocytosis within the male and female reproductive tracts. This apoptotic cascade appears to be triggered by oxidative stress and lipid peroxidation, which leads to activation of mitochondrial reactive oxygen species (ROS) generation in a self-perpetuating redox cycle. The electrophilic aldehydes generated as a result of lipid peroxidation also lead to a rapid loss of sperm motility followed some hours later by caspase activation and phosphatidylserine exposure on the sperm surface. The nuclear DNA suffers oxidative damage during this process but there is no immediate DNA cleavage by endonucleases as there is in somatic cells. The reasons for this deviation from the normal pattern of apoptosis involve the unusual physical architecture of spermatozoa and the limited capacity these cells possess for base-excision repair. These findings have practical implications for the approaches that might be used to detect and prevent DNA damage in spermatozoa.


Identification of two plastid proteins in the dinoflagellate Alexandrium affine that are substantially down-regulated by nitrogen-depletion.
The formation of harmful algal blooms (HABs) by dinoflagellates has been correlated with the nitrogen load in coastal waters. Nitrogen is implicated as an important factor in the initiation and maintenance of phytoplankton blooms. To characterize the cellular response to nitrogen, 2DE was used to compare protein expressions from dinoflagellates grown under nitrogen depleted and nitrogen replete conditions. A total of 17 differentially expressed protein spots were found, nine of which showed a roughly 16-fold decrease in N-depleted conditions. Five of these nine spots were all identified as isoforms of the plastid Form II ribulose-1,5 bisphosphate carboxylase/oxygenase (Rubisco II), while an additional four protein spots with a molecular weight of 50 kDa were identified as isoforms of a novel protein named nitrogen-associated protein 50 (NAP50). NAP50 was located in the plastids as shown by the presence of an N-terminal plastid targeting leader sequence and by immunohistochemistry. Levels of both Rubisco II and NAP50 decrease sharply between 24 and 36 h following nitrogen depletion and the decrease can be blocked if the N source is replenished before degradation occurs. Both proteins are rapidly resynthesized if the nitrogen source is replenished after degradation has occurred. These results are a first step in the dissection of the behavior of the dinoflagellate proteome under nitrogen stress conditions and may provide new insights into the relationship between dinoflagellate blooms and the nitrogen budget.


A controlled trial of renal denervation for resistant hypertension.
Prior unblinded studies have suggested that catheter-based renal-artery denervation reduces blood pressure in patients with resistant hypertension. We designed a prospective, single-blind, randomized, sham-controlled trial. Patients with severe resistant hypertension were randomly assigned in a 2:1 ratio to undergo renal denervation or a sham procedure. Before randomization, patients were receiving a stable antihypertensive regimen involving maximally tolerated doses of at least three drugs, including a diuretic. The primary efficacy end point was the change in office systolic blood pressure at 6 months; a secondary efficacy end point was the change in mean 24-hour ambulatory systolic blood pressure. The primary safety end point was a composite of death, end-stage renal disease, embolic events resulting in end-organ damage, renovascular complications, or hypertensive crisis at 1 month or new renal-artery stenosis of more than 70% at 6 months. A total of 535 patients underwent randomization. The mean (±SD) change in systolic blood pressure at 6 months was -14.13±23.93 mm Hg in the denervation group as compared with -11.74±25.94 mm Hg in the sham-procedure group (P<0.001 for both comparisons of the change from baseline), for a difference of -2.39 mm Hg (95% confidence interval [CI], -6.89 to 2.12; P=0.26 for superiority with a margin of 5 mm Hg). The change in 24-hour ambulatory systolic blood pressure was -6.75±15.11 mm Hg in the denervation group and -4.79±17.25 mm Hg in the sham-procedure group, for a difference of -1.96 mm Hg (95% CI, -4.97 to 1.06; P=0.98 for superiority with a margin of 2 mm Hg). There were no significant differences in safety between the two groups. This blinded trial did not show a significant reduction of systolic blood pressure in patients with resistant hypertension 6 months after renal-artery denervation as compared with a sham control. (Funded by Medtronic; SYMPLICITY HTN-3 ClinicalTrials.gov number, NCT01418261.).


Reconstructing coral calcification fluid dissolved inorganic carbon chemistry from skeletal boron: An exploration of potential controls on coral aragonite B/Ca.
The boron geochemistry of coral skeletons reflects the dissolved inorganic carbon (DIC) chemistry of the calcification fluid from which the skeletons precipitates and may be a valuable tool to investigate the effects of climate change on coral calcification. In this paper I calculate the predicted B/Ca of aragonite precipitating from seawater based fluids as a function of pH, [DIC] and [Ca2+]. I consider how different co-precipitating DIC species affect aragonite B/Ca and also estimate the impact of variations in the B(OH)4-/co-precipitating DIC aragonite partition coefficient (KD), which may be associated with changes in the DIC and Ca2+ chemistry of the calcification fluid. The coral skeletal B/Ca versus calcification fluid pH relationships reported previously can be reproduced by estimating B(OH)4- and co-precipitating DIC speciation as a function of pHCF and assuming that KD are constant i.e. unaffected by calcification fluid saturation state. Assuming that B(OH)4- co-precipitates with CO32-, then observed patterns can be reproduced by a fluid with approximately constant [DIC] i.e. increasing pHCF concentrates CO32-, as a function of DIC speciation. Assuming that B(OH)4- co-precipitates with HCO3- only or CO32- + HCO3- then the observed patterns can be reproduced if [DIC]CF and pHCF are positively related i.e. if DIC is increasingly concentrated in the calcification fluid at higher pHCF probably by CO2 diffusion into the calcification site.


Determination of ReQuest-based symptom thresholds to define symptom relief in GERD clinical studies.
The growing importance of symptom assessment is evident from the numerous clinical studies on gastroesophageal reflux disease (GERD) assessing treatment-induced symptom relief. However, to date, the a priori selection of criteria defining symptom relief has been arbitrary. The present study was designed to prospectively identify GERD symptom thresholds for the broad spectrum of GERD-related symptoms assessed by the validated reflux questionnaire (ReQuest) and its subscales, ReQuest-GI (gastrointestinal symptoms) and ReQuest-WSO (general well-being, sleep disturbances, other complaints), in individuals without evidence of GERD. In this 4-day evaluation in Germany, 385 individuals without evidence of GERD were included. On the first day, participants completed the ReQuest, the Gastrointestinal Symptom Rating Scale, and the Psychological General Well-Being scale. On the other days, participants filled in the ReQuest only. GERD symptom thresholds were calculated for ReQuest and its subscales, based on the respective 90th percentiles. GERD symptom thresholds were 3.37 for ReQuest, 0.95 for ReQuest-GI, and 2.46 for ReQuest-WSO. Even individuals without evidence of GERD may experience some mild symptoms that are commonly ascribed to GERD. GERD symptom thresholds derived in this study can be used to define the global symptom relief in patients with GERD.


[Biotypes and antibiotic resistance patterns of Gardnerella vaginalis strains isolated from healthy women and women with bacterial vaginosis].
As Gardnerella vaginalis is accepted as a member of normal vaginal flora, it is one of the dominant species which has been related to bacterial vaginosis (BV). The aim of this study was to determine the isolation rate, biotypes and antibiotic resistance patterns of G.vaginalis from the vaginal swab samples of 408 women who were admitted to the outpatient clinics of Family Planning Center. Hippurate hydrolysis, lipase and beta-galactosidase tests were performed for biotyping the isolates, and agar dilution (for metronidazole) and disk diffusion (for clindamycin) tests were used for the detection of antibiotic resistance patterns. As a result, by Nugent's BV scoring protocol, 122 (29.9%), 20 (29.4%), 137 (33.6%), and 18 (4.4%) of the women were diagnosed as BV, intermediate form, normal vaginal flora (NVF) and mycotic vaginosis, respectively. The overall isolation rate of G.vaginalis was found as 23% (94/408). Of them, 56.4% (53/94) and 8.5% (8/94) were isolated from samples of BV cases and subjects with NVF, respectively, and the difference was statistically significant (p<0.05). The biotyping results showed that the most frequently detected types were biotype 1 (44%), 5 (20%) and 4 (18%). There was no statistically significant difference between the biotype distribution of BV patients and the subjects who have NVF (p=0.687). The results of antibiotic susceptibility tests indicated that 70% and 53% of the isolates were resistant to metronidazole and clindamycin, respectively. It was of interest that MIC values for metronidazole was > or =128 microg/ml in 57% of resistant strains. The data of this study has emphasized that the metronidazole resistance is very high in our population, and the large scale studies are needed to clarify the relationship between BV and G.vaginalis biotypes, which can be found in the normal vaginal flora.


Effects of shutter transients in molecular beam epitaxy.
: We have studied the effects of shutter transients (STs) in molecular beam epitaxy (MBE). Two series of samples were grown by MBE and evaluated by X-ray diffraction (XRD) and X-ray reflectivity (XRR) measurements. The effects of STs were evaluated by growth rate (GR) analysis using a combination of growth time (GT) and thickness evaluated by XRD and XRR measurements. We revealed two opposite effects of STs: (1) overshoot of GR and (2) increase in GR with GT and subsequent saturation. Each effect was consistent with the previous studies; however, the previous studies showed no relationships between these two effects. By considering closing time of the shutter, the two opposite effects were well understood.


Nitazoxanide inhibits the replication of Japanese encephalitis virus in cultured cells and in a mouse model.
Japanese encephalitis virus (JEV) has a significant impact on public health. An estimated three billion people in 'at-risk' regions remain unvaccinated and the number of unvaccinated individuals in certain Asian countries is increasing. Consequently, there is an urgent need for the development of novel therapeutic agents against Japanese encephalitis. Nitazoxanide (NTZ) is a thiazolide anti-infective licensed for the treatment of parasitic gastroenteritis. Recently, NTZ has been demonstrated to have antiviral properties. In this study, the anti-JEV activity of NTZ was evaluated in cultured cells and in a mouse model. JEV-infected cells were treated with NTZ at different concentrations. The replication of JEV in the mock- and NTZ-treated cells was examined by virus titration. NTZ was administered at different time points of JEV infection to determine the stage at which NTZ affected JEV replication. Mice were infected with a lethal dose of JEV and intragastrically administered with NTZ from 1 day post-infection. The protective effect of NTZ on the JEV-infected mice was evaluated. NTZ significantly inhibited the replication of JEV in cultured cells in a dose dependent manner with 50% effective concentration value of 0.12 ± 0.04 μg/ml, a non-toxic concentration in cultured cells (50% cytotoxic concentration = 18.59 ± 0.31 μg/ml). The chemotherapeutic index calculated was 154.92. The viral yields of the NTZ-treated cells were significantly reduced at 12, 24, 36 and 48 h post-infection compared with the mock-treated cells. NTZ was found to exert its anti-JEV effect at the early-mid stage of viral infection. The anti-JEV effect of NTZ was also demonstrated in vivo, where 90% of mice that were treated by daily intragastric administration of 100 mg/kg/day of NTZ were protected from a lethal challenge dose of JEV. Both in vitro and in vivo data indicated that NTZ has anti-JEV activity, suggesting the potential application of NTZ in the treatment of Japanese encephalitis.


The prevalence of mental and physical health disorders among older methadone patients.
The aging opioid-addicted cohort from the 1970s has begun to alter the demographic characteristics of individuals in need of services for heroin addiction. Yet, despite clear trends that indicate the population of older methadone patients is increasing, little is known about their well-being and service needs. The goal of this study was to assess the physical and mental health status of older methadone patients. Face-to-face interviews were conducted with study participants. This study was conducted at a free-standing methadone clinic in a Midwestern industrial city. A clinic sample of 140 adult methadone patients over the age of 50 was recruited for face-to-face interviews. Mental health status was assessed by the Composite International Diagnostic Interview. The SF-12v2 was administered to measure a range of physical health issues. Participants were also asked about a variety of chronic conditions. In addition, respondents provided access to their drug screen results from monthly urine tests for illegal drug use for 1 year before and 1 year after the interview. Findings revealed that over half (57.1%) of respondents had at least one mental health disorder in the past year. In the year before the interview, the most prevalent mental health disorder experienced by older adult patients was major depressive episode (32.9%). The most prevalent anxiety disorders were posttraumatic stress disorder (27.8%) and generalized anxiety disorder (29.7%). Additionally, women experienced significantly higher levels of depression than males (43.8% versus 27.2%), and nearly twice the prevalence rate of agoraphobia and panic disorders. Regarding physical health, respondents reported high rates of health problems in the past year, including arthritis (54.3%) and hypertension (44.9%). The majority of respondents reported having fair to poor physical health (57.7%). When examining the entire 24-month period during which urine data were collected, three quarters (76.4%) of the respondents had at least 1 month where the urine screen detected illegal drug use. In the next decade, the growing and aging substance abusing population will require clinicians trained in both geriatrics and substance abuse. Health and mental health professionals have the opportunity to address the specialized needs of this population and prepare for the shifting service needs these older patients will require.


Clinical and biomarker changes in dominantly inherited Alzheimer's disease.
The order and magnitude of pathologic processes in Alzheimer's disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer's disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease. In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant's age at baseline assessment and the parent's age at the onset of symptoms of Alzheimer's disease to calculate the estimated years from expected symptom onset (age of the participant minus parent's age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes. Concentrations of amyloid-beta (Aβ)(42) in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini-Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset. We found that autosomal dominant Alzheimer's disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer's disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer's disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.).


Serum cytokine concentrations and acute graft-versus-host disease after allogeneic peripheral blood stem cell transplantation: concurrent measurement of ten cytokines and their respective ratios using cytometric bead array.
Both inflammatory and anti-inflammatory cytokines have been reported to be associated with acute graft-versus-host disease (aGVHD). However, their role and possible mutual interactions during aGVHD are not well understood. Eight patients with aGVHD and eight without who had undergone allogeneic HLA-identical peripheral blood stem cell transplantation were studied. The patients had no other complications known to affect serum concentration of cytokines, including infection. Serum concentrations of IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, TNF-alpha and IFN-gamma were concurrently measured by a new technique, the cytometric bead array (CBA). We found that serum concentrations of IL-5, IL-6 and IL-10 were significantly higher in patients with aGVHD than in patients without it. By ratiometric analysis, the ratios of IL-5/IL-2, IL-5/IL-4, IL-6/IL-4 in patients with aGVHD were increased compared to the patients with no evidence of aGVHD. ROC analysis demonstrated that the ratio of IL-5/IL-4 was the most sensitive parameter associated with aGVHD. The second best marker of aGVHD was increased IL-5 concentration. Thus, our results indicate that the ratio of a particular cytokine/cytokine could be a potential diagnostic marker for aGVHD, more sensitive that the serum level of a given cytokine. This observation is consistent with a cross-talk among some cytokines and their possible interactions via respective receptors on cytokine-producing cells; these interactions may play an important role in pathogenesis of aGVHD. Further studies including a large number of patients and concurrent measurement of a variety of cytokines are needed to fully assess the diagnostic value of the cytokine ratiometric analysis. The CBA methodology provides a convenient and useful tool in such studies.


Strategy for the creation of clinical grade hESC line banks that HLA-match a target population.
Here, we describe a pre-derivation embryo haplotyping strategy that we developed in order to maximize the efficiency and minimize the costs of establishing banks of clinical grade hESC lines in which human leukocyte antigen (HLA) haplotypes match a significant proportion of the population. Using whole genome amplification followed by medium resolution HLA typing using PCR amplification with sequence-specific primers (PCR-SSP), we have typed the parents, embryos and hESC lines from three families as well as our eight clinical grade hESC lines and shown that this technical approach is rapid, reliable and accurate. By employing this pre-derivation strategy where, based on HLA match, embryos are selected for a GMP route on day 3-4 of development, we would have drastically reduced our cGMP laboratory running costs.


Characteristics of catheter-related bloodstream infections in children with intestinal failure: implications for clinical management.
Catheter-related bloodstream infection is a major cause of mortality and morbidity in the intestinal-failure population. This study reports characteristics of CRBSI with implications for clinical management in parenteral nutrition-dependent children with intestinal failure. The researchers report the rate of central catheter infections, and the causative organisms, as well as identify risk factors in our intestinal-failure patients that would be amenable to preventive measures.The study is a retrospective review of the medical records of 101 patients with intestinal failure (IF), seen in the Intestinal Rehabilitation Clinic at Children's Medical Center of Dallas from May 2005 to March 2007. Catheter-related bloodstream infections (CRBSIs) were categorized as nosocomial or community-acquired. Data collected for each episode include microorganisms isolated from blood and potential risk factors. Z test was done to compare the infection rates.There were 92 episodes of CRBSIs in 45 parenteral nutrition (PN)-dependent patients with central venous catheters (CVC) in place for a total of 13,978 days. Eighty-three percent (n = 76) of CRBSIs developed in the community at a rate of 7.0 per 1,000 days. Seventeen percent (n = 16) nosocomial CRBSIs were observed at a rate of 5.5 per 1,000 catheter days. CRBSI rate was not statistically different between the two groups (7.0 vs. 5.5, p = .378).CRBSI in the intestinal-failure population is due to a wide variety of organisms with numerous risk factors. Education of CVC management with the practice of consistent guidelines may reduce CRBSI incidence, thus reducing the morbidity and mortality in the intestinal-failure patients.


A generic support vector machine model for preoperative glioma survival associations.
To develop a generic support vector machine (SVM) model by using magnetic resonance (MR) imaging-based blood volume distribution data for preoperative glioma survival associations and to prospectively evaluate the diagnostic effectiveness of this model in autonomous patient data. Institutional and regional medical ethics committees approved the study, and all patients signed a consent form. Two hundred thirty-five preoperative adult patients from two institutions with a subsequent histologically confirmed diagnosis of glioma after surgery were included retrospectively. An SVM learning technique was applied to MR imaging-based whole-tumor relative cerebral blood volume (rCBV) histograms. SVM models with the highest diagnostic accuracy for 6-month and 1-, 2-, and 3-year survival associations were trained on 101 patients from the first institution. With Cox survival analysis, the diagnostic effectiveness of the SVM models was tested on independent data from 134 patients at the second institution. were adjusted for known survival predictors, including patient age, tumor size, neurologic status, and postsurgery treatment, and were compared with survival associations from an expert reader. Compared with total qualitative assessment by an expert reader, the whole-tumor rCBV-based SVM model was the strongest parameter associated with 6-month and 1-, 2-, and 3-year survival in the independent patient data (area under the receiver operating characteristic curve, 0.794-0.851; hazard ratio, 5.4-21.2). Machine learning by means of SVM in combination with whole-tumor rCBV histogram analysis can be used to identify early patient survival in aggressive gliomas. The SVM model returned higher diagnostic accuracy values than an expert reader, and the model appears to be insensitive to patient, observer, and institutional variations.


Pseudo-spectral Analysis of Radially-Diagonalized Maxwell's Equations in Cylindrical Co-ordinates.
We present a robust and accuracy enhanced method for analyzing the propagation behavior of EM waves in z-periodic structures in (r, ö, z)-cylindrical co-ordinates. A cylindrical disk, characterized by the radius a and the periodicity length Lz, defines the fundamental cell in our problem. The permittivity of the dielectric inside this cell is characterized by an arbitrary, single-valued function å(r, ö, z) of all three spatial co-ordinates. We consider both open and closed boundary problems. Irrespective of the type of the boundary conditions on the surface r = a, our method requires the discretization of the fields in the interior of the disk only. Inside the disk volume, we expand the fields in terms of planewaves on discrete cylindrical surfaces ri = i, with being the discretization step length. The fields on the nested surfaces ri = i in the interior of the simulation domain are interrelated by the application of a simple, yet, powerful finite difference scheme. In free space outside the disk, the fields are xpanded in terms of the closed-form eigensolutions of the Maxwell's equations in cylindrical co-ordinates. In order to uniquely determine the involved unknown coefficients, the solutions in the interior- and exterior domains are matched on the disk's bounding surface. Our formulation utilizes a radially-diagonalized form of Maxwell's equations, and merely involves four (out of the six) field components. It is demonstrated that our formulation is perfectly suited, but by no means limited, to cylindrical symmetric problems.


Estimating the burden of shigellosis in Thailand: 36-month population-based surveillance study.
To estimate incidence of shigellosis in the Kaengkhoi district, Saraburi Province, Thailand. Population-based surveillance of shigellosis based in treatment centres. The detected rates of treated shigellosis were corrected for the number of cases missed due to the low sensitivity of microbiological culture methods and participants' use of health-care providers not participating in the study. The overall uncorrected incidence of shigellosis was 0.6/1000 population per year (95% confidence interval (CI) = 0.5-0.8). The unadjusted incidence of treated shigellosis was highest among children less than 5 years old (4/1000 children per year; 95% CI = 3-6) and significantly lower among people aged > 5 years (0.3/1000 population per year; 95% CI = 0.2-0.5; P < 0.001). Adjusting for cases likely to be missed as a result of culture and surveillance methods increased estimates approximately five times. The majority of Shigella isolates (122/146; 84%) were S. sonnei; the rest were S. flexneri. Of the 22 S. flexneri isolates, the three most frequently encountered serotypes were 2a (36%), 1b (23%) and 3b (28%). A total of 90-95% of S. sonnei and S. flexneri isolates were resistant to tetracycline and co-trimoxazole. In contrast to S. sonnei isolates, more than 90% of the S. flexneri isolates were also resistant to ampicillin and chloramphenicol (P < 0.0001). Estimates of incidence of Shigella infection in the community are 10-fold to 100-fold greater than those found from routine government surveillance. The high prevalence of Shigella strains resistant to multiple antibiotics adds urgency to the development of a vaccine to protect against shigellosis in this region of Thailand.


Kallmann syndrome: MR evaluation of olfactory system.
To describe the MR appearance of the olfactory bulbs and tracts and temporal lobes in patients with Kallmann syndrome, a disorder characterized by hypogonadotropic hypogonadism and anosmia. High-resolution MR scans with a surface coil placed over the nasion were performed in two patients with Kallmann syndrome. Coronal 3-mm thick contiguous sections were obtained through the olfactory bulbs and tracts. MR scans included volumetric analysis of the bulbs, tracts, temporal lobes, and hippocampi. No olfactory bulbs or tracts could be identified in patients with Kallmann syndrome. In comparison, the olfactory bulbs and tracts were identifiable in seven healthy volunteers. The temporal lobe and hippocampal volumes were comparable between control subjects and Kallmann patients. High-resolution surface-coil MR can identify the absence of olfactory bulbs and tracts in patients with Kallmann syndrome. Normal olfactory bulbs and tracts are easily discerned with surface-coil imaging.


Acute pancreatitis with giant pancreatic pseudocyst as a complication of extracorporeal shock wave lithotripsy: A case report and literature review.
Extracorporeal shock wave lithotripsy has been confirmed as the least invasive and the most widely used treatment for kidney and ureteral stones. However, as with any other type of therapy, potential complications do exist. Herein, we describe a 55-year-old male patient who developed symptoms of acute pancreatitis one day after extracorporeal shock wave lithotripsy for left renal stones. The patient used to manage himself with NSAIDs till he presented to the emergency department with severe epigastric pain and tenderness due to giant pancreatic pseudocyst formation. The pseudocyst was treated by endoscopic cystogastrostomy using metallic stent with uneventful recovery. In addition, we extensively reviewed all available literature studies of pancreatitis and pancreatic pseudocyst occurring after extracorporeal shock wave lithotripsy. We summarized all reported cases and presented them in a comprehensive table. Post ESWL acute pancreatitis is a rare clinical entity with only 11 reported cases. In all cases, abdominal pain was the most common symptom that occurs in less than 24h following ESWL treatment. So it should be considered in the differential diagnosis of acute abdominal pain after ESWL. Although ESWL is generally considered safe and effective treatment; however, major complications have been reported to occur in less than 1% of patients. One of the extremely rare complications is the development of pancreatitis and pancreatic pseudocyst.


Validation of an activity monitor for children who are partly or completely wheelchair-dependent.
Children who are wheelchair-dependent are at risk for developing unfavorable physical behavior; therefore, assessment, monitoring and efforts to improve physical behavior should start early in life. VitaMove is an accelerometer-based activity monitor and can be used to detect and distinguish different categories of physical behavior, including activities performed in a wheelchair and activities using the legs. The purpose of this study was to assess the validity of the VitaMove activity monitor to quantify physical behavior in children who are partly or completely wheelchair-dependent. Twelve children with spina bifida (SB) or cerebral palsy (CP) (mean age, 14 ± 4 years) performed a series of wheelchair activities (wheelchair protocol) and, if possible, activities using their legs (n = 5, leg protocol). Activities were performed at their own home or school. In children who were completely wheelchair-dependent, VitaMove monitoring consisted of one accelerometer-based recorder attached to the sternum and one to each wrist. For children who were partly ambulatory, an additional recorder was attached to each thigh. Using video-recordings as a reference, primary the total duration of active behavior, including wheeled activity and leg activity, and secondary agreement, sensitivity and specificity scores were determined. Detection of active behaviour with the VitaMove activity monitor showed absolute percentage errors of 6% for the wheelchair protocol and 10% for the leg protocol. For the wheelchair protocol, the mean agreement was 84%, sensitivity was 80% and specificity was 85%. For the leg protocol, the mean agreement was 83%, sensitivity was 78% and specificity was 90%. Validity scores were lower in severely affected children with CP. The VitaMove activity monitor is a valid device to quantify physical behavior in children who are partly or completely wheelchair-dependent, except for severely affected children and for bicycling.


Helping Doctors and Patients Make Sense of Health Statistics.
Many doctors, patients, journalists, and politicians alike do not understand what health statistics mean or draw wrong conclusions without noticing. Collective statistical illiteracy refers to the widespread inability to understand the meaning of numbers. For instance, many citizens are unaware that higher survival rates with cancer screening do not imply longer life, or that the statement that mammography screening reduces the risk of dying from breast cancer by 25% in fact means that 1 less woman out of 1,000 will die of the disease. We provide evidence that statistical illiteracy (a) is common to patients, journalists, and physicians; (b) is created by nontransparent framing of information that is sometimes an unintentional result of lack of understanding but can also be a result of intentional efforts to manipulate or persuade people; and (c) can have serious consequences for health. The causes of statistical illiteracy should not be attributed to cognitive biases alone, but to the emotional nature of the doctor-patient relationship and conflicts of interest in the healthcare system. The classic doctor-patient relation is based on (the physician's) paternalism and (the patient's) trust in authority, which make statistical literacy seem unnecessary; so does the traditional combination of determinism (physicians who seek causes, not chances) and the illusion of certainty (patients who seek certainty when there is none). We show that information pamphlets, Web sites, leaflets distributed to doctors by the pharmaceutical industry, and even medical journals often report evidence in nontransparent forms that suggest big benefits of featured interventions and small harms. Without understanding the numbers involved, the public is susceptible to political and commercial manipulation of their anxieties and hopes, which undermines the goals of informed consent and shared decision making. What can be done? We discuss the importance of teaching statistical thinking and transparent representations in primary and secondary education as well as in medical school. Yet this requires familiarizing children early on with the concept of probability and teaching statistical literacy as the art of solving real-world problems rather than applying formulas to toy problems about coins and dice. A major precondition for statistical literacy is transparent risk communication. We recommend using frequency statements instead of single-event probabilities, absolute risks instead of relative risks, mortality rates instead of survival rates, and natural frequencies instead of conditional probabilities. Psychological research on transparent visual and numerical forms of risk communication, as well as training of physicians in their use, is called for. Statistical literacy is a necessary precondition for an educated citizenship in a technological democracy. Understanding risks and asking critical questions can also shape the emotional climate in a society so that hopes and anxieties are no longer as easily manipulated from outside and citizens can develop a better-informed and more relaxed attitude toward their health.


Diversity of the Escherichia coli type 1 fimbrial lectin. Differential binding to mannosides and uroepithelial cells.
Type 1 fimbriae are the most common adhesive organelles of Escherichia coli. Because of their virtual ubiquity, previous epidemiological studies have not found a correlation between the presence of type 1 fimbriae and urinary tract infections (UTIs). Recently it has become clear that type 1 fimbriae exhibit several different phenotypes, due to allelic variation of the gene for the lectin subunit, FimH, and that these phenotypes are differentially distributed among fecal and UTI isolates. In this study, we have analyzed in more detail the ability of isogenic, recombinant strains of E. coli expressing fimH genes of the predominant fecal and UTI phenotypes to adhere to glycoproteins and to uroepithelial cells. Evidence was obtained to indicate that type 1 fimbriae differ in their ability to recognize various mannosides, utilizing at least two different mechanisms. All FimH subunits studied to date are capable of mediating adhesion via trimannosyl residues, but only certain variants are capable of mediating high levels of adhesion via monomannosyl residues. The ability of the FimH lectins to interact with monomannosyl residues strongly correlates with their ability to mediate E. coli adhesion to uroepithelial cells. In this way, it would be possible for certain phenotypic variants of type 1 fimbriae to contribute more than others to virulence of E. coli in the urinary tract.


Readiness to change alcohol use after trauma.
Alcohol is the leading risk factor for severe injury. This study examined whether patients hospitalized after an alcohol-related injury are motivated to change alcohol use, thus making them potential candidates for brief motivational interventions. Fifty patients hospitalized in a Level I trauma center, admitted with a positive blood alcohol concentration, were assessed for motivation to change alcohol-related behavior using validated questionnaires. Information was gathered regarding level of alcohol use, consequences of use, and motivation to change drinking habits. Demographic variables, alcohol use measures, perception of alcohol's contribution to the current injury, and negative consequences of use were evaluated by linear regression to predict readiness to change drinking. Mean blood alcohol concentration was 197 mg/dL at admission. Patients reported a pattern of binge drinking, with 86% reporting at least one binge-drinking episode in the past month, and a mean of 3.4 days of binge drinking per month. Most patients (84%) reported considering making a change (cutting down or quitting) in their drinking. Finally, patients reported experiencing an average of 22.5 negative lifetime consequences to their drinking. Having more negative consequences was found to significantly predict readiness to change drinking (p < 0.001). In this study, most patients were motivated to change their drinking. An increased number of negative consequences of alcohol use before admission predicted readiness to change drinking habits. Brief motivational interventions would be a reasonable option in this group of patients.


Hierarchical data visualization using a fast rectangle-packing algorithm.
This paper presents a technique for the representation of large-scale hierarchical data which aims to provide good overviews of complete structures and the content of the data in one display space. The technique represents the data by using nested rectangles. It first packs icons or thumbnails of the lowest-level data and then generates rectangular borders that enclose the packed data. It repeats the process of generating rectangles that enclose the lower-level rectangles until the highest-level rectangles are packed. This paper presents two rectangle-packing algorithms for placing items of hierarchical data onto display spaces. The algorithms refer to Delaunay triangular meshes connecting the centers of rectangles to find gaps where rectangles can be placed. The first algorithm places rectangles where they do not overlap each other and where the extension of the layout area is minimal. The second algorithm places rectangles by referring to templates describing the ideal positions for nodes of input data. It places rectangles where they do not overlap each other and where the combination of the layout area and the distances between the positions described in the template and the actual positions is minimal. It can smoothly represent time-varying data by referring to templates that describe previous layout results. It is also suitable for semantics-based or design-based data layout by generating templates according to the semantics or design.


Three-Year Sustained Clinical Efficacy of Drug-Coated Balloon Angioplasty in a Real-World Femoropopliteal Cohort.
Purpose: To report the 36-month outcomes from the prospective, multicenter, single-arm IN.PACT Global Study (ClinicalTrials.gov identifier NCT01609296) evaluating the performance of the IN.PACT Admiral drug-coated balloon (DCB) in real-world patients with femoropopliteal occlusive disease. Materials and Methods: The IN.PACT Global Study was conducted at 64 international sites and enrolled 1535 patients with complex lesions, which included bilateral disease, multiple lesions, de novo in-stent restenosis, long lesions, and chronic total occlusions. The predefined full clinical cohort included 1406 patients (mean age 68.6 years; 67.8% men) with claudication or rest pain treated with the study DCB. Mean lesion length was 12.09±9.54 cm; 18.0% had in-stent restenosis, 35.5% were totally occluded, and 68.7% were calcified. Freedom from clinically-driven target lesion revascularization (CD-TLR) was evaluated through 36 months. The safety composite endpoint was freedom from device- and procedure-related death through 30 days and freedom from major target limb amputation and clinically-driven target vessel revascularization within 36 months. All safety and revascularization events were reviewed by an independent clinical events committee. Results: The Kaplan-Meier estimate of freedom from CD-TLR through 36 months was 76.9%. The composite safety endpoint was achieved in 75.6% of patients. The 36-month all-cause mortality rate was 11.6%, and the major target limb amputation rate was 1.0%. The Kaplan-Meier estimate of freedom from CD-TLR through 36 months was significantly lower in patients with chronic limb-threatening ischemia (CLTI) compared with claudicants (67.6% vs 78.0%; p=0.003). Lesions affecting both the superficial femoral artery (SFA) and popliteal artery had lower Kaplan-Meier freedom from CD-TLR through 36 months (69.2%) than either isolated SFA (79.7%) or popliteal artery lesions (76.5%; log- rank p<0.001). Predictors of CD-TLR through 36 months included increased lesion length, reference vessel diameter ≤4.5 mm, in-stent restenosis, bilateral disease, CLTI, and hyperlipidemia. Conclusion: DCB angioplasty with the IN.PACT Admiral DCB for femoropopliteal disease in a diverse and complex real-world population is associated with sustained clinical efficacy and low rates of reinterventions at 3 years after the initial procedure.


Live teleophthalmology avoids escalation of referrals to secondary care during COVID-19 lockdown.
Following the COVID-19 lockdown, uptake of slitlamp-enabled live teleophthalmology increased. Its use contributed to a reduction of referrals escalated to secondary care during-lockdown (avoided: 64% pre-lockdown vs 86% during-lockdown). Live teleophthalmology using video conferencing allows real-time, three-way consultation between secondary care, community providers and patients, improving interpretation of slit lamp findings and potentially reducing referrals to secondary care. NHS Forth Valley implemented live teleophthalmology in March 2019. In March 2020, the COVID-19 pandemic created urgency to deliver ophthalmic care while minimising the risk of contracting or spreading the disease. We aim to compare the uptake and two outcomes (number of avoided secondary care referrals; pattern of presenting conditions) of live teleophthalmology consultations in NHS Forth Valley before and during the COVID-19 national lockdown. An NHS secure video conferencing platform connected the video slit lamps of optometrists, or an iPad mounted on a slit lamp and viewing through the eyepieces, to a secondary care ophthalmologist via a virtual live clinic/waiting area. Data about avoiding a secondary care referral were extracted from a post-consultation ophthalmologist survey for 14 months of data. Pre- and during-lockdown intervals were before/after 23 March 2020, when routine eyecare appointments were suspended. Numbers of avoided referrals to secondary care and patterns of presenting conditions were compared for pre- and during-lockdown periods. The COVID-19 pandemic markedly increased use of live teleophthalmology in NHS Forth Valley. Surveys were completed for 164 of 250 (66%) teleophthalmology consultations over the study period. Data from 154 surveys were analysed, 78 and 76 for the pre- and during-lockdown periods, respectively. Significantly more during-lockdown (86%) than pre-lockdown (64%; difference 21%, 95% CI 8-34%, p = 0.001) surveys indicated that referrals to secondary care were avoided. Survey data from ophthalmologists suggest significantly fewer escalations to secondary care due to teleophthalmology use.


Occult nasolacrimal duct ectasia in a child with acute sinusitis: clinicopathological considerations and literature review.
Enlargement of the nasolacrimal duct (NLD) in the absence of neoplasm is rare. As there are few reports on this condition in the literature, its pathologic significance and proper management remain unclear. We report a case of asymptomatic NLD enlargement incidentally discovered on high resolution computed tomography scan performed for a complicated acute sinusitis. Case report and literature review. NLD enlargement, defined as a truly isolated asymptomatic dilatation of the NLD, is rarely encountered. Etiology and clinical significance are unclear although the absence of nasolacrimal pathway or sinonasal disease and radiological findings of bone remodelling suggest that it may be congenital. In such cases, diagnosis may be incidental and based on imaging studies, and the term NLD ectasia seems to be more appropriate to describe this distinct entity. NLD enlargement may favour osteomeatal complex obstruction, thus leading to severe acute sinusitis.


Diode-pumped quasi-three-level CW Nd:CLNGG and Nd:CNGG lasers.
We have demonstrated what is to our knowledge the first quasi-three-level CW Nd:CLNGG laser with simple linear resonator. When the pump power was 18.2 W, a maximum output power of 1.63 W was obtained at the dual-wavelength of 935 nm and 928 nm. The optical-to-optical conversion efficiency was 9.0% and the slope efficiency was 11.5%. Lasing characteristics of a quasi-three-level CW Nd:CNGG laser were also investigated. A maximum output power of 1.87 W was obtained at the single-wavelength of 935 nm with 15.2 W pump power, corresponding to an optical-to-optical conversion efficiency of 12.3% and a slope efficiency of 15.6%.


Use of aortic extension cuffs for preserving hypogastric blood flow in endovascular aneurysm repair with aneurysmal involvement of common iliac arteries.
Intentional hypogastric artery covering during endovascular repair of abdominal aortic aneurysms (EVAR) can carry a non-negligible rate of complications; to preserve pelvic blood flow, several approaches are in use, such as sandwich techniques, branched iliac devices, or the use of aortic extender cuffs in a bell-bottom configuration. We assess the performance of the latter for treatment of common iliac artery aneurysms during EVAR. Prospective gathering of data in 21 dilated common iliac arteries (18-25 mm) with coexisting abdominal aorta aneurysm, which were treated from 2005 to 2010 and received a GORE(®) Excluder endograft and one (n = 14) or several aortic extenders in a bell-bottom configuration. Control group consisted of 136 EVARs performed with the same device in the same time frame. Median follow-up was of 47 months, with contrast-enhanced computed tomography assessment 1 month after the procedure and yearly thereafter. Age and comorbidities were homogeneously distributed among groups, although the aortic aneurysm diameter was lower in the bell-bottom group (50 mm vs. 58.2 mm, P < 0.001). There was no 30-day mortality registered in this group, and only one patient died during follow-up (5.3%), without relation with the aneurysmal disease. No significant differences were found in reintervention (15.8% vs. 14.7%, P = 0.707) or endoleak rates (36.8% vs. 38.9%, Fisher P = 1). There were no type I and four type II endoleaks, two of which precised treatment for sac growth. Endoleak-free survival (P = 0.994) and reintervention-free survival (P = 0.563) did not show differences either. Bell-bottom technique is a feasible and safe alternative for preserving hypogastric blood flow, and does not imply a higher risk of reintervention or endoleak at 3-year follow-up.


Primary peritonitis in children with nephrotic syndrome: results of a 5-year multicenter study.
Primary peritonitis is a well-described infectious complication of nephrotic syndrome. Current data on the true incidence of peritonitis and efficacy of preventive pneumococcal vaccination are not clear in this group of children. In this nationwide study, among a total of 268 patients with an initial diagnosis of steroid sensitive nephrotic syndrome, eight episodes of primary peritonitis were detected in seven patients during 5 years. All eight attacks of peritonitis occurred in the relapse period. Seven of these peritonitis episodes occurred in the first 2 years of nephrotic syndrome, three of them during the first attack. One patient had two attacks with a 6-month interval. Only two of the patients were steroid sensitive, while four of them were steroid dependent, and one was steroid resistant at the diagnosis of peritonitis. The causing microorganism was identified in three patients (Streptococcus hemolyticus, Streptococcus pneumoniae, and alpha-hemolytic Streptococcus). Incidence of peritonitis (2.6%) in our series was not high when compared with previous reports. None of the patients had been immunized against pneumococcus before or after the peritonitis attack. It raises the question if the vaccine is necessary for every child with steroid sensitive nephrotic syndrome. However, we suggest that immunization against pneumococcus is not indicated in children with steroid-responsive nephrotic syndrome (NS) and should be reserved for the small number of children who have steroid-dependent or steroid-resistant NS.