Testing for Zika virus infection in pregnancy: key concepts to deal with an emerging epidemic.
Zika virus is an emerging mosquito-borne (Aedes genus) arbovirus of the Flaviviridae family. Following epidemics in Micronesia and French Polynesia during the past decade, more recent Zika virus infection outbreaks were first reported in South America as early as May 2013 and spread to now 50 countries throughout the Americas. Although no other flavivirus has previously been known to cause major fetal malformations following perinatal infection, reports of a causal link between Zika virus and microcephaly, brain and ocular malformations, and fetal loss emerged from hard-hit regions of Brazil by October 2015. Among the minority of infected women with symptoms, clinical manifestations of Zika virus infection may include fever, headache, arthralgia, myalgia, and maculopapular rash; however, only 1 of every 4-5 people who are infected have any symptoms. Thus, clinical symptom reporting is an ineffective screening tool for the relative risk assessment of Zika virus infection in the majority of patients. As previously occurred with other largely asymptomatic viral infections posing perinatal transmission risk (such as HIV or cytomegalovirus), we must develop and implement rapid, sensitive, and specific screening and diagnostic testing for both viral detection and estimation of timing of exposure. Unfortunately, despite an unprecedented surge in attempts to rapidly advance perinatal clinical testing for a previously obscure arbovirus, there are several ongoing hindrances to molecular- and sonographic-based screening and diagnosis of congenital Zika virus infection. These include the following: (1) difficulty in estimating the timing of exposure for women living in endemic areas and thus limited interpretability of immunoglobulin M serologies; (2) cross-reaction of immunoglobulin serologies with other endemic flaviruses, such as dengue; (3) persistent viremia and viruria in pregnancy weeks to months after primary exposure; and (4) fetal brain malformations and anomalies preceding the sonographic detection of microcephaly. In this commentary, we discuss screening and diagnostic considerations that are grounded not only in the realities of current obstetrical practice in a largely global population but also in basic immunology and virology. We review recent epidemiological data pertaining to the risk of congenital Zika virus malformations based on trimester of exposure and consider side by side with emerging data demonstrating replication of Zika virus in placental and fetal tissue throughout gestation. We discuss limitations to ultrasound based strategies that rely largely or solely on the detection of microcephaly and provide alternative neurosonographic approaches for the detection of malformations that may precede or occur independent of a small head circumference. This expert review provides information that is of value for the following: (1) obstetrician, maternal-fetal medicine specialist, midwife, patient, and family in cases of suspected Zika virus infection; (2) review of the methodology for laboratory testing to explore the presence of the virus and the immune response; (3) ultrasound-based assessment of the fetus suspected to be exposed to Zika virus with particular emphasis on the central nervous system; and (4) identification of areas ready for development.


A Novel Approach to Chemical Mixture Risk Assessment-Linking Data from Population-Based Epidemiology and Experimental Animal Tests.
Humans are continuously exposed to chemicals with suspected or proven endocrine disrupting chemicals (EDCs). Risk management of EDCs presents a major unmet challenge because the available data for adverse health effects are generated by examining one compound at a time, whereas real-life exposures are to mixtures of chemicals. In this work, we integrate epidemiological and experimental evidence toward a whole mixture strategy for risk assessment. To illustrate, we conduct the following four steps in a case study: (1) identification of single EDCs ("bad actors")-measured in prenatal blood/urine in the SELMA study-that are associated with a shorter anogenital distance (AGD) in baby boys; (2) definition and construction of a "typical" mixture consisting of the "bad actors" identified in Step 1; (3) experimentally testing this mixture in an in vivo animal model to estimate a dose-response relationship and determine a point of departure (i.e., reference dose [RfD]) associated with an adverse health outcome; and (4) use a statistical measure of "sufficient similarity" to compare the experimental RfD (from Step 3) to the exposure measured in the human population and generate a "similar mixture risk indicator" (SMRI). The objective of this exercise is to generate a proof of concept for the systematic integration of epidemiological and experimental evidence with mixture risk assessment strategies. Using a whole mixture approach, we could find a higher rate of pregnant women under risk (13%) when comparing with the data from more traditional models of additivity (3%), or a compound-by-compound strategy (1.6%).


Pulmonary embolism: prognostic CT findings.
To retrospectively determine whether three computed tomographic (CT) findings-ventricular septal bowing (VSB), ratio between the diameters of right ventricle (RV) and left ventricle (LV), and embolic burden-are associated with short-term death, defined as in-hospital death or death within 30 days of CT, whichever was longer, due to acute pulmonary embolism (PE). Institutional Review Board approval was obtained, and patient information was reviewed in compliance with HIPAA regulations. A total of 1193 patients with CT scans positive for PE from January 1, 1997, to December 31, 2002, who had given authorization for retrospective research were included. Scans were independently reviewed by two observers. CT findings were compared with risk of death by using univariate analysis (chi(2) statistic) and multivariate logistic regression. Interobserver variability (kappa statistic or intraclass correlation coefficient), sensitivity, and specificity of CT findings for predicting death were calculated. A third observer reviewed discrepant cases post hoc. Fifty-four percent of patients were women and 46% were men (mean age, 63 years +/- 16). For observer 1, VSB was associated with death in univariate (odds ratio [OR], 1.98; P = .04) and multivariate modeling (OR, 1.97; P = .05). Interobserver variability was only fair (kappa = 0.54) for VSB, and observer 2 found no association with death (OR, 1.52; P = .22). For both observers, VSB had low sensitivity (21% and 18%) and high specificity (88% and 87%) for predicting death. Neither RV/LV diameter ratio nor embolic burden was associated with increased risk of death. For observer 3, VSB was associated with death in univariate (OR, 2.10; P = .05) and multivariate analyses (OR, 2.18; P = .05). CT-depicted VSB is predictive of death due to PE, but with low sensitivity and high interobserver variability. RV/LV diameter ratio and embolic burden are not associated with short-term death due to PE.


Cardiac surgical outcome prediction by blood pressure variability indices Poincaré plot and coefficient of variation: a retrospective study.
Recent literature suggests a significant association between blood pressure variability (BPV) and postoperative outcomes after cardiac surgery. However, its outcome prediction ability remains unclear. Current prediction models use static preoperative patient factors. We explored the ability of Poincaré plots and coefficient of variation (CV) by measuring intraoperative BPV in predicting adverse outcomes. In this retrospective, observational, cohort study, 3687 adult patients (> 18 years) undergoing cardiac surgery requiring cardio-pulmonary bypass from 2008 to 2014 were included. Blood pressure variability was computed by Poincare plots and CV. Standard descriptors (SD) SD1, SD2 were measured with Poincare plots by ellipse fitting technique. The outcomes analyzed were the 30-day mortality and postoperative renal failure. Logistic regression models adjusted for preoperative and surgical factors were constructed to evaluate the association between BPV parameters and outcomes. C-statistics were used to analyse the predictive ability. Analysis found that, 99 (2.7%) patients died within 30 days and 105 (2.8%) patients suffered from in-hospital renal failure. Logistic regression models including BPV parameters (standard descriptors from Poincare plots and CV) performed poorly in predicting postoperative 30-day mortality and renal failure [Concordance(C)-Statistic around 0.5]. They did not add any significant value to the standard STS risk score [C-statistic: STS alone 0.7, STS + BPV parmeters 0.7]. In conclusion, BP variability computed from Poincare plots and CV were not predictive of mortality and renal failure in cardiac surgical patients. Patient comorbid conditions and other preoperative factors are still the gold standard for outcome prediction. Future directions include analysis of dynamic parameters such as complexity of physiological signals in identifying high risk patients and tailoring management accordingly.


Global targeting of subcellular heat shock protein-90 networks for therapy of glioblastoma.
Drug discovery for complex and heterogeneous tumors now aims at dismantling global networks of disease maintenance, but the subcellular requirements of this approach are not understood. Here, we simultaneously targeted the multiple subcellular compartments of the molecular chaperone heat shock protein-90 (Hsp90) in a model of glioblastoma, a highly lethal human malignancy in urgent need of fresh therapeutic strategies. Treatment of cultured or patient-derived glioblastoma cells with Shepherdin, a dual peptidomimetic inhibitor of mitochondrial and cytosolic Hsp90, caused irreversible collapse of mitochondria, degradation of Hsp90 client proteins in the cytosol, and tumor cell killing by apoptosis and autophagy. Stereotactic or systemic delivery of Shepherdin was well tolerated and suppressed intracranial glioma growth via inhibition of cell proliferation, induction of apoptosis, and reduction of angiogenesis in vivo. These data show that disabling Hsp90 cancer networks in their multiple subcellular compartments improves strategies for drug discovery and may provide novel molecular therapy for highly recalcitrant human tumors.


Latent profile analysis of young adolescents' physical activity across locations on schooldays.
To investigate whether adolescents cluster into profiles based on where they accumulate moderate-to-vigorous physical activity (MVPA), if overall MVPA differs across profiles, and if walking to school and participant and neighborhood characteristics explain profile membership. Adolescents (N=528; mean age=14.12±1.44; 50% girls) wore accelerometers and Global Positioning Systems (GPS) trackers for 3.9±1.5 days to assess MVPA minutes in five locations: at home, at school, in home neighborhood, in school neighborhood, and other. Walking to school and participant characteristics were assessed by questionnaire, and neighborhood environment by Geographic Information Systems (GIS). Latent profile analysis (LPA) was used to identify profiles/groups of participants based on accumulation of physical activity across the five locations. Mixed-effects regression tested differences in overall MVPA, walking to school, and other characteristics across profiles. Four initial profiles emerged: one Insufficiently Active profile and three "Active" profiles (Active Around School, Active Home Neighborhood, and Active Other Locations). The Insufficiently Active profile emerging from the first LPA (90% of participants) was further separated into four profiles in a second LPA: Insufficiently Active, and three additional "Active" profiles (Moderately-Active Around School, Moderately-Active Home Neighborhood, and Active At Home). Those in the six Active profiles had more overall MVPA (41.1-92.7 minutes/day) than those in the two Insufficiently Active profiles (34.5-38.3 minutes/day). Variables that differed across profiles included walking to school, sports/athletic ability, and neighborhood walkability. Although most participants did not meet the MVPA guideline, the six Active profiles showed the places in which many adolescents were able to achieve the 60-minute/day guideline. The home and school neighborhood (partly through walking to school), "other" locations, and to a lesser extent the home, appeared to be key sources for physical activity that distinguished active from insufficiently active adolescents. Finding the right match between the individual and physical activity source/location may be a promising strategy for increasing active travel and MVPA in adolescents.


Molecular cloning, expression profiling, and yeast complementation of 19 beta-tubulin cDNAs from developing cotton ovules.
Microtubules are a major structural component of the cytoskeleton and participate in cell division, intracellular transport, and cell morphogenesis. In the present study, 795 cotton tubulin expressed sequence tags were analysed and 19 beta-tubulin genes (TUB) cloned from a cotton cDNA library. Among the group, 12 cotton TUBs (GhTUBs) are reported for the first time here. Transcription profiling revealed that nine GhTUBs were highly expressed in elongating fibre cells as compared with fuzzless-lintless mutant ovules. Treating cultured wild-type cotton ovules with exogenous phytohormones showed that individual genes can be induced by different agents. Gibberellin induced expression of GhTUB1 and GhTUB3, ethylene induced expression of GhTUB5, GhTUB9, and GhTUB12, brassinosteroids induced expression of GhTUB1, GhTUB3, GhTUB9, and GhTUB12, and lignoceric acid induced expression of GhTUB1, GhTUB3, and GhTUB12. When GhTUBs were transformed into the Saccharomyces cerevisiae inviable mutant, tub2, which is deficient in beta-tubulin, one ovule-specific and eight of nine fibre-preferential GhTUBs rescued this lethality. This study suggests that the proteins encoded by cotton GhTUBs are involved during cotton fibre development.


Ergothioneine Antioxidant Function: From Chemistry to Cardiovascular Therapeutic Potential.
Ergothioneine (ESH), the betaine of 2-mercapto-L-histidine, is a water-soluble naturally occurring amino acid with antioxidant properties. ESH accumulates in several human and animal tissues up to millimolar concentration through its high affinity transporter, namely the organic cation transporter 1 (OCTN1). ESH, first isolated from the ergot fungus (Claviceps purpurea), is synthesized only by Actinomycetales and non-yeast-like fungi. Plants absorb ESH via symbiotic associations between their roots and soil fungi, whereas mammals acquire it solely from dietary sources. Numerous evidence demonstrated the antioxidant and cytoprotective effects of ESH, including protection against cardiovascular diseases, chronic inflammatory conditions, ultraviolet radiation damages, and neuronal injuries. Although more than a century after its discovery has gone by, our understanding on the in vivo ESH mechanism is limited and this compound still intrigues researchers. However, recent evidence about differences in chemical redox behavior between ESH and alkylthiols, such as cysteine and glutathione, has opened new perspectives on the role of ESH during oxidative damage. In this short review, we discuss the role of ESH in the complex machinery of the cellular antioxidant defense focusing on the current knowledge on its chemical mechanism of action in the protection against cardiovascular disease.


Electrical Manipulation of Topological Phases in a Quantum Anomalous Hall Insulator.
Quantum anomalous Hall phases arising from the inverted band topology in magnetically doped topological insulators have emerged as an important subject of research for quantization at zero magnetic fields. Though necessary for practical implementation, sophisticated electrical control of molecular beam epitaxy (MBE)-grown quantum anomalous Hall matter have been stymied by growth and fabrication challenges. Here, a novel procedure is demonstrated, employing a combination of thin-film deposition and 2D material stacking techniques, to create dual-gated devices of the MBE-grown quantum anomalous Hall insulator, Cr-doped (Bi,Sb)2 Te3 . In these devices, orthogonal control over the field-induced charge density and the electric displacement field is demonstrated. A thorough examination of material responses to tuning along each control axis is presented, realizing magnetic property control along the former and a novel capability to manipulate the surface exchange gap along the latter. Through electrically addressing the exchange gap, the capabilities to either strengthen the quantum anomalous Hall state or suppress it entirely and drive a topological phase transition to a trivial state are demonstrated. The experimental result is explained using first principle theoretical calculations, and establishes a practical route for in situ control of quantum anomalous Hall states and topology.


[Effect of serotoninergic and antiserotoninergic preparations on convulsions induced by the endogenous convulsants kynurenine and quinolinic acid].
Serotoninergic drugs DL-5-hydroxytryptophan, 5-methoxytryptamine (mexamine) and 5-hydroxytryptamine (serotonin) were found to reduce clonic convulsions induced by intracerebroventricular administration of DL-kynurenine sulfate in mice. Serotonin antagonist deseril weakened the antikynurenine effect of DL-5-hydroxytryptophan and mexamine. Quinolinic acid-induced convulsions could be attenuated only by DL-5-hydroxytryptophan. Deseril and metergoline and destruction of the cerebral serotoninergic neurons by 5,6-dihydroxytryptamine potentiated the convulsant effect of quinolinic acid but not kynurenine. The serotoninergic protective anticonvulsant mechanism is probably better developed against kynurenine rather than quinolinic acid.


Pharmacokinetic analysis of factors determining elimination pathways for sulfate and glucuronide metabolites of xenobiotics II: Studies with isolated perfused rat liver.
1. To elucidate the determining factors for elimination pathways of sulfate and glucuronide metabolites of xenobiotics, a single-pass perfusion of 4-methylumbelliferone (4MU) or p-nitrophenol (pNP) was performed with an isolated rat liver preparation. 2. Without bovine serum albumin in the perfusion system, clearance calculated based on the unbound concentration in the liver clearly showed that the net efflux clearances (CLeff) of sulfates from the sinusoidal membrane were much higher than those of glucuronides and that the biliary excretion clearances (CLb) of glucuronides were approximately two times larger than those of sulfates. 3. The ratios of CLeff to CLb were much higher for sulfates than those for glucuronides. The bile-oriented elimination of glucuronides or sinusoidal efflux-oriented elimination of sulfates was observed even using the perfusate including 3% bovine serum albumin, but the sinusoidal efflux of sulfates was extensively enhanced by bovine serum albumin in the perfusate. The mechanisms behind this stimulatory effect remain to be elucidated. 4. For both compounds, CLb of glucuronide was comparable with CLb of sulfate, meaning that CLb is not responsible for the biliary excretion of glucuronides at extensively higher rate than sulfates. 5. Higher concentration of glucuronides in the liver, partly caused by much lower CLeff of glucuronides than that of sulfates, is likely responsible for the bile-oriented excretion of glucuronides. The extensive sinusoidal efflux of sulfates, leading to the urine-oriented excretion, is attributed to the substantially higher CLeff than CLb. 6. In conclusion, the sinusoidal efflux is an important factor for determining elimination pathways of both sulfates and glucuronides, although further studies are needed to clarify the mechanisms of the sinusoidal efflux.


Variation of the serum N-glycosylation during the pregnancy of a MPI-CDG patient.
For the first time the glycosylation of a patient with a MPI-CDG during pregnancy is monitored. MPI-CDG, is characterised by a deficiency in mannose-6-phosphate isomerase (MPI) leading to a reduced pool of glycosylation precursors, impairing the biosynthesis of N-glycans leading to N-glycosylation defects. The abnormal N-glycosylation profile with an elevation of asialotransferrin and disialotransferrin, typical of CDG type I, is assessable by transferrin isoelectrofocusing. Oral D-mannose supplementation for MPI-CDG patients has been widely used and improves clinical manifestations. The glycosylation of a MPI-CDG patient during pregnancy without mannose supplementation was studied using carbohydrate deficient transferrin (CDT) assay, transferrin isoelectrofocusing (IEF) and mass spectrometry of total serum N-glycans. A general improvement of the glycosylation profile of the patient due to a better transfer of the glycan precursors as well as an increase of the triantennary glycans (and sialylation) was observed. In conclusion, in the absence of mannose supplementation, the previously observed glycosylation abnormality of the MPI-CDG patient was corrected. The molecular mechanism underlying this N-glycosylation rescue during MPI-CDG pregnancy further needs to be investigated.


A minor modification of Lichtenstein repair of primary inguinal hernia: postoperative discomfort evaluation.
The aim of this study was to evaluate the usefulness of a modification of the Lichtenstein hernioplasty procedure by evaluating its impact on postoperative discomfort. From December 1999 to May 2006, the Lichtenstein inguinal hernioplasty was performed in 406 patients with noncomplicated unilateral inguinal hernia. During reconstruction, the mesh was fixed to the inguinal canal floor without stitching its upper margin to the internal oblique muscle. Control of postoperative pain proved to be satisfactory; 72 hours after surgery, 26.1 per cent of patients no longer felt any pain, whereas 54.4 per cent had slight pain without the need for painkillers; on Day 7, 92.8 per cent felt no pain at all. After 10 days, 86.7 per cent of those with sedentary jobs were able to return to work, whereas 79.1 per cent of those with heavier jobs resumed work in 11 to 15 days. Our modification of the original Lichtenstein procedure permitted us to obtain satisfactory results with regard to the control of postoperative chronic pain and a rapid reprisal of normal working activity.


Impact of a Common Genetic Variation Associated With Putamen Volume on Neural Mechanisms of Attention-Deficit/Hyperactivity Disorder.
In a recent genomewide association study of subcortical brain volumes, a common genetic variation at rs945270 was identified as having the strongest effect on putamen volume, a brain measurement linked to familial risk for attention-deficit/hyperactivity disorder (ADHD). To determine whether rs945270 might be a genetic determinant of ADHD, its effects on ADHD-related symptoms and neural mechanisms of ADHD, such as response inhibition and reward sensitivity, were explored. A large population sample of 1,834 14-year-old adolescents was used to test the effects of rs945270 on ADHD symptoms assessed through the Strengths and Difficulties Questionnaire and region-of-interest analyses of putamen activation by functional magnetic resonance imaging using the stop signal and monetary incentive delay tasks, assessing response inhibition and reward sensitivity, respectively. There was a significant link between rs945270 and ADHD symptom scores, with the C allele associated with lower symptom scores, most notably hyperactivity. In addition, there were sex-specific effects of this variant on the brain. In boys, the C allele was associated with lower putamen activity during successful response inhibition, a brain response that was not associated with ADHD symptoms. In girls, putamen activation during reward anticipation increased with the number of C alleles, most significantly in the right putamen. Remarkably, right putamen activation during reward anticipation tended to negatively correlate with ADHD symptoms. These results indicate that rs945270 might contribute to the genetic risk of ADHD partly through its effects on hyperactivity and reward processing in girls.


Adherence to Oral Medications for Hypertension and Diabetes in Veterans with Comorbid Airflow Limitation.
Diabetes and hypertension are common among patients with airflow limitation and contribute to cardiovascular (CV) mortality, one of the leading causes of death among patients with airflow limitation. Our goal was to examine the association of severity of airflow limitation with adherence to medications for hypertension and diabetes. We identified 7,359 veterans with hypertension and/or diabetes in the Veterans Integrated Service Network-20. Entry date into the cohort was defined as the date of a patient's first pulmonary function testing (PFT). Diagnostic codes (ICD-9), PFT, and pharmacy data were available via the electronic medical record or via direct interrogation of PFT equipment. Our primary exposure was airflow limitation defined as FEV1 ≥ 80% predicted (normal), 80 > FEV1 ≥ 50% predicted (mild/moderate), 50 > FEV1 ≥ 30% predicted (severe), and FEV1 < 30% predicted (very severe). We assessed adherence using a validated method based on electronic pharmacy refill data and defined adherence as ≥ 80% medication possession for the period 6-12 months after enrollment. Medications of interest included β-blockers, calcium channel blockers, thiazides, and angiotensin-converting-enzyme inhibitors for patients with hypertension, and metformin and sulfonylureas for patients with diabetes. We used logistic regression models to assess the association between severity of airflow limitation and adherence, adjusted for demographics, health behaviors, and comorbidities. Overall adherence was poor (44.6-55.1%). Among patients with hypertension, when compared with subjects with normal FEV1, subjects with each category lower of FEV1 were less adherent to β-blockers, with an odds ratio (OR) of 0.87 (95% confidence interval [CI], 0.80-0.95); calcium channel blockers, with an OR of 0.83 (95% CI, 0.74-0.93); and angiotensin-converting-enzyme inhibitors with an OR of 0.91 (95% CI, 0.84-0.99). Airflow limitation was not associated with adherence to thiazides. Among patients with diabetes, we found no significant association of FEV1 with adherence, although a similar lower trend with increasing airflow limitation. In a sensitivity analysis limited to patients with chronic obstructive pulmonary disease, we found a nonstatistically significant trend for decreased adherence to β-blockers, calcium channel blockers, and angiotensin-converting-enzyme inhibitors in subjects with higher GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage. Severity of airflow limitation is associated with decreased adherence to β-blockers, calcium channel blockers, and angiotensin-converting-enzyme inhibitors. The decreased adherence to these medications may be related to adverse effects on symptoms in patients with lung disease, and may partially explain excess CV mortality in these patients.


Analysis of conformational parameters in nucleic acid fragments. I. Single crystals of nucleosides and nucleotides.
A study has been undertaken of conformational parameters in single crystal structures of nucleosides and nucleotides using the techniques of helical conformational analysis. A "quasi-helix" was generated from the geometry of base-paired structures, using published data extracted from the Cambridge structural database. A total of 54 base-pairs were found in these structures, for each of which were calculated hydrogen bond parameters, propeller twist, buckle and C1'-C1' separations. These were analysed according to various classifications. Propeller twists are found to show a wide range of values and the magnitude of twist appears to be unrelated to hydrogen bond parameters or C1'-C1' separation. The values of the buckle parameter vary over a smaller range of values and are unrelated to propeller twist magnitude. There is found to be a greater tendency to form homo-base-pairs among compounds containing adenine bases.


Dermal lymphatic invasion and inflammatory breast cancer are independent predictors of outcome after postmastectomy radiation.
Inflammatory breast cancer (IBC) is a clinical staging based on history and physical findings. Dermal lymphatic invasion (DLI) can occur with or without IBC. We examine how these independently affect outcome in women treated with postmastectomy radiation. Four hundred thirty-two patients treated with postmastectomy radiation for invasive mammary cancer were assessed. Kaplan-Meier methodology was used to calculate rates of locoregional recurrence (LRR), distant metastases (DM) and overall survival (OS). Variables entered into univariate and multivariate analysis included T stage, IBC, DLI, estrogen receptor/progesterone receptor status, HER-2/neu status, N stage, extracapsular node extension (ECE), and use of chemotherapy (CT). Median follow-up is 58 months. For all 432 patients, the rate of LRR was 3% and DM 28%. Seven percent are alive with disease (AWD) and 26% are dead of disease (DOD). Thirty-one patients had IBC without DLI, 21 had DLI without IBC, and 18 had both IBC and DLI. For DLI 10% developed LRR, 45% DM, 7.5% are AWD and 50% are DOD. Of patients with IBC, 8% developed LRR, 44% DM, 8% are AWD and 48% DOD. DLI was the only significant independent predictor for LRR (HR 4.8, P < 0.05). Predictors of DM and OS were IBC, > or =4 positive nodes, and CT. DLI and IBC are independent predictors of poor outcome after postmastectomy radiation. DLI is associated with an increased risk for LRR, and IBC with worse rates of DM and OS. Patients with both features have worse outcome than those with either alone.


RESPONSE OF TRACHYDISCUS MINUTUS (XANTHOPHYCEAE) TO TEMPERATURE AND LIGHT(1).
The effects of different temperatures and light intensities on growth, pigments, sugars, lipids, and proteins, as well as on some antioxidant and proteolytic enzymes of Trachydiscus minutus (Bourr.) H. Ettl, were investigated. The optimum growth temperature and light intensity were 25°C and 2 × 132 μmol photons · m(-2 ) · s(-1) , respectively. Under these conditions, proteins were the main biomass components (33.45% dry weight [dwt]), with high levels of carbohydrates (29% dwt) and lipids (21.77% dwt). T. minutus tolerated temperatures between 20°C and 32°C, with only moderate changes in cell growth and biochemical composition. Extremely low (15°C) and high (40°C) temperatures decreased chl and RUBISCO contents and inhibited cell growth. The biochemical response of the alga to both unfavorable conditions was an increase in lipid content (up to 35.19% dwt) and a decrease in carbohydrates (down to 13.64% dwt) with much less of a change in total protein content (in the range of 30.51%-38.13% dwt). At the same time, the defense system of T. minutus was regulated differently in response to heat or cold treatments. Generally, at 40°C, the activities of superoxide dismutase (SOD), catalase (CAT), and proteases were drastically elevated, and three polypeptides were overexpressed, whereas the glutathione reductase (GR) and peroxidase (POD) activities were reduced. In contrast, at 15°C, all these enzymes except GR were suppressed. The effect of light was to enhance or decrease the temperature stress responses, depending on intensity. Our studies demonstrate the broad temperature adaptability of T. minutus as well as the potential for the production of valuable algal biomass.


Development of an internally quenched fluorescent substrate for Escherichia coli leader peptidase.
Escherichia coli leader peptidase, an integral membrane protein, is responsible for the cleavage of the signal sequence of many exported proteins. Recent studies suggest that it is a novel serine protease that utilizes a serine-lysine catalytic dyad. In an effort to further understand the mechanism of this enzyme, an internally quenched fluorescent peptide substrate incorporating the leader peptidase cleavage site of maltose binding protein signal peptide, Y(NO2)-F-S-A-S-A-L-A-K-I-K(Abz) (anthraniloyl), was designed and synthesized. In the intact peptide, the fluorescence of the anthraniloyl group is quenched by the 3-nitrotyrosine. This quenched fluorescence is liberated upon cleavage of the peptide by the leader peptidase, resulting in increased fluorescence that could then be monitored fluorometrically. The designed substrate can be cleaved effectively by E. coli leader peptidase as detected by both HPLC and fluorescent spectroscopy. Mass spectra of cleavage products demonstrated that the cleavage occurs at the predicted site (A-K). The cleavage of the peptide substrate has a linear dependence on the enzyme concentration (0.1 to 1.9 microM) and the kcat/K(m) was calculated to be 71.1 M-1 s-1. These data are comparable with the unmodified peptide substrate. This report represents the first direct continuous assay based on fluorescence resonance energy transfer for E. coli leader peptidase.


Human growth hormone. Its use and abuse.
The use of hGH may become a significant challenge to the sports world. Scientific and ethical questions regarding its use may become more pressing if synthetic hGH becomes available to the public. The potential appeal of hGH to athletic competitors is obvious, but at present no benefits of this hormone as an ergogenic aid have been clearly demonstrated. Indeed, clinical experience with acromegalics suggests that prolonged exposure to elevated doses of hGH produces detrimental neuromuscular responses. Perhaps an even more intense ethical issue concerns the use of hGH in children and adolescents. The use of hGH to increase height and thereby increase chances for athletic success may be tempting to both coaches and parents. Athletes, parents, coaches, and team physicians must be aware that hGH has not been shown to enhance athletic performance and that its potential long-term side effects are irreversible and even may be life threatening.


Origin of Haemophilus influenzae R factors.
The Haemophilus influenzae R plasmids specifying resistance against one, two, or three antibiotics which have emerged in different parts of the world were shown to have closely related but not identical plasmid cores. The gene for ampicillin resistance in the H. influenzae plasmid pKRE5367 is part of a transposon similar to Tn3, which was transposed from pKRE5367 onto RSF1010 in Escherichia coli. An indigenous H. influenzae plasmid (pW266) was isolated. Its properties correspond to those of the H. influenzae R plasmids, except for the presence of a drug resistance transposon. The in vitro-generated H. influenzae R plasmids carrying an ampicillin resistance transposon, a tetracycline resistance transposon, and a transposon for combined tetracycline-chloramphenicol resistance resembled the natural isolates. The findings support the hypothesis that the R plasmids of H. influenzae are of multiclonal evolutionary origin.


Long-term outcomes of Sweden's Contact Family Program for children.
To assess the long-term impacts of Sweden's Contact Family Program (CFP) for children on participants' future outcome profiles, here conceptualized as combinations of outcomes related to mental health problems, public welfare receipt, illicit drug use, placement in out-of-home care, educational achievement, and offending. We analyzed longitudinal register data on more than 950,000 children born 1980-90, including 6693 children who entered CFP at 2-5 years of age, with a follow-up until 2008. Children's outcome profiles were identified by latent class analysis. The average program impact was estimated by means of propensity score matching. Long-term outcomes for those who had received the intervention were not better than for matched peers who did not receive the intervention. Simulation-based sensitivity analyses indicate that some of our estimated negative treatment effects may be affected by unobserved factors related to program participation and outcomes. However, both selection and outcome effects must be extremely strong in order to generate notable positive effects of CFP participation. The results did not find support for CFP effectiveness in reducing risks of compromised long-term development in children. Since the intervention reaches a high-risk group of children and is popular among users, volunteer families and professionals, the program should be reinforced with knowledge-based components that target known risk factors for child welfare recipients.


Outcome in patients with profound biotinidase deficiency: relevance of newborn screening.
Profound biotinidase deficiency (PBD) is an autosomal recessively inherited disorder of biotin metabolism, which can be detected by newborn screening and treated with biotin supplementation. Children were investigated in whom PBD was detected by newborn screening and who were treated presymptomatically, or who were not screened but were diagnosed and treated after experiencing initial clinical symptoms (symptomatic children). In a follow-up of our study group, differences in development, social and behavioural adaptation, and signs of residual impairment were examined. Parents and physicians of children with PBD completed questionnaires which included the Child Behavior Checklist and Vineland Adaptive Behavior Scales. Information was obtained for 37 children (24 males, 13 females; median age at recruitment 6 years 8 months, range to 6 months-20 years; median length of follow-up 6 years 6 months, range 5 months to 18 years 3 months). All 11 symptomatic children had residual enzyme activity of <1%, or variants of the Michaelis-Menten constant which were not detected by newborn screening. Some symptomatic children showed residual impairments: hearing impairment (n=2), optic atrophy (n=2), both hearing impairment and optic atrophy (n=2). In addition, symptomatic children had a higher risk of delayed motor and speech development. No child with PBD detected by newborn screening (n=25) had auditory or visual loss; and milestones of speech development and motor skills were reached at an appropriate age. There was no significant difference in social adaptation or behavioural problems between symptomatic and asymptomatic children. Symptomatic children often have developmental delay and are at risk of irreversible damage to auditory, visual, or central nervous functions; whereas children with PBD (established presymptomatically following newborn screening) treated with biotin supplementation, do not experience these effects.


Development of a Yellow Flag Assessment Tool for Orthopaedic Physical Therapists: Results From the Optimal Screening for Prediction of Referral and Outcome (OSPRO) Cohort.
Study Design Clinical measurement, cross-sectional. Background Pain-associated psychological distress adversely influences outcomes for patients with musculoskeletal pain. However, assessment of pain-associated psychological distress (ie, yellow flags) is not routinely performed in orthopaedic physical therapy practice. A standardized yellow flag assessment tool will better inform treatment decision making related to psychologically informed practice. Objectives To describe the development of a concise, multidimensional yellow flag assessment tool for application in orthopaedic physical therapy clinical practice. Methods A 136-item yellow flag item bank was developed from validated psychological questionnaires across domains related to pain vulnerability (negative mood, fear avoidance) and resilience (positive affect/coping). Patients seeking physical therapy with neck, back, knee, or shoulder pain completed the item bank. Iterative statistical analyses determined minimal item sets meeting thresholds for identifying elevated vulnerability or low resilience (ie, upper or lower quartile, as indicated). Further item reduction yielded a concise yellow flag assessment tool to assess 11 psychological constructs measuring pain-associated psychological distress. Correlations between the assessment tool and individual psychological questionnaires were measured and compared between anatomical regions. Concurrent validity was assessed by determining variance explained in pain and disability scores by the assessment tool. Results Subjects with elevated vulnerability and decreased resilience were identified with a high degree of accuracy (minimum of 85%) using a 17-item tool. Correlations were moderate to high between the 17-item tool and individual psychological questionnaires, with no significant differences in correlations between different anatomical regions. Shorter 10- and 7-item versions of the assessment tool allow clinicians the flexibility to assess for yellow flags quickly with acceptable trade-offs in accuracy (81% and 75%, respectively). All versions of the tool explained significant additional variance in pain and disability scores (range, 19.3%-36.7%) after accounting for demographics, historical variables, and anatomical region of pain. Conclusion Concise assessment of yellow flags is feasible in outpatient physical therapy settings. This multidimensional tool advances assessment of pain-associated psychological distress through the addition of positive affect/coping constructs and estimation of full questionnaire scores. Further study is warranted to determine how this tool complements established risk-assessment tools by providing the option for efficient treatment monitoring. J Orthop Sports Phys Ther 2016;46(5):327-345. Epub 21 Mar 2016. doi:10.2519/jospt.2016.6487.


Barriers to Increasing Diversity in Orthopaedics: The Residency Program Perspective.
There are little data to explain why the surgical subspecialty of orthopaedic surgery struggles with improving the racial/ethnic composition of its workforce. The current work sought to determine what orthopaedic residency program directors and coordinators believe are the barriers to improving diversity at their own programs. Between November 17, 2018, and April 1, 2019, a 17-question survey was electronically distributed to the program directors and coordinators of 155 allopathic orthopaedic surgery residency programs. Seventy-five of 155 programs (48.4%) responded to the survey. A p-value of < 0.05 was used to determine statistical significance. The most commonly stated barriers to increasing diversity within the orthopaedic surgery programs were the following: "We do not have enough minority faculty, which may deter the applicants" (69.3%), "We consistently rank minority applicants high but can never seem to match them" (56%), and "Not enough minorities are applying to our program" (54.7%). Programs with higher percentages of underrepresented minority (URM) faculty had higher percentages of URM residents (p = 0.001). Programs participating in the Nth Dimensions and/or Perry Initiative programs had a higher percentage of URM faculty as compared to the residency programs that did not participate in these programs (p = 0.004). URM residents represented 17.5% of all residents who resigned and/or were dismissed in the 10 years preceding the survey while also only representing 6% of all orthopaedic residents during the same time period. From the orthopaedic residency program perspective, the greatest perceived barrier to increasing the racial/ethnic diversity of residents in their program is their lack of URM faculty. Surveyed programs with more URM faculty had more URM residents, and programs participating in Nth Dimensions and/or Perry Initiative programs had a higher percentage of URM faculty.


Serological relationship among porcine cytomegalovirus Japanese isolates and a UK isolate.
We isolated porcine cytomegaloviruses (PCMVs) from lung samples of fattening pigs collected in the slaughter houses of 4 prefectures of Japan. Seven isolates were obtained and used for a comparison of serological characteristics by ELISA. J1, the first field isolate in Japan, and B6 which was isolated in the UK were also used in the study. The serological relationships between the isolates were analysed by the method of Archetti and Horsfall. OF1 showed serological differences with Chiba2 and Hiroshima. Differences were also observed between Chiba2 and ChibaC, ChibaC and Kagawa. B6 showed differences with OF2, Chiba3, ChibaC and Hiroshima.


Validation of an equation for resting metabolic rate in older obese, critically ill patients.
In previous studies, the Penn State (PSU) equation was found to be a valid way to predict resting metabolic rate (RMR) in critically ill patients, with the exception of those who were aged 60 years or older and had a body mass index (BMI) ≥30 kg/m(2). A modification of the equation was proposed in this specific patient population. The current study was designed to test the validity of that equation and to retest the validity of the original equation. RMR was measured using a standardized evidence-based protocol. Metabolic rates predicted with the PSU equation and a modification of it (PSU[m]) were compared with the measured values. Fifty patients were studied prospectively. Data were used from an additional 75 subjects from previous studies that had not been used to develop either of the equations being tested in the current study. This brought the final number of subjects for each equation to 74 for PSU(m) and 106 for PSU. The PSU(m) equation was found to be biased by a narrow margin (95% confidence interval, -87 to -4 kcal/d), but both versions of the equation were precise. Accuracy rate for the PSU(m) equation was 74%, compared with 58% for the PSU equation (P < .04). The PSU(m) equation for predicting RMR in critically ill, mechanically ventilated patients is valid in patients aged cases where age is ≥60 years or older whose BMI is ≥30 kg/m(2).


Modulation of poly(A)-specific ribonuclease (PARN): current knowledge and perspectives.
Deadenylation is the exoribonucleolytic shortening of eukaryotic poly(A) tails. It is often the first and rate-limiting step for mRNA decay and translational silencing. The process is catalysed by a diversity of deadenylases, which provide robust and flexible means to control mRNA levels and gene expression. Poly(A)-specific ribonuclease (PARN) is a major mammalian deadenylase and the only known to concurrently bind the 5' cap-structure and the 3' poly(A), thus enhancing the degradation rate and amplifying its processivity. PARN is important during oocyte maturation, embryogenesis, early development, DNA damage, and in cell-cycle progression, but also in processes beyond mRNA metabolism, such as the maturation of snoRNAs. The enzyme also participates in nonsense-mediated mRNA decay and in the regulation of cytoplasmic polyadenylation. Importantly, PARN is involved in the degradation of several cancer-related genes, while its expression is altered in cancer. Apart from the direct interaction with the cap structure, several strategies regulate PARN activity, such as phosphorylation, interaction with RNA-binding proteins (RBPs), and natural nucleotides. Recent studies have focused on the regulation of its activity by synthetic nucleoside analogues with therapeutic potential. In this context, the wide repertoire of RBPs and molecules that regulate PARN activity, together with the established role of deadenylases in miRNA-mediated regulation of mRNA expression, suggest that mRNA turnover is more complex than it was previously thought and PARN holds a key role in this process. In this review, we highlight the importance of PARN during RNA's lifecycle and discuss clinical perspectives of modulating its activity.


Association of intraoperative hypotension with acute kidney injury after elective noncardiac surgery.
Intraoperative hypotension (IOH) may be associated with postoperative acute kidney injury (AKI), but the duration of hypotension for triggering harm is unclear. The authors investigated the association between varying periods of IOH with mean arterial pressure (MAP) less than 55, less than 60, and less than 65 mmHg with AKI. The authors conducted a retrospective cohort study of 5,127 patients undergoing noncardiac surgery (2009 to 2012) with invasive MAP monitoring and length of stay of 1 or more days. Exclusion criteria were preoperative MAP less than 65 mmHg, dialysis dependence, urologic surgery, and surgical duration less than 30 min. The primary exposure was IOH. The primary outcome was AKI (50% or 0.3 mg/dl increase in creatinine) during the first 2 postoperative days. Multivariable logistic regression was used to model the exposure-outcome relationship. AKI occurred in 324 (6.3%) patients and was associated with MAP less than 60 mmHg for 11 to 20 min and MAP less than 55 mmHg for more than 10 min in a graded fashion. The adjusted odds ratio of AKI for MAP less than 55 mmHg was 2.34 (1.35 to 4.05) for 11- to 20-min exposure and 3.53 (1.51 to 8.25) for more than 20 min. For MAP less than 60 mmHg, the adjusted odds ratio for AKI was 1.84 (1.11 to 3.06) for 11- to 20-min exposure. In this analysis, postoperative AKI is associated with sustained intraoperative periods of MAP less than 55 and less than 60 mmHg. This study provides an impetus for clinical trials to determine whether interventions that promptly treat IOH and are tailored to individual patient physiology could help reduce the risk of AKI.


Hazards of delivery room resuscitation using oral methods of endotracheal suctioning.
Between 1978 and 1982 at least eight physicians at our institution were exposed to infectious secretions while performing mouth-to-tube resuscitation. A questionnaire revealed that 74% of responding pediatric physicians accidentally ingested secretions in 1982. The risk of cross-contamination between newborn patients and resuscitating physicians with the oral methods of oropharyngeal and endotracheal suctioning is considerable.


Autophagy is involved in high glucose-induced heart tube malformation.
Both pre-gestational and gestational diabetes have an adverse impact on heart development, but little is known about the influence on the early stage of heart tube formation. Using early gastrulating chick embryos, we investigated the influence of high glucose on the process of heart tube formation, specifically during the primary heart field phase. We demonstrated that high-glucose exposure resulted in 3 types of heart tube malformation: 1) ventricular hypertrophy, 2) ventricular hypertrophy with dextrocardia and 3) ventricular hypertrophy and dextrocardia with the fusion anomaly of a bilateral primary heart tube. Next, we found that these malformation phenotypes of heart tubes might mainly originate from the migratory anomaly of gastrulating precardiac mesoderm cells rather than cell proliferation in the developmental process of bilateral primary heart field primordia. The treatment of rapamycin (RAPA), an autophagy inducer, led to a similar heart tube malformation phenotype as high glucose. Additionally, high-glucose exposure promoted the expression of the key autophagy protein LC3B in early chick tissue. Atg7 is strongly expressed in the fusion site of bilateral primary heart tubes. All of these data imply that autophagy could be involved in the process of high-glucose-induced malformation of the heart tube.


Group Testing for Severe Acute Respiratory Syndrome- Coronavirus 2 to Enable Rapid Scale-up of Testing and Real-Time Surveillance of Incidence.
High-throughput molecular testing for severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) may be enabled by group testing in which pools of specimens are screened, and individual specimens tested only after a pool tests positive. Several laboratories have recently published examples of pooling strategies applied to SARS-CoV-2 specimens, but overall guidance on efficient pooling strategies is lacking. Therefore we developed a model of the efficiency and accuracy of specimen pooling algorithms based on available data on SAR-CoV-2 viral dynamics. For a fixed number of tests, we estimate that programs using group testing could screen 2-20 times as many specimens compared with individual testing, increase the total number of true positive infections identified, and improve the positive predictive value of results. We compare outcomes that may be expected in different testing situations and provide general recommendations for group testing implementation. A free, publicly-available Web calculator is provided to help inform laboratory decisions on SARS-CoV-2 pooling algorithms.


Properties of a suggested commensurate monolayer solid of Kr/NaCl(001).
It is shown that a commensurate square monolayer solid of Kr/NaCl(001) can be stabilized with a model incorporating a rather large energy corrugation amplitude. Then a square bilayer is formed under a compression and preempts the formation of an incommensurate triangular monolayer lattice. The lattice dynamics of the commensurate monolayer may be complex, because the modeling admits the possibility that it has a (2 × 2) unit cell with four Kr atoms.


[Wounds and injuries to the colon].
On the basis of a retrospective analysis of results of treatment of 1097 patients with wounds and injuries of the colon of the peace and war time as well as of experiments in 160 dogs it has been established that the level of lethal outcomes and amount of complications are dependent on the size, number and localization of the colon wounds, severity of peritonitis by the moment of primary operation, degree of traumatic shock, blood loss volume, severity of the coexisting injuries and the chosen method of surgical treatment. A classification of the wounds according to the volume of injuries of the colon is proposed. Different variants of surgical treatment and outcomes are considered. Experiments in dogs have shown the indisputable effectiveness of precise one-row sero-musculo-submucous sutures with the present-day sutural material as compared with other methods of treatment of wounds of the colon. The peritoneal sorption with liquid colloid sorbents at the early postoperative period facilitate the prophylaxis and treatment of peritonitis, reduce lethality. A surgical classification of injuries of the colon is developed and types of operative interventions are recommended.


Bacterial metabolism of methylated amines and identification of novel methylotrophs in Movile Cave.
Movile Cave, Romania, is an unusual underground ecosystem that has been sealed off from the outside world for several million years and is sustained by non-phototrophic carbon fixation. Methane and sulfur-oxidising bacteria are the main primary producers, supporting a complex food web that includes bacteria, fungi and cave-adapted invertebrates. A range of methylotrophic bacteria in Movile Cave grow on one-carbon compounds including methylated amines, which are produced via decomposition of organic-rich microbial mats. The role of methylated amines as a carbon and nitrogen source for bacteria in Movile Cave was investigated using a combination of cultivation studies and DNA stable isotope probing (DNA-SIP) using (13)C-monomethylamine (MMA). Two newly developed primer sets targeting the gene for gamma-glutamylmethylamide synthetase (gmaS), the first enzyme of the recently-discovered indirect MMA-oxidation pathway, were applied in functional gene probing. SIP experiments revealed that the obligate methylotroph Methylotenera mobilis is one of the dominant MMA utilisers in the cave. DNA-SIP experiments also showed that a new facultative methylotroph isolated in this study, Catellibacterium sp. LW-1 is probably one of the most active MMA utilisers in Movile Cave. Methylated amines were also used as a nitrogen source by a wide range of non-methylotrophic bacteria in Movile Cave. PCR-based screening of bacterial isolates suggested that the indirect MMA-oxidation pathway involving GMA and N-methylglutamate is widespread among both methylotrophic and non-methylotrophic MMA utilisers from the cave.


Effortful control as predictor of adolescents' psychological and physiological responses to a social stress test: the Tracking Adolescents' Individual Lives Survey.
Effortful control is thought to foster adaptive action in defensive contexts and may thereby protect individuals against anxious inhibition and focus on their own distress. We examined if effortful control predicted adolescents' perceived arousal, unpleasantness, and control as well as autonomic (heart rate [HR]) and hypothalamic-pituitary-adrenal axis (cortisol) responses during social stress. The data came from a focus sample of the Tracking Adolescents' Individual Lives Survey, a prospective population study of Dutch adolescents (N = 715, 50.9% girls; mean age = 16.11, SD = 0.59), who participated in a laboratory session including a social stress task (public speaking and mental arithmetic). Perceived and physiological stress measures were assessed before, during, and after the social stress task. Effortful control was measured using various questionnaires and informants, as well as by means of a reaction time (RT) task assessing response inhibition. Overall, adolescents with high questionnaire-based effortful control tended to feel more relaxed, pleasant, and in control during the laboratory session than adolescents with lower levels of control and had stronger HR responses to the stress test. Adolescent girls with high inhibitory control as measured by the RT task also had strong HR responses, but inhibitory control was associated with high rather than low perceived arousal. Our results suggest that both questionnaire and RT measures of effortful control predict strong HR responses to challenging situations, but associational patterns diverge with regard to perceived stress measures.


Effect of an inhaled antihistamine on exercise-induced asthma.
The ability of the H1 receptor antagonist clemastine to prevent exercise-induced asthma (EIA) has been studied in 10 adult asthmatic subjects. Exercise was performed for eight minutes on a cycle ergometer on two occasions on each of two days. The first test each day was without premedication and the second was preceded by inhalation of 0.05% clemastine or saline placebo given single blind in random order. Ventilatory function was assessed by serial measurements of peak expiratory flow rate (PEFR) and forced expiratory volume in one second (FEV1). All four tests for each patient were closely matched in terms of oxygen uptake and total ventilation which were monitored throughout exercise. The response to exercise after clemastine or placebo has been compared both directly and in terms of the degree of protection afforded against EIA compared with the initial test on the same day. Clemastine was significantly better than placebo for both PEFR and FEV1. All 10 subjects had less EIA after clemastine, which suggests an important role for histamine in its production. Other mechanisms may also be involved to a variable degree in different individuals.


[Effect of ionic strength of a solution on the protonation of DNA molecule].
The influence of the ionic strength of solution on the DNA molecule protonation was studied by means of circular dichroism (CD), spectrophotometric and potentiometric titration methods over a wide range of the supporting electrolyte concentrations [( NaCl] = 0.0005 divided by 4 M). Consideration of the obtained CD spectra shown that the acidation of the solution induces two cooperative structural transitions in the double stranded DNA molecule in the pre-denaturation pH region. Further decrease in the solution pH results in acidic melting of the DNA molecule. Analysis of the potentiometric data shows that diluted DNA solutions exhibit marked buffer capacity at pH greater than 4.2. A concept of local pH dependent on the electrostatic potential in the vicinity of the polyion was used for interpreting the obtained results. A phase diagram, which describes the polymorphic transformations of the protonated macromolecule, was constructed in terms of pHloc and -log[Na+]. Consideration of this phase diagram allows to hypothesize that: 1) in the neutral diluted DNA solution with a very low supporting electrolyte content the macromolecule exists in a polymorphic state; 2) at [NaCl] greater than or equal to 0.001 M the acid-base equilibrium in the DNA molecule is invariant in respect to the ionic strength of the solution.


Senior Oral Health: A Community-Based, Interprofessional Educational Experience for Nursing and Dental Students.
The current article highlights an interprofessional, older adult oral health community program, created through an Accelerating Interprofessional Community-Based Education and Practice grant from the National Center for Interprofessional Practice and Education, designed to address the gap between older adult health education and care delivery. This project developed an advanced practice, nurse-led partnership among The Hartford Institute for Geriatric Nursing and the Oral Health Nursing Education and Practice Program (both located at New York University Rory Meyers College of Nursing), New York University College of Dentistry, and Regional Aid for Interim Needs (RAIN), a community service organization for older adults in the Bronx. Teams of nursing (n = 26), nurse practitioner (n = 16), and dental (n = 64) students provided oral health education and oral hygiene instruction using Tooth Wisdom® educational materials to older adults, home health aides (HHAs), and volunteers in nine RAIN senior centers. Students demonstrated increases in their self-reported interprofessional competencies based on the Interprofessional Collaborative Competency Attainment Survey. Results also revealed that older adults (n = 500), HHAs (n = 142), and volunteers (n = 21) at the RAIN senior centers who attended the Tooth Wisdom presentation demonstrated an increase in oral health knowledge. [Journal of Gerontological Nursing, 46(8), 37-45.].


Waveform correlation by tree matching.
A waveform correlation scheme is presented. The scheme consists of four parts: 1) the representation of waveforms by trees, 2) the definition of basic operations on tree nodes and tree distance, 3) a tree matching algorithm, and 4) a backtracking procedure to find the best node-to-node correlation. This correlation scheme has been implemented. Results show that the scheme has the capability of handling distortions that result from stretching or shrinking of intervals or from missing intervals.


Habitat-specific environmental conditions primarily control the microbiomes of the coral Seriatopora hystrix.
Reef-building corals form complex relationships with a range of microorganisms including bacteria, archaea, fungi and the unicellular microalgae of the genus Symbiodinium, which together form the coral holobiont. These symbionts are known to have both beneficial and deleterious effects on their coral host, but little is known about what the governing factors of these relationships are, or the interactions that exist between the different members of the holobiont and their environment. Here we used 16S ribosomal RNA gene amplicon sequencing to investigate how archaeal and bacterial communities associated with the widespread scleractinian coral Seriatopora hystrix are influenced by extrinsic (reef habitat and geographic location) and intrinsic (host genotype and Symbiodinium subclade) factors. Bacteria dominate the microbiome of S. hystrix, with members of the Alphaproteobacteria, Gammaproteobacteria and Bacteriodetes being the most predominant in all samples. The richness and evenness of these communities varied between reef habitats, but there was no significant difference between distinct coral host lineages or corals hosting distinct Symbiodinium subclades. The coral microbiomes correlated to reef habitat (depth) and geographic location, with a negative correlation between Alpha- and Gammaproteobacteria, driven by the key members of both groups (Rhodobacteraceae and Hahellaceae, respectively), which showed significant differences between location and depth. This study suggests that the control of microbial communities associated with the scleractinian coral S. hystrix is driven primarily by external environmental conditions rather than by those directly associated with the coral holobiont.


Kinetic Effects of Transferrin-Conjugated Gold Nanoparticles on the Antioxidant Glutathione-Thioredoxin Pathway.
Nanoparticle-based therapeutics are being clinically translated for treating cancer. Even when thought to be biocompatible, nanoparticles are being increasingly identified as altering cell regulation and homeostasis. Antioxidant pathways are important for maintaining cell redox homeostasis and play important roles by maintaining ROS levels within tolerable ranges. Here, we sought to understand how a model of a relatively inert nanoparticle without any therapeutic agent itself could antagonize a cancer cell lines' antioxidant mechanism. A label-free protein expression approach was used to assess the glutathione-thioredoxin antioxidative pathway in a prostate cancer cell line (PC-3) after exposure to gold nanoparticles conjugated with a targeting moiety (transferrin). The impact of the nanoparticles was also corroborated through morphological analysis with TEM and classification of pro-apoptotic cells by way of the sub-G0/G1 population via the cell cycle and annexin V apoptosis assay. After a two-hour exposure to nanoparticles, major proteins associated with the glutathione-thioredoxin antioxidant pathway were downregulated. However, this response was acute, and in terms of protein expression, cells quickly recovered within 24 h once nanoparticle exposure ceased. The impact on PRDX-family proteins appears as the most influential factor in how these nanoparticles induced an oxidative stress response in the PC-3 cells. An apparent adaptive response was observed if exposure to nanoparticles continued. Acute exposure was observed to have a detrimental effect on cell viability compared to continuously exposed cells. Nanoparticle effects on cell regulation likely provide a compounding therapeutic advantage under some circumstances, in addition to the action of any cytotoxic agents; however, any therapeutic advantage offered by nanoparticles themselves with regard to vulnerabilities specific to the glutathione-thioredoxin antioxidative pathway is highly temporal.


Challenges for gene editing in common variable immunodeficiency disorders: Current and future prospects.
The original CRISPR Cas9 gene editing system and subsequent innovations offers unprecedented opportunities to correct severe genetic defects including those causing Primary Immunodeficiencies (PIDs). Common Variable Immunodeficiency Disorders (CVID) are the most frequent symptomatic PID in adults and children. Unlike many other PIDs, patients meeting CVID criteria do not have a definable genetic defect and cannot be considered to have an inborn error of immunity (IEI). Patients with a CVID phenotype carrying a causative mutation are deemed to have a CVID-like disorder consequent to an IEI. Patients from consanguineous families often have highly penetrant early-onset autosomal recessive forms of CVID-like disorders. Individuals from non-consanguineous families may have autosomal dominant CVID-like disorders with variable penetrance and expressivity. This essay explores the potential clinical utility as well as the current limitations and risks of gene editing including collateral genotoxicity. In the immediate future the main application of this technology is likely to be the in vitro investigation of epigenetic and polygenic mechanisms, which are likely to underlie many cases of CVID and CVID-like disorders. In the longer-term, the CRISPR Cas9 system and other gene-based therapies could be utilized to treat CVID-like disorders, where the underlying IEI is known.


Treating panel traps with a fluoropolymer enhances their efficiency in capturing cerambycid beetles.
The most effective traps for capturing cerambycids and other saproxylic beetles are intercept designs such as funnel traps and cross-vane panel traps. We have observed that adult cerambycids of many species often alight and walk upon panel traps, and few are actually captured. In an effort to improve trap capture and retention, researchers have treated intercept traps with Rain-X, a polysiloxane formulation that renders surfaces more slippery. Here, we summarize experiments that compared the efficacies of Rain-X and Fluon, a PTFE fluoropolymer dispersion, assurface treatments for panel traps that are deployed to capture cerambycid beetles, using untreated traps as controls. Fluon-treated traps captured on average > 14x the total number of beetles, and many more cerambycid species, than were captured by Rain-X-treated or control traps. Beetles captured by Fluon-treated traps ranged in body length by 350%. They could not walk on vertical panels treated with Fluon but easily walked on those treated with Rain-X and on untreated traps. Moreover, a single Fluon treatment remained effective for the entire field season, even in inclement weather. We conclude that treating panel traps with Fluon greatly improves their efficiency in capturing cerambycid beetles. This increased efficacy will be particularly important when traps are deployed to detect very low-density populations, such as incursions of exotic species, or remnant communities of rare and endangered species. The influence of Fluon on trap efficiency may vary with product formulation and its source and also with climatic conditions.


The accuracy of matching target insertion gains with open-fit hearing aids.
To assess the accuracy with which target insertion gains were matched for a single type of open-fit hearing aid, both on initial fitting and after adjustment. The hearing aids were fitted using the first-fit setting in the programming software and the target formula was selected as NAL-NL1. The difference between the real ear insertion gain (REIG) and the NAL-NL1 target REIG was recorded. The initial fitting was considered acceptable if the difference was less than 10 dB at all frequencies. If an initial fitting was not acceptable, the frequency-gain response was modified. The difference between the final REIG and the NAL-NL1 target REIG was recorded as final target mismatch. Of the 51 initial fittings, 36 (71%) failed to achieve a match within ±10 dB of the NAL-NL1 insertion gain target at 1 or more frequencies between 0.25 and 4 kHz. After the authors adjusted the frequency-gain response of the hearing aids, only 9 fittings (18%) failed to achieve a match. These outcomes suggest that target insertion gains for the open-fit hearing aids used here are rarely achieved with a first fitting but can usually be achieved through adjustments based on REIG measurements.


The genetic origins of the relationship between psychological traits and social trust.
Recent studies have shown that trusting attitudes and behavior are biologically influenced. Focusing on the classic trust game, it has been demonstrated that oxytocin increases trust and that humans are endowed with genetic variation that influences their behavior in the game. Moreover, several studies have shown that a large share of the variation in survey responses to trust items is accounted for by an additive genetic component. Against this backdrop, this article makes two important contributions. First, utilizing a unique sample of more than 2,000 complete Swedish twin pairs, we provide further evidence of the heritability of social trust. Our estimates of the additive genetic component in social trust were consistent across the sexes -- .33 for males and .39 for females -- and are similar to the results reported in earlier studies. Secondly, we show that social trust is phenotypically related to three psychological traits -- extraversion, personal control, and intelligence - and that genetic factors account for most of these correlations. Jointly, these psychological factors share around 30% of the genetic influence on social trust both for males and females. Future studies should further explore the possible causal pathways between genes and trust using panel data on both psychological traits and social trust.


Evaluation of a microchip electrophoresis-mass spectrometry platform deploying a pressure-driven make-up flow.
Integration of a pressure-driven make-up flow (MUF) into a microchip electrophoresis (MCE) platform in order to facilitate its coupling with electrospray ionization-mass spectrometric detection (ESI-MS) is described. In the glass/PDMS hybrid microchip, a MUF channel was made to intersect with the MCE separation channel at an angle of 45°. The MUF was generated by a syringe pump. Microscopic image results from simulation studies showed that the pressure-driven MUF and the potential-driven electroosmotic flow in the MCE separation channel could be run separately without interfering with each other and mixed well at the joint point by adjusting either the MUF flow rate or the potential applied for MCE separation. The MUF had several desirable functions, including making the start of electrospray easy and cleaning the nanoESI emitter continuously when not spraying. High separation efficiency was achieved with the proposed MCE-nanoESI-MS system in separating an amino acid mixture containing glutamine, serine, threonine, phenylalanine, and glutamic acid. All of them were baseline separated from each other within 3 min. Plate numbers of >10,000 (on a 2.5 cm MCE separation channel) were obtained. The analytical platform also showed a linear response for quantification of DOPA with a detection limit (S/N=3) of 0.10 μM. In addition, on-line derivatization of MCE elutes in order to enhance MS detection sensitivity was easily carried out by adding the tagging reagent into the MUF. These results indicated that the present system might have a good potential in MCE-MS applications.


Prevalence, outcome, and women's experiences of external cephalic version in a low-risk population.
Until recently, external cephalic version to prevent breech presentation at birth was not widely accepted. The objective of our study was to assess the prevalence, outcomes, and women's experiences of external cephalic version to improve the implementation of the procedure in the Netherlands. A prospective cohort study was conducted of 167 women under the care of a midwife with confirmed breech presentation at a gestational age of 33 completed weeks or more. Between June 2007 and January 2008, 167 women with a confirmed breech presentation were offered an external cephalic version. Of this group, 123 women (73.7%, 95% CI: 65.5-80.5) subsequently received the version. These women had about a ninefold increased probability of a cephalic presentation at birth compared with women who did not undergo a version (relative risk [RR]: 8.8, 95% CI: 2.2-34.8). The chance of a vaginal birth after an external cephalic version was almost threefold (RR: 2.7, 95% CI: 1.5-5.0). The success rate was 39 percent, although considerable differences existed associated with region and parity. Ninety-four percent of women with a successful version rated it as a good experience compared with 71 percent of women who had a failed version (p = 0.015). Significant pain during the version was experienced by 34 percent of women, of whom 18 percent also experienced fear during the version, compared with no women who reported little or no pain (p = 0.006). Women who reported significant pain or fear during the version experienced the version more negatively (OR: 6.0, 95% CI: 3.3-12.2 and OR: 2.7, 95% CI: 1.1-6.0, respectively). One in every four women with a breech presentation in independent midwifery care did not receive an external cephalic version. Of the women who received a version one third experienced significant pain during the procedure. Considerable regional variation in success rate existed.


Subpopulations of the peripheral lymphocytes in the early clinical forms of Lyme disease.
The evaluation of the changes of lymphocytes: T(CD3), B (CD19), subpopulations CD4, CD8, active lymphocytes CD3 + HLA-DR+, lymphocytes with the receptor for IL2(CD3 + CD25+), NK cells as well as the CD4/CD8 ratio in 30 patients with the early localized (group I n = 7) and early disseminated (group II n = 23) type of Lyme disease, before (examination 1) and after the antibiotic therapy (examination 2) was performed. Group III was composed of 90 healthy people. Measurements were carried out in an COULTER EPIC XL cytoflowmeter, using Becton Dickinson antibodies. Statistical analysis was performed using AnStat software. In the examined groups, a decrease of the subpopulations of CD4, CD8 lymphocytes in comparison with healthy subjects was revealed, as well as a decrease of the CD4/CD8 ratio after treatment. A considerably lower percentage value of active lymphocytes CD3 + HLA-DR+ in both groups and the reduction of the NK subpopulation before and after treatment of early disseminated Lyme disease in comparison with healthy people was observed. The higher percentage values of the lymphocytes with IL-2 receptor were not statistically significant. The indicated essential changes in the subpopulations of T lymphocytes, characterized by a decrease before the antibiotic therapy and by the tendency towards an increase after that therapy of the percentage of CD4, CD8, NK and CD3 + HLA-DR+ lymphocytes in peripheral blood, point out their role in the immunopathogenesis of the Lyme disease. The absence of the complete normalization of the examined parameters after the treatment, on the one hand, may provide evidence for some inertia of the elements of the immune system, on the other hand can also result from too short antibiotic therapy and maintenance of the antigenic stimulation.


Multiple-organ harvesting for models of isolated hemoperfused organs of slaughtered pigs.
Single- and multiorgan transplantations for the treatment of terminal cardiac, pulmonary, hepatic and renal diseases gain therapeutic importance and transplantation research using mammalian models of isolated perfused organs resembles a major field for the improvement of transplantation techniques. We established a new method of multiple organ harvesting from slaughterhouse pigs which may be used to reduce numbers of laboratory animals. 492 organs (hearts n = 191, lungs n = 108, livers n = 48, kidneys n = 145) were harvested, perfused with autologous blood to prevent artificial perfusion effects and examined for optimal organ harvesting and preservation conditions by analysing organ specific perfusion parameters. For each organ, specific techniques in regard to dissection, cannulation and periods of ischemia have to be applied to guarantee appropriate organ perfusion. In summary, our data indicate that porcine organs obtained by multiple organ harvesting from commercial slaughterhouse animals can be efficiently used for isolated and perfused organ models. The harvesting process did not disturb the commercial use of the animals. Thus, multiple or single organ harvesting may be a useful method to reduce the use of laboratory animals.


Structure of the carbonic anhydrase VI (CA6) gene: evidence for two distinct groups within the alpha-CA gene family.
The secreted carbonic anhydrase (CA VI) is believed to be one of the oldest mammalian CAs in evolutionary terms. To elucidate its gene structure and compare it with other members of the alpha-CA family, we cloned genomic fragments encoding the bovine CA6 gene and determined its exon/intron organization. The gene spans approx. 25 kb and consists of eight exons and seven introns. Exon 1 encodes the 5' untranslated region, the signal peptide and the N-terminus of the mature enzyme. Exon 8 encodes the 3' untranslated region and the C-terminal extension that is unique to CA VI. Exons 2-7 encode the CA domain, which shows significant sequence similarity to other CAs. Two distinct groups exist in the alpha-CA family on the basis of a comparison of the known gene structures. One group consists of the cytoplasmic (CA I, II, III and VII) and mitochondrial (CA V) members. The other group consists of the membrane-bound (CA IV and IX) and secreted (CA VI) members. In particular, the seven exon/intron boundaries in the CA domain of the CA6 gene are conserved in the CA9 gene, which encodes the multidomain protein CA IX that is overexpressed in tumours and has transforming potential.


Interpretation and identification of causal mediation.
This article reviews the foundations of causal mediation analysis and offers a general and transparent account of the conditions necessary for the identification of natural direct and indirect effects, thus facilitating a more informed judgment of the plausibility of these conditions in specific applications. I show that the conditions usually cited in the literature are overly restrictive and can be relaxed substantially without compromising identification. In particular, I show that natural effects can be identified by methods that go beyond standard adjustment for confounders, applicable to observational studies in which treatment assignment remains confounded with the mediator or with the outcome. These identification conditions can be validated algorithmically from the diagrammatic description of one's model and are guaranteed to produce unbiased results whenever the description is correct. The identification conditions can be further relaxed in parametric models, possibly including interactions, and permit one to compare the relative importance of several pathways, mediated by interdependent variables.


Mapping of glycolytic enzyme-binding sites on human erythrocyte band 3.
Previous work has shown that GAPDH (glyceraldehyde-3-phosphate dehydrogenase), aldolase, PFK (phosphofructokinase), PK (pyruvate kinase) and LDH (lactate dehydrogenase) assemble into a GE (glycolytic enzyme) complex on the inner surface of the human erythrocyte membrane. In an effort to define the molecular architecture of this complex, we have undertaken to localize the binding sites of these enzymes more accurately. We report that: (i) a major aldolase-binding site on the erythrocyte membrane is located within N-terminal residues 1-23 of band 3 and that both consensus sequences D6DYED10 and E19EYED23 are necessary to form a single enzyme-binding site; (ii) GAPDH has two tandem binding sites on band 3, located in residues 1-11 and residues 12-23 respectively; (iii) a PFK-binding site resides between residues 12 and 23 of band 3; (iv) no GEs bind to the third consensus sequence (residues D902EYDE906) at the C-terminus of band 3; and (v) the LDH- and PK-binding sites on the erythrocyte membrane do not reside on band 3. Taken together, these results argue that band 3 provides a nucleation site for the GE complex on the human erythrocyte membrane and that other components near band 3 must also participate in organizing the enzyme complex.


Potassium channel complex autoimmunity induced by inhaled brain tissue aerosol.
To test the hypothesis that autoimmunity induced by inhalation of aerosolized brain tissue caused outbreaks of sensory-predominant polyradiculoneuropathy among swine abattoir employees in the Midwestern United States. Mice were exposed intranasally, 5 days per week, to liquefied brain tissue. Serum from exposed mice, patients, and unaffected abattoir employees were analyzed for clinically pertinent neural autoantibodies. Patients, coworkers, and mice exposed to liquefied brain tissue had an autoantibody profile dominated by neural cation channel immunoglobulin Gs (IgGs). The most compelling link between patients and exposed mice was magnetic resonance imaging (MRI) evidence of grossly swollen spinal nerve roots. Autoantibody responses in patients and mice were dose-dependent and declined after antigen exposure ceased. Autoantibodies detected most frequently, and at high levels, bound to detergent-solubilized macromolecular complexes containing neuronal voltage-gated potassium channels ligated with a high affinity Kv1 channel antagonist, 125I-α-dendrotoxin. Exposed mice exhibited a behavioral phenotype consistent with potassium channel dysfunction recognized in drosophila with mutant ("shaker") channels: reduced sensitivity to isoflurane-induced anesthesia. Pathological and electrophysiological findings in patients supported peripheral nerve hyperexcitability over destructive axonal loss. The pain-predominant symptoms were consistent with sensory nerve hyperexcitability. Our observations establish that inhaled neural antigens readily induce neurological autoimmunity and identify voltage-gated potassium channel complexes as a major immunogen.


Diagnostic Performance of Technetium-99m Methoxy-Isobutyl-Isonitrile for Differentiation of Malignant Thyroid Nodules: A Systematic Review and Meta-Analysis.
The purpose of the current study was to investigate the diagnostic performance of technetium-99m (Tc-99m) methoxy-isobutyl-isonitrile (MIBI) for differentiation of malignant thyroid nodules (TN) through a systematic review and meta-analysis. The MEDLINE/PubMed and EMBASE database, from the earliest available date of indexing through January 31, 2018, were searched for studies evaluating the diagnostic performance of Tc-99m MIBI for TN. The sensitivities and specificities were determined across studies, positive and negative likelihood ratios (LR+ and LR-) were calculated, and summary receiver operating characteristic curves were constructed. Across 22 studies (2421 patients), the pooled sensitivity for Tc-99m MIBI thyroid scan was 0.87 [confidence interval (CI) 0.76-0.93] with heterogeneity (I2 = 92.3) and a pooled specificity of 0.78 [CI 0.67-0.86] with heterogeneity (I2 = 96.4). LR syntheses gave an overall LR+ of 4.0 [CI 2.5-6.3] and LR- of 0.17 [CI 0.09-0.32]. The pooled diagnostic odds ratio was 24 [CI 63-176]. The hierarchical summary receiver operating characteristic curve indicates that the area under the curve was 0.90 [CI 0.87-0.92]. In meta-regression analysis, no definite variable was the source of the study heterogeneity. The current meta-analysis shows a moderate sensitivity and specificity of Tc-99m MIBI thyroid scan for differentiation of malignant TN. However, the diagnostic odds ratio was relatively low and the LR scattergram indicated that Tc-99m MIBI thyroid scan is not useful for confirming the presence of malignant TN or for its exclusion. Therefore, Tc-99m MIBI thyroid scans should be used restrictively and interpreted cautiously when assessing TN for malignancy.


Demonstration of high-affinity Mn2+ uptake in Saccharomyces cerevisiae: specificity and kinetics.
The existence of multiple transport systems for Mn2+ in Saccharomyces cerevisiae has been demonstrated in this study. Mn2+ (supplied as MnCl2) was accumulated by S. cerevisiae at all Mn2+ concentrations examined (25 nM-1 mM) but a log-log plot of uptake rates and total amounts accumulated revealed the existence of at least two Mn(2+)-concentration-dependent transport systems. Over a low Mn2+ concentration range (25-1000 nM), high-affinity Mn2+ uptake occurred with a Km value of 0.3 microM, while transformation of kinetic data obtained over the concentration range 5-200 microM revealed another system with a Km of 62 microM. Meaningful kinetic analyses were not possible at high Mn2+ concentrations because of toxicity: only about 30% of cells remained viable after 30 min incubation with 1000 microM MnCl2. Release of K+ accompanied Mn2+ accumulation and this increased with increasing Mn2+ concentration. However, even in non-toxic Mn2+ concentration, the ratio of Mn2+ uptake to K+ release greatly exceeded electroneutral stoichiometric exchange. In 50 microM MnCl2, the ratio was 1:123 and this increased to 1:2670 in 1000 microM MnCl2, a toxic concentration. External Mg2+ was found to decrease Mn2+ accumulation at all concentrations examined, but to differing extents. Over the low Mn2+ concentration range (5-200 microM), Mg2+ competitively inhibited Mn2+ uptake with a half-maximal inhibitory concentration, Ki, of 5.5 microM Mg2+. However, even in the presence of a 50-fold excess of Mg2+, inhibition of Mn2+ uptake was of the order of 72% and it appears that the cellular requirement for Mn2+ could be maintained even in the presence of such a large excess of Mg2+. Over the high Mn2+ concentration range (5-200 microM), the Ki for Mg2+ was 25.2 microM. At low Mn2+ concentrations, Zn2+ and Co2+, but not Cd2+, inhibited Mn2+ uptake, which indicated that the high-affinity Mn2+ uptake system was of low specificity, while at higher Mn2+ concentrations, where the lower-affinity Mn2+ transport system operated, inhibition was less marked. However, competition studies with potentially toxic metal cations were complicated due to toxic effects, particularly noticeable at 50 microM Co2+ and Cd2+.


Evaluating Efficacy of Peptide-Delivered Oligonucleotides Using the Severe Taiwanese SMA Mouse Model.
Oligonucleotides (ONs) are therapeutic macromolecules with great potential for the treatment of neurological conditions, including spinal muscular atrophy (SMA), a neurodegenerative disease. However, the neurovascular unit severely limits their distribution to the neural parenchyma of the brain and the spinal cord. Cell-penetrating peptides (CPPs) can be conjugated to oligonucleotides to increase their delivery across biological barriers. In this chapter, we describe the synthesis and conjugation of CPPs to oligonucleotides, and the use of a severe SMA mouse model to test in vivo the efficacy of CPP-delivered oligonucleotides, using ELISA, western blot, and TaqMan™ RT-qPCR assays.


Superficial fungal infections in children and adolescents.
Children with superficial fungal infections are commonly seen in clinical practice. Although tinea capitis and tinea corporis are the most common childhood mycoses, thrush and candida diaper dermatitis also occur frequently in infants. At times, diagnosis can be a challenge, but is made easier with the use of the potassium hydroxide microscopy and fungal cultures. Most childhood superficial fungal infections are adequately treated with topical antifungal medication. These medications are effective and the majority are safe for use in children. Oral antifungal drugs are required for children with tinea capitis, tinea unguium, and those who are immunosuppressed either from disease or therapy. Griseofulvin is the current systemic drug of choice to use in children. Several newer systemic antimycotics are currently being investigated for pediatric use. Terbinafine appears to have the best safety profile and the least risk of drug interactions. Itraconazole and fluconazole are also potential substitutes for griseofulvin in the future. The new agents, fluconazole, itraconazole, and terbinafine, have definitely improved the treatment of tinea unguium. Despite the availability of effective medications for treatment of superficial fungal infections, failure to take local and environmental measures to prevent transmission and reinfection will nullify the use of any treatment.


[Changes in the cardiometric parameters in ischemic heart disease].
Study of planimetric and weight indices of individual parts of the heart in 55 males (average age 51.2 +/- 2.7 years) who died of the first or repeated (primarily early) myocardial infarction has revealed the appearance (prior to the first major coronary event) of compensatory myocardial hypertrophy of all parts of the heart. Even in cases of the first infarction it was followed by dilatation of all cardiac chambers. Moreover, myocardial dilatation was exceeded by hypertrophy in all parts of the heart except left ventricle where both processes were found to be of the same extent. In the repeated myocardial infarction group, further increase of hypertrophy and dilatation was noted in the left parts of the heart only. In the ventricle both processes were of a similar degree while hypertrophy was prevalent in the atrium. The hypertrophy and dilatation of individual parts of the heart could be used for more accurate diagnosis--both clinical and postmortem--of early phases of ischemic heart disease and for the assessment of the heart pumping state.


[The sense of work in a formation project for nursing professionals].
The purpose of this study was to analyze the sense of the supervision work in a project for the professionalization of mid-level workers. In the theoretical and methodological framework of the historical and dialectical materialism, supervision was taken as an instrument of the work process, described in interview with the projects' supervisor (12) and coordinating (7) nurses. Their speeches were submitted to qualitative analysis and presented in thematic phrases. The investigation revealed, in particular, a supervision still based on old-fashioned modes of control.


Antimicrobial prescribing in residential homes.
Research in residential homes has been limited to date and the extent of systemic and topical antimicrobial prescribing is largely unknown. The aim of this study was to investigate antimicrobial prescribing in residential homes in Northern Ireland (NI). Point prevalence studies (PPSs) were completed in November 2010 (PPS1) and April 2011 (PPS2) in 30 residential homes. Data were obtained from care plans, medication administration records and staff in relation to antimicrobial prescribing and facility and resident characteristics, and analysed descriptively. The point prevalence of systemic antimicrobial prescribing was 9.4% in PPS1 and 9.2% in PPS2 (range 0.0%-33.3% during both PPSs). Trimethoprim was the most commonly prescribed systemic antimicrobial and the main indication was the prevention of urinary tract infections. Almost 25% of systemic antimicrobials were prescribed at inappropriate doses. The point prevalence of topical antimicrobial prescribing was 6.4% (range 0.0%-22.2%) in PPS1 and 5.9% (range 0.0%-21.1%) in PPS2. The most commonly prescribed topical antimicrobials were chloramphenicol eye preparations in PPS1 and fusidic acid skin preparations in PPS2; treatment with these topical antimicrobials was generally prolonged. More than 25% of all systemic and 55% of all topical antimicrobials were initiated following telephone consultations as opposed to face-to-face consultations. The prevalence of systemic antimicrobial prescribing in residential homes in NI is relatively high compared with care homes (particularly nursing homes) in other countries. Systemic and topical antimicrobial prescribing is not always appropriate in terms of the doses prescribed and the duration of use. It is apparent that current strategies employed in NI are insufficient to ensure prudent antimicrobial prescribing within this environment.


Tensor Robust Principal Component Analysis with a New Tensor Nuclear Norm.
In this paper, we consider the Tensor Robust Principal Component Analysis (TRPCA) problem, which aims to exactly recover the low-rank and sparse components from their sum. Our model is based on the recently proposed tensor-tensor product (or t-product) [14]. Induced by the t-product, we first rigorously deduce the tensor spectral norm, tensor nuclear norm, and tensor average rank, and show that the tensor nuclear norm is the convex envelope of the tensor average rank within the unit ball of the tensor spectral norm. These definitions, their relationships and properties are consistent with matrix cases. Equipped with the new tensor nuclear norm, we then solve the TRPCA problem by solving a convex program and provide the theoretical guarantee for the exact recovery. Our TRPCA model and recovery guarantee include matrix RPCA as a special case. Numerical experiments verify our results, and the applications to image recovery and background modeling problems demonstrate the effectiveness of our method.


[Use of NSAIDs in traumatology].
In traumatology, non-steroidal anti-inflammatory drugs (NSAIDs) are widely used, due to their efficacy in controlling pain and safety profile. Nonetheless, experimental and retrospective studies about the use of NSAIDs in traumatology raise the question about a possible negative influence on bone remodeling through inhibition of prostaglandin synthesis. The results from these studies must be interpreted with caution, as bone repair can be influenced by several parameters. When used in the case of sprains or tendinitis, unwanted side effects of NSAIDs seem to be limited; on the other hand, benefits in terms of antalgic effect are less clear. We have conducted a review of the literature aimed to suggest practical solutions for the use of NSAIDs in traumatology.


Diurnal variation of the human adipose transcriptome and the link to metabolic disease.
Circadian (diurnal) rhythm is an integral part of the physiology of the body; specifically, sleep, feeding behavior and metabolism are tightly linked to the light-dark cycle dictated by earth's rotation. The present study examines the effect of diurnal rhythm on gene expression in the subcutaneous adipose tissue of overweight to mildly obese, healthy individuals. In this well-controlled clinical study, adipose biopsies were taken in the morning, afternoon and evening from individuals in three study arms: treatment with the weight loss drug sibutramine/fasted, placebo/fed and placebo/fasted. The results indicated that diurnal rhythm was the most significant driver of gene expression variation in the human adipose tissue, with at least 25% of the genes having had significant changes in their expression levels during the course of the day. The mRNA expression levels of core clock genes at a specific time of day were consistent across multiple subjects on different days in all three arms, indicating robust diurnal regulation irrespective of potential confounding factors. The genes essential for energy metabolism and tissue physiology were part of the diurnal signature. We hypothesize that the diurnal transition of the expression of energy metabolism genes reflects the shift in the adipose tissue from an energy-expending state in the morning to an energy-storing state in the evening. Consistent with this hypothesis, the diurnal transition was delayed by fasting and treatment with sibutramine. Finally, an in silico comparison of the diurnal signature with data from the publicly-available Connectivity Map demonstrated a significant association with transcripts that were repressed by mTOR inhibitors, suggesting a possible link between mTOR signaling, diurnal gene expression and metabolic regulation. Diurnal rhythm plays an important role in the physiology and regulation of energy metabolism in the adipose tissue and should be considered in the selection of novel targets for the treatment of obesity and other metabolic disorders.