Effects of public health emergencies of international concern on disease control: a systematic review.
To assess the accumulated knowledge of the effects of public health emergencies of international concern on disease control and local health systems, and contribute to a better understanding of their effects on health programs and systems. This was a systematic review of published and gray literature (in English, Portuguese, or Spanish). Electronic databases (BVS/LILACS, PubMed, and SciELO) and Google Scholar were searched. Search terms were: COVID-19 OR H1N1 OR Ebola OR Zika OR poliomyelitis AND (outbreaks OR epidemics) AND (public health systems OR public health surveillance). A total of 3 508 studies were retrieved, of which 31 met the inclusion criteria. The studies addressed the effects of the emergencies on: communicable diseases notification systems; malaria, HIV/AIDS, tuberculosis, poliomyelitis, and malaria surveillance, control, and treatment; microcephaly; dengue; and vaccinations. The populations affected by the emergencies experienced reduced health services, which included fewer health visits, failures in the diagnostic chain, decrease in vaccination, and increased incidence or underreporting of notifiable diseases. Socioeconomic inequity is a determinant of the effects of public health emergencies of international concern within affected populations. The diversion of resources and attention from health authorities disproportionately affects vulnerable populations and can lead, over time, to a weakening of health systems. The analysis of the effects of public health emergencies is important for the development of new protocols that can better respond to future crises.


Contraction kinetics of intact and skinned frog muscle fibers and degree of activation. Effects of intracellular Ca2+ on unloaded shortening.
This study addresses a long-standing controversy on the effects of the degree of activation on cross-bridge kinetics in vivo, by utilizing isolated intact and skinned fiber preparations. Steady force levels ranging from 0.1 to 0.76 P0 were achieved at 0 degrees C with temperature-step stimulation of intact fibers by varying the amount of caffeine in the bathing medium. The speed of unloaded shortening (by slack test) was found to be practically constant, which suggests that intracellular Ca2+ in the intact preparation has relatively little effect on isotonic shortening. Along with the results on tetanically stimulated fibers (force, P0), we observed a minor but significant trend for the speed to decline with lowered force levels. This trend is explained by the presence of a constant internal load equaling approximately 1% P0. The effect of Ca2+ on the shortening behavior of skinned fibers was examined at 0 and 10 degrees C. At 0 degrees C, there was practically no effect of Ca2+ on the shortening response in slack tests. At 10 degrees C, there was also no Ca2+ effect during the first activation cycle, but in subsequent cycles the speed of shortening was reduced during partial activation, which indicates that there were permanent changes in the fiber properties under these experimental conditions. The latter result could be explained if the internal load had increased to approximately 5% P0 in the modified skinned fiber (compared with 1% P0 in intact fiber). These findings show that isotonic contraction of frog fibers is intrinsically unaffected by the variations in intracellular Ca2+ that modulated the force over a nearly complete range. The results provide support for the idea that Ca2+ influences the force development in vivo by on-off switching mechanisms.


[Some properties of a mutant of Streptomyces globisporus 1912 supersensitive to ultraviolet radiation].
A well-sporulating mutant Spo 1 has been isolated after the action of defective phage from the zone of total lysis of Streptomyces globisporus 1912. It has been shown, that mutant Spo 1 is supersensitive to the action of ultraviolet radiation and has the increased sensitivity to the action of methyl-methane-sulfonate, has mutation in the cluster of genes of synthesis of landomycin E and is not sensitive to the action of nitrous acid and hydrogen peroxide. Spo 1 also has a high level of UV-mutability. After the action of UV on spores 4620 colonies were analysed and 17 auxotrophic mutants (0.36%) were selected. Four auxotrophs restored their ability to produce landomycin E and a partial block of synthesis of the antibiotic was observed in six auxotrophs. Seven of white (lnd E) auxotrophs were analysed with the help of a system "secretor-conventer" and it has been shown that two mutants do not synthesize daidzeine flavonoide and have genotype lnd E dai aux uvs, five of them were capable to synthesize this flavonoide and have genotype lnd dai(+) aux uvs. Initial species of S. globisporus 1912 has increased sensitivity to lethal action of UV. It is supposed that mutant Spo 1 bears two uvs-mutations.


Treatment of schizophrenia in childhood and adolescence.
This paper reviews the management of schizophrenia occurring during childhood and adolescence. It considers the clinical features of the disorder particular to its early onset before providing a practical framework for assessment and treatment based upon a critical review of the available literature. A multi-modal approach to treatment encompassing the individual and their family is adopted with the roles of pharmacological, psychological, and environmental interventions all considered. The place of the newer "atypical" antipsychotic agents and the likelihood that they will soon become the first-line drugs of choice is particularly discussed.


Climate change is associated with male:female ratios of fetal deaths and newborn infants in Japan.
To evaluate whether climate change is associated with male:female ratios (sex ratios) of fetal deaths and births in Japan. A population-based cohort study. Not applicable. Newborn infants and fetuses spontaneously aborted after 12 weeks of gestation. None. Yearly sex ratios of fetal deaths and newborn infants and monthly fetal death rates and sex ratios of newborn infants. A statistically significant positive association was found between yearly temperature differences and sex ratios of fetal deaths; a statistically significant negative association was found between temperature differences and sex ratios of newborn infants from 1968 to 2012, and between sex ratios of births and of fetal deaths. The sex ratios of fetal deaths have been increasing steadily along with temperature differences, whereas the sex ratios of newborn infants have been decreasing since the 1970s. Two climate extremes, a very hot summer in 2010 and a very cold winter in January 2011, showed not only statistically significant declines in sex ratios of newborn infants 9 months later in June 2011 and October 2011 but also statistically significant increases of fetal death rates immediately, in September 2010 and January 2011. The recent temperature fluctuations in Japan seem to be linked to a lower male:female sex ratio of newborn infants, partly via increased male fetal deaths. Male concepti seem to be especially vulnerable to external stress factors, including climate changes.


Further antigenic characterization of porcine rotavirus YM.
We recently reported that the serotype specificity of YM, a group A porcine rotavirus, is different from those of the previously established rotavirus serotypes, 1 to 6 (A. M. Ruiz, I. V. Lopez, S. Lopez, R. T. Espejo, and C. F. Arias, J. Virol. 62:4331-4336, 1988). Here we demonstrate by cross-neutralization studies that rotavirus YM is also antigenically distinct from prototype rotavirus strains of serotypes 7 (Ty1), 8 (69M), 9 (WI61), and 10 (B223). A comparison of the serotype-determining amino acid regions of the YM surface glycoprotein, VP7, with the reported homologous sequences of rotavirus strains Gottfried, 69M, B37, F45, and WI61 further supported the serotypic individuality of the rotavirus YM VP7 protein.


Clinical Phenotype of Endothelial Dysfunction in Romanian Scleroderma Patients.
To identify the particularities of the clinical phenotype of endothelial dysfunction in a lot of Romanian patients from a reference center and compare it to data reported by international registries. 51 patients were included in a cross-sectional study. The patients were evaluated for the pattern of disease, main visceral involvement, serum markers of disease. 41.2% patients had history of digital ulcers, 27.45% had pulmonary arterial hypertension; cardiovascular involvement also included: diastolic dysfunction in 31.1% of the patients, global systolic dysfunction in 9.8%, rhythm and conduction disturbances in 19.6%, peripheral vascular disease in 19.6%. Scleroderma renal crisis was identified in 2 patients. Vascular complications are a major cause of morbidity and mortality in systemic sclerosis. Earlier therapeutic intervention demands improved screening and diagnosis in all cases.


Urologic disorders after forty.
New trends have emerged in the management of urologic disorders that commonly present after 40. Surgical treatment of stone disease has largely been replaced by reliable nonoperative methods. Advances have been made in the design of penile prostheses. New concepts of the natural history of urinary tract infection and incontinence have made diagnosis and treatment more effective and less costly. Lack of progress in treating disseminated urologic cancer has reinforced the urgency of prompt diagnosis and treatment.


Structure and functional analysis of wheat ICE (inducer of CBF expression) genes.
Two different inducers of CBF expression (ICE1-like genes), TaICE41 and TaICE87, were isolated from a cDNA library prepared from cold-treated wheat aerial tissues. TaICE41 encodes a protein of 381 aa with a predicted MW of 39.5 kDa while TaICE87 encodes a protein of 443 aa with a predicted MW of 46.5 kDa. TaICE41 and TaICE87 share 46% identity while they share 50 and 47% identity with Arabidopsis AtICE1 respectively. Expression analysis revealed that mRNA accumulation was not altered by cold treatment suggesting that both genes are expressed constitutively. Gel mobility shift analysis showed that TaICE41 and TaICE87 bind to different MYC elements in the wheat TaCBFIVd-B9 promoter. Transient expression assays in Nicotiana benthamiana, showed that both TaICE proteins can activate TaCBFIVd-B9 transcription. The different affinities of TaICE41 and TaICE87 for MYC variants suggest that ICE binding specificity may be involved in the differential expression of wheat CBF genes. Furthermore, analysis of MYC elements demonstrates that a specific variant is present in the wheat CBF group IV that is associated with freezing tolerance. Overexpression of either TaICE41 or TaICE87 genes in Arabidopsis enhanced freezing tolerance only upon cold acclimation suggesting that other factors induced by low temperature are required for their activity. The increased freezing tolerance in transgenic Arabidopsis is associated with a higher expression of the cold responsive activators AtCBF2, AtCBF3, and of several cold-regulated genes.


Active suppression of host-vs-graft reaction in pregnant mice. VI. Soluble suppressor activity obtained from decidua of allopregnant mice blocks the response to IL 2.
The mammalian fetus expresses a variety of antigens against which the maternal immune system can react and which in an allogeneic mating bears paternal transplantation antigens. Although these antigens may be expressed on the fetal trophoblast cells that contact maternal uterine decidua, the "fetal allograft" is not usually rejected. Previous studies have demonstrated the presence of nonspecific non-thymus-derived suppressor cells in the lymph nodes draining the uterus and in decidua of laboratory mice undergoing first allogeneic pregnancy. These suppressor cells appeared to be small lymphocyte cells that inhibit the generation of cytotoxic T lymphocytes (CTL) in vitro and in vivo and elaborate a nonspecific non-MHC-restricted soluble suppressor activity when cultured for 48 hours at 37 degrees C in vitro. We now report that soluble suppressor activity obtained from the decidua (DS) of allopregnant C3H/HeJ mice inhibits both the primary and secondary (memory) CTL response in vitro but does not inhibit lysis of target cells by preformed CTL. DS did not suppress the proliferation of YAC lymphoma cells, P-815 cells, or a C3H placental trophoblastoma line. Suppressor activity was obtained from anti-thy-1.2 + complement-resistant cells in the decidua, could also be obtained from the decidua of allopregnant CD1 nu/nu mice, and was associated with a single peak of activity of approximately 100,000 daltons on Sephacryl 200 chromatography. Suppression could not be overcome by adding either crude or HPLC-purified IL 2 to the mixed lymphocyte cultures in vitro, and both crude and column-purified suppressor factor inhibited the IL 2-dependent proliferation of H-Y cells (a cloned T cell line with NK activity). Furthermore, DS inhibited the IL 2-dependent generation of cytotoxic effector cells in vitro in the absence of allogeneic stimulator cells. Thus, a soluble suppressor factor obtained from non-T cells present in the decidua of successfully allopregnant mice could block the response to IL 2 and inhibit the generation of both specific and nonspecific cytotoxic effector cells. The significance of this inhibition with respect to survival of the "fetal allograft" is discussed.


Modification of the convexity prior but not the light-from-above prior in visual search with shaded objects.
Studies of visual search performance with shaded stimuli, in which the target is rotated by 180 degrees relative to the distracters, typically demonstrate more efficient performance in stimuli with vertical compared to horizontal shading gradients. In addition, performance is usually better for vertically shaded stimuli with top-light (seen as convex) distracters compared to those with bottom-light (seen as concave) distracters. These findings have been cited as evidence for the use of the prior assumptions of overhead lighting and convexity in the interpretation of shaded stimuli and suggest that these priors affect preattentive processing. Here we attempt to modify these priors by providing observers with visual-haptic training in an environment inconsistent with their priors. Observers' performance was measured in a visual search task and a shape judgment task before and after training. Following training, we found a reduced asymmetry between visual search performance with convex and concave distracters, suggesting a modification of the convexity prior. However, although evidence of a change in the light-from-above prior was found in the shape judgment task, no change was found in the visual search task. We conclude that experience can modify the convexity prior at a preattentive stage in processing; however, our training did not modify the light-from-above prior that is measured via visual search.


Effectiveness of a website and mobile phone based physical activity and nutrition intervention for middle-aged males: trial protocol and baseline findings of the ManUp Study.
Compared to females, males experience higher rates of chronic disease and mortality, yet few health promotion initiatives are specifically aimed at men. Therefore, the aim of the ManUp Study is to examine the effectiveness of an IT-based intervention to increase the physical activity and nutrition behaviour and literacy in middle-aged males (aged 35-54 years). The study design was a two-arm randomised controlled trial, having an IT-based (applying website and mobile phones) and a print-based intervention arm, to deliver intervention materials and to promote self-monitoring of physical activity and nutrition behaviours. Participants (n = 317) were randomised on a 2:1 ratio in favour of the IT-based intervention arm. Both intervention arms completed assessments at baseline, 3, and 9 months. All participants completed self-report assessments of physical activity, sitting time, nutrition behaviours, physical activity and nutrition literacy, perceived health status and socio-demographic characteristics. A randomly selected sub-sample in the IT-based (n = 61) and print-based (n = 30) intervention arms completed objective measures of height, weight, waist circumference, and physical activity as measured by accelerometer (Actigraph GT3X). The average age of participants in the IT-based and print-based intervention arm was 44.2 and 43.8 years respectively. The majority of participants were employed in professional occupations (IT-based 57.6%, Print-based 54.2%) and were overweight or obese (IT-based 90.8%, Print-based 87.3%). At baseline a lower proportion of participants in the IT-based (70.2%) group agreed that 30 minutes of physical activity each day is enough to improve health compared to the print-based (82.3%) group (p = .026). The IT-based group consumed a significantly lower number of serves of red meat in the previous week, compared to the print-based group (p = .017). No other significant between-group differences were observed at baseline. The ManUp Study will examine the effectiveness of an IT-based approach to improve physical activity and nutrition behaviour and literacy. Study outcomes will provide much needed information on the efficacy of this approach in middle aged males, which is important due to the large proportions of males at risk, and the potential reach of IT-based interventions. ACTRN12611000081910.


Materials for the onset. A story of necessity and chance.
We review the reactions that take place in the HCN/NH2COH/catalysts system. In a vision of origin-of-life as emergence of new properties in complexity, the effectiveness of HCN/NH2COH chemistry is so robust and variegate to look unreasonable. In a logic close to Occamian simplicity, this chemistry embodies necessity. The evolution of the necessary fruits of this chemistry towards organismic level entails Darwinism. The role of chance enters into the process as an answer to evolving environments.


Diplopod hemocyanin sequence and the phylogenetic position of the Myriapoda.
Hemocyanins are copper-containing respiratory proteins of the Arthropoda that have so far been thoroughly investigated only in the Chelicerata and the Crustacea but have remained unstudied until now in the Myriapoda. Here we report the first sequence of a myriapod hemocyanin. The hemocyanin of Spirostreptus sp. (Diplopoda: Spirostreptidae) is composed of two distinct subunits that are arranged in a 6 x 6 native molecule. The cloned hemocyanin subunit cDNA codes of for a polypeptide of 653 amino acids (75.5 kDa) that includes a signal peptide of 18 amino acids. The sequence closely resembles that of the chelicerate hemocyanins. Molecular phylogenetic analyses reject with high statistical confidence the integrity of the Tracheata (i.e., Myriapoda + Insecta) but give conflicting results on the position of the myriapod hemocyanin. While distance matrix and maximum-likelihood methods support a basal position of the Spirostreptus hemocyanin with respect to the other hemocyanins, parsimony analysis suggests a sister group relationship with the chelicerate hemocyanins. The latter topology is also supported by a unique shared deletion of an alpha-helix. A common ancestry of Myriapoda and Chelicerata should be seriously considered.


Dynamical epidemic suppression using stochastic prediction and control.
We consider the effects of noise on a model of epidemic outbreaks, where the outbreaks appear randomly. Using a constructive transition approach that predicts large outbreaks prior to their occurrence, we derive an adaptive control scheme that prevents large outbreaks from occurring. The theory is applicable to a wide range of stochastic processes with underlying deterministic structure.


CLDN15 is a novel diagnostic marker for malignant pleural mesothelioma.
Malignant mesothelioma is a cancer with a poor survival rate. It is difficult to diagnose mesotheliomas because they show a variety of histological patterns similar to those of various other cancers. However, since currently used positive markers for mesotheliomas may show false positives or false negatives, a novel mesothelial positive marker is required. In the present study, we screened 25 claudins and found that claudin-15 is expressed in the mesothelial cells. We made new rat anti-human claudin-15 (CLDN15) monoclonal antibodies that selectively recognize CLDN15, and investigated whether CLDN15 is a good positive marker for malignant pleural mesotheliomas (MPMs) using MPM tissue samples by immunohistochemistry and semi-quantification of the expression level using an immunoreactive score (IRS) method. Of 42 MPM samples, 83% were positive for CLDN15. The positive ratio was equal to or greater than other positive markers for MPMs including calretinin (81%), WT-1 (50%), and D2-40 (81%). In 50 lung adenocarcinoma sections, four cases were positive for CLDN15 and the specificity (92%) was comparable with other markers (90-100%). Notably, CLDN15 was rarely detected in 24 non-mesothelial tumors in the tissue microarray (12/327 cases). In conclusion, CLDN15 can be used in the clinical setting as a positive marker for MPM diagnosis.


Intraspecific genetic diversity of Oenococcus oeni as derived from DNA fingerprinting and sequence analyses.
The intraspecific genetic diversity of Oenococcus oeni, the key organism in the malolactic fermentation of wine, has been evaluated by random amplified polymorphic DNA (RAPD), ribotyping, small-plasmid content, and sequencing of RAPD markers with widespread distribution among the strains. Collection strains representing the diversity of this species have been studied together with some new isolates, many of which were obtained from wines produced by spontaneous malolactic fermentation. The RAPD profiles were strain specific and discerned two main groups of strains coincident with clusters obtained by macrorestriction typing in a previous work. Ribotyping and the conservation of RAPD markers indicates that O. oeni is a relatively homogeneous species. Furthermore, identical DNA sequences of some RAPD markers among strains representative of the most divergent RAPD clusters indicates that O. oeni is indeed a phylogenetically tight group, probably corresponding to a single clone, or clonal line of descent, specialized to grow in the wine environment and universally spread.


Neuropsychological effect of temporal lobe resection in preadolescent children with epilepsy.
Numerous studies have demonstrated changes in cognitive, memory, and language functioning in adults and adolescents after temporal lobectomy, yet little information is available regarding neuropsychological outcome in preadolescent children. We studied pre- and postoperative neuropsychological test results from 14 children who underwent temporal lobe resection for intractable epilepsy at age 7-12 years (mean 9.4 years). Thirteen patients (93%) had no seizures or less than one seizure a year at follow-up 23-48 months (mean 34 months) after operation. Postoperative neuropsychological testing was performed 6-9 months (mean 7 months) after surgery in 13 patients and 36 months after the first operation in 1 patient who underwent two-stage resection of a tumor. Verbal, Performance, and Full Scale IQ were initially in the low-average range, with no significant change across the pre- and postoperative evaluations. Immediate verbal memory performance decreased significantly in children who initially performed above the median preoperatively and tended to decrease in children who had left rather than right temporal lobe resection. Significant postoperative decreases in delayed memory scores were independent of preoperative ability or side of resection. Our small study suggests vulnerability to postoperative decline in immediate verbal memory scores in preadolescent children who have higher baseline immediate memory function or undergo left rather than right temporal lobe resection, similar to that observed in adolescents in adults. The entire group exhibited a statistically significant decrease in delayed verbal memory. Study of larger series of patients will be important to clarify further the short- and long-term risks and benefits of temporal lobe resection in childhood.


Dietary Sialyllactose Influences Sialic Acid Concentrations in the Prefrontal Cortex and Magnetic Resonance Imaging Measures in Corpus Callosum of Young Pigs.
Sialic acid (SA) is a key component of gangliosides and neural cell adhesion molecules important during neurodevelopment. Human milk contains SA in the form of sialyllactose (SL) an abundant oligosaccharide. To better understand the potential role of dietary SL on neurodevelopment, the effects of varying doses of dietary SL on brain SA content and neuroimaging markers of development were assessed in a newborn piglet model. Thirty-eight male pigs were provided one of four experimental diets from 2 to 32 days of age. Diets were formulated to contain: 0 mg SL/L (CON), 130 mg SL/L (LOW), 380 mg SL/L (MOD) or 760 mg SL/L (HIGH). At 32 or 33 days of age, all pigs were subjected to magnetic resonance imaging (MRI) to assess brain development. After MRI, pig serum and brains were collected and total, free and bound SA was analyzed. Results from this study indicate dietary SL influenced (p = 0.05) bound SA in the prefrontal cortex and the ratio of free SA to bound SA in the hippocampus (p = 0.04). Diffusion tensor imaging indicated treatment effects in mean (p < 0.01), axial (p < 0.01) and radial (p = 0.01) diffusivity in the corpus callosum. Tract-based spatial statistics (TBSS) indicated differences (p < 0.05) in white matter tracts and voxel-based morphometry (VBM) indicated differences (p < 0.05) in grey matter between LOW and MOD pigs. CONT and HIGH pigs were not included in the TBSS and VBM assessments. These findings suggest the corpus callosum, prefrontal cortex and hippocampus may be differentially sensitive to dietary SL supplementation.


Root zone-specific localization of AMTs determines ammonium transport pathways and nitrogen allocation to shoots.
In plants, nutrient provision of shoots depends on the uptake and transport of nutrients across the root tissue to the vascular system. Nutrient delivery to the vasculature is mediated via the apoplastic transport pathway (ATP), which uses the free space in the cell walls and is controlled by apoplastic barriers and nutrient transporters at the endodermis, or via the symplastic transport pathway (STP). However, the relative importance of these transport routes remains elusive. Here, we show that the STP, mediated by the epidermal ammonium transporter 1;3 (AMT1;3), dominates the radial movement of ammonium across the root tissue when external ammonium is low, whereas apoplastic transport controlled by AMT1;2 at the endodermis prevails at high external ammonium. Then, AMT1;2 favors nitrogen (N) allocation to the shoot, revealing a major importance of the ATP for nutrient partitioning to shoots. When an endodermal bypass was introduced by abolishing Casparian strip (CS) formation, apoplastic ammonium transport decreased. By contrast, symplastic transport was increased, indicating synergism between the STP and the endodermal bypass. We further establish that the formation of apoplastic barriers alters the cell type-specific localization of AMTs and determines STP and ATP contributions. These results show how radial transport pathways vary along the longitudinal gradient of the root axis and contribute to nutrient partitioning between roots and shoots.


Nitric oxide expression in the spleen, but not in the liver, correlates with resistance to blood-stage malaria in mice.
The production and function of nitric oxide during the early phase of blood-stage infection with Plasmodium chabaudi AS was analyzed using two inbred strains of mice that differ in the level of resistance to this parasite. Northern blot analysis of in vivo expression of inducible nitric oxide synthase (iNOS) revealed that early during infection resistant C57BL/6 mice, which clear the infection by 4 wk, have higher levels of iNOS mRNA in the spleen than susceptible A/J mice. In contrast, susceptible A/J mice have significantly increased levels of iNOS mRNA in the liver later in the course of infection just before death occurs. Splenic macrophages recovered from resistant C57BL/6 mice on day 7 postinfection express iNOS mRNA which is up-regulated following overnight stimulation of the cells with LPS. Furthermore, during the first week postinfection, splenic macrophages recovered from resistant hosts produce significantly higher levels of nitrite (NO2-) in vitro in response to LPS than similarly stimulated macrophages from susceptible A/J mice. Increased levels of nitrate (NO3-) were only detected in serum of resistant C57BL/6 mice at the time of peak parasitemia. Treatment with the iNOS inhibitor, aminoguanidine, reduced NO3- levels in serum of C57BL/6 mice and eliminated resistance of these hosts to P. chabaudi AS malaria without affecting parasitemia. These results demonstrate that the ability to produce high amounts of nitric oxide (NO) early during infection with blood-stage P. chabaudi AS correlates with resistance, but that NO may not be involved in parasite killing. Moreover, the tissue site of NO production, that is, spleen vs liver, appears to be critical and correlates with resistance vs susceptibility to P. chabaudi AS malaria, respectively.


Paediatric obsessive-compulsive disorder, a neurodevelopmental disorder? Evidence from neuroimaging.
To present an overview of neuroimaging data on paediatric obsessive-compulsive disorder (OCD) and discuss implications for further research. Medline PsycINFO databases and reference lists were searched for relevant articles. All neuroimaging studies up to October 1, 2008 involving children and adolescents with obsessive-compulsive disorder were included. Twenty-eight neuroimaging studies using various neuroimaging techniques (CT (2) MRI (15) MRS (8) and SPECT (2) fMRI (2) but no PET or DTI) including a total of 462 paediatric patients were identified. A number of findings indicate a dysfunction of the prefrontal-striatal-thalamic circuit with the involvement of other basal ganglia structures (putamen globus pallidus) and the thalamus in contrast to adult studies which report mainly involvement of the caudate nucleus and orbitofrontal cortex. Several findings point at an aberrant development of the brain in paediatric OCD, patients when compared with healthy controls. Neuroimaging studies have contributed to our understanding of the neurobiological basis of paediatric OCD. This review provides an agenda for further theory driven research in particular aimed at identifying a critical window of abnormal maturation of prefrontal-striatal-thalamic and limbic circuitry in paediatric OCD patients.


Detecting local diversity-dependence in diversification.
Whether there are ecological limits to species diversification is a hotly debated topic. Molecular phylogenies show slowdowns in lineage accumulation, suggesting that speciation rates decline with increasing diversity. A maximum-likelihood (ML) method to detect diversity-dependent (DD) diversification from phylogenetic branching times exists, but it assumes that diversity-dependence is a global phenomenon and therefore ignores that the underlying species interactions are mostly local, and not all species in the phylogeny co-occur locally. Here, we explore whether this ML method based on the nonspatial diversity-dependence model can detect local diversity-dependence, by applying it to phylogenies, simulated with a spatial stochastic model of local DD speciation, extinction, and dispersal between two local communities. We find that type I errors (falsely detecting diversity-dependence) are low, and the power to detect diversity-dependence is high when dispersal rates are not too low. Interestingly, when dispersal is high the power to detect diversity-dependence is even higher than in the nonspatial model. Moreover, estimates of intrinsic speciation rate, extinction rate, and ecological limit strongly depend on dispersal rate. We conclude that the nonspatial DD approach can be used to detect diversity-dependence in clades of species that live in not too disconnected areas, but parameter estimates must be interpreted cautiously.


Hemodynamic effects of primary closure of omphalocele/gastroschisis in human newborns.
To determine whether they could establish reliable, objective criteria that would predict safe, primary closure of abdominal wall defects (omphalocele/gastroschisis) in newborn infants, the authors measured intraoperative changes in intra-gastric pressure (IGP), central venous pressure (CVP), cardiac index (CI), systolic arterial blood pressure (BP), and heart rate (HR). Eleven neonates, who averaged 2.7 kg (range 1.5-4.1 kg) and 36 weeks gestation (range 30-41 weeks) were anesthetized with fentanyl (7.5-12.5 micrograms/kg), metocurine (0.3 mg/kg), and oxygen. Three infants had defects that were too large to close primarily. Of the eight infants who underwent primary closure, four required re-operation within 24 h because of oliguria or poor peripheral perfusion. Infants who required re-operation had intra-gastric pressures of 20 mmHg or more, a decrease in CI of 0.78 1.min.m2 or more, and an increase in CVP of 4 mmHg or more. Heart rate, BP, and systemic vascular resistance did not differ in infants requiring and not requiring re-operation. The authors conclude that intraoperative measurement of changes in IGP, CVP, and/or CI can reliably predict success or failure of primary operative repair of abdominal wall defects in human neonates.


Risk factors for urinary frequency in Taiwanese women aged 20-59 years.
To evaluate the risk factors for daytime urinary frequency in Taiwanese women aged 20-59 years. In 1998, there were about 5.9 million female residents aged 29-59 years in Taiwan. A random sample of 4,549 women within this age group was chosen by multistage sampling. Face-to-face interviews with 3,537 women were completed by well-trained professional interviewers within 3 months of the subjects being selected. Answers to questions about lower urinary tract symptoms, sociodemography and past histories were recorded. The factors were assessed by frequency analysis and logistic regression analysis using a significance level of less than 0.05. The prevalence of daytime urinary frequency was significantly related to diabetes mellitus (p = 0.038), hypertension (p = 0.016) and previous gynecologic surgery (p = 0.005). However, there was no relationship between urinary frequency and body mass index, drug allergy, smoking, alcohol consumption, marital status, childbirth, parity, hysterectomy, menopause, hormone replacement therapy or age. The results of this study show relatively high risk of urinary frequency development in patients with diabetes mellitus or hypertension. Better quality health education of these women, drawing their attention to the possibility of gynecologic surgery, is the most important factor in making current gynecologic surgery more effective. In addition, more attention given to associated factors that are preventable, modifiable or controllable, for example diabetes or hypertension, may have an impact on the prevalence of urinary frequency.


Uncoupling ITIM receptor G6b-B from tyrosine phosphatases Shp1 and Shp2 disrupts murine platelet homeostasis.
The immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing receptor G6b-B has emerged as a key regulator of platelet homeostasis. However, it remains unclear how it mediates its effects. Tyrosine phosphorylation of ITIM and immunoreceptor tyrosine-based switch motif (ITSM) within the cytoplasmic tail of G6b-B provides a docking site for Src homology 2 domain-containing protein-tyrosine phosphatases Shp1 and Shp2, which are also critical regulators of platelet production and function. In this study, we investigate the physiological consequences of uncoupling G6b-B from Shp1 and Shp2. To address this, we generated a transgenic mouse model expressing a mutant form of G6b-B in which tyrosine residues 212 and 238 within ITIM and ITSM were mutated to phenylalanine. Mice homozygous for the mutation (G6b-B diY/F) were macrothrombocytopenic, as a result of the reduction in platelet production, and had large clusters of megakaryocytes and myelofibrosis at sites of hematopoiesis, similar to those observed in G6b-deficient mice and patients. Platelets from G6b-B diY/F mice were hyporesponsive to collagen, as a result of the significant reduction in the expression of the immunoreceptor tyrosine-based activation motif (ITAM)-containing collagen receptor complex GPVI-FcR γ-chain, as well as thrombin, which could be partially rescued by costimulating the platelets with adenosine diphosphate. In contrast, platelets from G6b-B diY/F, G6b KO, and megakaryocyte-specific Shp2 KO mice were hyperresponsive to antibody-mediated cross-linking of the hemi-ITAM-containing podoplanin receptor CLEC-2, suggesting that G6b-B inhibits CLEC-2-mediated platelet activation through Shp2. Findings from this study demonstrate that G6b-B must engage with Shp1 and Shp2 to mediate its regulatory effects on platelet homeostasis.


Non conversion of sputum smears in new smear positive pulmonary tuberculosis patients in Yaoundé, Cameroon.
To identify clinical, radiological and microbiological factors associated with the non conversion of sputum smears in new smear positive cases of pulmonary tuberculosis after two months of treatment and to evaluate the influence of non-smear conversion on treatment outcomes. A prospective cohort study. Tuberculosis centre of Hôpital Jamot in Yaoundé- Cameroon from April 2006 to September 2007. A total of 413 patients were studied. Sputum smear status at two months of treatment, favourable treatment outcome (cured, treatment completed), unfavourable treatment outcome (death, treatment failure, default from treatment) and transferred out. A total of 413 patients were studied; There were 234 (56.8%) males and 178 (43.2%) females with a mean age of 33 years (range 9.80 years). Sputum smears did not convert in 55 (13.4%) patients at the end of two months of treatment. Logistic regression analysis showed that age above or equal to 40 years (OR=2.716, 95% CI:1.412-5.223, p=0.003), and a bacillary load of 3+ on pre-treatment sputum smears (OR=1.955; 95% CI: 1.039-3.68, p=0.037) were significantly associated with non conversion of sputum smears at the end of two months of treatment. Persistent positive smears at the end of two months of treatment were significantly associated with unfavourable treatment outcomes (p=0.025) especially default during the course of treatment. In Yaoundé, Cameroon, non conversion of positive sputum smears in new patients with pulmonary tuberculosis at the end of two months of treatment is associated with an unfavourable outcome particularly defaulting later in the course of treatment. Non conversion of sputum smears at two months of treatment is significantly associated with age above or equal to 40 years and the presence of numerous bacilli (3+) on pre-treatment sputum smears. Patients with these factors who do not smear convert after two months of treatment should be given a fully supervised treatment for the entire duration of therapy so as to prevent in particular treatment default.


Ictal high frequency oscillations distinguish two types of seizure territories in humans.
High frequency oscillations have been proposed as a clinically useful biomarker of seizure generating sites. We used a unique set of human microelectrode array recordings (four patients, 10 seizures), in which propagating seizure wavefronts could be readily identified, to investigate the basis of ictal high frequency activity at the cortical (subdural) surface. Sustained, repetitive transient increases in high gamma (80-150 Hz) amplitude, phase-locked to the low-frequency (1-25 Hz) ictal rhythm, correlated with strong multi-unit firing bursts synchronized across the core territory of the seizure. These repetitive high frequency oscillations were seen in recordings from subdural electrodes adjacent to the microelectrode array several seconds after seizure onset, following ictal wavefront passage. Conversely, microelectrode recordings demonstrating only low-level, heterogeneous neural firing correlated with a lack of high frequency oscillations in adjacent subdural recording sites, despite the presence of a strong low-frequency signature. Previously, we reported that this pattern indicates a failure of the seizure to invade the area, because of a feedforward inhibitory veto mechanism. Because multi-unit firing rate and high gamma amplitude are closely related, high frequency oscillations can be used as a surrogate marker to distinguish the core seizure territory from the surrounding penumbra. We developed an efficient measure to detect delayed-onset, sustained ictal high frequency oscillations based on cross-frequency coupling between high gamma amplitude and the low-frequency (1-25 Hz) ictal rhythm. When applied to the broader subdural recording, this measure consistently predicted the timing or failure of ictal invasion, and revealed a surprisingly small and slowly spreading seizure core surrounded by a far larger penumbral territory. Our findings thus establish an underlying neural mechanism for delayed-onset, sustained ictal high frequency oscillations, and provide a practical, efficient method for using them to identify the small ictal core regions. Our observations suggest that it may be possible to reduce substantially the extent of cortical resections in epilepsy surgery procedures without compromising seizure control.


Understanding the role of R266K mutation in cystathionine β-synthase (CBS) enzyme: an in silico study.
Human cystathionine β-synthase (hCBS) is a Heme-containing, unique pyridoxal 5'-phosphate (PLP) dependent enzyme. CBS catalyzes the bio-chemical condensation reactions in the transsulfuration pathway. The role of Heme in the catalytic activities of the hCBS enzyme is still unknown, even though various experimental studies indicated its participation in the bi-directional electronic communication with the PLP center. The hypothesis is, Heme acts as an electron density reservoir for the catalytic reaction center rather than a redox electron source. In this work, we have investigated In Silico dynamical aspects of the bi-directional communications by performing classical molecular dynamics (MD) simulations upon developing the necessary force field parameters for the cysteine and histidine bound hexa-coordinated Heme. The comparative aspects, of electron density overlap across the communicating pathways, were investigated adopting the Density Functional Theory (DFT) in conjunction with the hybrid exchange-correlation functional for the CBSWT (wild-type) and CBSR266K (mutated) enzymes. The molecular dynamics simulations and subsequent explorations of the electronic structures confirm the reported observations. It also provides an in-depth mechanistic understanding of how the non-covalent hydrogen bonding interactions with Cys52 control such long-distance communication. Our study also provides a convincing answer to the reduced enzymatic activities in the R266K mutated hCBS compared to the wild-type enzymes. The difference in hydrogen-bonding patterns and salt-bridge interactions play the pivotal roles in such long distant bi-directional communications.Communicated by Ramaswamy H. Sarma.


FCDECOMP: decomposition of metabolic networks based on flux coupling relations.
A metabolic network model provides a computational framework to study the metabolism of a cell at the system level. Due to their large sizes and complexity, rational decomposition of these networks into subsystems is a strategy to obtain better insight into the metabolic functions. Additionally, decomposing metabolic networks paves the way to use computational methods that will be otherwise very slow when run on the original genome-scale network. In the present study, we propose FCDECOMP decomposition method based on flux coupling relations (FCRs) between pairs of reaction fluxes. This approach utilizes a genetic algorithm (GA) to obtain subsystems that can be analyzed in isolation, i.e. without considering the reactions of the original network in the analysis. Therefore, we propose that our method is useful for discovering biologically meaningful modules in metabolic networks. As a case study, we show that when this method is applied to the metabolic networks of barley seeds and yeast, the modules are in good agreement with the biological compartments of these networks.


The family covenant and genetic testing.
The physician-patient relationship has changed over the last several decades, requiring a systematic reevaluation of the competing demands of patients, physicians, and families. In the era of genetic testing, using a model of patient care known as the family covenant may prove effective in accounting for these demands. The family covenant articulates the roles of the physician, patient, and the family prior to genetic testing, as the participants consensually define them. The initial argument defines the boundaries of autonomy and benefit for all participating family members. The physician may then serve as a facilitator in the relationship, working with all parties in resolving potential conflicts regarding genetic information. The family covenant promotes a fuller discussion of the competing ethical claims that may come to bear after genetic test results are received.


Vaccination Coverage and Risk Factors Associated With Incomplete Vaccination Among Children in Cambodia, Madagascar, and Senegal.
Vaccination reduces mortality from infectious disease, which is the leading cause of death in children under 5 and bears a particularly high burden in low- and middle-income countries. The Global Vaccine Action Plan (2011-2020) has set a target of 90% vaccine coverage for all vaccines included in national immunization programs by 2020. The objectives of this study were to estimate vaccine coverage among children in Madagascar, Cambodia, and Senegal and to identify the risk factors associated with incomplete vaccination. Using data from a community-based prospective cohort that included all newborn of some areas from 2012 to 2018 in these 3 countries, vaccine coverage was estimated for BCG, hepatitis B, oral polio, pentavalent (targeting diphtheria, tetanus, pertussis, hepatitis B, and Haemophilus influenzae type b), and measles vaccines. Risk factor analysis was performed with logistic regression models to identify correlates of incomplete vaccination. A total of 3606 children were followed up, and vaccine coverage was below the 90% threshold for most vaccines in all countries. Coverage was higher for vaccines recommended at birth and at 6 weeks, while a decrease in coverage for subsequent doses was observed for vaccines requiring several doses (23-47 points). Low birth weight (<2500 g) was an important risk factor for nonvaccination for vaccines recommended at birth in all 3 countries (adjusted odds ratio [95% confidence interval] ranging from 1.93 [1.11-3.38] to 4.28 [1.85-9.37]). Vaccine coverage for common childhood vaccines was lower than World Health Organization recommendations, and multidisciplinary approaches may help to improve vaccine coverage and timeliness.


Ultrahigh Piezocatalytic Performance of Perovskite Ferroelectric Powder via Oxygen Vacancy Engineering.
Piezocatalysis has increasingly gained prominence due to its enormous potential for addressing energy shortages and environmental pollution issues. Nonetheless, the low piezocatalytic activity of state-of-the-art materials seriously inhibits the practical applications of piezocatalysis. Here, it is proposed to greatly enhance the piezocatalytic activity for a perovskite ferroelectric, i.e., Sm-doped 0.68Pb(Mg1/3 Nb2/3 )-0.32PbTiO3 (Sm-PMN-PT, a solid solution with ultrahigh piezoelectricity), by introducing oxygen vacancies (OVs). The results show that the presence of OVs promotes the production of reactive oxygen species while enhancing the adsorption and activation of organic pollutants to improve piezocatalytic performance. The OV-Sm-PMN-PT is found to possess a superior piezocatalytic degradation rate constant of 0.073 min-1 under ultrasonic vibration, which is ≈4.9 times higher than that of pristine Sm-PMN-PT. Furthermore, the OV-Sm-PMN-PT can efficiently remove RhB under 400 rpm stirring, making it a promising candidate for water purification using low-frequency mechanical energy from nature. This research sheds light on the design of piezocatalytic materials via defect engineering.


Core deficits and quality of survival after childhood medulloblastoma: a review.
Medulloblastoma is the most common malignant central nervous system tumor in children. Treatment most often includes surgical resection, craniospinal irradiation, and adjuvant chemotherapy. Although survival has improved dramatically, the tumor and its treatments have devastating long-term side effects that negatively impact quality of survival (QoS). The objective was to review the literature on QoS following childhood medulloblastoma. This narrative review is based on a Medline database search and examination of the reference lists of papers selected. Frequent problems after medulloblastoma treatment include medical complications, such as long-term neurological and sensory (hearing loss) impairments; endocrine deficits, including growth problems; and secondary tumors. Neurocognitive impairment is repeatedly reported, with decreasing cognitive performances over time. Although all cognitive domains may be affected, low processing speed, attention difficulties, and working memory difficulties are described as the core cognitive deficits resulting from both cerebellar damage and the negative effect of radiation on white matter development. Long-term psychosocial limitations include low academic achievement, unemployment, and poor community integration with social isolation. Important negative prognostic factors include young age at diagnosis, conventional craniospinal radiotherapy, presence of postoperative cerebellar mutism, and perioperative complications. The influence of environmental factors, such as family background and interventions, remains understudied. Future studies should focus on the respective impact of radiation, cerebellar damage, genomic and molecular subgroup parameters, and environmental factors on cognitive and psychosocial outcomes. Long-term (probably lifelong) follow-up into adulthood is required in order to monitor development and implement timely, suitable, multi-disciplinary rehabilitation interventions and special education or support when necessary.


A critique of the European Commission document, "State of the Art Assessment of Endocrine Disrupters".
In this commentary, we critique a recently finalized document titled "State of the Art Assessment of Endocrine Disrupters" (SOA Assessment). The SOA Assessment was commissioned by the European Union Directorate-General for the Environment to provide a basis for developing scientific criteria for identifying endocrine disruptors and reviewing and possibly revising the European Community Strategy on Endocrine Disrupters. In our view, the SOA Assessment takes an anecdotal approach rather than attempting a comprehensive assessment of the state of the art or synthesis of current knowledge. To do the latter, the document would have had to (i) distinguish between apparent associations of outcomes with exposure and the inference of an endocrine-disruption (ED) basis for those outcomes; (ii) constitute a complete and unbiased survey of new literature since 2002 (when the WHO/IPCS document, "Global Assessment of the State-of-the-Science of Endocrine Disruptors" was published); (iii) consider strengths and weaknesses and issues in interpretation of the cited literature; (iv) follow a weight-of-evidence methodology to evaluate evidence of ED; (v) document the evidence for its conclusions or the reasoning behind them; and (vi) present the evidence for or reasoning behind why conclusions that differ from those drawn in the 2002 WHO/IPCS document need to be changed. In its present form, the SOA Assessment fails to provide a balanced and critical assessment or synthesis of literature relevant to ED. We urge further evidence-based evaluations to develop the needed scientific basis to support future policy decisions.


Tool use in a social insect and its implications for competitive interactions.
Four species of myrmicine ants, Aphaenogaster rudis, A. treatae, A. tennesseensis, and A. fulva, use pieces of leaf, mud, and sand grains as tools to carry soft foods from distant sources to the colony. Tools are tended on the food and removed by colony members without regard to which individual brought the tool. Food is gathered more efficiently by tool use than by internal transport. Tool-using behavior may increase the competitive ability of A. rudis in an interspecific dominance hierarchy.


Management of direct antiviral agent failures.
The current standard of care for patients with chronic hepatitis C virus (HCV) infection is a combination of direct-acting antiviral agents (DAAs). Most HCV patients treated with these drugs achieve viral elimination, but 1% to 15% fail to attain this objective. Treatment failures are usually related to relapse, and less often to on-treatment viral breakthrough. HCV drug resistant associated substitutions are detected in most patients who do not eliminate the virus. The risk of developing these variants depends on host- and virus-related factors, the properties of the drugs used, and the treatment strategies applied. Patients who carry Resistant Associated Substitutions (RASs) may not obtain benefits from treatment, and are at a risk of disease progression. Whether HCV RASs persist depends on their type: NS3-4A variants often disappear gradually after DAA therapy is stopped, whereas NS5A variants tend to persist for more than 2 years. The best way to prevent emergence of resistant variants is to eliminate the virus at the first treatment using highly potent DAAs with genetic barriers to resistance. For those who fail an NS5A inhibitor, deferral of treatment is recommended pending the availability of additional data if they do not have cirrhosis or reasons for urgent re-treatment. If re-treatment is needed, the most commonly used strategy is sofosbuvir as backbone therapy plus a drug from a class other than that previously used, for 24 weeks. Unless it is contraindicated, weight-based ribavirin should also be added. If available, nucleotide-based (eg, sofosbuvir) triple or quadruple DAA regimens may be considered. The optimal treatment for patients who fail an NS5A inhibitor and those with multidrug-resistant variants remains to be defined, and research efforts should continue to focus on treatment for these patients.


Pro-opiomelanocortin (POMC) gene expression, as identified by in situ hybridization, in purified populations of interstitial macrophages and Leydig cells of the adult rat testis.
The presence of testicular pro-opiomelanocortin (POMC) mRNA and POMC-derived peptides has recently been demonstrated in purified preparations of interstitial macrophages and in Leydig cells of the adult rat testis by Northern blot analysis and immunocytochemistry. In the present study, in situ hybridization provided further evidence that the POMC gene is expressed by both purified interstitial macrophages and Leydig cells. The cellular localization of the POMC transcripts was similar for both cell types, silver grains being predominantly located in the cytoplasm. The specificity of the labelling was demonstrated by the lack of silver grains in the preparations pretreated with RNAase or hybridized with an insulin cDNA probe, a gene known not to be expressed in these cell types. An additional control was provided by hybridization with a sense POMC RNA probe, which gave a less intense signal when compared with the antisense RNA probe under the same experimental conditions. The results confirm POMC gene expression in both macrophages and Leydig cells in the adult rat testis.


An improved cartilage digestion method for research and clinical applications.
Enzymatic isolation of chondrocytes from a cartilage biopsy is the first step to establish in vitro models of chondrogenesis or to generate cell-based grafts for cartilage repair. Such process is based on manually operated procedures and typically results in yields lower than 20% of the total available cells. In this study, we hypothesized that, as compared to conventionally used protocols, the enzymatic digestion of human articular cartilage in the presence of ascorbic acid 2-phosphate (AscA2P) or of sodium chloride (NaCl), in combination with the use of a perfusion bioreactor system, leads to a higher and more reproducible yield of cell populations with high proliferation and chondrogenic capacity. The addition of AscA2P within the enzymatic digestion medium did not significantly increase the cell yield, but resulted in a significant decrease of the intradonor variability in cell yield (-17.8% ± 10.7%, p = 0.0247) and in a significant increase of the proliferation rate of the isolated chondrocytes (+19.0% ± 1.4%, p < 0.05) with respect to the control group. The addition of NaCl during cartilage digestion did not modulate cell yield. When the cartilage digestion was further performed under direct perfusion flow, beneficial synergistic effects were achieved, with an overall increase of 34.7% ± 6.8% (p < 0.001) in the cell yield and an average decrease of 57.8% ± 11.2% (p < 0.01) in the coefficient of variation with respect to the control group. Importantly, by implementing this strategy it was possible to retrieve clonal subpopulations more efficiently capable of undergoing chondrogenesis, both in vitro and in vivo. Our findings bear relevance for the preparation of human chondrocytes for laboratory investigations, and in the perspective of efficient and streamlined manufacturing of cell/tissue grafts for articular cartilage repair.


A technique for the replacement of multiple missing anterior teeth in the presence of a mutilated alveolar ridge.
The intent of this paper is to demonstrate a clinical technique for the replacement of multiple missing anterior teeth in the presence of a mutilated ridge. It also reviews basic rules governing the replacement of multiple adjacent missing teeth. The two cases presented clearly demonstrate that multiple adjacent missing teeth can be esthetically restored and still preserve that which remains; teeth, periodontium and soft tissues. The long-term success or failure of prosthodontic restorations relies heavily upon careful consideration of esthetic and foundational requirements. A technique has been described which incorporates the benefits of both fixed and removable dentures to restore multiple missing teeth in the presence of a mutilated alveolar ridge. The first patient was treated approximately twenty years ago. The anterior teeth and alveolar ridge were lost due to an automobile accident. The entire labial alveolar ridge was lost to the base of the nasal spine, thereby making a simple six-unit anterior fixed partial denture a complex and difficult problem. The second patient was recently treated. This patient's alveolar ridge and buccal plate were destroyed by a horse's hoof, again making a restoration procedure a difficult one.


Accounting for absorption saturatio effects in pulsed infrared laser-excited photothermal spectroscopy.
Equations that relate photothermal lens focal lengths and photothermal deflection angles to saturation absorption coefficients are derived. These equations are derived for two-level absorbers with both homogeneously and inhomogeneously broadened transitions. Initial and time-dependent photothermal lens signals are calculated. Equations describing the zero-time signals are exact to within the simplifying assumptions of the derivation, while the time-dependent signals are approximate. The approximation is performed by the use of a finite series of Gaussian functions to model the temperature change profile distorted by nonlinear absorption. The excitation irradiance-dependent signal behavior for rectangular and exponential excitation pulse time profiles for homogeneously and inhomogeneously broadened transitions are compared. Absorbed energies are used to calculate effective absorbances obtained by the use of conventional and photothermal lensing spectrometry. The conclusions drawn from these comparisons are tha pulsed laser photothermal spectroscopy is sensitive to the excitationlaser's pulse temporal profile and the transition broadening mechanism.


Low prevalence of (pre) malignant lesions in the breast and high prevalence in the ovary and Fallopian tube in women at hereditary high risk of breast and ovarian cancer.
To analyse the prevalence of (pre) malignant lesions occurring in breast and adnexal tissue at prophylactic surgery in women at hereditary high risk of breast and/or ovarian cancers. Tissue was obtained from 85 women who underwent prophylactic bilateral salpingo-oophorectomy (pBSO) and from 59 women who underwent prophylactic mastectomy (pM). Control tissue samples were obtained from women undergoing breast reduction surgery (N = 99) or adnexal surgery for benign reasons (N = 72). In women with a BRCA1/2 mutation, the prevalence of a (pre) malignant adnexal lesion was 50% (95% CI 26-74) if older than 40 years and 14% (95% CI 0-58) if younger. The prevalences of (pre) malignant breast lesions in women older than 40 years, with and without a BRCA1/2 mutation, were 0% (95% CI 0-16) and 47% (95% CI 21-73), respectively. No association was found between (pre) malignant lesions in breast and adnexal tissue occurring in 28 women who underwent surgery on both organs (R = 0.155, p = 0.432), but the prevalence of lesions was significantly higher in adnexal tissue than in the breast (p = 0.023). Compared to controls, women at hereditary high risk had a higher chance of (pre) malignant lesions in the breast and an even higher chance of such lesions in the adnexal tissue. There was no indication for concomitant presence of such lesions in both organs at the time of prophylactic surgery. The high frequency of (pre) malignant lesions in the adnexal tissue stresses further the importance of pBSO from the age of 40 onwards in women at hereditary high risk.


What is the economic value of digoxin therapy in congestive heart failure patients? Results from the DIG trial.
The Digitalis Investigation Group (DIG) clinical train randomized 6800 congestive heart failure patients (ejection fraction > or =45%) to a daily regimen of either digoxin or placebo. At 37 months average follow-up, patients in both groups had similar mortality. We determined the incremental costs associated with the use of digoxin in this high-risk population. Hospitalizations and medical costs were compared by using a societal perspective. Hospitalizations were assigned Medicare DRG codes by using descriptive information from the clinical trial. Digoxin use was assigned a cost by using the 1998 average wholesale price as reported by Red Book. On average, there were fewer hospitalizations in digoxin-treated patients. These patients had lower heart failure yet higher non-heart failure hospitalization costs than placebo patients. Digoxin therapy was cost saving versus placebo in only 27% of 1000 bootstrap samples using Medicare costs (mean costs 12,648 dollars vs. 12,362 dollars) and in 44% of samples using commercial carrier costs (mean costs 17,400 dollars vs. 17,306 dollars). How ever, digoxin was cost saving in >50% of samples for several higher-risk patient subgroups. The use of digoxin therapy versus placebo was associated with reduced hospitalizations. Moreover, the resulting cost-savings could cover the costs of this inexpensive therapy in selected subgroups of higher-risk patients. In the remainder, there is a modest cost associated with this therapy.


Sequence around the 159 degree region of the Bacillus subtilis genome: the pksX locus spans 33.6 kb.
The nucleotide sequence of 20 kb contiguous to the pksX locus of Bacillus subtilis was determined. Six ORFs were recognized, one of which extended for 13,341 nucleotides. Their predicted products have significant similarities to proteins with known functions involved in the synthesis of polypeptides and polyketides or in fatty acid metabolism. At the nucleotide level, three regions with a high level of sequence identity (49-54%) to the Aspergillus nidulans wA gene, responsible for the synthesis of a polyketide pigment, were recognized. The observed similarities suggest that the 20 kb region and the previously reported 13.6 kb region containing pksX are part of the same locus, possibly involved in secondary metabolism.


Molecular and Antigenic Characterization of Piscine orthoreovirus (PRV) from Rainbow Trout (Oncorhynchus mykiss).
Piscine orthoreovirus (PRV-1) causes heart and skeletal muscle inflammation (HSMI) in farmed Atlantic salmon (Salmo salar). Recently, a novel PRV (formerly PRV-Om, here called PRV-3), was found in rainbow trout (Oncorhynchus mykiss) with HSMI-like disease. PRV is considered to be an emerging pathogen in farmed salmonids. In this study, molecular and antigenic characterization of PRV-3 was performed. Erythrocytes are the main target cells for PRV, and blood samples that were collected from experimentally challenged fish were used as source of virus. Virus particles were purified by gradient ultracentrifugation and the complete coding sequences of PRV-3 were obtained by Illumina sequencing. When compared to PRV-1, the nucleotide identity of the coding regions was 80.1%, and the amino acid identities of the predicted PRV-3 proteins varied from 96.7% (λ1) to 79.1% (σ3). Phylogenetic analysis showed that PRV-3 belongs to a separate cluster. The region encoding σ3 were sequenced from PRV-3 isolates collected from rainbow trout in Europe. These sequences clustered together, but were distant from PRV-3 that was isolated from rainbow trout in Norway. Bioinformatic analyses of PRV-3 proteins revealed that predicted secondary structures and functional domains were conserved between PRV-3 and PRV-1. Rabbit antisera raised against purified virus or various recombinant virus proteins from PRV-1 all cross-reacted with PRV-3. Our findings indicate that despite different species preferences of the PRV subtypes, several genetic, antigenic, and structural properties are conserved between PRV-1 and-3.


Role of smeU1VWU2X Operon in Alleviation of Oxidative Stresses and Occurrence of Sulfamethoxazole-Trimethoprim-Resistant Mutants in Stenotrophomonas maltophilia.
Overexpression of resistance-nodulation-division (RND)-type efflux pumps is an important mechanism for bacteria to combat antimicrobials. RND efflux pumps are also critical for bacterial physiology, such as oxidative stress tolerance. Stenotrophomonas maltophilia, a multidrug-resistant opportunistic pathogen, harbors eight RND-type efflux pump operons. Of these, the smeU1VWU2X operon is unique for its possession of two additional genes, smeU1 and smeU2, which encode proteins of the short-chain dehydrogenase/reductase (SDR) family. Overexpression of the SmeVWX pump is known to contribute to the acquired resistance to chloramphenicol, quinolone, and tetracycline; however, SmeU1 and SmeU2 are little involved in this phenotype. In the study described in this article, we further linked the smeU1VWU2X operon to oxidative stress alleviation and sulfamethoxazole-trimethoprim (SXT)-resistant mutant occurrence. The smeU1VWU2X operon was inducibly expressed upon challenge with menadione (MD), plumbagin (PL), and hydrogen peroxide (H2O2), as verified by the use of the chromosomal smeU1VWU2X-xylE transcriptional fusion construct and quantitative real-time PCR (qRT-PCR). The MD-mediated smeU1VWU2X upexpression was totally dependent on SoxR and partially relied on SmeRv but was less relevant to OxyR. SmeRv, but not SoxR and OxyR, played a regulatory role in the H2O2-mediated smeU1VWU2X upexpression. The significance of smeU1VWU2X upexpression was investigated with respect to oxidative stress alleviation and SXT-resistant mutant occurrence. Overexpression of the smeU1VWU2X operon contributed to the alleviation of MD-mediated oxidative stress. Of the encoded proteins, the SmeVWX pump and SmeU2, rather than SmeU1, participated in MD tolerance. Furthermore, we also demonstrated that the MD-mediated expression of the smeU1VWU2X operon decreased the SXT resistance frequency when S. maltophilia was grown in a reactive oxygen species (ROS)-rich environment.


Farnesoid X receptor is inhibited after ileum transposition in diabetic rats: its hypoglycemic effect.
Background: Aim to investigate bile acid profile changes and the Farnesoid X receptor (FXR) status after ileotransposition (IT), and reveal its possible hypoglycemic mechanism. Methods: Twenty male diabetic rats were randomly assigned into the IT group and the sham IT (SH) group. Bile acid profiles were measured using an ultra-performance liquid chromatography-tandem mass spectrometry. Glucose metabolism was monitored after oral administration of FXR inhibitor and agonist. And the expression of key FXR target genes were measured. Results: The levels of β-muricholic acid (P = 0.047), tauro-α-muricholic acid and tauro-β-muricholic acid (P < 0.001) in plasma in the IT group were higher than those in the SH group, and the levels of taurocholic acid (P = 0.049) and turoursodeoxycholic acid (P = 0.030) were lower than those in the SH group. After inhibition of intestinal FXR, the glucose metabolism in the SH group was improved. When FXR agonist was given, the blood glucose level was increased in both groups. After sacrifice, the levels of glycoursodeoxycholic acid, tauro-α-muricholic acid and tauro-β-muricholic acid in liver and ileum tissues were higher than those in the SH group (P < 0.05), the level of α- muricholic acid (P < 0.001) in liver tissues were lower than that in the SH group. Moreover, the expression of CYP7A1 mRNA (P < 0.001) and FGF15 mRNA (P = 0.001) in the IT group was significantly higher, and the expression of PEPCK mRNA (P = 0.004), SREPB1c mRNA (P = 0.005) and SRB1 mRNA (P = 0.001) were significantly lower than that in the SH group. Conclusions: We demonstrate a remarkable heterogeneity of BA profiles after IT, FXR activation might has a detrimental effect on glucose metabolism.


The APDS General Surgery Education Quality Improvement Program (EQIP).
Although the ACGME has called for outcomes-based evaluation of residency programs, few metrics or benchmarks exist connecting educational processes with resident educational outcomes. To address this deficiency, a national Education Quality Improvement Program (EQIP) for General Surgery training is proposed. We describe the initial efforts to create this platform. In addition, a national survey was administered to 330 Program Directors to assess their interest in and concerns about a continuous educational quality improvement project. We demonstrate that through a collaborative process and the support of the Association of Program Directors in Surgery (APDS), we were able to develop the groundwork for a national surgical educational improvement project, now called EQIP. The survey response rate was 45.8% (152 of 332 programs) representing a mix of university (55.3%), university-affiliated (18.4%), independent (24.3%), and military (2.0%) programs. Most respondents (66.2%) had not previously heard of EQIP. Most respondents (69.7%) believe that educational outcomes can be measured. The majority of respondents indicated they believed EQIP could be successful (57%). Only 2.3% thought EQIP would not be successful. Almost all programs (98.7%) expressed a willingness to participate, although 19.1% did not believe that they had adequate resources to participate. The APDS EQIP platform holds promise as a useful and achievable method to obtain educational outcomes data. These data can be used as a basis for continuous surgical educational quality improvement. General Surgery Program Directors have expressed enthusiasm for EQIP and are willing to participate in the program examining outcomes of General Surgery training programs, with an ultimate goal of improving overall residency training.


Atherosclerosis: perspectives of anti-inflammatory therapy.
According to modern ideas, chronic low-grade inflammation, which development is associated with uncontrolled activation of both innate and adaptive immunity, plays a fundamental role in all stages of the atherosclerotic process. The contribution of inflammation to the development of atherosclerotic vascular lesions attracts attention to the similarity of the mechanisms of immunopathogenesis of atherosclerosis and classic inflammatory rheumatic disease - rheumatoid arthritis. In the aspect of participation in the pathogenesis of atherosclerotic vascular lesions and as a promising therapeutic "target" of particular interest is interleukin-1β (IL-1β), which plays an important role in the development of many acute and chronic immunosuppressive diseases. The mechanisms of atherosclerosis associated with IL-1β determine the ability of cholesterol crystals and other "Pro-atherogenic" factors to induce the synthesis of IL-1β by activating NLRP3 inflammasome. The mechanisms of atherosclerosis associated with IL-1β determine the ability of cholesterol crystals and other "proatherogenic" factors to induce the synthesis of IL-1β by activating NLRP3 inflammasome. Convincing evidence for the role of inflammation in development of atherosclerosis in General and good prospects of anti-inflammatory therapy in particular obtained in a randomized placebo-controlled study called CANTOS (Canakinumab Anti-inflammatory Thrombosis Otcomes Study), which studied the effectiveness of treatment with monoclonal antibodies to IL-1β canakinumab (Novartis International AG) in patients with severe atherosclerotic vascular lesions as a new approach to secondary prevention of cardiovascular complications. The results of CАNTOS research, as well as the experience gained in rheumatology in regard to cardiovascular effects of innovative anti-inflammatory drugs, have great importance for the improvement of secondary prevention of atherosclerosis-related cardiovascular complications.


Clinical application of biotechnically cultured autologous chondrocytes as novel graft material for nasal augmentation.
A new method of nasal augmentation has been developed, in which cultured autologous chondrocytes are transplanted. Using biotechnology, a piece of the choncha cartilage 1 cm2 is cultured into a gel-type mass of chondrocytes, which then is transplanted by injection into a surgically created subperiosteal skin pocket on the nasal dorsum. The augmented nose is taped and protected for 1 week. The grafted chondrocytes develop into mature cartilaginous tissue after approximately 1 month. This method was used in eight cases of nasal augmentation, and one case of chin augmentation (performed simultaneously), and one case of depressed deformity on the forehead. The results obtained by this method to date have been satisfactory after a follow-up time of 6 to 24 months. The authors believe that this method may at least partially be able to replace silicone implantation for nasal augmentation.


Roles of Periostin in Respiratory Disorders.
Periostin is a matricellular protein that has been implicated in many disease states. It interacts with multiple signaling cascades to modulate the expression of downstream genes that regulate cellular interactions within the extracellular matrix. This review focuses on the role of periostin in respiratory diseases, including asthma and idiopathic pulmonary fibrosis, and its potential to help guide treatment or assess prognosis. Epithelial injury is a common feature of many respiratory diseases, resulting in the secretion, among others, of periostin, which is subsequently involved in airway remodeling and other aspects of pulmonary pathophysiology. In asthma, periostin is recognized as a biomarker of type 2 inflammation; POSTN gene expression is up-regulated in bronchial epithelial cells by IL-13 and IL-4. Serum periostin has been evaluated for the identification of patients with increased clinical benefit from treatment with anti-IL-13 (lebrikizumab, tralokinumab) and anti-IgE (omalizumab) therapy and may be prognostic for increased risk of asthma exacerbations and progressive lung function decline. Furthermore, in asthma, periostin may regulate subepithelial fibrosis and mucus production and may serve as a systemic biomarker of eosinophilic airway inflammation. Periostin is also highly expressed in the lungs of patients with idiopathic pulmonary fibrosis, and its serum levels may predict clinical progression. Overall, periostin contributes to multiple pathogenic processes across respiratory diseases, and peripheral blood levels of periostin may have utility as a biomarker of treatment response and disease progression.


Liver stiffness measured by MR elastography is a predictor of early HCC recurrence after treatment.
Magnetic resonance elastography (MRE) is a non-invasive tool for measuring liver stiffness (LS) with high diagnostic accuracy. This study investigated whether quantified LS by MRE could predict early recurrence of patients with hepatocellular carcinoma (HCC) within the Milan criteria. A prospectively collected cohort, which included the HCC patients who underwent MRE before treatment (an HCC-MRE cohort), was analyzed. In the HCC-MRE cohort, only patients under the Milan criteria, who underwent hepatic resection, radiofrequency ablation (RFA), or transarterial chemoembolization (TACE), were reviewed. We investigated whether LS assessed by MRE was an independent predictor of early recurrence using Cox regressions and Kaplan-Meier analyses. A total of 192 HCC patients under the Milan criteria who underwent hepatic resection (n = 96), RFA (n = 23), or TACE (n = 73) were included. Higher LS ratings (kPa; hazard ratio [HR] = 1.12; 95% confidence interval [CI] = 1.01-1.25; p = 0.040) emerged as an independent risk factor for early tumor recurrence. In the subgroup analysis, higher LS ratings were associated with higher risks of early HCC recurrence in both the resection/RFA group (> 4.5 kPa; HR = 2.95; 95% CI = 1.26-6.94; p = 0.013) and the TACE group (> 6 kPa; HR = 2.94; 95% CI = 1.27-6.83; p = 0.012). LS assessed by MRE was an independent predictor of early recurrence among HCC patients under the Milan criteria after achieving a complete response. • Liver parenchymal stiffness measured by MRE predicts early recurrence of treated HCC under Milan criteria. • A liver stiffness > 5.5 kPa was associated with worse recurrence-free survival. • Patients with high pre-treatment LS may benefit from stringent follow-up.


[Frequency of reoperations after amniotic membrane transplantation].
Retrospective evaluation of the frequency of reoperations after amniotic membrane transplantation for different pathologic entities. We included 81 cases of amniotic membrane transplantation (AMT), which were operated on at the university eye clinic Tübingen since 1997 and which had been followed up for at least 12 months. Patient diagnoses were subdivided as follows: conjunctival defects after tumour excision (N = 2), bullous keratopathy (N = 5), external fistula after glaucoma filtering surgery (N = 3), recurrent pterygium (N = 5), symblepharon (N = 6), corneal ulcer with descemetocele (N = 3), non-perforated corneal ulcer (N = 51), perforated corneal ulcer (N = 1), other (n = 5). The overall reoperation rate was determined to be 42 % after a follow-up period of one year. Most frequently, a second AMT (N = 16) and a perforating keratoplasty (N = 16) were performed after the initial AMT. The following reoperation rates were determined for the subgroups: Conjunctival defects after tumour excision (0 %), Bullous keratopathy (60 %), External fistula after glaucoma filtering surgery (67 %), Recurrent pterygium (60 %), Symblepharon (67 %), Corneal ulcer with descemetocele (67 %), Non-perforated corneal ulcer (49 %), Perforated corneal ulcer (100 %). Particularly in patients with conjunctival defects after tumour excision and with non-perforated corneal ulcers, stabilisation of the ocular surface homeostasis can be achieved with a single amniotic membrane transplantation for at least one year.


Are malnourished patients complex patients? Health status and care complexity of malnourished patients detected by the Short Nutritional Assessment Questionnaire (SNAQ).
This article describes the characteristics of patients identified as malnourished using the Short Nutritional Assessment Questionnaire (SNAQ) in terms of health status (quality of life, functional capacity, and body composition) and care complexity. We expected that by using the quick and easy SNAQ method of screening on malnutrition, inferences could be made about general health status and care complexity. This information can be used for optimal multi-disciplinary treatment of the malnourished patient. The research population consisted of a group of 588 patients admitted to internal medicine and surgery wards of the VU university medical center. Patients with a SNAQ score of at least 3 points were considered malnourished. The SNAQ score was compared to the health status, which was determined by serum albumin, hand grip strength, quality of life, body composition, and estimated care complexity. At admission, 172 patients (29%) had a SNAQ score of at least 3 points. These patients had a significantly poorer quality of life, poorer physical functioning, a lower fat free mass index, and higher care complexity. These findings confirm our assumption that a considerable proportion of malnourished patients should be considered as complex patients and that malnutrition is an important aspect and indicator of overall health status of the patients. The SNAQ is a simple malnutrition screening tool, applicable in the current complex hospital situation, to identify these complex, malnourished patients.


Pemphigoid gestationis: a case report and review of the literature.
Pemphigoid gestationis (PG) is an uncommon autoimmune bullous disease that almost exclusively presents during pregnancy. Patients typically present with a diffuse blistering and intensely pruritic eruption that begins periumbilically and spreads to involve the rest of the body. Direct immunofluorescence demonstrating C3 in a linear pattern along the dermoepidermal junction confirms the diagnosis of PG. Corticosteroids remain the choice of therapy and early intervention is essential because of possible adverse effects of PG on the fetus. We report a case of PG and review the literature.


Reproductive health preventive screening among clinic vs. over-the-counter oral contraceptive users.
Interest is growing in moving oral contraceptives over-the-counter (OTC), although concerns exist about whether women would continue to get preventive health screening. We recruited cohorts of US-resident women who obtained oral contraceptives from US family planning clinics (n=532) and OTC from pharmacies in Mexico (n=514) and interviewed them four times over 9 months. Based on self-reports of having a Pap smear within 3 years or ever having had a pelvic exam, clinical breast exam and testing for sexually transmitted infections (STIs), we assessed the prevalence of preventive screening using Poisson regression models. The prevalence of screening was high for both groups (>88% for Pap smear, pelvic exam and clinical breast exam and >71% for STI screening), while the prevalence ratios for screening were higher for clinic users, even after multivariable adjustment. Results suggest that most women would obtain reproductive health preventive screening if oral contraceptives were available OTC, and also highlight the need to improve access to preventive screening for all low-income women.


Sex differences in spatial visualization and episodic memory as a function of alcohol consumption.
Sex differences in visuospatial ability as well as episodic memory have been reliably demonstrated, irrespective of alcoholism. Studies in alcoholics have consistently documented cognitive deficits in visuospatial ability, problem solving and memory function. This cross-sectional, population-based study examined if sex differences in cognitive performance could be impacted by alcohol consumption. Drinking data were collected from 2224 randomly sampled adults, aged between 35 and 85 years, who participated in the Betula study on memory, health and aging. Participants were classified into non-, light, moderate and heavy drinking subgroups based on sex-adjusted normative values. Cognitive tasks demonstrating clear sex differences, such as episodic memory tasks (favouring women) and spatial visualization tasks (favouring men), were conducted and performance was assessed by sex and the drinking group. After controlling for age and education, overall analyses found expected sex differences in episodic memory and spatial visualization that were apparent across the entire population. When these sex differences were examined by drinking group, visuospatial performance favouring men disappeared for the moderate to heavy drinking groups, but higher performance by women on episodic memory tasks was consistent across all levels of alcohol consumption. Traditional biomarkers of increased alcohol consumption (GGT and MCV) correlated with the reported drinks/day. These results lend support to the theory that moderate alcohol intake may be beneficial to cognitive function in women, but not necessarily in men.


Laryngeal carcinoma associated with multiple additional primary tumors. Immunologic studies.
Four malignant tumors and one benign in a 76-year-old man appeared. Three of the neoplasms were in the respiratory system, and one was a bladder carcinoma; all were linked to heavy smoking habits. The patient underwent immunologic investigations consisting of in vivo testing for cutaneous reactivity, in vitro lymphocyte blastogenesis studies, T- and B-cell level studies, and serum immunoglobulin level studies. The studies have demonstrated anergy to recall antigens, decreased lymphocyte responses to phytohemagglutinin, and low levels of peripheral T-lymphocytes. The serum immunoglobulins were at the upper limit of the normal. The relationship between the patient's immunologic status and the occurrence of multiple primary neoplasms is discussed.


Traumatic pneumocephaly: trapped air from where?
Traumatic pneumocephaly is literally defined as 'air in the head' after trauma. While this phenomenon has been well described in the literature, our case report is unique in describing diffuse pneumocephalus in the subaponeurotic space, subdural space, subarachnoid space, brain and ventricles without a break in the cranial vault: a 26-year-old man fell from a =9 meter scaffolding in a water tower. Following an arduous and delayed extrication, the patient was unresponsive with loss of pulse requiring intubation, cardiopulmonary resuscitation and release of tension pneumothorax with bilateral thoracostomy tubes. Examination remained poor with a Glasgow Coma Scale of 3. Immediate exploratory laparotomy was performed for a small right retroperitoneal haematoma on Focused Assessment with Sonography for Trauma. Postoperative imaging revealed diffuse pneumocephaly without facial fractures. This case presentation explores unusual causes of fistulous connections with the atmosphere that may lead to air trapped in and around the cranial vault.


Maternal obesity is associated with ovarian inflammation and upregulation of early growth response factor 1.
Obesity impairs reproductive functions through multiple mechanisms, possibly through disruption of ovarian function. We hypothesized that increased adiposity will lead to a proinflammatory gene signature and upregulation of Egr-1 protein in ovaries from obese (OB; n = 7) compared with lean (LN; n = 10) female Sprague-Dawley rats during the peri-implantation period at 4.5 days postcoitus (dpc). Obesity was induced by overfeeding (40% excess calories for 28 days) via total enteral nutrition prior to mating. OB dams had higher body weight (P < 0.001), greater fat mass (P < 0.001), and reduced lean mass (P < 0.05) and developed metabolic dysfunction with elevated serum lipids, insulin, leptin, and CCL2 (P < 0.05) compared with LN dams. Microarray analyses identified 284 differentially expressed genes between ovaries from LN vs. OB dams (±1.3 fold, P < 0.05). RT-qPCR confirmed a decrease in expression of glucose transporters GLUT4 and GLUT9 and elevation of proinflammatory genes, including CCL2, CXCL10, CXCL11, CCR2, CXCR1, and TNFα in ovaries from OB compared with LN (P < 0.05). Protein levels of PI3K and phosphorylated Akt were significantly decreased (P < 0.05), whereas nuclear levels of Egr-1 (P < 0.05) were increased in OB compared with LN ovaries. Moreover, Egr-1 was localized to granulosa cells, with the highest expression in cumulus cells of preovulatory follicles. mRNA expression of VCAN, AURKB, and PLAT (P < 0.05) correlated with %visceral fat weight (r = 0.51, -0.77, and -0.57, respectively, P ≤ 0.05), suggesting alterations in ovarian function with obesity. In summary, maternal obesity led to an upregulation of inflammatory genes and Egr-1 expression in peri-implantation ovarian tissue and a concurrent downregulation of GLUTs and Akt and PI3K protein levels.


Asymmetric gibberellin signaling regulates vacuolar trafficking of PIN auxin transporters during root gravitropism.
Gravitropic bending of plant organs is mediated by an asymmetric signaling of the plant hormone auxin between the upper and lower side of the respective organ. Here, we show that also another plant hormone, gibberellic acid (GA), shows asymmetric action during gravitropic responses. Immunodetection using an antibody against GA and monitoring GA signaling output by downstream degradation of DELLA proteins revealed an asymmetric GA distribution and response with the maximum at the lower side of gravistimulated roots. Genetic or pharmacological manipulation of GA levels or response affects gravity-mediated auxin redistribution and root bending response. The higher GA levels at the lower side of the root correlate with increased amounts of PIN-FORMED2 (PIN2) auxin transporter at the plasma membrane. The observed increase in PIN2 stability is caused by a specific GA effect on trafficking of PIN proteins to lytic vacuoles that presumably occurs downstream of brefeldin A-sensitive endosomes. Our results suggest that asymmetric auxin distribution instructive for gravity-induced differential growth is consolidated by the asymmetric action of GA that stabilizes the PIN-dependent auxin stream along the lower side of gravistimulated roots.


Can pragmatic research, real-world data and digital technologies aid the development of psychedelic medicine?
Favourable regulatory assessments, liberal policy changes, new research centres and substantial commercial investment signal that psychedelic therapy is making a major comeback. Positive findings from modern trials are catalysing developments, but it is questionable whether current confirmatory trials are sufficient for advancing our understanding of safety and best practice. Here we suggest supplementing traditional confirmatory trials with pragmatic trials, real-world data initiatives and digital health solutions to better support the discovery of optimal and personalised treatment protocols and parameters. These recommendations are intended to help support the development of safe, effective and cost-efficient psychedelic therapy, which, given its history, is vulnerable to excesses of hype and regulation.


Inflammation-associated adherent-invasive Escherichia coli are enriched in pathways for use of propanediol and iron and M-cell translocation.
Perturbations of the intestinal microbiome, termed dysbiosis, are linked to intestinal inflammation. Isolation of adherent-invasive Escherichia coli (AIEC) from intestines of patients with Crohn's disease (CD), dogs with granulomatous colitis, and mice with acute ileitis suggests these bacteria share pathoadaptive virulence factors that promote inflammation. To identify genes associated with AIEC, we sequenced the genomes of phylogenetically diverse AIEC strains isolated from people with CD (4), dogs with granulomatous colitis (2), and mice with ileitis (2) and 1 non-AIEC strain from CD ileum and compared them with 38 genome sequences of E. coli and Shigella. We then determined the prevalence of AIEC-associated genes in 49 E. coli strains from patients with CD and controls and correlated genotype with invasion of intestinal epithelial cells, persistence within macrophages, AIEC pathotype, and growth in standardized conditions. Genes encoding propanediol utilization (pdu operon) and iron acquisition (yersiniabactin, chu operon) were overrepresented in AIEC relative to nonpathogenic E. coli. PduC (propanediol dehydratase) was enriched in CD-derived AIEC, correlated with increased cellular invasion, and persistence in vitro and was increasingly expressed in fucose-containing media. Growth of AIEC required iron, and the presence of chuA (heme acquisition) correlated with persistence in macrophages. CD-associated AIEC with lpfA 154 (long polar fimbriae) demonstrated increased invasion of epithelial cells and translocation across M cells. Our findings provide novel insights into the genetic basis of the AIEC pathotype, supporting the concept that AIEC are equipped to exploit and promote intestinal inflammation and reveal potential targets for intervention against AIEC and inflammation-associated dysbiosis.


[Effect of proteolytic enzymes on kanamycin pharmacokinetics in experimental suppurative infection].
The effect of the proteolytic enzyme trypsin on kanamycin pharmacokinetics in rats with experimental purulent infection was studied. An increase in the kanamycin serum levels after administration of the drugs in combination was observed as compared to the control. In a dose of 0.03 mg per animal trypsin had no effect on the kanamycin pharmacokinetics in the rats with experimental peritonitis.


Temporomandibular disorder in a child.
Temporomandibular (TM) disorders among children are uncommon. Their many etiologies include interferences with the formative process, malocclusion, and muscle disharmony. Facial pain, earache, headache, difficulty with chewing, and joint noise during mandibular function are symptoms. The two year course of a TM disorder that first became symptomatic in a six month old child is described.


Electroretinographic assessment of retinal function at high altitude.
Although hypoxia plays a key role in the pathophysiology of many common and well studied retinal diseases, little is known about the effects of high-altitude hypoxia on retinal function. The aim of the present study was to assess retinal function during exposure to high-altitude hypoxia using electroretinography (ERG). This work is related to the Tübingen High Altitude Ophthalmology (THAO) study. Electroretinography was performed in 14 subjects in Tübingen, Germany (341 m) and at high altitude at La Capanna Regina Margherita, Italy (4,559 m) using an extended protocol to assess functional integrity of various retinal layers. To place findings in the context of acute mountain sickness, correlations between ERG measurements and oxygen saturation, heart rate, and scores of acute mountain sickness (AMS) were calculated. At high altitude, the maximum response of the scotopic sensitivity function, the implicit times of the a- and b-wave of the combined rod-cone responses, and the implicit times of the photopic negative responses (PhNR) were significantly altered. A-wave slopes and i-waves were significantly decreased at high altitude. The strongest correlation was found for PhNR and O2 saturation (r = 0.68; P < 0.05). Of all tested correlations, only the photopic b-wave implicit time (10 cd·s/m(2)) was significantly correlated with severity of AMS (r = 0.57; P < 0.05). ERG data show that retinal function of inner, outer, and ganglion cell layer is altered at high-altitude hypoxia. Interestingly, the most affected ERG parameters are related to combined rod-cone responses, which indicate that phototransduction and visual processing, especially under conditions of rod-cone interaction, are primarily affected at high altitude.


Occupational injuries for consecutive and cumulative shifts among hospital registered nurses and patient care associates: a case-control study.
Nontraditional work shifts for hospital registered nurses and patient care associates and associated injuries were examined through a case-control study. Inpatient care requires that many staff work nontraditional shifts, including nights and 12-hour shifts, but some characteristics remain unexplored, especially consecutive shifts. A total of 502 cases (injured workers) were matched to single controls based on their hospital, unit type, job type, gender, and age (± 5 years). Conditional logistic regression was used for the analysis, controlling for weekly hours scheduled. For both, consecutive shifts of 2 or more days and some various cumulative shifts over a week and month period, especially night shifts, were associated with increased odds of injury. More investigations on the phenomenon of consecutive shifts are recommended. Additionally, the assessment of shift policy and subsequent injury outcomes is necessary before implementing intervention strategies.