Student nurses' experiences of preserved dignity in perioperative practice - Part I.
In recent years, operating theatre nurse students' education focussed on ethical value issues and how the patient's dignity is respected in the perioperative practice. Health professionals are frequently confronted with ethical issues that can impact on patient's care during surgery. The objective of this study was to present what operating theatre nurse students experienced and interpreted as preserved dignity in perioperative practice. The study has a descriptive design with a hermeneutic approach. Data were collected using Flanagan's critical incident technique. Operating theatre nurse students from Sweden and Norway participated and collected data in 2011, after education in ethics and dignity. Data consisting of 47 written stories and the text were analysed with hermeneutical text interpretation. The study was conducted accordance with the Declaration of Helsinki and approved by a local University Ethics Research Committee. The findings revealed that students experienced that operating theatre nurses perserved patient's dignity in perioperative practice by being present for each other and making themselves known to the patient. Operating theatre nurses caring for the patient by being compassionate and preserved the patient privacy. The new understanding that emerged was that the operating theatre nurse students understood that the operating theatre nurse wanted to care for the patient like a human being. In the discussion, we have illuminated how professional ethics may be threatened by more pragmatic and utilitarian arguments contained in regulations and transplant act. Preserved dignity is an ethical and caring act. Ethical questions and how to preserve dignity in perioperative practice should be discussed more both in educations of healthcare professionals and in clinical practice.


Role of regular follow-up after curative surgery for colorectal cancer.
This investigation aimed to estimate the value of regular follow-up programs after curative resection for colorectal cancer. We compared the recurrence rate, rate of curative re-resection, and survival rate between groups who had either regular or irregular follow-up. The medical records of 397 consecutive patients, who underwent a curative resection for colorectal cancer between January 1994 and December 1997, were analyzed retrospectively. The recurrence rate was 19.4% and 20.8% in the regular and irregular follow-up groups (P > 0.05), respectively. There was a significant difference in the asymptomatic recurrence rate (62.9 vs. 18.7%; P = 0.021), but curative re-resection was possible in 18 (29.0%) of those patients with cancer recurrence in the regular follow-up group, and in 2 (12.5%) in the irregular follow-up group, which was not significantly different (P > 0.05). 5-year survival rate between the groups was not significantly different (78.1 vs. 61.2%; P > 0.05). A regular follow-up program after a curative resection for colorectal cancer, although facilitating detection of recurrence before symptoms developed, was unlikely to succeed in increasing the rate of a curative intent re-resection and survival remarkably.


Biomedical nanoparticles modulate specific CD4+ T cell stimulation by inhibition of antigen processing in dendritic cells.
Understanding how nanoparticles may affect immune responses is an essential prerequisite to developing novel clinical applications. To investigate nanoparticle-dependent outcomes on immune responses, dendritic cells (DCs) were treated with model biomedical poly(vinylalcohol)-coated super-paramagnetic iron oxide nanoparticles (PVA-SPIONs). PVA-SPIONs uptake by human monocyte-derived DCs (MDDCs) was analyzed by flow cytometry (FACS) and advanced imaging techniques. Viability, activation, function, and stimulatory capacity of MDDCs were assessed by FACS and an in vitro CD4+ T cell assay. PVA-SPION uptake was dose-dependent, decreased by lipopolysaccharide (LPS)-induced MDDC maturation at higher particle concentrations, and was inhibited by cytochalasin D pre-treatment. PVA-SPIONs did not alter surface marker expression (CD80, CD83, CD86, myeloid/plasmacytoid DC markers) or antigen-uptake, but decreased the capacity of MDDCs to process antigen, stimulate CD4+ T cells, and induce cytokines. The decreased antigen processing and CD4+ T cell stimulation capability of MDDCs following PVA-SPION treatment suggests that MDDCs may revert to a more functionally immature state following particle exposure.


Hexokinase Domain Containing 1 (HKDC1) Gene Variants and their Association with Gestational Diabetes Mellitus in a South Indian Population.
Hexokinase domain containing 1 (HKDC1), a novel human hexokinase gene, is known to affect glucose metabolism and was shown to have a strong association with 2-h plasma glucose in pregnant women in a recent genome wide association study. This study aimed to evaluate the association of these regulatory variants of HKDC1 (rs1076224, rs4746822, rs2394529 and rs9645501) with gestational diabetes mellitus (GDM) in a South Indian population. The regulatory variants of HKDC1 were genotyped in unrelated 500 women with GDM and 510 non-GDM individuals by using the MassARRAY system and by direct DNA sequencing. The minor alleles of the HKDC1 gene regulatory variants, namely rs10762264 and rs4746822, showed a significant association with GDM and these alleles conferred as much as 1.24 and 1.34 times higher risk for GDM, respectively. This is the first study to demonstrate the association of HKDC1 genetic variants with susceptibility to GDM.


The effect of remodelling and contractility of the actin cytoskeleton on the shear resistance of single cells: a computational and experimental investigation.
The biomechanisms that govern the response of chondrocytes to mechanical stimuli are poorly understood. In this study, a series of in vitro tests are performed, in which single chondrocytes are subjected to shear deformation by a horizontally moving probe. Dramatically different probe force-indentation curves are obtained for untreated cells and for cells in which the actin cytoskeleton has been disrupted. Untreated cells exhibit a rapid increase in force upon probe contact followed by yielding behaviour. Cells in which the contractile actin cytoskeleton was removed exhibit a linear force-indentation response. In order to investigate the mechanisms underlying this behaviour, a three-dimensional active modelling framework incorporating stress fibre (SF) remodelling and contractility is used to simulate the in vitro tests. Simulations reveal that the characteristic force-indentation curve observed for untreated chondrocytes occurs as a result of two factors: (i) yielding of SFs due to stretching of the cytoplasm near the probe and (ii) dissociation of SFs due to reduced cytoplasm tension at the front of the cell. In contrast, a passive hyperelastic model predicts a linear force-indentation curve similar to that observed for cells in which the actin cytoskeleton has been disrupted. This combined modelling-experimental study offers a novel insight into the role of the active contractility and remodelling of the actin cytoskeleton in the response of chondrocytes to mechanical loading.


Durable and scalable icephobic surfaces: similarities and distinctions from superhydrophobic surfaces.
Formation, adhesion, and accumulation of ice, snow, frost, glaze, rime, or their mixtures can cause severe problems for solar panels, wind turbines, aircrafts, heat pumps, power lines, telecommunication equipment, and submarines. These problems can decrease efficiency in power generation, increase energy consumption, result in mechanical and/or electrical failure, and generate safety hazards. To address these issues, the fundamentals of interfaces between liquids and surfaces at low temperatures have been extensively studied. This has lead to development of so called "icephobic" surfaces, which possess a number of overlapping, yet distinctive, characteristics from superhydrophobic surfaces. Less attention has been given to distinguishing differences between formation and adhesion of ice, snow, glaze, rime, and frost or to developing a clear definition for icephobic, or more correctly pagophobic, surfaces. In this review, we strive to clarify these differences and distinctions, while providing a comprehensive definition of icephobicity. We classify different canonical families of icephobic (pagophobic) surfaces providing a review of those with potential for scalable and robust development.


Exclusion of malignancy in thyroid nodules with indeterminate fine-needle aspiration cytology after negative 18F-fluorodeoxyglucose positron emission tomography: interim analysis.
In all, 20% of fine-needle aspiration (FNA) biopsies of thyroid nodules have an indeterminate diagnosis; of these, 80% are found to be benign after thyroidectomy. Some previous reports indicate that positron emission tomography (PET) with (18)F-fluorodeoxyglucose (FDG) imaging may predict malignancy status. We now report results on the first 51 patients in the largest prospective study of FDG-PET in patients with an indeterminate thyroid nodule FNA. Eligible patients had a dominant thyroid nodule that was palpable or >or=1 cm in greatest dimension as seen by ultrasonography, and indeterminate histology of the FNA biopsy specimen. Participants underwent preoperative neck FDG-PET alone or FDG-PET with computed tomography (FDG-PET/CT). Images were evaluated qualitatively and semiquantitatively using the maximum standardized uptake value (SUV(max)). Final diagnosis was determined by histopathologic analysis after thyroidectomy. Descriptive statistical analysis was performed. A total of 51 patients underwent preoperative FDG-PET or FDG-PET/CT. Studies without focally increased uptake localized to the lesion were considered negative. For all lesions (10 malignant, 41 benign), the sensitivity, specificity, positive-predictive value (PPV), and negative-predictive value (NPV) were 80%, 61%, 33%, and 93%, respectively. Postoperatively, two malignant and six benign lesions were found to be <1 cm by pathology examination; one lesion was not measured. When these lesions were excluded, the sensitivity, specificity, PPV, and NPV were 100%, 59%, 36%, and 100%, respectively. Based on these preliminary data, FDG-PET may have a role in excluding malignancy in thyroid nodules with an indeterminate FNA biopsy. This finding justifies ongoing accrual to our target population of 125 participants.


Smart computer-assisted markets.
The deregulation movement has motivated the experimental study of auction markets designed for interdependent network industries such as natural gas pipelines or electric power systems. Decentralized agents submit bids to buy commodity and offers to sell transportation and commodity to a computerized dispatch center. Computer algorithms determine prices and allocations that maximize the gains from exchange in the system relative to the submitted bids and offers. The problem is important, because traditionally the scale and coordination economies in such industries were thought to require regulation. Laboratory experiments are used to study feasibility, limitations, incentives, and performance of proposed market designs for deregulation, providing motivation for new theory.


Platelet-rich plasma inhibits demineralized bone matrix-induced bone formation in nude mice.
It is unclear whether platelet-rich plasma is a clinically effective adjunct to osteoinductive agents such as demineralized bone matrix. It contains platelet-derived growth factor (PDGF), which decreases osteoinduction by human demineralized bone matrix in nude-mouse muscle, suggesting that platelet-rich plasma may also have a negative impact. This study tested the hypothesis that platelet-rich plasma reduces demineralized bone matrix-induced bone formation and that this effect varies with donor-dependent differences in platelet-rich plasma and demineralized bone matrix. Human platelet-rich plasma was prepared from blood from six men (average age [and standard error of the mean], 29.2 +/- 2.4 years). Platelet numbers were determined, and growth factors were quantified before and after platelet activation. Human demineralized bone matrix from two donors (demineralized bone matrix-1 and demineralized bone matrix-2) was mixed with activated platelet-rich plasma and was implanted bilaterally in the gastrocnemius muscle in eighty male nude mice (eight implants per variable). Fifty-six days after implantation, the hindlimb calf muscles were harvested for histological analysis. Osteoinduction was evaluated with use of a qualitative score and morphometric measurements of ossicle size, new bone formation, and residual demineralized bone matrix. Compared with platelet-poor plasma, platelet-rich plasma preparations exhibited a fourfold increase in the platelet count, a fifteenfold increase in the amount of transforming growth factor-beta, a sixfold increase in the amount of PDGF-BB, a fivefold increase in the amount of PDGF-AA, and a twofold increase in the amount of PDGF-AB. Demineralized bone matrix-1 was more osteoinductive than demineralized bone matrix-2, as determined on the basis of a greater ossicle area. The effect of platelet-rich plasma was either neutral or inhibitory depending on the demineralized bone matrix batch. When used with demineralized bone matrix-1, platelet-rich plasma did not alter the qualitative score or overall ossicle size, but it decreased the new bone area. When used with demineralized bone matrix-2, platelet-rich plasma reduced the qualitative score, ossicle area, and new bone area and increased the amount of residual demineralized bone matrix. The effects on osteoinduction also varied with the donor of the platelet-rich plasma. Platelet-rich plasma decreased the osteoinductivity of demineralized bone matrix implanted in immunocom-promised mice, and the activities of both demineralized bone matrix and platelet-rich plasma were donor-dependent.


Highly active antiretroviral therapy drug combination induces oxidative stress and mitochondrial dysfunction in immortalized human blood-brain barrier endothelial cells.
The era of highly active antiretroviral therapy (HAART) has controlled AIDS and its related disorders considerably; however, the prevalence of HIV-1-associated neurocognitive disorders has been on the rise in the post-HAART era. In view of these developments, we investigated whether a HAART drug combination of 3'-azido-2',3'-deoxythymidine (AZT) and indinavir (IDV) can alter the functionality of the blood-brain barrier (BBB) endothelial cells, thereby exacerbating this condition. The viability of hCMEC/D3 cells (in vitro model of BBB) that were exposed to these drugs was significantly reduced after 72h treatment, in a dose-dependent manner. Reactive oxygen species were highly elevated after the exposure, indicating that mechanisms that induce oxidative stress were involved. Measures of oxidative stress parameters, such as glutathione and malondialdehyde, were altered in the treated groups. Loss of mitochondrial membrane potential, as assessed by fluorescence microscopy and decreased levels of ATP, indicated that cytotoxicity was mediated through mitochondrial dysfunction. Furthermore, AZT+IDV treatment caused apoptosis in endothelial cells, as assessed by the expression of cytochrome c and procaspase-3 proteins. Pretreatment with the thiol antioxidant N-acetylcysteine amide reversed some of the pro-oxidant effects of AZT+IDV. Results from our in vitro studies indicate that the AZT+IDV combination may affect the BBB in HIV-infected individuals treated with HAART drugs.


Validating maps from single particle electron cryomicroscopy.
Progress in single particle cryo-EM, most recently due to the introduction of direct detector devices, has made the high-resolution structure determination of biological assemblies smaller than 500kDa more routine, but has also increased attention on the need for tools to demonstrate the validity of single particle maps. Although map validation is a continuing subject of research, some consensus has been reached on procedures that reduce model bias and over-fitting during map refinement as well as specific tests that demonstrate map validity. Tilt-pair analysis may be used as a method for demonstrating the consistency at low resolution of a map with image data. For higher-resolution maps, new procedures for more robust resolution assessment and for validating the refinement of atomic coordinate models into single particle maps have been developed.


[A case of anaphylaxis caused by the health food chitosan].
Chitosan is a linear polysaccharide with about 10(5)-10(6) molecular weight existing in cell walls of zygomycetes. Chitosan decreases serum neutral fat and cholesterol levels and has dietary fiber action, and many products have recently been sold as health foods. Here, we report a case of immediate-type allergy for chitosan-containing health food with a review of the literature. The patient was a 47-year-old female person who developed systemic urticaria and difficulty in breathing after oral ingestion of chitosan. Since skin tests (prick test and scratch patch test) were positive, the test was done using another commercial chitosan, and was positive. The patient was diagnosed as having chitosan-induced immediately-type allergy, and was instructed to avoid ingestion of chitosan. The patient has developed no symptom thereafter. Regarding allergic reactions to chitin and chitosan, contact dermatitis induced by chitosan-containing cream has been reported from France and Portugal, but to our knowledge, there has been no report of immediate-type allergic reactions. Chitosan is a polysaccharide, not protein, but may have functioned as a food allergen because of its molecular weight and general properties.


Informed consent for medical student involvement in patient care: an updated consensus statement.
Enabling patients to consent to or decline involvement of medical students in their care is an essential aspect of ethically sound, patient-centred, mana-enhancing healthcare. It is required by Aotearoa New Zealand law and Te Kaunihera Rata o Aotearoa Medical Council of New Zealand policy. This requirement was affirmed and explored in a 2015 Consensus Statement jointly authored by the Auckland and Otago Medical Schools. Student reporting through published studies, reflective assignments and anecdotal experiences of students and teachers indicate procedures for obtaining patient consent to student involvement in care remain substandard at times. Between 2020 and 2023 senior leaders of Aotearoa New Zealand's two medical schools, and faculty involved with teaching ethics and professionalism, met to discuss these challenges and reflect on ways they could be addressed. Key stakeholders were engaged to inform proposed responses. This updated consensus statement is the result. It does not establish new standards but outlines Aotearoa New Zealand's existing cultural, ethical, legal and regulatory requirements, and considers how these may be reasonably and feasibly met using some examples.


A model for studying the hemostatic consumption or destruction of platelets.
A fundamental issue in understanding homeostasis of the hematopoietic system is to what extent intrinsic and extrinsic factors regulate cell fate. We recently revisited this issue for the case of blood platelets and concluded that platelet life span is largely regulated by internal factors, in contrast to the long-held view that accumulated damage from the environment triggers clearance. However, it is known that in humans there is an ongoing fixed requirement for platelets to maintain hemostasis and prevent bleeding; hence a proportion of platelets may be consumed in such processes before the end of their natural life span. Whether it is possible to detect this random loss of platelets in normal individuals at steady-state is unknown. To address this question, we have developed a mathematical model that independently incorporates age-independent random loss and age-dependent natural senescent clearance. By fitting to population survival curves, we illustrate the application of the model in quantifying the fixed requirement for platelets to maintain hemostasis in mice, and discuss the relationship with previous work in humans. Our results suggest a higher requirement for platelets in mice than in humans, however experimental uncertainty in the data limits our ability to constrain this quantity. We then explored the relationship between experimental uncertainty and parameter constraint using simulated data. We conclude that in order to provide useful constraint on the random loss fraction the standard error in the mean of the data must be reduced substantially, either through improving experimental uncertainty or increasing the number of experimental replicates to impractical levels. Finally we find that parameter constraint is improved at higher values of the random loss fraction; thus the model find utility in situations where the random loss fraction is expected to be high, for example during active bleeding or some types of thrombocytopenia.


Influences on the quality of young children's diets: the importance of maternal food choices.
It is recognised that eating habits established in early childhood may track into adult life. Developing effective interventions to promote healthier patterns of eating throughout the life course requires a greater understanding of the diets of young children and the factors that influence early dietary patterns. In a longitudinal UK cohort study, we assessed the diets of 1640 children at age 3 years using an interviewer-administered FFQ and examined the influence of maternal and family factors on the quality of the children's diets. To describe dietary quality, we used a principal components analysis-defined pattern of foods that is consistent with healthy eating recommendations. This was termed a 'prudent' diet pattern and was characterised by high intakes of fruit, vegetables and wholemeal bread, but by low intakes of white bread, confectionery, chips and roast potatoes. The key influence on the quality of the children's diets was the quality of their mother's diets; alone it accounted for almost a third of the variance in child's dietary quality. Mothers who had better-quality diets, which complied with dietary recommendations, were more likely to have children with comparable diets. This relationship remained strong even after adjustment for all other factors considered, including maternal educational attainment, BMI and smoking, and the child's birth order and the time spent watching television. Our data provide strong evidence of shared family patterns of diet and suggest that interventions to improve the quality of young women's diets could be effective in improving the quality of their children's diets.


A phase II study of gefitinib and irradiation in children with newly diagnosed brainstem gliomas: a report from the Pediatric Brain Tumor Consortium.
This phase II study was designed to assess the safety and efficacy of gefitinib given with and following radiation therapy in children newly diagnosed with a poor prognosis brainstem glioma. Eligible patients were those with a previously untreated nondisseminated diffuse intrinsic brainstem glioma. Histological confirmation was not required, provided patients had a characteristic clinical history and MRI findings. Treatment consisted of gefitinib, administered orally, 250 mg/m(2)/day, during standard external beam radiotherapy, continuing for up to 13 monthly courses in the absence of disease progression or unacceptable toxicity. Toxicities, particularly intratumoral hemorrhage, were monitored. Pharmacokinetics and investigational imaging studies were performed in consenting patients. Forty-three eligible patients were included in the study. Therapy was well tolerated; only 4 patients were withdrawn from the study for dose-limiting toxicity after receiving therapy for 6, 9, 17, and 24 weeks. The 12- and 24-month progression-free survival rates were 20.9 ±5.6 % and 9.3 ±4%, respectively. Overall survival rates were 56.4 ±7.6% and 19.6 ±5.9%, respectively, which appear nominally superior to other contemporaneous Pediatric Brain Tumor Consortium trials. Three patients remain progression-free survivors with ≥36 months follow-up. The observation that a subset of children with this generally fatal tumor experienced long-term progression-free survival, coupled with recent observations regarding the molecular features of brainstem gliomas, raises the possibility that prospective molecular characterization may allow enrichment of treatment responders and improvement in outcome results in future studies of biologically targeted agents.


Identification of traditional medicinal plant extracts with novel anti-influenza activity.
The emergence of drug resistant variants of the influenza virus has led to a need to identify novel and effective antiviral agents. As an alternative to synthetic drugs, the consolidation of empirical knowledge with ethnopharmacological evidence of medicinal plants offers a novel platform for the development of antiviral drugs. The aim of this study was to identify plant extracts with proven activity against the influenza virus. Extracts of fifty medicinal plants, originating from the tropical rainforests of Borneo used as herbal medicines by traditional healers to treat flu-like symptoms, were tested against the H1N1 and H3N1 subtypes of the virus. In the initial phase, in vitro micro-inhibition assays along with cytotoxicity screening were performed on MDCK cells. Most plant extracts were found to be minimally cytotoxic, indicating that the compounds linked to an ethnomedical framework were relatively innocuous, and eleven crude extracts exhibited viral inhibition against both the strains. All extracts inhibited the enzymatic activity of viral neuraminidase and four extracts were also shown to act through the hemagglutination inhibition (HI) pathway. Moreover, the samples that acted through both HI and neuraminidase inhibition (NI) evidenced more than 90% reduction in virus adsorption and penetration, thereby indicating potent action in the early stages of viral replication. Concurrent studies involving Receptor Destroying Enzyme treatments of HI extracts indicated the presence of sialic acid-like component(s) that could be responsible for hemagglutination inhibition. The manifestation of both modes of viral inhibition in a single extract suggests that there may be a synergistic effect implicating more than one active component. Overall, our results provide substantive support for the use of Borneo traditional plants as promising sources of novel anti-influenza drug candidates. Furthermore, the pathways involving inhibition of hemagglutination could be a solution to the global occurrence of viral strains resistant to neuraminidase drugs.


Utilization of self-medication and prescription drugs among 15-year-old children from the German GINIplus birth cohort.
The objective was to analyse paediatric drug utilization in relation to self-medication, prescription drugs, and the most reported therapeutic drug categories. Data were collected for 3013 children on their utilization of drugs (4-week prevalence) from a German birth cohort study (GINIplus, 15-year follow-up) using a self-administered questionnaire. The drugs were grouped into over-the-counter drugs and prescription drugs, and were classified according to the anatomical therapeutic chemical classification system. Predictors were analysed using a logistic regression model with four independent variables (gender, study area, maternal education, and parental income). Some 69% of the reported 2489 drugs were over-the-counter drugs, and 31% were prescription drugs. The 4-week prevalence for using any type of drug was 41.0%. Drug categories with high prevalence rates of use were antiinflammatory drugs (10.3%), analgesics (7.1%), and antiallergics (5.0%). Factors associated with higher use of over-the-counter drugs were female gender (OR = 1.56, p < 0.0001) and higher maternal education (OR = 1.60, p = 0.0021; university degree vs. secondary high school). Maternal education was correlated with the use of prescribed or self-medicated antiallergics (positive association) and contraceptives (negative association). The use of antibiotics, methylphenidate, and drugs for thyroid therapy was associated with lower parental income. The use of over-the-counter drugs in 15-year-old children from the GINIplus birth cohort is very common and is predicted by socioeconomic factors such as maternal education. This has to be considered by health care managers when deciding about the exclusion of over-the-counter drugs (normally used for self-medication) from reimbursement or the deregulation of drug sales.


Antitumor activity of the MEK inhibitor TAK-733 against melanoma cell lines and patient-derived tumor explants.
The goal of this study was to investigate the activity of the selective MEK1/2 inhibitor TAK-733 in both melanoma cell lines and patient-derived melanoma xenograft models. In vitro cell proliferation assays using the sulforhodamine B assay were conducted to determine TAK-733 potency and melanoma responsiveness. In vivo murine modeling with eleven patient-derived melanoma explants evaluated daily dosing of TAK-733 at 25 or 10 mg/kg. Immunoblotting was performed to evaluate on-target activity and downstream inhibition by TAK-733 in both in vitro and in vivo studies. TAK-733 demonstrated broad activity in most melanoma cell lines with relative resistance observed at IC50 > 0.1 μmol/L in vitro. TAK-733 also exhibited activity in 10 out of 11 patient-derived explants with tumor growth inhibition ranging from 0% to 100% (P < 0.001-0.03). Interestingly, BRAF(V600E) and NRAS mutational status did not correlate with responsiveness to TAK-733. Pharmacodynamically, pERK was suppressed in sensitive cell lines and tumor explants, confirming TAK-733-mediated inhibition of MEK1/2, although the demonstration of similar effects in the relatively resistant cell lines and tumor explants suggests that escape pathways are contributing to melanoma survival and proliferation. These data demonstrate that TAK-733 exhibits robust tumor growth inhibition and regression against human melanoma cell lines and patient-derived xenograft models, suggesting that further clinical development in melanoma is of scientific interest. Particularly interesting is the activity in BRAF wild-type models, where current approved therapy such as vemurafenib has been reported not to be active.


Revisited: the inertia tensor as a proprioceptive invariant in humans.
A multitude of tasks that we perform on a daily basis require precise information about the orientation of our limbs with respect to the environment and the objects located within it. Recent studies have suggested that the inertia tensor, a physical property whose values are time- and co-ordinate-independent, may be an important informational invariant used by the proprioceptive system to control the movements of our limbs (Pagano et al., Ecol. Psychol. 8 (1996) 43; Pagano and Turvey, Percept. Psychophys. 52 (1992) 617; Pagano and Turvey, J. Exp. Psychol. Hum. Percept. Perform. 21 (1995) 1070). We tested this hypothesis by recording the angular errors made by subjects when pointing to virtual targets in the dark. Close examination of the pointing errors made did not show any significant effects of the inertia tensor modifications on pointing accuracy. The kinematics of the pointing movements did not indicate that any on-line adjustments were being made to compensate for the inertia tensor changes. The implications of these findings with respect to the functioning of the proprioceptive system are discussed.


Alterations in Synovial Fluid Biomarker Levels in Knees With Meniscal Injury as Compared With Asymptomatic Contralateral Knees.
Changes in the joint microenvironment after an injury to the articular surface of the knee have been implicated in the pathogenesis of osteoarthritis. While prior studies focused on changes in this microenvironment after anterior cruciate ligament ruptures, few have explored the biomarker changes that occur in the setting of meniscal injuries. To determine whether meniscal injury results in significant alterations to synovial fluid biomarker concentrations as compared with noninjured contralateral knees. Additionally, to explore the relationship between synovial fluid biomarkers and the degree of cartilage injury seen in these patients. Cross-sectional study; Level of evidence, 3. Patients undergoing surgery for unilateral meniscal injury were prospectively enrolled from October 2011 to December 2016, forming a cohort that had synovial fluid samples collected from both the injured knee and the contralateral uninjured knee at the time of meniscal surgery. Synovial fluid samples were collected just before incision, and the concentrations of 10 biomarkers of interest were determined with a multiplex magnetic bead immunoassay. The concentrations of synovial fluid biomarkers from the operative and contralateral knees were compared. Additionally, the synovial fluid biomarker concentrations of operative knees from patients with associated high-grade cartilage lesions were compared with those with low-grade lesions. The current analysis included synovial fluid samples from 82 knees (41 operative and 41 contralateral) from 41 patients undergoing arthroscopic surgery to treat a symptomatic meniscal injury. The mean ± SD age of patients was 49.86 ± 11.75 years. There were significantly greater concentrations of 4 of the 5 proinflammatory biomarkers (IL-6, MCP-1, MIP-1β, and MMP-3) in symptomatic knees as compared with asymptomatic knees when controlling for the duration of symptoms, body mass index, age, and the random effects of by-patient variability. In the injured knees, associated high-grade cartilage lesions were predictive of elevated MCP-1, MIP-1β, and VEGF levels. Low synovial fluid concentration of TIMP-1 or a greater ratio of MMP-3 to TIMP-1 was associated with the presence of synovitis. Increasing age was found to be an independent predictor of increased IL-6, MCP-1, and VEGF concentrations in the setting of symptomatic meniscal injury. The authors identified 4 proinflammatory synovial fluid biomarkers whose concentrations were significantly different after meniscal injury as compared with uninjured contralateral knees. Furthermore, they describe the effects of associated cartilage damage, synovitis, and patient age on biomarker concentrations.


Enhanced in vitro proliferation and in vivo tumorigenic potential of mammary epithelium from BALB/c mice exposed in vivo to gamma-radiation and/or 7,12-dimethylbenz[a]anthracene.
Virgin female BALB/c mice were exposed in vivo to whole body gamma-radiation and/or to 7,12-dimethylbenz[a]anthracene (DMBA) p.o. Mammary epithelial cells were isolated and assayed for carcinogen altered cell populations both in vitro by an epithelial focus assay and in vivo by injection into cleared fat pads of syngeneic host mice. Five groups of mice were exposed as follows: (a) sham controls; (b) 50-rad gamma-radiation; (c) 100-rad gamma-radiation; (d) 75 micrograms DMBA; or (e) 50-rad gamma-radiation followed in 1 week by 75 micrograms DMBA. Mammary epithelial cells were isolated and assayed at 24 h and at 1, 4, 16, and 52 weeks after in vivo exposure. Four to 12 mice per treatment per time point were individually assayed. Altered in vitro growth potential was characterized by the proliferation of carcinogen exposed (but not control) cells as epithelial foci which persisted at least 12 weeks in primary culture. Epithelial foci which could then be subcultured at least four times were termed subculturable epithelial foci. Altered in vivo morphogenic potential was characterized by dysplastic or neoplastic growth in host fat pads. With increased time in situ between exposure and assay, cell populations emerged which exhibited both increased in vitro subculturability and enhanced tumorigenic potential including a host response upon injection in vivo. Further, combined radiation and DMBA resulted in higher frequencies of subculturable epithelial foci than either treatment alone. The relevance of these progressive cellular changes to the process of mammary tumor development is discussed.


Active site and laminarin binding in glycoside hydrolase family 55.
The Carbohydrate Active Enzyme (CAZy) database indicates that glycoside hydrolase family 55 (GH55) contains both endo- and exo-β-1,3-glucanases. The founding structure in the GH55 is PcLam55A from the white rot fungus Phanerochaete chrysosporium (Ishida, T., Fushinobu, S., Kawai, R., Kitaoka, M., Igarashi, K., and Samejima, M. (2009) Crystal structure of glycoside hydrolase family 55 β-1,3-glucanase from the basidiomycete Phanerochaete chrysosporium. J. Biol. Chem. 284, 10100-10109). Here, we present high resolution crystal structures of bacterial SacteLam55A from the highly cellulolytic Streptomyces sp. SirexAA-E with bound substrates and product. These structures, along with mutagenesis and kinetic studies, implicate Glu-502 as the catalytic acid (as proposed earlier for Glu-663 in PcLam55A) and a proton relay network of four residues in activating water as the nucleophile. Further, a set of conserved aromatic residues that define the active site apparently enforce an exo-glucanase reactivity as demonstrated by exhaustive hydrolysis reactions with purified laminarioligosaccharides. Two additional aromatic residues that line the substrate-binding channel show substrate-dependent conformational flexibility that may promote processive reactivity of the bound oligosaccharide in the bacterial enzymes. Gene synthesis carried out on ∼30% of the GH55 family gave 34 active enzymes (19% functional coverage of the nonredundant members of GH55). These active enzymes reacted with only laminarin from a panel of 10 different soluble and insoluble polysaccharides and displayed a broad range of specific activities and optima for pH and temperature. Application of this experimental method provides a new, systematic way to annotate glycoside hydrolase phylogenetic space for functional properties.


Endoscopic third ventriculostomy in the treatment of childhood hydrocephalus in Uganda: report of a scoring system that predicts success.
In Uganda, childhood hydrocephalus is common and difficult to treat. In some children, endoscopic third ventriculostomy (ETV) can be successful and avoid dependence on a shunt. This can be especially beneficial in Uganda, because of the high risk of infection and long-term failure associated with shunting. Therefore, the authors developed and validated a model to predict the chances of ETV success, taking into account the unique characteristics of a large sub-Saharan African population. All children presenting with hydrocephalus at CURE Children's Hospital of Uganda (CCHU) between 2001 and 2007 were offered ETV as first-line treatment and were prospectively followed up. A multivariable logistic regression model was built using ETV success at 6 months as the outcome. The model was derived on 70% of the sample (training set) and validated on the remaining 30% (validation set). Endoscopic third ventriculostomy was attempted in 1406 patients. Of these, 427 were lost to follow-up prior to 6 months. In the remaining 979 patients, the ETV was aborted in 281 due to poor anatomy/visibility and in 310 the ETV failed during the first 6 months. Therefore, a total of 388 of 979 (39.6% and [55.6% of completed ETVs]) procedures were successful at 6 months. The mean age at ETV was 12.6 months, and 57.8% of cases were postinfectious in origin. The authors' logistic regression model contained the following significant variables: patient age at ETV, cause of hydrocephalus, and whether choroid plexus cauterization was performed. In the training set (676 patients) and validation set (303 patients), the model was able to accurately predict the probability of successful ETV (Hosmer-Lemeshow p value > 0.60 and C statistic > 0.70). The authors developed the simplified CCHU ETV Success Score that can be used in the field to predict the probability of ETV success. The authors' model will allow clinicians to accurately identify children with a good chance of successful outcome with ETV, taking into account the unique characteristics and circumstances of the Ugandan population.


A common genetic variant within SCN10A modulates cardiac SCN5A expression.
Variants in SCN10A, which encodes a voltage-gated sodium channel, are associated with alterations of cardiac conduction parameters and the cardiac rhythm disorder Brugada syndrome; however, it is unclear how SCN10A variants promote dysfunctional cardiac conduction. Here we showed by high-resolution 4C-seq analysis of the Scn10a-Scn5a locus in murine heart tissue that a cardiac enhancer located in Scn10a, encompassing SCN10A functional variant rs6801957, interacts with the promoter of Scn5a, a sodium channel-encoding gene that is critical for cardiac conduction. We observed that SCN5A transcript levels were several orders of magnitude higher than SCN10A transcript levels in both adult human and mouse heart tissue. Analysis of BAC transgenic mouse strains harboring an engineered deletion of the enhancer within Scn10a revealed that the enhancer was essential for Scn5a expression in cardiac tissue. Furthermore, the common SCN10A variant rs6801957 modulated Scn5a expression in the heart. In humans, the SCN10A variant rs6801957, which correlated with slowed conduction, was associated with reduced SCN5A expression. These observations establish a genomic mechanism for how a common genetic variation at SCN10A influences cardiac physiology and predisposes to arrhythmia.


Conserved localization of Pax6 and Pax7 transcripts in the brain of representatives of sarcopterygian vertebrates during development supports homologous brain regionalization.
Many of the genes involved in brain patterning during development are highly conserved in vertebrates and similarities in their expression patterns help to recognize homologous cell types or brain regions. Among these genes, Pax6 and Pax7 are expressed in regionally restricted patterns in the brain and are essential for its development. In the present immunohistochemical study we analyzed the distribution of Pax6 and Pax7 cells in the brain of six representative species of tetrapods and lungfishes, the closest living relatives of tetrapods, at several developmental stages. The distribution patterns of these transcription factors were largely comparable across species. In all species only Pax6 was expressed in the telencephalon, including the olfactory bulbs, septum, striatum, and amygdaloid complex. In the diencephalon, Pax6 and Pax7 were distinct in the alar and basal parts, mainly in prosomeres 1 and 3. Pax7 specifically labeled cells in the optic tectum (superior colliculus) and Pax6, but not Pax7, cells were found in the tegmentum. Pax6 was found in most granule cells of the cerebellum and Pax7 labeling was detected in cells of the ventricular zone of the rostral alar plate and in migrated cells in the basal plate, including the griseum centrale and the interpeduncular nucleus. Caudally, Pax6 cells formed a column, whereas the ventricular zone of the alar plate expressed Pax7. Since the observed Pax6 and Pax7 expression patterns are largely conserved they can be used to identify subdivisions in the brain across vertebrates that are not clearly discernible with classical techniques.


The PsbW protein stabilizes the supramolecular organization of photosystem II in higher plants.
PsbW, a 6.1-kDa low-molecular-weight protein, is exclusive to photosynthetic eukaryotes, and associates with the photosystem II (PSII) protein complex. In vivo and in vitro comparison of Arabidopsis thaliana wild-type plants with T-DNA insertion knock-out mutants completely lacking the PsbW protein, or with antisense inhibition plants exhibiting decreased levels of PsbW, demonstrated that the loss of PsbW destabilizes the supramolecular organization of PSII. No PSII-LHCII supercomplexes could be detected or isolated in the absence of the PsbW protein. These changes in macro-organization were accompanied by a minor decrease in the chlorophyll fluorescence parameter F(V) /F(M) , a strongly decreased PSII core protein phosphorylation and a modification of the redox state of the plastoquinone (PQ) pool in dark-adapted leaves. In addition, the absence of PsbW protein led to faster redox changes in the PQ pool, i.e. transitions from state 1 to state 2, as measured by changes in stationary fluorescence (F(S) ) kinetics, compared with the wild type. Despite these dramatic effects on macromolecular structure, the transgenic plants exhibited no significant phenotype under normal growth conditions. We suggest that the PsbW protein is located close to the minor antenna of the PSII complex, and is important for the contact and stability between several PSII-LHCII supercomplexes.


Antitumor and antioxidant activity of Polyalthia longifolia stem bark ethanol extract.
In the present study, the ethanol extract of stem bark of Polyalthia longifolia Benth. and Hook (Annonaceae) was screened for its in vitro and in vivo antitumor activity. In vitro cytotoxicity of P. longifolia extract was assessed in murine cancer cells and in human cancer cells by Trypan blue exclusion assay and MTT assay, respectively. P. longifolia extract showed concentration-dependent cytotoxicity in Ehrlich's ascites carcinoma (EAC) and Dalton's ascites lymphoma (DLA) cells with IC50 values of 45.77 and 52.52 microg/mL, respectively. In the MTT assay, the IC50 values of P. longifolia extract against HeLa and MCF-7 cells were 25.24 and 50.49 microg/mL, respectively. In vivo antitumor activity against Ehrlich's ascites tumor and Dalton's solid tumor models was assessed by administering 50 and 100 mg/kg of P. longifolia extract, i.p., for 7 consecutive days. P. longifolia extract, at a dose of 100 mg/kg, significantly enhanced mean survival time (MST) and marginally improved hematological parameters when compared to EAC control mice. And the same dose significantly reduced the tumor volume as compared to control DLA inoculated mice. Positive control, cisplatin (3.5 mg/kg, i.p., single dose), significantly enhanced MST and improved hematological parameters when compared to EAC and significantly reduced the tumor volume when compared to DLA control. In vitro antioxidant potential of P. longifolia extract was also determined owing to the role of reactive oxygen species in tumor initiation and progression. P. longifolia extract scavenged DPPH radicals, reduced ferric ions and inhibited lipid peroxidation with IC50 values of 18.14, 155.41 and 73.33 microg/mL, respectively.


Octanoyl-homoserine lactone is the cognate signal for Burkholderia mallei BmaR1-BmaI1 quorum sensing.
Acyl-homoserine lactones (HSLs) serve as quorum-sensing signals for many Proteobacteria. Members of the LuxI family of signal generators catalyze the production of acyl-HSLs, which bind to a cognate receptor in the LuxR family of transcription factors. The obligate animal pathogen Burkholderia mallei produces several acyl-HSLs, and the B. mallei genome has four luxR and two luxI homologs, each of which has been established as a virulence factor. To begin to delineate the relevant acyl-HSL signals for B. mallei LuxR homologs, we analyzed the BmaR1-BmaI1 system. A comparison of acyl-HSL profiles from B. mallei ATCC 23344 and a B. mallei bmaI1 mutant indicates that octanoyl-HSL synthesis is BmaI1 dependent. Furthermore, octanoyl-HSL is the predominant acyl-HSL produced by BmaI1 in recombinant Escherichia coli. The synthesis of soluble BmaR1 in recombinant E. coli requires octanoyl-HSL or decanoyl-HSL. Insoluble aggregates of BmaR1 are produced in the presence of other acyl-HSLs and in the absence of acyl-HSLs. The bmaI1 promoter is activated by BmaR1 and octanoyl-HSL, and a 20-bp inverted repeat in the bmaI1 promoter is required for bmaI1 activation. Purified BmaR1 binds to this promoter region. These findings implicate octanoyl-HSL as the signal for BmaR1-BmaI1 quorum sensing and show that octanoyl-HSL and BmaR1 activate bmaI1 transcription.


The Influence of Smoking Status on the Health Profiles of Older Chinese American Men.
To examine the influence of smoking status on the health profiles of community-dwelling older Chinese American men in the greater Chicago, IL, area. This study utilized a cross-sectional study design to analyze data obtained from the larger Population Study of Chinese Elderly in Chicago (PINE). A population-based study conducted in Chicago. Baseline data from Chinese American men who participated in PINE (N = 1492). Demographic characteristics measured included age, education years, marital status, income, health insurance coverage, and smoking pack-years. Self-reported smoking status included never smoker, current smoker, and former smoker. Health profile indicators included perceived health status, past 12-month changes in health, chronic medical conditions (heart diseases, stroke, cancer, diabetes, hypertension, high cholesterol, thyroid disease, and osteoarthritis), quality of life, and depression and anxiety. The mean age of the study sample was 72.5 years. Of the sample, 65% reported a smoking history, with 25.1% current smokers and 40.1% former smokers. Current smokers were younger, less educated, and uninsured. Former smokers had the poorest overall health profiles. Compared to former smokers, current smokers were less likely to have heart disease (odds ratio [OR] = 0.59; 95% confidence interval [CI] = 0.39-0.90), hypertension (OR = 0.54; 95% CI = 0.41-0.72), high cholesterol (OR = 0.74; 95% CI = 0.56-0.99), thyroid disease (OR = 0.44; 95% CI = 0.21-0.90), depression (rate ratio [RR] = 0.76; 95% CI = 0.58-0.99), and anxiety (RR = 0.72; 95% CI = 0.59-0.89), and they had fewer overall chronic medical conditions (RR = 0.79; 95% CI = 0.70-0.88) after controlling for demographic factors and smoking pack-year history. Compared to never smokers, former and current smokers reported poorer self-rated health (OR = 1.58; 95% CI = 1.11-2.26) and lower perceived quality of life (OR = 2.11; 95% CI = 1.04-4.29). Consistent with prior research, smoking rates were elevated among this sample of older Chinese men. Counter to study hypotheses, former smokers had worse overall health. Study findings suggest the need for health promotion interventions for both current and former smokers. J Am Geriatr Soc 67:S577-S583, 2019.


Asynchronous binaural spatial audition sensor with 2 × 64 × 4 channel output.
This paper proposes an integrated event-based binaural silicon cochlea system aimed at efficient spatial audition and auditory scene analysis. The cochlea chip has a matched pair of digitally-calibrated 64-stage cascaded analog second-order filter banks with 512 pulse-frequency modulated (PFM) address-event representation (AER) outputs. The quality factors (Qs) of channels are individually adjusted by local DACs. The 2P4M 0.35 um CMOS chip consumes an average power of 14 mW including its integrated microphone preamplifiers and biasing circuits. Typical speech data rates are 10 k to 100 k events per second (eps) with peak output rates of 10 Meps. The event timing jitter is 2 us for a 250 mVpp input. It is shown that the computational cost of an event-driven source localization application can be up to 40 times lower when compared to a conventional cross-correlation approach.


The X-linked retinitis pigmentosa protein RP2 facilitates G protein traffic.
The X-linked retinitis pigmentosa protein RP2 is a GTPase activating protein (GAP) for the small GTPase Arl3 and both proteins are implicated in the traffic of proteins to the primary cilia. Here, we show that RP2 can facilitate the traffic of the Gβ subunit of transducin (Gβ1). Glutathione S-transferase (GST)-RP2 pulled down Gβ from retinal lysates and the interaction was specific to Gβ1, as Gβ3 or Gβ5L did not bind RP2. RP2 did not appear to interact with the Gβ:Gγ heterodimer, in contrast Gγ1 competed with RP2 for Gβ binding. Overexpression of Gβ1 in SK-N-SH cells led to a cytoplasmic accumulation of Gβ1, while co-expression of RP2 or Gγ1 with Gβ1 restored membrane association of Gβ1. Furthermore, RP2 small interfering RNA in ARPE19 cells resulted in a reduction in Gβ1 membrane association that was rescued by Gγ1 overexpression. The interaction of RP2 with Gβ1 required RP2 N-terminal myristolyation and the co-factor C (TBCC) homology domain. The interaction was also disrupted by the pathogenic mutation R118H, which blocks Arl3 GAP activity. Interestingly, Arl3-Q71L competed with Gβ1 for RP2 binding, suggesting that Arl3-GTP binding by RP2 would release Gβ1. RP2 also stimulated the association of Gβ1 with Rab11 vesicles. Collectively, the data support a role for RP2 in facilitating the membrane association and traffic of Gβ1, potentially prior to the formation of the obligate Gβ:Gγ heterodimer. Combined with other recent evidence, this suggests that RP2 may co-operate with Arl3 and its effectors in the cilia-associated traffic of G proteins.


Linear coding of voice onset time.
Voice onset time (VOT) provides an important auditory cue for recognizing spoken consonant-vowel syllables. Although changes in the neuromagnetic response to consonant-vowel syllables with different VOT have been examined, such experiments have only manipulated VOT with respect to voicing. We utilized the characteristics of a previously developed asymmetric VOT continuum [Liederman, J., Frye, R. E., McGraw Fisher, J., Greenwood, K., & Alexander, R. A temporally dynamic contextual effect that disrupts voice onset time discrimination of rapidly successive stimuli. Psychonomic Bulletin and Review, 12, 380-386, 2005] to determine if changes in the prominent M100 neuromagnetic response were linearly modulated by VOT. Eight right-handed, English-speaking, normally developing participants performed a VOT discrimination task during a whole-head neuromagnetic recording. The M100 was identified in the gradiometers overlying the right and left temporal cortices and single dipoles were fit to each M100 waveform. A repeated measures analysis of variance with post hoc contrast test for linear trend was used to determine whether characteristics of the M100 were linearly modulated by VOT. The morphology of the M100 gradiometer waveform and the peak latency of the dipole waveform were linearly modulated by VOT. This modulation was much greater in the left, as compared to the right, hemisphere. The M100 dipole moved in a linear fashion as VOT increased in both hemispheres, but along different axes in each hemisphere. This study suggests that VOT may linearly modulate characteristics of the M100, predominately in the left hemisphere, and suggests that the VOT of consonant-vowel syllables, instead of, or in addition to, voicing, should be examined in future experiments.


Nanoscale three-dimensional single particle tracking.
Single particle tracking (SPT) in biological systems is a quickly growing field. Many new technologies are being developed providing new tracking capabilities, which also lead to higher demands and expectations for SPT. Following a single biomolecule as it performs its function provides quantitative mechanistic information that cannot be obtained in classical ensemble methods. From the 3D trajectory, information is available over the diffusional behavior of the particle and precise position information can also be used to elucidate interactions of the tracked particle with its surroundings. Thus, three-dimensional (3D) SPT is a very valuable tool for investigating cellular processes. This review presents recent progress in 3D SPT, from image-based techniques toward more sophisticated feedback approaches. We focus mainly on the feedback technique known as orbital tracking. We present here a modified version of the original orbital tracking in which the intensities from two z-planes are simultaneously measured allowing a concomitant wide-field imaging. The system can track single particles with a precision down to 5 nm in the x-y plane and 7 nm in the axial direction. The capabilities of the system are demonstrated using single virus tracing to follow the infection pathway of Prototype Foamy Virus in living cells.


Use of birth certificates to examine maternal occupational exposures and autism spectrum disorders in offspring.
The continuing rise in the prevalence of autism spectrum disorders has led to heightened interest in the role of nongenetic factors, including exogenous exposures, but little research has been conducted. To explore a possible role in autism etiology, we used data available from our prior studies to examine potential occupational exposures, as these may occur at higher levels than environmental exposures. Parental occupation was obtained from birth certificates for 284 children with autism and 659 controls, born in 1994 in the San Francisco Bay Area. Self-reported occupation and industry were coded into eight exposure/chemical groups based on potential neurotoxicity or reprotoxicity by a board-certified physician in occupational medicine and an industrial hygienist blinded to case-control status. Mothers of autistic children were twice as likely to work in occupations considered exposed (14.4%) as mothers of controls (7.2%) (adjusted odds ratio [AOR] 2.3 [95% confidence interval {CI} 1.3-4.2]). The exposure categories of the greatest frequency among case mothers were exhaust and combustion products (AOR = 12.0 [95% CI 1.4-104.6]) and disinfectants (AOR = 4.0 [95% CI 1.4-12.0]). Paternal occupational exposure was not associated with autism, potentially consistent with a direct in-utero exposure effect. There are several limitations of this hypothesis-generating study, including lack of detail on workplace and job duties, leading to possible misclassification and low proportion exposed. However, this misclassification would not be biased by case-control status and is unlikely to explain the associations we did find, suggesting that further research on exogenous exposures may yield useful etiologic clues.


Cardiac resynchronization therapy and phase resetting of the sinoatrial node: a conjecture.
Congestive heart failure is a severe chronic disease often associated with disorders that alter the mechanisms of excitation-contraction coupling that may result in an asynchronous left ventricular motion which may further impair the ability of the failing heart to eject blood. In recent years a therapeutic approach to resynchronize the ventricles (cardiac resynchronization therapy, CRT) has been performed through the use of a pacemaker device able to provide atrial-based biventricular stimulation. Atrial lead senses the spontaneous occurrence of cells depolarization and sends the information to the generator which, in turn, after a settled delay [atrioventricular (AV) delay], sends electrical impulses to both ventricles to stimulate their synchronous contraction. Recent studies performed on heart rate behavior of chronically implanted patients at different epochs after implantation have shown that CRT can lead to sustained overall improvement of heart function with a reduction in morbidity and mortality. At this moment, however, there are no studies about CRT effects on spontaneous heart activity of chronically implanted patients. We performed an experimental study in which the electrocardiographic signal of five subjects under chronic CRT was recorded during the activity of the pacemaker programmed at different AV delays and under spontaneous cardiac activity after pacemaker deactivation. The different behavior of heart rate variability during pacemaker activity and after pacemaker deactivation suggested the hypothesis of a phase resetting mechanism induced by the pacemaker stimulus on the sinoatrial (SA) node, a phenomenon already known in literature for aggregate of cardiac cells, but still unexplored in vivo. The constraints imposed by the nature of our study (in vivo tests) made it impossible to plan an experiment to prove our hypothesis directly. We therefore considered the best attainable result would be to prove the accordance of our data to the conjecture through the use of models and physical considerations. We first used the data of literature on far-field effects of cardiac defibrillators to prove that the pacemaker impulses delivered to the two ventricles were able to induce modifications in membrane voltage at the level of the SA node. To simulate a phase resetting mechanism of the SA node, we used a Van der Pol modified model to allow the possibility of changing the refractory period and the firing frequency of the cells separately. With appropriate parameters of the model we reproduced phase response curves that can account for our experimental data. Furthermore, the simulated curves closely resemble the functional form proposed in literature for perturbed aggregate of cardiac cells. Despite the small sample of subjects investigated and the limited number of ECG recordings at different AV delays, we think we have proved the plausibility of the proposed conjecture.


Glucose-induced alterations of cytosolic free calcium in cultured rat tail artery vascular smooth muscle cells.
We have previously suggested that hyperglycemia per se may contribute to diabetic hypertensive and vascular disease by altering cellular ion content. To more directly investigate the potential role of glucose in this process, we measured cytosolic free calcium in primary cultures of vascular smooth muscle cells isolated from Sprague-Dawley rat tail artery before and after incubation with 5 (basal), 10, 15, and 20 mM glucose. Glucose significantly elevated cytosolic free calcium in a dose- and time-dependent manner, from 110.0 +/- 5.4 to 124.5 +/- 9.0, 192.7 +/- 20.4, and 228.4 +/- 21.9 nM at 5, 10, 15, and 20 mM glucose concentrations, respectively. This glucose-induced cytosolic free calcium elevation was also specific, no change being observed after incubation with equivalent concentrations of L-glucose or mannitol. This glucose effect was also dependent on extracellular calcium and pH, since these calcium changes were inhibited in an acidotic or a calcium-free medium, or by the competitive calcium antagonist lanthanum. We conclude that ambient glucose concentrations within clinically observed limits may alter cellular calcium ion homeostasis in vascular smooth muscle cells. We suggest that these cellular ionic effects of hyperglycemia may underlie the predisposition to hypertension and vascular diseases among diabetic subjects and/or those with impaired glucose tolerance.


Changes over time in the incidence and case-fatality rates of primary ventricular fibrillation complicating acute myocardial infarction: perspectives from the Worcester Heart Attack Study.
Limited population-based data are available that describe temporal and recent trends in the incidence and case-fatality rates in patients with primary ventricular fibrillation (VF) complicating acute myocardial infarction (AMI). The purpose of this study was to describe changes over a 22-year period (1975 through 1997) in the incidence and hospital case-fatality rates of primary VF complicating AMI from a multihospital, community-wide perspective. This was an observational study of metropolitan Worcester residents hospitalized with a validated uncomplicated AMI (n = 5020) in all hospitals in the Worcester, Massachusetts, metropolitan area (1990 census population = 437,000) during 11 1-year periods between 1975 and 1997. The overall incidence rate of primary VF complicating AMI was 4.7%. The crude as well as multivariable adjusted odds of the development of VF did not change significantly over the 22-year period under study. The overall in-hospital case-fatality rate of patients with primary VF was 44%, which was significantly greater in comparison with AMI patients in whom VF did not develop (5%). Hospital mortality rates associated with primary VF declined over time. Improved survival was observed in patients who had primary VF in the 1990s after adjusting for potential prognostic confounders. The results of this community-wide study failed to indicate changes over time in the incidence rates of primary VF in patients hospitalized with AMI between 1975 and 1997. On the other hand, hospital death rates in patients with primary VF have shown encouraging declines during more recent periods. These mortality trends are likely to be the results of improvements in the treatment and more careful surveillance of patients with AMI.


Integration of women veterans into VA quality improvement research efforts: what researchers need to know.
The Department of Veterans Affairs (VA) and other federal agencies require funded researchers to include women in their studies. Historically, many researchers have indicated they will include women in proportion to their VA representation or pointed to their numerical minority as justification for exclusion. However, women's participation in the military-currently 14% of active military-is rapidly changing veteran demographics, with women among the fastest growing segments of new VA users. These changes will require researchers to meet the challenge of finding ways to adequately represent women veterans for meaningful analysis. We describe women veterans' health and health-care use, note how VA care is organized to meet their needs, report gender differences in quality, highlight national plans for women veterans' quality improvement, and discuss VA women's health research. We then discuss challenges and potential solutions for increasing representation of women veterans in VA research, including steps for implementation research.


Lack of association between folate receptor autoantibodies and conotruncal congenital heart defects.
Conotruncal cardiac defects are partially prevented by maternal folic acid supplementation. However, the biochemical mechanism is unknown. Maternal autoantibodies to folate receptors, previously associated with increased risk for neural tube defects, also may account for this effect. This study aimed to examine the titers of folate receptor-blocking autoantibodies in mothers of children with conotruncal congenital heart defects and to compare them with those in the general population. Serum samples were obtained from 22 women whose pregnancies were complicated by conotruncal congenital heart malformations. Groups of samples were analyzed for autoantibodies against [(3)H] folic acid-labeled folate receptors, quantitative amounts of immunoglobulin G (IgG) and IgM autoantibodies to the folate receptor, and for ability to block-bind folic acid to receptors. No elevated levels of antibodies binding to [(3)H] folic acid-labeled folate receptors were found. No difference was found in antifolate receptor alpha-IgG or IgM median levels between cases (261 vs. 240 μg/mL) and control subjects (773 vs. 924 μg/mL). There was no increased blocking of folic acid binding between cases [0.69 ng/mL; 95 % confidence interval (CI), 0.006-0.01] and control subjects (0.69 ng/mL; 95 % CI, 0.003-0.013). Although epidemiologic evidence suggests that periconceptual folic acid may prevent many conotruncal congenital heart defects, the current study suggests that this effect is unlikely to be explained by the presence of maternal autoantibodies to folate receptor. These data suggest that a strategy of screening women for such autoantibodies will not identify a high-risk group of women to target for supplemental folic acid to prevent congenital heart defects.


Susceptibility to Ebbinghaus and Müller-Lyer illusions in autistic children: a comparison of three different methods.
Studies reporting altered susceptibility to visual illusions in autistic individuals compared to that typically developing individuals have been taken to reflect differences in perception (e.g. reduced global processing), but could instead reflect differences in higher-level decision-making strategies. We measured susceptibility to two contextual illusions (Ebbinghaus, Müller-Lyer) in autistic children aged 6-14 years and typically developing children matched in age and non-verbal ability using three methods. In experiment 1, we used a new two-alternative-forced-choice method with a roving pedestal designed to minimise cognitive biases. Here, children judged which of two comparison stimuli was most similar in size to a reference stimulus. In experiments 2 and 3, we used methods previously used with autistic populations. In experiment 2, children judged whether stimuli were the 'same' or 'different', and in experiment 3, we used a method-of-adjustment task. Across all tasks, autistic children were equally susceptible to the Ebbinghaus illusion as typically developing children. Autistic children showed a heightened susceptibility to the Müller-Lyer illusion, but only in the method-of-adjustment task. This result may reflect differences in decisional criteria. Our results are inconsistent with theories proposing reduced contextual integration in autism and suggest that previous reports of altered susceptibility to illusions may arise from differences in decision-making, rather than differences in perception per se. Our findings help to elucidate the underlying reasons for atypical responses to perceptual illusions in autism and call for the use of methods that reduce cognitive bias when measuring illusion susceptibility.


The role of photodynamic therapy in overcoming cancer drug resistance.
Many modalities of cancer therapy induce mechanisms of treatment resistance and escape pathways during chronic treatments, including photodynamic therapy (PDT). It is conceivable that resistance induced by one treatment might be overcome by another treatment. Emerging evidence suggests that the unique mechanisms of tumor cell and microenvironment damage produced by PDT could be utilized to overcome cancer drug resistance, to mitigate the compensatory induction of survival pathways and even to re-sensitize resistant cells to standard therapies. Approaches that capture the unique features of PDT, therefore, offer promising factors for increasing the efficacy of a broad range of therapeutic modalities. Here, we highlight key preclinical findings utilizing PDT to overcome classical drug resistance or escape pathways and thus enhance the efficacy of many pharmaceuticals, possibly explaining the clinical observations of the PDT response to otherwise treatment-resistant diseases. With the development of nanotechnology, it is possible that light activation may be used not only to damage and sensitize tumors but also to enable controlled drug release to inhibit escape pathways that may lead to resistance or cell proliferation.


Phototransformable fluorescent proteins: which one for which application?
In these last two decades , fluorescent proteins (FPs) have become highly valued imaging tools for cell biology, owing to their compatibility with living samples, their low levels of invasiveness and the possibility to specifically fuse them to a variety of proteins of interest. Remarkably, the recent development of phototransformable fluorescent proteins (PTFPs) has made it possible to conceive optical imaging experiments that were unimaginable only a few years ago. For example, it is nowadays possible to monitor intra- or intercellular trafficking, to optically individualize single cells in tissues or to observe single molecules in live cells. The tagging specificity brought by these genetically encoded highlighters leads to constant progress in the engineering of increasingly powerful, versatile and non-cytotoxic FPs. This review is focused on the recent developments of PTFPs and highlights their contribution to studies within cells, tissues and even living organisms. The aspects of single-molecule localization microscopy, intracellular tracking of photoactivated molecules, applications of PTFPs in biotechnology/optobiology and complementarities between PTFPs and other microscopy techniques are particularly discussed.


Comparison of full-length sequences of interferon-sensitive and resistant hepatitis C virus 1b. Sensitivity to interferon is conferred by amino acid substitutions in the NS5A region.
We have previously demonstrated that sensitivity to interferon is different among hepatitis C virus (HCV) quasispecies simultaneously detected in same individuals and that interferon-resistant HCV quasispecies are selected during the treatment. To determine the genetic basis of their resistance to interferon, HCV genotype-1b was obtained from serum of three patients before and during interferon therapy, and their full-length nucleotide and deduced amino acid sequences were determined. Comparison of the pairs of interferon-resistant and interferon-sensitive HCV isolates in respective individuals demonstrated clusters of amino acid differences in the COOH-terminal half of the NS5A region (codon 2154-2383), which contained a common unique amino acid difference at codon 2218. Additional sequence data of the COOH-terminal half of the NS5A region obtained from six interferon-resistant and nine interferon-sensitive HCV confirmed the exclusive existence of missense mutations in a 40 amino acid stretch of the NS5A region around codon 2218 (from codon 2209 to 2248) in interferon-sensitive HCV. On the other hand, this region of interferon-resistant HCV was identical to that of prototype HCV genotype-1b (HCV-J, HCV-JTa, or HC-J4). We designated this region as the interferon sensitivity determining region. Thus, HCV genotype-1b with the prototype interferon sensitivity determining region appears to be interferon-resistant strains. The specific nature of these mutations might make it possible to predict prognostic effects of interferon treatment.


Healing Relationships: A Qualitative Study of Healers and Their Clients in Germany.
Background. The aim of this study was to investigate the nature of the relationships between healers and their clients in Germany. Methods. An interdisciplinary research team performed semistructured interviews with healers and clients and participatory observation of healing sessions. All interviews were digitally recorded, transcribed, and analyzed using content analysis. Results. Fifteen healers and sixteen clients were included. The healer-client relationship was described as a profound and unique experience, which brought forth interpersonal and spiritual connections. The healers were seen as role models for healing to occur and support for being connected spiritually. The clients had to be open-minded and responsible. The importance of the healers' empathy was emphasized. Discussion. The relationship between healer and client can be seen as a triangular connection between client, healer, and a transcendent source which is not the case in typical patient-doctor relationships. The spiritual connection is also said to enhance the empathetic understanding of the healer. The personality and a partner-like attitude of the healer supported the client in giving a more positive meaning to his life, in reconnecting to his spirituality, and in taking responsibility. Future studies should address the role of spirituality in health care and the development of enduring healer-client relationships.


Reduced metabotropic glutamate receptor 5 in the Flinders Sensitive Line of rats, an animal model of depression: an autoradiographic study.
Depression is a brain disorder and there is still only a partial understanding of its underlying pathophysiology. Antidepressant medications with a fast onset have not yet been developed. In addition to the monoaminergic systems, the brain glutaminergic system has been implicated in the etiology of depression. Animal studies of depression have gained importance because they permit a more invasive manipulation of the subjects than human studies. In the present study, we measured the densities of the brain regional metabotropic glutaminergic receptor 5 (mGluR5) in the Flinders Sensitive Line (FSL) rat model of depression and two groups of control rats, the Flinders Resistant Line (FRL) and Sprague Dawley (SPD), the parent strain for both the FSL and FRL rats. The FSL rats showed lower densities of mGluR5 in many brain regions compared to either the SPD and/or FRL rats. In addition, the densities in the FRL rats were larger than in the SPD rats, suggesting possible problems in using FRL rats as controls. The presented data suggest that mGluR5 is lower in animal models of depression which could be related to the cognitive and emotional dysfunctions in the FSL rat model of depression and could be relevant to a better understanding of depression in humans.


Comparison of bacterial 16S rRNA variable regions for microbiome surveys of ticks.
Ticks vector diverse pathogenic bacteria that are important to identify in public health and veterinary contexts. Technological advances in high throughput sequencing have given an unprecedented opportunity to comprehensively characterize bacterial associates of ticks, but recent studies have used different 16S rRNA variable regions and sequence read lengths with little consideration of whether they reveal the same bacterial diversity. We compare the effectiveness of bacterial surveys using three library preparations across nine 16S variable regions and a set of 12 tick specimens (Acari: Ixodidae). We identify the bacterial assemblages present in extractions from wild-collected Ixodes scapularis from two regions of Canada, and provide the first microbiome survey for Ixodes angustus. Four bacterial families accounted for most diversity, with Rickettsiaceae being replaced as most common by Enterobacteriaceae or Pseudomonadaceae in some I. scapularis, and Francisellaceae being most abundant in I. angustus. The commercially available Ion 16S kit, based on 6 amplicons representing 16S regions V2, V3, V4, V67, V8 and V9, gave the most comprehensive estimates of bacterial families, with the Ion V4 amplicon generally giving the highest estimated diversity. Sequencing of the V4 amplicon by the MR DNA commercial service also provided cost effective assays of tick microbiomes that were within the range of results from the Ion 16S kit. Subtraction of the number of reads found in an extraction control sample lowered estimates of the number of bacterial families by approximately half. Our study shows that diversity patterns obtained from 16S microbiome surveys depend on the amplicon and protocol used, demonstrating that more than one marker region is needed to provide reliable inferences.


Controlled production of sub-millimeter liquid core hydrogel capsules for parallelized 3D cell culture.
Liquid core capsules having a hydrogel membrane are becoming a versatile tool for three-dimensional culture of micro-organisms and mammalian cells. Making sub-millimeter capsules at a high rate, via the breakup of a compound jet in air, opens the way to high-throughput screening applications. However, control of the capsule size monodispersity, especially required for quantitative bioassays, was still lacking. Here, we report how the understanding of the underlying hydrodynamic instabilities that occur during the process can lead to calibrated core-shell bioreactors. The requirements are: i) damping the shear layer instability that develops inside the injector arising from the co-annular flow configuration of liquid phases having contrasting viscoelastic properties; ii) controlling the capillary instability of the compound jet by superposing a harmonic perturbation onto the shell flow; iii) avoiding coalescence of drops during jet fragmentation as well as during drop flight towards the gelling bath; iv) ensuring proper engulfment of the compound drops into the gelling bath for building a closed hydrogel shell. We end up with the creation of numerous identical compartments in which cells are able to form multicellular aggregates, namely spheroids. In addition, we implement an intermediate composite hydrogel layer, composed of alginate and collagen, allowing cell adhesion and thus the formation of epithelia or monolayers of cells.


Multivariate analyses of Burkholderia species in soil: effect of crop and land use history.
The assessment of Burkholderia diversity in agricultural areas is important considering the potential use of this genus for agronomic and environmental applications. Therefore, the aim of this work was to ascertain how plant species and land use management drive the diversity of the genus Burkholderia. In a greenhouse experiment, different crops, i.e., maize, oat, barley, and grass, were planted in pots containing soils with different land use histories, i.e., maize monoculture, crop rotation, and permanent grassland, for three consecutive growth cycles. The diversity of Burkholderia spp. in the rhizosphere soil was assessed by genus-specific PCR-denaturing gradient gel electrophoresis (DGGE) and analyzed by canonical correspondence analysis (CCA). CCA ordination plots showed that previous land use was the main factor affecting the composition of the Burkholderia community. Although most variation in the Burkholderia community structure was observed between the permanent grassland and agricultural areas, differences between the crop rotation and maize monoculture groups were also observed. Plant species affected Burkholderia community structure to a lesser extent than did land use history. Similarities were observed between Burkholderia populations associated with maize and grass, on the one hand, and between those associated with barley and oat, on the other hand. Additionally, CCA ordination plots demonstrated that these two groups (maize/grass versus barley/oat) had a negative correlation. The identification of bands from the DGGE patterns demonstrated that the species correlated with the environmental variables were mainly affiliated with Burkholderia species that are commonly isolated from soil, in particular Burkholderia glathei, B. caledonica, B. hospita, and B. caribiensis.


The impact of parent socio-economic status on executive functioning and cortical morphology in individuals with schizophrenia and healthy controls.
Relatively lower executive functioning is characteristic of individuals with schizophrenia. As low socio-economic status (SES) early in life (i.e. parent SES) has been linked with lower executive skills in healthy children, we hypothesized that parental SES (pSES) would be more strongly related to executive functioning in individuals with schizophrenia than in controls and have a greater impact on prefrontal cortical morphology. Healthy controls (n = 125) and individuals with schizophrenia (n = 102) completed tests assessing executive functioning and intelligence. The groups were matched on pSES, which was evaluated with the Hollingshead-Redlich scale. A principal components analysis (PCA) was conducted on 10 variables from six executive tests, yielding three specific components (fluency, planning and response inhibition). Voxel-based morphometry (VBM) was used to evaluate effects of pSES on gray matter (GM) concentration. Lower pSES was associated with lower scores across the three executive functioning components, and a significant group by pSES interaction was observed such that low pSES, in particular, affected individuals with schizophrenia. These effects remained significant when intellectual ability, education and self-SES (sSES) were added as covariates. VBM revealed that lower pSES was associated with reduced GM volume in several anterior brain regions, especially the superior frontal gyrus, in patients but not in controls. These findings suggest that individuals with schizophrenia may be particularly vulnerable to the adverse impact of low pSES, in terms of both lower executive skills and reduced anterior GM volumes.


Parathyroid hormone deficiency after total thyroidectomy: incidence and time.
Parathyroid hormone (PTH) deficiency or hypoparathyroidism after total thyroidectomy is not an uncommon postoperative complication. Patients who have PTH deficiency will develop profound hypocalcemia if not properly treated with oral calcium supplementation and activated vitamin D (1,25-dihydroxycholecalciferol or calcitriol). However, there is little published on the long-term outcomes of these patients. The aim of this study was to determine the incidence of PTH deficiency and the time course to resolution after total thyroidectomy. We identified 271 consecutive patients who underwent total thyroidectomy from January 2006 to December 2008. All patients had serum PTH levels tested 4 h after surgery and the morning after surgery. Patients were diagnosed with PTH deficiency if their serum PTH was <10 pg/mL. The outcomes of patients with PTH deficiency (group 1) were then compared with patients who did not have PTH deficiency (group 2). Patients in group 1 were evaluated for parathyroid function by measuring serum PTH levels as well as documenting usage of supplemental calcium and 1,25-dihydroxycholecalciferol. Of the 271 patients, 33 (12%) were found to have PTH deficiency. In comparing PTH deficient patients (group 1) with patients in group 2, there were no differences in age, gender, thyroid pathology, the incidence of thyroiditis, or other factors that would predict hypoparathyroidism. Twenty-four patients (73%) had recovery of their PTH levels to > or =10 pg/mL at their 1 wk follow-up appointment, while 9 (27%) patients still had PTH levels <10 pg/mL. With long term follow-up, 27 (82%) patients had recovered with a PTH level of > or = 10 pg/mL, while 6 (18%) patients had a serum PTH level <10 pg/mL. However, three of the 33 patients in group 1 (9%) required long-term 1,25-dihydroxycholecalciferol, but only two of these patients had undetectable PTH levels. Thus, the overall rate of hypocalemia requiring 1,25-dihydroxycholecalciferol was <1% (two of 271 total patients). We concluded that approximately 12% (33 of 271) of patients undergoing total thyroidectomy will develop PTH deficiency. Of the PTH deficient patients, 73% will return to normal parathyroid function within 1 wk of surgery. Furthermore, 82% of these PTH deficient patients will return to normal parathyroid function with long-term follow-up. Less than 1% (two of 271) of patients undergoing total thyroidectomy will require 1,25-dihydroxycholecalciferol for long-term hypocalcemia.


Reduced GSK-3beta mRNA levels in postmortem dorsolateral prefrontal cortex of schizophrenic patients.
Glycogen Synthase Kinase (GSK)-3 is a ubiquitous serine/threonine protein kinase highly abundant in brain which plays a key role in neural development and neuron survival. We have previously reported that GSK-3beta protein levels and GSK-3 activity are reduced by over 40% in postmortem prefrontal cortex of schizophrenic patients compared to patients with bipolar illness, unipolar depression and to normal controls, and Emamian et al. have recently presented convergent evidence for impaired AKT1-GSK-3beta signaling in schizophrenia. Using specimens of dorsolateral prefrontal cortex tissue obtained from The Stanley Medical Research Institute's Brain Collection, from the same subjects used previously, we now show that GSK-3beta, but not GSK-3alpha, mRNA levels are 36% lower in the patients with schizophrenia compared to all other comparison groups. The present study lends further support to the finding of low GSK-3beta levels in schizophrenia and extends this observation by suggesting that the decrease in GSK-3beta may be due to reduced protein synthesis possibly due to altered transcriptional drive of the GSK-3beta gene.


Profile and survival of tongue cancer patients in "Dharmais" Cancer Hospital, Jakarta.
Tongue cancer is still a major health problem in most developing countries around the world. Statistics shown the number of tongue cancers, especially in early age, to be increasing, with poor survival. To analyze the characteristic profile of tongue cancer patients in Indonesia as well as the survival rate. A cross sectional study was conducted in Dharmais National Cancer Hospital by collecting general, clinical, and survival data of tongue cancer patients from medical records for January 2009 to April 2012. Tongue cancer incidence increased year by year. The average age of tongue cancer patients was 47.5 years, and males predominated, accounting for 64.5% of cases. Most patients presented at an advanced stage (69.6%). The histopathology type was squamous cell carcinoma in the vast majoriy (96.8%). The therapies applied were surgery (45.6%), radiation (63.6%) and chemotherapy (57.6%). The survival rate after one year is 60.6% and after two years was 12.1%. In addition, median survival of tongue cancer patients was 20 months (95% confidence interval 9.07-30.9). The significant factor affecting survival was size of tumor with a hazard ratio of 3.18 (95% CI, 1.02-9.93; p 0.046) for largest versus smallest categories. In each year, the number of tongue cancer incidents in Indonesia is increasing. The age of tongue cancer patients in Indonesia is younger compared to other countries. Moreover, the survival rates are not high.


Team Training of Inter-Professional Students (TTIPS) for improving teamwork.
In surgery, dysfunctional teamwork is perpetuated by a 'silo' mentality modelled by students. Interprofessional education using high-fidelity simulation-based training (SBT) may counteract such modelling. We sought to determine whether SBT of interprofessional student teams (1) changes long-term teamwork attitudes and (2) is an effective form of team training. A quasiexperimental, pre/postintervention comparison design was employed at an academic health sciences institution. High-fidelity simulation-based training of 42 interprofessional teams of third year surgery clerkship medical students and senior undergraduate nursing students was undertaken using a two-scenario format with immediate after action debriefing. Pre/postintervention TeamSTEPPS Teamwork Attitudes questionnaires (5 subscales, 30 items, Likert type) were given to the medical student and undergraduate nursing student classes. Pre/postsession Readiness for Inter-Professional Learning (RIPL; 19 items, Likert type) surveys and postscenario participant-rated and observer-rated Teamwork Assessment Scales (3 subscales, 11 items, Likert type) were given during each training session. Mean TeamSTEPPS Teamwork Attitudes Questionnaire, RIPL and Teamwork Assessment Scales scores were calculated; matched pre/postscore differences and trained versus non-trained TeamSTEPPS Teamwork Attitudes Questionnaire scores were compared using paired t-test or analysis of variance. Both student groups had 10 significantly improved RIPL items as well as TeamSTEPPS Teamwork Attitudes Questionnaire (TTAQ) mutual support subscales. Medical students had a significantly improved TTAQ team structure subscale. Over a simulation-based training session, each observer-rated Teamwork Assessment Scales subscale and two self-rated Teamwork Assessment Scales subscales significantly improved. Trained students had significantly higher TTAQ team structure subscales than non-trained students. Interprofessional education using high-fidelity simulation-based training of students is effective at teaching teamwork, changing interprofessional attitudes and improving long-term teamwork attitudes.


Estimating upper bounds for occupancy and number of manatees in areas potentially affected by oil from the Deepwater Horizon oil spill.
The explosion of the Deepwater Horizon drilling platform created the largest marine oil spill in U.S. history. As part of the Natural Resource Damage Assessment process, we applied an innovative modeling approach to obtain upper estimates for occupancy and for number of manatees in areas potentially affected by the oil spill. Our data consisted of aerial survey counts in waters of the Florida Panhandle, Alabama and Mississippi. Our method, which uses a Bayesian approach, allows for the propagation of uncertainty associated with estimates from empirical data and from the published literature. We illustrate that it is possible to derive estimates of occupancy rate and upper estimates of the number of manatees present at the time of sampling, even when no manatees were observed in our sampled plots during surveys. We estimated that fewer than 2.4% of potentially affected manatee habitat in our Florida study area may have been occupied by manatees. The upper estimate for the number of manatees present in potentially impacted areas (within our study area) was estimated with our model to be 74 (95%CI 46 to 107). This upper estimate for the number of manatees was conditioned on the upper 95%CI value of the occupancy rate. In other words, based on our estimates, it is highly probable that there were 107 or fewer manatees in our study area during the time of our surveys. Because our analyses apply to habitats considered likely manatee habitats, our inference is restricted to these sites and to the time frame of our surveys. Given that manatees may be hard to see during aerial surveys, it was important to account for imperfect detection. The approach that we described can be useful for determining the best allocation of resources for monitoring and conservation.


Internal laryngopyocele presenting as acute airway obstruction.
A laryngopyocele forms when a laryngocele becomes infected and fills with mucopus. We report a case of an internal larngopyocele that presented as airway obstruction in a 34-year-old man; such a presenting sign is exceedingly rare. We also review the anatomy, etiology, and clinical course of the different types of laryngoceles.


Leveraging existing data sets to generate new insights into Alzheimer's disease biology in specific patient subsets.
To generate new insights into the biology of Alzheimer's Disease (AD), we developed methods to combine and reuse a wide variety of existing data sets in new ways. We first identified genes consistently associated with AD in each of four separate expression studies, and confirmed this result using a fifth study. We next developed algorithms to search hundreds of thousands of Gene Expression Omnibus (GEO) data sets, identifying a link between an AD-associated gene (NEUROD6) and gender. We therefore stratified patients by gender along with APOE4 status, and analyzed multiple SNP data sets to identify variants associated with AD. SNPs in either the region of NEUROD6 or SNAP25 were significantly associated with AD, in APOE4+ females and APOE4+ males, respectively. We developed algorithms to search Connectivity Map (CMAP) data for medicines that modulate AD-associated genes, identifying hypotheses that warrant further investigation for treating specific AD patient subsets. In contrast to other methods, this approach focused on integrating multiple gene expression datasets across platforms in order to achieve a robust intersection of disease-affected genes, and then leveraging these results in combination with genetic studies in order to prioritize potential genes for targeted therapy.


Baseline ophthalmic findings in the vitamin E, cataract and age-related maculopathy (VECAT) study.
To describe the methodology of eye examination and the baseline eye characteristics of the Vitamin E, Cataract and Age-Related Maculopathy (VECAT) study participants. A sample of volunteers from an urban area of Melbourne, Australia, were recruited to participate in a randomized, controlled trial investigating the effect of vitamin E on the development of cataract and age-related maculopathy Standardized eye examinations involved clinical assessment, which included Wilmer grading of the lens, digital photography of the lens with Nidek EAS-1000 lens camera and stereo photography of the macular area with the Nidek 3-DX fundus camera. All cases of ophthalmic findings were determined on the basis of pathology in the worse eye. Most eyes were free from abnormalities. The most frequent findings were cataract and age-related macular changes. Nuclear cataract (nuclear opacity grade >2) was present in 4.5%, cortical cataract (cortical opacity grade >2) in 14.3% and posterior subcapsular cataract in 3.0% of participants; in addition, coronary cataract was observed in 13.6%. Soft drusen larger than 125 pm were found in 11.4%, retinal pigment epithelium changes in 9.5%, epiretinal membrane in 6.6% and age-related macular degeneration in 0.5% of participants. Due to the selection criteria, the majority of participants had clear or minor lens changes and/or minor retinal age-related changes. Precise instrumental documentation will allow an accurate assessment of the incidence and dynamics of these changes throughout 4 years of observation.


A novel recurrent chromosomal inversion implicates the homeobox gene Dlx5 in T-cell lymphomas from Lck-Akt2 transgenic mice.
The oncogene v-akt was isolated from a retrovirus that induced murine thymic lymphomas. Transgenic mice expressing a constitutively activated form of the cellular homologue Akt2 specifically in immature T cells develop spontaneous thymic lymphomas. We hypothesized that tumors from these mice might exhibit oncogenic chromosomal rearrangements that cooperate with activated Akt2 in lymphomagenesis. Cytogenetic analysis revealed a recurrent clonal inversion of chromosome 6, inv(6), in thymic lymphomas from multiple transgenic founder lines, including one line in which 15 of 15 primary tumors exhibited this same rearrangement. Combined fluorescence in situ hybridization, PCR, and DNA sequence analyses showed that the distal inv(6) breakpoint resides at the T-cell receptor beta chain locus, Tcrb. The proximal breakpoint maps to a region near a locus comprising the linked homeobox/transcription factor genes Dlx5 and Dlx6. Expression analysis of genes translocated to the vicinity of the Tcrb enhancer revealed that Dlx5 and Dlx6 are overexpressed in tumors exhibiting the inv(6). Experimental overexpression of Dlx5 in mammalian cells resulted in enhanced cell proliferation and increased colony formation, and clonogenic assays revealed cooperativity when both Dlx5 and activated Akt2 were coexpressed. In addition, DLX5, but not DLX6, was found to be abundantly expressed in three of seven human T-cell lymphomas tested. These findings suggest that the Dlx5 can act as an oncogene by cooperating with Akt2 to promote lymphomagenesis.