Reducing non-contact electric arc injuries: an investigation of behavioral and organizational issues.
It is estimated that 5 to 10 arc flash explosions occur in electric equipment every day in the United States. In the mining industry the largest single injury category of electrical injuries are caused by non-contact electrical arcs. This investigation progressed in two phases: (a) 836 Mine Safety and Health Administration (MSHA) reports of electric arcing incidents that occurred over a period of 11 years were reviewed, and (b) personal interviews were conducted with 32 individuals. A theoretical Safe Job Performance Model guided the study. Behavioral dimensions were identified and included the effect of worker experience, judgment and decision-making ability, behavioral and organizational controls, and safety culture. The National Institute for Occupational Safety and Health (NIOSH) conducted an investigation of behavioral components associated with arc flash incidents and developed recommendations for interventions based on findings. This study fills a vacuum in electrical training with a focus on the organizational and behavioral aspects of arc flash incidents. The research is cross-cutting in its scope, in that the results apply not only to mining and construction, but many other industries employing electricians. Although the majority of mine electrical injuries are the results of burns from electrical arcs, few miners are aware that such a hazard exists. A safety training program, which includes a video and an instructor's discussion guide, was developed for electricians based on this study's findings. "Arc Flash Awareness" was released in 2007 (DHHS NIOSH Publication No.2007-116D) and is available through 1-800 CDC INFO. Phone: 1-800 232-4636 or email firstname.lastname@example.com. It is also available from MSHA at firstname.lastname@example.com or 304-256-3257 (DVD-576). Private industry is producing Portuguese and Spanish language translations.


Vandetanib, an inhibitor of VEGF receptor-2 and EGF receptor, suppresses tumor development and improves prognosis of liver cancer in mice.
VEGF, EGF, and TGF-α are expressed in hepatocellular carcinomas (HCC) and play a role in its growth. Vandetanib, a multikinase inhibitor, suppresses the phosphorylation of VEGF receptor 2 (VEGFR-2) and EGF receptor (EGFR). The aim of this study was to clarify the antitumor effect of vandetanib in mouse HCCs. We evaluated the effects of vandetanib on proliferation of human umbilical vein endothelial cells (HUVEC) and three hepatoma cell lines, as well as the phosphorylation of VEGFR-2 and EGFR in these cells. Mice were implanted with hepatoma cells subcutaneously or orthotopically in the liver and treated with 50 or 75 mg/kg vandetanib. We analyzed the effects of treatment on tumor cell proliferation and apoptosis, vessel density, phosphorylation of VEGFR-2 and EGFR, and production of VEGF, TGF-α, and EGF in tumor tissues. Adverse events on vandetanib administration were also investigated. Vandetanib suppressed phosphorylation of VEGFR-2 in HUVECs and EGFR in hepatoma cells and inhibited cell proliferation. In tumor-bearing mice, vandetanib suppressed phosphorylation of VEGFR-2 and EGFR in tumor tissues, significantly reduced tumor vessel density, enhanced tumor cell apoptosis, suppressed tumor growth, improved survival, reduced number of intrahepatic metastases, and upregulated VEGF, TGF-α, and EGF in tumor tissues. Treatment with vandetanib was not associated with serious adverse events, including alanine aminotransferase abnormality, bone marrow suppression, or body weight loss. The antitumor effects of vandetanib in mice suggest that it is a potentially suitable and safe chemotherapeutic agent for HCCs.


Elastic multipole method for describing deformation of infinite two-dimensional solids with circular inclusions.
Elastic materials with holes and inclusions are important in a large variety of contexts ranging from construction material to biological membranes. More recently, they have also been exploited in mechanical metamaterials, where the geometry of highly deformable structures is responsible for their unusual properties, such as negative Poisson's ratio, mechanical cloaking, and tunable phononic band gaps. Understanding how such structures deform in response to applied external loads is thus crucial for designing novel mechanical metamaterials. Here we present a method for predicting the linear response of infinite 2D solid structures with circular holes and inclusions by employing analogies with electrostatics. Just like an external electric field induces polarization (dipoles, quadrupoles, and other multipoles) of conductive and dielectric objects, external stress induces elastic multipoles inside holes and inclusions. Stresses generated by these induced elastic multipoles then lead to interactions between holes and inclusions, which induce additional polarization and thus additional deformation of holes and inclusions. We present a method that expands the induced polarization in a series of elastic multipoles, which systematically takes into account the interactions of inclusions and holes with the external stress field and also between them. The results of our method show good agreement with both linear finite element simulations and experiments.


Evaluating a Human Rights-Based Advocacy Approach to Expanding Access to Pain Medicines and Palliative Care: Global Advocacy and Case Studies from India, Kenya, and Ukraine.
Palliative care has been defined as care that is person-centered and attentive to physical symptoms and psychological, social, and existential distress in patients with severe or life-threatening illness. The identification of access to palliative care and pain treatment as a human rights issue first emerged among palliative care advocates, physicians, and lawyers in the 1990s, with a basis in the right to health and the right to be free from cruel, inhuman, and degrading treatment. Using a case study approach, we evaluate the results of a human rights-based advocacy approach on access to pain medicine and palliative care in India, Kenya, and Ukraine. In each country, human rights advocacy helped raise awareness of the issue, identify structural barriers to care, define government obligations, and contribute to the reform of laws, policies, and practices impeding the availability of palliative care services. In addition, advocacy efforts stimulated civil society engagement and high-level political leadership that fostered the implementation of human rights-based palliative care programs. Globally, access to palliative care was increasingly recognized by human rights bodies and within global health and drug policy organizations as a government obligation central to the right to health.


The nutritional management of hepatic encephalopathy in patients with cirrhosis: International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus.
Nitrogen metabolism plays a major role in the development of hepatic encephalopathy (HE) in patients with cirrhosis. Modulation of this relationship is key to the management of HE, but is not the only nutritional issue that needs to be addressed. The assessment of nutritional status in patients with cirrhosis is problematic. In addition, there are significant sex-related differences in body composition and in the characteristics of tissue loss, which limit the usefulness of techniques based on measures of muscle mass and function in women. Techniques that combine subjective and objective variables provide reasonably accurate information and are recommended. Energy and nitrogen requirements in patients with HE are unlikely to differ substantially from those recommended in patients with cirrhosis per se viz. 35-45 kcal/g and 1.2-1.5g/kg protein daily. Small meals evenly distributed throughout the day and a late-night snack of complex carbohydrates will help minimize protein utilization. Compliance is, however, likely to be a problem. Diets rich in vegetables and dairy protein may be beneficial and are therefore recommended, but tolerance varies considerably in relation to the nature of the staple diet. Branched chain amino acid supplements may be of value in the occasional patient intolerant of dietary protein. Increasing dietary fiber may be of value, but the utility of probiotics is, as yet, unclear. Short-term multivitamin supplementation should be considered in patients admitted with decompensated cirrhosis. Hyponatremia may worsen HE; it should be prevented as far as possible and should always be corrected slowly. Effective management of these patients requires an integrated multidimensional approach. However, further research is needed to fill the gaps in the current evidence base to optimize the nutritional management of patients with cirrhosis and HE.


Long-term physical workload in middle age and disability pension in men and women: a follow-up study of Swedish cohorts.
The study investigates the association between level of long-term physical workload in middle age and disability pension (DP) before 61 years of age with adjustments made for early life factors, level of education, and psychosocial working conditions. Associations with DP overall, DP due to musculoskeletal disorders and DP due to psychiatric disorders were examined. The study is based on cohorts of 21,809 Swedish men and women born in 1948 and 1953, with data on physical workload estimated with a job exposure matrix based on occupational titles in 1985 and 1990 and follow-up data on diagnosis-specific DP in the years 1991-2009. Data on paternal education and intelligence were collected in primary school. Data on level of education were taken from administrative records. Data on psychosocial working conditions were estimated with a job exposure matrix based on occupational titles in 1990. Long-term exposure to high physical workload measured 5 years apart at around age 40 was strongly associated with DP due to musculoskeletal disorders up to the age of 61 among both men (HR 5.44, 95 % CI 3.35-8.84) and women (HR 3.82, CI 95 % 2.88-5.08). For women, the association between high physical load and overall DP was also significantly increased (HR 2.33, CI 95 % 1.92-2.82). The increased risks remained but were clearly attenuated after adjustments for fathers' education, IQ in childhood, achieved education and level of control at work. Exposure to high physical workload is associated with long-term risk of DP due to musculoskeletal disorders, even though adjustments for early life factors, level of education and psychosocial working conditions clearly attenuated the risks.


Antibody combining site: the B polypeptide chain.
The antibody molecule consists of several polypeptide chains. Peptides, which appear to have been derived from the binding region of the rabbitantibody molecule directed against pazobenzenearsonate, have been isolated. The particular polypeptide chain from which these peptides are derived has now been identified as the B chain described by Fleischman, Pain, and Porter.


Interstitial laser anterior capsulotomy for obsessive-compulsive disorder: lesion size and tractography correlate with outcome.
Anterior capsulotomy is a well-established treatment for refractory obsessive-compulsive disorder (OCD). MRI-guided laser interstitial thermal therapy (LITT) allows creation of large, sharply demarcated lesions with the safeguard of real-time imaging. To characterise the outcomes of laser anterior capsulotomy, including radiographical predictors of improvement. Patients with severe OCD refractory to pharmacotherapy and cognitive-behavioural therapy underwent bilateral anterior capsulotomy via LITT. The primary outcome was per cent reduction in Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) score over time. Lesion size was measured on postablation MRI. Disconnection of the anterior limb of the internal capsule (ALIC) was assessed via individual and normative tractography. Eighteen patients underwent laser anterior capsulotomy. Median follow-up was 6 months (range 3-51 months). Time occupied by obsessions improved immediately (median Y-BOCS item 1 score 4-1, p=0.002). Mean (±SD) decrease in Y-BOCS score at last follow-up was 46%±32% (16±11 points, p<0.0001). Sixty-one per cent of patients were responders. Seven patients (39%) exhibited transient postoperative apathy. One patient had an asymptomatic intracerebral haemorrhage. Reduction in Y-BOCS score was positively associated with ablation volume (p=0.006). Individual tractography demonstrated durable ALIC disconnection. Normative tractography revealed a dorsal-ventral gradient, with disconnection of orbitofrontal streamlines most strongly associated with a positive response (p<0.0001). Laser anterior capsulotomy resulted in immediate, marked improvement in OCD symptom severity. Larger lesions permit greater disconnection of prefrontal-subcortical pathways involved in OCD. The importance of greater disconnection is presumably related to variation in ALIC structure and the complex role of the PFC in OCD.


Effects of palatability and learned satiety on energy density influences on breakfast intake in humans.
The present report explored firstly how palatability modified the effects of energy density (ED) on short-term food intake and changes in rated appetite within a single test meal, and secondly how repeated consumption altered these relationships. Experiment 1 contrasted disguised high (HED) and low (LED) versions of a food presented in bland and palatable forms. Mass consumed varied as an interaction of palatability and ED, with subjects eating least of the bland/HED version, suggesting some un-learned satiating effects. No such compensation for ED was seen in the palatable/HED condition, and overall energy intake increased with ED. Palatability had the expected stimulatory effect on appetite, but rated hunger decreased more rapidly as a function of energy consumed in the HED conditions. Experiment 2 introduced novel distinctive flavours to examine whether repeated experience of palatable HED and LED versions resulted in learned satiety. Participants ate the same mass of LED and HED versions on first exposure, but after two training days with each food, where they consumed a fixed amount, they subsequently ate a greater mass of the LED version, consistent with learned satiety. Increased intake was accompanied by a slower rate of decline in hunger in the LED condition. Despite these changes, energy intake remained higher with the HED version. Liking for the LED version was greater than the HED version at the end, possibly due to mild aversive qualities of eating a fixed portion of the HED food during training. Together these data suggest that energy density is the major determinant of short-term energy intake in the absence of orosensory cues predictive of energy differences, but that learning of flavour-energy associations can, to some extent, allow short-term energy consumption to be regulated.


Genome-wide interaction study of gene-by-occupational exposure and effects on FEV1 levels.
Chronic obstructive pulmonary disease (COPD) is a complex disease characterized by impaired lung function and airway obstruction resulting from interactions between multiple genes and multiple environmental exposures. Thus far, genome-wide association studies have largely disregarded environmental factors that might trigger the development of lung function impairment and COPD, such as occupational exposures, which are thought to contribute to 15% to 20% of the COPD prevalence. We performed a genome-wide interaction study to identify novel susceptibility loci for occupational exposure to biological dust, mineral dust, and gases and fumes in relation to FEV1 levels. We performed an identification analysis in 12,400 subjects from the LifeLines cohort study and verified our findings in 1436 subjects from a second independent cohort, the Vlagtwedde-Vlaardingen cohort. Additionally, we assessed whether replicated single nucleotide polymorphisms (SNPs) were cis-acting expression (mRNA) quantitative trait loci in lung tissue. Of the 7 replicated SNPs that interacted with one of the occupational exposures, several identified loci were plausible candidates that might be involved in biological pathways leading to lung function impairment, such as PCDH9 and GALNT13. Two of the 7 replicated SNPs were cis-acting expression quantitative trait loci associated with gene expression of PDE4D and TMEM176A in lung tissue. This genome-wide interaction study on occupational exposures in relation to the level of lung function identified several novel genes. Further research should determine whether the identified genes are true susceptibility loci for occupational exposures and whether these SNP-by-exposure interactions consequently contribute to the development of COPD.


The combination of specific IgM antibodies and IgG antibodies of low avidity does not always indicate primary infection with cytomegalovirus.
The detection of CMV specific IgM antibodies coupled with IgG antibodies of low avidity is taken as diagnostic of primary CMV infection. In a study of 64 pregnant women referred for avidity testing, six women were identified with bloods with positive IgM and low/equivocal avidity IgG on the Abbott Architect assay persisting over 18 weeks. Avidity increased to an "equivocal" level in two women over the course of follow up but remained "low" in four women. On repeat testing with the Diasorin Liaison assay, bloods from two women with low avidity with Architect gave high avidity results with Liaison. Blood from one woman giving low/equivocal results with Architect was reported as moderate avidity on repeat with Liaison. There is concern from these small numbers of cases that some women with positive IgM and low avidity IgG using the Abbott Architect assay may not have primary infections. This implies that they could be entered inappropriately into trials of experimental treatments aiming to prevent transmission of CMV to the fetus if the laboratory is asked to test patients for this purpose. It is suggested that larger series of patients should be examined to determine how frequently this phenomenon occurs.


Natural allelic variation defines a role for ATMYC1: trichome cell fate determination.
The molecular nature of biological variation is not well understood. Indeed, many questions persist regarding the types of molecular changes and the classes of genes that underlie morphological variation within and among species. Here we have taken a candidate gene approach based on previous mapping results to identify the gene and ultimately a polymorphism that underlies a trichome density QTL in Arabidopsis thaliana. Our results show that natural allelic variation in the transcription factor ATMYC1 alters trichome density in A. thaliana; this is the first reported function for ATMYC1. Using site-directed mutagenesis and yeast two-hybrid experiments, we demonstrate that a single amino acid replacement in ATMYC1, discovered in four ecotypes, eliminates known protein-protein interactions in the trichome initiation pathway. Additionally, in a broad screen for molecular variation at ATMYC1, including 72 A. thaliana ecotypes, a high-frequency block of variation was detected that results in >10% amino acid replacement within one of the eight exons of the gene. This sequence variation harbors a strong signal of divergent selection but has no measurable effect on trichome density. Homologs of ATMYC1 are pleiotropic, however, so this block of variation may be the result of natural selection having acted on another trait, while maintaining the trichome density role of the gene. These results show that ATMYC1 is an important source of variation for epidermal traits in A. thaliana and indicate that the transcription factors that make up the TTG1 genetic pathway generally may be important sources of epidermal variation in plants.


Novel oral anticoagulants in acute coronary syndrome: re-evaluating the thrombin hypothesis.
Despite widespread adoption of acetylsalicylic acid and P2Y12 receptor inhibitor therapy as the standard of care for secondary event prevention in patients with acute coronary syndrome (ACS), the rate of cardiovascular death or myocardial infarction following discharge is approximately 24-31% over five years, indicating an important unmet need to reduce further the risk of recurrent ACS events. Because thrombin has a role in arterial thrombus generation, a mechanistic rationale exists for adding an anticoagulant to dual antiplatelet therapy to reduce cardiovascular event rates and mortality. The direct thrombin inhibitor dabigatran and the direct Factor Xa inhibitors rivaroxaban and apixaban have been investigated for this application, with only rivaroxaban successfully completing a phase III trial. These results suggest that dose selection is of paramount importance in this indication, with lower anticoagulant doses (relative to those used in other indications, such as stroke prevention in atrial fibrillation) plus low-dose acetylsalicylic acid potentially improving cardiovascular outcomes. This article reviews clinical trial data of anticoagulants for secondary event prevention in patients with ACS; it also discusses the mechanistic reasons that may underlie these observations and looks towards the potential impact of findings from the ATLAS ACS 2 TIMI 51 trial on clinical practice.


Microwaves from UMTS/GSM mobile phones induce long-lasting inhibition of 53BP1/gamma-H2AX DNA repair foci in human lymphocytes.
We have recently described frequency-dependent effects of mobile phone microwaves (MWs) of global system for mobile communication (GSM) on human lymphocytes from persons reporting hypersensitivity to electromagnetic fields and healthy persons. Contrary to GSM, universal global telecommunications system (UMTS) mobile phones emit wide-band MW signals. Hypothetically, UMTS MWs may result in higher biological effects compared to GSM signal because of eventual "effective" frequencies within the wideband. Here, we report for the first time that UMTS MWs affect chromatin and inhibit formation of DNA double-strand breaks co-localizing 53BP1/gamma-H2AX DNA repair foci in human lymphocytes from hypersensitive and healthy persons and confirm that effects of GSM MWs depend on carrier frequency. Remarkably, the effects of MWs on 53BP1/gamma-H2AX foci persisted up to 72 h following exposure of cells, even longer than the stress response following heat shock. The data are in line with the hypothesis that the type of signal, UMTS MWs, may have higher biological efficiency and possibly larger health risk effects compared to GSM radiation emissions. No significant differences in effects between groups of healthy and hypersensitive subjects were observed, except for the effects of UMTS MWs and GSM-915 MHz MWs on the formation of the DNA repair foci, which were different for hypersensitive (P < 0.02[53BP1]//0.01[gamma-H2AX]) but not for control subjects (P > 0.05). The non-parametric statistics used here did not indicate specificity of the differences revealed between the effects of GSM and UMTS MWs on cells from hypersensitive subjects and more data are needed to study the nature of these differences.


Point-of-Care Ultrasonography Integration in Undergraduate Medical Education: A Student-Driven Approach.
The importance of medical ultrasonography (US) is well established, but given an already dense curriculum, integration of US into preclinical training can be difficult. Although there is no clear consensus on the best practice for integrating US into medical school curricula, growing student interest in US training demands investigation of potential solutions. To investigate whether US integration through peer-assisted learning (PAL) and extracurricular activities during preclinical training is perceived to be valuable by student participants. First- and second-year students at the West Virginia School of Osteopathic Medicine (WVSOM) were invited via email to attend 4 monthly PAL extracurricular US sessions on the following point-of-care US topics: (1) basic lung examination to assess pleural sliding, (2) extended focused assessment with sonography for trauma, (3) right upper quadrant biliary examination, and (4) US-guided central venous catheter placement. A brief survey using Likert-style questions inquired about participants' level of agreement with whether the given session was appropriately complex, increased comfort with US, was informative and interactive, and improved confidence in identifying anatomic structures (sessions 2 and 3 only). A final question asked participants whether they would attend more extracurricular US sessions. Fifty-eight students (36 unique students) attended the peer-led sessions. Of the 58 students, 50 responded to the survey for a response rate of 86.2%. Responses were overwhelmingly positive. All respondents strongly agreed or agreed that these sessions improved their confidence in identifying anatomic structures using US, and 49 (98%) strongly agreed or agreed that they would attend more US sessions. Respondents strongly endorsed the peer-led US sessions, which has facilitated the formal integration of an elective US course at WVSOM. The peer-led sessions introduced at WVSOM could provide the framework and motivation for similar courses at osteopathic medical schools across the country.


Interventions to prevent back pain and back injury in nurses: a systematic review.
A systematic literature review was undertaken to assess the effectiveness of interventions that aim to prevent back pain and back injury in nurses. Ten relevant databases were searched; these were examined and reference lists checked. Two reviewers applied selection criteria, assessed methodological quality and extracted data from trials. A qualitative synthesis of evidence was undertaken and sensitivity analyses performed. Eight randomised controlled trials and eight non-randomised controlled trials met eligibility criteria. Overall, study quality was poor, with only one trial classified as high quality. There was no strong evidence regarding the efficacy of any interventions aiming to prevent back pain and injury in nurses. The review identified moderate level evidence from multiple trials that manual handling training in isolation is not effective and multidimensional interventions are effective in preventing back pain and injury in nurses. Single trials provided moderate evidence that stress management programs do not prevent back pain and limited evidence that lumbar supports are effective in preventing back injury in nurses. There is conflicting evidence regarding the efficacy of exercise interventions and the provision of manual handling equipment and training. This review highlights the need for high quality randomised controlled studies to examine the effectiveness of interventions to prevent back pain and injury in nursing populations. Implications for future research are discussed.


DNA topology influences molecular machine lifetime in human serum.
DNA nanotechnology holds the potential for enabling new tools for biomedical engineering, including diagnosis, prognosis, and therapeutics. However, applications for DNA devices are thought to be limited by rapid enzymatic degradation in serum and blood. Here, we demonstrate that a key aspect of DNA nanotechnology-programmable molecular shape-plays a substantial role in device lifetimes. These results establish the ability to operate synthetic DNA devices in the presence of endogenous enzymes and challenge the textbook view of near instantaneous degradation.


Informatics in radiology (infoRAD): an open source framework for modification and communication of DICOM objects.
A configurable framework has been developed that can receive, modify, and export images in different picture archiving and communication system scenarios. The framework has three main components: a receiver for Digital Imaging and Communications in Medicine (DICOM) objects, a processing pipeline to apply one or more modifications to these objects, and one or more senders to send the processed objects to predefined addresses. The toolbox programming was implemented as an open source project in Java. The processing pipeline uses the concept of configurable plug-ins. One plug-in is user programmable by means of extensible stylesheet language files and allows conversion of DICOM objects to extensible markup language documents or other file types. Input and output channels are the DICOM Storage service, DICOM compact disks-read-only memory (CD-ROMs), and the local file system. The toolbox has been successfully applied to different clinical scenarios, including the correction of DICOM objects from non-Integrating the Healthcare Enterprise (IHE) conform modalities, pseudonaming of DICOM images, and use of the IHE Portable Data for Imaging profile with import and export of CD-ROMs. The toolbox has proved reliability in the clinical routine. Because of the open programming interfaces, the functionality can easily be adapted to future applications.


How Do Genomes Create Novel Phenotypes? Insights from the Loss of the Worker Caste in Ant Social Parasites.
A central goal of biology is to uncover the genetic basis for the origin of new phenotypes. A particularly effective approach is to examine the genomic architecture of species that have secondarily lost a phenotype with respect to their close relatives. In the eusocial Hymenoptera, queens and workers have divergent phenotypes that may be produced via either expression of alternative sets of caste-specific genes and pathways or differences in expression patterns of a shared set of multifunctional genes. To distinguish between these two hypotheses, we investigated how secondary loss of the worker phenotype in workerless ant social parasites impacted genome evolution across two independent origins of social parasitism in the ant genera Pogonomyrmex and Vollenhovia. We sequenced the genomes of three social parasites and their most-closely related eusocial host species and compared gene losses in social parasites with gene expression differences between host queens and workers. Virtually all annotated genes were expressed to some degree in both castes of the host, with most shifting in queen-worker bias across developmental stages. As a result, despite >1 My of divergence from the last common ancestor that had workers, the social parasites showed strikingly little evidence of gene loss, damaging mutations, or shifts in selection regime resulting from loss of the worker caste. This suggests that regulatory changes within a multifunctional genome, rather than sequence differences, have played a predominant role in the evolution of social parasitism, and perhaps also in the many gains and losses of phenotypes in the social insects.


Nurse-administered propofol sedation for endoscopy: a risk analysis during an implementation phase.
The aim of the present study was to perform a risk analysis during the implementation phase of nurse-administered propofol sedation (NAPS) and to validate our structured training program. A structured training program was developed both for endoscopists and for endoscopy nurses who were administering propofol sedation. The nurses' program comprised a 6-week course including theoretical and practical training in airway management, and the endoscopists' program consisted of 2.5 h of theory and a short course in practical airway management. In the implementation phase, data from 1822 endoscopic procedures in 1764 patients were prospectively collected. All adverse events related to sedation were recorded (defined as oxygen saturation < 92%, airway handling, assisted ventilation, need for intubation, change in blood pressure > 20 mmHg). 78 cases of hypoxemia were documented in 1764 patients (4.4%), in 56/983 upper endoscopies (5.7%) and 22/754 lower endoscopies (2.9%) (P = 0.007). Assisted ventilation was necessary in 19 cases (1.1%) and anesthesiologic assistance was requested 10 times. Two patients required endotracheal intubation. A change in blood pressure was recorded in 451 patients (26%). Independent risk factors were type of intervention and level of experience of the staff performing the sedation. These results were obtained after development of a structured training program both for endoscopists and nurses using propofol for sedation, and can be used as basis for further comparison. NAPS for endoscopic procedures is safe when performed by personnel properly trained in airway handling and sedation with propofol, and has considerable advantages compared with conventional sedation for endoscopy.


Photoacoustic microscopy: a potential new tool for evaluation of angiogenesis inhibitor.
The feasibility of photoacoustic microscopy (PAM) for evaluation of angiogenesis inhibitor was investigated on a chick embryo model in vivo. Different concentrations of the angiogenesis inhibitor, Sunitinib, were applied to the chorioallantoic membrane (CAM) of the chick embryos. Imaging of microvasculature in embryo CAMs was acquired using a laser-scanning PAM system; while the optical microscopy (OM) capturing the microvascular images of the same set of CAMs for comparison served as a gold standard for validating the results from PAM. The microvascular density as a function of applied Sunitinib concentration has been quantified in both PAM and OM images. The results from these two modalities have a good agreement, suggesting that PAM could provide an unbiased quantification of microvascular density for objective evaluation of anti-angiogenesis medication. In comparison with conventional OM which enables only two-dimensional enface imaging, PAM is capable of three-dimensional analysis of microvessels, including not only morphology but also functions, as demonstrated in part by the imaging result on a canine bladder model. The emerging PAM technique shows promise to be used in clinical and preclinical settings for comprehensive and objective evaluation of anti-angiogenesis medications.


Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML.
The BCL-2 inhibitor venetoclax combined with hypomethylating agents or low-dose cytarabine represents an important new therapy for older or unfit patients with acute myeloid leukemia (AML). We analyzed 81 patients receiving these venetoclax-based combinations to identify molecular correlates of durable remission, response followed by relapse (adaptive resistance), or refractory disease (primary resistance). High response rates and durable remissions were typically associated with NPM1 or IDH2 mutations, with prolonged molecular remissions prevalent for NPM1 mutations. Primary and adaptive resistance to venetoclax-based combinations was most commonly characterized by acquisition or enrichment of clones activating signaling pathways such as FLT3 or RAS or biallelically perturbing TP53. Single-cell studies highlighted the polyclonal nature of intratumoral resistance mechanisms in some cases. Among cases that were primary refractory, we identified heterogeneous and sometimes divergent interval changes in leukemic clones within a single cycle of therapy, highlighting the dynamic and rapid occurrence of therapeutic selection in AML. In functional studies, FLT3 internal tandem duplication gain or TP53 loss conferred cross-resistance to both venetoclax and cytotoxic-based therapies. Collectively, we highlight molecular determinants of outcome with clinical relevance to patients with AML receiving venetoclax-based combination therapies.


Cadherin-6, a cell adhesion molecule specifically expressed in the proximal renal tubule and renal cell carcinoma.
Cadherins are a family of calcium-dependent, cell-cell adhesion molecules that play an important morphoregulatory role in a wide variety of tissues. Alterations in cadherin function have been implicated in tumor progression in a number of adenocarcinomas. Despite the increasing number of new cadherins identified, little is known about cadherins in normal renal tissue and renal carcinomas. A novel cadherin transcript, cadherin-6, was recently described to be present in renal cancer cell lines and fetal kidney, but no data on protein expression nor tissue localization has been reported. In this study, we demonstrate that the expression of cadherin-6 is restricted to the proximal tubule epithelium. This finding is critical because these cells give rise to the majority of neoplasms of this organ. Furthermore we demonstrate typical cadherin features of cadherin-6, including cytoplasmic binding to alpha- and beta-catenin. We present data of cadherin-6 expression in a series of 32 primary renal cell cancers. Cadherin-6 expression tended to vary with histology in these samples. Whereas the majority of renal cell cancers with histology-associated poor prognosis (i.e., high grade clear cell carcinomas and sarcomatoid renal tumors) show aberrant expression of cadherin-6, in tumors with a favorable prognosis (i.e., low grade clear cell carcinomas and papillary cancers), normal cadherin-6 expression was predominant. Overall, these findings demonstrate specific expression of cadherin-6 in the proximal renal tubules in normal human kidney and suggest that alterations of cadherin-6 expression are associated with progression of renal cell carcinoma.


Enumerating all possible biosynthetic pathways in metabolic networks.
Exhaustive identification of all possible alternate pathways that exist in metabolic networks can provide valuable insights into cellular metabolism. With the growing number of metabolic reconstructions, there is a need for an efficient method to enumerate pathways, which can also scale well to large metabolic networks, such as those corresponding to microbial communities. We developed MetQuest, an efficient graph-theoretic algorithm to enumerate all possible pathways of a particular size between a given set of source and target molecules. Our algorithm employs a guided breadth-first search to identify all feasible reactions based on the availability of the precursor molecules, followed by a novel dynamic-programming based enumeration, which assembles these reactions into pathways of a specified size producing the target from the source. We demonstrate several interesting applications of our algorithm, ranging from identifying amino acid biosynthesis pathways to identifying the most diverse pathways involved in degradation of complex molecules. We also illustrate the scalability of our algorithm, by studying large graphs such as those corresponding to microbial communities, and identify several metabolic interactions happening therein. MetQuest is available as a Python package, and the source codes can be found at https://github.com/RamanLab/metquest .


Prevalence and risk factors for refractive errors in an adult inner city population.
To estimate the prevalence of refractive errors among adult black and white Americans and to identify risk factors associated with these refractive errors. Refractive error was measured in a population-based sample of black and white adults age 40 or older residing in east Baltimore from 1985 through 1988. Aphakic eyes were excluded from analysis. The prevalence of myopia varied from 10.5% among black men 80 years and older to 42.1% among white women 40 to 49 years of age. Hyperopia ranged from 11.8% among black men 40 to 49 years to 68.1% among white men 80 years of age and older. Astigmatism ranged from 15.8% to 45.2%, and anisometropia ranged from 2.8% to 8.1%, depending on age, race, and gender. Black persons had less myopia, hyperopia, astigmatism, and anisometropia than did white persons. Myopia (< -0.5 diopter [D] spherical equivalent) declined with age, whereas hyperopia (> +0.5 D), astigmatism (> 0.5 D of cylinder), and anisometropia (> 1.0 D between eyes) increased with age. Myopia increased with increasing years of education, although this association was stronger for white persons than for black persons and among younger subjects. Hyperopia declined with increasing years of education, and this association was stronger among younger than older subjects. Education was not associated with astigmatism or anisometropia. Black persons had lower rates of refractive error than did white persons, except for hyperopia prevalence, which was comparable in black and white women. Refractive errors are common among adult inner city Americans, but rates vary substantially by age, race, gender, and education levels.


Ohio Modified Arm-Motor Ability Test (OMAAT): An Optimized Measure of Upper Extremity Functional Limitation in Hemiparetic Stroke.
This secondary analysis quantified the psychometric properties of the Ohio Modified Arm-Motor Ability Test (OMAAT) in a sample of neurologically stable chronic stroke survivors (n = 67, 40 men; mean age 59.8 yr, standard deviation = 12.8; 42 White, 23 Black, 2 other; 92.5% right-sided lesion; 44 ischemic stroke). Findings indicate high OMAAT internal consistency (Cronbach's α = .97, ordinal α = .98, Gugiu's bootstrap reliability = .97), unidimensionality, and strong positive factor loadings for all 20 OMAAT items. Convergent validity between OMAAT and Action Research Arm Test total scores was strong (r = .90, p < .0001). The OMAAT is the first short measure of upper extremity functional limitation available to clinicians and researchers that includes an administration manual and that has been examined using nonparametric psychometrics. A detailed administration manual is provided as a supplement to this article.


Generation and analysis of expressed sequence tags from six developing xylem libraries in Pinus radiata D. Don.
Wood is a major renewable natural resource for the timber, fibre and bioenergy industry. Pinus radiata D. Don is the most important commercial plantation tree species in Australia and several other countries; however, genomic resources for this species are very limited in public databases. Our primary objective was to sequence a large number of expressed sequence tags (ESTs) from genes involved in wood formation in radiata pine. Six developing xylem cDNA libraries were constructed from earlywood and latewood tissues sampled at juvenile (7 yrs), transition (11 yrs) and mature (30 yrs) ages, respectively. These xylem tissues represent six typical development stages in a rotation period of radiata pine. A total of 6,389 high quality ESTs were collected from 5,952 cDNA clones. Assembly of 5,952 ESTs from 5' end sequences generated 3,304 unigenes including 952 contigs and 2,352 singletons. About 97.0% of the 5,952 ESTs and 96.1% of the unigenes have matches in the UniProt and TIGR databases. Of the 3,174 unigenes with matches, 42.9% were not assigned GO (Gene Ontology) terms and their functions are unknown or unclassified. More than half (52.1%) of the 5,952 ESTs have matches in the Pfam database and represent 772 known protein families. About 18.0% of the 5,952 ESTs matched cell wall related genes in the MAIZEWALL database, representing all 18 categories, 91 of all 174 families and possibly 557 genes. Fifteen cell wall-related genes are ranked in the 30 most abundant genes, including CesA, tubulin, AGP, SAMS, actin, laccase, CCoAMT, MetE, phytocyanin, pectate lyase, cellulase, SuSy, expansin, chitinase and UDP-glucose dehydrogenase. Based on the PlantTFDB database 41 of the 64 transcription factor families in the poplar genome were identified as being involved in radiata pine wood formation. Comparative analysis of GO term abundance revealed a distinct transcriptome in juvenile earlywood formation compared to other stages of wood development. The first large scale genomic resource in radiata pine was generated from six developing xylem cDNA libraries. Cell wall-related genes and transcription factors were identified. Juvenile earlywood has a distinct transcriptome, which is likely to contribute to the undesirable properties of juvenile wood in radiata pine. The publicly available resource of radiata pine will also be valuable for gene function studies and comparative genomics in forest trees.


Effects of sex, eye-side, diurnal variation on intraocular pressure in calves.
The aim of this study was to determine the effects of factors such as sex, eye-side and diurnal variation on intraocular pressure (IOP) values measured by Tono-Pen Vet® in healthy calves. Twenty four (12 males, 12 females) calves were used in this study. IOP measurements were per- formed in the morning (6:00 a.m.) and at night (8:00 p.m). Average IOP values in all calves were measured as 17.67±2.64 mmHg in the morning and 15.52±2.05 at night and the difference between these two time points was found to be statistically significant (p⟨0.0001). Average IOP values were measured as 16.04±2.82 mmHg in males and 17.15±2.23 mmHg in females with a statistically significant (p⟨0.05=0.023) difference between them. Average IOP values were 16.81±2.85 mmHg in right eyes and 16.37±2.23 mmHg in left eyes and the difference between these values were statistically insignificant (p>0.05). At the end of study, overall average IOP in all calves was measured as 16.59±2.59 mmHg. The present data showed a significant difference in terms of sex and diurnal variations and a non-significant difference in eye-side. In addition, this study is the first research article in which the intraocular pressure in calves was measured by Tono-Pen Vet®.


Genetically diverse uropathogenic Escherichia coli adopt a common transcriptional program in patients with UTIs.
Uropathogenic Escherichia coli (UPEC) is the major causative agent of uncomplicated urinary tract infections (UTIs). A common virulence genotype of UPEC strains responsible for UTIs is yet to be defined, due to the large variation of virulence factors observed in UPEC strains. We hypothesized that studying UPEC functional responses in patients might reveal universal UPEC features that enable pathogenesis. Here we identify a transcriptional program shared by genetically diverse UPEC strains isolated from 14 patients during uncomplicated UTIs. Strikingly, this in vivo gene expression program is marked by upregulation of translational machinery, providing a mechanism for the rapid growth within the host. Our analysis indicates that switching to a more specialized catabolism and scavenging lifestyle in the host allows for the increased translational output. Our study identifies a common transcriptional program underlying UTIs and illuminates the molecular underpinnings that likely facilitate the fast growth rate of UPEC in infected patients.


Making decisions for people with dementia who lack capacity: qualitative study of family carers in UK.
To identify common difficult decisions made by family carers on behalf of people with dementia, and facilitators of and barriers to such decisions, in order to produce information for family carers about overcoming barriers. Qualitative study to delineate decision areas through focus groups and complexity of decision making in individual interviews. Community settings in London. 43 family carers of people with dementia in focus groups and 46 carers who had already made such decisions in individual interviews. Family carers identified five core problematic areas of decision making: accessing dementia related health and social services; care homes; legal-financial matters; non-dementia related health care; and making plans for the person with dementia if the carer became too ill to care for them. They highlighted the difficulties in making proxy decisions, especially against active resistance, and their altered role of patient manager while still a family member. Families devised strategies to gain agreement in order to ensure that the person with dementia retained dignity. The following strategies helped with implementation of decisions: introducing change slowly; organising legal changes for the carer as well as the patient; involving a professional to persuade the patient to accept services; and emphasising that services optimised, not impeded, independence. To access services, carers made patients' general practice appointments, accompanied them to the surgery, pointed out symptoms, gained permission to receive confidential information, asked for referral to specialist services, and used professionals' authority to gain patients' agreement. End of life decisions were particularly difficult. They were helped by knowledge of the person with dementia's previous views, clear prognostic information, and family support. Information sheets to help carers to overcome barriers to proxy decision making have been developed; their impact in practice has yet to be evaluated.


Decrease in the prevalence of paediatric adiposity in Switzerland from 2002 to 2007.
A national study in Switzerland in 2002 suggested nearly one in five schoolchildren was overweight. Since then, many programmes have been introduced in an attempt to control the problem. The aim of the present study was to determine the prevalence of childhood overweight in Switzerland five years later. In both studies a cross-sectional, three-stage, probability-proportional-to-size cluster sampling of schools throughout Switzerland was used to obtain a representative sample of approximately 2500 children aged 6-13 years. Height and weight were measured and BMI calculated. The BMI references from the Centers for Disease Control and Prevention were used to determine the prevalences of underweight (<5th percentile), overweight (>or=85th and <95th percentile) and obesity (>or=95th percentile). In 2007 the prevalences of underweight, overweight and obesity in boys were 3.5 %, 11.3 % and 5.4 %, respectively; in girls they were 2.6 %, 9.9 % and 3.2 %. Compared with 2002, there was a significant decrease in the prevalence of overweight in girls and of obesity in both genders. In contrast to 2002, where there were no differences, in 2007 the prevalence of paediatric obesity was significantly higher in communities with a population >100 000 compared with smaller communities (P < 0.05). In summary, over the past 5 years, the prevalence of adiposity has decreased in Swiss children. These findings suggest that increased awareness combined with mainly school-based programmes aimed at physical activity and healthy nutrition may have helped to control this public health problem. Future monitoring in Switzerland will determine if these findings are sustained.


Investigation of the Causes of Shigatoxigenic Escherichia coli PCR Positive and Culture Negative Samples.
Molecular methods may reveal the presence of pathogens in samples through the detection of specific target gene(s) associated with microorganisms, but often, the subsequent cultural isolation of the pathogen is not possible. This discrepancy may be related to low concentration of the cells, presence of dead cells, competitive microflora, injured cells and cells in a viable but non-culturable state, free DNA and the presence of free bacteriophages which can carry the target gene causing the PCR-positive/culture-negative results. Shiga-toxigenic Escherichia coli (STEC) was used as a model for studying this phenomenon, based on the phage-encoded cytotoxins genes (Stx family) as the detection target in samples through real-time qPCR. Stx phages can be integrated in the STEC chromosome or can be isolated as free particles in the environment. In this study, a combination of PCR with culturing was used for investigating the presence of the stx1 and stx2 genes in 155 ovine recto-anal junction swab samples (method (a)-PCR). Samples which were PCR-positive and culture-negative were subjected to additional analyses including detection of dead STEC cells (method (b)-PCR-PMA dye assay), presence of Stx phages (method (c)-plaque assays) and inducible integrated phages (method (d)-phage induction). Method (a) showed that even though 121 samples gave a PCR-positive result (78%), only 68 samples yielded a culturable isolate (43.9%). Among the 53 (34.2%) PCR-positive/culture-negative samples, 21 (39.6%) samples were shown to have STEC dead cells only, eight (15.1%) had a combination of dead cells and inducible stx phage, while two samples (3.8%) had a combination of dead cells, inducible phage and free stx phage, and a further two samples had Stx1 free phages only (3.8%). It was thus possible to reduce the samples with no explanation to 20 (37.7% of 53 samples), representing a further step towards an improved understanding of the STEC PCR-positive/culture-negative phenomenon.


The effect on behavior and bone mineral density of individualized bone mineral density feedback and educational interventions in premenopausal women: a randomized controlled trial [NCT00273260].
Limited information is available on ways to influence osteoporosis risk in premenopausal women. This study tested four hypotheses regarding the effects of individualized bone density (BMD) feedback and different educational interventions on osteoporosis preventive behavior and BMD in pre-menopausal women, namely: that women are more likely to change calcium intake and physical activity if their BMD is low; that group education will be more efficacious at changing behavior than an information leaflet; that BMD feedback and group education have independent effects on behavior and BMD; and, that women who improve their physical activity or calcium intake will have a change in bone mass over 2 years that is better than those who do not alter their behavior. We performed a 2-year randomized controlled trial of BMD feedback according to T-score and either an osteoporosis information leaflet or small group education in a population-based random sample of 470 healthy women aged 25-44 years (response rate 64%). Main outcome measures were dietary calcium intake, calcium supplement use, smoking behavior, physical activity, endurance fitness, lower limb strength and BMD. We used paired t-tests, one-way ANOVA and linear regression techniques for data analysis. Women who had feedback of low BMD had a greater increase in femoral neck BMD than those with normal BMD (1.6% p.a. vs. 0.7% p.a., p = 0.0001), but there was no difference in lumbar spine BMD change between these groups (0.1% p.a. vs. 0.08% p.a., p = 0.9). Both educational interventions had similar increases in femoral neck BMD (Leaflet = +1.0% p.a., Osteoporosis self-management course = + 1.3% p.a., p = 0.4). Femoral neck BMD change was only significantly associated with starting calcium supplements (1.3 % p.a, 95%CI +0.49, +2.17) and persistent self-reported change in physical activity levels (0.7% p.a., 95%CI +0.22, +1.22). Individualized BMD feedback combined with a minimal educational intervention is effective at increasing hip but not spine bone density in premenopausal women. The changes in behavior through which this was mediated are potentially important in the prevention of other diseases, thus measuring BMD at a young age may have substantial public health benefits, particularly if these changes are sustained.


Stimulation by human interleukin 1 of cartilage breakdown and production of collagenase and proteoglycanase by human chondrocytes but not by human osteoblasts in vitro.
Human articular chondrocytes in culture synthesise collagenase and neutral proteoglycanase in response to addition of a 12-17 kDa protein produced by cultured human monocytes. This factor copurifies with interleukin 1, as assessed by lymphocyte activating factor activity, on gel filtration chromatography and isoelectric focusing. The interleukin 1 and chondrocyte-stimulating activities are destroyed by pretreatment of the material with phenylglyoxal. The same materials also promote the release of glycosaminoglycans from cultures of intact bovine nasal cartilage. The proteoglycanase activity release from chondrocytes appears to be a metalloproteinase because it is inhibited by EDTA and not by phenylmethylsulphonyl fluoride (PMSF), and because detection of its activity is dependent on the presence of 4-aminophenylmercuric acetate. Human osteoblast-like cells do not respond to this factor by increased proteinase production, but are stimulated to produce prostaglandins. These results suggest that interleukin 1 has activities upon non-immune cells which promote the degradation of connective tissue matrices. Human osteoblasts do not synthesise neutral collagen- and proteoglycan-degrading enzymes and thus are unlikely to be directly responsible for the matrix degradation which occurs during bone resorption.


In vitro drug sensitivity of cells from children with leukemia using the MTT assay with improved culture conditions.
The knowledge about drug resistance in childhood leukemias and acute lymphoblastic leukemia (ALL) in general is limited. This is because of the lack of a suitable in vitro drug sensitivity assay, which is in part due to low in vitro ALL cell survival. We recently adapted the highly efficient 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay to test cells from ALL patients and showed that its results were comparable with those of the DiSC assay, up to now the most valid but laborious assay. In this study, in vitro drug sensitivity was assessed in cells from 82 children with leukemia, 79 of whom had ALL, with the MTT assay. Dose response curves were obtained for 6-mercaptopurine, 6-thioguanine (6-TG), prednisolone (Pred), daunorubicin (DNR), vincristine (VCR), cytosine arabinoside (Ara-C), L-asparaginase (L-Asp), mafosfamide, and mustine. A cytotoxic effect of methotrexate could be detected in only a few cases. Large interindividual differences in drug sensitivity were detected. Compared with leukemia cells from newly diagnosed patients, leukemia cells from relapsed patients were significantly more in vitro resistant to 6-TG, Pred, Ara-C, mafosfamide and mustine but not to DNR, VCR, and L-Asp. Improvements of culture medium and methods to increase MTT reduction were studied. From 10 components tested, addition of insulin and bovine serum albumin to serum-containing medium improved ALL cell survival. Addition of succinate did not increase the amount of MTT reduction. We conclude that the in vitro MTT assay highly facilitates large-scale studies on drug resistance of ALL patients that can lead to rational improvements in existing treatment protocols.


Ethanol fixation of bladder irrigation specimens for flow cytometric analysis. A multiinstitutional study from the bladder cancer flow cytometry network.
Ethanol preservation of voided and catheterized urine has long been the standard for urinary cytologic study. In this report ethanol preservation of bladder irrigation specimens was evaluated for flow cytometric analysis in a multiinstitutional study requiring specimen transport. Specimens from ten patients obtained at one center were preserved for varying periods of time in 50% ethanol, then distributed by express mail to four other participating centers, up to 3000 miles distant. On receipt, from 1 to 3 weeks after collection, the samples were processed and examined by flow cytometric study using propidium iodide as the fluorochrome. Forty-six of the 50 (92%) analyzed specimens gave satisfactory histograms. In 41 of the 46 adequate samples (89%), an aneuploid peak in the alcohol preserved (propidium iodide stained) specimen correlated well with the fresh (acridine orange stained) specimen. However, there was variable loss of DNA stainability with a broadening of the coefficient of variation in some alcohol-preserved specimens and an increase in cellular debris so that measurements of DNA index and percent hyperdiploid cells were considered unreliable. The authors conclude that ethanol preservation of bladder irrigation specimens for short periods of time may be a feasible alternative when flow cytometric analysis cannot be carried out on fresh specimens, but that this is not optimal fixation for specimens that must be transported and further studies of other fixatives are recommended.


Ultrasound-Guided Femoral Nerve Blockage in A Patellar Dislocation: An Effective Technique for Emergency Physicians.
Patellar dislocation is an orthopedic emergency and its reduction can be painful. The aim of this case is to show that the ultrasound-guided femoral nerve blockage can be effectively used in the pain management of patellar reduction in the emergency department (ED). A 21-year-old man was admitted to our ED after suffering a fall down a flight of stairs. The initial physical examination and plain radiography showed a patellar dislocation in the right knee. We performed an ultrasound-guided femoral nerve blockage to provide a pain-free and comfortable patellar reduction. To our best knowledge, there is no manuscript except an old case series about use of the ultrasound-guided femoral nerve blockage in the management of patellar reduction in the medical literature. Procedural sedation is the preferred method used for this purpose in ED, but these medications need to be closely monitored because of their potential complications, such as nausea, vomiting, allergic reactions, and respiratory depression. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Ultrasound-guided femoral nerve blockage gave rapid and effective pain control without any complication during the reduction in this patient. Therefore, we suggest this technique be used for pain management during the reduction of a dislocated patella in the ED.


Pneumatic microfluidic cell compression device for high-throughput study of chondrocyte mechanobiology.
Hyaline cartilage is a specialized type of connective tissue that lines many moveable joints (articular cartilage) and contributes to bone growth (growth plate cartilage). Hyaline cartilage is composed of a single cell type, the chondrocyte, which produces a unique hydrated matrix to resist compressive stress. Although compressive stress has profound effects on transcriptional networks and matrix biosynthesis in chondrocytes, mechanistic relationships between strain, signal transduction, cell metabolism, and matrix production remain superficial. Here, we describe development and validation of a polydimethylsiloxane (PDMS)-based pneumatic microfluidic cell compression device which generates multiple compression conditions in a single platform. The device contained an array of PDMS balloons of different sizes which were actuated by pressurized air, and the balloons compressed chondrocytes cells in alginate hydrogel constructs. Our characterization and testing of the device showed that the developed platform could compress chondrocytes with various magnitudes simultaneously with negligible effect on cell viability. Also, the device is compatible with live cell imaging to probe early effects of compressive stress, and it can be rapidly dismantled to facilitate molecular studies of compressive stress on transcriptional networks. Therefore, the proposed device will enhance the productivity of chondrocyte mechanobiology studies, and it can be applied to study mechanobiology of other cell types.


Microstructure and chemical analysis of blood-contaminated mineral trioxide aggregate.
To test the hypothesis that blood contamination has a detrimental effect on the chemical properties of Mineral trioxide aggregate (MTA). The effects of whole, fresh human blood on the microstructure and elemental chemistry of MTA were evaluated using scanning electron microscopy and energy-dispersive X-ray analysis, respectively. The phase compositions of contaminated and uncontaminated MTA were also analysed using X-ray diffraction analysis. The hydration state of specimens partially mixed with blood were more complete than those mixed entirely with blood and less than those entirely mixed with water. Acicular crystals, characteristic of ettringite, were abundant in specimens mixed entirely with water and absent from specimens mixed partially or entirely with blood. Calcium hydroxide crystals were absent in specimens contaminated entirely with blood and the unhydrated MTA powder, but present in the other groups. Mixing MTA with blood resulted in the lack of formation of the crystalline calcium hydroxide in the early stage of the hydration process.


Redox state of coenzyme Q10 determines its membrane localization.
The interaction between oxidized (ubiquinone-10) and reduced (ubiquinol-10) coenzyme Q 10 with dimyristoylphosphatidylcholine has been examined by differential scanning microcalorimetry, X-ray diffraction, infrared spectroscopy, and (2)H NMR. Microcalorimetry experiments showed that ubiquinol-10 perturbed considerably more the phase transition of the phospholipids than ubiquinone-10, both forms giving rise to a shoulder of the main transition peak at lower temperatures. Small angle X-ray diffraction showed an increase in d-spacing suggesting a thicker membrane in the presence of both ubiquinone-10 and ubiquinol-10, below the phase transition and a remarkable broadening of the peaks indicating a loss of the repetitive pattern of the lipid multilamellar vesicles. Infrared spectroscopy showed an increase in wavenumbers of the maximum of the CH 2 stretching vibration at temperatures below the phase transition, in the presence of ubiquinol-10, indicating an increase in the proportion of gauche isomers in the gel phase, whereas this effect was smaller for ubiquinone-10. A very small effect was observed at temperatures above the phase transition. (2)H NMR spectroscopy of perdeuterated DMPC showed only modest changes in the spectra of the phospholipids occasioned by the presence of coenzyme Q 10. These small changes were reflected, in the presence of ubiquinol-10, by a decrease in resolution indicating that the interaction between coenzyme Q and phospholipids changed the motion of the lipids. The change was also visible in the first spectral moment (M1), which is related with membrane order, which was slightly decreased at temperatures below the phase transition especially with ubiquinol-10. A slight decrease in M 1 values was also observed above the phase transition but only for ubiquinol-10. These results can be interpreted to indicate that most ubiquinone-10 molecules are localized in the center of the bilayer, but a considerable proportion of ubiquinol-10 molecules may span the bilayer interacting more extensively with the phospholipid acyl chains.


The Effect of Nefopam on Postoperative Fentanyl Consumption: A Randomized, Double-blind Study.
Nefopam is a non-opioid, non-steroidal, centrally acting analgesic drug. The concomitant use of opioids and nefopam is believed to have many advantages over the administration of opioids alone for postoperative pain management. We conducted a randomized, double-blind study to determine the fentanyl-sparing effect of co-administration of nefopam with fentanyl for postoperative pain management via patient controlled analgesia (PCA). Ninety female patients who underwent laparoscopic total hysterectomy under general anesthesia were randomized into 3 groups, Group A, fentanyl 1,000 µg; Group B, fentanyl 500 µg + nefopam 200 mg; and Group C, fentanyl 500 µg + nefopam 400 mg, in a total volume of 100 ml PCA to be administered over the first 48 h postoperatively without basal infusion. The primary outcome was total fentanyl consumption during 48 h; secondary outcomes included pain scores and incidence of side effects. Eighty-one patients were included in the analysis. The overall fentanyl-sparing effects of PCA with concomitant administration of nefopam during the first 48 h postoperatively were 54.5% in Group B and 48.9% group C. Fentanyl use was not significantly different between Groups B and C despite the difference in the nefopam dose. There were no differences among the three groups in terms of PCA-related side effects, although the overall sedation score of Group B was significantly lower than that of Group A. The concomitant administration of nefopam with fentanyl for postoperative pain management may allow reduction of fentanyl dose, thereby reducing the risk of opioid-related adverse effects.


Neighborhood and community interactions determine the spatial pattern of tropical tree seedling survival.
Factors affecting survival and recruitment of 3531 individually mapped seedlings of Myristicaceae were examined over three years in a highly diverse neotropical rain forest, at spatial scales of 1-9 m and 25 ha. We found convincing evidence of a community compensatory trend (CCT) in seedling survival (i.e., more abundant species had higher seedling mortality at the 25-ha scale), which suggests that density-dependent mortality may contribute to the spatial dynamics of seedling recruitment. Unlike previous studies, we demonstrate that the CCT was not caused by differences in microhabitat preferences or life history strategy among the study species. In local neighborhood analyses, the spatial autocorrelation of seedling survival was important at small spatial scales (1-5 m) but decayed rapidly with increasing distance. Relative seedling height had the greatest effect on seedling survival. Conspecific seedling density had a more negative effect on survival than heterospecific seedling density and was stronger and extended farther in rare species than in common species. Taken together, the CCT and neighborhood analyses suggest that seedling mortality is coupled more strongly to the landscape-scale abundance of conspecific large trees in common species and the local density of conspecific seedlings in rare species. We conclude that negative density dependence could promote species coexistence in this rain forest community but that the scale dependence of interactions differs between rare and common species.


Anicteric hepatoxicity: a potential health risk of occupational exposures in Nigerian petroleum oil refining and distribution industry.
Literature abounds linking one's job to certain unpalatable health outcomes. Since exposures to hazardous conditions in industrial environments often results in sundry health effects among workers, we embarked on this study to investigate the hepatic health effects of occupational activities in the petroleum refining and distribution industry. Biochemical markers of liver functions were assayed in plasma, using Reflotron dry chemistry spectrophotometric system. The study was conducted on randomly selected workers of Port Harcourt Refining Company (PHRC) and Pipelines and Petroleum Product Marketing Company (PPMC) both in Alesa-Eleme near Port Harcourt, Nigeria, as well as non-oil work civil servants serving as control subjects. Results showed that, bilirubin ranged 0.3-1.6 mg/dl with a mean of 0.66±0.20mg/dl among the oil workers as against 0.5-1.00mg/dl with a mean of 0.58±0.13mg/dl in non-oil workers, Alkaline phosphatase ranged 50.00-296.00u/l (mean: 126.21±39.49u/l) in oil workers as against 40.20-111u/l (mean: 66.83±18.54u/l) for non-oil workers, Aspartic transaminases (AST) ranged 5.80-140.20u/l (mean: 21.81±11.49u/l) in oil workers against 18.00-44.00u/l (mean: 26.89±6.99u/l) for non-oil workers, while Alanine transaminases (ALT) ranged 4.90-86.00u/l (mean: 22.14±11.28u/l) in oil workers as against 10.00-86.60u/l (mean: 22.30±10.22u/l) for the non-oil workers. A close study of the results revealed that although the mean values for all the studied parameters were still within the parametric reference ranges, however, relative to the referents, there were significant increases (P<0.05) in plasma bilirubin (though anicteric) and alkaline phosphatase that was not matched with a corresponding increase in the plasma transaminases, suggesting a possibility that toxic anicteric hepatoxicity is part of the potential health effects of sundry exposures in the Nigeria petroleum oil refining and distribution industry. Gender differentiation data showed that though the mean values for the parameters were higher in males than females, the increases were not significant in most cases (P>0.05), whereas data for age and exposure period classifications revealed that irrespective of the age of the worker, the effects are likely to start after the first five years, manifesting fully after the first decade of occupational exposures. Thus, an update of industrial/occupational health measures is necessary for a safer and healthier work environment.


Qualitative assessment of 27 current-use pesticides in air at 20 sampling sites across Africa.
Increasing use of current-use pesticides (CUPs) in Africa raises environmental and public health concerns. But there is a large uncertainty about their occurrence and the composition of pesticide mixtures on this continent. This paper investigates the presence of 27 CUPs in air across 20 sampling sites in Africa. 166 passive air samples, consisting of polyurethane foam (PUF), were collected in 12 African countries between 2010 and 2018. Samples were extracted with methanol and analyzed via high-performance liquid chromatography coupled with tandem mass spectrometry. The detection frequencies of CUPs per site were compared to land use patterns and sampling years, while their similarities were assessed using hierarchical cluster analysis. Overall, 24 CUPs were detected at least once. In 93% of all samples, at least one CUP was detected, while 78% of the samples had mixtures of two or more CUPs (median 3, interquartile range 5). Atrazine and chlorpyrifos were detected in 19 out of 20 sampling sites. Carbaryl, metazachlor, simazine, tebuconazole and terbuthylazine had the highest detection frequencies at sampling sites dominated by croplands. Across all the sampling years, 16 CUPs were present. Seven CUPs were newly detected from 2016 onwards (azinfos-methyl, dimetachlor, chlorsulfuron, chlortoluron, isoproturon, prochloraz and pyrazon), while metamitron was only present before 2012. Sites within a radius of about 200 km showed similarities in detected CUP mixtures across all samples. Our results show the presence of CUP mixtures across multiple agricultural and urban locations in Africa which requires further investigation of related environmental and human health risks.


Alectinib in the treatment of ALK-positive metastatic non-small cell lung cancer: clinical trial evidence and experience with a focus on brain metastases.
Molecular profiling of metastatic nonsquamous non-small cell lung cancer (NSCLC) is required to guide the treatment strategy. Anaplastic lymphoma kinase ( ALK) gene rearrangements are found in approximately 5% of lung adenocarcinomas and are associated with specific clinical features including a high risk of brain metastases. Crizotinib was the first ALK inhibitor developed and it demonstrated improved outcomes in patients with ALK-positive advanced NSCLC in comparison with chemotherapy. However, despite an initial response, all ALK-positive NSCLC patients develop acquired resistance to crizotinib. Because the most frequent mechanism of resistance is the development of a secondary ALK mutation, second (ceritinib, alectinib, brigatinib) and third-generation (lorlatinib) ALK inhibitors were developed. Alectinib is a second-generation ALK inhibitor and was shown to be effective for a broad spectrum of ALK rearrangements and ALK mutations. It was also shown to have high intracranial efficacy. In this article, we review clinical trial evidence of alectinib efficacy as well as publications reporting the experience of alectinib in daily practice, with a focus on brain metastases.


Temporomandibular Joint Ankylosis in a Girl Child: Immunochemical Evaluation of Tissue Material Obtained from Repeated Arthroplasty Surgeries.
Temporomandibular joint ankylosis (TMJA) is a rare, but debilitating, condition that leads to TMJ joint hypomobility. Surgery is the mainstay for treatment, which is accompanied by rehabilitative and psychological support. Despite the advances in surgical techniques, the recurrence of TMJA post-surgery has been reported as a common complication. Therefore, it becomes essential to investigate and understand the histo-morpho-pathological processes governing these ankylotic changes. Given the lack of such studies in the literature, herein we present a case of a girl child who underwent primary surgery at the age of six years, followed by a second surgery at the age of twelve years. Ankylotic tissue samples collected during both surgeries were studied using various immunohistochemical markers for tissue remodeling, inflammation, antimicrobial activity, and transcriptional regulation. The expression of MMP-2 and -9 was downregulated in repeated surgery materials, whilst MMP-13 was rarely detected in both tissues. Strong MMP-8, TIMP-2, and TIMP-4 expressions were noted in both tissues, showing their anti-inflammatory and protective roles. Moderately strong expression of bFGF, FGFR-1, IL-1α, and TNF-α could indicate sustained tissue growth in the background of inflammation (wound healing). Interestingly, the expression of β-defensin-2 was found to be constant in both tissues, thereby indicating possible ECM remodeling and collagen breakdown. Finally, a moderate expression of RUNX-2, coupled with a low expression of WNT-1 and -3a, could indicate a slow and delayed bone regeneration process. Our results showcase the complex myriad of pathways that could be involved in the progression of TMJA and post-surgery healing processes. Immunopathological studies could aid in improving the diagnosis, treatment, and prognosis for patients affected with TMJA.


Transcription- and translation-dependent changes in membrane dynamics in bacteria: testing the transertion model for domain formation.
Cell cycle events have been proposed to be triggered by the formation of membrane domains in the process of coupled transcription, translation and insertion ('transertion') of nascent membrane and exported proteins. Disruption of domain structure should lead to changes in membrane dynamics. Membrane viscosity of Escherichia coli and Bacillus subtilis decreased after inhibition of protein synthesis by chloramphenicol or puromycin, or of RNA initiation by rifampicin, but not after inhibition of RNA elongation by streptolydigin or amino acid starvation of a stringent strain. The decrease caused by inhibitors of protein synthesis was prevented by streptolydigin if added simultaneously, but was not reversed if added later. The drug-induced decrease in membrane viscosity is energy dependent: it did not happen in KCN-treated cells. All treatments decreasing membrane viscosity also induced nucleoid compaction and fusion. Inhibition of macromolecular synthesis without membrane perturbation caused nucleoids to expand. Changes in membrane dynamics were also displayed during a nutritional shift-down transition that causes imbalance in macromolecular syntheses. The results are consistent with the transertion model, predicting dissipation of membrane domains by termination of protein synthesis or detachment of polysomes from DNA; domain structure is conserved if the transertion process is 'frozen'.


Rat hepatic CYP2E1 is induced by very low nicotine doses: an investigation of induction, time course, dose response, and mechanism.
CYP2E1 is an ethanol- and drug-metabolizing enzyme that can also activate procarcinogens and hepatotoxicants and generate reactive oxygen species; it has been implicated in the pathogenesis of liver diseases and cancer. Cigarette smoke increases CYP2E1 activity in rodents and in humans and we have shown that nicotine (0.1-1.0 mg/kg s.c. x 7 days) increases CYP2E1 protein and activity in the rat liver. In the current study, we have shown that the induction peaks at 4 h postnicotine (1 mg/kg s.c. x 7 days) treatment and recovers within 24 h. No induction was observed after a single injection, and 18 days of treatment did not increase the levels beyond that found at 7 days. We found that CYP2E1 is induced by very low doses of chronic (x 7 days) nicotine with an ED50 value of 0.01 mg/kg s.c.; 0.01 mg/kg in a rat model results in peak cotinine levels (nicotine metabolite) similar to those found in people exposed to environmental tobacco smoke (passive smokers; 2-7 ng/ml). Previously, we have shown no change in CYP2E1 mRNA, and our current mechanistic study indicates that nicotine does not regulate CYP2E1 expression by protein stabilization. We postulated that a nicotine metabolite could be causing the induction but found that cotinine (1 mg/kg x 7 days) did not increase CYP2E1. Our findings indicate that nicotine increases CYP2E1 at very low doses and may enhance CYP2E1-related toxicity in smokers, passive smokers, and people treated with nicotine (e.g., smokers, patients with Alzheimer's disease, ulcerative colitis or Parkinson's disease).


Polyvinyl chloride (PVC) plastic fragments release Pb additives that are bioavailable in zebrafish.
Plastic polymers such as polyvinyl chloride (PVC) may contain chemical additives, such as lead (Pb), that are leachable in aqueous solution. The fragmentation into microplastics (MPs) of plastics such as PVC may facilitate desorption of chemical additives and increase exposure of aquatic animals. In this study, the role of chemical additives in the aqueous toxicity of PVC, high-density polyethylene (HDPE) and polyethylene terephthalate (PET) MPs were investigated in early-life stage zebrafish (Danio rerio) by assessment of changes in expression of biomarkers. Exposure of zebrafish larvae to PVC for 24 h increased expression of metallothionein 2 (mt2), a metal-binding protein, but no changes in expression of biomarkers of estrogenic (vtg1) or organic (cyp1a) contaminants were observed. HDPE and PET caused no changes in expression of any biomarkers. A filtered leachate of the PVC also caused a significant increase in expression of mt2 and indicated that a desorbed metal additive likely elicited the response in zebrafish. Metal release was confirmed by acid-washing the MPs which mitigated the response in mt2. Metal analysis showed Pb leached from PVC into water during exposures; at 500 mg PVC L-1 in water, 84.3 ± 8.7 μg Pb L-1 was measured after 24 h. Exposure to a Pb-salt at this concentration caused a comparable mt2 increase in zebrafish as observed in exposures to PVC. These data indicated that PVC MPs elicited a response in zebrafish but the effect was indirect and mediated through desorption of Pb from PVC into the exposure water. Data also indicated that PVC MPs may act as longer-term environmental reservoirs of Pb for exposure of aquatic animals; the Pb leached from PVC in 24 h in freshwater equated to 2.52% of total Pb in MPs leachable by the acid-wash. Studies of MPs should consider the potential role of chemical additives in toxicity observed.


Anopheles bionomics in a malaria endemic area of southern Thailand.
Ivermectin mass drug administration (MDA) could accelerate malaria elimination in the Greater Mekong Subregion. This study was performed to characterize the bionomics of Anopheles in Surat Thani province, Thailand. Mosquitoes were collected via human landing collections between February and October 2019. Anopheles mosquitoes were morphologically identified to species. Primary Anopheles malaria vectors were dissected to assess parity status, and a subset were evaluated for molecular identification and Plasmodium detection. A total of 17,348 mosquitoes were collected during the study period; of these, 5777 were Anopheles mosquitoes. Morphological studies identified 15 Anopheles species, of which the most abundant were Anopheles minimus (s.l.) (87.16%, n = 5035), An. dirus s.l. (7.05%, n = 407) and An. barbirostris s.l. (2.86%, n = 165). Molecular identification confirmed that of the An. minimus s.l. mosquitoes collected, 99.80% were An. minimus (s.s.) (n = 484) and 0.2% were An. aconitus (n = 1), of the An. dirus (s.l.) collected, 100% were An. baimaii (n = 348), and of the An. maculatus (s.l.) collected, 93.62% were An. maculatus (s.s.) (n = 44) and 6.38% were An. sawadwongporni (n = 3). No Anopheles mosquito tested was Plasmodium positive (0/879). An average of 11.46 Anopheles were captured per collector per night. There were differences between species in hour of collection (Kruskal-Wallis H-test: χ2 = 80.89, P < 0.0001, n = 5666), with more An. barbirostris (s.l.) and An. maculatus (s.l.) caught earlier compared to An. minimus (s.l.) (P = 0.0001 and P < 0.0001, respectively) and An. dirus (s.l.) (P = 0.0082 and P < 0.001, respectively). The proportion of parous An. minimus (s.l.) captured by hour increased throughout the night (Wald Chi-square: χ2 = 17.31, P = 0.000, odds ratio = 1.0535, 95% confidence interval 1.0279-1.0796, n = 3400). Overall, An. minimus (s.l.) parity was 67.68% (2375/3509) with an intra-cluster correlation of 0.0378. A power calculation determined that an An. minimus (s.l.) parity reduction treatment effect size = 34%, with four clusters per treatment arm and a minimum of 300 mosquitoes dissected per cluster, at an α = 0.05, will provide 82% power to detect a significant difference following ivermectin MDA. The study area in Surat Thani province is an ideal location to evaluate the impact of ivermectin MDA on An. minimus parity.


Risk factors and pathological characteristics for intraductal tumor spread of submucosal gland in early esophageal squamous cell neoplasia.
The esophageal gland duct may serve as a pathway for the spread of early esophageal squamous cell neoplasia (ESCN) to a deeper layer. Deep intraductal tumor spreading cannot be completely eradicated by ablation therapy. However, the risk factors of ductal involvement (DI) in patients with ESCNs have yet to be investigated. We consecutively enrolled 160 early ESCNs, which were treated with endoscopic submucosal dissection. The resected specimens were reviewed for the number, morphology, resected margin, distribution and extension level of DI, which were then correlated to clinical factors. A total of 317 DIs (median:3, range 1-40 per-lesion) in 61 lesions (38.1%) were identified. Of these lesions, 14 have DIs maximally extended to the level of lamina propria mucosa, 17 to muscularis mucosae, and 30 to the submucosa. Multivariate logistic regression analysis showed that tumors located in the upper esophagus (OR = 2.93, 95% CI, 1.02-8.42), large tumor circumferential extension (OR = 5.39, 95% CI, 1.06-27.47), deep tumor invasion depth (OR = 4.12, 95% CI, 1.81-9.33) and numerous Lugol-voiding lesions in background esophageal mucosa (OR = 2.65, 95% CI, 1.10-6.37) were risk factors for DI. The maximally extended level of ducts involved were significantly correlated with the cancer invasion depth (P < 0.05). Notably, 245 (77%) of the involved ducts were located at the central-trisection of the lesions, and 52% of them (165/317) revealed dilatation of esophageal glandular ducts. Five (1.6%) of the involved ducts revealed cancer cell invasion through the glandular structures. In conclusion, DI is not uncommon in early ESCN and may be a major limitation of endoscopic ablation therapy.


Is something better than nothing? An evaluation of early childhood programs in Cambodia.
This study evaluated the relative effectiveness of home-based, community-based, and state-run early childhood programs across Cambodia. A total of 880 five-year-olds (55% girls) from 6 rural provinces in Cambodia attending State Preschools, Community Preschools, Home-Based Programs, or no programs were assessed twice using the Cambodian Developmental Assessment Test. Controlling for baseline differences, children who participated in any early childhood programs performed significantly better in posttest than those of children who did not participate in any programs. Children in State Preschools scored significantly higher than those in either Community Preschools or Home-Based Programs; scores did not differ as a function of attending Community Preschools or Home-Based Programs. The results indicate that some preschool experience is better than none at all.


Greater vertical impact loading in female runners with medically diagnosed injuries: a prospective investigation.
Running has been critical to human survival. Therefore, the high rate of injuries experienced by modern day runners is puzzling. Landing on the heel, as most modern day shod runners do, results in a distinct vertical impact force that has been shown to be associated with running-related injuries. However, these injury studies were retrospective in nature and do not establish cause and effect. To determine whether runners with high impacts are at greater risk for developing medically diagnosed injuries. 249 female runners underwent a gait analysis to measure vertical instantaneous loading rate, vertical average loading rate (VALR), vertical impact peak (VIP) and peak vertical force. Participants then recorded their mileage and any running-related injuries monthly in a web-based, database programme. Variables were first compared between the entire injured (INJ; n=144) and uninjured (n=105) groups. However, the focus of this study was on those injured runners seeking medical attention (n=103) and those who had never injured (n=21). There were no differences between the entire group of injured and uninjured groups. However, all impact-related variables were higher in those with medically diagnosed injuries compared with those who had never been injured. (effect size (ES) 0.4-0.59). When VALR was >66.0 body weight (BW)/s, the odds of being DX_INJ were 2.72 (95% CI 1.0 to 7.4). Impact loading was associated with bony and soft-tissue injuries. Vertical average loading rate was lower in female runners classified as 'never injured' compared with those who had been injured and sought medical attention.


Androgen receptor and follicle-stimulating hormone receptor in the pig ovary during the follicular phase of the estrous cycle.
Follicle-stimulating hormone (FSH) is an important regulator of follicular development. Some effects of FSH on ovarian follicles might be enhanced by androgens. The main objectives of the present study were to examine expression of the androgen receptor (AR) and FSH receptor (FSHR) in late developing follicles in pigs. Ovaries were collected from gilts on days 13, 15, 17, and 19 of the estrous cycle (day 0 = first day of estrus, n = 4 gilts/day), a period coincident with the follicular phase. One ovary was processed for immunohistochemistry (IHC) of AR. Samples of surface wall from the largest follicles (4-5 per gilt) were dissected from the other ovary, pooled and processed for determination of AR and FSHR mRNAs using reverse transcription-polymerase chain reaction (RT-PCR). Intense AR immunostaining was present in nuclei of granulosa cells of preantral and antral follicles. AR immunoreactivity was also present in the nuclei of oocytes. Weak staining for AR was observed in cells of the theca interna, ovarian surface epithelium, and in most cells of the ovarian stroma. Relative amounts of immunoreactive AR in granulosa cells of late developing follicles, or small antral follicles (< 2 mm), did not differ between days 13, 15, 17, and 19. However, amounts of AR in granulosa cells of small antral follicles was greater (P < 0.05) than in the largest follicles present in the same ovary. The relative amounts of AR mRNA in tissue from the largest follicles on days 13, 15, 17, and 19 did not differ; however, amounts of FSHR mRNA in the same follicles were not different between days 13, 15, and 17, but decreased (P < 0.05) by day 19. Results indicate that during the follicular phase in gilts, the AR protein is mainly present in granulosa cells. Relative amounts of AR protein in granulosa cells and mRNA in walls of late developing follicles did not significantly change from day 13 to 19; however, amounts of FSHR mRNA decreased in preovulatory follicles by day 19 of the estrous cycle.


Conducting online virtual environment experiments with uncompensated, unsupervised samples.
Web-based experimentation with uncompensated and unsupervised samples allows for a larger and more diverse sample population, more generalizable results, and faster theory to experiment cycle. Given that participants are unsupervised, it is still unknown whether the data collected in such settings would be of sufficiently high quality to support robust conclusions. Therefore, we investigated the feasibility of conducting such experiments online using virtual environment technologies. We conducted a conceptual replication of two prior experiments that have been conducted in virtual environments. Our results replicate findings previously obtained in conventional laboratory settings. These results hold across different device types of participants (ranging from desktop, through mobile devices to immersive virtual reality headsets), suggesting that experiments can be conducted online with uncompensated samples in virtual environments.


Methylpiperidinopyrazole Attenuates Estrogen-Induced Mitochondrial Energy Production and Subsequent Osteoblast Maturation via an Estrogen Receptor Alpha-Dependent Mechanism.
An estrogen deficiency is the main cause of osteoporosis in postmenopausal women. In bone remodeling, estrogen receptors (ERs) can mediate estrogen-transducing signals. Methylpiperidinopyrazole (MPP) is a highly specific antagonist of ER-alpha (ERα). This study was designed to evaluate the effects of MPP on estrogen-induced energy production, subsequent osteoblast maturation, and the possible mechanisms. Exposure of primary osteoblasts isolated from neonatal rat calvarias to MPP did not affect cell morphology or survival. Estradiol can induce translocation of ERα into mitochondria from the cytoplasm. Interestingly, pretreatment of rat calvarial osteoblasts with MPP lowered estrogen-induced ERα translocation. Sequentially, estrogen-triggered expressions of mitochondrial energy production-linked cytochrome c oxidase (COX) I and COX II messenger (m)RNAs were inhibited following pretreatment with MPP. Consequently, MPP caused decreases in estrogen-triggered augmentation of the activities of mitochondrial respiratory complex enzymes and levels of cellular adenosine phosphate (ATP). During progression of osteoblast maturation, estrogen induced bone morphogenetic protein (BMP)-6 and type I collagen mRNA expressions, but MPP treatment inhibited such induction. Consequently, estrogen-induced osteoblast activation and mineralization were attenuated after exposure to MPP. Taken together, MPP suppressed estrogen-induced osteoblast maturation through decreasing chromosomal osteogenesis-related BMP-6 and type I collagen mRNA expressions and mitochondrial ATP synthesis due to inhibiting energy production-linked COX I and II mRNA expressions. MPP can appropriately be applied to evaluate estrogen-involved bioenergetics and osteoblast maturation.


Opposing effects of interferon produced in bacteria and of tumor promoters on myogenesis in human myoblast cultures.
We have studied the effects of human leukocyte interferon produced in bacteria and diterpene phorbol ester tumor promoters on differentiation of normal human myoblast cultures derived from mature skeletal muscle. Interferon (100-5,000 units/ml) induced an acceleration of myotube formation and creatine kinase (CK; EC 188.8.131.52) isoenzyme transition from CK-BB to CK-MM. Heat-inactivated or trypsin-treated interferon did not affect the differentiation process. In contrast, the potent tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA), but not its inactive structural analogues phorbol and 4 alpha-phorbol 12,13-didecanoate, caused a dose-dependent (0.01-100 ng/ml) inhibition of myotube formation and CK isoenzyme transition. Neither interferon nor TPA had a significant effect on myoblast proliferation prior to fusion, and the cloning efficiencies were similar as well. Opposing effects of interferon and TPA were also demonstrated by simultaneous application of these agents to the cultures. These studies suggest that some of the antitumor effects of interferon may relate to its capacity to modulate cellular differentiation.


[Childhood obesity and its association with the feeling of unhappiness and low levels of self-esteem in children of public schools].
overweight children are at increased risk for psychosocial disorders. the purpose of this research was to relate the condition of overweight and obesity to the levels of self-esteem and happiness in schoolchildren of public schools. a total of 364 schoolchildren (180 boys and 184 girls) were enrolled between eleven and 13 years old (12.44 ± 1.14 years old). Anthropometric measurements were performed and the levels of self-esteem and happiness were evaluated through the School Self-Esteem Test (APT). RESULS: school self-esteem was significantly higher in boys (p < 0.001); 55.49% (n = 204) of the students evaluated were overweight. Overweight and obese subjects had lower levels of self-esteem compared to normal weight children (p = 0.032). In addition, 43 students had very low self-esteem, and a relationship between very low and low self-esteem levels (n = 119) and the overweight and obesity was observed (p = 0.033). In relation to the question "Am I a happy person?", a greater proportion of students answered positively (n = 296). The negative response to the question was associated with weight excess (p = 0.042). overweight and obesity were related to low levels of self-esteem and happiness in schoolchildren. These results are alarming since self-esteem is one's appreciation of oneself and happiness is an index of subjective personal well-being and is a topic that concerns families and the entire education system.


Clinical features, image findings, and prognosis of inflammatory pseudotumor of the liver: a multicenter experience of 45 cases.
Inflammatory pseudotumor (IPT) of the liver is a rare disease characterized by chronic infiltration of inflammatory cells. However, the clinical characteristics and outcomes of IPT remain uncertain. Clinical features, image findings, and outcomes of 55 patients with histologically proven IPT were evaluated. They consisted of 26 men and 19 women with median age of 65 years. Serum carcinoembryonal antigen and carbohydrate antigen 19-9 levels were normal in 42 patients (93.3%). Enhanced CT scans indicated poorly defined peripheral enhancement (82.5%) at the arterial phase and poorly defined hyperattenuating lesions with internal hypoattenuating areas at the equilibrium phase (77.0%). Gadolinium-enhancement MRI revealed poorly defined peripheral rim-like enhancement (77.8%). Ten patients underwent surgical resection and 35 were treated conservatively with or without antibiotics. No recurrence was noted after surgical resection during follow-up (1 to 48 months). In all patients who received conservative treatment, complete resolution or size reduction was noted during follow-up (1 to 192 months). CT and MRI provide clues to the diagnosis of IPT in patients with liver masses and normal tumor markers. However, due to the lack of pathognomonic findings, the clinician's suspicion and histological diagnosis are necessary to make an accurate diagnosis of IPT.