Incidence of gastroenteritis in Norway--a population-based survey.
In 1999-2000 we conducted a one-year, retrospective population-based survey in Norway to estimate the incidence of gastroenteritis and study the association with selected exposures. A self-administered questionnaire was mailed to 3000 persons selected at random from the population registry, with 250 persons being contacted each month. The response rate was 61%. The incidence of acute gastroenteritis was 1.2 per person-year. The incidence was higher for women than for men. Of the total of 171 cases, 29 (17%) consulted a physician, 13 (8%) reported that a stool sample was taken, and 7 (4%) were admitted to hospital. Among children aged less than 15 years, drinking water from a private water supply was associated with illness, while using chlorinated water was protective. Among adults aged 20-40 years, travelling abroad was associated with illness. The incidence in our survey is similar to rates found by FoodNet in United States.


Distribution of lung vascular resistance after chronic systemic-to-pulmonary shunts.
Congenital cardiac shunts produce pathological lesions on the arterial side of the lung vasculature. We examined the effects of chronic shunts (14.2 +/- 1.2 mo) in 10 young dogs, between the left subclavian and the left lower lobe (LLL) artery, on pulmonary vascular pressure and flow (P-Q) relationships, segmental resistance with arterial and venous occlusion (AVO), and sensitivity to drugs. At final thoracotomy, mean LLL pulmonary arterial pressure (Ppa) was 23.2 +/- 4.3 mmHg compared with 11.9 +/- 0.9 in the right lung (P less than 0.05); two animals had LLL Ppa of 41 and 48 mmHg. The LLL artery and vein were cannulated, and pressure-flow (P-Q) and AVO measurements were made and compared with previous control LLL (n = 11) and contralateral right lower lobe (RLL, n = 5). Responses to serotonin, histamine, and vasodilators (diltiazem and isoproterenol) were evaluated. Comparisons of morphometric measurements were made between LLL and RLL. We found a significant increase in arterial resistance as measured with AVO and a hypersensitivity to serotonin in the shunt LLL, without changes in total pulmonary vascular resistance or P-Q measurements; vasodilators had a small effect only in the hypertensive lobes. Our data suggest that chronic shunts to the pulmonary circulation increase arterial resistance and sensitivity to serotonin, even in the absence of discernible morphometric changes, and that vasoconstriction may be an important precursor to the development of morphological lesions.


In vitro restoration of polyclonal hematopoiesis in a chronic myelogenous leukemia after in vitro treatment with 4-hydroperoxycyclophosphamide.
Bone marrow cells of a 45-year-old female with Philadelphia chromosome (Ph1)-positive, early-phase chronic myelogenous leukemia (CML), who was heterozygous for the glucose-6-phosphate dehydrogenase (G6PD) locus, were pretreated in vitro with 4-hydroperoxycyclophosphamide (4-HC) and tested for G6PD activity in several colony formation assays and for karyotypic abnormalities. All cells within the mixed (CFU-GEMM), the erythroid burst (BFU-E), and the granulocyte-macrophage (CFU-GM) colonies expressed type A and type B G6PD activity and a normal karyotype, whereas untreated cells expressed type A G6PD and the Ph1 chromosome. This reversal of G6PD activity type and the disappearance of the Ph1 chromosome in colonies grown from 4-HC-treated cells indicate that this cytotoxic agent spares a residual normal stem cell population in bone marrow cells of early-phase CML patients. This finding, in turn, suggests a therapeutic approach in CML based on in vitro chemotherapy of autologous bone marrow grafts.


Rate of replication of the murine immunoglobulin heavy-chain locus: evidence that the region is part of a single replicon.
We measured the temporal order of replication of EcoRI segments from the murine immunoglobulin heavy-chain constant region (IgCH) gene cluster, including the joining (J) and diversity (D) loci and encompassing approximately 300 kilobases. The relative concentrations of EcoRI segments in bromouracil-labeled DNA that replicated during selected intervals of the S phase in Friend virus-transformed murine erythroleukemia (MEL) cells were measured. From these results, we calculated the nuclear DNA content (C value; the haploid DNA content of a cell in the G1 phase of the cell cycle) at the time each segment replicated during the S phase. We observed that IgCH genes replicate in the following order: alpha, epsilon, gamma 2a, gamma 2b, gamma 1, gamma 3, delta, and mu, followed by the J and D segments. The C value at which each segment replicates increased as a linear function of its distance from C alpha. The average rate of DNA replication in the IgCH gene cluster was determined from these data to be 1.7 to 1.9 kilobases/min, similar to the rate measured for mammalian replicons by autoradiography and electron microscopy (for a review, see H. J. Edenberg and J. A. Huberman, Annu. Rev. Genet. 9:245-284, 1975, and R. G. Martin, Adv. Cancer Res. 34:1-55, 1981). Similar results were obtained with other murine non-B cell lines, including a fibroblast cell line (L60T) and a hepatoma cell line (Hepa 1.6). In contrast, we observed that IgCh segments in a B-cell plasmacytoma (MPC11) and two Abelson murine leukemia virus-transformed pre-B cell lines (22D6 and 300-19O) replicated as early as (300-19P) or earlier than (MPC11 and 22D6) C alpha in MEL cells. Unlike MEL cells, however, all of the IgCH segments in a given B cell line replicated at very similar times during the S phase, so that a temporal directionality in the replication of the IgCH gene cluster was not apparent from these data. These results provide evidence that in murine non-B cells the IgCH, J, and D loci are part of a single replicon.


The role of illness-related cognition in the relationships between resilience and depression/anxiety in nasopharyngeal cancer patients.
Resilience has been reported as an important predictor of better mental health and prognoses in cancer patients, while its mechanisms were not clearly elucidated. In this study, we surveyed a large sample of nasopharyngeal carcinoma patients to investigate the mediating role of illness-related cognition (illness perception, stigma and meaning in life) on the associations between resilience and symptoms of anxiety and depression. This cross-sectional study involved 773 participants diagnosed with nasopharyngeal carcinoma. Participants completed a self-reported structured questionnaire to assess their illness perception, stigma and meaning in life, resilience and symptoms of anxiety and depression. Structural equation models (SEM) were employed to explore the relationship between resilience and symptoms of anxiety and depression in the entire sample, as well as in two subgroups: Subgroup I (0-1 year since diagnosis), and Subgroup II (over 1 year since diagnosis). In the entire sample, after adjusting for potential confounders, illness perception, stigma and meaning in life were found to mediate the protective effect of resilience on symptoms of depression (mediating effect proportion: 65.25%) and anxiety (mediating effect proportion: 67.63%). In Subgroup I, direct effects were dominant in the associations between resilience and symptoms of anxiety (mediating effect proportion: 37.95%) and depression (mediating effect proportion: 29.13%). However, in Subgroup II, the associations between resilience and symptoms of anxiety (mediating effect proportion: 98.92%) and depression (mediating effect proportion: 81.04%) were completely mediated. Our study suggests that direct and indirect effects of resilience on depression and anxiety dominate in early periods (0-1 year) and long-term periods (over 1 year) following the cancer diagnosis, respectively. The findings indicate that comprehensive intervention considering both the direct effect of resilience in early stages (e.g., health education prescription and social support groups) and the indirect effects of illness cognition in long-term periods (e.g., cognitive behavioral therapies) are likely to yield the most favorable outcomes for cancer patients.


Cleft Palate Repair Using Single Flap Palatoplasty in Patient With Associated Palatal Hemangioma.
Hemangiomas are the most common tumors of childhood with an average incidence of 10%. It is unusual for hemangiomas, which are already rarely seen isolated on the palate, to coexist with cleft palate as in the authors' patient. Four months old baby was admitted with isolated Veau 2 cleft palate and a red-purple colored raised lesion involving almost the whole right side of the hard palate. Magnetic resonance imaging revealed intensive contrasting solid nodule with a lobulated contour that was covering the right half of the hard palate, measuring 2.2×1.3 cm. To reduce the size of the vascular lesion 7 mg/d oral propranolol treatment was initiated. Following reduction in the size of hemangioma, the cleft palate was repaired at 11 months of age. Single mucoperiosteal flap from the left side of the palate preserving the major palatine artery was elevated whereas right mucoperisteal flap was minimally dissected not to interfere with the hemangioma. No intraoperative and postoperative complications in both the early and late term were experienced. As a result, since early palatal repair is important to obtain ideal speech outcomes in cleft patients, repair should be performed in similar patients with hemangiomas without delaying the timing.


Role of Gamma Knife Radiosurgery in Small Cell Lung Cancer: A Multi-Institutional Retrospective Study of the International Radiosurgery Research Foundation (IRRF).
Despite a high incidence of brain metastases in patients with small-cell lung cancer (SCLC), limited data exist on the use of stereotactic radiosurgery (SRS), specifically Gamma Knife™ radiosurgery (Elekta AB), for SCLC brain metastases. To provide a detailed analysis of SCLC patients treated with SRS, focusing on local failure, distant brain failure, and overall survival (OS). A multi-institutional retrospective review was performed on 293 patients undergoing SRS for SCLC brain metastases at 10 medical centers from 1991 to 2017. Data collection was performed according to individual institutional review boards, and analyses were performed using binary logistic regression, Cox-proportional hazard models, Kaplan-Meier survival analysis, and competing risks analysis. Two hundred thirty-two (79%) patients received SRS as salvage following prior whole-brain irradiation (WBRT) or prophylactic cranial irradiation, with a median marginal dose of 18 Gy. At median follow-up after SRS of 6.4 and 18.0 mo for surviving patients, the 1-yr local failure, distant brain failure, and OS were 31%, 49%, and 28%. The interval between WBRT and SRS was predictive of improved OS for patients receiving SRS more than 1 yr after initial treatment (21%, <1 yr vs 36%, >1 yr, P = .01). On multivariate analysis, older age was the only significant predictor for OS (hazard ratio 1.63, 95% CI 1.16-2.29, P = .005). SRS plays an important role in the management of brain metastases from SCLC, especially in salvage therapy following WBRT. Ongoing prospective trials will better assess the value of radiosurgery in the primary management of SCLC brain metastases and potentially challenge the standard application of WBRT in SCLC patients.


Indirect activation of pregnane X receptor in the induction of hepatic CYP3A11 by high-dose rifampicin in mice.
Rifampicin (RIF), a typical ligand of human pregnane X receptor (PXR), powerfully induces the expression of cytochrome P450 3A4 (CYP3A4) in humans. Although it is thought that RIF is not a ligand of rodent PXR, treatment with high-dose RIF (e.g. more than 20 mg/kg) increases the expression of CYP3A in the mouse liver. In this study, we investigated whether the induction of CYP3A by high-dose RIF in the mouse liver is mediated via indirect activation of mouse PXR (mPXR). The results showed that high-dose RIF increased the expression of CYP3A11 and other PXR-target genes in the liver of wild-type mice but not PXR-knockout mice. However, the results of reporter gene and ligand-dependent assembly assays showed that RIF does not activate mPXR in a ligand-dependent manner. In addition, high-dose RIF stimulated nuclear accumulation of mPXR in the mouse liver, and geldanamycin and okadaic acid attenuated the induction of Cyp3a11 and other PXR-target genes in primary hepatocytes, suggesting that high-dose RIF triggers nuclear translocation of mPXR. In conclusion, the present study suggests that high-dose RIF stimulates nuclear translocation of mPXR in the liver of mice by indirect activation, resulting in the transactivation of Cyp3a11 and other PXR-target genes.


Patient case mix measurement using outpatient drug dispense data.
This article outlines issues concerned with the development of case mix measurement using outpatient drug dispense databases, particularly as this method is being explored at Kaiser Permanente. Development is oriented to a population-based measure that emphasizes identification of major chronic diseases, such as diabetes, heart disease, hypertension, and asthma. Examples illustrate potential applications in the areas of utilization management and resource allocation. Questions concerning the integrity of this method--that is, how reliably the method represents population morbidity--are addressed.


Insights into the biochemical and genetic basis of glucokinase activation from naturally occurring hypoglycemia mutations.
Glucokinase (GCK) is a key regulatory enzyme in the pancreatic beta-cell and catalyzes the rate-limiting step for beta-cell glucose metabolism. We report two novel GCK mutations (T65I and W99R) that have arisen de novo in two families with familial hypoglycemia. Insulin levels, although inappropriately high for the degree of hypoglycemia, remain regulated by fluctuations in glycemia, and pancreatic histology was normal. These mutations are within the recently identified heterotropic allosteric activator site in the theoretical model of human beta-cell glucokinase. Functional analysis of the purified recombinant glutathionyl S-transferase fusion proteins of T65I and W99R GCK revealed that the kinetic changes result in a relative increased activity index (a measure of the enzyme's phosphorylating potential) of 9.81 and 6.36, respectively, compared with wild-type. The predicted thresholds for glucose-stimulated insulin release using mathematical modeling were 3.1 (T65I) and 2.8 (W99R) mmol/l, which were in line with the patients' fasting glucose. In conclusion, we have identified two novel spontaneous GCK-activating mutations whose clinical phenotype clearly differs from mutations in ATP-sensitive K(+) channel genes. In vitro studies confirm the validity of structural and functional models of GCK and the putative allosteric activator site, which is a potential drug target for the treatment of type 2 diabetes.


Selective hypersensitivity to granulocyte-macrophage colony-stimulating factor by juvenile chronic myeloid leukemia hematopoietic progenitors.
Juvenile chronic myelogenous leukemia (JCML) is a good model for the study of myeloproliferation because JCML hematopoietic progenitor cells grow in vitro at very low cell densities without the addition of exogenous stimulus. Previous studies have demonstrated that this proliferation is dependent on granulocyte-macrophage colony-stimulating factor (GM-CSF), and that removal of monocytes from the cell population before culture eliminates this "spontaneous" myeloproliferation, suggesting a paracrine role of monocyte stimulation. However, subsequent studies have shown that increased GM-CSF production from the JCML monocytes is not a consistent finding and therefore not a plausible sole mechanism. In examining hematopoietic growth factor dose-response curves, both JCML GM and erythroid nonadherent progenitor cell populations displayed a marked and selective hypersensitivity to GM-CSF. Responses to interleukin-3 and G-CSF were identical to control dose-response curves. This is the first demonstration of a myeloid leukemia in which hypersensitivity to a specific growth factor appears to be involved in the pathogenesis of the disease.


[Immunogenetics and veterinary medicine].
Combining immunology and genetics has become a highly productive line of research in recent years, namely the study of the effects of genetic factors on immunological processes and differences in susceptibility to disease caused by these factors. The implications of this new field of research are discussed in the present paper. Particular attention is paid to one of the most exhaustively studied immunogenetic systems, the Major Histocompatibility Complex.


Evaluation of the Zucker diabetic fatty (ZDF) rat as a model for human disease based on urinary peptidomic profiles.
Representative animal models for diabetes-associated vascular complications are extremely relevant in assessing potential therapeutic drugs. While several rodent models for type 2 diabetes (T2D) are available, their relevance in recapitulating renal and cardiovascular features of diabetes in man is not entirely clear. Here we evaluate at the molecular level the similarity between Zucker diabetic fatty (ZDF) rats, as a model of T2D-associated vascular complications, and human disease by urinary proteome analysis. Urine analysis of ZDF rats at early and late stages of disease compared to age- matched LEAN rats identified 180 peptides as potentially associated with diabetes complications. Overlaps with human chronic kidney disease (CKD) and cardiovascular disease (CVD) biomarkers were observed, corresponding to proteins marking kidney damage (eg albumin, alpha-1 antitrypsin) or related to disease development (collagen). Concordance in regulation of these peptides in rats versus humans was more pronounced in the CVD compared to the CKD panels. In addition, disease-associated predicted protease activities in ZDF rats showed higher similarities to the predicted activities in human CVD. Based on urinary peptidomic analysis, the ZDF rat model displays similarity to human CVD but might not be the most appropriate model to display human CKD on a molecular level.


PKA-mediated phosphorylation of the human K(ATP) channel: separate roles of Kir6.2 and SUR1 subunit phosphorylation.
ATP-sensitive potassium (K(ATP)) channels play important roles in many cellular functions such as hormone secretion and excitability of muscles and neurons. Classical ATP-sensitive potassium (K(ATP)) channels are heteromultimeric membrane proteins comprising the pore-forming Kir6.2 subunits and the sulfonylurea receptor subunits (SUR1 or SUR2). The molecular mechanism by which hormones and neurotransmitters modulate K(ATP) channels via protein kinase A (PKA) is poorly understood. We mutated the PKA consensus sequences of the human SUR1 and Kir6.2 subunits and tested their phosphorylation capacities in Xenopus oocyte homogenates and in intact cells. We identified the sites responsible for PKA phosphorylation in the C-terminus of Kir6.2 (S372) and SUR1 (S1571). Kir6.2 can be phosphorylated at its PKA phosphorylation site in intact cells after G-protein (Gs)-coupled receptor or direct PKA stimulation. While the phosphorylation of Kir6.2 increases channel activity, the phosphorylation of SUR1 contributes to the basal channel properties by decreasing burst duration, interburst interval and open probability, and also increasing the number of functional channels at the cell surface. Moreover, the effect of PKA could be mimicked by introducing negative charges in the PKA phosphorylation sites. These data demonstrate direct phosphorylation by PKA of the K(ATP) channel, and may explain the mechanism by which Gs-coupled receptors stimulate channel activity. Importantly, they also describe a model of heteromultimeric ion channels in which there are functionally distinct roles of the phosphorylation of the different subunits.


Long-Term Results of Laparoscopic Partial Versus Total Adrenalectomy for Aldosterone Producing Adenoma.
Laparoscopy surgery is the gold standard for the treatment of aldosterone-producing adenomas (APA). However, the effectiveness between laparoscopic total and partial adrenalectomy is controversial. Therefore, we retrospectively analyzed the postoperative and follow-up outcomes of these two procedures. A total of 96 APA patients underwent laparoscopic surgery in our hospital between January 2012 and December 2017. A total of 65 patients who underwent laparoscopic partial adrenalectomy (group 1) were compared with 31 patients who underwent laparoscopic total adrenalectomy (group 2). The mean follow-up time was 32.3 months and 40.8 months, respectively. Patient's preoperative characteristics, date during surgery, and postoperative clinical results of the two groups were analyzed. In both groups of patients, laparoscopic adrenalectomy was successfully carried out. The laparoscopic partial adrenalectomy group had a shorter operation time when compared to total adrenalectomy (P = .01). However, patients in the laparoscopic total adrenalectomy group were older (P = .04) and had a higher proportion of multiple adenomas (P = .01) compared to partial adrenalectomy. Five patients (7.7%) who underwent partial adrenalectomy did not show improvement in hypertension and/or serum potassium below normal levels, and review of plasma aldosterone concentration (PAC) and/or computerized tomography (CT) indicated that surgery was not successful in these patients. All 31 patients who underwent total adrenalectomy showed improvement or recovery from hypertension, and all PAC and serum potassium levels returned to normal levels after surgery. Although both surgical procedures were technically safe and feasible, laparoscopic partial adrenalectomy showed a higher failure rate (7.7%) for patients with APA. Therefore, choosing laparoscopic partial adrenalectomy requires careful consideration, and we selected laparoscopic total adrenalectomy in patients with unilateral APA.


Chemical modification of the haem propionate of cytochrome c.
The significance of the exposed haem edge in cytochrome c was directly probed by chemically modifying the partially exposed haem propionate in the crevice region around residues threonine-78 and threonine-49. Reaction of tuna heart cytochrome c with a water-soluble carbodi-imide at pH 3.7 in the absence of any added nucleophilic base leads to the covalent addition of substituted N-acylureas to the protein at two sites. One site has been shown to be a haem propionate by isotope-tracer and i.r.-spectral analysis of haem purified from the apoprotein. The other site is aspartial acid-62 on the back of the molecule. The modified cytochrome c demonstrates abnormal properties, including auto-oxidizability, a reduction potential of + 105mV, a reversible transition to a high-spin species below pH 5.3, no 695 nm charge-transfer band in the ferric state and abnormal binding to mitochondrial membranes. The derivative does react with cytochrome oxidase in deoxycholate-treated submitochondrial particles or in purified preparations with a specific activity of 43-65% compared with that obtained with native cytochrome c. The results are consistent with the view that an intact haem crevice is essential for normal values for physiochemical characteristics, but the significant residual enzymic activity suggests that the electron-transfer interface and/or the cytochrome oxidase-binding site cannot be localized solely in the region of the exposed haem propionate.


Tackling medication non-adherence in severe mental illness: where are we going wrong?
Although people with schizophrenia require medication to manage symptoms such as hearing voices, most do not take it as prescribed (they are non-adherent). We talked to psychiatrists, nurses and pharmacists about how they work with patients to help them be better at sticking with their medication. Although the professionals that we talked to recognized that treatment adherence was a major issue in their clinical work, they did not make best use of evidence-based interventions to address the problem. Often their practice was based on what they believed would work (e.g. patient education) even when the research shows that way of working to be ineffective. As far as we can determine, this is the first study to examine what interventions different mental health professionals report that they use in clinical practice to address patient's medication non-adherence. Non-adherence with medication is common in patients with schizophrenia. Addressing adherence to treatment may enhance clinical outcomes. Our aim was to explore mental health professionals experience and practise managing medication adherence in patients with schizophrenia. In this qualitative study, we interviewed mental health professionals from three key groups involved in promoting adherence: pharmacists, psychiatrists and nurses. Interviews were transcribed and analysed using a thematic approach. Thirty-five health professionals participated. From these interviews, we identified five main themes: my beliefs inform my practice; withholding information; adherence is important; who is responsible for promoting adherence?; and is it ok to pay people to take medication? Our overarching meta-theme was that practice with regard to promoting adherence was informed by beliefs and not by evidence. To the best of our knowledge, this is the first study to explore different mental health professionals' approaches to working with patients who do not want to take medication. The significance of participants' personal beliefs is an important observation. Our findings suggest that to support clinicians to more effectively help patients manage their medication, it may be first necessary to challenge pre-existing beliefs about adherence.


pyComBat, a Python tool for batch effects correction in high-throughput molecular data using empirical Bayes methods.
Variability in datasets is not only the product of biological processes: they are also the product of technical biases. ComBat and ComBat-Seq are among the most widely used tools for correcting those technical biases, called batch effects, in, respectively, microarray and RNA-Seq expression data. In this technical note, we present a new Python implementation of ComBat and ComBat-Seq. While the mathematical framework is strictly the same, we show here that our implementations: (i) have similar results in terms of batch effects correction; (ii) are as fast or faster than the original implementations in R and; (iii) offer new tools for the bioinformatics community to participate in its development. pyComBat is implemented in the Python language and is distributed under GPL-3.0 ( https://www.gnu.org/licenses/gpl-3.0.en.html ) license as a module of the inmoose package. Source code is available at https://github.com/epigenelabs/inmoose and Python package at https://pypi.org/project/inmoose . We present a new Python implementation of state-of-the-art tools ComBat and ComBat-Seq for the correction of batch effects in microarray and RNA-Seq data. This new implementation, based on the same mathematical frameworks as ComBat and ComBat-Seq, offers similar power for batch effect correction, at reduced computational cost.


[Transurethral contact electroimpulse ureteropyelolithotripsy].
Transurethral contact electroimpulse ureteropyelolithotripsy (TCEUT) was conducted in 161 patients aged 18 to 84 years (mean age 47 +/- 14 years) admitted to the urological department of Zhukovsky city hospital in 2006-2009. Female/male proportion 1.4:1. Overall efficacy of TCEUT was 98%, the concrement was destructed completely during the first TCEUT session in 98%, partially in 2% cases. The method was feasible in all the patients if the instrument could reach the concrement. Duration of the session providing complete elimination of the concrements varied from 1 to 6 months.Contact electroimpulse ureterolithotripsy is conducted with single impulses beginning with low energy (0.45 J). Contact electroimpulse pyelolithotripsy requires a higher initial impulse energy (0.6 J). TCEUT is a highly effective method of the treatment of concrements of the upper urinary tract. Side effects were registered in maximum 5%. Long-term existence of the concrement in the urinary system raises the risk of intraoperative complications.


Constructing violence as a public health problem.
Once viewed primarily as a criminal justice problem, violence and its prevention are now often claimed by public health professionals as being within their purview. The author reviewed 282 articles published in public health and medical journals from 1985 through 1995 that discussed violence as a public health problem. She found that while authors tended to identify social and structural causes for violence, they suggested interventions that targeted individuals' attitudes or behaviors and improved public health practice. Her study illuminates the tension between public health professionals' vision of the social precursors of violence and their attempts to apply a traditional set of remedies. In targeting individuals to rid the nation of violence, the public health community is deemphasizing societal causes.


Mantis Shrimp Navigate Home Using Celestial and Idiothetic Path Integration.
Path integration is a robust mechanism that many animals employ to return to specific locations, typically their homes, during navigation. This efficient navigational strategy has never been demonstrated in a fully aquatic animal, where sensory cues used for orientation may differ dramatically from those available above the water's surface. Here, we report that the mantis shrimp, Neogonodactylus oerstedii, uses path integration informed by a hierarchical reliance on the sun, overhead polarization patterns, and idiothetic (internal) orientation cues to return home when foraging, making them the first fully aquatic path-integrating animals yet discovered. We show that mantis shrimp rely on navigational strategies closely resembling those used by insect navigators, opening a new avenue for the investigation of the neural basis of navigation behaviors and the evolution of these strategies in arthropods and potentially other animals as well. VIDEO ABSTRACT.


Light-up and FRET aptamer reporters; evaluating their applications for imaging transcription in eukaryotic cells.
The regulation of RNA transcription is central to cellular function. Changes in gene expression drive differentiation and cellular responses to events such as injury. RNA trafficking can also have a large impact on protein expression and its localization. Thus, the ability to image RNA transcription and trafficking in real time and in living cells is a worthwhile goal that has been difficult to achieve. The availability of "light-up" aptamers that cause an increase in fluorescence of their ligands when bound by the aptamer have shown promise for reporting on RNA production and localization in vivo. Here we have investigated two light-up aptamers (the malachite green aptamer and the Spinach aptamers) for their suitabilities as reporters of RNA expression in vivo using two eukaryotic cell types, yeast and mammalian. Our analysis focused on the aptamer ligands, their contributions to background noise, and the impact of tandem aptamer strings on signal strength and ligand affinity. Whereas the background fluorescence is very low in vitro, this is not always true for cell imaging. Our results suggest the need for caution in using light-up aptamers as reporters for imaging RNA. In particular, images should be collected and analyzed by operators blinded to the sample identities. The appropriate control condition of ligand with the cells in the absence of aptamer expression must be included in each experiment. This control condition establishes that the specific interaction of ligand with aptamer, rather than nonspecific interactions with unknown cell elements, is responsible for the observed fluorescent signals. High background signals due to nonspecific interactions of aptamer ligands with cell components can be minimized by using IMAGEtags (Intracellular Multiaptamer GEnetic tags), which signal by FRET and are promising RNA reporters for imaging transcription.


Gastroesophageal scintigraphy in children: a comparison of posterior and anterior imaging.
The purpose of this study was to compare the posterior dynamic imaging with the anterior imaging in the evaluation of children with gastroesophageal reflux (GER). Sixty-eight children (26 female, 42 male; age range 4 months to 7 years, median 21 months) were studied. After 4-hour fasting, all the subjects underwent gastroesophageal scintigraphy. Synchronous dynamic imaging in the anterior and posterior projections was performed with the subject in the supine position with a dual-head gamma camera equipped with low-energy general-purpose collimators at a rate of 30 s/frame for 40 min. The anterior and posterior images were visually evaluated for the presence of gastroesophageal reflux by two nuclear medicine physicians. The anterior and posterior images were correlated by Pearson correlation analysis, and inter-observer variability was evaluated by paired t-test and kappa value. There was a good correlation between the two projections with r-values of 0.906-0.990. The inter-observer agreement for interpretation of the anterior and posterior imaging was excellent (k: 0.83). In conclusion, anterior and posterior dynamic imaging showed excellent correlation in detection of GER in children. Posterior imaging is superior to anterior imaging in that it is more comfortable, and it reduces motion artifacts, especially for infants and anxious children; thus, it may be preferred over anterior imaging.


The role of URO17™ biomarker to enhance diagnosis of urothelial cancer in new hematuria patients-First European Data.
Novel biomarker research is vital for the progression of safe and thorough diagnostic medicine. There is now a need to improve the diagnosis of bladder cancer via a noninvasive urine test while balancing the risks of harm from investigational procedures, such as cystoscopy and radiological tests, against the likelihood of malignancy. We evaluate the diagnostic accuracy and sensitivity of Uro17™ urinary biomarker for the detection of urothelial cancer in hematuria patients in a prospective blinded validation study. Uro17™ is an immunobiomarker which binds to the oncoprotein Keratin 17, which is involved in the replication cycle of malignant cells. This study compared cystoscopic and histological investigations against Uro17™ results in patients being investigated for symptoms of urothelial cancer. After receiving both local and national ethics/protocol approval, 71 patients were consented and recruited into the study. All patients were scheduled to undergo cystoscopic investigation, and following recruitment, a urine sample was collected. Urine samples were anonymized and processed as per standard cytology protocols and stained using Uro17™ immunobiomarker. The pathologists assessing the results were blinded to the patient and background history, and the results were compared to the biopsy histology. The full cohort of enrolled patients consisted of 71 participants included. There were 55 males and 16 females, with an average age of 70. Thirteen were current smokers, 42 ex-smokers, and 16 nonsmokers. The malignancies detected included both muscle-invasive (n = 6) and non-muscle-invasive tumors (n = 38), and tumors of all grades and carcinoma in situ. Uro17™ was shown to have an overall sensitivity of 100% and a specificity of 92.6%, with a positive predictive value of 0.957 and negative predictive value of 1. Uro17™ investigation was positive in every case of urothelial malignancy. Our current data indicates Uro17™ is a highly sensitive noninvasive bladder cancer urine detection test that can improve the diagnosis of Bladder cancer. This can further improve diagnostic capabilities in primary care, reduce the number of referrals to Urology department, and reduce the number of unnecessary invasive procedures for new patients with a suspected urinary bladder cancer.


Helping callers to the National Suicide Prevention Lifeline who are at imminent risk of suicide: the importance of active engagement, active rescue, and collaboration between crisis and emergency services.
In 2012, the SAMHSA-funded National Suicide Prevention Lifeline (Lifeline) completed implementation of the first national Policy for Helping Callers at Imminent Risk of Suicide across its network of crisis centers. The policy sought to: (1) provide a clear definition of imminent risk; (2) reflect the state of evidence, field experience, and promising practices related to reducing imminent risk through hotline interventions; and (3) provide a uniform policy and approach that could be applied across crisis center settings. The resulting policy established three essential principles: active engagement, active rescue, and collaboration between crisis and emergency services. A sample of the research and rationale that underpinned the development of this policy is provided here. In addition, policy implementation, challenges and successes, and implications for interventions to help Lifeline callers at imminent risk of suicide are detailed.


Dynamical characteristics of surface EMG signals of hand grasps via recurrence plot.
Recognizing human hand grasp movements through surface electromyogram (sEMG) is a challenging task. In this paper, we investigated nonlinear measures based on recurrence plot, as a tool to evaluate the hidden dynamical characteristics of sEMG during four different hand movements. A series of experimental tests in this study show that the dynamical characteristics of sEMG data with recurrence quantification analysis (RQA) can distinguish different hand grasp movements. Meanwhile, adaptive neuro-fuzzy inference system (ANFIS) is applied to evaluate the performance of the aforementioned measures to identify the grasp movements. The experimental results show that the recognition rate (99.1%) based on the combination of linear and nonlinear measures is much higher than those with only linear measures (93.4%) or nonlinear measures (88.1%). These results suggest that the RQA measures might be a potential tool to reveal the sEMG hidden characteristics of hand grasp movements and an effective supplement for the traditional linear grasp recognition methods.


A Threshold of Objectively-Assessed Daily Sedentary Time for All-Cause Mortality in Older Adults: A Meta-Regression of Prospective Cohort Studies.
Background: This meta-analysis aimed to estimate the shape of the dose-response association between objectively-assessed daily sedentary time (ST) and all-cause mortality, and to explore whether there is a threshold of ST above which there is an increase in mortality risk in older adults. Methods: Searches for prospective cohort studies providing effect estimates of daily ST (exposure) on all-cause mortality (outcome) were undertaken in five databases up to 31 March 2019. A random-effects meta-regression model was conducted to quantify the dose-response relationship between daily ST and all-cause mortality. Sensitivity analyses were also performed to test the stability of the results. Results: Our analysis of pooled data from 11 eligible studies did not reveal a consistent shape of association between ST and mortality. After excluding three studies with potential confounding bias, there was a log-linear dose-response relationship between daily ST and all-cause mortality. Overall, higher amounts of time spent in sedentary behaviors were associated with elevated mortality risks in older adults. Visual assessments of dose-response relationships based on meta-regression analyses indicated that increased mortality risks became significant when total ST exceeded approximately 9 h/day. Conclusions: Based on a limited number of studies, this meta-analysis provides a starting point for considering a cut-off of daily sedentary time, suggesting older adults spend less time in daily sitting.


Analytical and preparative chiral supercritical fluid chromatography resolutions using crown ether-derived column.
In this study, crown ether-derived column Crownpak® CR-I (+) was evaluated under SFC conditions using 12 primary amines, and the chromatographic results were compared against eight immobilized polysaccharide-based columns. Crownpak® CR-I (+) achieved a significantly higher success rate. It was found that the addition of 5% water to the modifier dramatically improved the peak shape for chiral separation of primary amines on Crownpak® CR-I (+). The first reported preparative SFC separations on Crownpak® CR-I (+) are shown, offering a new approach for the preparative resolution of primary amines. The case studies demonstrate that Crownpak® CR-I (+) is a very useful column in the chiral separation of challenging compounds that contain a primary amine group in the pharmaceutical industry.


A mechanism of the glycogenolytic action of bacterial endotoxin.
These experiments have demonstrated that liver glycogen may rise or fall after endotoxin administration, depending upon the antecedent diet and that total adrenalectomy followed by corticosteroid replacement abolishes the glycogenolytic effect of sublethal doses of endotoxin. It is concluded that the derangements of carbohydrate metabolism observed following the administration of sublethal quantities of bacterial endotoxin represent, not a direct hepatotoxic effect of endotoxin, but rather the passive consequence of epinephrine release.


Homogeneous self-aligned liquid crystals on wrinkled-wall poly(dimethylsiloxane) via localised ion-beam irradiation.
We demonstrate self-aligned liquid crystals (LCs) using a wrinkled-wall polydimethylsiloxane (PDMS) wrinkle structure, which is a key factor to obtain a stable homogeneous alignment state with positive LCs. We constructed the wrinkled walls via localised surface exposure to IB radiation, which passed through a long length localised pattern mask. The creation of the wrinkled wall helped to align the LC molecules homogeneously because the wrinkled wall acted as a guide for the arrangement of positive LC molecules. In addition, we confirmed the stability of the alignment state as the width of the wrinkled wall was changed. Although this wrinkled-wall method is a non-contact method, LC alignment is achieved via an anisotropic topographical guide, which provides the LC molecules with stable homogeneous alignment.


To Serve Those Who Served: Advances in Plastic and Reconstructive Surgery During War and Peace.
The industrialization of modern warfare dating back to WWI led to an increase in combat-related injuries with unprecedented levels of severity. The necessity of addressing the clinical challenges that ensued led to the emergence of modern reconstructive surgery and subsequently a robust healthcare initiative for veterans in the form of the Department of Veterans Affairs. In the following article, a literature review was conducted to examine the interplay between combat injuries, veterans' care, and reconstructive surgery. We found that the relationship between military trauma and reconstructive surgery has led to an increase in survival rates and advances in mass casualty response while allowing the survivors to maintain a high quality of life. The relationship between the Veterans Affairs hospitals and plastic surgery has only strengthened over time as these hospitals play a major role in training the next generation of plastic surgeons throughout the nation. It is imperative to maintain this cooperative relationship to ensure a high level of care for our veterans and a comprehensive training experience for plastic surgery residents.


Cell surface receptors for herpes simplex virus are heparan sulfate proteoglycans.
The role of cell surface heparan sulfate in herpes simplex virus (HSV) infection was investigated using CHO cell mutants defective in various aspects of glycosaminoglycan synthesis. Binding of radiolabeled virus to the cells and infection were assessed in mutant and wild-type cells. Virus bound efficiently to wild-type cells and initiated an abortive infection in which immediate-early or alpha viral genes were expressed, despite limited production of late viral proteins and progeny virus. Binding of virus to heparan sulfate-deficient mutant cells was severely impaired and mutant cells were resistant to HSV infection. Intermediate levels of binding and infection were observed for a CHO cell mutant that produced undersulfated heparan sulfate. These results show that heparan sulfate moieties of cell surface proteoglycans serve as receptors for HSV.


Are the Comments on HaNDL Syndrome in the ICHD-II Sufficient?
A 33-year-old man was admitted to our emergency department for severe frontal headache followed by a state of consciousness disturbance and right-sided hemiparesis. No previous febrile disease, head trauma, vascular risk factor, and medication for any systemic disease were defined in his history. He had experienced a similar disorder three years ago and had recovered completely. Cerebrospinal fluid (CSF) analysis revealed pleocytosis and electroencephalography (EEG) showed diffuse slow wave activity. Hyperintense foci on T2 and FLAIR sequences representing bilateral cortical ischemia, prominent on the right hemisphere, were seen on MRI. Contrast-enhanced T1 images showed marked leptomeningeal thickening with enhancement. The patient was considered as having CSF lymphocytosis (HaNDL syndrome) due to temporary headache with neurologic deficit and CSF pleocytosis. Diagnostic criteria have been identified for this syndrome according to the International Classification of Headache Disorders, 2nd edition (ICHD-II). According to these criteria, neuroimaging should be normal. Positive neuroimaging findings and impairment of consciousness have been reported in a limited number of HaNDL cases so far. Diversity of neurological signs, duration and distinctness from migraine headache have been described in comment section under the diagnostic criteria. Comments are inadequate in this regard.


Advanced brain ageing in Parkinson's disease is related to disease duration and individual impairment.
Machine learning can reliably predict individual age from MRI data, revealing that patients with neurodegenerative disorders show an elevated biological age. A surprising gap in the literature, however, pertains to Parkinson's disease. Here, we evaluate brain age in two cohorts of Parkinson's patients and investigated the relationship between individual brain age and clinical characteristics. We assessed 372 patients with idiopathic Parkinson's disease, newly diagnosed cases from the Parkinson's Progression Marker Initiative database and a more chronic local sample, as well as age- and sex-matched healthy controls. Following morphometric preprocessing and atlas-based compression, individual brain age was predicted using a multivariate machine learning model trained on an independent, multi-site reference sample. Across cohorts, healthy controls were well predicted with a mean error of 4.4 years. In turn, Parkinson's patients showed a significant (controlling for age, gender and site) increase in brain age of ∼3 years. While this effect was already present in the newly diagnosed sample, advanced biological age was significantly related to disease duration as well as worse cognitive and motor impairment. While biological age is increased in patients with Parkinson's disease, the effect is at the lower end of what is found for other neurological and psychiatric disorders. We argue that this may reflect a heterochronicity between forebrain atrophy and small but behaviourally salient midbrain pathology. Finally, we point to the need to disentangle physiological ageing trajectories, lifestyle effects and core pathological changes.


Effect of anesthesia on glucose production and utilization in rats.
This study was undertaken to determine the effects of pentobarbital anesthesia (50 mg/kg ip) on glucose kinetics and individual tissue glucose utilization in vivo, in chronically catheterized rats. Glucose turnover studies were carried out using [3-3H]glucose as tracer. A transient hyperglycemia and an increased glucose production were observed 3 min after induction of anesthesia. However, 40 min after induction of anesthesia, glycemia returned to the level observed in awake animals, whereas glucose turnover was decreased by 30% as compared with unanesthetized rats. These results are discussed with regard to the variations observed in plasma insulin, glucagon, and catecholamine levels. Glucose utilization by individual tissues was studied by the 2-[1-3H]deoxyglucose technique. A four- to fivefold decrease in glucose utilization was observed in postural muscles (soleus and adductor longus), while in other nonpostural muscles (epitrochlearis, tibialis anterior, extensor digitorum longus, and diaphragm) and other tissues (white and brown adipose tissues) anesthesia did not modify the rate of glucose utilization. A decrease in glucose utilization was also observed in the brain.


Involvement of apoptosis inhibitor of macrophages in a rat hypertension model with nephrosclerosis: possible mechanisms of action of olmesartan and azelnidipine.
Stroke-prone spontaneously hypertensive (SHRsp) rats develop severe hypertension resulting in renal injury. We investigated apoptosis inhibitor of macrophages (AIM) expression in nephrosclerotic rats and the involvement of AIM in olmesartan (OLM)- and azelnidipine (AZN)-induced decreases in the number of macrophages infiltrating the kidney. We randomly assigned 20-week-old male SHRsp rats to receive one of the following substances every day for 12 weeks: water (vehicle), hydralazine (HYD), OLM, or AZN. Renal damage was assessed by Masson trichrome staining. Expressions of ED-1, AIM, and oxidized low-density lipoprotein (oxLDL) were immunohistochemically detected. Apoptosis was analyzed by terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL) staining. All treatment groups showed significantly less renal interstitial fibrosis than the vehicle group. AZN and OLM groups had significantly fewer AIM-expressing cells than the HYD and vehicle groups. The ratios AIM-positive cells/ED-1-positive macrophages and TUNEL-positive cells/ED-1-positive macrophages in the AZN and OLM groups were lower and higher, respectively, than the the HYD and vehicle groups. oxLDL expression in the renal interstitium was significantly lower in treatment groups compared to vehicle group. OLM and AZN inhibited interstitial fibrosis progression in SHRsp rats by suppressing AIM expression in macrophages, followed by reducing the number of infiltrating macrophages.


[Body mass index and triponderal index in abnormal uterine bleed].
Abnormal uterine bleeding (AUB) is the most common cause of blood loss. Obesity and overweight are risk factors for AUB. To compare the association between body mass index (BMI) and tri-ponderal mass index (TMI) with the presence of acute AUB and chronic AUB. Observational, cross-sectional and analytical study. Women between 18 and 45 years of age with an alteration in the regular uterine bleeding pattern were included. Postmenopausal women, carriers of an intrauterine device as a method of family planning who have developed alterations in the menstrual rhythm after it, those who suffered from chronic diseases (chronic kidney disease, diabetes mellitus and uncontrolled hypothyroidism) and those with medication consumption that alter coagulation were not included. Pregnant patients were excluded. A total of 292 women with AUB were analyzed, with a median age of 38.5 (IQR 33-41), with bleeding of 205.4 mL (±142.9) and 116 (39.86%) of them with overweight. When analyzing the BMI with SUA, we found no significant difference in the presence of acute or chronic bleeding in the overweight (p = 0.46) and obese (p = 0.41) groups. When analyzing the IMT with the presence of acute or chronic AUB, it was not possible to find a significant difference in the overweight (p = 0.98) and obesity (p = 0.93) groups. The BMI was compared with the TMI for the presence of AUB, without finding a significant association.


Using Wearable Devices in a Healthcare Facility: An Empirical Study with Alzheimer's Patients.
Smart Wearables are considered a very promising solution for monitoring and helping people affected by cognitive decline or dementia and, in particular, Alzheimer Disease (AD). Nonetheless, the acceptability and wearability of such devices for AD patients pose certain challenges. To address this, an empirical study has been conducted with a group of patients with mild to moderate AD, wearing wristbands E4 by Empatica for a duration of three months. The experiment has been integrated into the regular healthcare activities, with active involvement from nurses and physicians. The paper reports the feedbacks of the caregivers and discusses wearability and acceptability issues.


Fluorescent substrates for soluble epoxide hydrolase and application to inhibition studies.
Inhibition of the mammalian soluble epoxide hydrolase (sEH) is a promising new therapy in the treatment of disorders resulting from hypertension and vascular inflammation. A spectrophotometric assay (4-nitrophenyl-trans-2,3-epoxy-3-phenylpropyl carbonate, NEPC) is currently used to screen libraries of chemicals; however this assay lacks the required sensitivity to differentiate the most potent inhibitors. A series of fluorescent alpha-cyanoester and alpha-cyanocarbonate epoxides that produce a strong fluorescent signal on epoxide hydrolysis by both human and murine sEH were designed as potential substrates for an in vitro inhibition assay. The murine enzyme showed a broad range of specificities, whereas the human enzyme showed the highest specificity for cyano(6-methoxy-naphthalen-2-yl)methyl trans-[(3-phenyloxiran-2-yl)methyl] carbonate. An in vitro inhibition assay was developed using this substrate and recombinant enzyme. The utility of the fluorescent assay was confirmed by determining the IC(50) values for a series of known inhibitors. The new IC(50) values were compared with those determined by spectrophotometric NEPC and radioactive tDPPO assays. The fluorescent assay ranked these inhibitors on the basis of IC(50) values, whereas the NEPC assay did not. The ranking of inhibitor potency generally agreed with that determined using the tDPPO assay. These results show that the fluorescence-based assay is a valuable tool in the development of sEH inhibitors by revealing structure-activity relationships that previously were seen only by using the costly and labor-intensive radioactive tDPPO assay.


A New Method to Evaluate Pressure Distribution Using a 3D-Printed C2-C3 Cervical Spine Model with an Embedded Sensor Array.
Cervical degenerative disc diseases such as myelopathy and radiculopathy often require conventional treatments like artificial cervical disc replacement or anterior cervical discectomy and fusion (ACDF). When designing a medical device, like the stand-alone cage, there are many design inputs to consider. However, the precise biomechanics of the force between the vertebrae and implanted devices under certain conditions require further investigation. In this study, a new method was developed to evaluate the pressure between the vertebrae and implanted devices by embedding a sensor array into a 3D-printed C2-C3 cervical spine. The 3D-printed cervical spine model was subjected to a range of axial loads while under flexion, extension, bending and compression conditions. Cables were used for the application of a preload and a robotic arm was used to recreate the natural spine motions (flexion, extension, and bending). To verify and predict the total pressure between the vertebrae and the implanted devices, a 3D finite element (FE) numerical mathematical model was developed. A preload was represented by applying 22 N of force on each of the anterior tubercles for the C2 vertebra. The results of this study suggest that the sensor is useful in identifying static pressure. The pressure with the robot arm was verified from the FE results under all conditions. This study indicates that the sensor array has promising potential to reduce the trial and error with implants for various surgical procedures, including multi-level artificial cervical disk replacement and ACDF, which may help clinicians to reduce pain, suffering, and costly follow-up procedures.


An increase in the EPA/AA ratio is associated with improved arterial stiffness in obese patients with dyslipidemia.
Previous epidemiological studies demonstrated that the ratio of n-6 to n-3 polyunsaturated fatty acids is associated with cardiovascular diseases. We herein investigated whether the beneficial effect of highly purified eicosapentaenoic acid(EPA) on arterial stiffness is associated with changes in the ratio of polyunsaturated fatty acids, such as EPA, docosahexaenoic acid(DHA) and dihomo-γ-linolenic acid(DGLA), relative to arachidonic acid(AA), in obese Japanese patients with dyslipidemia. The EPA/AA, DHA/AA and DGLA/AA ratios were compared between obese patients with(n=94) and without (n=31) dyslipidemia. Among the former group, 88 patients received either highly purified EPA treatment(1.8g daily, n=45) or treatment without EPA(control, n=43). At baseline, the ratios of DHA/AA and DGLA/AA were significantly(P<0.05) higher in obese patients with dyslipidemia than in those without, while the EPA/AA ratio was similar between patients with and without dyslipidemia. EPA significantly reduced the hemoglobin A1c, total cholesterol, triglycerides, CRP, cardio-ankle vascular index(CAVI)(an index of arterial stiffness) and the DGLA/AA ratio relative to the control at three months after the treatment. On the other hand, EPA significantly increased the adiponectin level and EPA/AA ratio(P<0.05). A multivariate regression analysis revealed that only age, an increase in the EPA/AA ratio and a decrease in the CRP level were significant determinants of a reduction of the CAVI by EPA. These findings suggest that EPA improves the arterial stiffness in association with an increase in the EPA/AA ratio and a decrease in inflammation in obese patients with dyslipidemia.


Assessing bioequivalence of generic modified-release antiepileptic drugs.
The purpose of this study was to determine how closely generic modified-release antiepileptic drugs (MR-AEDs) resemble reference (brand) formulations by comparing peak concentrations (Cmax), total absorption (area under the curve [AUC]), time to Cmax (Tmax), intersubject variability, and food effects between generic and reference products. We tabulated Cmax and AUC data from the bioequivalence (BE) studies used to support the approvals of generic Food and Drug Administration-approved MR-AEDs. We compared differences in 90% confidence intervals of the generic/reference AUC and Cmax geometric mean ratios, and intersubject variability, Tmax and delivery profiles and food effects. Forty-two MR-AED formulations were studied in 3,175 healthy participants without epilepsy in 97 BE studies. BE ratios for AUC and Cmax were similar between most generic and reference products: AUC ratios varied by >15% in 11.4% of BE studies; Cmax varied by >15% in 25.8% of studies. Tmax was more variable, with >30% difference in 13 studies (usually delayed in the fed compared to fasting BE studies). Generic and reference MR products had similar intersubject variability. Immediate-release AEDs showed less intersubject variability in AUC than did MR-AEDs. Most generic and reference MR-AEDs have similar AUC and Cmax values. Ratios for some products, however, are near acceptance limits and Tmax values may vary. Food effects are common with MR-AED products. High variability in pharmacokinetic values for once-a-day MR-AEDs suggests their major advantage compared to immediate-release AED formulations may be the convenience of less frequent dosing to improve adherence.


Diet-induced changes in titer support a discrete response of Wolbachia-associated plastic recombination in Drosophila melanogaster.
Plastic recombination in Drosophila melanogaster has been associated with a variety of extrinsic and intrinsic factors such as temperature, starvation, and parasite infection. The bacterial endosymbiont Wolbachia pipientis has also been associated with plastic recombination in D. melanogaster. Wolbachia infection is pervasive in arthropods and this infection induces a variety of phenotypes in its hosts, the strength of which can depend on bacterial titer. Here, we test the hypothesis that the magnitude of Wolbachia-associated plastic recombination in D. melanogaster depends on titer. To manipulate titer, we raised Wolbachia-infected and uninfected flies on diets that have previously been shown to increase or decrease Wolbachia titer relative to controls. We measured recombination in treated and control individuals using a standard backcrossing scheme with two X-linked visible markers. Our results recapitulate previous findings that Wolbachia infection is associated with increased recombination rate across the yellow-vermillion interval of the X chromosome. Our data show no significant effect of diet or diet by Wolbachia interactions on recombination, suggesting that diet-induced changes in Wolbachia titer have no effect on the magnitude of plastic recombination. These findings represent one of the first steps toward investigating Wolbachia-associated plastic recombination and demonstrate that the phenotype is a discrete response rather than a continuous one.


Polypeptide synthesis catalyzed by p-hydroxymercuribenzoate-modified ribosomes.
The stimulation of poly(U)-directed polyphenylalanine synthesis produced by modification of Escherichia coli ribosomes with p-hydroxymercuribenzoate, at low molar ratios of reagent to ribosomes, is due to an increase in the average chain length of polyphenylalanine synthesized, and not to the activation of inactive ribosomes. At a higher molar ratio of p-hydroxymercuribenzoate to ribosomes, which produces no overall change in activity, approximately 50% of the active ribosomes present in the untreated preparation have been completely inactivated, and the remaining active ones, like the ribosomes of the stimulated preparation, synthesize polyphenylalanine at an increased rate as compared with the untreated ribosomes.


Surgical management of large rotator cuff tears combined with instability in elite rugby football players.
Large rotator cuff tears are extremely uncommon in young people and when they occur they may be associated with shoulder instability. This paper reports on a series of six elite rugby union and rugby league footballers who presented with shoulder instability and large rotator cuff tears. They were treated with a two stage procedure: an open rotator cuff repair followed by an open shoulder stabilisation some 10 weeks later. All had successful outcomes. The paper also highlights the risk of tearing the rotator cuff when a patient continues to play contact sport with an untreated unstable shoulder.


Substantial influence of psychological factors on return to sports after anterior shoulder instability surgery: a systematic review and meta-analysis.
This systematic review and meta-analysis aimed to (1) determine the proportion of patients who underwent anterior shoulder instability surgery and did not return to sports for psychological reasons and (2) estimate differences in psychological readiness scores between patients who did and did not return to sports. The EBSCOhost/SPORTDiscus, PubMed/Medline, Scopus, EMBASE and Cochrane Library databases were searched for relevant studies. The data synthesis included the proportion of patients who did not return to sports for psychological reasons and the mean differences in the psychological readiness of athletes who returned and those who did not return to sports. Non-binomial data were analysed using the inverse-variance approach and expressed as the mean difference with 95% confidence intervals. The search yielded 700 records, of which 13 (1093 patients) were included. Fourteen psychological factors were identified as potential causes for not returning to sports. The rates of return to sports at any level or to the preinjury level were 79.3% and 61.9%, respectively. A total of 55.9% of the patients cited psychological factors as the primary reason for not returning to sports. The pooled estimate showed that patients who returned to sports had a significantly higher Shoulder Instability-Return to Sport After Injury score (P < 0.00001) than those who did not, with a mean difference of 30.24 (95% CI 24.95-35.53; I2 = 0%; n.s.). Psychological factors have a substantial impact on the rate of return to sports after anterior shoulder instability surgery. Patients who returned to sports had significantly higher psychological readiness than those who did not return to sports. Based on these results, healthcare professionals should include psychological and functional measurements when assessing athletes' readiness to return to sports. Level IV.


Disease and anatomic specificity of ethanolamine plasmalogen deficiency in Alzheimer's disease brain.
A significant and selective deficiency of ethanolamine plasmalogen (PPE) relative to phosphatidylethanolamine was identified in post mortem brain samples from patients with Alzheimer's disease (AD). This lipid defect showed anatomic specificity, being more marked at a site of neurodegeneration in AD brain than in a region relatively spared by the disease (mid-temporal cortex vs. cerebellum) and disease specificity for AD: it was not observed at the primary site of neurodegeneration in Huntington's disease (caudate nucleus) nor Parkinson's disease (substantia nigra). PPE deficiency parallels an inherent tendency towards membrane bilayer instability previously detected in AD brain which is necessarily due to a change in membrane lipid composition, and which may contribute to AD pathogenesis.


Risk of First Hemorrhage of Brain Arteriovenous Malformations During Pregnancy: A Systematic Review of the Literature.
Recommendations on the management of brain arteriovenous malformations (bAVM) with respect to pregnancy are based upon conflicting literature. To systematically review the reported risk and annualized rate of first intracranial hemorrhage (ICH) from bAVM during pregnancy and puerperium. MEDLINE, EMBASE, and Scopus databases were searched for relevant articles in English published before April 2018. Studies providing a quantitative risk of ICH in bAVM during pregnancy were eligible. From 7 initially eligible studies, 3 studies met the criteria for providing quantitative risk of first ICH bAVM during pregnancy. Data from 47 bAVM ICH during pregnancy across 4 cohorts were extracted for analysis. Due to differences in methodology and definitions of exposure period, it was not appropriate to combine the cases. The annualized risk of first ICH during pregnancy for these 4 cohorts was 3.0% (95% confidence interval [CI]: 1.7-5.2%); 3.5% (95% CI: 2.4-4.5%); 8.6% (95% CI: 1.8-25%); and 30% (95% CI: 18-49%). Only the last result from the last cohort could be considered significantly increased in comparison with the nonpregnant period (relative rate 6.8, 95% CI: 3.6-13). The limited number of eligible studies and variability in results highlighted the need for enhanced rigor of future research. There is no conclusive evidence of an increased risk of first hemorrhage during pregnancy from bAVM. Because advice to women with bAVM may influence the management of pregnancy or bAVM with significant consequences, we believe that a retrospective multicenter, case crossover study is urgently required.


Silencing of TGF-beta signalling by the pseudoreceptor BAMBI.
Members of the transforming growth factor-beta (TGF-beta) superfamily, including TGF-beta, bone morphogenetic proteins (BMPs), activins and nodals, are vital for regulating growth and differentiation. These growth factors transduce their signals through pairs of transmembrane type I and type II receptor kinases. Here, we have cloned a transmembrane protein, BAMBI, which is related to TGF-beta-family type I receptors but lacks an intracellular kinase domain. We show that BAMBI is co-expressed with the ventralizing morphogen BMP4 (refs 5, 6) during Xenopus embryogenesis and that it requires BMP signalling for its expression. The protein stably associates with TGF-beta-family receptors and inhibits BMP and activin as well as TGF-beta signalling. Finally, we provide evidence that BAMBI's inhibitory effects are mediated by its intracellular domain, which resembles the homodimerization interface of a type I receptor and prevents the formation of receptor complexes. The results indicate that BAMBI negatively regulates TGF-beta-family signalling by a regulatory mechanism involving the interaction of signalling receptors with a pseudoreceptor.


Bladder sensory physiology: neuroactive compounds and receptors, sensory transducers, and target-derived growth factors as targets to improve function.
Urinary bladder dysfunction presents a major problem in the clinical management of patients suffering from pathological conditions and neurological injuries or disorders. Currently, the etiology underlying altered visceral sensations from the urinary bladder that accompany the chronic pain syndrome, bladder pain syndrome (BPS)/interstitial cystitis (IC), is not known. Bladder irritation and inflammation are histopathological features that may underlie BPS/IC that can change the properties of lower urinary tract sensory pathways (e.g., peripheral and central sensitization, neurochemical plasticity) and contribute to exaggerated responses of peripheral bladder sensory pathways. Among the potential mediators of peripheral nociceptor sensitization and urinary bladder dysfunction are neuroactive compounds (e.g., purinergic and neuropeptide and receptor pathways), sensory transducers (e.g., transient receptor potential channels) and target-derived growth factors (e.g., nerve growth factor). We review studies related to the organization of the afferent limb of the micturition reflex and discuss neuroplasticity in an animal model of urinary bladder inflammation to increase the understanding of functional bladder disorders and to identify potential novel targets for development of therapeutic interventions. Given the heterogeneity of BPS/IC and the lack of consistent treatment benefits, it is unlikely that a single treatment directed at a single target in micturition reflex pathways will have a mass benefit. Thus, the identification of multiple targets is a prudent approach, and use of cocktail treatments directed at multiple targets should be considered.


Interpenetrating polymer networks as a route to tunable multi-responsive biomaterials: development of novel concepts.
Novel concepts are proposed for interpenetrating polymer networks (IPNs) that can be used in biomaterials responsive to multiple types of environmental stimuli. The IPNs can be a route to the tunable biomaterials whose chemical structure and/or morphology can be adjusted to the type of task to be performed. The significance of utilizing new types of processes in polymer chemistry such as the Suzuki polycondensation and living/controlled radical polymerizations to the possibility of extending/modifying component networks in the IPNs and fine-tuning their properties is emphasized. Incorporation of nanofillers into IPNs and application of monomers other than traditional alkylacrylamides as a way to enhance versatility of IPNs are also considered.


Reinterpreting recapitulation: systematics of needlefishes and their allies (Teleostei: Beloniformes).
As needlefishes (Belonidae) grow, their jaws pass through a "halfbeak" stage that resembles the adult jaw condition of the closely related family of halfbeaks (Hemiramphidae). Based on this pattern, some authors have suggested that halfbeaks are "developmentally arrested" or paedomorphic needlefish derivatives, whereas others have supported the notion that needlefishes are descended from halfbeak-like ancestors and that needlefish ontogeny thereby recapitulates phylogeny. To test these ideas and to better understand evolutionary changes in jaw ontogeny, phylogenetic relationships among genera of needlefishes, sauries (Scomberesocidae), halfbeaks, and flyingfishes (Exocoetidae) were assessed using mitochondrial (cytochrome b and 16S), nuclear (Tmo-4C4), and morphological characters. The resultant tree provides several novel taxonomic findings: (1) flyingfishes appear to be nested within halfbeaks; (2) sauries appear to be nested within needlefishes; and (3) the Indo-West Pacific freshwater halfbeaks appear to be most closely related to the needlefish/saury clade. The structure of the tree falsifies the idea that halfbeaks are paedomorphic needlefishes. Instead, halfbeaks are basal relative to needlefishes, fitting the pattern predicted by the hypothesis of recapitulation. I discuss limitations to phylogenetic perspectives on recapitulation based on discrete character data by comparing aspects of von Baerian and Haeckelian views of the relation between ontogeny and phylogeny.


Graphic display of urinary risk factors for renal stone formation.
From the analysis of various urinary constituents and the estimation of urinary saturation of stone-forming salts, it is now possible to identify risk factors responsible for or contributing to stone formation. Metabolic factors included calcium, oxalate, uric acid, citrate and pH. Environmental factors were total volume, sodium, sulfate, phosphate and magnesium. Physicochemical factors represented saturation of calcium oxalate, brushite, monosodium urate, struvite and uric acid. A scheme for graphic display of risk factors was developed to allow ready visual recognition of important risk factors presumed to cause stone formation. This graphic display had diagnostic use as well as practical value in following response to treatment. For example, a low urinary pH and high urinary concentration of undissociated uric acid could be discerned readily in cases of uric acid lithiasis, as were high urinary pH and exaggerated urinary supersaturation of struvite in cases of infection lithiasis. In a patient with absorptive hypercalciuria and hypocitraturia treatment with thiazide and potassium citrate could be shown to abolish high risks (hypercalciuria, hypocitraturia and relative supersaturation of calcium oxalate) displayed before treatment.


Inhibition by adenosine of catecholamine-induced increase in rat atrial contractility.
Because adenosine has been shown to attenuate the catecholamine-induced increase in myocardial cAMP formation and glycogen phosphorylase activity (Circ. Res. 43: 785-792, 1978), the present study was undertaken to determine whether the nucleoside inhibits the catecholamine-elicited increase in cardiac contractile state. Isolated rat atria were bathed in oxygenated physiologic saline and stimulated to contract isometrically at 2/s. Isoproterenol (0.1 microM) increased peak contractile force (PCF) by 96% and the rate of force development (+dF/dt) by 107%. Adenosine (10 microM) alone had no effect on these contractile parameters. Isoproterenol in the presence of adenosine increased PCF and +dF/dt only 15 and 14%, respectively. Elevation of bathing medium Ca2+ or administration of dibutyryl cAMP (DBcAMP) increased PCF and +dF/dt, but these responses were not decreased by adenosine. Inosine, adenine, adenosine 5'-monophosphate, and guanosine inhibited the isoproterenol-induced responses 5-22%. The results indicate that adenosine markedly inhibits, whereas some related purines only mildly attenuate, the catecholamine-elicited, but not the Ca2+- or DBcAMP-elicited, increases in contractility. Thus, adenosine may antagonize catecholamine-elicited glycogenolysis and enhanced contractile state in the heart by exerting an effect at the level of, or proximal to, cAMP formation.


Goal planning in person-centred care supports older adults receiving case management to attain their health-related goals.
Care for older adults should preferably be provided in a person-centred way that includes goal planning. The aim of the present cohort study is to gain an insight into the results of goal planning, in a person-centred care setting for community-living older adults. Within Embrace, a person-centred and integrated care service, older adults set goals with the aim to improve health-related problems. For every goal, they rated severity scores ranging from 0 (no problem) to 10 (extremely severe): a baseline score, a target score and, within one year, an end score to evaluate these goals. The differences between baseline and end scores (goal progress) and target and end scores (goal attainment), and the percentage of goals attained were calculated and compared between health-related domains (i.e., mental health, physical health, mobility, and support). Among 233 older adults, 836 goal plans were formulated of which 74% (95% Confidence Interval: 71-77) were attained. Goals related to physical health were the most likely to be attained and goals for mobility and pain the least likely. Older adults are able to attain health-related goals through collaborative goal planning. We recommend future integrated care programmes for older adults to incorporate goal-planning methods to achieve person-centred care.IMPLICATIONS FOR REHABILITATIONOlder adults experiencing frailty or complex care needs and receiving individual support within an integrated care setting are able to formulate and attain goals using goal planning with severity scores.Goal plans of community-living older adults mostly aim at improving health-related problems concerning physical health, mobility, or support.Goals related to physical health are the most likely to be attained, while goals for mobility and pain are the least likely to be attained.


Fine tuning breath-hold-based cerebrovascular reactivity analysis models.
We elaborate on existing analysis methods for breath-hold (BH)-derived cerebrovascular reactivity (CVR) measurements and describe novel insights and models toward more exact CVR interpretation. Five blood-oxygen-level-dependent (BOLD) fMRI datasets of neurovascular patients with unilateral hemispheric hemodynamic impairment were used to test various BH CVR analysis methods. Temporal lag (phase), percent BOLD signal change (CVR), and explained variance (coherence) maps were calculated using three different sine models and two novel "Optimal Signal" model-free methods based on the unaffected hemisphere and the sagittal sinus fMRI signal time series, respectively. All models showed significant differences in CVR and coherence between the affected-hemodynamic impaired-and unaffected hemisphere. Voxel-wise phase determination significantly increases CVR (0.60 ± 0.18 vs. 0.82 ± 0.27; P < 0.05). Incorporating different durations of breath hold and resting period in one sine model (two-task) did increase coherence in the unaffected hemisphere, as well as eliminating negative phase commonly obtained by one-task frequency models. The novel model-free "optimal signal" methods both explained the BOLD MR data similar to the two task sine model. Our CVR analysis demonstrates an improved CVR and coherence after implementation of voxel-wise phase and frequency adjustment. The novel "optimal signal" methods provide a robust and feasible alternative to the sine models, as both are model-free and independent of compliance. Here, the sagittal sinus model may be advantageous, as it is independent of hemispheric CVR impairment.


Nitric oxide-mediated nitrosation of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline potentiated by hemin and myeloperoxidase.
N-Nitrosamines formed by nitrosation of heterocyclic amines might initiate colon cancer in individuals consuming well-done red meat diets and with inflammatory conditions in their colon. This study investigates nitric oxide (NO)-mediated nitrosation of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and the influence of dietary (hemin) and inflammatory [NO, myeloperoxidase (MPO), and H(2)O(2)] components on nitrosation. Using the NO donor spermine NONOate (1.2 microM NO/min) at pH 7.4 with 0.005 mM MeIQx, a product due to NO autoxidation was at the limit of detection (1% of total radioactivity recovered by HPLC). Product formation increased 13- or 16-fold in the presence of 10 microM hemin or 85 nM MPO, respectively, with an in situ system for generating H(2)O(2) (glucose oxidase/glucose). The nitrosation product and its chloro derivative were analyzed by electrospray ionization mass spectrometry, and the product was determined to be 2-nitrosoamino-3,8-dimethylimidazo[4,5-f]quinoxaline (N-NO-MeIQx). Nitrosation by NO autoxidation was only detected at > or =1.2 microM NO/min and was not affected by H(2)O(2). Investigations with hemin determined minimum effective components necessary for potentiation: 1 microM hemin, 1 microM H(2)O(2)/min, and 0.012 microM NO/min. The reactive nitrogen oxygen species (RNOS) produced by hemin and MPO had a 4- and 3-fold, respectively, greater affinity for MeIQx than those produced by NO autoxidation. Test agents were used to characterize nitrosation. Results with catalase, SOD, azide, and NADH are consistent with multiple RNOS, the lack of peroxynitrite involvement in nitrosation, and peroxidatic potentiation by oxidative nitrosylation rather than nitrosation. Using phorbol ester stimulated human neutrophils, the formation of N-NO-MeIQx and its modification by test agents was consistent with MPO and not peroxynitrite. Thus, nitrosation of MeIQx and its potentiation by hemin and MPO provide a mechanism by which well-done red meat consumption and inflammation can generate N-nitroso compounds and initiate colon cancer under inflammatory conditions, such as colitis.


Protocol for replacing coding intronic MiMIC and CRIMIC lines with T2A-split-GAL4 lines in Drosophila using genetic crosses.
Here, we present a protocol for generating gene-specific split-GAL4 drivers from coding intronic Minos-mediated integration cassette/CRISPR-mediated integration cassette (MiMIC/CRIMIC) lines in Drosophila. We describe steps for four rounds of in vivo genetic crosses, PCR genotyping, and fluorescence imaging to ensure correct orientation of split-GAL4 integration before establishing stable fly stocks. This protocol offers a cost-effective alternative to traditional microinjection techniques for converting coding intronic MiMIC/CRIMIC lines into gene-specific split-GAL4 lines that are adaptable for fly researchers working on different tissues. For complete details on the use and execution of this protocol, please refer to Chen et al.1.


Mechanisms of opening and closing of the bacterial replicative helicase.
Assembly of bacterial ring-shaped hexameric replicative helicases on single-stranded (ss) DNA requires specialized loading factors. However, mechanisms implemented by these factors during opening and closing of the helicase, which enable and restrict access to an internal chamber, are not known. Here, we investigate these mechanisms in the Escherichia coli DnaB helicase•bacteriophage λ helicase loader (λP) complex. We show that five copies of λP bind at DnaB subunit interfaces and reconfigure the helicase into an open spiral conformation that is intermediate to previously observed closed ring and closed spiral forms; reconfiguration also produces openings large enough to admit ssDNA into the inner chamber. The helicase is also observed in a restrained inactive configuration that poises it to close on activating signal, and transition to the translocation state. Our findings provide insights into helicase opening, delivery to the origin and ssDNA entry, and closing in preparation for translocation.


Variational calculation of transport coefficients in diffusive lattice gases.
A diffusive lattice gas is characterized by the diffusion coefficient depending only on the density. The Green-Kubo formula for diffusivity can be represented as a variational formula, but even when the equilibrium properties of a lattice gas are analytically known, the diffusion coefficient can be computed only in the exceptional situation when the lattice gas is gradient. In the general case, minimization over an infinite-dimensional space is required. We propose an approximation scheme based on minimizing over finite-dimensional subspaces of functions. The procedure is demonstrated for one-dimensional generalized exclusion processes in which each site can accommodate at most two particles. Our analytical predictions provide upper bounds for the diffusivity that are very close to simulation results throughout the entire density range. We also analyze nonequilibrium density profiles for finite chains coupled to reservoirs. The predictions for the profiles are in excellent agreement with simulations.


[Factors associated with benzodiazepines dependence in insomnia patients].
The use of benzodiazepines as a treatment for insomnia can have side effects such as impaired coordination causing falls in adults and even dependence. To assess the factors associated with dependence on benzodiazepines in patients with insomnia. Observational, cross-sectional, prospective, and analytical study, at the first level of care. Patients older than 18 years with a diagnosis of insomnia and a benzodiazepine prescription were selected. The dependency was measured with the International Neuropsychiatric Interview. 107 patients were included. Median age 67 years, predominantly female (72%), 74% attended secondary school or more, 71% had more than 3 years of diagnosis, 84% used clonazepam. The 54% presented dependency. In the bivariate analysis, schooling RM 0.392 (95%CI: 0.15-0.96) p = 0.038, moderate and severe clinical insomnia RM 3.618 (95%CI: 1.44-9.08) p = 0.005 and more than 3 years of diagnosis RM 2.428 (95%CI: 1.03-5.71) p = 0.040. In the multivariate model, schooling (p = 0.084), years of diagnosis (p = 0.062) and frequency of consumption (p = 0.065) obtained an R2 of 0.13. Primary schooling showed a lower risk of presenting dependence on benzodiazepines. The risk was increased in those with more than 3 years of diagnosis, and in those with moderate and severe insomnia.


Histamine release inhibitory activity of Piper nigrum leaf.
Oral administration of a methanolic extract of Piper nigrum leaf (PN-ext, 50, 200 and 500 mg/kg) showed a potent dose-dependent inhibition of dinitrofluorobenzene (DNFB)-induced cutaneous reaction at 1 h [immediate phase response (IPR)] after and 24 h [late phase response (LPR)] after DNFB challenge in mice which were passively sensitized with anti-dinitrophenyl (DNP) IgE antibody. Ear swelling inhibitory effect of PN-ext (50, 200 and 500 mg/kg, per os (p.o.)) on very late phase response (vLPR) in the model mice was significant but weaker than that on IPR. Oral administration of PN-ext (50, 200 and 500 mg/kg for 7 d) inhibited picryl chloride (PC)-induced ear swelling in PC sensitized mice. PN-ext exhibited in vitro inhibitory effect on compound 48/80-induced histamine release from rat peritoneal mast cells. Two lignans of PN-ext, (-)-cubebin (1) and (-)-3,4-dimethoxy-3,4-desmethylenedioxycubebin (2), were identified as major active principles having histamine release inhibitory activity.


Prevalence of developmental enamel defects of the first permanent molars among school children in Western Australia.
The prevalence of enamel defects in the first permanent molars among children has been reported to be high and may be on the increase, particularly in the European countries. Little information is available on the prevalence of enamel defects in the first permanent molars among children in Australia. The aim of this study was to describe the prevalence of enamel defects in the first permanent molars among school children in Western Australia. Informed consent was obtained from parents of children attending pre-primary schools within an administrative area of the School Dental Service of Western Australia in metropolitan Perth to participate in the study in 2005. Parents completed a questionnaire about the mother's health status during pregnancy, and their child's health status for the first three years. Participating children were examined during 2006 and 2007 by one examiner. Teeth were classified on the type and extent of enamel defects using the modified DDE index, and deciduous tooth caries experience of molars and canines was recorded using the WHO criteria. Parents of 634 children out of the eligible 1135 (56 per cent participation) completed the questionnaire. Five hundred and eleven children with at least one erupted first permanent molar were examined (mean age 7.1 years, SD 0.5). Of the first permanent molars, 42 per cent upper right; 37 per cent upper left; 47 per cent lower left; and 45 per cent lower right were without enamel defects. White diffuse opacities were the predominant enamel defects found with 46 per cent upper right; 47 per cent upper left; 40 per cent lower left and 41 per cent lower right molars affected. Demarcated opacities alone or in association with other defects affected 11 per cent upper right; 14 per cent upper left; 10 per cent lower left and 9 per cent lower right molars. At the individual level, 71 per cent had permanent molars with enamel defects; 47 per cent with white diffuse opacities and 22 per cent with demarcated opacities. Prevalence of enamel defects among this school population is high. Majority of defects were white diffuse opacities and the prevalence of demarcated opacities is at the high end of that reported for some European countries. Possible risk factors for enamel defects remains to be tested.


Rapid decline in 51Cr-ethylenediaminetetraacetic acid-measured renal function during the first weeks following liver transplantation.
Renal dysfunction is a serious late complication after liver transplantation (LTX), but there are no studies addressing the early changes associated with this complication. We prospectively studied glomerular filtration rate (GFR) before and at 1, 3 and 12 weeks after LTX using 51Cr-labelled ethylenediaminetetraacetic acid clearance in 37 adult consecutive patients who underwent non-acute first LTX. The mean (±SD) age was 49.5 ± 9.5 years, and the male:female sex ratio was 21:16. Diagnoses were autoimmune liver diseases (17), alcoholic cirrhosis (10) and other diseases (10). Immunosuppressive treatment consisted predominantly of triple-drug therapy. A total of 27 of the 37 patients were eligible for GFR analysis at all times. The mean (±SD) GFR was 86 ± 26 mL/min/1.73 m2 before LTX, and 77 ± 30 mL/min/1.73 m2 at 1 week, 64 ± 27 mL/min/1.73 m2 at 3 weeks and 64 ± 23 mL/min/1.73 m2 at 12 weeks after LTX, comparable to a reduction in mean GFR compared with baseline values of 10% (P = 0.1907), 25% (P = 0.0010) and 26% (P = 0.0007). Age and number of blood transfusions during surgery were identified as risk factors for this decline as well as gender, but not pre-transplant diagnosis, model of end-stage liver disease score, cold ischaemia time or post-transplant area under the curve tacrolimus during Days 0-14. Using measured rather than estimated GFR, our results show that severe renal impairment occurs during the first week after LTX. These results emphasize the need for more studies addressing renoprotective treatment strategies.


Central auditory processing in urban black children, normal and learning disabled.
Normative data from Windham et al (1985) for urban Black children aged 7-10 yrs on the SSW test and the Willeford central auditory processing battery were used to compare those norms with scores of 40 children of similar age and from the same population who were referred from the Howard University Child Development Center as being at risk for learning disability (LD). The L-competing, L-non-competing, and Total Error Score indexes from the SSW test, and the L-ear score from Willeford's Competing Sentences subtest, differentiated the LD Ss as a group from normals (p less than .05). Other tests were of questionable or no value in this regard for this population. It is suggested that it would be wise to view the results of these tests with caution and preferably in connection with other audiological testing when applied to LD Ss, especially if normative data for the particular subpopulation have not been collected.


αVβ3 integrin-targeted microSPECT/CT imaging of inflamed atherosclerotic plaques in mice.
αVβ3-integrin is expressed by activated endothelial cells and macrophages in atherosclerotic plaques and may represent a valuable marker of high-risk plaques. We evaluated (99m)Tc-maraciclatide, an integrin-specific tracer, for imaging vascular inflammation in atherosclerotic lesions in mice. Apolipoprotein E-negative (ApoE(-/-)) mice on a Western diet (n = 10) and normally fed adult C57BL/6 control mice (n = 4) were injected with (99m)Tc-maraciclatide (51.8 ± 3.7 MBq). A blocking peptide was infused in three ApoE(-/-) mice; this condition served as another control. After 90 min, the animals were imaged via single-photon emission computed tomography (SPECT). While maintained in the same position, the mice were transferred to computed tomography (CT) to obtain contrast-enhanced images of the aortic arch. Images from both modalities were fused, and signal was quantified in the aortic arch and in the vena cava for subtraction of blood-pool activity. The aorta was carefully dissected after imaging for gamma counting, autoradiography, and histology. Tracer uptake was significantly higher in ApoE(-/-) mice than in both groups of control mice (1.56 ± 0.33 vs. 0.82 ± 0.24 vs. 0.98 ± 0.11, respectively; P = 0.006). Furthermore, higher tracer activity was detected via gamma counting in the aorta of hypercholesterolemic mice than in both groups of control mice (1.52 ± 0.43 vs. 0.78 ± 0.19 vs. 0.47 ± 0.31 (99m)Tc-maraciclatide %ID/g, respectively; P = 0.018). Autoradiography showed significantly higher tracer uptake in the atherosclerotic aorta than in the control aorta (P = 0.026). Finally, in the atherosclerotic aorta, immunostaining indicated that the integrin signal came predominantly from macrophages and was correlated with the macrophage CD68 immunomarker (r = 0.73). (99m)Tc-maraciclatide allows in vivo detection of inflamed atherosclerotic plaques in mice and may represent a non-invasive approach for identifying high-risk plaques in patients.


Parity and time interval since childbirth influence survival in endometrial cancer patients.
Parity and time interval since last birth have been found to be associated with the risk of endometrial cancer, but few previous studies have examined whether these reproductive factors have prognostic impact. We examined this issue among 740 nulliparous and 3355 parous endometrial cancer patients diagnosed in Norway during the period 1961-1999. The mean age at diagnosis was 55.7 years (range, 25-74 years). Hazard ratios (HRs) with 95% confidence intervals were calculated in Cox proportional regression models. Parous women had significantly (P < 0.001) better prognosis than nulliparous women. In analyses adjusted for age at diagnosis, clinical stage, and histological type, the HR for parous versus nulliparous women was 0.68 (95% confidence interval, 0.57-0.82). The prognostic impact of parity was restricted to patients with endometrioid tumors (P = 0.014, test for interaction) and appeared to be most pronounced in women without metastases (P = 0.14, test for interaction). Moreover, the improved prognosis was strongest for women with the shortest time interval since last childbirth. The HRs (nulliparous women as reference) were 0.51, 0.60, and 0.80 for women less than 15, 15 to 24, and 25 years or more since birth (P < 0.001). The observed beneficial effect of pregnancies may be related to a strong exposure to progesterone during pregnancy. However, it is possible that tumors developing in nulliparous and parous women have different biological features. Further knowledge on this issue may provide valuable information that can be used for individualized treatment.


Optogenetic Inhibition of Glutamatergic Neurons in the Dysgranular Posterior Insular Cortex Modulates Trigeminal Neuropathic Pain in CCI-ION Rat.
In individuals with chronic neuropathic pain, the posterior insular cortex (PIC) has been found to exhibit increased glutamatergic activity, and the dysgranular portion of PIC (DPIC) has been investigated as a novel cortical target for pain modulation. However, the role of DPIC glutamatergic neurons (DPICg) in trigeminal neuropathic pain (TNP) remains unclear. Here, we examined the outcomes of DPICg inhibition in a rat model of chronic constriction injury of the infraorbital nerve (CCI-ION). Animals were randomly divided into TNP, sham, and control groups. TNP animals underwent CCI-ION surgery. Either optogenetic or null viruses were delivered to the contralateral DPICg of TNP and sham animals. In vivo single-unit extracellular recordings from the ipsilateral spinal trigeminal nucleus caudalis (TNC) and contralateral ventral posteromedial (VPM) thalamus were obtained under both "ON" and "OFF" stimulation states. Behavioral responses during the stimulation-OFF and stimulation-ON phases were examined. Expression of c-Fos, pERK, and CREB immunopositive neurons were also observed. Optogenetic inhibition of contralateral DPICg decreased the neural firing rate in both TNC and VPM thalamus, the expression of sensory-responsive cell bodies, and transcriptional factors in the DPIC of TNP group. Improvements in hyperalgesia, allodynia, and anxiety-like responses in TNP animals were also observed during stimulation-ON condition. In fine, descending pain processing is influenced by neuroanatomical projections from the DPIC to the pain matrix areas, and DPICg could play a necessary role in this neural circuitry. Therefore, the antinociceptive effect of DPICg inhibition in this study may provide evidence for the therapeutic potential of DPICg in TNP.