Accurate MR Image Registration to Anatomical Reference Space for Diffuse Glioma.
To summarize the distribution of glioma location within a patient population, registration of individual MR images to anatomical reference space is required. In this study, we quantified the accuracy of MR image registration to anatomical reference space with linear and non-linear transformations using estimated tumor targets of glioblastoma and lower-grade glioma, and anatomical landmarks at pre- and post-operative time-points using six commonly used registration packages (FSL, SPM5, DARTEL, ANTs, Elastix, and NiftyReg). Routine clinical pre- and post-operative, post-contrast T1-weighted images of 20 patients with glioblastoma and 20 with lower-grade glioma were collected. The 2009a Montreal Neurological Institute brain template was used as anatomical reference space. Tumors were manually segmented in the patient space and corresponding healthy tissue was delineated as a target volume in the anatomical reference space. Accuracy of the tumor alignment was quantified using the Dice score and the Hausdorff distance. To measure the accuracy of general brain alignment, anatomical landmarks were placed in patient and in anatomical reference space, and the landmark distance after registration was quantified. Lower-grade gliomas were registered more accurately than glioblastoma. Registration accuracy for pre- and post-operative MR images did not differ. SPM5 and DARTEL registered tumors most accurate, and FSL least accurate. Non-linear transformations resulted in more accurate general brain alignment than linear transformations, but tumor alignment was similar between linear and non-linear transformation. We conclude that linear transformation suffices to summarize glioma locations in anatomical reference space.


Severe inflammatory and keloidal, allergic reaction due to para-phenylenediamine in temporary tattoos.
Hair coloring with henna has been popular in Turkey for years. In recent years since the tattoos are applied by the street vendors in most of the beach places in Turkey, skin coloring with henna has also increased. Henna can be used alone or in combination with other coloring agents. Henna alone can be safe but due to additives such as para-phenylenediamine (PPD), p-toluenediamine and various essential oils, allergic contact reactions may occur. We report a 22-year-old man who developed severe inflammatory and keloidal, moderately bullous allergic reaction after henna paint-on tattoo. We did a patch test separately with these painting products (henna powder, PPD) and with the European standard series. PPD was strongly positive (+++) on day 2 and remained positive for following days. After treating with topical clobetasol-17 butyrate, resolution was obtained in two weeks. But some keloidal reaction remained.


Oxygen sensing and the transcriptional regulation of oxygen-responsive genes in yeast.
The budding yeast Saccharomyces cerevisiae is a facultative aerobe that responds to changes in oxygen availability (and carbon source) by initiating a biochemically complex program that ensures that energy demands are met under two different physiological states: aerobic growth, supported by oxidative and fermentative pathways, and anaerobic growth, supported solely by fermentative processes. This program includes the differential expression of a large number of genes, many of which are involved in the direct utilization of oxygen. Research over the past decade has defined many of the cis-sites and trans-acting factors that control the transcription of these oxygen-responsive genes. However, the manner in which oxygen is sensed and the subsequent steps involved in the transduction of this signal have not been precisely determined. Heme is known to play a pivotal role in the expression of these genes, acting as a positive modulator for the transcription of the aerobic genes and as a negative modulator for the transcription of the hypoxic genes. Consequently, cellular concentrations of heme, whose biosynthesis is oxygen-dependent, are thought to provide a gauge of oxygen availability and dictate which set of genes will be transcribed. But the precise role of heme in oxygen sensing and the transcriptional regulation of oxygen-responsive genes is presently unclear. Here, we provide an overview of the transcriptional regulation of oxygen-responsive genes, address the functional roles that heme and hemoproteins may play in this regulation, and discuss possible mechanisms of oxygen sensing in this simple eukaryotic organism.


Citizen Science Models in Health Research: an Australian Commentary.
This qualitative review explores how established citizen science models can inform and support meaningful engagement of public in health research in Australia. In particular, with the growth in participatory health research approaches and increasing consumer participation in contributing to this research through digital technologies, there are gaps in our understanding of best practice in health and biomedical citizen science research to address these paradigm shifts. Notable gaps are how we might more clearly define the parameters of such research and which citizen science models might best support digitally-enabled participation falling within these. Further work in this area is expected to lead to how established citizen science methods may help improve the quality of and the translation of public engagement in health research.


Suppression of Cytochrome P450 3A4 Function by UDP-Glucuronosyltransferase 2B7 through a Protein-Protein Interaction: Cooperative Roles of the Cytosolic Carboxyl-Terminal Domain and the Luminal Anchoring Region.
There is a large discrepancy between the interindividual difference in the hepatic expression level of cytochrome P450 3A4 (CYP3A4) and that of drug clearance mediated by this enzyme. However, the reason for this discrepancy remains largely unknown. Because CYP3A4 interacts with UDP-glucuronosyltransferase 2B7 (UGT2B7) to alter its function, the reverse regulation is expected to modulate CYP3A4-catalyzed activity. To address this issue, we investigated whether protein-protein interaction between CYP3A4 and UGT2B7 modulates CYP3A4 function. For this purpose, we coexpressed CYP3A4, NADPH-cytochrome P450 reductase, and UGT2B7 using a baculovirus-insect cell system. The activity of CYP3A4 was significantly suppressed by coexpressing UGT2B7, and this suppressive effect was lost when UGT2B7 was replaced with calnexin (CNX). These results strongly suggest that UGT2B7 negatively regulates CYP3A4 activity through a protein-protein interaction. To identify the UGT2B7 domain associated with CYP3A4 suppression we generated 12 mutants including chimeras with CNX. Mutations introduced into the UGT2B7 carboxyl-terminal transmembrane helix caused a loss of the suppressive effect on CYP3A4. Thus, this hydrophobic region is necessary for the suppression of CYP3A4 activity. Replacement of the hydrophilic end of UGT2B7 with that of CNX produced a similar suppressive effect as the native enzyme. The data using chimeric protein demonstrated that the internal membrane-anchoring region of UGT2B7 is also needed for the association with CYP3A4. These data suggest that 1) UGT2B7 suppresses CYP3A4 function, and 2) both hydrophobic domains located near the C terminus and within UGT2B7 are needed for interaction with CYP3A4.


The Breast Cancer Quality of Care Study (BQUAL): a multi-center study to determine causes for noncompliance with breast cancer adjuvant therapy.
In oncology, quality of care is a major issue for patients and providers. Significant variations in care, including nonreceipt of adjuvant systemic therapy, nonadherence to therapy, and/or early discontinuation of therapy, occur frequently and may impact survival. Reasons for these variations are not well understood, but may play a role in the prominent disparity in breast cancer survival between blacks and whites. Since May 2006, the Breast Cancer Quality of Care Study (BQUAL) has recruited 1158 women with nonmetastatic breast cancer from several centers across the country, with completed data on 1057 participants to date. Detailed information on demographic, behavioral, biomedical, and emotional factors related to chemotherapy use was collected on each participant at baseline and at two follow-up interviews during the first 6 months. In addition, for women with ER+ tumors, further questionnaires were completed every 6 months regarding hormonal therapy use. Each participant was also asked to provide a DNA sample, and to allow medical record review. We surveyed physicians providing care to the study participants regarding attitudes toward adjuvant treatment. The mean age of participants was 58 years (SD 11.6), and 15% (n = 160) were black. The majority had an annual household income <$90,000 (n = 683), had college education or higher (n = 802), 55.9% were married, and 57.9% were not currently employed. Seventy-six percent had hormone-receptor-positive tumors, 49.9% initiated chemotherapy and 82.7% started hormonal therapy. Blacks were more likely to have lower annual household income (p < 0001), less education (p = 0.0005), ER negative tumor status (p = 0.02), and poorly differentiated cancer (p = 0.0002). The main endpoints of the study are noninitiation of chemotherapy or hormonal therapy, nonadherence to therapy and early discontinuation of therapy. Treatment and outcomes will be compared on the 15% of participants who are black versus other participants. The BQUAL Study will be a rich ongoing source of information regarding reasons for differences in receipt of both adjuvant chemotherapy and hormonal therapy. This information may be useful in planning interventions to improve quality of care.


Structure and Dynamics of FosA-Mediated Fosfomycin Resistance in Klebsiella pneumoniae and Escherichia coli.
Fosfomycin exhibits broad-spectrum antibacterial activity and is being reevaluated for the treatment of extensively drug-resistant pathogens. Its activity in Gram-negative organisms, however, can be compromised by expression of FosA, a metal-dependent transferase that catalyzes the conjugation of glutathione to fosfomycin, rendering the antibiotic inactive. In this study, we solved the crystal structures of two of the most clinically relevant FosA enzymes: plasmid-encoded FosA3 from Escherichia coli and chromosomally encoded FosA from Klebsiella pneumoniae (FosAKP). The structure, molecular dynamics, catalytic activity, and fosfomycin resistance of FosA3 and FosAKP were also compared to those of FosA from Pseudomonas aeruginosa (FosAPA), for which prior crystal structures exist. E. coli TOP10 transformants expressing FosA3 and FosAKP conferred significantly greater fosfomycin resistance (MIC, >1,024 μg/ml) than those expressing FosAPA (MIC, 16 μg/ml), which could be explained in part by the higher catalytic efficiencies of the FosA3 and FosAKP enzymes. Interestingly, these differences in enzyme activity could not be attributed to structural differences at their active sites. Instead, molecular dynamics simulations and hydrogen-deuterium exchange experiments with FosAKP revealed dynamic interconnectivity between its active sites and a loop structure that extends from the active site of each monomer and traverses the dimer interface. This dimer interface loop is longer and more extended in FosAKP and FosA3 than in FosAPA, and kinetic analyses of FosAKP and FosAPA loop-swapped chimeric enzymes highlighted its importance in FosA activity. Collectively, these data yield novel insights into fosfomycin resistance that could be leveraged to develop new strategies to inhibit FosA and potentiate fosfomycin activity.


The monosaccharide binding site of lentil lectin: an X-ray and molecular modelling study.
The X-ray crystal structure of lentil lectin in complex with alpha-D-glucopyranose has been determined by molecular replacement and refined to an R-value of 0.20 at 3.0 A resolution. The glucose interacts with the protein in a manner similar to that found in the mannose complexes of concanavalin A, pea lectin and isolectin I from Lathyrus ochrus. The complex is stabilized by a network of hydrogen bonds involving the carbohydrate oxygens O6, O4, O3 and O5. In addition, the alpha-D-glucopyranose residue makes van der Waals contacts with the protein, involving the phenyl ring of Phe123 beta. The overall structure of lentil lectin, at this resolution, does not differ significantly from the highly refined structures of the uncomplexed lectin. Molecular docking studies were performed with mannose and its 2-O and 3-O-m-nitro-benzyl derivatives to explain their high affinity binding. The interactions of the modelled mannose with lentil lectin agree well with those observed experimentally for the protein-carbohydrate complex. The highly flexible Me-2-O-(m-nitro-benzyl)-alpha-D-mannopyranoside and Me-3-O-(m-nitro-benzyl)-alpha-D-mannopyranoside become conformationally restricted upon binding to lentil lectin. For best orientations of the two substrates in the combining site, the loss of entropy is accompanied by the formation of a strong hydrogen bond between the nitro group and one amino acid, Gly97 beta and Asn125 beta, respectively, along with the establishment of van der Waals interactions between the benzyl group and the aromatic amino acids Tyr100 beta and Trp128 beta.


Evaluation of cleaning methods applied in home environments after renovation and remodeling activities.
We conducted a cleaning trial in 40 northern New Jersey homes where home renovation and remodeling (R&R) activities were undertaken. Two cleaning protocols were used in the study: a specific method recommended by the US Department of Housing and Urban Development (HUD), in the 1995 "Guidelines for the Evaluation and Control of Lead-Based Paint Hazards in Housing," using a high-efficiency particulate air (HEPA)-filtered vacuum cleaner and a tri-sodium phosphate solution (TSP); and an alternative method using a household vacuum cleaner and a household detergent. Eligible homes were built before the 1970s with potential lead-based paint and had recent R&R activities without thorough cleaning. The two cleaning protocols were randomly assigned to the participants' homes and followed the HUD-recommended three-step procedure: vacuuming, wet washing, and repeat vacuuming. Wipe sampling was conducted on floor surfaces or windowsills before and after cleaning to evaluate the efficacy. All floor and windowsill data indicated that both methods (TSP/HEPA and non-TSP/non-HEPA) were effective in reducing lead loading on the surfaces (P < 0.001). When cleaning was applied to surfaces with initial lead loading above the clearance standards, the reductions were even greater, above 95% for either cleaning method. The mixed-effect model analysis showed no significant difference between the two methods. Baseline lead loading was found to be associated with lead loading reduction significantly on floors (P < 0.001) and marginally on windowsills (P = 0.077). Such relations were different between the two cleaning methods significantly on floors (P < 0.001) and marginally on windowsills (P = 0.066), with the TSP/HEPA method being favored for higher baseline levels and the non-TSP/non-HEPA method for lower baseline levels. For the 10 homes with lead abatement, almost all post-cleaning lead loadings were below the standards using either cleaning method. Based on our results, we recommend that contractors or homeowners can use a household vacuum cleaner and a household detergent to clean lead-contaminated environments after R&R activities when HUD-recommended equipment is not available.


Laparoscopic gonadectomy in a dog with 78,XX/78,XY chimerism and underdeveloped reproductive organs.
A 1-year-old externally sexually intact female Great Dane was referred for further evaluation of abnormal and underdeveloped internal reproductive organs. Physical examination findings included a cranioventrally displaced vulva and a grade 2/6 left apical systolic heart murmur. No uterus or ovaries were identified during abdominal ultrasonography. Computed tomography with retrograde vaginourethrography revealed an underdeveloped uterus and possible left intra-abdominal gonad. Karyotyping revealed mixed sex chromosomes (70% XY and 30% XX). Analysis of a serum sample yielded positive results for anti-Müllerian hormone; other findings included mid range estradiol concentration (48.2 pg/mL [within reference intervals for sexually intact and neutered males and females]), low progesterone concentration (< 0.2 ng/mL [within reference intervals for anestrous females]), and low testosterone concentration (< 20 ng/dL [similar to the expected concentration in neutered males]). Overall, the results of the sex hormone analyses were consistent with findings for either a sexually intact female or a neutered male dog. The dog's cardiac structure and function were echocardiographically normal. The dog was anesthetized and underwent laparoscopic gonadectomy. The gonads, although abnormal and underdeveloped, were readily identified intraoperatively and successfully removed. On the basis of histologic findings, the removed gonads were confirmed to be rudimentary testicles. The dog recovered from anesthesia and surgery without complications. Laparoscopic surgery was effective for visualization of abnormal and hypoplastic reproductive organs when abdominal ultrasonography and CT were of limited diagnostic usefulness, and laparoscopic surgery allowed straightforward gonadectomy in a 78,XX/78,XY chimeric dog.


Obesity and obligation.
The belief that obese people ought to lose weight and keep it off is widespread, and has a profound negative impact on the lives of the obese. I argue in this paper that most obese people have no such obligation, even if obesity is bad, and caused by calorie input exceeding output. Obese people do not have an obligation to achieve long-term weight loss if this is impossible for them, is worse than the alternative, or requires such an enormous effort in relation to what stands to be gained that this option is supererogatory rather than obligatory. It is highly plausible that most obese people fall into one of these three groups. Politicians may still have obligations to fight obesity, but they ought to do so through progressive politics rather than blaming and shaming.


Large variation in detection of histidine-rich protein 2 in Plasmodium falciparum isolates from Colombia.
Most rapid diagnostic tests (RDTs) available use histidine-rich protein 2 (HRP2) as a target. However, it has been reported that sequence variations of this protein affects its sensitivity. Currently, there is insufficient evidence for HRP2 variability in Plasmodium falciparum isolates from Colombia and its relationship with RDT performance. To determine possible geographic differences and their effects on the performance of RDTs, 22 blood samples from patients with P. falciparum malaria from Tumaco and Buenaventura, Colombia were assessed by measurement of HRP2 concentration by an HRP2 enzyme-linked immunosorbent assay, RDTs, and thick blood smear. Statistical analysis showed an association between RDT performance and HRP2 concentrations. No significant difference was found between locations. A large variation of antigen concentration in samples was found at same parasitemia. In contrast to previously reports, there was no correlation between initial parasitemia and HRP2 concentration. Our results indicate that antigen quantity should be studied more carefully because the sensitivity of the RDT is affected more by antigen concentration than by parasitemia.


Cell-sized liposome doublets reveal active tension build-up driven by acto-myosin dynamics.
Cells modulate their shape to fulfill specific functions, mediated by the cell cortex, a thin actin shell bound to the plasma membrane. Myosin motor activity, together with actin dynamics, contributes to cortical tension. Here, we examine the individual contributions of actin polymerization and myosin activity to tension increase with a non-invasive method. Cell-sized liposome doublets are covered with either a stabilized actin cortex of preformed actin filaments, or a dynamic branched actin network polymerizing at the membrane. The addition of myosin II minifilaments in both cases triggers a change in doublet shape that is unambiguously related to a tension increase. Preformed actin filaments allow us to evaluate the effect of myosin alone while, with dynamic actin cortices, we examine the synergy of actin polymerization and myosin motors in driving shape changes. Our assay paves the way for a quantification of tension changes triggered by various actin-associated proteins in a cell-sized system.


Assisted vaginal delivery in low and middle income countries: an overview.
To assess the use of assisted vaginal delivery (AVD) in low- and middle-income countries (LMICs), highlighting what level of care procedures were performed and identifying systemic barriers to its use. Cross-sectional health facility assessments. Up to 40 countries in Latin America, sub-Saharan Africa and Asia. Assessments tended to be national in scope and included all hospitals and samples of midlevel facilities in public and private sectors. Descriptive secondary data analysis. Percentage of facilities where health workers performed AVD in the 3 months prior to the assessment, instrument preference, which health workers performed the procedure, and reasons AVD was not practiced. Fewer than 20% of facilities in Latin America reported performing AVD in the last 3 months. In sub-Saharan Africa, 53% of 1728 hospitals had performed AVD but only 6% of nearly 10 000 health centres had done so. It was not uncommon to find <1% of institutional births delivered by AVD. Vacuum extraction appears preferred over forceps. Lack of equipment and trained health workers were the most frequent reasons for non-performance. The low use of AVD in LMICs is in contrast with many high-income countries, where high caesarean rates are also associated with significant rates of AVD. In many LMICs, rising caesarean rates have not been associated with maintenance of skills and practice of AVD. AVD is underused precisely in countries where pregnant women continue to face hardships accessing emergency obstetric care and where caesarean delivery can be relatively unsafe. Many LMICs exhibit low use of assisted vaginal delivery where access to EmONC continues to be a hardship.


Predicting Overwintering of Wheat Stripe Rust in Central and Northwestern China.
Stripe rust, caused by Puccinia striiformis Westend. f. sp. tritici Erikss. (Pst), is an important disease of wheat. In China, Pst management has focused on the Gansu region where the pathogen can complete its annual cycle, including oversummering and overwintering. From this region, Pst inoculum is dispersed to the southern Yangtze River region in the late autumn/early winter and then to the main wheat production regions in the following spring. We used historical weather data (1995 to 2016) and field stripe rust assessment data (8 years) in the spring to evaluate the performance of a published model for predicting the potential of Pst overwintering in the Gansu region. Both predicted and observed values of rust overwintering in the Gansu region varied greatly between years and between sites within a single year, indicating the value of predicting rust overwintering for disease management. The model predictions fitted with observed values satisfactorily. All high incidences of rust in the spring were observed in the fields of the monitoring sites where the high potential of overwintering was predicted. Conversely, the predicted rust overwintering potential was also close to zero in the fields where rust was not observed in the spring. There were many false-positive predictions, which may be attributable to the absence of rust in autumn seedlings. This model can be used to target rust management in the spring and its effectiveness will be further improved if autumn rust assessment can be carried out.


A case of bullous pemphigoid with antibodies against intercellular 130 kd antigen.
Pemphigus and bullous pemphigoid are two typical autoimmune bullous diseases that involve circulating autoantibodies directed against the epidermal cell surface and the epidermal basement membrane zone, respectively. The coexistence of pemphigus and bullous pemphigoid is rare. We describe a case of a 79-year-old man who had tense bullae and erythematous, erosive lesions on his trunk and four extremities. Histopathology revealed subepidermal blister formation without any evidence of intraepidermal acantholytic changes. Direct immunofluorescence study demonstrated deposition of IgG on the epidermal intercellular spaces, as well as along the basement membrane zone; C3 was detected only on the latter. Indirect immunofluorescence study using monkey esophagus as a substrate demonstrated the presence of circulating antibodies against both junctional and intercellular antigens. In order to analyze the precise nature of this patient's antibodies, indirect immunofluorescence study using cultured human keratinocytes and immunoblot analyses were performed. Pemphigus vulgaris sera showed smooth and uniform staining on intercellular spaces. The patient's serum showed a granular and uneven staining pattern. Immunoblot analysis showed that the patient's serum reacted with the typical 230 kd (bullous pemphigoid) antigen and 130 kd antigen, which is close to the pemphigus vulgaris antigen.


Nervous glucose sensing regulates postnatal β cell proliferation and glucose homeostasis.
How glucose sensing by the nervous system impacts the regulation of β cell mass and function during postnatal development and throughout adulthood is incompletely understood. Here, we studied mice with inactivation of glucose transporter 2 (Glut2) in the nervous system (NG2KO mice). These mice displayed normal energy homeostasis but developed late-onset glucose intolerance due to reduced insulin secretion, which was precipitated by high-fat diet feeding. The β cell mass of adult NG2KO mice was reduced compared with that of WT mice due to lower β cell proliferation rates in NG2KO mice during the early postnatal period. The difference in proliferation between NG2KO and control islets was abolished by ganglionic blockade or by weaning the mice on a carbohydrate-free diet. In adult NG2KO mice, first-phase insulin secretion was lost, and these glucose-intolerant mice developed impaired glucagon secretion when fed a high-fat diet. Electrophysiological recordings showed reduced parasympathetic nerve activity in the basal state and no stimulation by glucose. Furthermore, sympathetic activity was also insensitive to glucose. Collectively, our data show that GLUT2-dependent control of parasympathetic activity defines a nervous system/endocrine pancreas axis that is critical for β cell mass establishment in the postnatal period and for long-term maintenance of β cell function.


Estimating the date of origin of an HIV-1 circulating recombinant form.
HIV is capable of frequent genetic exchange through recombination. Despite the pandemic spread of HIV-1 recombinants, their times of origin are not well understood. We investigate the epidemic history of a HIV-1 circulating recombinant form (CRF) by estimating the time of the recombination event that lead to the emergence of CRF33_01B, a recently described recombinant descended from CRF01_AE and subtype B. The gag, pol and env genes were analyzed using a combined coalescent and relaxed molecular clock model, implemented in a Bayesian Markov chain Monte Carlo framework. Using linked genealogical trees we calculated the time interval between the common ancestor of CRF33_01B and the ancestors it shares with closely related parental lineages. The recombination event that generated CRF33_01B (t(rec)) occurred sometime between 1991 and 1993, suggesting that recombination is common in the early evolutionary history of HIV-1. The proof-of-concept approach provides a new tool for the investigation of HIV molecular epidemiology and evolution.


Inhibition of telomere recombination by inactivation of KEOPS subunit Cgi121 promotes cell longevity.
DNA double strand break (DSB) is one of the major damages that cause genome instability and cellular aging. The homologous recombination (HR)-mediated repair of DSBs plays an essential role in assurance of genome stability and cell longevity. Telomeres resemble DSBs and are competent for HR. Here we show that in budding yeast Saccharomyces cerevisiae telomere recombination elicits genome instability and accelerates cellular aging. Inactivation of KEOPS subunit Cgi121 specifically inhibits telomere recombination, and significantly extends cell longevity in both telomerase-positive and pre-senescing telomerase-negative cells. Deletion of CGI121 in the short-lived yku80(tel) mutant restores lifespan to cgi121Δ level, supporting the function of Cgi121 in telomeric single-stranded DNA generation and thus in promotion of telomere recombination. Strikingly, inhibition of telomere recombination is able to further slow down the aging process in long-lived fob1Δ cells, in which rDNA recombination is restrained. Our study indicates that HR activity at telomeres interferes with telomerase to pose a negative impact on cellular longevity.


Parent Experiences With Electronic Medication Monitoring in Pediatric Asthma Management: Qualitative Study.
Electronic medication monitoring (EMM) is a digital tool that can be used for tracking daily medication use. Previous studies of EMM in asthma management have been conducted in adults or have examined pediatric interventions that use EMM for less than 1 year. To understand how to improve EMM-enhanced interventions, it is necessary to explore the experiences of parents of children with asthma, recruited from outpatient practices, who completed a 12-month intervention trial. The objective of our study was to use qualitative inquiry to answer the following questions: (1) how did using an EMM-enhanced intervention change parents'/caregivers' experiences of managing their child's asthma, and (2) what do parents recommend for improving the intervention in the future? Parents were recruited from the intervention arm of a multicomponent health intervention enhanced by Bluetooth-enabled sensors placed on inhaler medications. Semistructured interviews were conducted with 20 parents of children aged 4-12 years with asthma. Interviews were audio-recorded, transcribed, and inductively analyzed using a constant comparative approach. Interview participants reflected an even mix of publicly and privately insured children and a diverse racial-ethnic demographic. Parents discussed 6 key themes related to their experience with the EMM-enhanced intervention for the management of their child's asthma: (1) compatibility with the family's lifestyle, (2) impact on asthma management, (3) impact on the child's health, (4) emotional impact of the intervention, (5) child's engagement in asthma management with the intervention, and (6) recommendations for future intervention design. Overall, parents reported that the 12-month EMM intervention was compatible with their daily lives, positively influenced their preventive and acute asthma management, and promoted their child's engagement in their own asthma management. While parents found the intervention acceptable and generally favorable, some parents identified compatibility issues for families with multiple caregivers and frustration when the technology malfunctioned. Parents generally viewed the intervention as a positive influence on the management of their child's asthma. However, our study also highlighted technology challenges related to having multiple caregivers, which will need to be addressed in future iterations for families. Attention must be paid to the needs of parents from low socioeconomic households, who may have more limited access to reliable internet or depend on other relatives for childcare. Understanding these family factors will help refine how a digital tool can be adopted into daily disease management of pediatric asthma.


Oligocene niche shift, Miocene diversification - cold tolerance and accelerated speciation rates in the St. John's Worts (Hypericum, Hypericaceae).
Our aim is to understand the evolution of species-rich plant groups that shifted from tropical into cold/temperate biomes. It is well known that climate affects evolutionary processes, such as how fast species diversify, species range shifts, and species distributions. Many plant lineages may have gone extinct in the Northern Hemisphere due to Late Eocene climate cooling, while some tropical lineages may have adapted to temperate conditions and radiated; the hyper-diverse and geographically widespread genus Hypericum is one of these. To investigate the effect of macroecological niche shifts on evolutionary success we combine historical biogeography with analyses of diversification dynamics and climatic niche shifts in a phylogenetic framework. Hypericum evolved cold tolerance c. 30 million years ago, and successfully colonized all ice-free continents, where today ~500 species exist. The other members of Hypericaceae stayed in their tropical habitats and evolved into ~120 species. We identified a 15-20 million year lag between the initial change in temperature preference in Hypericum and subsequent diversification rate shifts in the Miocene. Contrary to the dramatic niche shift early in the evolution of Hypericum most extant species occur in temperate climates including high elevations in the tropics. These cold/temperate niches are a distinctive characteristic of Hypericum. We conclude that the initial release from an evolutionary constraint (from tropical to temperate climates) is an important novelty in Hypericum. However, the initial shift in the adaptive landscape into colder climates appears to be a precondition, and may not be directly related to increased diversification rates. Instead, subsequent events of mountain formation and further climate cooling may better explain distribution patterns and species-richness in Hypericum. These findings exemplify important macroevolutionary patterns of plant diversification during large-scale global climate change.


Validation of FRC, a fracture risk assessment tool, in a cohort of older men: the Osteoporotic Fractures in Men (MrOS) Study.
We evaluated the performance of the Fracture Risk Calculator (FRC) in 5893 men who participated in the baseline visit (March 2000-April 2002) of the Osteoporotic Fractures in Men Study. FRC estimates for 10-yr hip and major osteoporotic (hip, clinical spine, forearm, and shoulder) fractures were calculated and compared with observed 10-yr fracture probabilities. Possible enhancement of the tool's performance when bone mineral density (BMD) was included was evaluated by comparing areas under receiver operating characteristic curves and by Net Reclassification Improvement (NRI). A total of 5893 men were followed-up for an average of 8.4 yr. For most quintiles of predicted fracture risk, the ratios of observed to predicted probabilities were close to unity. Area under the curves improved when BMD was included (p<0.001; 0.79 vs 0.71 for hip fracture and 0.70 vs 0.66 for major osteoporotic fracture, respectively). Using National Osteoporosis Foundation clinical treatment thresholds, BMD inclusion increased NRI significantly, 8.5% (p<0.01) for hip and 4.0% (p=0.01) for major osteoporotic fracture. We conclude that the FRC calibrates well with hip and major osteoporotic fractures observed among older men. Further, addition of BMD to the fracture risk calculation improves the tool's performance.


Tumor vascularization is critical for oncolytic vaccinia virus treatment of peritoneal carcinomatosis.
Peritoneal carcinomatosis (PC) represents a significant clinical challenge for which there are few treatment options. Oncolytic viruses are ideal candidates for PC treatment because of their high tumor specificity, excellent safety profile and suitability for peritoneal delivery. Here, we described the use of vvDD-SR-RFP, a recombinant vaccinia virus, in xenograft and syngeneic models of colorectal PC. Colorectal cancer cell lines were highly susceptible to vvDD-SR-RFP replication and cytotoxicity. Intraperitoneal delivery of vvDD-SR-RFP on Day 12 to mice with colorectal carcinomatosis significantly improved survival whereas survival was not improved following virus treatment on Day 8, when tumors were smaller. Immunohistochemistry revealed early tumors had a poorly distributed network of blood vessels and lower proliferation index compared to later tumors. Virus infection was also restricted to tumor rims following Day 8 treatment, whereas it was disseminated in tumors treated on Day 12. Additionally, direct infection of tumor endothelium was observed and virus infection correlated with a loss of endothelial staining and induction of cell death. Our results demonstrate that tumor vasculature has a critical role in virus delivery and tumor response. This will have significant implications in the clinical setting, both in understanding timing of therapies and in designing combination treatment strategies.


Association between Internet addiction and depression in Thai medical students at Faculty of Medicine, Ramathibodi Hospital.
To study the extent of Internet addiction (IA) and its association with depression in Thai medical students. A cross-sectional study was conducted at Faculty of Medicine, Ramathibodi Hospital. Participants were first- to fifth-year medical students who agreed to participate in this study. Demographic characteristics and stress-related factors were derived from self-rated questionnaires. Depression was assessed using the Thai version of Patient Health Questionnaire (PHQ-9). A total score of five or greater derived from the Thai version of Young Diagnostic Questionnaire for Internet Addiction was classified as "possible IA". Then chi-square test and logistic regression were used to evaluate the associations between possible IA, depression and associated factors. From 705 participants, 24.4% had possible IA and 28.8% had depression. There was statistically significant association between possible IA and depression (odds ratio (OR) 1.92, 95% confidence interval (CI): 1.34-2.77, P-value <0.001). Logistic regression analysis illustrated that the odds of depression in possible IA group was 1.58 times of the group of normal Internet use (95% CI: 1.04-2.38, P-value = 0.031). Academic problems were found to be a significant predictor of both possible IA and depression. IA was likely to be a common psychiatric problem among Thai medical students. The research has also shown that possible IA was associated with depression and academic problems. We suggest that surveillance of IA should be considered in medical schools.


Guidelines on nuclear medicine imaging in neuroblastoma.
Nuclear medicine has a central role in the diagnosis, staging, response assessment and long-term follow-up of neuroblastoma, the most common solid extracranial tumour in children. These EANM guidelines include updated information on 123I-mIBG, the most common study in nuclear medicine for the evaluation of neuroblastoma, and on PET/CT imaging with 18F-FDG, 18F-DOPA and 68Ga-DOTA peptides. These PET/CT studies are increasingly employed in clinical practice. Indications, advantages and limitations are presented along with recommendations on study protocols, interpretation of findings and reporting results.


A comparative study of five technologically diverse CFTR testing platforms.
Multiple cystic fibrosis (CF) testing platforms, using diverse and rapidly evolving technologies, are available to clinical laboratories commercially or for evaluation. Considerations when choosing a CF platform may include: sensitivity, specificity, accuracy, signal discrimination, ability to genotype, ability to reflex test, no calls/repeat rate, composition of mutation panel, hands-on time, start-to-finish time, integration into laboratory workflow, data analysis methods, flexibility regarding custom test design, and required instrumentation. Mindful of these considerations, we evaluated five technologically diverse CF platforms: 1) eSensor, an electronic detection assay system; 2) InPlex, a signal amplification methodology using a microfluidics card; 3) oligonucleotide ligation assay, an electrophoretic-based separation of amplicon-derived ligation-generated products; and two liquid bead arrays; 4) Signature, a direct hybridization assay using allele-specific capture probes; and 5) Tag-It, an assay using allele-specific primer extension and a universal microarray. A core of 150 samples, focusing on mutations in the American College of Medical Genetics/American College of Obstetricians and Gynecologists mutation panel, was tested throughout several runs for each platform. All of the platforms performed comparably in respect to sensitivity, specificity, and no-call rate. As our results indicate, consideration of all of the parameters evaluated may be useful when selecting the most appropriate platform for the specific setting.


Seasonal simulated photoperiods influence melatonin release and immune markers of pike perch Sander lucioperca.
Melatonin is considered as the time-keeping hormone acting on important physiological functions of teleosts. While the influence of melatonin on reproduction and development is well described, its potential role on immune functions has little been considered. In order to better define an immune modulation by the melatonin hormone, we hypothesized that natural variations of photoperiod and subsequent changes in melatonin release profile may act on immune status of pikeperch. Therefore, we investigated during 70 days the effects of two photoperiod regimes simulating the fall and spring in western Europe, on pikeperch physiological and immune responses. Samples were collected at 04:00 and 15:00 at days 1, 37 and 70. Growth, plasma melatonin levels, innate immune markers and expression of immune-relevant genes in head kidney tissue were assessed. While growth and stress level were not affected by the seasonal simulated photoperiods, nocturnal levels of plasma melatonin were photoperiod-dependent. Innate immune markers, including lysozyme, complement, peroxidase and phagocytic activities, were stimulated by the fall-simulated photoperiod and a significant correlation was made with plasma melatonin. In addition to bring the first evidence of changes in fish immunocompetence related to photoperiod, our results provide an additional indication supporting the immunomodulatory action of melatonin in teleosts.


Negotiations of distress between East Timorese and Vietnamese refugees and their family doctors in Melbourne.
Recent critiques of depression have contested its coherence as a concept and highlighted its performance in medicalising distress. Studies of depression in a cross-cultural context have focused on language and belief systems as technical barriers to practice that need to be overcome in enacting depression work. This paper seeks to locate culture within the broader socio-structural context of depression care in general practice. The paper draws on interviews with five general practitioners (GPs), and 24 patients from Vietnamese and East Timorese backgrounds who predominantly have left their home as refugees. Each had been diagnosed with depression or prescribed antidepressants. These patients gave accounts of distress deeply embedded within, and inseparable from, lives fraught with frightening pre-migration experiences, traumatic escape and profound dislocation and alienation in their new 'home'. Fragmented lives were contrasted with the nourishing social fabric of homes left behind. GP participants were involved in a process of engaging with a profoundly communal and structural account of emotional distress while defending and drawing on an individualised notion of depression in performing their work and accounting for the pain presented to them.


Patient, practice and organisational influences on asthma control: observational data from a national study on primary care in the United Kingdom.
Achieving asthma control is central to optimising patient quality of life and clinical outcome. Contemporary models of chronic disease management across a variety of countries point to the importance of micro, meso and macro level influences on patient care and outcome. However, asthma outcomes research has almost invariably concentrated on identifying and addressing patient predictors. Little is known about higher level organisational influences. This paper explores the contribution of organisational factors on poor asthma control, allowing for patient factors, at three organisational levels: the individual patient, local service deliverers, and strategic regional providers. Prospective cross-sectional observational cohort study of 64,929 people with asthma from 1205 primary care practices spread throughout the United Kingdom (UK). Patient clinical data were recorded during a routine asthma review. Data were analysed using simple descriptive, multiple regression and complex multi-level modelling techniques, accounting for practice clustering of patients. Poor asthma control was associated with areas of higher deprivation [regression coefficient 0.026 (95% confidence intervals 0.006; 0.046)] and urban practice [-0.155 (-0.275; -0.035)] but not all local and regional variation was explained by the data. In contrast, patient level predictors of poor control were: short acting bronchodilator overuse [2.129 (2.091; 2.164)], days-off due to asthma [1.203 (1.148; 1.258)], PEFR<80 [0.76 (0.666; 0.854)], non-use of a self-management plan (SMP) [0.554 (0.515; 0.593)], poor inhaler technique [0.53 (0.475; 0.585)], poor medication compliance [0.385 (-0.007; 0.777)], and gender [0.314 (0.281; 0.347)]. Pattern of medication use, smoking history, age, body mass index (BMI), and health service resource use were also significant factors for predicting control. Targeting of health service resource requires knowledge of the factors associated with poor control of asthma symptoms. In the UK the contribution of local and regional structures appears minimal in explaining variation in asthma outcomes. However, unexplained variation in the data suggests other unrecorded factors may play a part. While patient personal characteristics (including self-management plan use, inhaler technique, medication compliance) appear to be the predominant influence the complex nature of the disease means that some, perhaps more subtle, influences are affecting the variability at all levels and this variance needs to be explored. Further research in other international contexts is required to identify the likely applicability of these findings to other health care systems.


Complications after pinning of supracondylar distal humerus fractures.
Supracondylar distal humerus fractures are one of the most common skeletal injuries in children. The current treatment of choice in North America is closed reduction and percutaneous pin fixation. Often surgeons leave the pins exposed beneath a cast but outside the skin. Great variation exists with respect to preoperative skin preparation, and perioperative antibiotic administration. Few data exist regarding the rate of infection and other complications. The purpose of this study is to review a large series of children to evaluate the rate of infection and other complications. A retrospective review was carried out of all patients treated at our institution over an 11-year period. A total of 622 patients were identified that were followed for a minimum of 2 weeks after pin removal. Seventeen patients had flexion-type fractures, 294 had type II fractures, and 311 had type III fractures. Seventy-four fractures (11.9%) had preoperative nerve deficits with anterior interosseous palsies being the most common (33 fractures, 5.3%). Preoperative antibiotics were given to 163 patients (26.2%). Spray and towel draping were used in 362 patients, paint and towel draping were used in 65 patients, alcohol paint and towel draping were used in 146 patients, and a full preparation and draping were used in 13 patients. The pins were left exposed under the cast in 591 fractures (95%), and buried beneath the skin in 31 fractures (5.0%). A medial pin was placed in 311 fractures with a small incision made to aid placement in 18 of these cases. The most common complication was pin migration necessitating unexpected return to the operating room for pin removal in 11 patients (1.8%). One patient developed a deep infection with septic arthritis and osteomyelitis (0.2%). Five additional patients had superficial skin infections and were treated with oral antibiotics for a total infection rate of 6 of 622 patients (1.0%). One patient ultimately had a malunion and 4 others returned to the operating room for repeat reduction and pinning. Three patients developed compartment syndromes. Ulnar nerve injury was rare with only 1 postoperative ulnar nerve injury occurring in 311 patients treated with a medial pin (0.3%). Closed reduction with percutaneous pinning is effective and has a low complication rate with a very low rate of infection even when simple betadine preparation and towel draping are used. Preoperative antibiotics seem to have little effect on infection rate. Level III retrospective comparative study.


A disorganized innervation of the inner ear persists in the absence of ErbB2.
ErbB2 protein is essential for the development of Schwann cells and for the normal fiber growth and myelin formation of peripheral nerves. We have investigated the fate of the otocyst-derived inner ear sensory neurons in the absence of ErbB2 using ErbB2 null mutants. Afferent innervation of the ear sensory epithelia shows numerous fibers overshooting the organ of Corti, followed by a reduction of those fibers in near term embryos. This suggests that mature Schwann cells do not play a role in targeting or maintaining the inner ear innervation. Comparable to the overshooting of nerve fibers, sensory neurons migrate beyond their normal locations into unusual positions in the modiolus. They may miss a stop signal provided by the Schwann cells that are absent as revealed with detailed histology. Reduction of overshooting afferents may be enhanced by a reduction of the neurotrophin Ntf3 transcript to about 25% of wild type. Ntf3 transcript reductions are comparable to an adult model that uses a dominant negative form of ErbB4 expressed in the supporting cells and Schwann cells of the organ of Corti. ErbB2 null mice retain afferents to inner hair cells possibly because of the prominent expression of the neurotrophin Bdnf in developing hair cells. Despite the normal presence of Bdnf transcript, afferent fibers are disoriented near the organ of Corti. Efferent fibers do not form an intraganglionic spiral bundle in the absence of spiral ganglia and appear reduced and disorganized. This suggests that either ErbB2 mediated alterations in sensory neurons or the absence of Schwann cells affects efferent fiber growth to the organ of Corti.


Procambarus (Girardiella) holifieldi, a new species of crayfish (Decapoda: Cambaridae) from Alabama with a revision of the Hagenianus Group in the subgenus Girardiella.
Procambarus (Girardiella) holifieldi, new species, is a primary burrowing crayfish from a low-lying field in Perry County, Alabama. It belongs to the Hagenianus Group in the subgenus Girardiella. The new species is morphologically most similar to Procambarus (Girardiella) barbiger. They differ in the size and shape of the caudal processes. Procambarus barbiger has a beard along the mesial margin of the palm of the chela, while the new species lacks the beard. In addition to the description of the new species, the Hagenianus Group is reviewed and new synonymies are provided. We demonstrate that a cephalic process is indeed present in the Hagenianus Group.


Overview of approved and upcoming vaccines for SARS-CoV-2: a living review.
The rapid design and implementation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines is testament to a successfully coordinated global research effort. While employing a variety of different technologies, some of which have been used for the first time, all approved vaccines demonstrate high levels of efficacy with excellent safety profiles. Despite this, there remains an urgent global demand for coronavirus disease 2019 vaccines that require further candidates to pass phase 3 clinical trials. In the expectation of SARS-CoV-2 becoming endemic, researchers are looking to adjust the vaccine constructs to tackle emerging variants. In this review, we outline different platforms used for approved vaccines and summarize latest research data with regards to immunogenicity, dosing regimens and efficiency against emerging variants.


Impact of the Affordable Care Act on access to care for US adults with diabetes, 2011-2012.
Lack of health insurance is a barrier to medical care, which may increase the risk of diabetes complications and costs. The objective of this study was to assess the potential of the Affordable Care Act (ACA) of 2010 to improve diabetes care through increased health care access by comparing health care and health outcomes of insured and uninsured people with diabetes. We examined demographics, access to care, health care use, and health care expenditures of adults aged 19 to 64 years with diabetes by using the 2011 and 2012 Medical Expenditure Panel Survey. Bivariate descriptive statistics comparing insured and uninsured persons were evaluated separately by income above and below 138% of the federal poverty level (FPL), (a threshold for expanded Medicaid eligibility in select states under the ACA) using the t test and proportion and median tests. Uninsured adults reported poorer access to care than insured adults, such as having a usual source of health care (69.0% vs 89.5% [≤138% FPL], 77.1% vs 94.6% [>138% FPL], both P < .001) and having lower rates of 6 key diabetes preventive care services (P ≤ .05). Insured adults with diabetes had significantly higher health care expenditures than uninsured adults ($13,706 vs $4,367, $10,838 vs $4,419, respectively, both P < .001). Uninsured adults with diabetes had less access to health care and lower levels of preventive care, health care use, and expenditures than insured adults. To the extent that the ACA increases access and coverage, uninsured people with diabetes are likely to significantly increase their health care use, which may lead to reduced incidence of diabetes complications and improved health.


Can leisure activities slow dementia progression in nursing home residents? A cluster-randomized controlled trial.
To examine the effects of complex cognitive (mahjong) and physical (Tai Chi) activities on dementia severity in nursing home residents with dementia. Cluster-randomized open-label controlled design. 110 residents were randomized by nursing home into three conditions: mahjong, Tai Chi, and simple handicrafts (control). Activities were conducted three times a week for 12 weeks. Clinical Dementia Rating (CDR) was taken at 0 (baseline), 3 (post-treatment), 6, and 9 months. The outcome measure was CDR sum-of-box, which is a composite measure of both cognitive and functional deterioration in dementia. Intent-to-treat analyses were performed using multilevel regression models. Apolipoprotein E ε4 allele and education were included as covariates. Neither treatments had effects on the cognitive and functional components of the CDR, but mahjong had a significant interaction with time on the CDR sum-of-box total, suggesting a slower rate of global deterioration in the mahjong group as compared with the control group. Mahjong led to a gradual improvement in global functioning and a slightly slower rate of dementia progression over time. The effect was generalized and was not specific to cognition or daily functioning.


Determination of Quality Standards for Draksharishta, a Polyherbal Ayurvedic Formulation.
Draksharishta is an ayurvedic polyherbal formulation is prescribed for digestive impairment, respiratory disorders and weakness. Though the formula composition and therapeutic claims of draksharishta are part of the Ayurvedic Formulary of India, the scientific methods for its quality and safety evaluation are yet to be documented. The current work is an attempt to evaluate the quality parameters of draksharishta which has been checked vis a vis herbs used in the formulation by modern scientific control procedures like macroscopic and microscopic study, physico-chemical analysis, preliminary phytochemical analysis, thin layer chromatography and high performance thin layer chromatography to fix the quality standard of this formulation with reference to two marketed formulations i.e. M1 and M2, respectively. The quality control parameters were within the limit as per the Ayurvedic Pharmacopeia of India which signifies good quality and purity of the plant materials. Thin layer chromatography profiles showed the presence of gallic acid, catechin and resveratrol and further it was confirmed by HPTLC fingerprints. The results obtained can be used by pharmaceutical companies as quality control parameters in order to have a proper quality check during processing.


[Perineal urethrostomy in complex anterior urethral stricture].
Staged urethroplasty is a well-known procedure for urethral reconstruction that had already been described by Russell in 1914 and was later popularized by Johanson, Turner-Warwick, Blandy, and Schreiter. It lends itself to the treatment of complex anterior urethral stricture in combination with lichen sclerosus, failed correction of hypospadias, fistula, via falsa, abscess, carcinoma, or previously unsuccessful urethroplasty. Perineal urethrostomy can be performed as a temporary or definitive measure. Some patients even decline further urethral reconstruction because they perceive subjective satisfaction after perineal urethrostomy that was originally intended to be temporary.


Comparative physical maps derived from BAC end sequences of tilapia (Oreochromis niloticus).
The Nile tilapia is the second most important fish in aquaculture. It is an excellent laboratory model, and is closely related to the African lake cichlids famous for their rapid rates of speciation. A suite of genomic resources has been developed for this species, including genetic maps and ESTs. Here we analyze BAC end-sequences to develop comparative physical maps, and estimate the number of genome rearrangements, between tilapia and other model fish species. We obtained sequence from one or both ends of 106,259 tilapia BACs. BLAST analysis against the genome assemblies of stickleback, medaka and pufferfish allowed identification of homologies for approximately 25,000 BACs for each species. We calculate that rearrangement breakpoints between tilapia and these species occur about every 3 Mb across the genome. Analysis of 35,000 clones previously assembled into contigs by restriction fingerprints allowed identification of longer-range syntenies. Our data suggest that chromosomal evolution in recent teleosts is dominated by alternate loss of gene duplicates, and by intra-chromosomal rearrangements (~one per million years). These physical maps are a useful resource for comparative positional cloning of traits in cichlid fishes. The paired BAC end sequences from these clones will be an important resource for scaffolding forthcoming shotgun sequence assemblies of the tilapia genome.


Ramadan fasting and infectious diseases: a systematic review.
Ramadan represents the fourth of the five pillars of the Islamic creed. Although patients are exempted from observing this duty, they may be eager to share this moment of the year with their peers. However, there are no guidelines that can help physicians to address the concerns of patients with infectious diseases fasting during Ramadan. For this purpose, we performed a systematic review. of 51 articles. Our main findings are that: 1) patients suffering from diabetes at risk of developing infectious complications should not fast; 2) Ramadan fasting has little impact on diarrheal patients; 3) HIV represents a challenge, and ad hoc drug combinations should be recommended to patients, and the patients should be advised not to take fatty meals that could interfere with the treatment; 4) Ramadan has no effect on the effectiveness of anti-helminthic therapy; and 5) patients with active ulcers should not fast, as they have a higher probability of developing complications.


Transport limits in defect-engineered LaAlO3/SrTiO3 bilayers.
The electrical properties of the metallic interface in LaAlO3/SrTiO3 (LAO/STO) bilayers are investigated with focus on the role of cationic defects in thin film STO. Systematic growth-control of the STO thin film cation stoichiometry (defect-engineering) yields a relation between cationic defects in the STO layer and electronic properties of the bilayer-interface. Hall measurements reveal a stoichiometry-effect primarily on the electron mobility. The results indicate an enhancement of scattering processes in as-grown non-stoichiometric samples indicating an increased density of defects. Furthermore, we discuss the thermodynamic processes and defect-exchange reactions at the LAO/STO-bilayer interface determined in high temperature equilibrium. By quenching defined defect states from high temperature equilibrium, we finally connect equilibrium thermodynamics with room temperature transport. The results are consistent with the defect-chemistry model suggested for LAO/STO interfaces. Moreover, they reveal an additional healing process of extended defects in thin film STO.


Lactoferrin, a unique molecule with diverse therapeutical and nanotechnological applications.
Lactoferrin (LF) is a naturally glycoprotein with iron-binding properties and diverse biological applications including; antiviral, anti-inflammatory, antioxidant, anti-cancer and immune stimulating effects. In addition, LF was found to be an ideal nanocarrier for some hydrophobic therapeutics because of its active targeting potential due to overexpression of its receptor on the surface of many cells. Moreover, it was proven to be a good candidate for fabrication of nanocarriers to specifically deliver drugs in case of brain tumors owing to the capability of LF to cross the blood brain barrier (BBB). Consequently, it seems to be a promising molecule with multiple applications in the field of cancer therapy and nanomedicine.


How many neurons can we see with current spike sorting algorithms?
Recent studies highlighted the disagreement between the typical number of neurons observed with extracellular recordings and the ones to be expected based on anatomical and physiological considerations. This disagreement has been mainly attributed to the presence of sparsely firing neurons. However, it is also possible that this is due to limitations of the spike sorting algorithms used to process the data. To address this issue, we used realistic simulations of extracellular recordings and found a relatively poor spike sorting performance for simulations containing a large number of neurons. In fact, the number of correctly identified neurons for single-channel recordings showed an asymptotic behavior saturating at about 8-10 units, when up to 20 units were present in the data. This performance was significantly poorer for neurons with low firing rates, as these units were twice more likely to be missed than the ones with high firing rates in simulations containing many neurons. These results uncover one of the main reasons for the relatively low number of neurons found in extracellular recording and also stress the importance of further developments of spike sorting algorithms.


Misaligned spinal rods can induce high internal forces consistent with those observed to cause screw pullout and disc degeneration.
Manual contouring of spinal rods is often required intraoperatively for proper alignment of the rods within the pedicle screw heads. Residual misalignments are frequently reduced by using dedicated reduction devices. The forces exerted by these devices, however, are uncontrolled and may lead to excessive reaction forces. As a consequence, screw pullout might be provoked and surrounding tissue may experience unfavorable biomechanical loads. The corresponding loads and induced tissue deformations are however not well identified. Additionally, whether the forced reduction alters the biomechanical behavior of the lumbar spine during physiological movements postoperatively, remains unexplored. To predict whether the reduction of misaligned posterior instrumentation might result in clinical complications directly after reduction and during a subsequent physiological flexion movement. Finite element analysis. A patient-specific, total lumbar (L1-S1) spine finite element model was available from previous research. The model consists of poro-elastic intervertebral discs with Pfirrmann grade-dependent material parameters, with linear elastic bone tissue with stiffness values related to the local bone density, and with the seven major ligaments per spinal motion segment described as nonlinear materials. Titanium instrumentation was implemented in this model to simulate a L4, L5, and S1 posterolateral fusion. Next, coronal and sagittal misalignments of 6 mm each were introduced between the rod and the screw head at L4. These misalignments were computationally reduced and a physiological flexion movement of 15° was prescribed. Non-instrumented and well-aligned instrumented models were used as control groups. Pulling forces up to 1.0 kN were required to correct the induced misalignments of 6 mm. These forces affected the posture of the total lumbar spine, as motion segments were predicted to rotate up to 3 degrees and rotations propagated proximally to and even affect the L1-2 level. The facet contact pressures in the corrected misaligned models were asymmetrical suggesting non-physiological joint loading in the misaligned models. In addition, the discs and vertebrae experienced abnormally high forces as a result of the correction procedure. These effects were more pronounced after a 15° flexion movement following forced reduction. The results of this study indicate that the correction of misaligned posterior instrumentation can result in high forces at the screws consistent with those reported to cause screw pullout, and may cause high-tissue strains in adjacent and downstream spinal segments. Proper alignment of spinal posterior instrumentation may reduce clinical complications secondary to unfavorable biomechanics.


Lipid-soluble ginseng extract inhibits invasion and metastasis of B16F10 melanoma cells.
This study was performed to elucidate the effect of a lipid-soluble ginseng extract (LSGE) on cancer invasion and metastasis. The LSGE, even at noncytotoxic concentrations, potently inhibited invasion and migration of B16F10 mouse melanoma cells in a dose-dependent manner. In the presence of 3 μg/mL of LSGE, the invasion and migration of B16F10 cells were significantly inhibited by 98.1% and 71.4%, respectively. Furthermore, the LSGE decreased mRNA and protein levels of matrix metalloproteinase (MMP)-2 in B16F10 cells, leading to a decrease in MMP-2 activity. After B16F10 cells were intravenously injected in the tail vein of C57BL/6 mice, 1000 mg/kg/day of LSGE was orally administered for 13 days, after which lung metastasis of cancer cells was inhibited by 59.3%. These findings indicate that LSGE inhibits cancer cell invasion and migration in vitro and lung metastasis of melanoma cells in vivo by inhibiting MMP-2 expression.


Effectiveness of the multi-component dynamic work intervention to reduce sitting time in office workers - Results from a pragmatic cluster randomised controlled trial.
Prolonged sitting, which is highly prevalent in office workers, has been associated with several health risks. The aim of this study was to evaluate the Dynamic Work intervention by determining its effect on total sitting time at the 8-month follow-up in comparison to the control. This two-arm pragmatic cluster randomised controlled trial included 244 office workers from 14 different departments of a large, Dutch insurance company. The Dynamic Work intervention was a real-life, worksite intervention that included environmental components (i.e. sit-stand workstations), organisational components (i.e. group sessions), and individual components (e.g. activity/sitting trackers). Outcomes were assessed at baseline, 4-month follow-up, and 8-month follow-up. The primary outcome was total sitting time per day, objectively assessed using the activPAL activity monitor at 8-month follow-up. Secondary outcomes included other total and occupational movement behaviour outcomes, health-related outcomes, and work-related outcomes. Data analyses were performed using linear and logistic mixed models. Total sitting time did not differ between the intervention and control group at the 8-month follow-up. Secondary outcomes also showed no difference between the intervention and control group at either the 4-month or at 8-month follow-up, with the exception of number of occupational steps, which showed a statistically significant effect at 4-month follow-up (but not at 8-month follow-up) of 913 (95% CI = 381-1445) steps/8-h working day. This study evaluated the effectiveness of a real-life worksite intervention to reduce sitting time and showed little to no effect. This may be due to the relatively low intensity of the intervention, i.e. that it only involved the replacement of 25% of sitting workstations with sit-stand workstations. Future research should focus on the evaluation of more intensive real-life worksite interventions that are still feasible for implementation in daily practice. CLINICALTRIALS. NCT03115645.


Fast model-based X-ray CT reconstruction using spatially nonhomogeneous ICD optimization.
Recent applications of model-based iterative reconstruction (MBIR) algorithms to multislice helical CT reconstructions have shown that MBIR can greatly improve image quality by increasing resolution as well as reducing noise and some artifacts. However, high computational cost and long reconstruction times remain as a barrier to the use of MBIR in practical applications. Among the various iterative methods that have been studied for MBIR, iterative coordinate descent (ICD) has been found to have relatively low overall computational requirements due to its fast convergence. This paper presents a fast model-based iterative reconstruction algorithm using spatially nonhomogeneous ICD (NH-ICD) optimization. The NH-ICD algorithm speeds up convergence by focusing computation where it is most needed. The NH-ICD algorithm has a mechanism that adaptively selects voxels for update. First, a voxel selection criterion VSC determines the voxels in greatest need of update. Then a voxel selection algorithm VSA selects the order of successive voxel updates based upon the need for repeated updates of some locations, while retaining characteristics for global convergence. In order to speed up each voxel update, we also propose a fast 1-D optimization algorithm that uses a quadratic substitute function to upper bound the local 1-D objective function, so that a closed form solution can be obtained rather than using a computationally expensive line search algorithm. We examine the performance of the proposed algorithm using several clinical data sets of various anatomy. The experimental results show that the proposed method accelerates the reconstructions by roughly a factor of three on average for typical 3-D multislice geometries.


Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease.
Gene-modified autologous hematopoietic stem cells (HSC) can provide ample clinical benefits to subjects suffering from X-linked chronic granulomatous disease (X-CGD), a rare inherited immunodeficiency characterized by recurrent, often life-threatening bacterial and fungal infections. Here we report on the molecular and cellular events observed in two young adults with X-CGD treated by gene therapy in 2004. After the initial resolution of bacterial and fungal infections, both subjects showed silencing of transgene expression due to methylation of the viral promoter, and myelodysplasia with monosomy 7 as a result of insertional activation of ecotropic viral integration site 1 (EVI1). One subject died from overwhelming sepsis 27 months after gene therapy, whereas a second subject underwent an allogeneic HSC transplantation. Our data show that forced overexpression of EVI1 in human cells disrupts normal centrosome duplication, linking EVI1 activation to the development of genomic instability, monosomy 7 and clonal progression toward myelodysplasia.


Deciphering host immunity to malaria using systems immunology.
A century of conceptual and technological advances in infectious disease research has changed the face of medicine. However, there remains a lack of effective interventions and a poor understanding of host immunity to the most significant and complex pathogens, including malaria. The development of successful interventions against such intractable diseases requires a comprehensive understanding of host-pathogen immune responses. A major advance of the past decade has been a paradigm switch in thinking from the contemporary reductionist (gene-by-gene or protein-by-protein) view to a more holistic (whole organism) view. Also, a recognition that host-pathogen immunity is composed of complex, dynamic interactions of cellular and molecular components and networks that cannot be represented by any individual component in isolation. Systems immunology integrates the field of immunology with omics technologies and computational sciences to comprehensively interrogate the immune response at a systems level. Herein, we describe the system immunology toolkit and report recent studies deploying systems-level approaches in the context of natural exposure to malaria or controlled human malaria infection. We contribute our perspective on the potential of systems immunity for the rational design and development of effective interventions to improve global public health.


3-T high-resolution MR neurography of sciatic neuropathy.
The sciatic nerve may normally exhibit mild T2 hyperintensity in MR neurography (MRN) images, rendering assessment of sciatic neuropathy difficult. The purpose of this case-control study was to evaluate whether a quantitative and qualitative analysis of the sciatic nerves and regional skeletal muscles increases the accuracy of MRN in detecting sciatic neuropathy. We retrospectively reviewed the MRN studies of the pelvis and thighs of 34 subjects (12 men and 22 women; mean [± SD] age, 50 ± 15 years), of which 17 had a final diagnosis of sciatic neuropathy according to electrodiagnostic or surgical confirmation, and 17 had no evidence of sciatic neuropathy and served as control subjects. On each side, the sciatic nerves were evaluated for signal intensity (SI), size, course, and fascicular shape, whereas the regional skeletal muscles were evaluated for edema, fatty replacement, and atrophy. In addition, the nerve-to-vessel SI ratio was registered for each side at the same time and 8 months later. The sciatic nerves of the abnormal sides exhibited higher nerve-to-vessel SI ratios and higher incidences of T2 hyperintensity, enlargement, and abnormal fascicular shape compared to the nerves of the normal sides. The regional muscles of the abnormal sides demonstrated a higher grade of fatty infiltration and higher frequencies of edema and atrophy. A cutoff value of nerve-to-vessel SI ratio of 0.89 exhibited high sensitivity and specificity in predicting sciatic neuropathy. Calculation of the nerve-to-vessel SI ratio demonstrated excellent inter- and intraobserver reliability. Both qualitative and quantitative criteria should be used to suggest the MRN diagnosis of sciatic neuropathy.


Genetic and environmental sex differences in mental rotation ability: a Japanese twin study.
Sex differences in mental rotation ability have been observed in many countries. A previous study of Finnish participants reported that genetic and environmental influences on mental rotation ability differ between sexes. In this study, we assessed genetic and environmental influences on variance in mental rotation ability in 649 Japanese twins using a mental rotation test. To explain the influence of sex on variance in mental rotation ability, we applied genetic analysis using the sex limitation model. The following two factors explained variance in mental rotation ability: (1) the additive genetic factor, which reflects the accumulated small influence of many genes, and (2) the unique environmental factor, which is a type of environmental factor that differs between co-twins. The shared environmental factor, a type of environmental factor common for co-twins, could not explain the variance in mental rotation ability. Furthermore, the additive genetic factor was the same between sexes (i.e., not qualitative sex differences for the additive genetic factor), indicating that the same genes affect mental rotation ability in both sexes. Despite this observation, the additive genetic influence was greater in males than in females. In contrast, the unique environmental influence was not different between sexes. Considering the current results and those of a previous study, the quantitative sex difference for the additive genetic influences in mental rotation ability may be universal, while the unique environmental differences may depend on the characteristics of specific populations.


Transfemoral Stenting of Stenoses at the Common Carotid Artery Origin Using an Anchoring Technique With a Balloon Protection Device.
Transfemoral stenting of stenoses at the common carotid artery (CCA) origin is technically difficult because of poor stability of the guiding catheter. To describe an anchoring technique using a balloon protection device that provides excellent stability of the guiding catheter. Four patients (5 stenotic lesions) with stenosis of the CCA origin underwent transfemoral stenting with a balloon protection device (PercuSurge GuardWire; Medtronic, Santa Rosa, California). These 5 stenotic lesions of the CCA origin included 1 on the right side and 4 on the left side. Two of the stenoses were symptomatic, and 3 were asymptomatic. A balloon-expandable stent (Express LD stent; Boston Scientific, Natick, Massachusetts) was used in all patients. All stenoses were successfully dilated. With the balloon protection device as an anchor in all patients, the guiding catheter was highly stable during the procedure. There were no intraprocedural or periprocedural ischemic complications in any patients. None of the patients developed a stroke during a mean follow-up period of 8.4 months. The anchoring technique using a balloon protection device is useful for transfemoral stenting of stenoses at the CCA origin. CCA, common carotid arteryECA, external carotid arteryICA, internal carotid arteryPTA, percutaneous transluminal angioplasty.


Associations of Salmonella hospitalizations with ambient temperature, humidity and rainfall in Hong Kong.
Little is known about the relationship between Salmonella infection and meteorological parameters other than air temperature. This study aimed to explore associations of Salmonella hospitalizations with temperature, relative humidity (RH) and rainfall. With negative binomial distribution assumed, time-series regression model adjusting for season and time trend were constructed employing distributed lag non-linear models and generalized additive models. Meteorological variables including mean temperature, RH, and daily total rainfall as well as indicator variables including day of the week and public holiday were incorporated in the models. Higher temperature was strongly associated with more hospitalizations over the entire range of temperatures observed. There was a net 6.13 (95%Confidence Interval (CI) 3.52-10.67) relative risk of hospitalization at a temperature of 30.5 °C, relative to 13 °C, lag 0-16 days. Positive associations were found for RH above 60% and rainfall between 0 and 0.14 mm. Extreme high humidity (96%) and trace rainfall (0.02 mm) were associated with 2.06 (95%CI 1.35-3.14), lag 0-17 day, and 1.30 (95%CI 1.01-1.67), lag 0-26 days, relative risks of hospitalizations, relative to 60% and no rain, respectively. High temperatures, high RH and light rainfall are positively associated with Salmonella hospitalizations. The very strong association with temperatures implies that hotter days will lead to increases in Salmonella morbidity in the absence of other changes, and the public health implications of this could be exacerbated by global climate change.


Molecular systematics of five Onchocerca species (Nematoda: Filarioidea) including the human parasite, O. volvulus, suggest sympatric speciation.
The genus Onchocerca (Nematoda: Filarioidea) consists of parasites of ungulate mammals with the exception of O. volvulus, which is a human parasite. The relationship between O. volvulus, O. ochengi and O. gibsoni remains unresolved. Based on morphology of the microfilariae and infective larvae, vector transmission and geographical distribution, O. ochengi and O. volvulus have been placed as sister species. Nevertheless, the cuticle morphology and chromosomal data (O. volvulus and O. gibsoni have n=4 while O. ochengi is n=5) suggest that O. gibsoni could be more closely related to O. volvulus than O. ochengi. Sequences from the 12S rRNA, 16S rRNA and ND5 mitochondrial genes have been used to reconstruct the phylogeny of five Onchocerca species including O. volvulus. Analyses with maximum likelihood and maximum parsimony showed that O. ochengi is the sister species of O. volvulus, in accordance with the classification based on morphology and geographical location. The separate specific status of the species O. gutturosa and O. lienalis was supported, although their phylogenetic relationship was not well resolved. The analyses indicated that the basal species was O. gibsoni, a South-East Asian and Australasian species, but this result was not statistically significant. The possible involvement of sympatric speciation in the evolution of this group of parasites is discussed.


The voodoo doll task: Introducing and validating a novel method for studying aggressive inclinations.
Aggression pervades modern life. To understand the root causes of aggression, researchers have developed several methods to assess aggressive inclinations. The current article introduces a new behavioral method-the voodoo doll task (VDT)-that offers a reliable and valid trait and state measure of aggressive inclinations across settings and relationship contexts. Drawing on theory and research on the law of similarity and magical beliefs (Rozin, Millman, & Nemeroff [1986], Journal of Personality and Social Psychology, 50, 703-712), we propose that people transfer characteristics of a person onto a voodoo doll representing that person. As a result, causing harm to a voodoo doll by stabbing it with pins may have important psychological similarities to causing actual harm to the person the voodoo doll represents. Nine methodologically diverse studies (total N = 1,376) showed that the VDT had strong reliability, construct validity, and convergent validity. Discussion centers on the importance of magical beliefs in understanding the causes of aggressive inclinations.


Phase mapping and wavefront analysis based on multi-illumination light fields generated by a spatial light modulator.
We present a new multi-illumination technique for the determination of the phase maps of unknown phase objects and wavefronts based on their diffraction patterns. A spatial light modulator is used to generate a sequence of probe-light fields that illuminate the unknown object producing different diffraction patterns. Compared with similar diffraction-pattern-based approaches, our technique benefits from a motionless multiview operation and a significantly improved deconvolution algorithm convergence speed (tens of iterations versus hundreds). Computer simulations indicate that the extra information brought by the different diffraction patterns prevents convergence of the phase retrieval algorithm to spurious local minima solutions and results in faster convergence. We describe an experimental system built based on our approach using readily available, relatively low-cost components. Successful reconstructions of test targets from experimental diffraction patterns confirm the feasibility of the technique. Major sources of error are identified, solutions to these problems suggested, and potential extensions to multiresolution analysis of unknown wavefronts are proposed.


Off-label use of inhaled nitric oxide after release of NIH consensus statement.
Inhaled nitric oxide (iNO) therapy is an off-label medication in infants <34 weeks' gestational age. In 2011, the National Institutes of Health released a statement discouraging routine iNO use in premature infants. The objective of this study was to describe utilization patterns of iNO in American NICUs in the years surrounding the release of the National Institutes of Health statement. We hypothesized that iNO prescription rates in premature infants have remained unchanged since 2011. The Pediatrix Medical Group Clinical Data Warehouse was queried for the years 2009-2013 to describe first exposure iNO use among all admitted neonates stratified by gestational age. Between 2009 and 2013, the rate of iNO utilization in 23- to 29-week neonates increased from 5.03% to 6.19%, a relative increase of 23% (confidence interval: 8%-40%; P = .003). Of all neonates who received iNO therapy in 2013, nearly half were <34 weeks' gestation, with these infants accounting for more than half of all first exposure iNO days each year of the study period. The rates of off-label iNO use in preterm infants continue to rise despite evidence revealing no clear benefit in this population. This pattern of iNO prescription is not benign and comes with economic consequences.


Impact of molecular structure on the physicochemical properties of starches isolated from different field pea (Pisum sativum L.) cultivars grown in Saskatchewan, Canada.
The objective of this study was to determine the molecular structure and properties of recently released cultivars of field peas [CDC Golden (CDCG), Abarth (ABAR), CDC Patrick (CDCP) and CDC Amarillo (CDCA)] grown at different locations in Saskatchewan, Canada. Starch yield (on whole seed basis), apparent amylose, total lipid and specific surface area were in the range 34-37%, 38.2-42.6%, 1.07-1.38% and 0.31-0.38m2/g, respectively. The proportion of short (DP 6-12) amylopectin chains, amylopectin branching density, molecular order, crystallinity, crystalline heterogeneity, gelatinization transition temperatures, pasting temperatures, peak viscosity, extent of acid hydrolysis, and resistant starch content were higher in CDCG and ABAR. However, amylopectin long chains (DP 13-26), average chain length and thermal stability were higher in CDCP and CDCA. The results of this study showed that differences in physicochemical properties among cultivars were mainly influenced by amylopectin chain length distribution, amylopectin branching density and co-crystallization of amylose with amylopectin.


Decoding Nonconscious Thought Representations during Successful Thought Suppression.
Controlling our thoughts is central to mental well-being, and its failure is at the crux of a number of mental disorders. Paradoxically, behavioral evidence shows that thought suppression often fails. Despite the broad importance of understanding the mechanisms of thought control, little is known about the fate of neural representations of suppressed thoughts. Using fMRI, we investigated the brain areas involved in controlling visual thoughts and tracked suppressed thought representations using multivoxel pattern analysis. Participants were asked to either visualize a vegetable/fruit or suppress any visual thoughts about those objects. Surprisingly, the content (object identity) of successfully suppressed thoughts was still decodable in visual areas with algorithms trained on imagery. This suggests that visual representations of suppressed thoughts are still present despite reports that they are not. Thought generation was associated with the left hemisphere, and thought suppression was associated with right hemisphere engagement. Furthermore, general linear model analyses showed that subjective success in thought suppression was correlated with engagement of executive areas, whereas thought-suppression failure was associated with engagement of visual and memory-related areas. These results suggest that the content of suppressed thoughts exists hidden from awareness, seemingly without an individual's knowledge, providing a compelling reason why thought suppression is so ineffective. These data inform models of unconscious thought production and could be used to develop new treatment approaches to disorders involving maladaptive thoughts.


Generation and analysis of expressed sequence tags from Botrytis cinerea.
Botrytis cinerea is a filamentous plant pathogen of a wide range of plant species, and its infection may cause enormous damage both during plant growth and in the post-harvest phase. We have constructed a cDNA library from an isolate of B. cinerea and have sequenced 11,482 expressed sequence tags that were assembled into 1,003 contigs sequences and 3,032 singletons. Approximately 81% of the unigenes showed significant similarity to genes coding for proteins with known functions: more than 50% of the sequences code for genes involved in cellular metabolism, 12% for transport of metabolites, and approximately 10% for cellular organization. Other functional categories include responses to biotic and abiotic stimuli, cell communication, cell homeostasis, and cell development. We carried out pair-wise comparisons with fungal databases to determine the B. cinerea unisequence set with relevant similarity to genes in other fungal pathogenic counterparts. Among the 4,035 non-redundant B. cinerea unigenes, 1,338 (23%) have significant homology with Fusarium verticillioides unigenes. Similar values were obtained for Saccharomyces cerevisiae and Aspergillus nidulans (22% and 24%, respectively). The lower percentages of homology were with Magnaporthe grisae and Neurospora crassa (13% and 19%, respectively). Several genes involved in putative and known fungal virulence and general pathogenicity were identified. The results provide important information for future research on this fungal pathogen.


Surveillance activities and molecular analysis of H5N1 highly pathogenic avian influenza viruses from Thailand, 2004-2005.
Avian influenza (AI) outbreaks were first reported in Thailand in January 2004. In the past 2 yr, AI viruses have caused three epidemic waves. Disease prevention and control in all aspects have been actively carried out. Active and passive surveillance based on clinical observation and laboratory analysis were intensively conducted, as well as monitoring of genetic variation of the viruses. H5N1 viruses isolated from different avian species from different cases and locations were selected. We have sequenced specific genes (HA, NA, M, Ns, and part of PB2 genes) of 58 H5N1 isolates, as well as whole genome sequencing of 21 Thai influenza A (H5N1) viruses isolated during the 2004-2005 outbreak. Cluster analysis study showed that AI isolates were identified as highly pathogenic avian influenza (HPAI) and belonged to genotype Z. The virus had a multiple basic amino acid motif at the cleavage site of HA, deletions in the NA stalk region, a five amino acid deletion in the NS1 gene, and genetic markers for amantadine resistance in the M2 gene. All 58 H5N1 isolates were closely related and grouped into the same cluster, together with isolates from wild birds, cats, tigers, and humans. Phylogenetic analysis also revealed that Thai isolates were in the same cluster as Vietnamese isolates but aligned in a different cluster from Indonesian, Hong Kong, and Chinese viruses. In addition, genetic analysis showed that most avian influenza virus (AIV) isolates from Thailand had no major genetic changes in each gene such as HA (HA cleavage site, receptor binding site, N-link glycosylation site), NA (NA stalk region, oseltamivir resistance marker), M (the amantadine resistance marker, host specificity site), NS (five amino acid deletion site), and PB2 (host specificity site). All Thai poultry isolates contained the amantadine resistance marker while none of them had the oseltamivir resistance marker. To this end, the molecular characterization of H5N1 viruses from Thailand showed that there were no significant point mutations in the critical regions, and there was no evidence of changes in the viruses that indicate they are capable of sustained human-to-human transmission.


Ultrasound-guided versus nonguided tibiotalar joint and sinus tarsi injections: a cadaveric study.
To compare the relative accuracy rates of ultrasound (US)-guided versus nonguided ankle (tibiotalar) joint and sinus tarsi injections in a cadaveric model. Prospective human cadaveric study with injection technique randomized and accuracy assessed by skilled observers blinded to injection technique. Procedural skills laboratory in a tertiary care academic medical center. Twelve embalmed and 8 unembalmed cadavers (40 ankles) were used for this investigation. Using a predetermined randomization process, 1 ankle of each cadaver was injected with US guidance and the other without. Tibiotalar joint injections were performed via an anterior approach and sinus tarsi injections performed via an anterolateral approach. All injections were performed by the senior author using a 22-gauge, 1.5-inch needle to place 3 mL of 50% diluted blue latex solution into the target area. Two anatomists blinded to the injection technique dissected each ankle and determined injection accuracy based on previously agreed upon criteria. Injection accuracy, where an accurate injection delivered injectate within the tibiotalar joint or into the mid-portion of the sinus tarsi. The accuracy rate for US-guided tibiotalar joint injections was 100% (20/20) versus 85% (17/20) for nonguided injections. The accuracy rate for US-guided sinus tarsi injections was 90% (18/20) versus 35% (7/20) for nonguided injections. In this cadaveric study, US guidance produced superior accuracy compared with nonguided injections with respect to both the tibiotalar joint and sinus tarsi. Although further research is warranted, clinicians should consider US guidance to optimize injectate placement into these areas when optimal accuracy is necessary for diagnostic or therapeutic purposes.


Spt10 and Spt21 are required for transcriptional silencing in Saccharomyces cerevisiae.
In Saccharomyces cerevisiae, transcriptional silencing occurs at three classes of genomic regions: near the telomeres, at the silent mating type loci, and within the ribosomal DNA (rDNA) repeats. In all three cases, silencing depends upon several factors, including specific types of histone modifications. In this work we have investigated the roles in silencing for Spt10 and Spt21, two proteins previously shown to control transcription of particular histone genes. Building on a recent study showing that Spt10 is required for telomeric silencing, our results show that in both spt10 and spt21 mutants, silencing is reduced near telomeres and at HMLα, while it is increased at the rDNA. Both spt10 and spt21 mutations cause modest effects on Sir protein recruitment and histone modifications at telomeric regions, and they cause significant changes in chromatin structure, as judged by its accessibility to dam methylase. These silencing and chromatin changes are not seen upon deletion of HTA2-HTB2, the primary histone locus regulated by Spt10 and Spt21. These results suggest that Spt10 and Spt21 control silencing in S. cerevisiae by altering chromatin structure through roles beyond the control of histone gene expression.


High ionic strength and low pH detain activated skinned rabbit skeletal muscle crossbridges in a low force state.
The effects of varying pH and ionic strength on the force-velocity relations and tension transients of skinned rabbit skeletal muscle were studied at 1-2 degrees C. Both decreasing pH from 7.35 to 6.35 and raising ionic strength from 125 to 360 mM reduced isometric force by about half and decreased sarcomere stiffness by about one-fourth, so that the stiffness/force ratio was increased by half. Lowering pH also decreased maximum shortening velocity by approximately 29%, while increasing ionic strength had little effect on velocity. These effects on velocity were correlated with asymmetrical effects on stiffness. The increase in the stiffness/force ratio with both interventions was manifest as a greater relative force change associated with a sarcomere length step. This force difference persisted for a variable time after the step. At the high ionic strength the force difference was long-lasting after stretches but relaxed quickly after releases, suggesting that the structures responsible would not impose much resistance to steady-state shortening. The opposite was found in the low pH experiments. The force difference relaxed quickly after stretches but persisted for a long time after releases. Furthermore, this force difference reached a constant value of approximately 8% of isometric force with intermediate sizes of release, and was not increased with larger releases. This value was almost identical to the value of an internal load that would be sufficient to account for the reduction in maximum velocity seen at the low pH. The results are interpreted as showing that both low pH and high ionic strength inhibit the movement of crossbridges into the force-generating parts of their cycle after they have attached to the actin filaments, with very few other effects on the cycle. The two interventions are different, however, in that detained bridges can be detached readily by shortening when the detention is caused by high ionic strength but not when it is caused by low pH.