Supplementation with gliadin-combined plant superoxide dismutase extract promotes antioxidant defences and protects against oxidative stress.
The potential benefits to health of antioxidant enzymes supplied either through dietary intake or supplementation is still a matter of controversy. The development of dietary delivery systems using wheat gliadin biopolymers as a natural carrier represents a new alternative. Combination of antioxidant enzymes with this natural carrier not only delayed their degradation (i.e. the superoxide dismutase, SOD) during the gastrointestinal digestive process, but also promoted, in vivo, the cellular defences by strengthening the antioxidant status. The effects of supplementation for 28 days with a standardized melon SOD extract either combined (Glisodin) or not with gliadin, were evaluated on various oxidative-stress biomarkers. As already described there was no change either in superoxide dismutase, catalase or glutathione peroxidase activities in blood circulation or in the liver following non-protected SOD supplementation. However, animals supplemented with Glisodin showed a significant elevation in circulated antioxidant enzymes activities, correlated with an increased resistance of red blood cells to oxidative stress-induced hemolysis. In the presence of Sin-1, a chemical donor of peroxynitrites, mitochondria from hepatocytes regularly underwent membrane depolarization as the primary biological event of the apoptosis cascade. Hepatocytes isolated from animals supplemented with Glisodin presented a delayed depolarization response and an enhanced resistance to oxidative stress-induced apoptosis. It is concluded that supplementation with gliadin-combined standardized melon SOD extract (Glisodin) promoted the cellular antioxidant status and protected against oxidative stress-induced cell death.


Discovery and Characterization of Waitea circinata var. circinata Affecting Annual Bluegrass from the Western United States.
Waitea circinata var. circinata was identified as the causal agent of a new disease of annual bluegrass (Poa annua) in the United States. This pathogen is also known to cause brown ring patch on creeping bentgrass (Agrostis stolonifera) in Japan, but it had not been reported on any turf species outside of Japan. Symptoms on annual bluegrass caused by this fungus included regular to irregular yellow rings several centimeters to 1 m in diameter, typically at maximum daytime temperatures of 15 to 35°C. A total of 26 isolates were collected from diseased annual bluegrass. Twenty-two of these isolates were multinucleate, grew optimally at 25 to 30°C, and in culture formed irregular sclerotia approximately 2 to 5 mm in size that were white to orange and remained orange or turned brown to dark brown over a 28-day period. The remaining four isolates were characterized as being W. circinata var. zeae (Rhizoctonia zeae), which is a known pathogen of annual bluegrass in the United States. Sequence analysis of the internal transcribed spacer (ITS) regions of rDNA on a subset of isolates confirmed the identifications of W. circinata var. circinata (n = 8) and W. circinata var. zeae (n = 1) based on deposited sequences in GenBank. The identity of the remaining 14 isolates suspected to be W. circinata var. circinata was confirmed by HapII digestion of the amplified rDNA ITS region. Pathogenicity of four W. circinata var. circinata isolates was confirmed on both annual bluegrass and creeping bentgrass. This study is the first morphological and molecular confirmation of the presence of W. circinata var. circinata as a pathogen of turfgrass in the United States.


Electronic opioid risk assessment program for chronic pain patients: barriers and benefits of implementation.
A preliminary electronic pain assessment program known as Pain Assessment Interview Network, Clinical Advisory System (painCAS), was implemented in 2 pain centers over the course of 10 months to understand the tool's impact on opioid risk assessment documentation and clinical workflow. The program contains validated electronic versions of screeners for opioid misuse risk (SOAPP-R and Current Opioid Misuse Measure). Charts of patients with an initial and 2 follow-up visits were randomly selected for review of presence of opioid risk assessments before and after implementation of the electronic assessment program. Clinical and administrative staff members were interviewed to gain their perceptions of the impact of the program. Significant increases were observed in the documentation of opioid risk assessments between the baseline patient chart reviews before implementation of the program (n = 66) and the postintervention patient chart reviews after the implementation of the program (n = 39), for both initial and follow-up clinic visits (P < 0.001). Specific benefits of the program identified by 7 clinicians and 8 administrators included ease of use, reduced paperwork, completion of the assessment before the clinic visit, and incorporation of information directly into an electronic medical record (EMR). Perceived barriers to implementation included poor patient compliance, changes in administration workflow, and difficulties associated with patients with no email addresses, and limited computer skills. Implementation of an opioid risk electronic pain assessment program significantly increased the likelihood that a risk assessment would be included in the medical record, which has implications for improvement of quality of care.


A stochastic model for the aggregation of Onchocerca volvulus in nodules.
A model is presented which describes the aggregation of female Onchocerca volvulus in nodules and their distribution in the human population. The basic model is based on a single parameter, the formation probability q, which represents the probability with which incoming larvae form a new nodule. This parameter describes parasite behaviour which cannot easily be recognized in available data without modelling. The estimate for the average formation probability of muq = 0.39 suggests an attraction of the invading infective larvae to already existing nodules or resident worms with probability 0.61. No significant difference in muq was found between the forest and savanna parasite strains. The model can be used inversely to estimate the worm burden of persons from palpation data. The observed variance in the number of nodules per person requires the assumption of a variance-increasing mechanism which was implemented by heterogeneity within the host population (extended model with 2 parameters). Possible reasons for this heterogeneity are presented and its implications concerning the reproductive biology of the parasite are discussed.


Impact of temperature on postdiapause and diapause of the Asian gypsy moth, Lymantria dispar asiatica.
Lymantria dispar asiatica (Vnukovskij) (Lepidoptera: Lymantridae) is one of three gypsy moth subspecies found in East Asia. Understanding the diapause and postdiapause phases of its eggs is important in characterizing its life cycle. The effects of different constant temperatures for different lengths of times on field-collected, postdiapause eggs were tested during the first year. In the second year, the effects of the same treatments on laboratory-raised eggs in diapause were investigated. The effects of temperature on percent egg hatching, time to hatching, and hatching duration were determined. When field-collected eggs were held at 0 and 5°C, they terminated postdiapause within 11 days. The percent hatching tended to decline with an increased duration of exposure at temperatures greater than 5°C. Diapause terminated slowly (> 37 days) and with a high percentage of hatching for postdiapause eggs held at 10°C. There was a positive correlation between temperature and the speed of postdiapause development for field-collected eggs held at constant temperatures between 10 and 25°C. However, the number of days to the first hatch was significantly longer than for eggs treated with lower temperatures before being transferred to 25°C. Freshly oviposited eggs treated at a constant 0 or 5°C for 200 days were unable to develop into pharate larva. However, eggs treated at a constant 20 or 25°C for 200 days developed into pharate larva but did not hatch even after a subsequent chill. This result suggests why L. dispar asiatica is not found in tropical areas and helps us to predict the distribution of the gypsy moth in China.


Towards tricking a pathogen's protease into fighting infection: the 3D structure of a stable circularly permuted onconase variant cleavedby HIV-1 protease.
Onconase® is a highly cytotoxic amphibian homolog of Ribonuclease A. Here, we describe the construction of circularly permuted Onconase® variants by connecting the N- and C-termini of this enzyme with amino acid residues that are recognized and cleaved by the human immunodeficiency virus protease. Uncleaved circularly permuted Onconase® variants are unusually stable, non-cytotoxic and can internalize in human T-lymphocyte Jurkat cells. The structure, stability and dynamics of an intact and a cleaved circularly permuted Onconase® variant were determined by Nuclear Magnetic Resonance spectroscopy and provide valuable insight into the changes in catalytic efficiency caused by the cleavage. The understanding of the structural environment and the dynamics of the activation process represents a first step toward the development of more effective drugs for the treatment of diseases related to pathogens expressing a specific protease. By taking advantage of the protease's activity to initiate a cytotoxic cascade, this approach is thought to be less susceptible to known resistance mechanisms.


Perceptions of social mobility: development of a new psychosocial indicator associated with adolescent risk behaviors.
Social class gradients have been explored in adults and children, but not extensively during adolescence. The first objective of this study was to examine the association between adolescent risk behaviors and a new indicator of adolescent relative social position, adolescent "perceived social mobility." Second, it investigated potential underlying demographic, socioeconomic, and psychosocial determinants of this indicator. Data were taken from the 2004 urban adolescent module of Oportunidades, a cross-sectional study of Mexican adolescents living in poverty. Perceived social mobility was calculated for each subject by taking the difference between their rankings on two 10-rung ladder scales that measured (1) projected future social status and (2) current subjective social status within Mexican society. Adolescents with higher perceived social mobility were significantly less likely to report alcohol consumption, drinking with repercussions, compensated sex, police detainment, physical fighting, consumption of junk food or soda, or watching ≥4 h of television during the last viewing. They were significantly more likely to report exercising during the past week and using a condom during last sexual intercourse. These associations remained significant with the inclusion of covariates, including parental education and household expenditures. Multiple logistic regression analyses show higher perceived social mobility to be associated with staying in school longer and having higher perceived control. The present study provides evidence for the usefulness of perceived social mobility as an indicator for understanding the social gradient in health during adolescence. This research suggests the possibility of implementing policies and interventions that provide adolescents with real reasons to be hopeful about their trajectories.


E-MAP-115, encoding a microtubule-associated protein, is a retinoic acid-inducible gene required for spermatogenesis.
Cell type-specific microtubules, such as the Sertoli cell microtubules and the manchette and flagellum microtubules of the spermatids, play essential roles in spermatogenesis. We identified the gene encoding E-MAP-115 (epithelial microtubule-associated protein of 115 kD) as a retinoic acid-inducible gene using gene trap mutagenesis in mouse embryonic stem cells. The gene trap insertion led to a null allele of the E-MAP-115 gene and, in agreement with its high expression in the testis, male mice homozygous for the mutation were sterile because of deformation of spermatid nuclei and subsequent gradual loss of germ cells. Consistent with a possible role for E-MAP-115 in stabilizing microtubules, microtubule associations in the mutant were morphologically abnormal in the manchette of spermatids and in Sertoli cells. We hypothesize that the abnormal microtubules in these two cell types are responsible for deformation of spermatid nuclei and germ cell loss, respectively, and indicate an essential role for E-MAP-115 in microtubule functions required for spermatogenesis.


Comparative study of 13 candidate genes applying multi-reference normalization to detect the expression of different fineness in skin tissues of wool sheep.
Fiber diameter is a useful indicator of wool traits and it is the main determinant of wool quality and value. A comparative study was conducted to analyze the abundance and expression of 13 candidate genes using expression profile microarray analysis and to identify novel molecular markers associated with wool traits to provide a molecular basis for improving wool quality in sheep. Genes associated with fineness of skin tissue were identified using a real-time reverse transcriptase-polymerase chain reaction method with 18SrRNA, β-Actin, and GAPDH used for multi-reference normalization. The results indicated that the expression levels of TXNIP, TFDP1, and FAIM genes in super-fine type wool sheep were higher than those in fine-type wool sheep; the corresponding expression ratios of super-fine to fine wool sheep were 1.45, 1.57, and 2.55, respectively. The expression levels of PIK3CA, ADAM9, and FZD3 genes were lower in super-fine wool sheep compared with fine-type wool sheep; the corresponding expression ratios were 0.61, 0.65, and 0.52, respectively. The other genes tested (RPS6KA, ABCG2, GSTA1, PTPN13, GJB3, PPARD, and LAMB1) were similarly expressed in both types of wool sheep. These results infer that lower expression of PIK3CA, ADAM9, and FZD3 genes was associated with lower fiber diameter, whereas lower expression of TXNIP, TFDP1, and FAIM genes was associated with higher fiber diameter.


A functional and regulatory network associated with PIP expression in human breast cancer.
The PIP (prolactin-inducible protein) gene has been shown to be expressed in breast cancers, with contradictory results concerning its implication. As both the physiological role and the molecular pathways in which PIP is involved are poorly understood, we conducted combined gene expression profiling and network analysis studies on selected breast cancer cell lines presenting distinct PIP expression levels and hormonal receptor status, to explore the functional and regulatory network of PIP co-modulated genes. Microarray analysis allowed identification of genes co-modulated with PIP independently of modulations resulting from hormonal treatment or cell line heterogeneity. Relevant clusters of genes that can discriminate between [PIP+] and [PIP-] cells were identified. Functional and regulatory network analyses based on a knowledge database revealed a master network of PIP co-modulated genes, including many interconnecting oncogenes and tumor suppressor genes, half of which were detected as differentially expressed through high-precision measurements. The network identified appears associated with an inhibition of proliferation coupled with an increase of apoptosis and an enhancement of cell adhesion in breast cancer cell lines, and contains many genes with a STAT5 regulatory motif in their promoters. Our global exploratory approach identified biological pathways modulated along with PIP expression, providing further support for its good prognostic value of disease-free survival in breast cancer. Moreover, our data pointed to the importance of a regulatory subnetwork associated with PIP expression in which STAT5 appears as a potential transcriptional regulator.


New insights into the health effects of dietary saturated and omega-6 and omega-3 polyunsaturated fatty acids.
Cardiovascular diseases and cancers are leading causes of morbidity and mortality. Reducing dietary saturated fat and replacing it with polyunsaturated fat is still the main dietary strategy to prevent cardiovascular diseases, although major flaws have been reported in the analyses supporting this approach. Recent studies introducing the concept of myocardial preconditioning have opened new avenues to understand the complex interplay between the various lipids and the risk of cardiovascular diseases. The optimal dietary fat profile includes a low intake of both saturated and omega-6 fatty acids and a moderate intake of omega-3 fatty acids. This profile is quite similar to the Mediterranean diet. On the other hand, recent studies have found a positive association between omega-6 and breast cancer risk. In contrast, omega-3 fatty acids do have anticancer properties. It has been shown that certain (Mediterranean) polyphenols significantly increase the endogenous synthesis of omega-3 whereas high intake of omega-6 decreases it. Finally, epidemiological studies suggest that a high omega-3 to omega-6 ratio may be the optimal strategy to decrease breast cancer risk. Thus, the present high intake of omega-6 in many countries is definitely not the optimal strategy to prevent cardiovascular disease and cancers. A moderate intake of plant and marine omega-3 in the context of the traditional Mediterranean diet (low in saturated and omega-6 fatty acids but high in plant monounsaturated fat) appears to be the best approach to reduce the risk of both cardiovascular diseases and cancers, in particular breast cancer.


Absent Audiovisual Integration Elicited by Peripheral Stimuli in Parkinson's Disease.
The basal ganglia, which have been shown to be a significant multisensory hub, are disordered in Parkinson's disease (PD). This study was to investigate the audiovisual integration of peripheral stimuli in PD patients with/without sleep disturbances. Thirty-six age-matched normal controls (NC) and 30 PD patients were recruited for an auditory/visual discrimination experiment. The mean response times for each participant were analyzed using repeated measures ANOVA and race model. The results showed that the response to all stimuli was significantly delayed for PD compared to NC (all p < 0.01). The response to audiovisual stimuli was significantly faster than that to unimodal stimuli in both NC and PD (p < 0.001). Additionally, audiovisual integration was absent in PD; however, it did occur in NC. Further analysis showed that there was no significant audiovisual integration in PD with/without cognitive impairment or in PD with/without sleep disturbances. Furthermore, audiovisual facilitation was not associated with Hoehn and Yahr stage, disease duration, or the presence of sleep disturbances (all p > 0.05). The current results showed that audiovisual multisensory integration for peripheral stimuli is absent in PD regardless of sleep disturbances and further suggested the abnormal audiovisual integration might be a potential early manifestation of PD.


Coral mass spawning predicted by rapid seasonal rise in ocean temperature.
Coral spawning times have been linked to multiple environmental factors; however, to what extent these factors act as generalized cues across multiple species and large spatial scales is unknown. We used a unique dataset of coral spawning from 34 reefs in the Indian and Pacific Oceans to test if month of spawning and peak spawning month in assemblages of Acropora spp. can be predicted by sea surface temperature (SST), photosynthetically available radiation, wind speed, current speed, rainfall or sunset time. Contrary to the classic view that high mean SST initiates coral spawning, we found rapid increases in SST to be the best predictor in both cases (month of spawning: R(2) = 0.73, peak: R(2) = 0.62). Our findings suggest that a rapid increase in SST provides the dominant proximate cue for coral mass spawning over large geographical scales. We hypothesize that coral spawning is ultimately timed to ensure optimal fertilization success.


Language-specific and universal influences in children's syntactic packaging of Manner and Path: a comparison of English, Japanese, and Turkish.
Different languages map semantic elements of spatial relations onto different lexical and syntactic units. These crosslinguistic differences raise important questions for language development in terms of how this variation is learned by children. We investigated how Turkish-, English-, and Japanese-speaking children (mean age 3;8) package the semantic elements of Manner and Path onto syntactic units when both the Manner and the Path of the moving Figure occur simultaneously and are salient in the event depicted. Both universal and language-specific patterns were evident in our data. Children used the semantic-syntactic mappings preferred by adult speakers of their own languages, and even expressed subtle syntactic differences that encode different relations between Manner and Path in the same way as their adult counterparts (i.e., Manner causing vs. incidental to Path). However, not all types of semantics-syntax mappings were easy for children to learn (e.g., expressing Manner and Path elements in two verbal clauses). In such cases, Turkish- and Japanese-speaking children frequently used syntactic patterns that were not typical in the target language but were similar to patterns used by English-speaking children, suggesting some universal influence. Thus, both language-specific and universal tendencies guide the development of complex spatial expressions.


Diurnal blood pressure pattern and development of prehypertension or hypertension in young adults: the CARDIA study.
Nondippers (people whose sleep systolic blood pressure [SBP] fails to decrease >10% from daytime SBP) have increased risk of cardiovascular disease. The prevalence of nondipping in younger adults has not been well studied, nor has its value for predicting hypertension. We examined the prevalence of nondipping in a substudy of the Coronary Artery Risk Development in Young Adults (CARDIA) Study. We used Cox regression to estimate the hazard ratio (HR) conferred by nondipping for incident prehypertension or hypertension (preHTN/HTN) over 15 years. Of the 264 nonhypertensive participants at baseline, 118 (45%) were nondippers. Blacks were more likely than whites to be nondippers (52% versus 33%, P = .004). The incidence rate of preHTN/HTN was 29.2/1000 person-years among dippers and 36.2/1000 person-years among nondippers. Compared with those in the lowest quartile of nighttime to daytime SBP, those in the highest quartile were more likely to develop preHTN/HTN (HR 1.61; P = .06), but this relationship was attenuated after adjustment (HR 1.34; P = .27). Our results demonstrate that nondipping is common in young, nonhypertensive adults, and is more common in blacks than whites. Nondipping might predate a meaningful clinically detected increase in BP in some people, but more research in larger study samples is needed.


Regulation of Retroviral and SARS-CoV-2 Protease Dimerization and Activity through Reversible Oxidation.
Most viruses encode their own proteases to carry out viral maturation and these often require dimerization for activity. Studies on human immunodeficiency virus type 1 (HIV-1), type 2 (HIV-2) and human T-cell leukemia virus (HTLV-1) proteases have shown that the activity of these proteases can be reversibly regulated by cysteine (Cys) glutathionylation and/or methionine oxidation (for HIV-2). These modifications lead to inhibition of protease dimerization and therefore loss of activity. These changes are reversible with the cellular enzymes, glutaredoxin or methionine sulfoxide reductase. Perhaps more importantly, as a result, the maturation of retroviral particles can also be regulated through reversible oxidation and this has been demonstrated for HIV-1, HIV-2, Mason-Pfizer monkey virus (M-PMV) and murine leukemia virus (MLV). More recently, our group has learned that SARS-CoV-2 main protease (Mpro) dimerization and activity can also be regulated through reversible glutathionylation of Cys300. Overall, these studies reveal a conserved way for viruses to regulate viral polyprotein processing particularly during oxidative stress and reveal novel targets for the development of inhibitors of dimerization and activity of these important viral enzyme targets.


Through the dark continent: African trypanosome development in the tsetse fly.
African trypanosomes are unicellular flagellated parasites causing trypanosomiases in Africa, a group of severe diseases also known as sleeping sickness in human and nagana in cattle. These parasites are almost exclusively transmitted by the bite of the tsetse fly. In this review, we describe and compare the three developmental programs of the main trypanosome species impacting human and animal health, with focus on the most recent observations. From here, some reflections are made on research issues concerning trypanosome developmental biology in the tsetse fly that are to be addressed in the future.


Ground Contact Time Imbalances Strongly Related to Impaired Running Economy.
Running economy (RE) is defined as the oxygen consumption (VO2) or caloric unit cost required to move at a specific velocity and is an important performance marker. Ground contact time (GCT) has been associated with RE; however, it has not been established how GCT imbalances between feet impact RE. Determine the relationship between cadence, GCT, and GCT imbalances and RE. 11 NCAA Division I distance runners (7 male) completed a graded exercise test on a treadmill to determine lactate threshold (LT) and VO2max. Body composition was also assessed via DEXA. Subjects ran with a heart rate monitor capable of measuring cadence, GCT, and GCT balance between feet. VO2 and respiratory exchange ratio were recorded over the last minute of the 5-minute stages. RE expressed as caloric unit cost (kcal·kg-1·km-1) was calculated for the stage determined to be just below the LT (prior to > 4mmol/L) and was correlated with cadence, GCT, and GCT imbalance by Pearson correlations. Pearson correlations between RE and the running dynamics measures were as follows: cadence (r = -.444, p = .171), GCT (r = .492, p = .125), GCT Imbalance (r = .808, p < .005). An independent t-test revealed greater (p = .023) leg lean mass imbalances in runners with larger GCT imbalances compared to runners with smaller GCT imbalances. GCT imbalances are strongly related to impaired RE. Future research should determine how to improve GCT imbalances and if doing so improves RE.


Long-term results of laparoscopic sleeve gastrectomy for obesity.
To determine the mid- and long-term efficacy and possible side effects of laparoscopic sleeve gastrectomy as treatment for morbid obesity. Laparoscopic sleeve gastrectomy is still controversial as single and final treatment for morbid obesity. Some favorable short-term results have been published, however long-term results are still lacking. In the period between November 2001 and October 2002, 53 consecutive morbidly obese patients who, according to our personal algorithm, were qualified for restrictive surgery were selected for laparoscopic sleeve gastrectomy. Of the 53 patients, 11 received an additional malabsorptive procedure at a later stage because of weight regain. The percentage of excess weight loss (EWL) was assessed at 3 and 6 years postoperatively. A retrospective review of a prospectively collected database was performed for evaluation after 3 years. Recently, after the sixth postoperative year, patients were again contacted and invited to fill out a questionnaire. Full cooperation was obtained in 41 patients, a response rate of 78%. Although after 3 years a mean EWL of 72.8% was documented, after 6 years EWL had dropped to 57.3%, which according to the Reinhold criteria is still satisfactory. These results included 11 patients who had benefited from an additional malabsorptive procedure (duodenal switch) and 2 patients who underwent a "resleeve" between the third and sixth postoperative year. Analyzing the results of the subgroup of 30 patients receiving only sleeve gastrectomy, we found a 3-year %EWL of 77.5% and 6+ year %EWL of 53.3%. The differences between the third and sixth postoperative year were statistically significant in both groups. Concerning long-term quality of life patient acceptance stayed good after 6 + years despite the fact that late, new gastro-esophageal reflux complaints appeared in 21% of patients. In this long-term report of laparoscopic sleeve gastrectomy, it appears that after 6+ years the mean excess weight loss exceeds 50%. However, weight regain and de novo gastroesophageal reflux symptoms appear between the third and the sixth postoperative year. This unfavorable evolution might have been prevented in some patients by continued follow-up office visits beyond the third year. Patient acceptance remains good after 6+ years.


Optimisation of the bovine whole in vitro embryo system as a sentinel for toxicity screening: a cadmium challenge.
Developmental toxicity testing could greatly benefit from the availability of an in vitro alternative model based on the use of animal embryos that have better human-like physiology than the currently-used alternative models. These current models are insufficient, as extrapolation of the results can be challenging. Therefore, an in vitro bovine embryo culture system was used to expose individual morulae to test substances, and to study developmental characteristics up to the blastocyst stage. Cadmium was chosen as the reference toxicant to investigate the sensitivity of the bovine morulae to various concentrations and exposure times. Oocytes from slaughterhouse-obtained bovine ovaries, were maturated, fertilised and cultured up until the morula stage. Morulae were exposed to different cadmium concentrations for 18 or 70 hours, and developmental competence, embryo quality and the expression of cadmium exposure-related genes were evaluated. Cadmium exposure hampered embryonic developmental competence and quality. Compared with the 18-hour exposure, the 70-hour exposure induced a 20-fold higher toxic response with regard to developmental competence and a more 'cadmium-typical' transcript expression. The bovine morula might be a promising tool for toxicity testing as, following exposure, the embryos reacted in a sensitive and 'cadmium-typical' manner to our reference toxicant.


Efficient Heat Shielding of Steel with Multilayer Nanocomposite Thin Film.
In an effort to protect metal substrates from extreme heat, polymer-clay multilayer thin films are studied as expendable thermal barrier coatings. Nanocomposite films with a thickness ranging from 2 to 35 μm were deposited on steel plates and exposed to the flame from a butane torch. The 35 μm coating, composed of 14 deposited bilayers of tris(hydroxymethyl)aminomethane (THAM)-buffered polyethylenimine (PEI) and vermiculite clay (VMT), decreased the maximum temperature observed on the back side of a 0.32 cm thick steel plate by over 100 °C when heated with a butane torch. Upon exposure to high temperature, the polymer and amine salt undergo pyrolysis and intumesce, subsequently forming a char and blowing gas. The char encases the nanoclay platelets, and a ceramic bubble is formed. The macro-scale bubble, in tandem with the nanocomposite coating properties, increases resistance to heat transfer into the underlying metal substrate. This heat shielding behavior occurs through radiative effects and low aggregate through-plane conductivity resulting from multilayer nanodomains and intumesced porosity (i.e., conduction through the gas as the film expands to form a ceramic bubble). These relatively thin and lightweight films could be used to protect important metal parts (in automobiles, aircraft, etc.) from fire-related damage or other types of transient high-temperature situations.


Luminal B tumors are the most frequent molecular subtype in breast cancer of North African women: an immunohistochemical profile study from Morocco.
Breast cancer may be classified into luminal A, luminal B, HER2+/ER-, basal-like and normal-like subtypes based on gene expression profiling or immunohistochemical (IHC) characteristics. The aim of our study is to show the molecular profile characteristic of breast cancer in the North African population of Morocco. This work showed preliminary results and correlations with clinicopathological and histological parameters. Three hundred and ninety primary breast carcinomas tumor tissues were immunostained for ER, PR, HER2, CK5/6, CK8/18 and Ki67 using paraffin tissue. We reviewed 390 cases of breast cancer diagnosed on January 2008 to December 2011 at the Department of pathology, Hassan II teaching hospital, Fez, Morocco. Age, size tumor, metastatic profile, node involvement profile, histological type and immunohistochemical profile were studied. The average age was 46 years; our patients were diagnosed late with a high average tumor size. Luminal B subtype was more prevalent (41.8%), followed by luminal A (30.5%), basal-like (13, 6%), Her2-overexpressing (9, 2%), and unclassified subtype (4.9%). This study showed that molecular classification and biological profile may be different according to geographical distribution, to encourage further studies to know the genomic profile of tumors and the environment.


Novel approach to cell sampling from preimplantation ovine embryos and its potential use in embryonic genome analysis.
The major obstacle in the extensive analysis of the embryonic genome is the small number of cells typically obtained after the embryo biopsy. The object of the present study was to develop a simple approach that would allow the collection of a sufficient number of cells from a single embryo for use in further analyses. A micromanipulator was used to make a hole in the zona pellucida of 28 compacted morulae, 27 early blastocysts and 31 expanded blastocysts. After further culture, the trophoblastic cells, which herniated through this hole, were cut and cultured in vitro for different periods and used for embryo sexing. The results showed that biopsies can be taken successfully from 96.3% of early blastocysts, compared with 67.7% of expanded blastocysts and 71.4% of compacted morulae. The trophoblastic vesicles contained 20.8 +/- 6.7 cells (mean +/- SEM) and, when cultured, formed a confluent monolayer. The sex of cells cultured was assayed by PCR and the 12 lambs born after transfer of biopsied embryos confirmed its 100% accuracy. Moreover, no significant differences were found in the viability rates in vitro among blastocysts vitrified immediately after biopsy (77.8%), blastocysts biopsied and vitrified after 24 h culture (76.9%) and blastocysts vitrified without manipulation (88.5%). In experiments in vivo, the lambing rate of biopsied and vitrified blastocysts was significantly (P < 0.05) lower (40.0%) compared with vitrified control embryos (68.7%). This new approach to the biopsy of preimplantation embryos is a useful good model in the assisted reproductive technologies of domestic, wild and human species.


Researching the hard-to-reach: a scoping review protocol of digital health research in hidden, marginal and excluded populations.
There is a significant growth in the use of digital technology and methods in health-related research, further driven by the COVID-19 pandemic. This has offered a potential to apply digital health research in hidden, marginalised and excluded populations who are traditionally not easily reached due to economic, societal and legal barriers. To better inform future digital health studies of these vulnerable populations, we proposed a scoping review to comprehensively map published evidence and guidelines on the applications and challenges of digital health research methods to hard-to-reach communities. This review will follow the Arksey and O' Malley methodological framework for scoping reviews. The framework for the review will employ updated methods developed by the Joanna Briggs Institute including the Preferred Reporting Items for Systematic reviews and Meta-Analysis Scoping Review checklist. PubMed, the Cochrane Library, PsycINFO, Google Scholar and Greenfile are the identified databases for peer-reviewed quantitative and qualitative studies in-scope of the review. Grey literature focused on guidance and best practice in digital health research, and hard-to-reach populations will also be searched following published protocols. The review will focus on literature published between 1 February 2012 and 1 February 2022. Two reviewers are engaged in the review. After screening the title and abstract to determine the eligibility of each article, a thorough full-text review of eligible articles will be conducted using a data extraction framework. Key extracted information will be mapped in tabular and visualised summaries to categorise the breadth of literature and identify key digital methods, including their limitations and potential, for use in hard-to-reach populations. This scoping review does not require ethical approval. The results of the scoping review will consist of peer-reviewed publications, presentations and knowledge mobilisation activities including a lay summary posted via social media channels and production of a policy brief.


Estimating the effect of the 2005 change in BCG policy in England: a retrospective cohort study, 2000 to 2015.
BackgroundIn 2005 in England, universal Bacillus Calmette-Guérin (BCG) vaccination of school-age children was replaced by targeted BCG vaccination of high-risk neonates.AimEstimate the impact of the 2005 change in BCG policy on tuberculosis (TB) incidence rates in England.MethodsWe conducted an observational study by combining notifications from the Enhanced Tuberculosis Surveillance system, with demographic data from the Labour Force Survey to construct retrospective cohorts relevant to both the universal and targeted vaccination between 1 January 2000 and 31 December 2010. We then estimated incidence rates over a 5-year follow-up period and used regression modelling to estimate the impact of the change in policy on TB.ResultsIn the non-United Kingdom (UK) born, we found evidence for an association between a reduction in incidence rates and the change in BCG policy (school-age incidence rate ratio (IRR): 0.74; 95% credible interval (CrI): 0.61 to 0.88 and neonatal IRR: 0.62; 95%CrI: 0.44 to 0.88). We found some evidence that the change in policy was associated with an increase in incidence rates in the UK born school-age population (IRR: 1.08; 95%CrI: 0.97 to 1.19) and weaker evidence of an association with a reduction in incidence rates in UK born neonates (IRR: 0.96; 95%CrI: 0.82 to 1.14). Overall, we found that the change in policy was associated with directly preventing 385 (95%CrI: -105 to 881) cases.ConclusionsWithdrawing universal vaccination at school age and targeting vaccination towards high-risk neonates was associated with reduced incidence of TB. This was largely driven by reductions in the non-UK born with cases increasing in the UK born.


Patterns of violence-related skull trauma in Neolithic Southern Scandinavia.
This article examines evidence for violence as reflected in skull injuries in 378 individuals from Neolithic Denmark and Sweden (3,900-1,700 BC). It is the first large-scale crossregional study of skull trauma in southern Scandinavia, documenting skeletal evidence of violence at a population level. We also investigate the widely assumed hypothesis that Neolithic violence is male-dominated and results in primarily male injuries and fatalities. Considering crude prevalence and prevalence for individual bones of the skull allows for a more comprehensive understanding of interpersonal violence in the region, which is characterized by endemic levels of mostly nonlethal violence that affected both men and women. Crude prevalence for skull trauma reaches 9.4% in the Swedish and 16.9% in the Danish sample, whereas element-based prevalence varies between 6.2% for the right frontal and 0.6% for the left maxilla, with higher figures in the Danish sample. Significantly more males are affected by healed injuries but perimortem injuries affect males and females equally. These results suggest habitual male involvement in nonfatal violence but similar risks for both sexes for sustaining fatal injuries. In the Danish sample, a bias toward front and left-side injuries and right-side injuries in females support this scenario of differential involvement in habitual interpersonal violence, suggesting gendered differences in active engagement in conflict. It highlights the importance of large-scale studies for investigating the scale and context of violence in early agricultural societies, and the existence of varied regional patterns for overall injury prevalence as well as gendered differences in violence-related injuries.


Distinct and histone-specific modifications mediate positive versus negative transcriptional regulation of TSHalpha promoter.
Hormonally-regulated histone modifications that govern positive versus negative transcription of target genes are poorly characterized despite their importance for normal and pathological endocrine function. There have been only a few studies examining chromatin modifications on target gene promoters by nuclear hormone receptors. Moreover, these studies have focused on positively-regulated target genes. TSHalpha, a heterodimer partner for thyrotropin (TSH), is secreted by the pituitary gland. T(3) negatively regulates TSHalpha gene expression via thyroid hormone receptors (TRs) which belong to the nuclear hormone receptor superfamily, whereas thyrotropin releasing hormone (TRH) positively regulates via the TRH receptor, a G protein-coupled receptor. We studied regulation of the TSHalpha gene by cAMP and T(3) using chromatin immunoprecipitation (ChIP) assays in stably-transfected rat pituitary cells containing the human TSHalpha promoter. Interestingly, cAMP selectively increased histone H4 acetylation whereas, as previously reported, T(3) induced histone H3 acetylation. In particular, cAMP increased H4K5 and H4K8 acetylation and decreased H4K20 trimethylation, modifications associated with transcriptional activation. T(3) increased H3K9 and H3K18 acetylation and H3K4 trimethylation; however, it also decreased H3K27 acetylation and increased H3K27 trimethylation which are associated with transcriptional repression. Of note, cAMP recruited pCREB, CBP/p300, and PCAF to the promoter whereas T(3) caused dissociation of NCoR/SMRT and HDAC3. Overexpression of a dominant negative mutant thyroid hormone receptor (TR) from a patient with resistance to thyroid hormone (RTH) led to less T(3)-dependent negative regulation and partially blocked histone H3 modifications of the TSHalpha promoter. Our findings show that non-overlapping and specific histone modifications determine positive versus negative transcriptional regulation, and integrate opposing hormonal and intracellular signals at the TSHalpha promoter. A mutant TR from a patient with RTH exerted dominant negative activity by blocking the histone modifications induced by T(3) on the TSHalpha promoter and likely contributes to the inappropriate TSH production observed in RTH.


The structure of the upper atmosphere of mars: In situ accelerometer measurements from mars global surveyor
The Mars Global Surveyor (MGS) z-axis accelerometer has obtained over 200 vertical structures of thermospheric density, temperature, and pressure, ranging from 110 to 170 kilometers, compared to only three previous such vertical structures. In November 1997, a regional dust storm in the Southern Hemisphere triggered an unexpectedly large thermospheric response at mid-northern latitudes, increasing the altitude of thermospheric pressure surfaces there by as much as 8 kilometers and indicating a strong global thermospheric response to a regional dust storm. Throughout the MGS mission, thermospheric density bulges have been detected on opposite sides of the planet near 90 degreesE and 90 degreesW, in the vicinity of maximum terrain heights. This wave 2 pattern may be caused by topographically-forced planetary waves propagating up from the lower atmosphere.


Physical Exercise Alleviates Health Defects, Symptoms, and Biomarkers in Schizophrenia Spectrum Disorder.
Schizophrenia spectrum disorders are characterized by symptom profiles consisting of positive and negative symptoms, cognitive impairment, and a plethora of genetic, epigenetic, and phenotypic biomarkers. Assorted animal models of these disorders and clinical neurodevelopmental indicators have implicated neurodegeneration as an element in the underlying pathophysiology. Physical exercise or activity regimes--whether aerobic, resistance, or endurance--ameliorate regional brain and functional deficits not only in affected individuals but also in animal models of the disorder. Cognitive deficits, often linked to regional deficits, were alleviated by exercise, as were quality-of-life, independent of disorder staging and risk level. Apoptotic processes intricate to the etiopathogenesis of schizophrenia were likewise attenuated by physical exercise. There is also evidence of manifest benefits endowed by physical exercise in preserving telomere length and integrity. Not least, exercise improves overall health and quality-of-life. The notion of scaffolding as the outcome of physical exercise implies the "buttressing" of regional network circuits, neurocognitive domains, anti-inflammatory defenses, maintenance of telomeric integrity, and neuro-reparative and regenerative processes.


A 3 kb sequence from the mouse cellular retinoic-acid-binding protein gene upstream region mediates spatial and temporal LacZ expression in transgenic mouse embryos.
A 3233 base pair (bp) sequence of the 5'-flanking region of the mouse cellular retinoic-acid-binding protein (CRABP) gene is determined. From this region, a 3 kb fragment located 150 bp upstream from the transcriptional initiation site is isolated and fused to a LacZ reporter sequence. Transgenic mouse embryos of this fusion gene show spatially and temporally specific expression of LacZ protein and the expression of this fusion gene at the RNA level is confirmed by RNAase protection assays, which detect specific fusion transcripts in RNA samples from tissues of transgenic mouse embryos. In contrast, transgenic mouse embryos of a shorter fusion gene containing only 583 bp from the same upstream region of the mouse CRABP gene fused to the same reporter sequence show no LacZ activities. Thus, it is concluded that the 3 kb sequence, but not the 583 bp sequence, of the mouse CRABP gene contains information for its temporally and spatially specific expression in mouse embryos.


The GENESIS project (GENeralized Early Sepsis Intervention Strategies): a multicenter quality improvement collaborative.
Improved outcomes for severe sepsis and septic shock have been consistently observed with implementation of early best practice intervention strategies or the 6-hour resuscitation bundle (RB) in single-center studies. This multicenter study examines the in-hospital mortality effect of GENeralized Early Sepsis Intervention Strategies (GENESIS) when utilized in community and tertiary care settings. This study was comprised of 2 strategies to assess treatment. The first was a prospective before-and-after observational comparison of historical controls to patients receiving the RB after implementation of GENESIS in 4 community and 4 tertiary hospitals. The second was a concurrent examination comparing patients not achieving all components of the RB to those achieving all components of the RB in 1 community and 2 tertiary care hospitals after implementation of GENESIS. These 4 subgroups merged to comprise a control (historical controls treated before GENESIS and RB not achieved after GENESIS) group and treatment (patients treated after GENESIS and RB achieved after GENESIS) group for comparison. The control group comprised 1554 patients not receiving the RB (952 before GENESIS and 602 RB not achieved after GENESIS). The treatment group comprised 4801 patients receiving the RB (4109 after GENESIS and 692 RB achieved after GENESIS). Patients receiving the RB (treatment group) experienced an in-hospital mortality reduction of 14% (42.8%-28.8%, P < .001) and a 5.1 day decrease in hospital length of stay (20.7 vs 15.6, P < .001) compared to those not receiving the RB (control group). Similar mortality reductions were seen in the before-and-after (43% vs 29%, P < .001) or concurrent RB not achieved versus achieved (42.5% vs 27.2%, P < .001) subgroup comparisons. Patients with severe sepsis and septic shock receiving the RB in community and tertiary hospitals experience similar and significant reductions in mortality and hospital length of stay. These findings remained consistent when examined in both before-and-after and concurrent analyses. Early sepsis intervention strategies are associated with 1 life being saved for every 7 treated.


Composition and fate of gas and oil released to the water column during the Deepwater Horizon oil spill.
Quantitative information regarding the endmember composition of the gas and oil that flowed from the Macondo well during the Deepwater Horizon oil spill is essential for determining the oil flow rate, total oil volume released, and trajectories and fates of hydrocarbon components in the marine environment. Using isobaric gas-tight samplers, we collected discrete samples directly above the Macondo well on June 21, 2010, and analyzed the gas and oil. We found that the fluids flowing from the Macondo well had a gas-to-oil ratio of 1,600 standard cubic feet per petroleum barrel. Based on the measured endmember gas-to-oil ratio and the Federally estimated net liquid oil release of 4.1 million barrels, the total amount of C(1)-C(5) hydrocarbons released to the water column was 1.7 10(11) g. The endmember gas and oil compositions then enabled us to study the fractionation of petroleum hydrocarbons in discrete water samples collected in June 2010 within a southwest trending hydrocarbon-enriched plume of neutrally buoyant water at a water depth of 1,100 m. The most abundant petroleum hydrocarbons larger than C(1)-C(5) were benzene, toluene, ethylbenzene, and total xylenes at concentrations up to 78 μg L(-1). Comparison of the endmember gas and oil composition with the composition of water column samples showed that the plume was preferentially enriched with water-soluble components, indicating that aqueous dissolution played a major role in plume formation, whereas the fates of relatively insoluble petroleum components were initially controlled by other processes.


Cognition Mediates Playfulness Development in Early Childhood: A Longitudinal Study of Typically Developing Children.
Play, children's central occupation, and playfulness, its behavioral manifestation, are the foci of occupational therapy intervention. However, information about the development of playfulness behavior and the role of cognitive function is limited. To explore the development of playfulness and its relation to cognitive functioning from infancy to toddlerhood. Longitudinal study with data collected at ages 6 mo, 18 mo, and 24 mo. Laboratory (age 6 mo) and home (ages 12 and 18 mo). Eighty-six typically developing children drawn from a convenience sample of 109 low-risk families of middle to upper socioeconomic status. The Mullen Scales of Early Learning (MSEL) to assess cognitive functioning and the Test of Playfulness (ToP) to assess children's playfulness. ToP scores were significantly higher at age 24 mo than at age 6 mo, t(88) = -60.30, p < .001, 95% confidence interval (CI) [-1.47, -1.38]. Correlation analysis revealed that the more playful the infant was at age 6 mo, the higher their cognitive functioning was at age 18 mo and the more playful they were at age 24 mo. Toddlers with higher cognitive performance at age 18 mo demonstrated more playful behavior at age 24 mo (β = 0.120, SE = 0.05, 95% CI [0.0377, -0.2276]). Children's playfulness is evident as early as age 6 mo and continues to develop through toddlerhood, depending on their cognitive growth. Occupational therapists play a key role in working with families with young children, promoting cognitive development to further the development of playfulness behaviors. What This Article Adds: Understanding the development of playfulness and exploring its relationship with cognitive functioning in typically developing children fills important gaps in occupational therapy knowledge and contributes to delivery of early intervention, especially when cognition or playfulness are at risk. Our findings confirmed that cognitive functioning contributes to the development of playfulness.


Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 8 Years - Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2018.
Autism spectrum disorder (ASD). 2018. The Autism and Developmental Disabilities Monitoring (ADDM) Network conducts active surveillance of ASD. This report focuses on the prevalence and characteristics of ASD among children aged 8 years in 2018 whose parents or guardians lived in 11 ADDM Network sites in the United States (Arizona, Arkansas, California, Georgia, Maryland, Minnesota, Missouri, New Jersey, Tennessee, Utah, and Wisconsin). To ascertain ASD among children aged 8 years, ADDM Network staff review and abstract developmental evaluations and records from community medical and educational service providers. In 2018, children met the case definition if their records documented 1) an ASD diagnostic statement in an evaluation (diagnosis), 2) a special education classification of ASD (eligibility), or 3) an ASD International Classification of Diseases (ICD) code. For 2018, across all 11 ADDM sites, ASD prevalence per 1,000 children aged 8 years ranged from 16.5 in Missouri to 38.9 in California. The overall ASD prevalence was 23.0 per 1,000 (one in 44) children aged 8 years, and ASD was 4.2 times as prevalent among boys as among girls. Overall ASD prevalence was similar across racial and ethnic groups, except American Indian/Alaska Native children had higher ASD prevalence than non-Hispanic White (White) children (29.0 versus 21.2 per 1,000 children aged 8 years). At multiple sites, Hispanic children had lower ASD prevalence than White children (Arizona, Arkansas, Georgia, and Utah), and non-Hispanic Black (Black) children (Georgia and Minnesota). The associations between ASD prevalence and neighborhood-level median household income varied by site. Among the 5,058 children who met the ASD case definition, 75.8% had a diagnostic statement of ASD in an evaluation, 18.8% had an ASD special education classification or eligibility and no ASD diagnostic statement, and 5.4% had an ASD ICD code only. ASD prevalence per 1,000 children aged 8 years that was based exclusively on documented ASD diagnostic statements was 17.4 overall (range: 11.2 in Maryland to 29.9 in California). The median age of earliest known ASD diagnosis ranged from 36 months in California to 63 months in Minnesota. Among the 3,007 children with ASD and data on cognitive ability, 35.2% were classified as having an intelligence quotient (IQ) score ≤70. The percentages of children with ASD with IQ scores ≤70 were 49.8%, 33.1%, and 29.7% among Black, Hispanic, and White children, respectively. Overall, children with ASD and IQ scores ≤70 had earlier median ages of ASD diagnosis than children with ASD and IQ scores >70 (44 versus 53 months). In 2018, one in 44 children aged 8 years was estimated to have ASD, and prevalence and median age of identification varied widely across sites. Whereas overall ASD prevalence was similar by race and ethnicity, at certain sites Hispanic children were less likely to be identified as having ASD than White or Black children. The higher proportion of Black children compared with White and Hispanic children classified as having intellectual disability was consistent with previous findings. The variability in ASD prevalence and community ASD identification practices among children with different racial, ethnic, and geographical characteristics highlights the importance of research into the causes of that variability and strategies to provide equitable access to developmental evaluations and services. These findings also underscore the need for enhanced infrastructure for diagnostic, treatment, and support services to meet the needs of all children.


Medication use and risk of non-Hodgkin's lymphoma.
Conflicting results from previous epidemiologic studies shed little light on whether medication use is associated with risk of non-Hodgkin's lymphoma (NHL). To investigate this question, the authors conducted a population-based case-control study in Denmark and Sweden from 1999 to 2002, including 3,055 incident NHL cases and 3,187 controls. Participants reported their past use of medications and history of particular medical conditions. Unconditional logistic regression was used to estimate multivariate odds ratios and 95% confidence intervals for the associations between medication use and risk of NHL; all statistical tests were two sided. Use of antibiotics more than 10 times during adulthood was positively associated with risk of NHL and most major NHL subtypes; when users were compared with nonusers, the odds ratio for NHL was 1.8 (95% confidence interval: 1.4, 2.3); p(trend) for total antibiotic use <0.001. In addition, high cumulative use of nonsteroidal anti-inflammatory drugs was marginally associated with elevated NHL risk. Other medications evaluated were not associated with risk of NHL or its most common subtypes. Findings suggest that inflammation, infections, susceptibility to infections, and/or use of antibiotics or nonsteroidal anti-inflammatory drugs to treat these conditions may increase the risk of NHL. However, most of the medications examined were not associated with NHL risk.


Charcot arthropathy of the foot and ankle associated with rheumatoid arthritis.
Diabetic peripheral neuropathy is now well recognized as the most common cause of Charcot arthropathy of the foot and ankle, but it may be associated with other peripheral neuropathies. While not well known, it is well documented that rheumatoid arthritis is correlated with peripheral neuropathy. However, despite rheumatoid neuropathy, Charcot arthropathy has never been associated with rheumatoid arthritis. We report a series of Charcot arthropathy patients with concomitant rheumatoid arthritis. The medical records of patients treated between 1986 and 2009 with Charcot arthropathy and rheumatoid arthritis were reviewed. Recorded data included neuropathy risk factors, medications, history of ulcerations, ambulatory status, shoe wear, and treatment course. Radiographs of Charcot joints were categorized according to the Brodsky anatomic classification. Patient care was based on published treatment algorithms, emphasizing accommodative, nonoperative treatment with selective surgical interventions. Surgery was indicated for recalcitrant, nonhealing lesions of the soft tissue and/or unbraceable, nonplantigrade feet. A successful outcome was considered an ambulatory patient without amputation and a closed skin envelope at last follow-up. Four men and 16 women met the diagnostic criteria, resulting in 33 feet in the series. Average age was 61 years, and average follow-up was 4.3 years. In addition to rheumatoid arthritis, 4 patients (7 feet) had hypothyroidism, 4 patients (6 feet) had diabetes, 1 patient (2 feet) had megaloblastic anemia and diabetes, and 1 patient (1 foot) had hypothyroidism and diabetes; however, 17 feet (52%) had no known sources for neuropathy. Charcot involvement was type 1-midfoot in 21 feet (64%), type 2-hindfoot in 7 (21%), type 3a-ankle in 4 (12%), and type 3b-calcaneus in 1 (3%). Twenty-three feet (70%) were treated with conservative modalities. Ten feet (30%) required 15 surgeries, of which an exostectomy was the most common procedure. Of the 33 feet, 3 had persistent ulcerations and 1 underwent major amputation, representing 4 failures. Raising awareness within the orthopaedic community, we report a Charcot arthropathy population with a concomitant rheumatoid arthritis diagnosis, emphasizing a relationship between the 2 diseases. Through a conservative treatment regimen combined with selective surgical interventions, satisfactory outcomes were achieved in 88% of the rheumatoid Charcot feet. While several patients had additional neuropathy sources which could cause Charcot arthropathy (eg, diabetes), the majority of feet had no etiologies accounting for neuropathy or neuroarthropathy except rheumatoid arthritis. Further study is required to expand on this relationship between the 2 diseases. Level IV, retrospective case series.


Ibrutinib Inhibits Platelet Integrin αIIbβ3 Outside-In Signaling and Thrombus Stability But Not Adhesion to Collagen.
Ibrutinib is an irreversible Bruton tyrosine kinase inhibitor approved for treatment of Waldenstrom macroglobulinemia, chronic lymphocytic leukemia, and mantle cell lymphoma that increases the risk of bleeding among patients. Platelets from ibrutinib-treated patients exhibit deficiencies in collagen-evoked signaling in suspension; however, the significance of this observation and how it relates to bleeding risk is unclear, as platelets encounter immobile collagen in vivo. We sought to clarify the effects of ibrutinib on platelet function to better understand the mechanism underlying bleeding risk. By comparing signaling in suspension and during adhesion to immobilized ligands, we found that the collagen signaling deficiency caused by ibrutinib is milder during adhesion to immobilized collagen. We also found that platelets in whole blood treated with ibrutinib adhered to collagen under arterial shear but formed unstable thrombi, suggesting that the collagen signaling deficiency caused by ibrutinib may not be the predominant cause of bleeding in vivo. However, clot retraction and signaling evoked by platelet adhesion to immobilized fibrinogen were also inhibited by ibrutinib, indicating that integrin αIIbβ3 outside-in signaling is also effected in addition to GPVI signaling. When ibrutinib was combined with the P2Y12 inhibitor, cangrelor, thrombus formation under arterial shear was inhibited additively. These findings suggest that (1) ibrutinib causes GPVI and integrin αIIbβ3 platelet signaling deficiencies that result in formation of unstable thrombi and may contribute toward bleeding observed in vivo and (2) combining ibrutinib with P2Y12 antagonists, which also inhibit thrombus stability, may have a detrimental effect on hemostasis.


The factor structure of the SF-36 Health Survey in 10 countries: results from the IQOLA Project. International Quality of Life Assessment.
Studies of the factor structure of the SF-36 Health Survey are an important step in its construct validation. Its structure is also the psychometric basis for scoring physical and mental health summary scales, which are proving useful in simplifying and interpreting statistical analyses. To test the generalizability of the SF-36 factor structure, product-moment correlations among the eight SF-36 Health Survey scales were estimated for representative samples of general populations in each of 10 countries. Matrices were independently factor analyzed using identical methods to test for hypothesized physical and mental health components, and results were compared with those published for the United States. Following simple orthogonal rotation of two principal components, they were easily interpreted as dimensions of physical and mental health in all countries. These components accounted for 76% to 85% of the reliable variance in scale scores across nine European countries, in comparison with 82% in the United States. Similar patterns of correlations between the eight scales and the components were observed across all countries and across age and gender subgroups within each country. Correlations with the physical component were highest (0.64 to 0.86) for the Physical Functioning, Role Physical, and Bodily Pain scales, whereas the Mental Health, Role Emotional, and Social Functioning scales correlated highest (0.62 to 0.91) with the mental component. Secondary correlations for both clusters of scales were much lower. Scales measuring General Health and Vitality correlated moderately with both physical and mental health components. These results support the construct validity of the SF-36 translations and the scoring of physical and mental health components in all countries studied.


Reduction in tonal discriminations predicts receptive emotion processing deficits in schizophrenia and schizoaffective disorder.
Schizophrenia patients show decreased ability to identify emotion based upon tone of voice (voice emotion recognition), along with deficits in basic auditory processing. Interrelationship among these measures is poorly understood. Forty-one patients with schizophrenia/schizoaffective disorder and 41 controls were asked to identify the emotional valence (happy, sad, angry, fear, or neutral) of 38 synthesized frequency-modulated (FM) tones designed to mimic key acoustic features of human vocal expressions. The mean (F0M) and variability (F0SD) of fundamental frequency (pitch) and absence or presence of high frequency energy (HF500) of the tones were independently manipulated to assess contributions on emotion identification. Forty patients and 39 controls also completed tone-matching and voice emotion recognition tasks. Both groups showed a nonrandom response pattern (P < .0001). Stimuli with highest and lowest F0M/F0SD were preferentially identified as happy and sad, respectively. Stimuli with low F0M and midrange F0SD values were identified as angry. Addition of HF500 increased rates of angry and decreased rates of sad identifications. Patients showed less differentiation of response across frequency changes, leading to a highly significant between-group difference in response pattern to maximally identifiable stimuli (d = 1.4). The differential identification pattern for FM tones correlated with deficits in basic tone-matching ability (P = .01), voice emotion recognition (P < .001), and negative symptoms (P < .001). Specific FM tones conveyed reliable emotional percepts in both patients and controls and correlated highly with deficits in ability to recognize information based upon tone of voice, suggesting significant bottom-up contributions to social cognition and negative symptom impairments in schizophrenia.


Efficacy of skin and nasal povidone-iodine preparation against mupirocin-resistant methicillin-resistant Staphylococcus aureus and S. aureus within the anterior nares.
Mupirocin decolonization of nasal Staphylococcus aureus prior to surgery decreases surgical-site infections; however, treatment requires 5 days, compliance is low, and resistance occurs. In 2010, 3M Company introduced povidone-iodine (PVP-I)-based skin and nasal antiseptic (Skin and Nasal Prep [SNP]). SNP has rapid, broad-spectrum antimicrobial activity. We tested SNP's efficacy using full-thickness tissue (porcine mucosal [PM] and human skin) explant models and human subjects. Prior to or following infection with methicillin-resistant Staphylococcus aureus (MRSA) (mupirocin sensitive and resistant), explants were treated with Betadine ophthalmic preparation (Bet), SNP, or mupirocin (Bactroban nasal ointment [BN]) or left untreated. One hour posttreatment, explants were washed with phosphate-buffered saline (PBS) plus 2% mucin. One, 6, or 12 h later, bacteria were recovered and enumerated. Alternatively, following baseline sampling, human subjects applied two consecutive applications of SNP or saline to their anterior nares. One, 6, and 12 h after application of the preparation (postprep), nasal swabs were obtained, and S. aureus was enumerated. We observed that treatment of infected PM or human skin explants with SNP resulted in >2.0 log10 CFU reduction in MRSA, regardless of mupirocin sensitivity, which was significantly different from the values for BN- and Bet-treated explants and untreated controls 1 h, 6 h, and 12 h after being washed with PBS plus mucin. Swabbing the anterior nares of human subjects with SNP significantly reduced resident S. aureus compared to saline 1, 6, and 12 h postprep. Finally, pretreatment of PM explants with SNP, followed by a mucin rinse prior to infection, completely prevented MRSA infection. We conclude that SNP may be an attractive alternative for reducing the bioburden of anterior nares prior to surgery.


Chemical reaction imaging within microfluidic devices using confocal raman spectroscopy: the case of water and deuterium oxide as a model system.
Microfluidic devices face presently a tremendous interest, especially for the development of labs-on-a-chip systems. One of the primary challenges for such applications is the ability to perform local chemical detection and analysis from various species. In this paper, we investigate the use of confocal Raman spectroscopy from both qualitative and quantitative sides, to obtain spatially resolved concentration maps of chemically reactive fluids flowing in different channels networks. As a model chemical reaction, we used the isotopic exchange reaction between D(2)O and H(2)O, which is diffusion-controlled and whose equilibrium states exhibit distinct Raman signatures depending on the composition. Two types of chip technologies were studied, which are typical of those used for chemical kinetics investigations. In the first one, reagent mixing occurs by molecular interdiffusion of the two streams (H(2)O and D(2)O) flowing side by side in the same channel; in the second one, reagents are hosted in droplets moving in winding channels that enhance the mixing. In the first series of experiments, we were able to extract Raman images of H(2)O, D(2)O, and HOD concentrations in the main channel together with an estimate of an interdiffusion coefficient, and in the second one, we evidenced the influence of channel wiggles on mixing efficiency.


Adhesion prevention with ancrod released via a tissue-adherent hydrogel.
The objective of this investigation was to evaluate the effect of ancrod, a fibrinogenolytic protease from Malayan pit viper venom, locally delivered through a photopolymerized biodegradable hydrogel in preventing postoperative adhesions. The experimental model involved ischemic and serosal injury to the uterine horns of rats with measurement of adhesions 7 days after injury. Ancrod was delivered intravenously for 5 days preoperatively through 3 days postoperatively, intraperitoneally for 5 days preoperatively, intraperitoneally for 3 days postoperatively, and locally via the hydrogel formed upon the uterine horns by photopolymerization of an aqueous precursor solution. Systemic defibrinogenation by intravenous administration pre-through postoperatively reduced the extent of adhesions by 63% without dose sensitivity from 5 to 20 units/kg/day. Preoperative defibrinogenation by intraperitoneal administration reduced adhesion extent by up to 57%, while postoperative administration was more effective, reducing adhesions by up to 84% with a dose-dependent response from 5 to 20 units/kg/day. Administration of ancrod by local release from a tissue-adherent hydrogel was more effective than either the hydrogel alone or the same amount of ancrod administered by postoperative intraperitoneal injection. Adhesions were reduced by 82% at a local dose of 10 units/kg, compared to a reduction of 68% due to the barrier properties of the gel alone (P < 0.01) and of 19% due to the same amount of drug given at the time of surgery (P < 0.001). Local delivery of ancrod from a tissue-adherent hydrogel barrier thus provided an efficacious prevention to postoperative adhesions while permitting administration of a low total dose of the protease.


Top Surgery in Transgender Men: How Far Can You Push the Envelope?
The authors present their grading scale and the outcomes of the largest cohort of top surgery published to date. Application of this grading system can help determine which patients will benefit from a subcutaneous mastectomy with free nipple graft versus a circumareolar technique, with the primary endpoint being need for aesthetic revisions. The authors reviewed their database of transgender males who underwent bilateral mastectomy between 2006 and 2015. Data collected included age, body mass index, American Society of Anesthesiologists class, smoking, diabetes, testosterone use, months of social transition, technique used, postoperative complications, and need for revision. Two techniques were used, circumareolar incision and free nipple graft technique. Between 2006 and 2015, 1686 consecutive mastectomies were performed on 843 patients. Of those, 548 patients were excluded because of inadequate follow-up. Of the 295 included, 109 were treated using a circumareolar incision and 186 were treated using a free nipple graft technique. There was no statistically significant difference in complications between the two groups; however, there was a statistically significant difference in the rate of aesthetic revisions in the grade 2B circumareolar incision group (34 percent versus 8.8 percent). The authors' outcomes are comparable to the literature, and demonstrate that these procedures can safely be performed in an outpatient setting. The authors' grading scale classifies patients and helps the surgeon select a surgical technique. The authors show a statistical difference in rates of aesthetic revisions in Fischer grade 2B patients when a circumareolar incision is selected over a free nipple graft technique. Therapeutic, III.


Nanosuspension delivery of paclitaxel to xenograft mice can alter drug disposition and anti-tumor activity.
Paclitaxel is a common chemotherapeutic agent that is effective against various cancers. The poor aqueous solubility of paclitaxel necessitates a large percentage of Cremophor EL:ethanol (USP) in its commercial formulation which leads to hypersensitivity reactions in patients. We evaluate the use of a crystalline nanosuspension versus the USP formulation to deliver paclitaxel to tumor-bearing xenograft mice. Anti-tumor efficacy was assessed following intravenous administration of three 20 mg/kg doses of paclitaxel. Paclitaxel pharmacokinetics and tissue distribution were evaluated, and differences were observed between the two formulations. Plasma clearance and tissue to plasma ratio of mice that were dosed with the nanosuspension are approximately 33- and 11-fold higher compared to those of mice that were given the USP formulation. Despite a higher tumor to plasma ratio for the nanosuspension treatment group, absolute paclitaxel tumor exposure was higher for the USP group. Accordingly, a higher anti-tumor effect was observed in the xenograft mice that were dosed with the USP formulation (90% versus 42% tumor growth inhibition). This reduction in activity of nanoparticle formulation appeared to result from a slower than anticipated dissolution in vivo. This study illustrates a need for careful consideration of both dose and systemic solubility prior utilizing nanosuspension as a mode of intravenous delivery.


Attitudes towards second hand smoke amongst a highly exposed workforce: survey of London casino workers.
To examine knowledge, attitudes and experiences of London casino workers regarding exposure to second hand smoke (SHS) in the workplace. Postal survey of 1568 London casino workers in 25 casinos who were members of the TGWU or GMB Trade Unions. Of the workers, 559 responded to the survey (36% response), 22% of whom were current smokers. Of the respondents, 71% report being nearly always exposed to heavy levels of SHS at work, and most (65%) want all working areas in their casino to be smoke-free. The majority (78%) are bothered by SHS at work, while 91% have wanted to move away from where they are working because of it. Fifty-seven per cent believe their health has suffered as a result of SHS. Of the workers who smoke at work, 59% believe that they would try to quit smoking if no one was allowed to smoke in the casino. The majority of responders are bothered by SHS, and many are concerned about the health impacts. Most want all working areas in their casino to be smoke-free. Despite difficulties in generalizing from this limited sample, these findings add weight to the argument that the legislation on smoking in public places in England should encompass all workplaces, without exemption.


Effect of habitat fragmentation on the genetic diversity and structure of peripheral populations of beech in Central Italy.
Fragmentation can affect the demographic and genetic structure of populations near the boundary of their biogeographic range. Higher genetic differentiation among populations coupled with lower level of within-population variability is expected as a consequence of reduced population size and isolation. The effects of these 2 factors have been rarely disentangled. Given their high gene flow, anemophilous forest trees should be more affected, in terms of loss of genetic diversity, by small population size rather than geographic isolation alone. We studied the impact of distance from the main range (a measure of isolation) and reduced population size on the within-population and among population components of genetic variability. We assayed 11 isozyme loci in a total of 856 individuals in 27 marginal populations of European beech (Fagus sylvatica L.) in Central Italy. Populations were divided into 3 groups with an increasing level of fragmentation. In the most fragmented group, the within-population genetic variability was slightly smaller and the among population differentiation significantly larger than in the other 2 groups. Isolation-by-distance was lost when only pairs of populations involving at least one from the most fragmented group were considered and maintained in the other groups. These results support the role of random genetic drift having a larger impact on the most fragmented group, whereas gene flow seems to balance genetic drift in the 2 less fragmented ones. Given that average distance from the main range is not different between the intermediate and the most fragmented group, but average population size is smaller, we can conclude that gene flow is effective, even at relatively long distances, in balancing the effect of fragmentation if population size is not too small.


Melanocortin-4 receptor expression in different classes of spinal and vagal primary afferent neurons in the mouse.
Melanocortin-4 receptor (MC4R) ligands are known to modulate nociception, but the site of action of MC4R signaling on nociception remains to be elucidated. The current study investigated MC4R expression in dorsal root ganglia (DRG) of the MC4R-GFP reporter mouse. Because MC4R is known to be expressed in vagal afferent neurons in the nodose ganglion (NG), we also systematically compared MC4R-expressing vagal and spinal afferent neurons. Abundant green fluorescent protein (GFP) immunoreactivity was found in about 45% of DRG neuronal profiles (at the mid-thoracic level), the majority being small-sized profiles. Immunohistochemistry combined with in situ hybridization confirmed that GFP was genuinely produced in MC4R-expressing neurons in the DRG. While a large number of GFP profiles in the DRG coexpressed Nav1.8 mRNA (84%) and bound isolectin B4 (72%), relatively few GFP profiles were positive for NF200 (16%) or CGRP (13%), suggesting preferential MC4R expression in C-fiber nonpeptidergic neurons. By contrast, GFP in the NG frequently colocalized with Nav1.8 mRNA (64%) and NF200 (29%), but only to a moderate extent with isolectin B4 (16%). Lastly, very few GFP profiles in the NG expressed CGRP (5%) or CART (4%). Together, our findings demonstrate variegated MC4R expression in different classes of vagal and spinal primary afferent neurons, and underscore the role of the melanocortin system in modulating nociceptive and nonnociceptive peripheral sensory modalities.


Vector bionomics and malaria transmission along the Thailand-Myanmar border: a baseline entomological survey.
Baseline entomological surveys were conducted in four sentinel sites along the Thailand-Myanmar border to address vector bionomics and malaria transmission in the context of a study on malaria elimination. Adult Anopheles mosquitoes were collected using human-landing catch and cow-bait collection in four villages during the rainy season from May-June, 2013. Mosquitoes were identified to species level by morphological characters and by AS-PCR. Sporozoite indexes were determined on head/thoraces of primary and secondary malaria vectors using real-time PCR. A total of 4,301 anopheles belonging to 12 anopheline taxa were identified. Anopheles minimus represented >98% of the Minimus Complex members (n=1,683), whereas the An. maculatus group was composed of two dominant species, An. sawadwongporni and An. maculatus. Overall, 25 Plasmodium-positive mosquitoes (of 2,323) were found, representing a sporozoite index of 1.1% [95%CI 0.66-1.50]. The transmission intensity as measured by the EIR strongly varied according to the village (ANOVA, F=17.67, df=3, P<0.0001). Our findings highlight the diversity and complexity of the biting pattern of malaria vectors along the Thailand-Myanmar border that represent a formidable challenge for malaria control and elimination.


Synthetic-biology-based discovery of a fungal macrolide from Macrophomina phaseolina.
A synthetic biology approach based on genome mining and heterologous biosynthesis is a powerful tool for discovering novel natural products from a tremendous gene resource. We carried out fungal genome mining guided by a polyketide synthase gene using a public database and found a putative macrolide biosynthetic gene cluster with a highly reducing polyketide synthase gene and a thioesterase gene in Macrophomina phaseolina. Reconstitution of the cluster in Aspergillus oryzae, a model heterologous host for fungal natural product biosynthesis, produced a new 12-membered macrolide, phaseolide A. The absolute stereochemistry was elucidated by vibrational circular dichroism spectroscopy and the crystalline sponge method.


Minimum variance unbiased subpixel centroid estimation of point image limited by photon shot noise.
An unbiased subpixel centroid estimation algorithm of point image is proposed through the compensation of the systematic error of the center of mass method. The Cramér-Rao lower bound on centroid estimation variances is derived under the photon shot noise condition and is utilized to evaluate the proposed algorithm. Numerical analysis shows that the proposed centroid estimator attains the required lower bound; thus the proposed algorithm can be asserted as a minimum variance estimator. Simulation results indicate that the centroid accuracy is maximized when the Gaussian width of the signal spot is 0.2-0.3 pixel and the estimator can attain subpixel accuracy close to 1/100 pixel when 1000 photons are detected.


Antiepileptic drugs and neurodevelopment: an update.
In utero exposure to some antiepileptic drugs (AEDs) is associated with an increased risk of impaired cognitive development. Specifically, valproate and polytherapy exposure are each associated with an increased risk of cognitive impairment in children compared with other antiepileptic medications. The data regarding the risk to neurocognitive development imposed by maternal use of other AEDs are conflicting or insufficient at this time to draw definitive conclusions. Behavioral dysfunction including autistic spectrum disorder is also associated with maternal use of AEDs during pregnancy. Whether treatment with AEDs during childhood permanently affects cognitive neurodevelopment is yet to be determined.


A culture substratum with net-like polyamide fibers promotes the differentiation of mouse and human pluripotent stem cells to insulin-producing cells.
Insulin-producing and -secreting cells derived from mouse pluripotent stem cells (PSCs) are useful for pancreatic development research and evaluating drugs that may induce insulin secretion. Previously, we have established a differentiation protocol to derive insulin-secreting cells from mouse embryonic stem cells (ESCs) using a combination of growth factors, recombinant proteins, and a culture substratum with net-like fibers. However, it has not been tested which materials and diameters of these fibers are more effective for the differentiation. Therefore, the present study aimed to produce net-like culture substratum formed from polyamide (PA) and polyacrylonitrile (PAN) fibers. Substrata were delineated into PA100, 300, 600, PAN100, 300, and 600 groups based on fiber diameters. The differentiation efficiencies of mouse ESCs cultured on the substrata were then examined by insulin 1 (Ins1) expression. Expression was found to be highest in PA300 differentiated cells, indicating the potential to produce high levels of insulin. To understand any differences in substratum properties, the adsorption capacities of laminin were measured, revealing that PA300 had the highest for it. We next examined the stage of differentiation affected by incubation with PA300. This showed that Sox17- and Pdx1-GFP-positive cells increased during the first step of differentiation. To show the production of insulin without absorption from the medium, we confirmed the expression of insulin C-peptide after differentiation. Finally, we tested the effects of PA300 on the differentiation of human-induced PSC, and found more Sox17-positive cells with the PA300 substratum at the definitive endoderm stage. Furthermore, these cells expressed insulin C-peptide and had glucose-responsive C-peptide secretion. In summary, our study identified and validated a novel substratum which is suitable for pancreatic differentiation of mouse and human PSCs.


Method Validation for Extraction of DNA from Human Stool Samples for Downstream Microbiome Analysis.
Background: A formal method validation for biospecimen processing in the context of accreditation in laboratories and biobanks is lacking. A previously optimized stool processing protocol was validated for fitness-for-purpose for downstream microbiome analysis. Materials and Methods: DNA extraction from human stool was validated with various collection tubes, stabilizing solutions and storage conditions in terms of fitness-for-purpose for downstream microbiome analysis, robustness, and sample stability. Acceptance criteria were based on accurate identification of a reference material, homogeneity of extracted samples, and sample stability in a 2-year period. Results: The automated DNA extraction using the chemagic™ Magnetic Separation Module I (MSM I) extracted 8 out of 8 bacteria in the ZymoBIOMICS® Microbial Community Standard. Seven tested stabilizing solutions (OMNIgene®•GUT, RNAlater®, AquaStool™, RNAssist, PerkinElmer SEB lysis buffer, and DNA Genotek's CP-150) were all compatible with the chemagic MSM I and showed no significant difference in microbiome alpha diversity and no significant difference in the overall microbiome composition compared to the baseline snap-frozen stool sample. None of the stabilizing solutions showed intensive polymerase chain reaction (PCR) inhibition in the SPUD assay. However, when we take into account more stringent criteria which include a higher double-stranded DNA yield, higher DNA purity, and absence of PCR inhibition, we recommend the use of OMNIgene•GUT, RNAlater, or AquaStool as alternatives to rapid freezing of samples. The highest sample homogeneity was achieved with RNAlater- and OMNIgene•GUT -stabilized samples. Sample stability after a 2-year storage in -80°C was seen with OMNIgene•GUT -stabilized samples. Conclusions: We validated a combination of a stool processing method with various collection methods, suitable for downstream microbiome applications. Sample collection, storage conditions and DNA extraction methods can influence the microbiome profile results. Laboratories and biobanks should ensure that these conditions are systematically recorded in the scope of accreditation.


The Diesel Exhaust in Miners Study: II. Exposure monitoring surveys and development of exposure groups.
Air monitoring surveys were conducted between 1998 and 2001 at seven non-metal mining facilities to assess exposure to respirable elemental carbon (REC), a component of diesel exhaust (DE), for an epidemiologic study of miners exposed to DE. Personal exposure measurements were taken on workers in a cross-section of jobs located underground and on the surface. Air samples taken to measure REC were also analyzed for respirable organic carbon (ROC). Concurrent measurements to assess exposure to nitric oxide (NO) and nitrogen dioxide (NO₂), two gaseous components of DE, were also taken. The REC measurements were used to develop quantitative estimates of average exposure levels by facility, department, and job title for the epidemiologic analysis. Each underground job was assigned to one of three sets of exposure groups from specific to general: (i) standardized job titles, (ii) groups of standardized job titles combined based on the percentage of time in the major underground areas, and (iii) larger groups based on similar area carbon monoxide (CO) air concentrations. Surface jobs were categorized based on their use of diesel equipment and proximity to DE. A total of 779 full-shift personal measurements were taken underground. The average REC exposure levels for underground jobs with five or more measurements ranged from 31 to 58 μg m⁻³ at the facility with the lowest average exposure levels and from 313 to 488 μg m⁻³ at the facility with the highest average exposure levels. The average REC exposure levels for surface workers ranged from 2 to 6 μg m⁻³ across the seven facilities. There was much less contrast in the ROC compared with REC exposure levels measured between surface and underground workers within each facility, as well as across the facilities. The average ROC levels underground ranged from 64 to 195 μg m⁻³, while on the surface, the average ROC levels ranged from 38 to 71 μg m⁻³ by facility, an ∼2- to 3-fold difference. The average NO and NO₂ levels underground ranged from 0.20 to 1.49 parts per million (ppm) and from 0.10 to 0.60 ppm, respectively, and were ∼10 times higher than levels on the surface, which ranged from 0.02 to 0.11 ppm and from 0.01 to 0.06 ppm, respectively. The ROC, NO, and NO₂ concentrations underground were correlated with the REC levels (r = 0.62, 0.71, and 0.62, respectively). A total of 80% of the underground jobs were assigned an exposure estimate based on measurements taken for the specific job title or for other jobs with a similar percentage of time spent in the major underground work areas. The average REC exposure levels by facility were from 15 to 64 times higher underground than on the surface. The large contrast in exposure levels measured underground versus on the surface, along with the differences between the mining facilities and between underground jobs within the facilities resulted in a wide distribution in the exposure estimates for evaluation of exposure-response relationships in the epidemiologic analyses.


High dose dipyridamole as a pharmacological stress test during cardiac catheterisation in patients with coronary artery disease.
To validate dipyridamole as a pharmacological stress test during cardiac catheterisation, allowing both functional and morphological estimation of stenosis severity. The study encompassed 74 patients: 62 patients with significant coronary artery disease (age 61 (SD 8) years; seven women, 55 men) and 12 controls. Regional wall motion, left ventricular ejection fraction and end diastolic pressure were analysed in the resting state and after high dose intravenous dipyridamole. Patients were subdivided into four groups: group I (n = 32, 43%) had stopped all anti-ischaemic treatment for > 24 h, group II (n = 14, 19%) was under treatment, group III (n = 16, 22%) had significant coronary artery disease only in regions with regional wall motion abnormalities at rest, and group IV consisted of 12 control patients (16%) with no significant coronary artery disease (age 62 (8) years, three women, nine men). The sensitivity of dipyridamole testing in patients with coronary artery disease was poor. The best sensitivity was obtained with regional wall motion analysis (26/62 = 42%) and with global left ventricular ejection fraction (25/62 = 40%). Specificity was 100% for regional wall motion and 100% for ejection fraction. Calculated positive and negative predictive values for regional wall motion were 100% and 63%, respectively. Although safe, handy, and inexpensive, dipyridamole is not an adequate pharmacological stress test during cardiac catheterisation because of its low sensitivity.


Production of mobile invertebrate communities on shallow reefs from temperate to tropical seas.
Primary productivity of marine ecosystems is largely driven by broad gradients in environmental and ecological properties. By contrast, secondary productivity tends to be more variable, influenced by bottom-up (resource-driven) and top-down (predatory) processes, other environmental drivers, and mediation by the physical structure of habitats. Here, we use a continental-scale dataset on small mobile invertebrates (epifauna), common on surfaces in all marine ecosystems, to test influences of potential drivers of temperature-standardized secondary production across a large biogeographic range. We found epifaunal production to be remarkably consistent along a temperate to tropical Australian latitudinal gradient of 28.6°, spanning kelp forests to coral reefs (approx. 3500 km). Using a model selection procedure, epifaunal production was primarily related to biogenic habitat group, which explained up to 45% of total variability. Production was otherwise invariant to predictors capturing primary productivity, the local biomass of fishes (proxy for predation pressure), and environmental, geographical, and human impacts. Highly predictable levels of epifaunal productivity associated with distinct habitat groups across continental scales should allow accurate modelling of the contributions of these ubiquitous invertebrates to coastal food webs, thus improving understanding of likely changes to food web structure with ocean warming and other anthropogenic impacts on marine ecosystems.


A predictive model for canine dilated cardiomyopathy-a meta-analysis of Doberman Pinscher data.
Dilated cardiomyopathy is a prevalent and often fatal disease in humans and dogs. Indeed dilated cardiomyopathy is the third most common form of cardiac disease in humans, reported to affect approximately 36 individuals per 100,000 individuals. In dogs, dilated cardiomyopathy is the second most common cardiac disease and is most prevalent in the Irish Wolfhound, Doberman Pinscher and Newfoundland breeds. Dilated cardiomyopathy is characterised by ventricular chamber enlargement and systolic dysfunction which often leads to congestive heart failure. Although multiple human loci have been implicated in the pathogenesis of dilated cardiomyopathy, the identified variants are typically associated with rare monogenic forms of dilated cardiomyopathy. The potential for multigenic interactions contributing to human dilated cardiomyopathy remains poorly understood. Consistent with this, several known human dilated cardiomyopathy loci have been excluded as common causes of canine dilated cardiomyopathy, although canine dilated cardiomyopathy resembles the human disease functionally. This suggests additional genetic factors contribute to the dilated cardiomyopathy phenotype.This study represents a meta-analysis of available canine dilated cardiomyopathy genetic datasets with the goal of determining potential multigenic interactions relating the sex chromosome genotype (XX vs. XY) with known dilated cardiomyopathy associated loci on chromosome 5 and the PDK4 gene in the incidence and progression of dilated cardiomyopathy. The results show an interaction between known canine dilated cardiomyopathy loci and an unknown X-linked locus. Our study is the first to test a multigenic contribution to dilated cardiomyopathy and suggest a genetic basis for the known sex-disparity in dilated cardiomyopathy outcomes.


circEPSTI1 as a Prognostic Marker and Mediator of Triple-Negative Breast Cancer Progression.
Circular RNAs (circRNAs) represent a class of non-coding RNAs that play a vital role in modulating gene expression and several pathological responses. However, the expression profile and function of circRNAs in triple-negative breast cancer (TNBC) remain unknown. In the current study, we investigated the expression profile of human circRNAs in TNBC tissues and identified circEPSTI1 (hsa_ circRNA_000479) as a significantly upregulated circRNA. Methods: We performed circular RNA microarray assays to screen circular RNA expression profiles of TNBC and further investigated circEPSTI1. We observed the effect of circEPSTI1 on proliferation, clonal formation and apoptosis in TNBC by knocking downcircEPSTI1 in three TNBC cell lines. Based on the MRE analysis and luciferase reporter assay, we found that circEPSTI1 binds to miRNAs as a miRNA sponge and the co-target genes of miRNAs. We performed xenograft experiments in mice to confirm our findings. We evaluated circEPSTI1 levels in 240 TNBC patients by ISH. Results: Knockdown of circEPSTI1 inhibits TNBC cell proliferation and induces apoptosis. In vitro and in vivo experiments indicated that circEPSTI1 binds to miR-4753 and miR-6809 as a miRNA sponge to regulate BCL11A expression and affect TNBC proliferation and apoptosis. High levels of circEPSTI1 correlate with reduced survival in TNBC patients. Conclusions: The circEPSTI1-miR-4753/6809-BCL11A axis affect the proliferation and apoptosis of triple-negative breast cancer through the mechanism of competing endogenous RNAs (ceRNA). In addition, our results identify circEPSTI1 as an independent prognostic marker for survival in patients with TNBC.