Unguarded tricuspid orifice with pulmonary atresia: successful radiofrequency ablation of an accessory pathway in an infant.
A male infant with the rare lesion of unguarded tricuspid orifice in the setting of pulmonary valve atresia, intact ventricular septum, and a hypoplastic right ventricle is described. The patient presented with cyanosis at 1 day old; transcutaneous oxygen saturations were between 20% and 30% in room air, and 60% in 100% inspired oxygen. Pre-excitation was found incidentally on the ECG and the potential for rapid antegrade conduction of atrial tachyarrhythmias, after eventual extended palliation with the Fontan procedure, was demonstrated at electrophysiological study. By 11 months old the patient was becoming increasingly cyanosed and interim palliation with a bidirectional cavopulmonary shunt was proposed. Successful radiofrequency ablation of the accessory pathway was performed before bidirectional cavopulmonary shunt, which would have prevented access to the heart via the superior vena cava. Difficulty with femoral venous access because of previous occlusion of a femoral vein was overcome by the use of 2 F pacing electrodes and a 5 F ablation catheter.


[The tolerance of tobacco genetically modified plants to aluminium].
Introduction of the vector constructions with rhamnolipid genes (rhlA and rhlB) into tobacco plants has resulted in development of genetically modified plants which were tolerant to high concentrations of aluminium. While under aluminium concentration of 200 mM in a soil (ionit resin) all control plants perished, transgenic tobacco plants continued to grow and were fertile.


A common adnexal mass in an uncommon patient: a case report.
Three years after a heart transplant, a woman presented with an adnexal mass that proved to be endometriosis. Her management and its results are presented.


Influence of reproductive mode on metabolic costs of reproduction: insight from the bimodal lizard Zootoca vivipara.
Examination of the selective forces behind the transition from oviparity to viviparity in vertebrates must include an understanding of the relative energy costs of the two reproductive modes. However, interspecific comparisons of reproductive mode are confounded by numerous other inherent differences among the species. Therefore, we compared oxygen consumption, as a reflection of energy costs, during reproduction in oviparous and viviparous females of the reproductively bimodal lizard Zootoca vivipara (Jaquin 1787). Female oxygen consumption progressively increased over the course of reproduction, peaking just prior to parition when it was 46% (oviparous form) and 82% (viviparous form) higher than it was at the pre-reproductive stage. Total increase in oxygen consumption (TIOC) during the pre-ovulation period was not different between the reproductive modes. Conversely, post-ovulation TIOC was more than three times higher in viviparous females, reflecting a dramatic increase in embryonic metabolism as well as maternal metabolic costs of pregnancy (MCP). MCP accounted for 22% of total metabolism in viviparous females, whereas it was negligible in oviparous females. Our results demonstrate that egg retention through the first third of development, as is typical of most oviparous squamates, entails minimal maternal energy demand, while extending retention imposes much greater metabolic constraints. Selection for transition from oviparity to viviparity must therefore provide benefits that outweigh not only the added burden associated with prolonged embryonic retention, but also the substantial additional energy costs that are incurred.


Risk of lymphoma in patients with inflammatory bowel disease treated with azathioprine and 6-mercaptopurine: a meta-analysis.
Thiopurine therapy for inflammatory bowel disease (IBD) has been associated with increased risk for lymphoma. We estimated the relative risk of lymphoma in patients with IBD exposed to thiopurines and compared relative risk values derived from population-based studies with those from referral center-based studies. We investigated whether active use increased risk compared with past use, and whether sex, age, or duration of use affects risk of lymphoma. We searched MEDLINE, EMBASE, and Cochrane databases, as well as conference abstracts and international publications, for the terms "6-MP and lymphoma," "6-mercaptopurine and lymphoma," "thiopurines and lymphoma," "azathioprine and cancer and IBD," "azathioprine and malignancy and IBD," "azathioprine and lymphoma," and "lymphoproliferative and thiopurines." Pooled standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were estimated. The deviance statistic from Poisson models was used to calculate heterogeneity. Eighteen studies (among 4383 citations) met our inclusion criteria. Overall, the SIR for lymphoma was 4.92 (95% CI, 3.10-7.78), ranging from 2.80 (95% CI, 1.82-4.32) in 8 population studies to 9.24 (95% CI, 4.69-18.2) in 10 referral studies. Population studies demonstrated an increased risk among current users (SIR = 5.71; 95% CI, 3.72-10.1) but not former users (SIR = 1.42; 95% CI, 0.86-2.34). Level of risk became significant after 1 year of exposure. Men have a greater risk than women (relative risk = 1.98; P < .05); both sexes were at increased risk for lymphoma (SIR for men = 4.50; 95% CI = 3.71-5.40 and SIR for women = 2.29; 95% CI = 1.69-3.05). Patients younger than 30 years had the highest relative risk (SIR = 6.99; 95% CI, 2.99-16.4); younger men had the highest risk. The absolute risk was highest in patients older than 50 years (1:354 cases per patient-year, with a relative risk of 4.78). Compared with studies from referral centers, population-based studies of IBD patients show a lower but significantly increased risk of lymphoma among patients taking thiopurines. The increased risk does not appear to persist after discontinuation of therapy. Patients over 50 have the highest absolute risk of lymphoma per year on thiopurines, while men under 35 may also be a high risk group. More study is needed to precisely understand groups highest at risk. The risks of lymphoma and potential benefits of therapy should be considered for all patients with IBD.


Adoption and implementation of a web-based self-management application "Oncokompas" in routine cancer care: a national pilot study.
A web-based self-management application "Oncokompas" was developed to monitor health-related quality of life and to support cancer survivors in finding and obtaining optimal supportive care. Access to this application is provided via a healthcare professional (HCP). The aim of this study was to explore the adoption and implementation of Oncokompas in routine clinical practice and to obtain insights in potentially relevant determinants of implementation. A pilot study was carried out among 65 hospitals throughout The Netherlands. HCPs filled out a questionnaire on the implementation of Oncokompas in their organization, consisting of study specific items and items based on the Measurement Instrument for Determinants of Innovations (MIDI). The MIDI comprises 29 determinants in four domains that predict the use of innovations: the innovation itself (Oncokompas), the user (HCP), the organization (hospital), and socio-political context. In total, 20/65 eligible hospitals agreed to implement Oncokompas (adoption rate 31%). In these 20 adopting hospitals, the majority of the responding HCPs (72/205) in this study (44/61) indicated their patients were offered access to Oncokompas (implementation rate 72%). Comparing those HCPs who did and did not implement Oncokompas, the groups differed significantly on innovation-related (procedural clarity, complexity) and user-related determinants (importance of outcome expectations, professional obligation, social support, and self-efficacy). During this 1-year study, nationwide adoption rate of Oncokompas was at 31%, and subsequent implementation rate was at 72%. The results of this study contribute to further optimize interventions and strategies to adopt and implement (online) self-management applications in cancer care.


[Metabolic system of acid-base homeostasis in the human and animal body].
Peculiarities of carbohydrate, lipid, amino acid nucleotide metabolism, of the tricarboxylic acid cycle functioning and of the oxidative phosphorylation have been studied in man and animals under conditions of changes in the acid-base equilibrium (ABE) state in the organism. The results of studies are analyzed and generalized. Strictly defined peculiarities of changes in the mentioned aspects of metabolism depending on the ABE state in the organism are revealed. Basing on a new interpretation of the experimental data and detected regularities in the metabolism, the author has drawn a conclusion on the existence of the previously unknown system of acid-base homeostasis in tissues. The physiological sense of this system functioning is the regulation of the intracellular acid-base equilibrium stability. The regulation mechanisms promoting functioning of this system are discussed. The system is shown to be of great applied significance for improvement of methods to cure a number of human and animal diseases as well as for an increase of the productivity of animals.


[Experience in studying various indicators of the deontological training of students before and after subinternship and the methods of its verification].
The paper is concerned with the results of a special study of the deontological potential of students prior to and after subinternship. Their attitude to occupation, the knowledge of the fundamentals of deontology, motivation of behavior in specific deontological situations and the reasoning of their actions and opinions were determined. A considerable gap between a high level of correct theoretical (declarative) ideas of deontology rules and inability to use them in everyday clinical practice was observed. Experience of the correction of graduates' deontological disposition was presented. The dialectic unity of inductive and deductive methods in mastering the fundamentals of deontology was stressed. Methods of the verification of deontological training of students in medical institutes were specified.


[Significance of clinico-immunologic correlations in different stages of alcoholism].
On the basis of clinico-immunological analysis (study of antibrain antibody), the authors validate the notion about the development of encephalopathic disturbances in the early post-drinking period of the first and second stages of alcoholism as a result of the integrated effect on the body at this period of alcoholic and metalcoholic toxicoses.


Dimerization between vasopressin V1b and corticotropin releasing hormone type 1 receptors.
1. Increasing evidence indicates that guanyl protein coupled receptors (GPCRs), including members of the vasopressin (VP) receptor family can act as homo- and heterodimers. Regulated expression and interaction of pituitary VP V1b receptor (V1bR) and corticotropin releasing hormone receptor type 1 (CRHR1) are critical for hypothalamic pituitary adrenal (HPA) axis adaptation, but it is unknown whether this involves physical interaction between these receptors.2. Bioluminescence resonance energy transfer (BRET) experiments using V1bR and CRHR1 fused to either Renilla luciferase (Rluc) or yellow fluorescent protein (YFP) at the N-terminus, but not the carboxyl-terminus, revealed specific interaction (BRET(50) = 0.39 +/- 0.08, V1bR) that was inhibited by untagged V1b or CRHR1 receptors, suggesting homo- and heterodimerization. The BRET data were confirmed by coimmunoprecipitation experiments using fully bioactive receptors tagged at the aminoterminus with c-myc and Flag epitopes, demonstrating specific homodimerization of the V1b receptor and heterodimerization of the V1b receptor with CRHR1 receptors.3. Heterodimerization between V1bR and CRHR1 is not ligand dependent since stimulation with CRH and AVP had no effect on coimmunoprecipitation. In membranes obtained from cells cotransfected with CRHR1 and V1bR, incubation with the heterologous nonpeptide antagonist did not alter the binding affinity or capacity of the receptor.4. The data demonstrate that V1bR and CRHR1 can form constitutive homo- and heterodimers and suggests that the heterodimerization does not influence the binding properties of these receptors.


Bcl-2 overexpression in type II epithelial cells does not prevent hyperoxia-induced acute lung injury in mice.
Bcl-2 is an anti-apoptotic molecule preventing oxidative stress damage and cell death. We have previously shown that Bcl-2 is able to prevent hyperoxia-induced cell death when overexpressed in a murine fibrosarcoma cell line L929. We hypothesized that its specific overexpression in pulmonary epithelial type II cells could prevent hyperoxia-induced lung injury by protecting the epithelial side of the alveolo-capillary barrier. In the present work, we first showed that in vitro Bcl-2 can rescue murine pulmonary epithelial cells (MLE12) from oxygen-induced cell apoptosis, as shown by analysis of LDH release, annexin V/propidium staining, and caspase-3 activity. We then generated transgenic mice overexpressing specifically Bcl-2 in lung epithelial type II cells under surfactant protein C (SP-C) promoter (Tg-Bcl-2) and exposed them to hyperoxia. Bcl-2 did not hinder hyperoxia-induced mitochondria and DNA oxidative damage of type II cell in vivo. Accordingly, lung damage was identical in both Tg-Bcl-2 and littermate mice strains, as measured by lung weight, bronchoalveolar lavage, and protein content. Nevertheless, we observed a significant lower number of TUNEL-positive cells in type II cells isolated from Tg-Bcl-2 mice exposed to hyperoxia compared with cells isolated from littermate mice. In summary, these results show that although Bcl-2 overexpression is able to prevent hyperoxia-induced cell death at single cell level in vitro and ex vivo, it is not sufficient to prevent cell death of parenchymal cells and to protect the lung from acute damage in mice.


Testing posttraumatic stress as a mediator of physical, sexual, and psychological intimate partner violence and substance problems among women.
This study examined whether posttraumatic stress specifically resulting from intimate partner violence (IPV-related posttraumatic stress) mediated relationships between types of IPV and drug and alcohol problems among 212 women currently experiencing IPV. Six-month prevalence was high for drug use (48%) and alcohol use (59%). Structural equation modeling revealed that the frequency of physical, sexual, and psychological IPV were significantly and positively related to greater IPV-related posttraumatic stress, and IPV-related posttraumatic stress was significantly and positively related to drug problems. Further, IPV-related posttraumatic stress mediated the relationships between physical IPV and drug problems and psychological IPV and drug problems. Findings suggest that prevention and intervention efforts targeting posttraumatic stress among IPV-exposed women may reduce drug problems in this population.


Rapid and direct transport of cell surface APP to the lysosome defines a novel selective pathway.
A central feature of Alzheimer's disease is the cleavage of the amyloid precursor protein (APP) to form beta-amyloid peptide (Abeta) by the beta-secretase and gamma-secretase enzymes. Although this has been shown to occur after endocytosis of APP from the cell surface, the exact compartments of APP processing are not well defined. We have previously demonstrated that APP and gamma-secretase proteins and activity are highly enriched in purified rat liver lysosomes. In order to examine the lysosomal distribution and trafficking of APP in cultured cells, we generated constructs containing APP fused to a C-terminal fluorescent protein tag and N-terminal HA-epitope tag. These were co-transfected with a panel of fluorescent-protein tagged compartment markers. Here we demonstrate using laser-scanning confocal microscopy that although APP is present throughout the endosomal/lysosomal system in transfected Cos7 and neuronal SN56 cell lines as well as in immunostained cultured mouse neurons, it is enriched in the lysosome. We also show that the Swedish and London mutations reduce the amount of APP in the lysosome. Surprisingly, in addition to its expected trafficking from the cell surface to the early and then late endosomes, we find that cell-surface labelled APP is transported rapidly and directly from the cell surface to lysosomes in both Cos7 and SN56 cells. This rapid transit to the lysosome is blocked by the presence of either the London or Swedish mutations. These results demonstrate the presence of a novel, rapid and specific transport pathway from the cell surface to the lysosomes. This suggests that regulation of lysosomal traffic could regulate APP processing and that the lysosome could play a central role in the pathophysiology of Alzheimer's disease.


ICU nurses' oral-care practices and the current best evidence.
The purpose of this study was to describe the oral-care practices of ICU nurses, to compare those practices with current evidence-based practice, and to determine if the use of evidence-based practice was associated with personal demographic or professional characteristics. A national survey of oral-care practices of ICU nurses was conducted using a convenience sample of 218 practicing ICU nurses in 2004-05. The survey instrument included questions about demographic and professional characteristics and a checklist of oral-care practices. Nurses rated their perceived level of priority concerning oral care on a scale from 0 to 100. A score was computed representing the sum of 14 items related to equipment, solutions, assessments, and techniques associated with the current best evidence. This score was then statistically analyzed using ANOVA to determine differences of EBP based on demographic and professional characteristics. The most commonly used equipment was gauze pads (84%), followed by tongue depressors (55%), and toothbrushes (34%). Chlorhexidine was the most common solution used (75%). Less than half (44%) reported brushing their patients' teeth. The majority performed an oral assessment before beginning oral care (71%); however, none could describe what assessment tool was used. Only 57% of nurses reported documenting their oral care. Nurses rated oral care of intubated patients with a priority of 67+/-27.1. Wide variations were noted within and between units in terms of which techniques, equipment, and solutions were used. No significant relationships were found between the use of an evidence-based protocol and demographic and professional characteristics or with the priority given to oral care. While nurses ranked oral care a high priority, many did not implement the latest evidence into their current practice. The level of research utilization was not related to personal or professional characteristics. Therefore attempts should be made to encourage all ICU nurses to introduce and use evidence-based, oral-care protocols. Practicing ICU nurses in this survey were often not adhering to the latest evidence-based practice and therefore need to be educated and encouraged to do so in order to improve patient care.


Validation of the factor structure of the adolescent dissociative experiences scale in a sample of trauma-exposed detained youth.
The inclusion of a dissociative subtype in the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM–5) criteria for the diagnosis of posttraumatic stress disorder (PTSD) has highlighted the need for valid and reliable measures of dissociative symptoms across developmental periods. The Adolescent Dissociative Experiences Scale (A-DES) is 1 of the few measures validated for young persons, but previous studies have yielded inconsistent results regarding its factor structure. Further, research to date on the A-DES has been based upon nonclinical samples of youth or those without a known history of trauma. To address these gaps in the literature, the present study investigated the factor structure and construct validity of the A-DES in a sample of highly trauma-exposed youth involved in the juvenile justice system. A sample of 784 youth (73.7% boys) recruited from a detention center completed self-report measures of trauma exposure and the A-DES, a subset of whom (n = 212) also completed a measure of PTSD symptoms. Confirmatory factor analyses revealed a best fitting 3-factor structure comprised of depersonalization or derealization, amnesia, and loss of conscious control, with configural and metric invariance across gender. Logistic regression analyses indicated that the depersonalization or derealization factor effectively distinguished between those youth who did and did not likely meet criteria for a diagnosis of PTSD as well as those with PTSD who did and did not likely meet criteria for the dissociative subtype. These results provide support for the multidimensionality of the construct of posttraumatic dissociation and contribute to the understanding of the dissociative subtype of PTSD among adolescents. (PsycINFO Database Record


Eating with peel or not: Investigation of the peel consumption situation and its nutrition, risk analysis, and dietary advice in China.
Nutritious, balanced, tasty and easy to eat, fruit is an indispensable health food for consumers. With consumers' increasing respect for the concept of health, green and nutrition, the peel, which has higher nutritional value compared to the pulp, is gradually being emphasized in the consumption process. The suitability of fruit peels for consumption is influenced by various factors, such as the amount of pesticide residues, nutrient content, ease of peeling, and fruit texture, but there is a lack of relevant studies to guide consumers' scientific intake of fruit peels. This review first investigated chineses consumers consumption of common fruits with peels, especially eight fruits that are controversial in terms of whether to consume them with peels, and the results showed that whether people consume peels depends mainly on their nutritional value and pesticide residues. Based on this, the paper discusses the common methods of pesticide detection and removal from fruit peels, as well as the nutrients contained in different fruit peels and their physiological activities, if the peels usually have stronger antioxidant, anti-inflammatory and anti-tumor activities than the pulp. Finally, reasonable dietary recommendations are made on whether fruits should be consumed with their peels, with a view to guiding chineses consumers towards scientific consumption and provide theoretical basis for relevant research in other countries.


Thymic-dependent anti-hapten response in congenitally athymic (nude) mice immunized with DNP-thymosin.
Immunization of congenitally athymic (nu/nu) and adult thymectomized, irradiated bone marrow, reconstituted (TxBm) mice with DNP5-thymosin (dinitrophenylated-bovine thymosin fraction 5) was found to elcit IgM and IgG anti-DNP plaque-forming cells in these animals. Further studies indicated that this response was antigen specific and not due to polyclonal activation. Since the hormonal properties of the thymosin were retained following linkage with hapten and DNP-thymosin was immunogenic in CBA/N and CBA/N female X DBA/2 male)F1 male mice, animals previously shown to have an X-linked inability to respond to thymus-independent antigens, it was concluded that DNP-thymosin functions both as a hormone and as a T-dependent antigen in eliciting an immune response in nu/nu and TxBm mice. Additional support for this conclusion was provided by the demonstration that DNP-thymosin could specifically prime for and elicit an anamnestic response in nu/nu mice. These results indicate that further investigation of the immune activities of DNP-thymosin may provide valuable insight in characterizing the maturation of helper T cells and their subsequent interaction with B cells.


Reconstitution premixes for assays using purified recombinant human cytochrome P450, NADPH-cytochrome P450 reductase, and cytochrome b5.
The development of enzyme and buffer premixes for in vitro biotransformation assays is described. The protein premixes contain a mixture of three recombinant human proteins, cytochrome P450 (P450) 3A4, NADPH-P450 reductase, cytochrome b5, and liposomes. The buffer premix contains reagents which, when diluted, provide for optimal metabolic activity with selected P450 3A4 substrates. P450 3A4 premixes were competent in the oxidation of known substrates including testosterone, midazolam, nifedipine, erythromycin, benzphetamine, and amitriptyline. Premixes stored at -80 degrees C for 2 months and those that underwent an additional five freeze/thaw cycles were able to hydroxylate testosterone at turnover rates similar to freshly prepared reconstitution mixes. In addition, premixes stored unfrozen at 4 degrees C for 2 weeks showed no significant loss in the rate of testosterone 6 beta-hydroxylation by P450 3A4. Premixes prepared with and without reduced glutathione, a component which had previously been found to be important for P450 3A4 reactions, were equally efficient at carrying out testosterone hydroxylation under these conditions. Kinetic parameters determined for the metabolism of testosterone, amitriptyline, nifedipine, and benzphetamine using P450 3A4 premixes were compared with human pooled microsomes and insect microsomes prepared from cells infected with a baculovirus containing two cDNA inserts coding for P450 3A4 and NADPH-P450 reductase. Each format gave different Vmax and K(m) values indicating different catalytic efficiencies. Analysis of P450 1A2 premixes which contained different lipid concentrations indicated that Vmax and K(m) could be altered. The availability of human P450 recombinant enzymes and the development of the P450 premixes that remain active after being stored frozen should allow for rapid identification of novel P450 substrates and inhibitors and the development of large-scale screening assays.


Photocatalytic Applications of Electrospun TiO2 Nanofibres Embedded with Bimodal Sized and Prismatic Gold Nanoparticles.
In this paper, we have synthesized electrospun TiO2 nanofibers embedded with bimodal sized and prismatic gold nanoparticles. The surface plasmons generated in the gold nanoparticles were used to enhance the performance of photocatalysis. The photocatalytic conversion efficiencies of these bimodal sized/prismatic gold nanoparticles when embedded in electrospun TiO2 fibres showed an enhancement of upto 60% over bare fiber systems and also show higher efficiencies than electrospun fibrous systems embedded with unimodal sized gold nanoparticles. Anisotropic bimodal gold nanoparticles show the highest degree of photocatalytic activity. This may be attributed to greater density/concentration of nanoparticles with higher effective surface area and formation of a junction between the smaller and larger nanoparticles. Such a bimodally distributed range of nanoparticles could also lead to greater trapping of charge carriers at the TiO2 conduction band edge and promoting catalytic reactions on account of these trapped charges. This enhanced photocatalytic activity is explained by invoking different operating mechanisms such as improved surface area, greater trapping, coarse plasmon resonance and band effects. Thus, a useful applicability of the gold nanoparticles is shown in the area of photocatalysis.


Optimal duration of oral anticoagulant therapy in venous thromboembolism.
Recent trials with sufficient statistical power have demonstrated that the duration of oral anticoagulation in many cases need to be extended well beyond 4-6 weeks. Since many individual factors, as risk of hemorrhage and of recurrence, compliance and cost have to be weighed into a decision, it is difficult to issue general recommendations. Several of these factors, especially those influencing the risk of recurrent event are reviewed here. The ideal solutions will perhaps only be achieved when we have learned how to combine the optimal duration with a time-adjusted decrease in oral anticoagulation.


Crisis Team Management in a Scarce Resource Setting: Angkor Hospital for Children in Siem Reap, Cambodia.
A crisis team management (CTM) simulation course was developed by volunteers from Health Volunteers Overseas for physicians and nurses at Angkor Hospital for Children (AHC) in Siem Reap, Cambodia. The framework for the course was adapted from crisis resource management (1, 2), crisis team training (3), and TeamSTEPPs© models (4). The CTM course focused on teaching physicians and nurses on the development of team performance knowledge, skills, and attitudes. Challenges to providing this course at AHC included availability of simulation equipment, cultural differences in learning, and language barriers. The purpose of this project was to evaluate the impact of a CTM simulation course at AHC on attitudes and perceptions of participants on concepts related to team performance. Each of the CTM courses consisted of three lectures, including team performance concepts, communication, and debriefing followed by rotation through four simulation scenarios. The evaluation instrument used to evaluate the AHC CTM course was developed for Cambodian staff at AHC based on TeamSTEPPs© instruments evaluating attitude and perceptions of team performance (5). CTM team performance concepts included in lectures, debriefing sessions, and the evaluation instrument were: team structure, leadership, situation monitoring, mutual support, and communication. The Wilcoxon signed-rank test was used to analyze pre- and post-test paired data from participants in the course. Of the 54 participants completing the three CTM courses at AHC, 27 were nurses, 6 were anesthetists, and 21 were physicians. Attitude and perception scores were found to significantly improve (p < 0.05) for team structure, leadership, situation monitoring, and communication. Team performance areas that improved the most were: discussion of team performance, communication, and exchange of information. Teaching of non-technical skills can be effective in a setting with scarce resources in a Southeastern Asian country.


Effect of exercise therapy compared with arthroscopic surgery on knee muscle strength and functional performance in middle-aged patients with degenerative meniscus tears: a 3-mo follow-up of a randomized controlled trial.
The aim of this study was to compare the effect of a 12-wk exercise therapy program and arthroscopic partial meniscectomy on knee strength and functional performance in middle-aged patients with degenerative meniscus tears. A total of 82 patients (mean age, 49 yrs; 35% women) with a symptomatic, unilateral, magnetic resonance imaging-verified degenerative meniscus tear and no or mild radiographic osteoarthritis were randomly assigned to a supervised neuromuscular and strength exercise program or arthroscopic partial meniscectomy. Outcomes assessed 3 mos after intervention initiation were isokinetic knee muscle strength, lower extremity performance, and self-reported global rating of change. Mean difference in isokinetic knee extension peak torque between the two groups was 16% (95% confidence interval, 7.1-24.0) (P < 0.0001), favoring the exercise group. Patients in the exercise group improved isokinetic knee extension peak by a mean of 25 Nm (range, 18-33 Nm) from baseline to follow-up. Furthermore, patients assigned to exercise therapy showed statistically significant improvements (P ≤ 0.002) in all other measured variables, with moderate to large effect sizes (0.5-1.3). Patients reported a similar and positive effect of both interventions. A 12-wk supervised exercise therapy program yielded clinically relevant and statistically significant improvement in isokinetic quadriceps strength immediately after completion of the program, as compared with treatment with arthroscopic partial meniscectomy.


Context-dependent partitioning of motor learning in bimanual movements.
Human subjects easily adapt to single dynamic or visuomotor perturbations. In contrast, when two opposing dynamic or visuomotor perturbations are presented sequentially, interference is often observed. We examined the effect of bimanual movement context on interference between opposing perturbations using pairs of contexts, in which the relative direction of movement between the two arms was different across the pair. When each perturbation direction was associated with a different bimanual context, such as movement of the arms in the same direction versus movement in the opposite direction, interference was dramatically reduced. This occurred over a short period of training and was seen for both dynamic and visuomotor perturbations, suggesting a partitioning of motor learning for the different bimanual contexts. Further support for this was found in a series of transfer experiments. Having learned a single dynamic or visuomotor perturbation in one bimanual context, subjects showed incomplete transfer of this learning when the context changed, even though the perturbation remained the same. In addition, we examined a bimanual context in which one arm was moved passively and show that the reduction in interference requires active movement. The sensory consequences of movement are thus insufficient to allow opposing perturbations to be co-represented. Our results suggest different bimanual movement contexts engage at least partially separate representations of dynamics and kinematics in the motor system.


Predictors of Health Among Refugee Adults from Myanmar and the Development of Their Children.
The objective of this study is to attempt to understand predictors of health among adult migrants from Myanmar to Thailand and predictors of development among their children. EQ5D5L scores and sociodemographic data were obtained among adult household members of children from two schools on the Thai/Myanmar border. Children were administered Ages and Stages questionnaires (ASQs). OLS and logistic regressions were used to examine predictors (e.g., witnessing gunfire) of various outcome measures (e.g., ASQ scores among children). In logistic regression analyses, maternal literacy proved to be a very strong predictor of the child's ASQ communication [17 ASQ points out of 60; 95% confidence interval (CI) 3, 31 points], problem solving (25 points; 95% CI 4, 45 points), and social skills (12 points; 95 % CI 1, 23 points) scores. A lower number of habitants/room predicted significantly better dentition among children [odds ratio (OR) 1.08, 95% CI 1.01, 1.67] and better social skills on the child's ASQ (12 points; 95% CI 1, 23 points). Appliance ownership was a weak predictor of adult health, with those who own a refrigerator having about an 8% higher score on the EQ5D5L (1.08; 95% CI 1.01, 1.16). Finally, parents who witnessed gunfire tended to have children with ASQ scores that were 14 points lower than average in problem solving (95% CI -24, -4). Maternal education programs may have a very large impact on the development of their children. However, identifying those households at greatest need of resources is not a simple task, and will require a more complete census of communities at risk.


The effect of aspirin on the size of the hemostatic plug.
The prolongation of the bleeding time by aspirin is presumably due to interfering with platelet function. Direct quantitative studies evaluating the effects of aspirin on the platelet component of the hemostatic plug have not been described. We measured blood loss from a standard ear injury in rabbits after treatment with either 5 mg or 200 mg/kg of aspirin (ASA) or sodium salicylate (SA), and related this observation to the number of platelets incorporated into the hemostatic plug. The high dose of aspirin was chosen since this dose inhibits PGI2 biosynthesis. Both doses of aspirin but not salicylate caused a significant increase on blood loss from the treated ear compared to the control (ASA 5 mg/kg, 0.012 +/- 0.009 ml, (m +/- SE), n = 44, p = 0.03; ASA 200 mg/kg, 0.02 +/- 0.007 ml, n = 17, p less than 0.05). Both doses of aspirin also caused a significant increase in the number of platelets incorporated into the hemostatic plug when compared to the SA treated animals (ASA 5 mg/kg, 3.52 +/- 0.34 X 10(6) platelets per incision, (m +/- SE), n = 59; SA 5 mg/kg, 1.9 +/- 0.15 X 10(6) platelets per incision, n = 54, p less than 0.001; ASA 200 mg/kg, 3.19 +/- 0.54 X 10(6) platelets per incision, n = 22; SA 200 mg/kg, 1.5 +/- 0.26 X 10(6) platelets per incision, n = 23, p less than 0.001). This study suggests that following aspirin administration hemostasis is achieved by the incorporation of a greater number of platelets into the platelet plug.(ABSTRACT TRUNCATED AT 250 WORDS)


Likelihood-free inference of population structure and local adaptation in a Bayesian hierarchical model.
We address the problem of finding evidence of natural selection from genetic data, accounting for the confounding effects of demographic history. In the absence of natural selection, gene genealogies should all be sampled from the same underlying distribution, often approximated by a coalescent model. Selection at a particular locus will lead to a modified genealogy, and this motivates a number of recent approaches for detecting the effects of natural selection in the genome as "outliers" under some models. The demographic history of a population affects the sampling distribution of genealogies, and therefore the observed genotypes and the classification of outliers. Since we cannot see genealogies directly, we have to infer them from the observed data under some model of mutation and demography. Thus the accuracy of an outlier-based approach depends to a greater or a lesser extent on the uncertainty about the demographic and mutational model. A natural modeling framework for this type of problem is provided by Bayesian hierarchical models, in which parameters, such as mutation rates and selection coefficients, are allowed to vary across loci. It has proved quite difficult computationally to implement fully probabilistic genealogical models with complex demographies, and this has motivated the development of approximations such as approximate Bayesian computation (ABC). In ABC the data are compressed into summary statistics, and computation of the likelihood function is replaced by simulation of data under the model. In a hierarchical setting one may be interested both in hyperparameters and parameters, and there may be very many of the latter--for example, in a genetic model, these may be parameters describing each of many loci or populations. This poses a problem for ABC in that one then requires summary statistics for each locus, which, if used naively, leads to a consequent difficulty in conditional density estimation. We develop a general method for applying ABC to Bayesian hierarchical models, and we apply it to detect microsatellite loci influenced by local selection. We demonstrate using receiver operating characteristic (ROC) analysis that this approach has comparable performance to a full-likelihood method and outperforms it when mutation rates are variable across loci.


CGRP antagonist infused into the bed nucleus of the stria terminalis impairs the acquisition and expression of context but not discretely cued fear.
Calcitonin gene-related peptide (CGRP) infusions into the bed nucleus of the stria terminalis (BNST) evoke increases in startle amplitude and increases in anxiety-like behavior in the plus maze. Conversely, intra-BNST infusions of the CGRP antagonist CGRP₈₋₃₇ block unconditioned startle increases produced by fox odor. Here we evaluate the contribution of CGRP signaling in the BNST to the development and expression of learned fear. Rats received five pairings of a 3.7-sec light and footshock and were tested for fear-potentiated startle one or more days later. Neither pre-training (Experiment 1) nor pre-test (Experiment 2) infusions of the CGRP antagonist CGRP₈₋₃₇ (800 ng/BNST) disrupted fear-potentiated startle to the 3.7-sec visual cue. However, in both experiments, CGRP₈₋₃₇ infusions disrupted baseline startle increases that occurred when rats were tested in the same context as that in which they previously received footshock (Experiment 3). Intra-BNST CGRP₈₋₃₇ infusions did not disrupt shock-evoked corticosterone release (Experiment 4). These data confirm previous findings implicating BNST CGRP receptors in fear and anxiety. They extend those results by showing an important contribution to learned fear and, specifically, to fear evoked by a shock-associated context rather than a discrete cue. This pattern is consistent with previous models of BNST function that have posited a preferential role in sustained anxiety as opposed to phasic fear responses. More generally, the results add to a growing body of evidence indicating behaviorally, possibly clinically, relevant modulation of BNST function by neuroactive peptides.


Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases.
Acute respiratory failure and a systemic coagulopathy are critical aspects of the morbidity and mortality characterizing infection with severe acute respiratory distress syndrome-associated coronavirus-2, the etiologic agent of Coronavirus disease 2019 (COVID-19). We examined skin and lung tissues from 5 patients with severe COVID-19 characterized by respiratory failure (n= 5) and purpuric skin rash (n = 3). COVID-19 pneumonitis was predominantly a pauci-inflammatory septal capillary injury with significant septal capillary mural and luminal fibrin deposition and permeation of the interalveolar septa by neutrophils. No viral cytopathic changes were observed and the diffuse alveolar damage (DAD) with hyaline membranes, inflammation, and type II pneumocyte hyperplasia, hallmarks of classic acute respiratory distress syndrome, were not prominent. These pulmonary findings were accompanied by significant deposits of terminal complement components C5b-9 (membrane attack complex), C4d, and mannose binding lectin (MBL)-associated serine protease (MASP)2, in the microvasculature, consistent with sustained, systemic activation of the complement pathways. The purpuric skin lesions similarly showed a pauci-inflammatory thrombogenic vasculopathy, with deposition of C5b-9 and C4d in both grossly involved and normally-appearing skin. In addition, there was co-localization of COVID-19 spike glycoproteins with C4d and C5b-9 in the interalveolar septa and the cutaneous microvasculature of 2 cases examined. In conclusion, at least a subset of sustained, severe COVID-19 may define a type of catastrophic microvascular injury syndrome mediated by activation of complement pathways and an associated procoagulant state. It provides a foundation for further exploration of the pathophysiologic importance of complement in COVID-19, and could suggest targets for specific intervention.


Chemical Analysis of Astragali Complanati Semen and Its Hypocholesterolemic Effect Using Serum Metabolomics Based on Gas Chromatography-Mass Spectrometry.
The hypocholesterolemic protective effect of the dried seed of Astragalus complanatus (ACS) was investigated in rats fed with normal diet, high cholesterol diet (HCD), and HCD plus 70% ethanol extract of ACS (600 mg/kg/day) by oral gavage for four weeks. ACS extract was tested to be rich in antioxidants, which may be contributed to its high content of phenolic compounds. Consumption of ACS remarkably suppressed the elevated total cholesterol (p < 0.01) and LDL-C (p < 0.001) induced by HCD. Chemical constituents of ACS extract were analyzed by ultra-performance liquid chromatography coupled with electrospray ionization orbitrap mass spectrometry and the results showed that the ACS extract mainly consisted of phenolic compounds including flavonoids and flavonoid glycosides. In addition, based on the serum fatty acid profiles, elucidated using gas chromatography-mass spectrometry, free and esterified fatty acids including docosapentaenoic acid, adrenic acid, dihomo-γ-linolenic acid and arachidonic acid were regulated in ACS treatment group. Western blot results further indicated the protein expression of peroxisome proliferator-activated receptor alpha (PPARα) (p < 0.05) in liver was upregulated in ACS treatment group. To conclude, our results clearly demonstrated that ACS provides beneficial effect on lowering HCD associated detrimental change.


Search for stratospheric bromine reservoir species: theoretical study of the photostability of mono-, tri-, and pentacoordinated bromine compounds.
Previous work has shown that pentacoordinated bromine compounds have their lowest excited electronic states shifted to the blue relative to monocoordinated bromine molecules, and that this shift may be large enough to render them photostable in the lower stratosphere. Our earlier work has also shown that certain pentacoordinated bromine compounds are thermodynamically stable relative to their mono- or tricoordinated isomers, suggesting that if a bromine stratospheric reservoir species exists, it may be a pentacoordinated compound. In this study we have examined the singlet and triplet excited electronic states of several bromine compounds, using time dependent density functional theory, to assess their photostability under stratospheric conditions and in order to elucidate the nature of lowest excited states in mono-, tri-, and pentacoordinated bromine molecules. The triplet states have been included due to the strong spin-orbit mixing in bromine. We have found several pentacoordinated bromine/oxygen compounds that could be photostable in the lower stratosphere, but we have also found that monovalent bromine compounds where the bromine atom is bonded to an atom with no lone-pair p-electrons is far and away the most photostable. Attachment/detachment electron density plots have been useful in ascertaining the nature of the excited electronic states and their likely path to photodissociation.


Is the assumed natural history of vulvar intraepithelial neoplasia III based on enough evidence? A systematic review of 3322 published patients.
To establish the true natural history of VIN III from literature data. In a systematic review, data of women with VIN III indexed in several computer databases were pooled. The effect of treatment was correlated with recurrences and progression of VIN III. Ninety-seven articles met the inclusion criteria. Data of 3322 patients were available. The mean age at diagnosis of VIN III was 46. This decreased over time, although not significantly (P = 0.08). Recurrences were seen as often after local excision as after vulvectomy. The percentage of recurrences was lower, but not absent, after free surgical margins than after involved surgical margins (P < 0.001). 6.5% of the 3322 patients progressed to an invasive vulvar carcinoma. Occult carcinomas were diagnosed in 3.2% of patients and 3.3% carcinomas were diagnosed during follow-up. The mean age at diagnosis of invasive vulvar carcinoma was 52 years. Nine percent of 88 untreated patients progressed in 12 to 96 months to invasive vulvar carcinoma. Only 1.2% of the 3322 patients showed complete regression, mostly during the first 10 months after diagnosis, 41% of which was related to pregnancy. Evidence exists that VIN III may progress to invasive vulvar carcinoma. However, the available literature suggests that the progression rate to invasive vulvar carcinoma is low. The incidence of invasion as found in this systematic review is probably even too high, because overreporting of (micro)invasive cases cannot be excluded. Only a prospective registration using a standardized pathology examination will provide information about the real natural history of VIN III.


How we do it: the Zurich Microsurgery Lab technique for placenta preparation.
Perfused placentas provide an excellent and accessible model for microvascular dissection, microsuturing and microanastomosis training - particularly in the early microsurgical learning curve. This way, a significant amount of live animals can be spared. We present the Zurich Microsurgery Lab protocol, detailing steps for obtaining, selecting, cleaning, flushing, cannulating, and preserving human placentas - as well as microsurgical training examples - in a tried-and-true, safe, cost-effective, and high-yield fashion. Our technique enables highly realistic microsurgical training (microdissection, microvascular repair, microanastomosis) based on readily available materials. Proper handling, preparation, and preservation of the perfused placenta models is key.


[Serotonergic regulation of motor activity of duodenum].
Objective--find the possible role of serotonin in the regulation of motor activity of the duodenum. It is shown that the activation of ganglionic 5-HT4, 5-HT3 receptors and 5-HT1--and 5-HT2 receptors of effector cells is accompanied by changes in electromotor activity of the intestine. Blockade of these receptors to varying degrees inhibit stimulatory effect of serotonin.


Highly active aluminium catalysts for the formation of organic carbonates from CO2 and oxiranes.
Al(III) complexes of amino-tris(phenolate) ligand scaffolds have been prepared to attain highly Lewis acidic catalysts. Combination of the aforementioned systems with ammonium halides provides highly active catalysts for the synthesis of organic carbonates through addition of carbon dioxide to oxiranes with initial turnover frequencies among the highest reported to date within the context of cyclic carbonate formation. Density functional theory (DFT) studies combined with kinetic data provides a rational for the relative high activity found for these Al(III) complexes, and the data are consistent with a monometallic mechanism. The activity and versatility of these Al(III) complexes has also been evaluated against some state-of-the-art catalysts and the combined results compare favorably in terms of catalyst construction, stability, activity, and applicability.


Sexual size dimorphism in shorebirds, gulls, and alcids: the influence of sexual and natural selection.
Charadrii (shorebirds, gulls, and alcids) have an unusual diversity in their sexual size dimorphism, ranging from monomorphism to either male-biased or female-biased dimorphism. We use comparative analyses to investigate whether this variation relates to sexual selection through competition for mates or natural selection through different use of resources by males and females. As predicted by sexual selection theory, we found that in taxa with socially polygynous mating systems, males were relatively larger than females compared with less polygynous species. Furthermore, evolution toward socially polyandrous mating systems was correlated with decreases in relative male size. These patterns depend on the kinds of courtship displays performed by males. In taxa with acrobatic flight displays, males are relatively smaller than in taxa in which courtship involves simple flights or displays from the ground. This result remains significant when the relationship with mating system is controlled statistically, thereby explaining the enigma of why males are often smaller than females in socially monogamous species. We did not find evidence that evolutionary changes in sexual dimorphism relate to niche division on the breeding grounds. In particular, biparental species did not have greater dimorphism in bill lengths than uniparental species, contrary to the hypothesis that selection for ecological divergence on the breeding grounds has been important as a general explanation for patterns of bill dimorphism. Taken together, these results strongly suggest that sexual selection has had a major influence on sexual size dimorphism in Charadrii, whereas divergence in the use of feeding resources while breeding was not supported by our analyses.


Selexipag, a selective prostacyclin receptor agonist in pulmonary arterial hypertension: a pharmacology review.
Pulmonary hypertension is defined by a mean pulmonary artery pressure ≥25 mm Hg at rest. Management of pulmonary arterial hypertension (PAH) includes specific drug therapy with calcium channel blockers in vasoreactive patients, or drugs approved for PAH in non-reactive patients that target the endothelin, nitric-oxide and prostacyclin pathways. Areas covered: The review covers receptor selectivity, pharmacokinetics, pharmacodynamics and adverse effects (AEs) of intravenous (IV) epoprostenol (synthetic prostacyclin); the prostacyclin analogs iloprost, beraprost, and treprostinil administered by IV, subcutaneous, inhaled or oral routes; and the oral selective prostacyclin receptor agonist selexipag. Expert commentary: Development of a selective prostacyclin receptor agonist has aimed at identifying compounds with improved pharmacological properties. The high selectivity of selexipag, and its active metabolite ACT-333679, for the prostacyclin receptor, in conjunction with pharmacokinetic properties that reduce peak-trough fluctuations and the up-titration regimen used at the start of treatment, are collectively considered to minimize AEs associated with prostacyclin use. In a large phase 3 study, selexipag-associated AEs were consistent with those observed with drugs that target the prostacyclin pathway, and mainly mild to moderate in severity. The dosing flexibility afforded by oral selexipag may facilitate achieving the maximum therapeutic effect with acceptable tolerability in patients with PAH.


Induction of chronic measles encephalitis in C57BL/6 mice.
Chronic measles encephalitis was induced in C57BL/6 mice with the hamster neurotropic strain of measles virus when virus which had been passaged at low dilution in the brains of suckling C57BL/6 mice was inoculated intracerebrally into 1- to 6-month-old mice. One-third to two-thirds of mice surviving the acute infection were consistently found to develop chronic neurologic dysfunction within 3 weeks to 1 year post-infection. The acute mortality was higher in males than in females and showed a slight decline with increasing age in males. Indirect immunofluorescence (IF) studies using measles virus-specific sera from a subacute sclerosing panencephalitis patient and from a hyperimmune rabbit demonstrated abundant viral antigen in regions of telencephalon and diencephalon correlated with the appearance of typical central nervous system signs in both acute and chronic disease. Viral antigen was found in infected neurons in the grey matter. Deposition of immune complexes was minimal as observed in adjacent brain sections stained with goat anti-mouse antibody by direct IF. Occasional necrotic foci and perivascular cuffing were observed in brains from chronically infected mice.


Protein-directed self-assembly of a fullerene crystal.
Learning to engineer self-assembly would enable the precise organization of molecules by design to create matter with tailored properties. Here we demonstrate that proteins can direct the self-assembly of buckminsterfullerene (C60) into ordered superstructures. A previously engineered tetrameric helical bundle binds C60 in solution, rendering it water soluble. Two tetramers associate with one C60, promoting further organization revealed in a 1.67-Å crystal structure. Fullerene groups occupy periodic lattice sites, sandwiched between two Tyr residues from adjacent tetramers. Strikingly, the assembly exhibits high charge conductance, whereas both the protein-alone crystal and amorphous C60 are electrically insulating. The affinity of C60 for its crystal-binding site is estimated to be in the nanomolar range, with lattices of known protein crystals geometrically compatible with incorporating the motif. Taken together, these findings suggest a new means of organizing fullerene molecules into a rich variety of lattices to generate new properties by design.


Fluid displacement from intraluminal thrombus of abdominal aortic aneurysm as a result of uniform compression.
Objectives The results after aneurysm repair with an endovascular aneurysm sealing (EVAS) system are dependent on the stability of the aneurysm sac and particularly the intraluminal abdominal aortic thrombus (ILT). The postprocedural ILT volume is decreased compared with preprocedural ILT volume in aortic aneurysm patients treated with EVAS. We hypothesize that ILT is not stable in all patients and pressurization of the ILT may result in displacement of fluids from the ILT, no differently than serum is displaced from whole blood when it settles. To date, the mechanism and quantification of fluid displacement from ILT are unknown. Methods The study included 21 patients who underwent elective open abdominal aortic aneurysm repair. The ILT was harvested as a routine procedure during the operation. After excision of a histologic sample of the ILT specimen in four patients, ILT volume was measured and the ILT was compressed in a dedicated compression setup designed to apply uniform compression of 200 mmHg for 5 min. After compression, the volumes of the remaining thrombus and the displaced fluid were measured. Results The median (interquartile-range) of ILT volume before compression was 60 (66) mL, and a median of 5.7 (8.4) mL of fluid was displaced from the ILT after compression, resulting in a median thrombus volume decrease of 11% (10%). Fluid components can be up to 31% of the entire ILT volume. Histologic examination of four ILT specimens showed a reduction of the medial layer of the ILT after compression, which was the result of compression of fluid-containing canaliculi. Conclusions Applying pressure of 200 mmHg to abdominal aortic aneurysm ILT resulted in the displacement of fluid, with a large variation among patients. Fluid displacement may result in decrease of ILT volume during and after EVAS, which might have implications on pre-EVAS volume planning and on stability of the endobags during follow-up which may lead to migration, endoleak or both.


[Vaccinating properties of the Kekava 55 strain of attenuated Marek's disease virus].
Two attenuated strains of oncogenic herpes virus, Marek's disease virus, were obtained: one by cultivation in chick fibroblast cultures at 37 degrees C, the other at 41 degrees C, i. e. at chicken body temperature. Both attenuated strains throughout a large number of passages retain high vaccination efficacy, on the average 76% and 77.3%, respectively. The virus attenuated at 41 degrees C is superior to that attenuated at 37 degrees C in higher reproduction rate in vitro and, possibly, in a greater range of passages during which good vaccinating properties are retained. Unlike turkey herpes virus, both attenuated strains reduce the spread of the infection markedly.


Production of bacterial cells from methane.
A mixed methane-oxidizing bacterial culture capable of stable and predictable growth in continuous culture was isolated. The culture consisted of two types of gram-negative nonsporulating rods resembling pseudomonads. The culture grew well at 45 C on an inorganic medium without asepsis. Specific metal requirements for Ca(2+), Cu(2+), MoO(4) (2-), Zn(2+), Mn(2+), Mg(2+), and Fe(3+) (or Fe(2+)) were shown. The cells grown in continuous culture contained 11.7 to 12.1% total nitrogen. From an animal nutrition standpoint, the distribution of amino acids was satisfactory. The continuous fermentation was operated over a range of steady-state dilution rates from 0.085 to 0.301 hr(-1). The maximum specific growth rate for the culture, mu(max), was 0.303 hr(-1) (doubling time 2.29 hr). The average yield for all fermentations analyzed was 0.616 g (dry weight of cells per g of methane used and 0.215 g (dry weight) of cells per g of oxygen used. The yields on both methane and oxygen were higher for the oxygen-limited than for the methane-limited fermentations. The maximum productivity attained in the fermentor was 2.39 g (dry weight) of cells per hr per liter at a dilution rate of 0.187 hr(-1) and a cell concentration of 12.8 g (dry weight) of cells per liter. The limit on maximum cell productivity was determined only by the mass transfer rate of oxygen in the fermentor. The simultaneous volumetric mass-transfer coefficients (k(L)a in hr(-1)) for oxygen and methane were determined. The results appear to indicate an oxygen to methane mass-transfer coefficient ratio of approximately 1.4.


The association of donor center characteristics with attrition from the national marrow donor registry.
The National Marrow Donor Program (NMDP) has approximately 5 million registered potential donors and continues to add more than 30,000 new recruits to the registry monthly. However, more than 30% of potential donors are not available or decline to donate at key decision points in the donation process. Although previous researchers have examined the association of individual donor characteristics with attrition from the registry, no published studies have investigated the role of donor center characteristics or features of the donor centers' environment on attrition rates. Donor center coordinators from 72 NMDP centers completed questionnaires that included items regarding donor center location and organization, recruitment strategies, and registry management. Center-specific registry composition data and attrition rates were gathered from the NMDP database. Analyses indicated that higher attrition was found at larger centers that needed more center staff and volunteers to deal with larger workloads and more DR-typing requests. Attrition was also higher among centers located in highly populated, urban environments, with larger minority and less stable populations. The results indicate that the NMDP may need to tailor donor center retention expectations to account for certain unchangeable characteristics (e.g., center size and population stability) and to develop internal strategies to address the unique characteristics of each donor center (e.g., current performance level or improvement needs).


Correlations between Sleep Bruxism and Temporomandibular Disorders.
The aim of this study was to identify correlations between sleep bruxism (SB) and temporomandibular disorders (TMD) as diagnosed by means of the research diagnostic criteria for temporomandibular disorders (RDC/TMD). Sleep bruxism was diagnosed on the basis of I) validated questionnaires, II) clinical symptoms, and III) electromyographic/electrocardiographic data. A total of 110 subjects were included in the study. Fifty-eight patients were identified as bruxers and 52 as nonbruxers. A psychosocial assessment was also performed. An RDC/TMD group-I diagnosis (myofascial pain) was made for 10 out of 58 bruxers, whereas none of the nonbruxers received a diagnosis of this type. No significant differences were found between bruxers and nonbruxers with regard to RDC/TMD group-II (disc displacement) and group-III (arthralgia, arthritis, arthrosis) diagnoses. Somatization was significantly more common among bruxers than nonbruxers. Multivariate logistic regression analysis revealed that somatization was the only factor significantly correlated with the diagnosis of myofascial pain. The results of this study indicate a correlation between myofascial pain, as diagnosed using the RDC/TMD, and somatization. It seems that somatization is a stronger predictor of an RDC/TMD diagnosis of myofascial pain than sleep bruxism is.


PITX2 isoform-specific regulation of atrial natriuretic factor expression: synergism and repression with Nkx2.5.
PITX2 and Nkx2.5 are two of the earliest known transcriptional markers of vertebrate heart development. Pitx2-/- mice present with severe cardiac malformations and embryonic lethality, demonstrating a role for PITX2 in heart development. However, little is known about the downstream targets of PITX2 in cardiogenesis. We report here that the atrial natriuretic factor (ANF) promoter is a target of PITX2. PITX2A, PITX2B, and PITX2C isoforms differentially activate the ANF promoter. However, only PITX2C can synergistically activate the ANF promoter in the presence of Nkx2.5. We further demonstrate that the procollagen lysyl hydroxylase (PLOD1) promoter is regulated by Nkx2.5. Mechanistically, PITX2C and Nkx2.5 synergistically regulate ANF and PLOD1 expression through binding to their respective DNA elements. Surprisingly, PITX2A activation of the ANF and PLOD1 promoters is repressed by co-transfection of Nkx2.5 in the C3H10T1/2 embryonic fibroblast cell line. Pitx2a and Pitx2c are endogenously expressed in C3H10T1/2 cells, and these cells express factors that differentially regulate PITX2 isoform activities. We provide a new mechanism for the regulation of heart development by PITX2 isoforms through the regulation of ANF and PLOD1 gene expression and Nkx2.5 transcriptional activity.


Mitoxantrone resistance in HL-60 leukemia cells: reduced nuclear topoisomerase II catalytic activity and drug-induced DNA cleavage in association with reduced expression of the topoisomerase II beta isoform.
Mitoxantrone-resistant variants of the human HL-60 leukemia cell line are cross-resistant to several natural product and synthetic antineoplastic agents. The resistant cells (HL-60/MX2) retain sensitivity to the Vinca alkaloids vincristine and vinblastine, drugs that are typically associated with the classical multidrug resistance phenotype. Mitoxantrone accumulation and retention are equivalent in the sensitive and resistant cell types, suggesting that mitoxantrone resistance in HL-60/MX2 cells might be associated with an alteration in the type II DNA topoisomerases. We discovered that topoisomerase II catalytic activity in 1.0 M NaCl nuclear extracts from the HL-60/MX2 variant, as measured by the decatenation of Crithidia fasciculata kinetoplast DNA, was reduced 4- to 5-fold compared to that in the parental HL-60 cells. Total cellular topoisomerase II activity in HL-60/MX2 cells was only 50% lower than that in HL-60 cells, however, because the "cytosolic fraction" of the HL-60/MX2 nuclear preparation contained high levels of decatenating activity. Antisera to calf thymus topoisomerase II defined a distinctive immunoreactive pattern of topoisomerase II proteins in crude nuclear extracts from the HL-60/MX2 cells. Both alpha (170 kDa) and beta (180 kDa) forms of topoisomerase II were detected in the HL-60 cell extracts, but only the alpha form was detected in extracts from HL-60/MX2 cells. This finding was associated with the appearance of a new 160-kDa immunoreactive species in nuclear extracts from HL-60/MX2 but not HL-60 cells. Studies were designed to minimize the proteolytic degradation of the topoisomerase II enzymes by extraction of whole cells with hot SDS.(ABSTRACT TRUNCATED AT 250 WORDS)


Stronger health systems for more effective HIV/AIDS prevention and care.
Of the 42 million living with HIV/AIDS world-wide some 90% live in developing countries. The international community acknowledges the devastating impact of HIV/AIDS on development and over the past few years resources to control HIV/AIDS have increased considerably. We argue that strengthening of health systems is a necessary prerequisite for improving the prevention of HIV infection and the care of HIV-infected persons. Sexual behaviour change requires a multidisciplinary approach, but health services play a crucial role in detection and treatment of other sexually transmitted infections; HIV counselling and testing; prevention of mother-to-child transmission of HIV; and care of HIV-infected patients. Increasing access to antiretroviral treatment especially poses formidable challenges to health authorities in developing countries. Additional resources for the prevention of HIV-infection and the care of HIV-infected persons may not have the desired impact if health systems in developing countries are not strengthened. Further, any activity in the area of HIV/AIDS prevention and care, carried out within health services, can have a positive ripple effect on other health care activities and vice versa. This interactive effect needs to be acknowledged and built on.


The Effect of a Hydrolyzed Polysaccharide Dietary Supplement on Biomarkers in Adults with Nonalcoholic Fatty Liver Disease.
The primary objective of the study was to evaluate the effect of a hydrolyzed polysaccharide, Rice Bran Arabinoxylan Compound (RBAC), on biomarkers in adults with nonalcoholic fatty liver disease (NAFLD). A 90-day randomized double-blind placebo-controlled trial examined the effect of RBAC on complete blood count, liver enzymes, lipids, oxidative stress markers, cytokines, and growth factors. Twenty-three adults with NAFLD were enrolled and randomly assigned to one of the two study conditions (n = 12 RBAC and n = 11 placebo) and consumed 1 gram/day of either compound for 90 days. Subjects were assessed at baseline and 45 and 90 days. No adverse effects were reported. Alkaline phosphatase significantly decreased (-3.1%; SD = 19.9; F[1,19] = 5.1, p = 0.03) in the RBAC group compared to placebo. Percent monocytes (17.9%; SD = 18.3; F[1,19] = 5.9, p = 0.02) and percent eosinophils (30.6%; SD = 30.5; F[1,19] = 12.3, p < 0.01) increased in the RBAC group. IFN-γ (156%; SD = 131.8; F[1,19] = 4.2, p = 0.06) and IL-18 (29.1%; SD = 64; F[1,19] = 5.3, p = 0.03) increased in the RBAC group compared to placebo. Other improvements were noted for platelets, neutrophils, neutrophil-lymphocyte ratio, γ-glutamyl transferase, and 4-hydroxynonenal. RBAC had beneficial effects on several biomarkers that add to the known immunomodulatory activities of RBAC, which may be promising for people with NAFLD.


Local cattle and badger populations affect the risk of confirmed tuberculosis in British cattle herds.
The control of bovine tuberculosis (bTB) remains a priority on the public health agenda in Great Britain, after launching in 1998 the Randomised Badger Culling Trial (RBCT) to evaluate the effectiveness of badger (Meles meles) culling as a control strategy. Our study complements previous analyses of the RBCT data (focusing on treatment effects) by presenting analyses of herd-level risks factors associated with the probability of a confirmed bTB breakdown in herds within each treatment: repeated widespread proactive culling, localized reactive culling and no culling (survey-only). New cases of bTB breakdowns were monitored inside the RBCT areas from the end of the first proactive badger cull to one year after the last proactive cull. The risk of a herd bTB breakdown was modeled using logistic regression and proportional hazard models adjusting for local farm-level risk factors. Inside survey-only and reactive areas, increased numbers of active badger setts and cattle herds within 1500 m of a farm were associated with an increased bTB risk. Inside proactive areas, the number of M. bovis positive badgers initially culled within 1500 m of a farm was the strongest predictor of the risk of a confirmed bTB breakdown. The use of herd-based models provide insights into how local cattle and badger populations affect the bTB breakdown risks of individual cattle herds in the absence of and in the presence of badger culling. These measures of local bTB risks could be integrated into a risk-based herd testing programme to improve the targeting of interventions aimed at reducing the risks of bTB transmission.


Association of PGC-1alpha polymorphisms with age of onset and risk of Parkinson's disease.
Peroxisome proliferator-activated receptor-γ co-activator (PGC)-1α is a transcriptional co-activator of antioxidant genes and a master regulator of mitochondrial biogenesis. Parkinson's disease (PD) is associated with oxidative stress and mitochondrial dysfunction and recent work suggests a role for PGC-1α. We hypothesized that the rs8192678 PGC-1α single nucleotide polymorphism (SNP) may influence risk or age of onset of PD. The A10398G mitochondrial SNP has been inversely associated with risk of PD in some studies. In the current study we analyzed whether rs8192678 or other PGC-1α SNPs affect PD risk or age of onset, singularly or in association with the A10398G SNP. Genomic DNA samples from 378 PD patients and 173 age-matched controls were analyzed by multiplexed probe sequencing, followed by statistical analyses of the association of each SNP, alone or in combination, with risk or age of onset of PD. Adjustments were made for age of onset being less than the age of sampling, and for the observed dependence between these two ages. The PD samples were obtained as two separate cohorts, therefore statistical methods accounted for different sampling methods between the two cohorts, and data were analyzed using Cox regression adjusted for sampling in the risk set definition and in the model. The rs8192678 PGC-1α SNP was not associated with the risk of PD. However, an association of the PGC-1α rs8192678 GG variant with longevity was seen in control subjects (p=0.019). Exploratory studies indicated that the CC variant of rs6821591 was associated with risk of early onset PD (p=0.029), with PD age of onset (p=0.047), and with longevity (p=0.022). The rs2970848 GG allele was associated with risk of late onset PD (p=0.027). These data reveal possible associations of the PGC-1α SNPs rs6821591 and rs2970848 with risk or age of onset of PD, and of the PGC-1α rs8192678 GG and the rs6821591 CC variants with longevity. If replicated in other datasets, these findings may have important implications regarding the role of PGC-1α in PD and longevity.


EVOLUTION OF A CATABOLIC PATHWAY IN BACTERIA.
Genetic derepression of ribitol dehydrogenase in a mutant of Aerobacter aerogenes, strain 1033, enabled it to grow on xylitol, a substrate of the enzyme, but not its inducer. A derivative strain with an improved rate of growth on xylitol was obtained from the first mutant. The faster growth rate was made possible by the production of an altered ribitol dehydrogenase, as demonstrated by an increase in its activity on xylitol relative to ribitol and by its decreased heat stability.


Guidelines for DC preparation and flow cytometry analysis of mouse lymphohematopoietic tissues.
This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state-of-the-art protocols for the preparation, phenotype analysis by flow cytometry, generation, fluorescence microscopy, and functional characterization of mouse and human DC from lymphoid organs, and various non-lymphoid tissues. Within this chapter, detailed protocols are presented that allow for the generation of single-cell suspensions from mouse lymphohematopoietic tissues including spleen, peripheral lymph nodes, and thymus, with a focus on the subsequent analysis of DC by flow cytometry. However, prepared single-cell suspensions can be subjected to other applications including sorting and cellular enrichment procedures, RNA sequencing, Western blotting, and many more. While all protocols were written by experienced scientists who routinely use them in their work, this article was also peer-reviewed by leading experts and approved by all co-authors, making it an essential resource for basic and clinical DC immunologists.


Co-assemblies of polydiacetylenes and metal ions for solvent sensing.
We demonstrate an easy and low-cost approach for the colorimetric differentiation of organic solvents using co-assemblies of polydiacetylenes (PDAs) and metal ions. The co-assemblies were prepared by the self-assembly of amphiphilic 10,12-tricosa diynoic acid with different metal ions (Zn2+, Cu2+, Ni2+, Ca2+) and subsequent photopolymerization. Different metal ions underwent different interactions with the carboxyl groups on the side chains of poly(10,12-tricosa diynoic acid), which influenced the stimuli-responsiveness of the PDA/metal ion co-assemblies. As a result, the PDA/metal ion co-assemblies with different metal ions showed different solvatochromism. Based on this property, the co-assemblies were used as sensors to differentiate organic solvents.


Effect of suckling on postpartum changes in 13,14-dihydro-15-keto-PGF2 alpha and progesterone and induced release of gonadotropins in autumn-lambing ewes.
Postpartum changes in concentrations of 13, 14-dihydro-15-keto-prostaglandin F2 alpha (PGFM) and progesterone and gonadotropin-releasing hormone (GnRH) induced release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were studied in two experiments on suckled and nonsuckled autumn-lambing ewes. In both experiments, one group of ewes had lambs weaned on d 3 +/- .5 postpartum and was compared with a second group of ewes that suckled one lamb each. In Exp. 1, jugular blood samples were collected daily from the day after lambing until d 50 postpartum for assay of PGFM and progesterone. On d 21 +/- .5 postpartum, ewes (eight suckled and eight nonsuckled) received GnRH (100 micrograms), and LH and FSH were measured in blood samples collected over a 340 min period. In Exp. 2, jugular blood samples were collected from the day of lambing until d 22 +/- .6 postpartum for assay of PGFM and progesterone. Ewes (six suckled and seven nonsuckled) received GnRH (100 micrograms) on d 22 +/- .6 postpartum, and LH and FSH were quantified in blood samples taken over a 185 min period. The pituitary was removed from each ewe 190 min after GnRH for LH and FSH determinations. Postpartum changes in concentrations of PGFM and progesterone did not differ with suckling in either experiment. In both experiments PGFM concentrations were high on d 1 postpartum, but declined to basal values by d 11. The release of LH after GnRH in Exp. 1 was greater (P less than .001) in suckled than in nonsuckled ewes. In Exp. 2, LH release after GnRH was not affected by suckling, but in both experiments suckled ewes had a greater (P less than .01) release of FSH than did nonsuckled ewes. Pituitaries from suckled ewes contained more FSH (P less than .01) than pituitaries from nonsuckled ewes. The resumption of ovarian cyclicity in well-fed autumn-lambing ewes appeared to be neither altered by suckling nor limited by the ability of the pituitary to respond to GnRH.


Apolipoprotein E, carbon dioxide vasoreactivity, and cognition in older adults: effect of hypertension.
To investigate the associations between the apolipoprotein E (APOE) ε4 allele, carbon dioxide (CO2 ) vasoreactivity, and cognitive performance and to explore the effect of CO2 vasoreactivity and hypertension on the associations between APOE and cognition. Observational. Community. Older adults (N = 625) enrolled in the Maintenance of Balance, Independent Living, Intellect and Zest in the Elderly of Boston Study. Change in cerebral blood flow velocity in response to CO2 challenge (CO2 ), measured using transcranial Doppler ultrasonography, Trail-Making Test Part B - A (TMT), Hopkins Verbal Learning Test delayed recall (HVLT). APOE-ε4 was associated with lower CO2 vasoreactivity (P = .009) and poorer performance on the TMT (P < .001) and HVLT (P < .001). Having hypertension and APOE-ε4 was associated with worse cognitive and CO2 vasoreactivity measures than having neither or either alone (P < .001 for TMT and HVLT, P = .01 for CO2 vasoreactivity). The association between APOE-ε4 and cognition was only significant if it was present concurrent with low CO2 vasoreactivity, defined as below the median of the sample (APOE by CO2 vasoreactivity interaction: P = .04 for TMT, P = .04 for HVLT). In hypertension, the association between APOE-ε4 and executive function was also only significant in participants with lower CO2 vasoreactivity (P = .005 for APOE by CO2 vasoreactivity). Individuals at risk of Alzheimer's disease (AD) because they have APOE-ε4 may have lower CO2 vasoreactivity, which in turn may be contributing to the observed lower cognitive performance associated with this allele. The cognitive effect of APOE-ε4 is magnified in hypertension and low CO2 vasoreactivity. This study offers evidence that APOE-ε4 may be associated with microvascular brain injury even in the absence of clinical AD.


Antiretroviral Treatment and Sexual Risk Behavior in South Africa.
The sexual behavior of individuals living with HIV determines the onward transmission of HIV. With the understanding that antiretroviral therapy (ART) prevents transmission of HIV, the sexual behaviors of the individuals not on ART with unsuppressed viral loads becomes of the greatest importance in elucidating transmission. We assessed the association between being on ART and sexual risk behavior among those living with HIV in a nationally representative population-based cross-sectional survey of households in South Africa that was conducted in 2012. Of 2237 adults (aged 15-49) who tested HIV-seropositive, 667 (29.8 %) had detectable antiretroviral drugs in their blood specimens. Among males, 77.7 % of those on ART reported having had sex in the past year contrasted with 88.4 % of those not on ART (p = 0.001); among females, 72.2 % of those on ART reported having had sex in the past year while 80.3 % of those not on ART did (p < 0.001). For males and females, the odds of reporting consistent condom use and condom use at last sex were statistically significantly higher for individuals on ART compared to those not on ART (males: consistent condom use aOR 2.8, 95 % CI 1.6-4.9, condom use at last sex aOR 2.6, 95 % CI 1.5-4.6; females: consistent condom use aOR 2.3, 95 % CI 1.7-3.1, condom use at last sex aOR 2.3, 95 % CI 1.7-3.1), while there were no statistically significant differences in odds of reporting multiple sexual partners in the past year. In this nationally representative population-based survey of South African adults, we found evidence of less risky sexual risk behavior among people living with HIV on ART compared to those not on ART.


Antiphospholipid antibodies and the risk of recurrence after a first episode of venous thromboembolism: a systematic review.
Laboratory evidence of antiphospholipid antibodies (APLA) in patients with a first episode of venous thromboembolism (VTE) is often considered an indication for indefinite anticoagulant therapy, but it is uncertain if this practice is justified. We performed a systematic review to determine whether the presence of APLA in patients with a first VTE is associated with an increased risk of recurrence. We searched PubMed, CINAHL, Cochrane, EMBASE, and Web of Knowledge through February 2012 and included prospective studies that met prespecified design criteria. There were 109 recurrent VTE in 588 patients with APLA and 374 recurrent VTE in 1914 patients without APLA (relative risk 1.41; 95% confidence interval [CI], 0.99 to 2.36). The unadjusted risk ratio for recurrent VTE after stopping anticoagulant therapy in patients with an anticardiolipin antibody was 1.53 (95% CI, 0.76-3.11), and with a lupus anticoagulant was 2.83 (95% CI, 0.83-9.64). All studies had important methodologic limitations and we judged the overall quality of the evidence as very low. Although a positive APLA test appears to predict an increased risk of recurrence in patients with a first VTE, the strength of this association is uncertain because the available evidence is of very low quality.


Myocardial bridging.
Myocardial bridging, a congenital coronary anomaly, is a clinical condition with several possible manifestations, and its clinical relevance is debated. This article reviews current knowledge about the anatomy, pathophysiology, clinical relevance, and treatment of myocardial bridging. Myocardial bridging is present when a segment of a major epicardial coronary artery, the 'tunnelled artery', runs intramurally through the myocardium. With each systole, the coronary artery is compressed. Myocardial bridging has been associated with angina, arrhythmia, depressed left ventricular function, myocardial stunning, early death after cardiac transplantation, and sudden death. Evidence indicates that the intima beneath the bridge is protected from atherosclerosis, and the proximal segment is more susceptible to development of atherosclerotic lesions because of haemodynamic disturbances. New techniques (e.g. intravascular ultrasonography and intracoronary Doppler studies) have revealed new characteristics and pathophysiologic processes such as diastolic flow abnormalities. Medical treatment generally includes beta-blockers. Nitrates should be avoided because symptoms may worsen. Intracoronary stents and surgery have been attempted in selected patients. Additional research is needed to define patients in whom myocardial bridging is potentially pathologic, and randomized multicentre long-term follow-up studies are needed to assess the natural history, patient selection, and therapeutic approaches.


Supplementation-dependent differences in the rates of embryonic stem cell self-renewal, differentiation, and apoptosis.
Although it is known that leukemia inhibitory factor (LIF) supports the derivation and expansion of murine embryonic stem (ES) cells, it is unclear whether this is due to inhibitory effects of LIF on ES cell differentiation or stimulatory effects on ES cell survival and proliferation. Using an ES cell line transgenic for green fluorescent protein (GFP) expression under control of the Oct4 promoter, we were able to simultaneously track the responses of live Oct4-GFP-positive (ES) and -negative (differentiated) fractions to LIF, serum, and other growth factors. Our findings show that, in addition to inhibiting differentiation of undifferentiated cells, the administration of LIF resulted in a distinct dose-dependent survival and proliferation advantage, thus enabling the long-term propagation of undifferentiated cells. Competitive responses from the differentiated cell fraction could only be elicited upon addition of serum, fibroblast growth factor-4 (FGF-4), or insulin-like growth factor-1 (IGF-1). The growth factors did not induce additional differentiation of ES cells, but rather they significantly improved the proliferation of already differentiated cells. Our analyses show that, by adjusting culture conditions, including the type and amount of growth factors or cytokines present, the frequency of media exchange, and the presence or absence of serum, we could selectively and specifically alter the survival, proliferation, and differentiation dynamics of the two subpopulations, and thus effectively control population outputs. Our findings therefore have important applications in engineering stem cell culture systems to predictably generate desired stem cells or their derivatives for various regenerative therapies.


Open pulled straw vitrification of goat embryos at various stages of development.
This investigation addresses the question whether it is possible to apply the open pulled straw (OPS) vitrification method, found to be effective for cryopreserving caprine (Capra aegagrus hircus) blastocysts, to other embryonal stages. Morulae, blastocysts and hatched blastocysts were cryopreserved by way of OPS vitrification and blastocysts and hatched blastocysts by conventional freezing. Morulae were not included with conventional freezing because in our experience the survival rate is very low. To assess the viability of the cryopreserved embryos, they were transferred to synchronized does; in most cases, two embryos per doe. After OPS vitrification, of nine does receiving morulae, not a single one became pregnant; of 11 does receiving blastocysts, nine (82%) became pregnant (all of which kidded and gave birth to, on average, 1.8 kids); and of nine does receiving hatched blastocysts, three (33%) became pregnant (two of which [22%] kidded, giving birth to a single kid each). After conventional freezing, of 10 does receiving blastocysts, five became pregnant (four of which [40%] carried to term and gave birth to a pair of twins each); and of nine does receiving hatched blastocysts, three (33%) became pregnant (and gave birth to a single kid each). Embryo survival (kids born/embryos transferred) after vitrification for morulae, blastocysts, and hatched blastocysts was 0, 70% (16 of 23), and 13% (2 of 16), respectively, and after conventional freezing for blastocysts and hatched blastocysts was 42% (8 of 19) and 19% (3 of 16), respectively. The difference in pregnancy and kidding rate between vitrified and conventionally frozen blastocysts was significant, and so was the difference in pregnancy rate between hatched and nonhatched blastocysts, regardless whether OPS-vitrified or conventionally frozen. The results of the current study indicate that OPS vitrification is a very effective means of cryopreserving caprine blastocysts. Unfortunately, the superiority of OPS vitrification over conventional freezing does not apply to caprine morulae and hatched blastocysts.


Effect of nano-hydroxyapatite toothpaste on microhardness ofartificial carious lesions created on extracted teeth.
Background. Many types of toothpastes contain substances that can remineralize initial enamel caries. This study aimed to assess the effect of nano-hydroxyapatite (NHA) on microhardness of artificially created carious lesions. Methods. In this in vitro study, NHA was prepared using sol-gel technique and added to the toothpaste with 7% concentration. A total of 80 extracted sound teeth were collected. The crowns were polished using 500-grit abrasive paper. The specimens were randomly coded from 1 to 80. Number 1 to 40 were assigned to group A and numbers 41 to 80 to group B. The microhardness was measured using HVS-1000 Vickers microhardness tester. The specimens were demineralized using 37% phosphoric acid for 3 minutes in order to create artificial carious lesions and then were rinsed with water, air-sprayed for 3 minutes and dried. Microhardness was measured again. Next, the specimens were brushed for 15 days, twice daily, for 15 seconds. After 15 days, microhardness was measured again. Toothpaste A contained NHA and fluoride and toothpaste B contained fluoride alone. Data were analyzed using SPSS 16, with one-sample Kolmogorov-Smirnov test and ANOVA at a significance level of P<0.05. Results. The microhardness of specimens significantly decreased following acid exposure (P<0.01) but increased again in both groups after exposure to toothpastes. The increase in microhardness was significantly greater in group A (P<0.01). Conclusion. The toothpaste containing NHA was more effective than the toothpaste without NHA for the purpose of remineralization.


A framework to evaluate the cultural appropriateness of intervention research.
Marked racial disparities exist in the prevalence, mortality, and treatment of asthma, between African American and White children and adolescents, despite increases in intervention trials to improve asthma outcomes. Yet, interventions to improve African American children's health must be culturally appropriate. To date, limited frameworks are available to decide whether an intervention tested with a targeted minority population employs a culturally appropriate design. In this article, we applied Bernal, Bonilla, and Bellido's ecological validity model to examine the cultural appropriateness of 12 randomized controlled trials of asthma self-management interventions published from 2000 to 2010. Most frequently met criteria were culturally appropriate methods of development and/or adaptation of interventions and inclusion of theoretical models. Least often met criteria were incorporating metaphors pertinent to participants and application of the language dimension. Based on this analysis, it is clear that an overarching framework is needed to guide the development of culturally targeted interventions.


Targeting tumor-intrinsic hexosamine biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy.
Pancreatic ductal adenocarcinoma (PDAC) is considered to be a highly immunosuppressive and heterogenous neoplasm. Despite improved knowledge regarding the genetic background of the tumor and better understanding of the tumor microenvironment, immune checkpoint inhibitor therapy (targeting CTLA4, PD1, PDL1) has not been very successful against PDAC. The robust desmoplastic stroma, along with an extensive extracellular matrix (ECM) that is rich in hyaluronan, plays an integral role in this immune evasion. Hexosamine biosynthesis pathway (HBP), a shunt pathway of glycolysis, is a metabolic node in cancer cells that can promote survival pathways on the one hand and influence the hyaluronan synthesis in the ECM on the other. The rate-limiting enzyme of the pathway, glutamine-fructose amidotransferase 1 (GFAT1), uses glutamine and fructose 6-phosphate to eventually synthesize uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). In the current manuscript, we targeted this glutamine-utilizing enzyme by a small molecule glutamine analog (6-diazo-5-oxo-l-norleucine [DON]). Our results showed that DON decreased the self-renewal potential and metastatic ability of tumor cells. Further, treatment with DON decreased hyaluronan and collagen in the tumor microenvironment, leading to an extensive remodeling of the ECM and an increased infiltration of CD8+ T cells. Additionally, treatment with DON sensitized pancreatic tumors to anti-PD1 therapy, resulting in tumor regression and prolonged survival.


PolyMorphine provides extended analgesic-like effects in mice with spared nerve injury.
Morphine is a well-characterized and effective analgesic commonly used to provide pain relief to patients suffering from both acute and chronic pain conditions. Despite its widespread use and effectiveness, one of the major drawbacks of morphine is its relatively short half-life of approximately 4 h. This short half-life often necessitates multiple administrations of the drug each day, which may contribute to both dependence and tolerance to morphine. Here, we tested the analgesic properties of a new polymer form of morphine known as PolyMorphine. This polymer has monomeric units of morphine incorporated into a poly(anhydride-ester) backbone that has been shown to hydrolyze into free morphine in vitro. Using an animal model of chronic pain, the spared nerve injury surgery, we showed that PolyMorphine is able to block spared nerve injury-induced hypersensitivity in mice for up to 24-h post-administration. Free morphine was shown to only block spared nerve injury-induced hypersensitivity for up to 2-h post-injection. PolyMorphine was also shown to act through the mu opioid receptor due to the ability of naloxone (a mu opioid receptor antagonist) to block PolyMorphine-induced analgesia in spared nerve injury animals pretreated with PolyMorphine. Additionally, we observed that PolyMorphine causes similar locomotor and constipation side effects as free morphine. Finally, we investigated if PolyMorphine had any effects in a non-evoked pain assay, conditioned place preference. Pretreatment of spared nerve injury mice with PolyMorphine blocked the development of conditioned place preference for 2-methyl-6-(phenylethynyl)pyridine (MPEP), a short-lasting mGluR5 antagonist with analgesic-like properties. Free morphine does not block the development of preference for MPEP, suggesting that PolyMorphine has longer lasting analgesic effects compared to free morphine. Together, these data show that PolyMorphine has the potential to provide analgesia for significantly longer than free morphine while likely working through the same receptor.


Carcass glycogen as a potential source of glucose during short-term starvation.
In small rats deprived of food for 19h (or 43h), 36% (or 39%) of the glycogen that disappeared was lost from the carcass and 64% (or 61%) from liver. Carcass glycogen is potentially a substantial source of glucose during short-term starvation via the Cori cycle.


Mitochondrial Bioenergetics and Fiber Type Assessments in Microbiopsy vs. Bergstrom Percutaneous Sampling of Human Skeletal Muscle.
Microbiopsies of human skeletal muscle are increasingly adopted by physiologists for a variety of experimental assays given the reduced invasiveness of this procedure compared to the classic Bergstrom percutaneous biopsy technique. However, a recent report demonstrated lower mitochondrial respiration in saponin-permeabilized muscle fiber bundles (PmFB) prepared from microbiopsies vs. Bergstrom biopsies. We hypothesized that ADP-induced contraction (rigor) of smaller length microbiopsy PmFB causes a greater reduction in maximal respiration vs. Bergstrom, such that respiration could be increased by a myosin II ATPase-inhibitor (Blebbistatin; BLEB). Eleven males and females each received a 2 mm diameter percutaneous microbiopsy and a 5 mm diameter Bergstrom percutaneous biopsy in opposite legs. Glutamate/malate (5/0.5 mM)-supported respiration in microbiopsy PmFB was lower than Bergstrom at submaximal concentrations of ADP. 5 μM BLEB reduced this impairment such that there were no differences relative to Bergstrom ± BLEB. Surprisingly, pyruvate (5 mM)-supported respiration was not different between either biopsy technique ±BLEB, whereas BLEB increased succinate-supported respiration in Bergstrom only. H2O2 emission was lower in microbiopsy PmFB compared to Bergstrom PmFB in the presence of BLEB. Microbiopsies contained fewer type I fibers (37 vs. 47%) and more type IIX fibers (20 vs. 8%) compared to Bergstrom possibly due to sampling site depth and/or longitudinal location. These findings suggest that smaller diameter percutaneous biopsies yield lower glutamate-supported mitochondrial respiratory kinetics which is increased by preventing ADP-induced rigor with myosin inhibition. Microbiopsies of human skeletal muscle can be utilized for assessing mitochondrial respiratory kinetics in PmFB when assay conditions are supplemented with BLEB, but fiber type differences with this method should be considered.