All-optical highly sensitive akinetic sensor for ultrasound detection and photoacoustic imaging.
A novel all-optical akinetic ultrasound sensor, consisting of a rigid, fiber-coupled Fabry-Pérot etalon with a transparent central opening is presented. The sensing principle relies exclusively on the detection of pressure-induced changes of the refractive index in the fluid filling the Fabry-Pérot cavity. This enables resonance-free, inherently linear signal detection over a broad bandwidth. We demonstrate that the sensor achieves a exceptionally low peak noise equivalent pressure (NEP) values of 2 Pa over a 20 MHz measurement bandwidth (without signal averaging), while maintaining a flat frequency response, and a detection bandwidth up to 22.5 MHz (-6 dB). The measured large full field of view of the sensor is 2.7 mm × 1.3 mm and the dynamic range is [Formula: see text] or 63 dB at 20 MHz bandwidth. For different required amplitude ranges the upper amplitude detection limit can be customized from at least 2 kPa to 2 MPa by using cavity mirrors with a lower optical reflectivity. Imaging tests on a resolution target and on biological tissue show the excellent suitability of the akinetic sensor for optical resolution photoacoustic microscopy (OR-PAM) applications.


miR‑222 regulates brain injury and inflammation following intracerebral hemorrhage by targeting ITGB8.
Intracerebral hemorrhage (ICH) is a disease associated with high mortality and morbidity. MicroRNAs (miRNAs) have been reported to be associated with the pathogenesis of numerous cerebrovascular diseases, including ICH. miR‑222 has been revealed to play important roles in various physiological and pathological processes in cardiovascular diseases. However, its role in ICH remains largely unknown. The aim of the present study was to evaluate the potential effect of miR‑222 on brain injury in ICH. The results revealed that the expression of miR‑222 was significantly increased in ICH, and downregulation of miR‑222 significantly reduced erythrocyte lysate‑induced cell apoptosis by decreasing the levels of cleaved caspase‑3, cleaved caspase‑9 and Bax and increasing the level of Bcl‑2. In addition, downregulation of miR‑222 suppressed the inflammatory responses in erythrocyte lysate‑induced microglia, and inhibited inflammation, brain water content and improved neurological functions in ICH mice. Mechanistically, integrin subunit β8 (ITGB8) was identified as a direct target of negative regulation by miR‑222 in microglia cells, and up‑regulation of ITGB8 led to the attenuation of inflammation and apoptosis. Collectively, the present findings indicated that miR‑222 was a crucial regulator of inflammation via targeting of ITGB8, and represented a promising therapeutic strategy for ICH.


Achieving high coverage in Rwanda's national human papillomavirus vaccination programme.
Virtually all women who have cervical cancer are infected with the human papillomavirus (HPV). Of the 275,000 women who die from cervical cancer every year, 88% live in developing countries. Two vaccines against the HPV have been approved. However, vaccine implementation in low-income countries tends to lag behind implementation in high-income countries by 15 to 20 years. In 2011, Rwanda's Ministry of Health partnered with Merck to offer the Gardasil HPV vaccine to all girls of appropriate age. The Ministry formed a "public-private community partnership" to ensure effective and equitable delivery. Thanks to a strong national focus on health systems strengthening, more than 90% of all Rwandan infants aged 12-23 months receive all basic immunizations recommended by the World Health Organization. In 2011, Rwanda's HPV vaccination programme achieved 93.23% coverage after the first three-dose course of vaccination among girls in grade six. This was made possible through school-based vaccination and community involvement in identifying girls absent from or not enrolled in school. A nationwide sensitization campaign preceded delivery of the first dose. Through a series of innovative partnerships, Rwanda reduced the historical two-decade gap in vaccine introduction between high- and low-income countries to just five years. High coverage rates were achieved due to a delivery strategy that built on Rwanda's strong vaccination system and human resources framework. Following the GAVI Alliance's decision to begin financing HPV vaccination, Rwanda's example should motivate other countries to explore universal HPV vaccine coverage, although implementation must be tailored to the local context.


Functional and radioligand binding characterization of the α1L-adrenoceptor subtype of the human vas deferens.
Alpha1 -adrenoceptor antagonists can cause ejaculatory dysfunction as an adverse effect. Contractions of the human vas deferens are mediated via α1A -adrenoceptors, and this study investigated whether the low affinity state of this receptor (α1L -adrenoceptor) is involved in mediating contractions of this tissue. The potency of agonists and the affinity of receptor subtype selective antagonists were determined in functional experiments and in [(3) H]tamsulosin binding experiments to identify the α1 -adrenoceptor subtype population present in the human vas deferens. The α1A -adrenoceptor selective agonist A61603 was a full agonist and was 250-fold more potent than noradrenaline. Prazosin antagonized contractile responses to phenylephrine with a low affinity (pKd = 8.6). Only high concentrations of RS17053 antagonized responses to phenylephrine and yielded a relatively low affinity estimate of 7.0. BMY7378 (α1D -adrenoceptor selective) gave a low affinity estimate (pKd = 6.7), whilst tamsulosin (α1A - and α1D -adrenoceptor selective) had a high affinity (pKd = 9.9). [(3) H]Tamsulosin bound to human vas deferens membranes with a high affinity (pKd = 10.0). Prazosin, RS17053 and BMY7378 competed with [(3) H]tamsulosin with low affinities for a single population of binding sites (pKd values of 8.5, 7.2 and 6.3, respectively). These functional and radioligand binding data indicate that the human vas deferens possesses a homogeneous population of α1 -adrenoceptors which have the pharmacological properties of the putative α1L -adrenoceptor, the same functional receptor previously identified in the human prostate.


Spontaneous isolated celiac artery dissection.
Dyspepsia with mild, stabbing epigastric discomfort without history of trauma is a very common symptom that emergency physicians see in their daily practice. Vascular emergencies, mostly the aortic dissection and aneurysm, are always described in the differential diagnosis with persistent symptoms. Isolated celiac artery dissection occurring spontaneously is a very rare diagnosis. The involvement of branch vessels is generally observed and patients show various clinical signs and symptoms according to the involved branch vessel. Here we are presenting a case with spontaneous isolated celiac artery dissection, without any branch vessel involvement or visceral damage, detected by computed tomography scans taken on admission.


Prognostic value of hTERT mRNA expression in surgical samples of lung cancer patients: the European Early Lung Cancer Project.
Lung cancer is the most important cause of cancer-related mortality. Resectability and eligibility for treatment with adjuvant chemotherapy is determined by staging according to the TNM classification. Other determinants of tumour behaviour that predict disease outcome, such as molecular markers, may improve decision-making. Activation of the gene encoding human telomerase reverse transcriptase (hTERT) is implicated in the pathogenesis of lung cancer, and consequently detection of hTERT mRNA might have prognostic value for patients with early stage lung cancer. A cohort of patients who underwent a complete resection for early stage lung cancer was recruited as part of the European Early Lung Cancer (EUELC) project. In 166 patients expression of hTERT mRNA was determined in tumour tissue by quantitative real-time RT-PCR and related to that of a house-keeping gene (PBGD). Of a subgroup of 130 patients tumour-distant normal tissue was additionally available for hTERT mRNA analysis. The correlation between hTERT levels of surgical samples and disease-free survival was determined using a Fine and Gray hazard model. Although hTERT mRNA positivity in tumour tissue was significantly associated with clinical stage (Fisher's exact test p=0.016), neither hTERT mRNA detectability nor hTERT mRNA levels in tumour tissue were associated with clinical outcome. Conversely, hTERT positivity in adjacent normal samples was associated with progressive disease, 28% of patients with progressive disease versus 7.5% of disease-free patients had detectable hTERT mRNA in normal tissue [adjusted HR: 3.60 (1.64-7.94), p=0.0015]. hTERT mRNA level in tumour tissue has no prognostic value for patients with early stage lung cancer. However, detection of hTERT mRNA expression in tumour-distant normal lung tissue may indicate an increased risk of progressive disease.


Characterization of a Murine Pressure Ulcer Model to Assess Efficacy of Adipose-derived Stromal Cells.
As the world's population lives longer, the number of individuals at risk for pressure ulcers will increase considerably in the coming decades. In developed countries, up to 18% of nursing home residents suffer from pressure ulcers and the resulting hospital costs can account for up to 4% of a nation's health care budget. Although full-thickness surgical skin wounds have been used as a model, preclinical rodent studies have demonstrated that repeated cycles of ischemia and reperfusion created by exposure to magnets most closely mimic the human pressure ulcer condition. This study uses in vivo and in vitro quantitative parameters to characterize the temporal kinetics and histology of pressure ulcers in young, female C57BL/6 mice exposed to 2 or 3 ischemia-reperfusion cycles. This pressure ulcer model was validated further in studies examining the efficacy of adipose-derived stromal/stem cell administration. Optimal results were obtained with the 2-cycle model based on the wound size, histology, and gene expression profile of representative angiogenic and reparative messenger RNAs. When treated with adipose-derived stromal/stem cells, pressure ulcer wounds displayed a dose-dependent and significant acceleration in wound closure rates and improved tissue histology. These findings document the utility of this simplified preclinical model for the evaluation of novel tissue engineering and medical approaches to treat pressure ulcers in humans.


Genome scan for QTLs underlying bone size variation at 10 refined skeletal sites: genetic heterogeneity and the significance of phenotype refinement.
To identify quantitative trait loci (QTLs) underlying variation in bone size, we conducted a whole-genome linkage scan in 53 pedigrees with 630 subjects using 380 microsatellite markers. Lumbar area 1, 2, 3, and 4 at the spine, femoral neck, trochanter, intertrochanter areas at the hip, ultradistal, mid-distal, and one-third distal areas at the wrist were measured by dual-energy X-ray absorptiometry (DXA), and adjusted for age, height, weight, and sex. Two-point and multipoint linkage analyses were performed for skeletal bone size at each site and their composite measurements using the SOLAR package. Two chromosomal regions (1q22 and 10q21) were identified with significant evidence of linkage (LOD > 4.32) to one-third distal area, and three were identified with suggestive evidence of linkage (LOD > 2.93) to bone size in one skeletal site. Our results indicated that the low power of QTLs mapping for composite phenotypic measurements may result from genetic heterogeneity of complex traits.


Fast Food Consumption Pattern and Its Association with Overweight Among High School Boys in Mangalore City of Southern India.
Fast foods are quite popular among children owing to taste, appearance and hype created by mass media. However, the increased incidence of lifestyle disorders seen now-a-days at an early age could be attributed to fast foods. This study was done to assess the awareness of health hazards, consumption pattern of fast foods and to find out its association with overweight among high school students. This cross-sectional study was done among boys of 3 private schools in Mangalore city in March 2012. Data was collected using a semi-structured self-administered questionnaire. Chi-square test, one-way ANOVA and binary logistic regression analysis was used for analysis. P-value ≤ 0.05 was considered as statistically significant association. Mean age of boys was 13.5±0.9 years. Out of 300 participants, 41(13.7%) were overweight and 8 (2.7%) were obese. 292(97.3%) were fast food users of which 42(14.4%) consumed it every day. Majority of participants were introduced to fast foods through television commercials 193(64.3%). 73(57%) developed this habit as they were bored with home food. Awareness of harmful effects of fast food consumption was known to 186(62%) students and this was found to be associated with the perceived need to control its usage (p<0.001). Parental consumption of fast foods was found to influence fast food consumption among children (p=0.024). As many as 68(22.7%) and 206(68.7%) children were not eating vegetables and fruits respectively every day. Increased frequency of fast food consumption in a week was found to be associated with overweight or obesity among children after adjusting the effects of confounders (p=0.003). Awareness on health hazards of fast foods needs to be taught at schools so as to minimize its consumption. Parents have to set an example themselves by not eating fast foods and improving home food to support discouragement of fast foods. This would minimize life style disorders among children to a greater extent.


Optimising primary care for people with dementia.
This review considers key areas in primary care regarding the diagnosis of dementia. Issues surrounding assessment, policy and incentives are considered. In addition, the relevance of non-medication approaches for dementia in primary care, which aim to enhance or maintain quality of life by maximising psychological and social function in the context of existing disabilities, is deliberated. Finally, key issues about primary care medication management are considered, and relevant therapeutic strategies with recommendation for a collaborative approach that improve outcomes by linking primary and secondary healthcare services - including general practice and pharmacy - with social care needs are weighed up. A key aspect of such a collaborative approach is to support informal carers in optimising medication.


Epidemiology of pathogenic enterobacteria in humans, livestock, and peridomestic rodents in rural Madagascar.
Among the families of enteric bacteria are globally important diarrheal agents. Despite their potential for zoonotic and environmental transmission, few studies have examined the epidemiology of these pathogens in rural systems characterized by extensive overlap among humans, domesticated and peridomestic animals. We investigated patterns of infection with Enterotoxigenic Escherichia coli, Shigella spp., Salmonella enterica, Vibrio cholerae, and Yersinia spp. (enterocolitica, and pseudotuberculosis) in Southeastern Madagascar where the potential for the aforementioned interactions is high. In this pilot project we conducted surveys to examine behaviors potentially associated with risk of infection and if infection with specific enterobacteria species was associated with diarrheal disease. PCR was conducted on DNA from human, livestock, and rodent fecal samples from three villages. Overall, human prevalence was highest (77%), followed by rodents (51%) and livestock (18%). Rodents were ∼2.8 times more likely than livestock to carry one of the bacteria. The incidence of individual species varied between villages, with the observation that, E. coli and Shigella spp. were consistently associated with co-infections. As an aggregate, there was a significant risk of infection linked to a water source in one village. Individually, different pathogens were associated with certain behaviors, including: those who had used medication, experienced diarrhea in the past four weeks, or do not use toilets. Different bacteria were associated with an elevated risk of infection for various human activities or characteristics. Certain bacteria may also predispose people to co-infections. These data suggest that a high potential for transmission among these groups, either directly or via contaminated water sources. As these bacteria were most prevalent in humans, it is possible that they are maintained in humans and that transmission to other species is infrequent. Further studies are needed to understand bacterial persistence, transmission dynamics, and associated consequences in this and similar systems.


Genomic hardwiring and phenotypic plasticity of terpenoid-based defenses in conifers.
Over evolutionary history, conifers have faced a myriad of threats from phloem- and xylem-feeding insects, defoliating insects, and fungal pathogens. Among the trees' defenses, terpenoids appear to play a major role by harming, disabling, deterring, repelling, or otherwise reducing the fitness of potential invaders. Each of the three classes of terpenoids in conifers, monoterpenes, sesquiterpenes, and diterpenes, are composed of a large number of representative compounds. In most cases, the presence of a particular terpenoid compound in the oleoresin or volatile emissions from a specific conifer can be accounted for by the expression of one of many committed terpene synthase (TPS) genes. However, while each TPS may produce one or a few major products, many produce a variety of minor products with relatively constant component ratios in the product blends. TPS genes exist in conifers in large and functionally diverse, yet monophyletic, gene families. Within these gene families, new biochemical functions of TPS appear to have evolved by gene duplication and changes in the amino acid sequence of the enzyme's active site. In addition, TPS genes may be differentially expressed prior to, during, and following attack by insects or pathogens. Thus, while the production of any particular terpenoid is hardwired into a conifer's genome, these trees have the capacity to change the mixture of terpenoids in oleoresin secretions and volatile emissions. Anatomical changes may also accompany induced terpenoid production, supplementing the plasticity of the molecular and biochemical events.


Bacterial contamination of frequently touched objects in a tertiary care hospital of Pokhara, Nepal: how safe are our hands?
Objects frequently touched by patients and healthcare workers in hospitals harbor potential pathogens and may act as source of infectious agents. This study aimed to determine the bacterial contamination of common hospital objects frequently touched by patients, visitors and healthcare workers. A total of 232 samples were collected from various sites like surface of biometric attendance devices, elevator buttons, door handles, staircase railings, telephone sets and water taps. Isolation, identification and antibiotic susceptibility testing of the isolates was performed by standard microbiological techniques. Biofilm forming ability of the S. aureus isolates was tested by a microtitre plate method. A total of 232 samples were collected and 219 bacterial isolates were recovered from 181 samples. Staphylococcus aureus was the most common bacterial isolate (44/219). Majority of S. aureus isolates were recovered from elevator buttons, biometric attendance devices and door handles. Among the S. aureus isolates, 36.3% (16/44) were methicillin resistant Staphylococcus aureus (MRSA) while remaining were methicillin sensitive Staphylococcus aureus (MSSA). Out of 44 S. aureus isolates, 12 (29.5%) were multidrug resistant and 14 (31.8%) were biofilm producers. The majority of MRSA isolates 62.5% (10/16) were biofilm producers. Acinetobacter was the most common Gram negative isolate followed by E coli and Pseudomonas species. High bacterial contamination of frequently touched objects with variety of potential pathogens and normal flora was detected. S. aureus was the most common bacterial isolate. Biofilm forming ability offers additional survival advantage to the organisms on these objects. Present study highlights the need of improved hand hygiene among healthcare workers and regular cleaning/disinfection of sites of frequent public contact.


Lipid oxidation in herring fillets (Clupea harengus) during ice storage measured by a commercial hybrid gas-sensor array system.
Volatile compounds released from herring fillets (Clupea harengus) during 15 days of storage on ice have been measured with a commercial hybrid gas-sensor array system. Using partial least-squares regression modeling, the sensor responses were correlated with data from chemical analyses (lipid oxidation products and antioxidants) and sensory analyses (odor). Eight of the 16 sensors proved significant in the correlation studies: 6 metal oxide semiconductor field effect transistor (MOSFET) sensors and 2 Taguchi type sensors. Correlation coefficients for chemical and sensory data ranged from 0.9 to 0.98 and from 0.49 to 0.92, respectively, with 0.92 referring to both "sharp/acrid" and "rancid" odors. Prediction errors ranged from 8 to 14% and from 11 to 25% for the chemical and sensory measures, respectively. That the prediction errors for oxidation product formation (5-9%) were close to the analytical errors of the chemical reference methods indicated close to "optimum" performance of the gas-sensor system. The sensor system predicted the storage time of the herring with a 1-day error. Results illustrate high potential of the gas-sensor technology in rapid nondestructive quality determination of ice-stored herring.


The Citrus Flavanone Naringenin Protects Myocardial Cells against Age-Associated Damage.
In recent years, the health-promoting effects of the citrus flavanone naringenin have been examined. The results have provided evidence for the modulation of some key mechanisms involved in cellular damage by this compound. In particular, naringenin has been revealed to have protective properties such as an antioxidant effect in cardiometabolic disorders. Very recently, beneficial effects of naringenin have been demonstrated in old rats. Because aging has been demonstrated to be directly related to the occurrence of cardiac disorders, in the present study, the ability of naringenin to prevent cardiac cell senescence was investigated. For this purpose, a cellular model of senescent myocardial cells was set up and evaluated using colorimetric, fluorimetric, and immunometric techniques. Relevant cellular senescence markers, such as X-gal staining, cell cycle regulator levels, and the percentage of cell cycle-arrested cells, were found to be reduced in the presence of naringenin. In addition, cardiac markers of aging-induced damage, including radical oxidative species levels, mitochondrial metabolic activity, mitochondrial calcium buffer capacity, and estrogenic signaling functions, were also modulated by the compound. These results suggested that naringenin has antiaging effects on myocardial cells.


DNA methylation of the p14ARF, RASSF1A and APC1A genes as an independent prognostic factor in colorectal cancer patients.
We quantitated the methylated fraction of CpG sites in the promoter regions of O6-MGMT, p14ARF, p16INK4a, RASSF1A and APC1A in tumor tissue from patients with colorectal cancer (CRC) in order to determine if promoter hypermethylation of any of these genes predicts survival. DNA was isolated from 111 primary CRC and 46 matched normal colorectal mucosa samples from the same patients, obtained at primary surgery and DNA methylation was examined by Pyrosequencing®. Follow-up time was up to 20 years. Patients showed partial promoter methylation in the following frequencies: O6-MGMT, 34%; p14ARF, 29%; p16INK4a, 28%; RASSF1A, 14%; and APC1A, 27%. Normal mucosa was always unmethylated. CRC patients with methylated p14ARF gene promoter had significantly worse prognosis (p=0.036), whereas those with methylated O6-MGMT had significantly better prognosis through the first 60 months post-treatment (RR 0.36; p=0.023). Methylation of one or more of the genes from the set p14ARF, RASSF1A and APC1A, was significantly (p=0.021) associated with worse prognosis even adjusting for tumor stage and differentiation (RR 2.2, p=0.037). Thus, DNA methylation of the p14ARF, RASSF1A and APC1A genes, diagnosed by Pyrosequencing, defines a poor prognosis subset of CRC patients independently of both tumor stage and differentiation. O6-MGMT methylation may play a protective role.


The isolated perfused human skin flap model: A missing link in skin penetration studies?
Development of effective (trans)dermal drug delivery systems requires reliable skin models to evaluate skin drug penetration. The isolated perfused human skin flap remains metabolically active tissue for up to 6h during in vitro perfusion. We introduce the isolated perfused human skin flap as a close-to-in vivo skin penetration model. To validate the model's ability to evaluate skin drug penetration the solutions of a hydrophilic (calcein) and a lipophilic (rhodamine) fluorescence marker were applied. The skin flaps were perfused with modified Krebs-Henseleit buffer (pH7.4). Infrared technology was used to monitor perfusion and to select a well-perfused skin area for administration of the markers. Flap perfusion and physiological parameters were maintained constant during the 6h experiments and the amount of markers in the perfusate was determined. Calcein was detected in the perfusate, whereas rhodamine was not detectable. Confocal images of skin cross-sections shoved that calcein was uniformly distributed through the skin, whereas rhodamine accumulated in the stratum corneum. For comparison, the penetration of both markers was evaluated on ex vivo human skin, pig skin and cellophane membrane. The proposed perfused flap model enabled us to distinguish between the penetrations of the two markers and could be a promising close-to-in vivo tool in skin penetration studies and optimization of formulations destined for skin administration.


The transcription factor Rfx3 regulates beta-cell differentiation, function, and glucokinase expression.
Pancreatic islets of perinatal mice lacking the transcription factor Rfx3 exhibit a marked reduction in insulin-producing beta-cells. The objective of this work was to unravel the cellular and molecular mechanisms underlying this deficiency. Immunofluorescence studies and quantitative RT-PCR experiments were used to study the emergence of insulin-positive cells, the expression of transcription factors implicated in the differentiation of beta-cells from endocrine progenitors, and the expression of mature beta-cell markers during development in Rfx3(-/-) and pancreas-specific Rfx3-knockout mice. RNA interference experiments were performed to document the consequences of downregulating Rfx3 expression in Min6 beta-cells. Quantitative chromatin immunoprecipitation (ChIP), ChIP sequencing, and bandshift experiments were used to identify Rfx3 target genes. Reduced development of insulin-positive cells in Rfx3(-/-) mice was not due to deficiencies in endocrine progenitors or beta-lineage specification, but reflected the accumulation of insulin-positive beta-cell precursors and defective beta-cells exhibiting reduced insulin, Glut-2, and Gck expression. Similar incompletely differentiated beta-cells developed in pancreas-specific Rfx3-deficient embryos. Defective beta-cells lacking Glut-2 and Gck expression dominate in Rfx3-deficent adults, leading to glucose intolerance. Attenuated Glut-2 and glucokinase expression, and impaired glucose-stimulated insulin secretion, were also induced by RNA interference-mediated inhibition of Rfx3 expression in Min6 cells. Finally, Rfx3 was found to bind in Min6 cells and human islets to two well-known regulatory sequences, Pal-1 and Pal-2, in the neuroendocrine promoter of the glucokinase gene. Our results show that Rfx3 is required for the differentiation and function of mature beta-cells and regulates the beta-cell promoter of the glucokinase gene.


Efficacy and safety of 10% HES 130/0.4 versus 10% HES 200/0.5 for plasma volume expansion in cardiac surgery patients.
Hydroxyethyl starch (HES) solutions are frequently used for perioperative volume replacement. Whereas older HES specimen tended to accumulate in the plasma and to cause negative effects on hemostasis, more recent products, e.g., HES 130/0.4, are characterised by improved pharmacological properties. The present study was designed to compare the efficacy and safety of 10% HES 130/0.4 and 10% HES 200/0.5. In this post-hoc analysis of a prospective, randomised, double-blind, multi-center therapeutic equivalence trial, 76 patients undergoing elective on-pump cardiac surgery received perioperative volume replacement using either 10% HES 130/0.4 (N.=37) or 10% HES 200/0.5 (N.=39) up to a maximum dose of 20 mL kg-1. Equivalent volumes of investigational medication were infused until 24 hours after the first administration (1577 vs. 1540 mL; treatment difference 37 [-150; 223] mL; P<0.0001 for equivalence). Whereas standard laboratory tests of coagulation were comparable between groups, von Willebrand factor activity on the first postoperative morning tended to be higher following treatment with 10% HES 130/0.4 as compared to 10% HES 200/0.5 (P=0.025) with this difference being statistically significant only in the per-protocol analysis (P=0.02). Treatment groups were comparable concerning other safety parameters and the incidence of adverse drug reactions. In particular, renal function was well preserved in both groups. Ten percent HES 130/0.4 was equally effective and safe as compared to 10% HES 200/0.5 for volume therapy in patients undergoing cardiovascular surgery. Postoperative coagulation and renal function, as measured by standard laboratory tests, were similar among groups.


Anisotropic connectivity implements motion-based prediction in a spiking neural network.
Predictive coding hypothesizes that the brain explicitly infers upcoming sensory input to establish a coherent representation of the world. Although it is becoming generally accepted, it is not clear on which level spiking neural networks may implement predictive coding and what function their connectivity may have. We present a network model of conductance-based integrate-and-fire neurons inspired by the architecture of retinotopic cortical areas that assumes predictive coding is implemented through network connectivity, namely in the connection delays and in selectiveness for the tuning properties of source and target cells. We show that the applied connection pattern leads to motion-based prediction in an experiment tracking a moving dot. In contrast to our proposed model, a network with random or isotropic connectivity fails to predict the path when the moving dot disappears. Furthermore, we show that a simple linear decoding approach is sufficient to transform neuronal spiking activity into a probabilistic estimate for reading out the target trajectory.


Methicillin-Resistant Staphylococcus aureus USA300 Latin American Variant in Patients Undergoing Hemodialysis and HIV Infected in a Hospital in Bogotá, Colombia.
We aimed to determine the prevalence of MRSA colonization and examine the molecular characteristics of colonizing isolates in patients receiving hemodialysis and HIV-infected in a Colombian hospital. Patients on hemodialysis and HIV-infected were prospectively followed between July 2011 and June 2012 in Bogota, Colombia. Nasal and axillary swabs were obtained and cultured. Colonizing S. aureus isolates were identified by standard and molecular techniques. Molecular typing was performed by using pulse-field gel electrophoresis and evaluating the presence of lukF-PV/lukS-PV by PCR. A total of 29% (n = 82) of HIV-infected and 45.5% (n = 15) of patients on hemodialysis exhibited S. aureus colonization. MSSA/MRSA colonization was observed in 28% and 3.6% of the HIV patients, respectively and in 42.4% and 13.3% of the hemodialysis patients, respectively. Staphylococcal cassette chromosome mec typing showed that four MRSA isolates harbored the type IV cassette, and one type I. In the hemodialysis group, two MRSA isolates were classified as belonging to the USA300-LV genetic lineage. Conversely, in the HIV infected group, no colonizing isolates belonging to the USA300-Latin American Variant (UDA300-LV) lineage were identified. Colonizing isolates recovered from the HIV-infected group belonged to the prevalent hospital-associated clones circulating in Latin America (Chilean [n = 1] and Pediatric [n = 2]). The prevalence of MRSA colonization in the study groups was 3.6% (HIV) and 13.3% (hemodialysis). Surveillance programs should be implemented in this group of patients in order to understand the dynamics of colonization and infection in high-risk patients.


The Analysis of Safety and Effectiveness Using Allograft in the Treatment of Spinal Tuberculosis-A Multicenter Retrospective Study
To evaluate the clinical efficacy and fusion characteristics of allografts in spinal tuberculosis (TB). The research reviewed 1196 patients with spinal tuberculosis who received treatment at six hospitals from January 2000 to January 2016. A total of 623 patients who had spinal tuberculosis were included in the study. All patients underwent debridement, decompression, allograft bone grafting, and instrumentation. Postoperative treatment consisted of a combination of anti-TB drug treatment for 18 months and brace fixed braking for 3–9 months. Clinical outcome, laboratory indexes, and radiological results were analysed. The average follow-up time was 34.1 months (12–60 months). Pain was relieved postoperatively in all cases, and 87.8% of patients were painless at the final follow-up. The erythrocyte sedimentation rate (ESR) significantly decreased and returned to normal at the final follow-up. The fusion rate of allografts was 30.2% and 98.4% at the 9- and 12-month follow-ups, respectively. At the final follow-up, the fusion rate was 100%. The application of allografts in the surgical management of spinal tuberculosis is safe and effective. Allografts can replace autografts in surgeries for spinal tuberculosis.


Population Dynamics of Sugar Beets, Rhizoctonia solani, and Laetisaria arvalis: Responses of a Host, Plant Pathogen, and Hyperparasite to Perturbation in the Field.
Rhizoctonia solani causes crown rot of sugar beets, a severe disease that has destroyed up to 60% of the plants in a test field in western Nebraska. Laetisaria arvalis, a natural hyperparasite of Rhizoctonia spp., was isolated from fields in western Nebraska. To test for the potential for biological control of R. solani, in November 1980 (following harvest) we applied various combinations of a nematicide (Telone II; Dow Chemical Co.), a nutrition source (sugar beet pulp), and an inoculum of L. arvalis in a randomized block design. Populations of R. solani, L. arvalis, and sugar beets were monitored monthly through October 1981 (just after harvest). In control and nematicide plots, the R. solani population did not change significantly through time. In plots inoculated with L. arvalis, the R. solani populations declined through March, concomitant with an increase in L. arvalis. L. arvalis then declined with a corresponding increase in the R. solani populations. Beet plant numbers declined significantly in all treatments. We suggest that reduction of the R. solani populations with the hyperparasite L. arvalis is possible but that a stable equilibrium naturally exists.


Multi-professional IAPT CBT training: clinical competence and patient outcomes.
There is international interest in the training of psychological therapists to deliver evidence-based treatment for common mental health problems. The UK Improving Access to Psychological Therapies (IAPT) programme, one of the largest training initiatives, relies on competent therapists to successfully deliver cognitive behaviour therapy (CBT) and promote good patient outcome. To evaluate an IAPT CBT training course by assessing if trainees' clinical skills improve during training and reach competency standards, and to report patient outcome for submitted training cases. To investigate a possible relationship between trainee competence and patient outcome. To explore professional differences during training. CBT trainee (n = 252) competence was assessed via audio recordings of therapy sessions at the beginning, middle and end of training. Patient pre- to post-treatment outcomes were extracted from submitted training cases (n = 1927). Differences in professional background were examined across competence, academic final grade and tutorial support. CBT trainees attained competence by the end of the course with 77% (anxiety recordings) and 72% (depression recordings) improving reliably. Training cases reported pre- to post-treatment effect sizes of 1.08-2.26 across disorders. CBT competence predicted a small variance in clinical outcome for depression cases. Differences in professional background emerged, with clinical psychologists demonstrating greater competence and higher academic grades. Trainees without a core professional background required more additional support to achieve competence. Part of a new CBT therapist workforce was successfully trained to deliver relatively brief treatment effectively. Trainees without a core profession can be successfully trained to competence, but may need additional support. This has implications for workforce training.


Radial versus raster spectral-domain optical coherence tomography scan patterns for detection of macular fluid in neovascular age-related macular degeneration.
To compare the 12-line radial to the 25-line raster spectral-domain optical coherence tomography (SD-OCT) acquisition patterns at detecting intraretinal or subretinal fluid in eyes with neovascular age-related macular degeneration (AMD). Retrospective cross-sectional analysis of 200 eyes with neovascular AMD. Sequential 12-line radial and 25-line raster scans were evaluated for the presence of intraretinal/subretinal fluid. A total of 394 SD-OCT scans were interpreted (1.97 scans per eye). The 12-line radial detected intraretinal/subretinal fluid in all but 7 of 394 scans (1.7%; 95% CI 0.7% to 3.6%), resulting in a sensitivity of 98.3%. The 25-line raster detected intraretinal/subretinal fluid in all but 10 of 394 scans (2.5%; 95% CI 1.2% to 4.6%), resulting in a sensitivity of 97.5%. This small difference in fluid detection between the two acquisition patterns for neovascular AMD was not found to be statistically significant (p=0.6276). The 12-line radial scan is statistically comparable with the 25-line raster scan in detecting the presence of intraretinal/subretinal fluid in neovascular AMD. The 12-line radial SD-OCT pattern alone may be adequate to guide day-to-day clinical decisions in a more time-efficient manner.


BMP4: a Possible Key Factor in Differentiation of Auditory Neuron-Like Cells from Bone-Derived Mesenchymal Stromal Cells.
Previous studies have shown that BMP4 may play an important part in the development of auditory neurons (ANs), which are degenerated in sensorineural hearing loss. However, whether BMP4 can promote sensory fate specification from mesenchymal stromal cells (MSCs) is unknown so far. MSCs isolated from Sprague-Dawley (SD) rats were confirmed by expression of MSC markers using flow cytometry and adipogenesis/osteogenesis using differentiation assays. MSCs treated with a complex of neurotrophic factors (BMP4 group and non-BMP4 group) were induced into auditory neuron-like cells, then the differences between the two groups were analyzed in morphological observation, cell growth curve, qRT-PCR, and immunofluorescence. Flow cytometric analysis showed that the isolated cells expressed typical MSC surface markers. After adipogenic and osteogenic induction, the cells were stained by oil red O and Alizarin Red. The neuronal induced cells were in the growth plateau and had special forms of neurons. In the presence of BMP4, the inner ear genes NF-M, Neurog1, GluR4, NeuroD, Calretinin, NeuN, Tau, and GATA3 were up-regulated in MSCs. MSCs have the capacity to differentiate into auditory neuron-like cells in vitro. As an effective inducer, BMP4 may play a key role in transdifferentiation.


Free energy functionals for efficient phase field crystal modeling of structural phase transformations.
The phase field crystal (PFC) method is a promising technique for modeling materials with atomic resolution on mesoscopic time scales. While numerically more efficient than classical density functional theory (CDFT), its single mode free energy limits the complexity of structural transformations that can be simulated. We introduce a new PFC model inspired by CDFT, which uses a systematic construction of two-particle correlation functions that allows for a broad class of structural transformations. Our approach considers planar spacings, lattice symmetries, planar atomic densities, and atomic vibrational amplitudes in the unit cell, and parameterizes temperature and anisotropic surface energies. The power of our approach is demonstrated by two examples of structural phase transformations.


Genetic characterization of norovirus strains in hospitalized children from Pakistan.
Norovirus is one of the most common causes of acute gastroenteritis among children in developing countries. No data on the prevalence and genetic variability of norovirus are available for Pakistan, where early childhood mortality due to acute gastroenteritis is common. We tested 255 fecal specimens from children under 5 years of age hospitalized between April 2006 and March 2008 with severe acute gastroenteritis in five hospitals in the four largest cities in Pakistan for norovirus by real-time RT-PCR. Positive samples were further genotyped by conventional RT-PCR targeting the 5'-end of the capsid gene followed by sequencing of the positive PCR products. Overall, 41 (16.1%) samples tested positive for norovirus with an equal frequency in rotavirus-positive and rotavirus-negative samples. Nine (22%) samples were genogroup (G)I positive, 30 (73%) GII positive and two (5%) samples contained a mixture of GI and GII viruses. Sequence analyses demonstrated co-circulation of 14 norovirus genotypes including four GI genotypes (GI.3, GI.5, GI.7, GI.8) and 10 GII genotypes (GII.2, GII.3, GII.4, GII.5, GII.6, GII.7, GII.9, GII.13, GII.16, and GII.21). The most prevalent genotypes were GI.7 and GII.4 both causing 12.2% of the infections. This report confirms the presence of multiple norovirus genotypes in hospitalized children with acute gastroenteritis in Pakistan and a lack of clear predominance of GII.4 viruses.


A clinico-radiological phenotype of voltage-gated potassium channel complex antibody-mediated disorder presenting with seizures and basal ganglia changes.
In childhood, central nervous system (CNS) presentations associated with antibodies to voltage-gated potassium channel (VGKC) complex include limbic encephalitis, status epilepticus, epileptic encephalopathy, and autistic regression. We report the cases of two individuals (a 6-year-old male and an 11-year-old female) who presented with an acute-onset explosive seizure disorder with positive VGKC complex antibodies and bilateral basal ganglia changes on magnetic resonance imaging (MRI). Both patients made a complete clinical recovery, without immunotherapy, with resolution of the MRI changes and normalization of the antibody levels. Extended antibody testing, including testing for leucine-rich glioma-inactivated 1 (LGI1), contactin-associated protein 2, and contactin-2 was negative. This could suggest that the clinico-radiological phenotype in our patients may in fact be associated with a novel autoreactive target(s) within the VGKC complex, as may be the case in other children with VGKC complex-mediated CNS disorders.


Diagnosis and management of antibody-mediated rejection: current status and novel approaches.
Advances in multimodal immunotherapy have significantly reduced acute rejection rates and substantially improved 1-year graft survival following renal transplantation. However, long-term (10-year) survival rates have stagnated over the past decade. Recent studies indicate that antibody-mediated rejection (ABMR) is among the most important barriers to improving long-term outcomes. Improved understanding of the roles of acute and chronic ABMR has evolved in recent years following major progress in the technical ability to detect and quantify recipient anti-HLA antibody production. Additionally, new knowledge of the immunobiology of B cells and plasma cells that pertains to allograft rejection and tolerance has emerged. Still, questions regarding the classification of ABMR, the precision of diagnostic approaches, and the efficacy of various strategies for managing affected patients abound. This review article provides an overview of current thinking and research surrounding the pathophysiology and diagnosis of ABMR, ABMR-related outcomes, ABMR prevention and treatment, as well as possible future directions in treatment.


A new species of the genus Oxyporus Fabricius (Coleoptera: Staphylinidae: Oxyporinae) in Yunnan Province, China.
A new species of the genus Oxyporus Fabricius, 1775 is described based on specimens collected in Yunnan Province, China, namely Oxyporus (Oxyporus) mojiangius Li, sp. nov. from Mojiang County. The number of Oxyporus species worldwide is thus increased to 132. Color images of the habitus and aedeagus of the new species are included. A key to the Oxyporus species of Yunnan Province is provided.


Laparoscopic retroperitoneal adrenalectomy: clinical experience with 120 consecutive cases.
Surgical parameters of laparoscopic retroperitoneal adrenalectomy (LRA) for the treatment of benign adrenal tumours were analysed to report the clinical outcomes and technical guidelines for this operation. Operative data from 120 consecutive patients who underwent LRA performed by a single surgeon were reviewed. Patients were categorized into one of four stages according to the major technical modifications made during the development of this procedure: needle insufflation, kidney localization, instrument refinement, and the final stage of finger dissection. The surgical parameters of different stages were evaluated, including operation time, operative blood loss, adenoma size, pathology, surgical complications, morbidity, and postoperative recovery. LRA was an evolving technique; operation time and conversion rate decreased gradually as the technique evolved over the years. Operation time was reduced particularly when finger dissection was used to develop the operative working space. Operation time reached a nadir of 80 minutes for patients with left adrenal aldosteronoma after 40 such cases. The overall conversion rate, regardless of the nature of the tumour, was 5%; phaeochromocytoma had the highest conversion rate (43%). A higher conversion rate and longer operation time were noted in patients with Cushing's adenoma or phaeochromocytoma compared to patients with aldosteronoma. LRA proved to be a safe and effective treatment for benign adrenal tumours, with few open conversions except for phaeochromocytomas. Finger-assisted dissection for space development was the major factor leading to shortened operation times.


Colocalization and regulated physical association of presynaptic serotonin transporters with A₃ adenosine receptors.
Activation of A₃ adenosine receptors (A₃ARs) rapidly enhances the activity of antidepressant-sensitive serotonin (5-HT) transporters (SERTs) in vitro, ex vivo, and in vivo. A₃AR agonist stimulation of SERT activity is lost in A₃AR knockout mice. A₃AR-stimulated SERT activity is mediated by protein kinase G1 (PKGI)- and p38 mitogen-activated protein kinase (MAPK)-linked pathways that support, respectively, enhanced SERT surface expression and catalytic activation. The mechanisms by which A₃ARs target SERTs among other potential effectors is unknown. Here we present evidence that A₃ARs are coexpressed with SERT in midbrain serotonergic neurons and form a physical complex in A₃AR/hSERT cotransfected cells. Treatment of A₃AR/SERT-cotransfected Chinese hamster ovary cells with the A₃AR agonist N⁶-(3-iodobenzyl)-N-methyl-5'-carbamoyladenosine (1 μM, 10 min), conditions previously reported to increase SERT surface expression and 5-HT uptake activity, enhanced the abundance of A₃AR/SERT complexes in a PKGI-dependent manner. Cotransfection of SERT with L90V-A₃AR, a hyperfunctional coding variant identified in subjects with autism spectrum disorder, resulted in a prolonged recovery of receptor/transporter complexes after A₃AR activation. Because PKGI and nitric-oxide synthetase are required for A₃AR stimulation of SERT activity, and proteins PKGI and NOS both form complexes with SERT, our findings suggest a mechanism by which signaling pathways coordinating A₃AR signaling to SERT can be spatially restricted and regulated, as well as compromised by neuropsychiatric disorders.


[Increase in pulmonary vascular permeability caused by increased expression of Mac-1 on the surface of polymorphonuclear leukocytes].
We studied the expression of adhesion molecules on the surface of human polymorphonuclear leukocytes (PMNs). The effects of mechanical stimulation were measured with a flow cytometer and pulmonary vascular injury due to accumulation of PMNs in the lungs was assessed by a gravimetric method. The accumulation of PMNs in the lungs was studied by measuring the amount of myeloperoxidase. PMNs were stimulated by gentle agitation in a glass container for 10 s. Mac-1 (CD11b/CD18) was upregulated on the surface of PMNs that were mechanically stimulated. When unstimulated PMNs were exposed to isolated rat lungs, the filtration coefficient did not change from that under baseline conditions. However, when mechanically stimulated PMNs were exposed to isolated rat lungs, the filtration coefficient was about 5 times higher than that measured at baseline. When mechanically stimulated PMNs treated with anti-CD18 antibody were used, the increase in the filtration coefficient was completely blocked. The assay of myeloperoxidase revealed that PMNs stuck to isolated rat lungs only after stimulated PMNs were added. We conclude that when the adhesiveness of PMNs is increased by mechanical stimulation, these cells adhere to pulmonary vessels and increase pulmonary vascular permeability.


The aryl hydrocarbon receptor is a tumor suppressor-like gene in glioblastoma.
The aryl hydrocarbon receptor (AhR) plays an important role in maintaining cellular homeostasis and also in pathophysiology. For example, the interplay between the gut microbiome and microbially derived AhR ligands protects against inflammation along the gut-brain axis. The AhR and its ligands also inhibit colon carcinogenesis, but it has been reported that the AhR and its ligand kynurenine enhance glioblastoma (GBM). In this study, using both established and patient-derived GBM cells, we re-examined the role of kynurenine and the AhR in GBM, observing that kynurenine does not modulate AhR-mediated gene expression and does not affect invasion of GBM cells. Therefore, using an array of approaches, including ChIP, quantitative real-time PCR, and cell migration assays, we primarily focused on investigating the role of the AhR in GBM at the functional molecular and genomic levels. The results of transient and stable CRISPR/Cas9-mediated AhR knockdown in GBM cells indicated that loss of AhR enhances GBM tumor growth in a mouse xenograft model, increases GBM cell invasion, and up-regulates expression of pro-invasion/pro-migration genes, as determined by ingenuity pathway analysis of RNA-Seq data. We conclude that the AhR is a tumor suppressor-like gene in GBM; future studies are required to investigate whether the AhR could be a potential drug target for treating patients with GBM who express this receptor.


The temporal structure of behaviour and sleep homeostasis.
The amount and architecture of vigilance states are governed by two distinct processes, which occur at different time scales. The first, a slow one, is related to a wake/sleep dependent homeostatic Process S, which occurs on a time scale of hours, and is reflected in the dynamics of NREM sleep EEG slow-wave activity. The second, a fast one, is manifested in a regular alternation of two sleep states--NREM and REM sleep, which occur, in rodents, on a time scale of ~5-10 minutes. Neither the mechanisms underlying the time constants of these two processes--the slow one and the fast one, nor their functional significance are understood. Notably, both processes are primarily apparent during sleep, while their potential manifestation during wakefulness is obscured by ongoing behaviour. Here, we find, in mice provided with running wheels, that the two sleep processes become clearly apparent also during waking at the level of behavior and brain activity. Specifically, the slow process was manifested in the total duration of waking periods starting from dark onset, while the fast process was apparent in a regular occurrence of running bouts during the waking periods. The dynamics of both processes were stable within individual animals, but showed large interindividual variability. Importantly, the two processes were not independent: the periodic structure of waking behaviour (fast process) appeared to be a strong predictor of the capacity to sustain continuous wakefulness (slow process). The data indicate that the temporal organization of vigilance states on both the fast and the slow time scales may arise from a common neurophysiologic mechanism.


Multitrait GWAS to connect disease variants and biological mechanisms.
Genome-wide association studies (GWASs) have uncovered a wealth of associations between common variants and human phenotypes. Here, we present an integrative analysis of GWAS summary statistics from 36 phenotypes to decipher multitrait genetic architecture and its link with biological mechanisms. Our framework incorporates multitrait association mapping along with an investigation of the breakdown of genetic associations into clusters of variants harboring similar multitrait association profiles. Focusing on two subsets of immunity and metabolism phenotypes, we then demonstrate how genetic variants within clusters can be mapped to biological pathways and disease mechanisms. Finally, for the metabolism set, we investigate the link between gene cluster assignment and the success of drug targets in randomized controlled trials.


Lessons from the hepatoblastoma-familial polyposis connection.
Approximately one-third of hepatoblastoma (HB) patients have associated congenital abnormalities, but familial recurrence is rare, except in association with familial adenomatous polyposis (FAP). This correlation may be missed if not actively sought, with implications for long-term outcome and management. We retrospectively investigated 3 families with an HB-familial polyposis connection, from a cohort of 113 FAP families (1989 - 2010). Data were analysed to assess clinical problem, treatment, complications and management. Long-term morbidity and functional outcome were analysed to identify management difficulties. Three FAP families (2.65%) had an HB association. In one case, undiagnosed FAP at the time of HB diagnosis was only detected 5 years later, when the mother presented with advanced colorectal carcinoma. A chromosome 5 APC gene mutation (exon 15 codon 793 C→T) was then identified. In a second case, a non-related male child presented with a stage 4 multifocal HB with lung metastases. Genetic studies identified an APC gene mutation (exon 6 codon 232 C→T). Further family investigation showed >20 related FAP patients. A third HB-FAP association was identified in a known FAP family early in the study, prior to the availability of genetic testing. Although a rare association, a family history of FAP in HB patients is an important 'hidden connection'. Germline variation may be outside the usual FAP gene site. Identifying families with unknown HB/FAP is important due to long-term management implications and follow-up.


Prognosis for neonates with enterovirus hepatitis and coagulopathy.
Neonatal enterovirus hepatitis and coagulopathy (EHC) can be a severe, life-threatening infection. However, the case-fatality rate of EHC and the prognosis for survivors are not well-defined. A search of a hospital medical records database and the investigator's files for the period 1983 to 2000 was performed. Patients with onset of enterovirus-associated illness at age < or = 30 days and either (1) aspartate aminotransferase or alanine aminotransferase > 3 times the upper limit of normal or (2) platelet count < 100 000 plus an abnormal coagulation profile were included. Sixteen cases were identified. Symptoms began at a mean of 3.8 days (range, 1 to 7 days). Frequent clinical and laboratory findings included jaundice, lethargy, anorexia, hepatomegaly, thrombocytopenia, clotting time prolongation, elevated transaminase and bilirubin values and decreased fibrinogen and albumin concentrations. Five patients had myocarditis and 4 had encephalitis. Hemorrhagic complications occurred in 10 (intracranial hemorrhage in 5). Five (31%) patients died. Features discriminating patients who died from survivors were concomitant myocarditis (5 of 5 vs. 0 of 11, P < 0.001), encephalitis (3 of 5 vs. 1 of 11, P = 0.06), prothrombin time > 30 s (4 of 5 vs. 1 of 9, P = 0.02) and intracranial hemorrhage (4 of 5 vs. 1 of 8, P = 0.03). Follow-up of 6 survivors revealed normalization of liver function and platelet counts, satisfactory growth and absence of significant medical problems. The case-fatality rate of 31% is evidence of the potentially devastating nature of EHC. Concomitant EHC and myocarditis are especially serious, but the prognosis for children who survive neonatal EHC is generally excellent.


Esterase autodisplay: enzyme engineering and whole-cell activity determination in microplates with pH sensors.
Among the GDSL family of serine esterases/lipases is a group of bacterial enzymes that posses C-terminal extensions involved in outer membrane anchoring or translocation. ApeE from Salmonella enterica serovar Typhimurium, a member of this group, has been expressed in Escherichia coli and was resistant to protease digestion when the protease was added to whole cells, indicating a periplasmic localization. The five consensus blocks conserved within all GDSL esterases were identified in ApeE by multiple sequence alignment and separated from the C-terminal extension. The DNA sequence spanning the four invariant residues Ser, Gly, Asn, and His, and hence representing the catalytic domains of ApeE, was amplified by PCR and fused in frame to the transport domains of the autodisplay system. The resulting artificial esterase, called EsjA, was overexpressed in the cell envelope of E. coli and was shown to be active by the use of alpha-naphthyl acetate (alpha-NA) as a substrate in an in-gel activity stain after sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Surface exposure of EsjA was indicated by its accessibility to protease added to whole cells. The esterase activity of whole cells displaying EsjA was determined by a pH agar assay and by the use of microplates with integrated pH-dependent optical sensors. alpha-NA, alpha-naphthyl butyrate, and alpha-naphthyl caproate were used as substrates, and it turned out that the substrate preferences of artificial EsjA were altered in comparison to original ApeE. Our results indicate that autodisplay of esterase in combination with pH sensor microplates can provide a new platform technology for the screening of tailor-made hydrolase activities.


On the road to universal health care in Indonesia, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.
As Indonesia moves to provide health coverage for all citizens, understanding patterns of morbidity and mortality is important to allocate resources and address inequality. The Global Burden of Disease 2016 study (GBD 2016) estimates sources of early death and disability, which can inform policies to improve health care. We used GBD 2016 results for cause-specific deaths, years of life lost, years lived with disability, disability-adjusted life-years (DALYs), life expectancy at birth, healthy life expectancy, and risk factors for 333 causes in Indonesia and in seven comparator countries. Estimates were produced by location, year, age, and sex using methods outlined in GBD 2016. Using the Socio-demographic Index, we generated expected values for each metric and compared these against observed results. In Indonesia between 1990 and 2016, life expectancy increased by 8·0 years (95% uncertainty interval [UI] 7·3-8·8) to 71·7 years (71·0-72·3): the increase was 7·4 years (6·4-8·6) for males and 8·7 years (7·8-9·5) for females. Total DALYs due to communicable, maternal, neonatal, and nutritional causes decreased by 58·6% (95% UI 55·6-61·6), from 43·8 million (95% UI 41·4-46·5) to 18·1 million (16·8-19·6), whereas total DALYs from non-communicable diseases rose. DALYs due to injuries decreased, both in crude rates and in age-standardised rates. The three leading causes of DALYs in 2016 were ischaemic heart disease, cerebrovascular disease, and diabetes. Dietary risks were a leading contributor to the DALY burden, accounting for 13·6% (11·8-15·4) of DALYs in 2016. Over the past 27 years, health across many indicators has improved in Indonesia. Improvements are partly offset by rising deaths and a growing burden of non-communicable diseases. To maintain and increase health gains, further work is needed to identify successful interventions and improve health equity. The Bill & Melinda Gates Foundation.


History of the solar nebula from meteorite paleomagnetism.
We review recent advances in our understanding of magnetism in the solar nebula and protoplanetary disks (PPDs). We discuss the implications of theory, meteorite measurements, and astronomical observations for planetary formation and nebular evolution. Paleomagnetic measurements indicate the presence of fields of 0.54 ± 0.21 G at ~1 to 3 astronomical units (AU) from the Sun and ≳0.06 G at 3 to 7 AU until >1.22 and >2.51 million years (Ma) after solar system formation, respectively. These intensities are consistent with those predicted to enable typical astronomically observed protostellar accretion rates of ~10-8 M ⊙year-1, suggesting that magnetism played a central role in mass transport in PPDs. Paleomagnetic studies also indicate fields <0.006 G and <0.003 G in the inner and outer solar system by 3.94 and 4.89 Ma, respectively, consistent with the nebular gas having dispersed by this time. This is similar to the observed lifetimes of extrasolar protoplanetary disks.


[Ultrasound-guided aspiration of pleural fluid].
We review the outcome of guided, percutaneous, catheter drainage of pleural collections in 102 patients over a 2-year period. In 87% diagnostic aspiration of small or loculated collections was performed. Drainage of malignant and nonmalignant effusions in high-risk patients, or after failure of drainage without imaging guidance, was performed in 13%. All aspirations were successful and the only complication was a small pneumothorax in a single patient. If the collection was a small pneumothorax in a single patient. If the collections were large and easy to aspirate, we marked the best location for aspiration on the skin and sent the patient back to the ward for aspiration. We conclude that the use of sonography increases the proportion of successful drainage of small pleural collections and results in few complications.


Modestobacter caceresii sp. nov., novel actinobacteria with an insight into their adaptive mechanisms for survival in extreme hyper-arid Atacama Desert soils.
A polyphasic study was designed to determine the taxonomic provenance of three Modestobacter strains isolated from an extreme hyper-arid Atacama Desert soil. The strains, isolates KNN 45-1a, KNN 45-2b(T) and KNN 45-3b, were shown to have chemotaxonomic and morphological properties in line with their classification in the genus Modestobacter. The isolates had identical 16S rRNA gene sequences and formed a branch in the Modestobacter gene tree that was most closely related to the type strain of Modestobacter marinus (99.6% similarity). All three isolates were distinguished readily from Modestobacter type strains by a broad range of phenotypic properties, by qualitative and quantitative differences in fatty acid profiles and by BOX fingerprint patterns. The whole genome sequence of isolate KNN 45-2b(T) showed 89.3% average nucleotide identity, 90.1% (SD: 10.97%) average amino acid identity and a digital DNA-DNA hybridization value of 42.4±3.1 against the genome sequence of M. marinus DSM 45201(T), values consistent with its assignment to a separate species. On the basis of all of these data, it is proposed that the isolates be assigned to the genus Modestobacter as Modestobacter caceresii sp. nov. with isolate KNN 45-2b(T) (CECT 9023(T)=DSM 101691(T)) as the type strain. Analysis of the whole-genome sequence of M. caceresii KNN 45-2b(T), with 4683 open reading frames and a genome size of ∽4.96Mb, revealed the presence of genes and gene-clusters that encode for properties relevant to its adaptability to harsh environmental conditions prevalent in extreme hyper arid Atacama Desert soils.


Neuronal computations with stochastic network states.
Neuronal networks in vivo are characterized by considerable spontaneous activity, which is highly complex and intrinsically generated by a combination of single-cell electrophysiological properties and recurrent circuits. As seen, for example, during waking compared with being asleep or under anesthesia, neuronal responsiveness differs, concomitant with the pattern of spontaneous brain activity. This pattern, which defines the state of the network, has a dramatic influence on how local networks are engaged by inputs and, therefore, on how information is represented. We review here experimental and theoretical evidence of the decisive role played by stochastic network states in sensory responsiveness with emphasis on activated states such as waking. From single cells to networks, experiments and computational models have addressed the relation between neuronal responsiveness and the complex spatiotemporal patterns of network activity. The understanding of the relation between network state dynamics and information representation is a major challenge that will require developing, in conjunction, specific experimental paradigms and theoretical frameworks.


[Validation of the ICE model to assess social class in the adult population].
Social class has commonly been defined by the type of employment and it is assessed as a categorical variable. However, this approach has a number of drawbacks. The objective of this article is to develop and validate a readily standardizable quantitative indicator of social class and to show its ability to measure the impact of social class as a health determinant. In 6729 individuals we measured income, crowding index, education, occupation and employment status. Two models were adjusted to study the neighborhood, dietary pattern and health problems. The model that included only income, crowding index and education (ICE) yielded an indicator that correlated with age (r = -0.28; p < 0.001) and consumption of potatoes (r = -0.17; p < 0.001) and salads (r = 0.10; p < 0.001). This indicator estimated that poor social classes were at significant risk for unemployment (OR = 5,), blue collar jobs (OR = 40,9), residing in poor neighborhoods (OR = 30.2), low salad consumption (OR = 2.2) and high consumption of potatoes (OR = 4.5). They also had, especially in women, a higher risk of sedentarism (OR = 1.8), obesity (OR = 4.4), metabolic syndrome (OR = 3.4) and diabetes mellitus (OR = 2.0). The ICE index was valid, not based on occupation or employment status, readily standardizable, and suitable for measuring social class and its impact of on health.


Human adipose tissue-derived mesenchymal stem/stromal cells adhere to and inhibit the growth of Staphylococcus aureus and Pseudomonas aeruginosa.
We have cultured and phenotyped human adipose tissue-derived mesenchymal stem/stromal cells (AT MSCs) and inoculated these cultures with bacteria common to infected skin wounds, i.e. Staphylococcus aureus and Pseudomonas aeruginosa. Cell interactions were examined by scanning electron microscopy (SEM), whilst bacterial growth was measured by colony forming unit (c.f.u.) and biofilm assays. AT MSCs appeared to attach to the bacteria and to engulf S. aureus. Significantly fewer bacterial c.f.u. were present in AT MSC : bacterial co-cultures compared with bacteria cultured alone. Antibacterial activity, including an inhibition of P. aeruginosa biofilm formation, was observed when bacteria were treated with conditioned medium harvested from the AT MSC : bacterial co-cultures, irrespective of the bacterial species to which the AT MSCs had been exposed to previously. Hence, we have demonstrated that AT MSCs inhibit the growth of two common bacterial species. This was associated with bacterial adhesion, potential engulfment or phagocytosis, and the secretion of antibacterial factors.


Programmed Death-Ligand 1 Immunohistochemistry in Lung Cancer: In what state is this art?
Therapeutic antibodies to programmed death receptor 1 (PD-1) and its ligand PD-L1 show promising clinical results. Anti-PD-L1 immunohistochemistry (IHC) may be a biomarker to select patients more likely to respond to these treatments. However, the development of at least four different therapeutics, each with a different anti-PD-L1 IHC assay, has raised concerns among pathologists and oncologists alike. This article reviews existing data on the IHC biomarker aspects of studies using these drugs in non-small-cell lung cancer (NSCLC) and considers the challenges ahead, should these drug/IHC assay combinations reach routine practice. For each the known biomarker assays in development, there is a different monoclonal IHC antibody clone, produced by one of two diagnostics companies. Each test requires proprietary staining platforms and uses different definitions of a "positive" test for PD-L1 expression, on tumor cells and, in one test, also on tumor infiltrating immune cells. There are still considerable gaps in our knowledge of the technical aspects of these tests, and of the biological implications and associations of PD-L1 expression in NSCLC, considering heterogeneity of expression, dynamic changes in expression, and prognostic implications among other factors. The International Association for the Study of Lung Cancer Pathology Committee raises the prospect of trying not only to harmonize and standardize testing for PD-L1 by IHC, at least at a technical level, but also, ideally, as a predictive marker, to facilitate availability of this test and a promising treatment for patients with NSCLC.


Induction of detoxifying enzymes by garlic organosulfur compounds through transcription factor Nrf2: effect of chemical structure and stress signals.
Garlic organosulfur compounds (OSCs) are recognized as a group of potential chemopreventive compounds. It is known that garlic OSCs can modulate drug metabolism systems, especially various phase II detoxifying enzymes, though the mechanism underlying their inductive effect on these enzymes remains largely unknown. In the present study, we investigated the transcriptional levels of NAD(P)H:quinone oxidoreductase 1 (NQO1) and heme oxygenase 1 (HO1) genes, the reporter activity mediated by antioxidant response element (ARE), and the protein level of transcription factor nuclear factor E2-related factor 2 (Nrf2), after administration of three major garlic OSCs--diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS)--in human hepatoma HepG2 cells. Our results showed that ARE activation and Nrf2 protein accumulation were well correlated with phase II gene expression induction. The structure-activity relationship study indicated that the third sulfur in the structure of OSCs contributed substantially to their bioactivities, and that allyl-containing OSCs were more potent than propyl-containing OSCs. To better understand the signaling events involved in the upregulation of detoxifying enzymes by DATS, ARE activity and Nrf2 protein levels were examined after transient transfection of HepG2 cells with mutant Nrf2, cotreatment with antioxidants, and pretreatment with protein kinase inhibitors. DATS-induced ARE activity was inhibited by dominant-negative Nrf2 Kelch-like ECH-associating protein 1 and constructs. Cotreatment with thiol antioxidants decreased the ARE activity and Nrf2 protein level induced by DATS. Three major mitogen-activated protein kinases (MAPKs)--extracellular signal-regulated protein kinase, c-Jun N-terminal kinase, and p38--were activated by DATS treatment. However, the inhibition of these MAPKs did not affect DATS-induced ARE activity. Pretreatment with various upstream protein kinase inhibitors showed that the protein kinase C pathway was not directly involved in DATS-induced ARE activity, but instead the calcium-dependent signaling pathway appeared to play a role in the DATS-induced cytoprotective effect.


The role of child care settings in obesity prevention.
Mary Story, Karen Kaphingst, and Simone French argue that researchers and policymakers focused on childhood obesity have paid insufficient attention to child care. Although child care settings can be a major force in shaping children's dietary intake, physical activity, and energy balance-and thus in combating the childhood obesity epidemic-researchers know relatively little about either the nutrition or the physical activity environment in the nation's child care facilities. What research exists suggests that the nutritional quality of meals and snacks may be poor and activity levels may be inadequate. Few uniform standards apply to nutrition or physical activity offerings in the nation's child care centers. With the exception of the federal Head Start program, child care facilities are regulated by states, and state rules vary widely. The authors argue that weak state standards governing physical activity and nutrition represent a missed opportunity to combat obesity. A relatively simple measure, such as specifying how much time children in day care should spend being physically active, could help promote healthful habits among young children. The authors note that several federal programs provide for the needs of low-income children in child care. The Child and Adult Care Food Program, administered by the Department of Agriculture, provides funds for meals and snacks for almost 3 million children in child care each day. Providers who receive funds must serve meals and snacks that meet certain minimal standards, but the authors argue for toughening those regulations so that meals and snacks meet specific nutrient-based standards. The authors cite Head Start, a federal preschool program serving some 900,000 low-income infants and children up to age five, as a model for other child care programs as it has federal performance standards for nutrition. Although many child care settings fall short in their nutritional and physical activity offerings, they offer untapped opportunities for developing and evaluating effective obesity-prevention strategies to reach both children and their parents.


Identification of critical isthmus using coherent mapping in patients with scar-related atrial tachycardia.
Accurate identification of slow conducting regions in patients with scar-related atrial tachycardia (AT) is difficult using conventional electrogram annotation for cardiac electroanatomic mapping (EAM). Estimating delays between neighboring mapping sites is a potential option for activation map computation. We describe our initial experience with CARTO 3 Coherent Mapping (Biosense Webster Inc,) in the ablation of complex ATs. Twenty patients (58 ± 10 y/o, 15 males) with complex ATs were included. We created three-dimensional EAMs using CARTO 3 system with CONFIDENSE and a high-resolution mapping catheter (Biosense Webster Inc). Local activation time and coherent maps were used to aid in the identification of conduction isthmus (CI) and focal origin sites. System-defined slow or nonconducting zones and CI, defined by concealed entrainment (postpacing interval < 20 ms), CV < 0.3 m/s and local fractionated electrograms were evaluated. Twenty-six complex ATs were mapped (mean: 1.3 ± 0.7 maps/pt; 4 focal, 22 isthmus-dependent). Coherent mapping was better in identifying CI/breakout sites where ablation terminated the tachycardia (96.2% vs 69.2%; P = .010) and identified significantly more CI (mean/chamber 2.0 ± 1.1 vs 1.0 ± 0.7; P < .001) with narrower width (19.8 ± 10.5 vs 43.0 ± 23.9 mm; P < .001) than conventional mapping. Ablation at origin and CI sites was successful in 25 (96.2%) with long-term recurrence in 25%. Coherent mapping with conduction velocity vectors derived from adjacent mapping sites significantly improved the identification of CI sites in scar-related ATs with isthmus-dependent re-entry better than conventional mapping. It may be used in conjunction with conventional mapping strategies to facilitate recognition of slow conduction areas and critical sites that are important targets of ablation.


Postural adaptation in elderly patients with instability and risk of falling after balance training using a virtual-reality system.
Our aim in this study was to assess postural control adaptation quantitatively in unsteady elderly patients at risk of falls in open spaces and given balance training with a virtual-reality system reproducing environmental stimulation. Using a balance rehabilitation unit based on a virtual-reality system that changes sensory information (visual, vestibular, and somatosensory), we treated 26 elderly, unsteady patients who were prone to falling (age range, 73-82 years) and who were enrolled in a customized vestibular rehabilitation program. We assessed postural responses by posturography before and after 6 weeks in the vestibular rehabilitation program under two conditions: (1) standing, eyes open, static visual field, and (2) standing, eyes open, dynamic visual field through virtual-reality goggles, generating horizontal optokinetic stimulation (70 degrees per second angular velocity). We recorded postural responses with a platform measuring the confidential ellipse of the center-of-pressure distribution area and sway velocity with a scalogram analyzing postural behavior by wavelets. After 6 weeks of treatment, postural response confidential ellipse and sway velocity values were lower, evincing decreased amplitudes and sway frequency contents in the scalogram by wavelet under both stimulation paradigm conditions. These findings suggest postural adaptation under the two perceptual conditions when patients had static and dynamic visual fields. The possibility of treating elderly fallers with balance disorders using a virtual-reality environmental stimulation reproduction system is discussed.


The role of psychiatry in death penalty defense.
The author describes his experience as an expert in evaluating defendants convicted of capital murder. He reviews the Supreme Court decisions and provisions of state law that have led defense attorneys to obtain psychiatric evaluations of their clients. Three illustrative cases are presented, one of an incompetent grossly impaired defendant, one of a defendant for whom the finding of mental health played a role in over turning his conviction, and one for a defendant who was later found to be retarded and therefore not executable. The clinical and social implications of psychiatric participation in these cases are discussed.


Variable detours in long-distance migration across ecological barriers and their relation to habitat availability at ground.
Migration detours, the spatial deviation from the shortest route, are a widespread phenomenon in migratory species, especially if barriers must be crossed. Moving longer distances causes additional efforts in energy and time, and to be adaptive, this should be counterbalanced by favorable condition en route. We compared migration patterns of nightingales that travelled along different flyways from their European breeding sites to the African nonbreeding sites. We tested for deviations from shortest routes and related the observed and expected routes to the habitat availability at ground during autumn and spring migration. All individuals flew detours of varying extent. Detours were largest and seasonally consistent in western flyway birds, whereas birds on the central and eastern flyways showed less detours during autumn migration, but large detours during spring migration (eastern flyway birds). Neither migration durations nor the time of arrival at destination were related to the lengths of detours. Arrival at the breeding site was nearly synchronous in birds flying different detours. Flying detours increased the potential availability of suitable broad-scale habitats en route only along the western flyway. Habitat availability on observed routes remained similar or even decreased for individuals flying detours on the central or the eastern flyway as compared to shortest routes. Thus, broad-scale habitat distribution may partially explain detour performance, but the weak detour-habitat association along central and eastern flyways suggests that other factors shape detour extent regionally. Prime candidate factors are the distribution of small suitable habitat patches at local scale as well as winds specific for the region and altitude.


Objective and Subjective Prevalence of Obstructive Sleep Apnoea/Hypopnoea Syndrome in UK Adults with Down Syndrome: A Strong Marker for Diurnal Behavioural Disturbances.
Prior to this study, the prevalence of obstructive sleep apnoea/hypopnoea syndrome (OSAHS) in adults with Down syndrome was unknown. We hypothesized that unrecognised OSAHS could have an additional deleterious impact on mood and behavioural disturbances in this group of people. To assess the prevalence of OSAHS in adults with Down syndrome in the United Kingdom, subjectively and objectively, and ascertain its association with diurnal behavioural disturbances. Cross-sectional questionnaire study with home sleep apnoea testing (HSAT) during 2011-2015 across the four nations of the United Kingdom. Participants were adults aged ≥16 years with Down syndrome. Main outcome measures were: self- or caregiver-completed questionnaire data, including the Pictorial Epworth Sleepiness Scale (pESS), selected domains of the Developmental Behavioural Checklist for Adults (DBC-A), anthropometric measures, and symptoms of OSAHS. Objective prevalence was undertaken in a sample of responders using HSAT. Responses were received from 1321/5270 participants (25%), with 1105 valid responses (21%). Eighty-one participants (7%) reported a prior diagnosis of OSA, of whom 38 were receiving therapy. Using validated algorithms, a diagnosis of OSAHS was probable in 366 participants (35%), who were younger, with higher BMI and higher mean total pESS (p < 0.0001). A total of 23% of participants had a pESS > 10. OSAHS was a strong marker for behavioural disturbances on the DBC-A depression, disruption and anti-social subscales (p < 0.001). Of 149 individuals who underwent HSAT, 42% were diagnosed with OSAHS. Untreated OSAHS in Down syndrome is common and associated with behavioural and mood disturbances. Improving awareness of OSAHS amongst adults with Down syndrome, their families and healthcare professionals is essential.


Carbon debt of Conservation Reserve Program (CRP) grasslands converted to bioenergy production.
Over 13 million ha of former cropland are enrolled in the US Conservation Reserve Program (CRP), providing well-recognized biodiversity, water quality, and carbon (C) sequestration benefits that could be lost on conversion back to agricultural production. Here we provide measurements of the greenhouse gas consequences of converting CRP land to continuous corn, corn-soybean, or perennial grass for biofuel production. No-till soybeans preceded the annual crops and created an initial carbon debt of 10.6 Mg CO(2) equivalents (CO(2)e)·ha(-1) that included agronomic inputs, changes in C stocks, altered N(2)O and CH(4) fluxes, and foregone C sequestration less a fossil fuel offset credit. Total debt, which includes future debt created by additional changes in soil C stocks and the loss of substantial future soil C sequestration, can be constrained to 68 Mg CO(2)e·ha(-1) if subsequent crops are under permanent no-till management. If tilled, however, total debt triples to 222 Mg CO(2)e·ha(-1) on account of further soil C loss. Projected C debt repayment periods under no-till management range from 29 to 40 y for corn-soybean and continuous corn, respectively. Under conventional tillage repayment periods are three times longer, from 89 to 123 y, respectively. Alternatively, the direct use of existing CRP grasslands for cellulosic feedstock production would avoid C debt entirely and provide modest climate change mitigation immediately. Incentives for permanent no till and especially permission to harvest CRP biomass for cellulosic biofuel would help to blunt the climate impact of future CRP conversion.


The effects of estrogen and androgen on tear secretion and matrix metalloproteinase-2 expression in lacrimal glands of ovariectomized rats.
Previous studies have shown that ovariectomy (OVX) induces lacrimal gland regression and that androgens are implicated. This study explored the effects of estrogen and androgen on tear secretion and matrix metalloproteinase 2 (MMP-2) expression in lacrimal glands of ovariectomized rats. Sixty-four adult female Wistar rats were randomly divided into three groups (control, sham operated, and OVX). Bilateral OVX was performed in the OVX group. After 5 months, the OVX group was further divided into six subgroups receiving topical ophthalmic or systemic treatment with corn oil vehicle, estradiol, or testosterone for 6 weeks. Schirmer test (SIT), assessment of tear film breakup time (BUT), corneal fluorescein staining, and measurement of estradiol and testosterone levels were performed before OVX and 1, 2, 3, 4, and 5 months after OVX, as well as after 6 weeks of treatment. Lacrimal glands were assessed for MMP-2 mRNA and protein expression. The mean (SD) tear film BUT decreased from 10.53 (0.79) to 9.98 (1.00) seconds (P < 0.01) in the first month after OVX, and the mean (SD) SIT result decreased by 50% from 7.32 (1.61) to 3.39 (1.15) mm (P < 0.01) in the third month after OVX. The mean (SD) corneal fluorescein staining score increased from 0.35 (0.11) to 6.02 (1.34) (P < 0.05) in the fourth month after OVX. The values increased or decreased in parallel with the time course (P < 0.01). In serum, ovariectomy resulted in a mean (SD) decline in estradiol levels from 44.38 (9.78) to 23.00 (3.78) pg/mL (P < 0.01), and the mean (SD) testosterone levels decreased from 2.42 (0.26) to 1.87 (0.15) ng/mL (P < 0.05). The mean (SD) estradiol level was elevated to 35.38 (3.34) pg/mL by systemic estradiol administration for 6 weeks, which also led to further mean (SD) decreases in tear film BUT from 5.28 (0.81) to 3.65 (0.55) seconds (P < 0.01) and in SIT result from 2.19 (1.01) to 1.47 (0.85) mm (P < 0.05), as well as a higher mean (SD) corneal fluorescein staining score from 7.39 (1.34) to 9.89 (1.27) (P < 0.05). However, the mean (SD) testosterone level was increased to 3.53 (0.67) ng/mL by systemic testosterone administration for 6 weeks. As a result, the mean (SD) tear film BUT increased from 5.08 (0.40) to 6.03 (1.48) seconds (P < 0.05), and the mean (SD) SIT result increased from 2.38 (1.20) to 3.66 (1.90) mm (P < 0.05). The mean (SD) corneal fluorescein staining score declined from 7.45 (0.73) to 4.56 (1.21) (P < 0.05). In the nontreated OVX group, the mean (SD) MMP-2 mRNA (0.66 [0.10]) and protein (0.55 [0.13]) expression in lacrimal glands was significantly increased compared with that in the sham-operated group (0.50 [0.09] and 0.40 [0.07], respectively) (P < 0.05). Systemic estradiol administration further increased the mean (SD) MMP-2 mRNA (0.83 [0.10]) and protein (0.69 [0.12]) expression (P < 0.05), while systemic testosterone administration decreased the mean (SD) MMP-2 mRNA (0.12 [0.04]) and protein (0.27 [0.07]) expression (P < 0.01). Topical ophthalmic administration of two sex hormones had no effect on the mean (SD) MMP-2 mRNA (0.59 [0.12] for estradiol and 0.57 [0.14] for testosterone) or protein (0.49 [0.11] for estradiol and 0.46 [0.13] for testosterone) expression (P > 0.05). Ovariectomy-induced ocular surface impairment may be associated with androgen deficiency. A pathogenetic role for estrogen in dry eye may involve upregulation of MMP-2 expression, while androgen suppresses MMP-2 expression.


Common polymorphisms in WNT10A affect tooth morphology as well as hair shape.
Hair and teeth are appendages of ectodermal origin, and there are common molecular backgrounds involved in their formation. To date, it has been revealed that a non-synonymous polymorphism in EDAR has effects on the morphological variation in both hair and teeth. Previous association studies have confirmed that single-nucleotide polymorphisms (SNPs) in/near THADA, FRAS1, WNT10A, NAF1 and FGFR2 are associated with hair morphology. In this study, we thus examined whether these SNPs are also associated with dental characteristics. We measured metric dental traits including crown size and also evaluated non-metric dental traits using plaster casts obtained from subjects (272 Japanese and 226 Koreans). DNA samples were prepared from the subjects and genotyped for the hair morphology-associated SNPs. We observed a significant association of crown size with an SNP in WNT10A (rs7349332), but not with SNPs in other genes. Therefore, we further examined four SNPs within and around WNT10A, among which rs10177996 had the strongest association with dental traits. World distribution of the derived allele in rs10177996, which is associated with larger teeth, showed that Eurasians have a higher allele frequency than Africans. Together with previous studies on hair morphology, this study demonstrated that common variations in WNT10A have pleiotropic effects on the morphology of ectodermal appendages.


Experimental characterization and mitigation of turbulence induced signal fades within an ad hoc FSO network.
Optical beams propagating through the turbulent atmospheric channel suffer from both the attenuation and phase distortion. Since future wireless networks are envisaged to be deployed in the ad hoc mesh topology, this paper presents the experimental laboratory characterization of mitigation of turbulence induced signal fades for two ad hoc scenarios. Results from measurements of the thermal structure constant along the propagation channels, changes of the coherence lengths for different turbulence regimes and the eye diagrams for partially correlated turbulences in free space optical channels are discussed. Based on these results future deployment of optical ad hoc networks can be more straightforwardly planned.


Patterns of dynamic hyperinflation during exercise and recovery in patients with severe chronic obstructive pulmonary disease.
Not all patients with severe chronic obstructive pulmonary disease (COPD) progressively hyperinflate during symptom limited exercise. The pattern of change in chest wall volumes (Vcw) was investigated in patients with severe COPD who progressively hyperinflate during exercise and those who do not. Twenty patients with forced expiratory volume in 1 second (FEV(1)) 35 (2)% predicted were studied during a ramp incremental cycling test to the limit of tolerance (Wpeak). Changes in Vcw at the end of expiration (EEVcw), end of inspiration (EIVcw), and at total lung capacity (TLCVcw) were computed by optoelectronic plethysmography (OEP) during exercise and recovery. Two significantly different patterns of change in EEVcw were observed during exercise. Twelve patients had a progressive significant increase in EEVcw during exercise (early hyperinflators, EH) amounting to 750 (90) ml at Wpeak. In contrast, in all eight remaining patients EEVcw remained unchanged up to 66% Wpeak but increased significantly by 210 (80) ml at Wpeak (late hyperinflators, LH). Although at the limit of tolerance the increase in EEVcw was significantly greater in EH, both groups reached similar Wpeak and breathed with a tidal EIVcw that closely approached TLCVcw (EIVcw/TLCVcw 93 (1)% and 93 (3)%, respectively). EEVcw was increased by 254 (130) ml above baseline 3 minutes after exercise only in EH. Patients with severe COPD exhibit two patterns during exercise: early and late hyperinflation. In those who hyperinflate early, it may take several minutes before the hyperinflation is fully reversed after termination of exercise.


Effect of mushroom Agaricus blazei on immune response and development of experimental cerebral malaria.
Cerebral malaria (CM) is debilitating and sometimes fatal. Disease severity has been associated with poor treatment access, therapeutic complexity and drug resistance and, thus, alternative therapies are increasingly necessary. In this study, the effect of the administration of Agaricus blazei, a mushroom of Brazilian origin in a model of CM caused by Plasmodium berghei, strain ANKA, was investigated in mice. C57BL/6 mice were pre-treated with aqueous extract or fractions of A. blazei, or chloroquine, infected with P. berghei ANKA and then followed by daily administration of A. blazei or chloroquine. Parasitaemia, body weight, survival and clinical signs of the disease were evaluated periodically. The concentration of pro-and anti-inflammatory cytokines, histopathology and in vitro analyses were performed. Mice treated with A. blazei aqueous extract or fraction C, that shows antioxidant activity, displayed lower parasitaemia, increased survival, reduced weight loss and protection against the development of CM. The administration of A. blazei resulted in reduced levels of TNF, IL-1β and IL-6 production when compared to untreated P. berghei-infected mice. Agaricus blazei (aqueous extract or fraction C) treated infected mice displayed reduction of brain lesions. Although chloroquine treatment reduced parasitaemia, there was increased production of proinflammatory cytokines and damage in the CNS not observed with A. blazei treatment. Moreover, the in vitro pretreatment of infected erythrocytes followed by in vivo infection resulted in lower parasitaemia, increased survival, and little evidence of clinical signs of disease. This study strongly suggests that the administration of A. blazei (aqueous extract or fraction C) was effective in improving the consequences of CM in mice and may provide novel therapeutic strategies.


Lifestyle and clinical factors associated with elevated C-reactive protein among newly diagnosed Type 2 diabetes mellitus patients: a cross-sectional study from the nationwide DD2 cohort.
We aimed to examine the prevalence of and modifiable factors associated with elevated C-reactive Protein (CRP), a marker of inflammation, in men and women with newly diagnosed Type 2 Diabetes mellitus (DM) in a population-based setting. CRP was measured in 1,037 patients (57% male) with newly diagnosed Type 2 DM included in the prospective nationwide Danish Centre for Strategic Research in Type 2 Diabetes (DD2) project. We assessed the prevalence of elevated CRP and calculated relative risks (RR) examining the association of CRP with lifestyle and clinical factors by Poisson regression, stratified by gender. We used linear regression to examine the association of CRP with other biomarkers. The median CRP value was 2.1 mg/L (interquartile range, 1.0 - 4.8 mg/L). In total, 405 out of the 1,037 Type 2 DM patients (40%) had elevated CRP levels (>3.0 mg/L). More women (46%) than men (34%) had elevated CRP. Among women, a lower risk of elevated CRP was observed in patients receiving statins (adjusted RR (aRR) 0.7 (95% confidence interval (CI) 0.6-0.9)), whereas a higher risk was seen in patients with central obesity (aRR 2.3 (95% CI 1.0-5.3)). For men, CRP was primarily elevated among patients with no regular physical activity (aRR 1.5 (95% CI 1.1-1.9)), previous cardiovascular disease (aRR1.5 (95% CI 1.2-1.9) and other comorbidity. For both genders, elevated CRP was 1.4-fold increased in those with weight gain >30 kg since age 20 years. Sensitivity analyses showed consistent results with the full analysis. The linear regression analysis conveyed an association between high CRP and increased fasting blood glucose. Among newly diagnosed Type 2 DM patients, 40% had elevated CRP levels. Important modifiable risk factors for elevated CRP may vary by gender, and include low physical activity for men and central obesity and absence of statin use for women.


Evaluation of Calcium Electroporation for the Treatment of Cutaneous Metastases: A Double Blinded Randomised Controlled Phase II Trial.
Calcium electroporation (Ca-EP) is a new anticancer treatment providing similar features to electrochemotherapy (ECT). The aim of our study is to compare the efficacy of Ca-EP with bleomycin-based ECT. This double-blinded randomized controlled phase II study was conducted at the Medical University of Szeged, Hungary. During this once only treatment up to ten measurable cutaneous metastases per patient were separately block randomized for intratumoral delivery of either calcium or bleomycin, which was followed by reversible electroporation. Tumour response was evaluated clinically and histologically six months after treatment. (ClinicalTrials.gov: NCT03628417, closed). Seven patients with 44 metastases (34 from malignant melanoma, 10 from breast cancer) were included in the study. Eleven metastases were taken for biopsies, and 33 metastases were randomised and treated once. The objective response rates were 33% (6/18) for Ca-EP and 53% (8/15) for bleomycin-based ECT, with 22% (4/18) and 40% (6/15) complete response rates, respectively. The CR was confirmed histologically in both arms. Serious adverse events were not registered. Ulceration and hyperpigmentation, both CTCA criteria grade I side effects, were observed more frequently after bleomycin-based ECT than for Ca-EP. Ca-EP was non-inferior to ECT, therefore, it should be considered as a feasible, effective and safe treatment option.