A hindbrain segmental scaffold specifying neuronal location in the adult goldfish, Carassius auratus.
The vertebrate hindbrain develops as a series of well-defined neuroepithelial segments or rhombomeres. While rhombomeres are visible in all vertebrate embryos, generally there is not any visible segmental anatomy in the brains of adults. Teleost fish are exceptional in retaining a rhombomeric pattern of reticulospinal neurons through embryonic, larval, and adult periods. We use this feature to map more precisely the segmental imprint in the reticular and motor basal hindbrain of adult goldfish. Analysis of serial sections cut in three planes and computer reconstructions of retrogradely labeled reticulospinal neurons yielded a segmental framework compatible with previous reports and more amenable to correlation with surrounding neuronal features. Cranial nerve motoneurons and octavolateral efferent neurons were aligned to the reticulospinal scaffold by mapping neurons immunopositive for choline acetyltransferase or retrogradely labeled from cranial nerve roots. The mapping corresponded well with the known ontogeny of these neurons and helps confirm the segmental territories defined by reticulospinal anatomy. Because both the reticulospinal and the motoneuronal segmental patterns persist in the hindbrain of adult goldfish, we hypothesize that a permanent "hindbrain framework" may be a general property that is retained in adult vertebrates. The establishment of a relationship between individual segments and neuronal phenotypes provides a convenient method for future studies that combine form, physiology, and function in adult vertebrates.


Antifungal Effect of Bacillus velezensis ZN-S10 against Plant Pathogen Colletotrichum changpingense and Its Inhibition Mechanism.
In order to optimize crop production and mitigate the adverse impacts associated with the utilization of chemical agents, it is necessary to explore new biocontrol agents. Bacillus velezensis has been widely studied as a biocontrol agent because of its efficient and ecofriendly plant disease control mechanisms. This study shows that the strain ZN-S10 effectively reduces the area of leaf spots caused by the pathogen Colletotrichum changpingense ZAFU0163-1, which affects conidia production and germination, inhibits mycelium growth, and induces mycelium deformation. In antifungal experiments with crude extracts, we observed a delay in the cell cycle of conidia, which may be responsible for the inhibition of conidial germination. Among the bioactive metabolites detected through integrated LC-MS- and GC-MS-based untargeted metabolomics, 7-O-Succinyl macrolactin A, telocinobufagin, and surfactin A may be the main antifungal metabolites of strain ZN-S10. The presence of 7-O-Succinyl macrolactin A could explain the cell damage in germ tubes. This is the first report of telocinobufagin detected in B. velezensis. These results are significant for understanding the inhibitory mechanisms employed by B. velezensis and should serve as a reference in the production of biocontrol agents.


Carry-over effects of periparturient endocrine changes on postpartum reproductive function of Holstein heifers bred to genetically different service sires.
Effects of fetal sire on postpartum reproductive changes of the dam were studied in 21 Holstein heifers whose pregnancy had been initiated by either Angus (n = 7), Holstein (n = 7) or Brahman (n = 7) bulls. After parturition, all heifers were managed uniformly. Heifers in each service-sire-breed group were bled via jugular venipuncture thrice weekly from d 160 to 265 of pregnancy, daily thereafter until 15 d postpartum, and three times per week until d 60 postpartum. Ability of heifers to release prolactin (PRL) and luteinizing hormone (LH) was evaluated on d 10 postpartum after a simultaneous injection of thyrotropin releasing hormone (TRH; 100 micrograms) and gonadotropin releasing hormone (GnRH; 100 micrograms). Between d 5 and 60 postpartum, the reproductive tract of each heifer was examined rectally thrice weekly after collection of blood samples. Basal concentrations of LH from d 1 to 10 postpartum, as well as ability of the pituitary gland to release LH and PRL after the GnRH-TRH challenge, did not differ between service-sire-breed groups (P greater than .1). Means and profiles of progesterone concentrations during the first 60 d postpartum did not differ between service-sire-breed groups (P greater than .1). However, increases in progesterone concentrations following the GnRH-TRH challenge were synchronized more precisely in Angus (P less than .02) than in Holstein- and Brahman-service-sire groups. Daily rates of reduction in cervical and uterine horn diameters were higher (P less than .01) in Holstein- and Brahman- than in Angus-service-sire groups and were associated with higher profiles of postpartum 15-keto-13,14-dihydro-prostaglandin F2 alpha (PGFM) concentrations. Within-cow PGFM concentrations were correlated positively with cervical (r = .36) and uterine horn (r = .32) diameters. Postpartum ovarian responsiveness and uterine involution in Holstein heifers may be affected by genotypes of the conceptus they bore during pregnancy.


Management of Mandible Fracture in 150 Children Across 7 Years in a US Tertiary Care Hospital.
Pediatric mandible fractures are the most common pediatric facial fracture requiring hospitalization, but data are lacking on management methods, outcomes, and complications. To analyze management methods, outcomes, and complications of pediatric mandible fractures at an urban academic tertiary care center. Single-institution cohort study conducted at 2 urban level 1 pediatric trauma centers including all patients aged 0 to 17 years diagnosed with mandible fractures between January 1, 2010, and December 31, 2016. Fractures were treated by multispecialty surgical teams. Data were analyzed between January 1, 2018, and March 1, 2018. Fracture distributions, mechanisms, treatment methods, complications, and follow-up. Of 150 patients with 310 total mandible fractures, the mean (SD) age was 12.8 (4.6) years; 108 (72.0%) were male; 107 (71.3%) were white; and 109 (72.7%) had 2 or more mandible fractures. There were 78 condylar or subcondylar fractures (60 patients), 75 ramus or angle fractures (69 patients), 69 body fractures (62 patients), 78 symphyseal or parasymphyseal fractures (76 patients), and 10 coronoid fractures (10 patients). The most common mechanisms of injury were assault and battery, motor vehicle collisions, falls or play, and sports-related mechanisms. Thirty-eight (25%) patients were treated with observation and a soft diet. Children 12 years and older were more likely to receive open reduction internal fixation (ORIF) (P = .02). Of 112 patients treated with surgery, 63 (56.2%) were treated with maxillomandibular fixation (MMF), 24 (21.4%) received ORIF, and 20 (17.9%) received both MMF and ORIF. Nonabsorbable plating was used in all but 1 of the ORIF procedures. Five of 44 (11.4%) patients receiving ORIF or ORIF and MMF had follow-up beyond 6 months, and 8 of the 44 (18.2%) had documented plating hardware removal; hardware was in place for a mean (SD) 180 (167) days. Sixty of the 150 patients (40.0%) had some form of follow-up, a mean (SD) 90 (113) days total after initial presentation. Thirteen patients experienced complications, for a total complication rate of 8.7%. Conservative management, using MMF and a soft diet, was favored for most operative pediatric mandible fractures. Open reduction internal fixation with titanium plating was less commonly used. Outcomes were favorable despite a lack of consistent follow-up. 4.


A framework for organ dose estimation in x-ray angiography and interventional radiology based on dose-related data in DICOM structured reports.
Although interventional x-ray angiography (XA) procedures involve relatively high radiation doses that can lead to deterministic tissue reactions in addition to stochastic effects, convenient and accurate estimation of absorbed organ doses has traditionally been out of reach. This has mainly been due to the absence of practical means to access dose-related data that describe the physical context of the numerous exposures during an XA procedure. The present work provides a comprehensive and general framework for the determination of absorbed organ dose, based on non-proprietary access to dose-related data by utilizing widely available DICOM radiation dose structured reports. The framework comprises a straightforward calculation workflow to determine the incident kerma and reconstruction of the geometrical relation between the projected x-ray beam and the patient's anatomy. The latter is difficult in practice, as the position of the patient on the table top is unknown. A novel patient-specific approach for reconstruction of the patient position on the table is presented. The proposed approach was evaluated for 150 patients by comparing the estimated position of the primary irradiated organs (the target organs) with their position in clinical DICOM images. The approach is shown to locate the target organ position with a mean (max) deviation of 1.3 (4.3), 1.8 (3.6) and 1.4 (2.9) cm for neurovascular, adult and paediatric cardiovascular procedures, respectively. To illustrate the utility of the framework for systematic and automated organ dose estimation in routine clinical practice, a prototype implementation of the framework with Monte Carlo simulations is included.


[Dissertations 25 year after date 18. Skin colour and facial prosthesis].
The traditional 'trial and error' methods for skin colour recording are not satisfactory. In 1982 a dissertation was published, titled 'Skin colour and facial prosthetics, a colorimetric study'. The dissertation was concerned with a clinical study of skin colour recording objectively in a random sample of 100 people, using subtraction colorimetry. Subsequently, facial prostheses were fabricated for a group of patients with a facial defect who had to undergo radiotherapy. From the results of the study the 3 following conclusions were drawn. Skin colour recording for producing a facial prosthesis need to be carried as close to the facial defect as possible. Alterations of skin colour are determined by light scattering in the skin as well as skin pigments. In patients with facial defects who have to undergo adjuvant radiotherapy, skin colour alterations are present until on average 13-14 weeks after completion of the radiotherapy and from that time point the skin colour remains rather stable. After publication of the dissertation, other research results demonstrated that light scattering in the skin, a sign of skin translucency, may be determined with a fiberoptic scattering meter (volume reflectometer). Using the fiberoptic scattering meter, a colour formula can be made, which by calculation shows the amount of pigments and scattering objects needed to produce the correct translucency and colour of a facial prosthesis. Currently, a small beam reflectometer is used for this purpose.


Interrelationships and metabolic effects of fatty acids in the perfused rat liver at hyperthermic temperatures.
Livers of fasted rats were perfused for 70 min at 37 degrees-43 degrees C in the presence or absence of acetate, octanoate or palmitate. Hepatic biosynthetic capacity was assessed by measuring rates of gluconeogenesis, ureogenesis, ketogenesis and O2 consumption. In the presence of each fatty acid, gluconeogenesis, ureogenesis and oxygen consumption were maintained at 37 degrees and 42 degrees C. At 43 degrees, the rate of glucose formation decreased markedly and rates of ureogenesis and oxygen consumption were distinctly lower. As the temperature was increased from 37 degrees to 43 degrees C without fatty acids, i.e. albumin only, there was a progressive decrease in the rate of gluconeogenesis while the ratio of net C3 utilized to glucose formed, increased successively. The values of this ratio in the presence of palmitate or octanoate at 43 degrees were smaller than those for albumin or acetate, but higher than the figure of 2 for complete conversion of C3 units to glucose. Although fatty acid was added in equimolar amounts of C2 units, total ketone formation was influenced significantly by chain length. Hepatic ketogenesis was similar at 37 degrees with albumin, palmitate, or acetate, but was stimulated significantly by octanoate at 37 degrees and 42 degrees C. At 42 degrees, ketone formation increased in the presence of palmitate. At 43 degrees C, ketogenesis with palmitate or octanoate decreased, while that with acetate or albumin was maintained at the same lower rates. The ratio of 3-hydroxybutyrate to acetoacetate in the perfusate was increased with palmitate at the end of perfusion at 37 degrees and 42 degrees C or octanoate at 42 degrees and 43 degrees C. Thus, long (palmitate)- and medium (octanoate)- but not short (acetate)-chain fatty acids enhance not only beta-oxidation, but influence the redox state of hepatic mitochondria with an increase in the state of reduction of the pyridine nucleotides. Such a shift in the redox state would be operable in the perfused liver even at 43 degrees C and may be responsible for improved conversion of lactate to glucose when medium- or long-chain fatty acids are present at hyperthermic temperatures.


The pathogenesis of measles revisited.
Measles continues to be an important cause of childhood mortality in developing countries. The causative agent, measles virus (MV), is a member of the family Paramyxoviridae, genus Morbillivirus, and is spread via the respiratory route. MV was originally thought to enter the host by infecting epithelial cells of the respiratory tract, followed by viremia mediated by infected monocytes. However, neither of these cell types express signaling lymphocyte activation molecule (SLAM, CD150), which has been identified as the main receptor for wild-type MV. Measles has a relatively long incubation time, which makes it difficult to study the early stages of MV infection in humans. The animal models that best reflect the pathogenesis of measles are based on nonhuman primates. The use of recombinant MV strains expressing fluorescent proteins has greatly facilitated studies on viral tropism in macaques. These studies indicate that dendritic cells and lymphocytes expressing CD150 are the primary target cells for MV infection. At late stages of the infection MV also infects epithelial cells, despite the fact that these do not express CD150. Whether these cells express an as yet unidentified additional MV receptor remains unclear. On basis of these data it could be envisaged that dendritic cells are the first target cells for MV infection. These antigen-presenting cells may traffic the virus to the regional lymph nodes where they can transmit the virus to lymphocytes, which during viremia disseminate the virus throughout the body.


Explanations for variations in clopidogrel prescribing in England.
The National Audit Office (NAO) has produced prescribing indicators that Primary Care Trusts (PCTs) can use to judge their performance. One of the indicators is for the antiplatelet clopidogrel, measured as defined daily dose (DDD) per cardiovascular Specific Therapeutic Age Related Prescribing Unit (STAR-PU). Clopidogrel is used as an indicator because it is a more expensive medicine than the alternative (aspirin) and there may be scope for cost reduction. We aimed to establish if the NAO indicator for clopidogrel prescribing is a valid measure of prescribing performance. Prescribing data for 152 PCTs and a range of explanatory variables were obtained. Correlation between variables was determined. A regression analysis was conducted to compare the dependent variable (prescribing) with the explanatory variables identified. The percentage of patients on the coronary heart disease register and Index of Multiple Deprivation explained 30% of the variation in prescribing (DDD/STAR-PU) between PCTs. Even though DDD/STAR-PU is adjusted for age and sex other measures of need still have an impact on prescribing. Using DDD/STAR-PU alone as a prescribing indicator might misidentify some PCTs, which are under- and over-using clopidogrel. Poor ranking against other PCTs using the NAO indicator should be fully explored taking into account other variables (cardiovascular morbidity and deprivation) before any corrective action is taken.


Is there a place for ontological hermeneutics in mental-health nursing research? A review of a hermeneutic study.
A lot of research carried out within the context of mental-health nursing using qualitative data collection tools claims that it is hermeneutical, with usually just a short section describing the hermeneutical methodology as though it is a very broad philosophical approach. Criticisms of the latter approach more often than not concentrate on the level of the data collection tools without getting to grips with the underlying hermeneutical philosophy. This paper examines the difference between methodological and ontological hermeneutics and then gives an example of a piece of research using the latter approach. It is then argued that criticisms of the hermeneutical approach usually only concentrate on methodological hermeneutics with the consequence that they seriously misapply their criticisms if the research is using ontological hermeneutics.


Effects of ovine maternal hyperglycemia on fetal regional blood flows and metabolism.
Fetal combined ventricular output (CVO) and regional distribution of blood flow were measured in 12 ewes in late gestation by the radiolabeled microsphere method. Three sets of determinations were made in sequence beginning with a control study and repeating the measurements after the ewe had received intravenous glucose at 0.35 g X min-1 for 90 min and again after the ewe had received glucose at 0.85 g X min-1 for a second 90-min period. Maternal whole blood glucose concentrations were 2.98 +/- 0.18 (means +/- SE), 10.43 +/- 0.45, and 21.59 +/- 0.90 mM during the respective study periods. Fetal CVO did not change during maternal hyperglycemia; however, it was redistributed, with a decrease in umbilical blood flow to the placenta from 43.5% of CVO to 31.9 and 30.8%, respectively. The fetal carcass, heart, intestines, kidneys, liver, and adrenals each received increased percent CVO; these increases equaled the decrease in placental blood flow. Fetuses became hypoxemic and developed a mixed acidemia during induced maternal hyperglycemia, but oxygen delivery to the heart, brain, and kidneys was unchanged. These observations indicate that maternal hyperglycemia results in previously unsuspected fetal cardiovascular responses.


Essential and nonredundant roles for Diaphanous formins in cortical microtubule capture and directed cell migration.
Formins constitute a large family of proteins that regulate the dynamics and organization of both the actin and microtubule cytoskeletons. Previously we showed that the formin mDia1 helps tether microtubules at the cell cortex, acting downstream of the ErbB2 receptor tyrosine kinase. Here we further study the contributions of mDia1 and its two most closely related formins, mDia2 and mDia3, to cortical microtubule capture and ErbB2-dependent breast carcinoma cell migration. We find that depletion of each of these three formins strongly disrupts chemotaxis without significantly affecting actin-based structures. Further, all three formins are required for formation of cortical microtubules in a nonredundant manner, and formin proteins defective in actin polymerization remain active for microtubule capture. Using affinity purification and mass spectrometry analysis, we identify differential binding partners of the formin-homology domain 2 (FH2) of mDia1, mDia2, and mDia3, which may explain their nonredundant roles in microtubule capture. The FH2 domain of mDia1 specifically interacts with Rab6-interacting protein 2 (Rab6IP2). Further, mDia1 is required for cortical localization of Rab6IP2, and concomitant depletion of Rab6IP2 and IQGAP1 severely disrupts cortical capture of microtubules, demonstrating the coinvolvement of mDia1, IQGAP1, and Rab6IP2 in microtubule tethering at the leading edge.


Phytosterol crystallisation within bulk and dispersed triacylglycerol matrices as influenced by oil droplet size and low molecular weight surfactant addition.
Phytosterols can lower LDL-cholesterol and are frequently used by the functional food industry. However, little is known regarding how phytosterol crystallisation can be controlled, despite solubilised phytosterols having improved bioaccessibility. This study investigates phytosterol crystallisation in bulk milk fat and in model dairy emulsion systems at two average droplet sizes, 1.0 and 0.2 µm. The effect of lecithin and monoacylglycerol addition on phytosterol crystallisation for both emulsion and bulk systems was also evaluated. Results demonstrated that lecithin and monoacylglycerols enrichment into the bulk system minimised phytosterol crystallisation. However, in emulsions, phytosterol crystallisation was mainly influenced by decreasing the droplet size. Smaller emulsion droplets containing lecithin showed the greatest potential for decreasing phytosterol crystallisation and had improved physicochemical stability. This information can be employed by the functional food industry to minimise phytosterol crystallisation and possibly improve bioaccessibility.


Supply chain viability: conceptualization, measurement, and nomological validation.
Supply chain viability (SCV) is an emerging concept of growing importance in operations management. This paper aims to conceptualize, develop, and validate a measurement scale for SCV. SCV is first defined and operationalized as a construct, followed by content validation and item measure development. Data have been collected through three independent samplings comprising a total of 558 respondents. Both exploratory and confirmatory factor analyses are used in a step-wise manner for scale development. Reliability and validity are evaluated. A nomological model is theorized and tested to evaluate nomological validity. For the first time, our study frames SCV as a novel and distinct construct. The findings show that SCV is a hierarchical and multidimensional construct, reflected in organizational structures, organizational resources, dynamic design capabilities, and operational aspects. The findings reveal that a central characteristic of SCV is the dynamic reconfiguration of SC structures in an adaptive manner to ensure survival in the long-term perspective. This research conceptualizes and provides specific, validated dimensions and item measures for SCV. Practitioner directed guidance and suggestions are offered for improving SCV during the COVID-19 pandemic and future severe disruptions.


Risk of Childhood Cancer by Maternal Birthplace: A Test of the Hispanic Paradox.
The Hispanic epidemiologic paradox is the phenomenon that non-US-born Hispanic mothers who immigrate to the United States have better pregnancy outcomes than their US-born counterparts. It is unknown whether this advantage extends to childhood cancer risk. To determine whether the risk for childhood cancers among Hispanic children varies by maternal birthplace. In this population-based case-control study conducted in June 2015, cohort members were identified through California birth records of children born in California from January 1, 1983, to December 31, 2011. Information on cancer diagnoses was obtained from California Cancer Registry records from 1988 to 2012. Cases (n = 13 666) were identified from among children younger than 6 years in the California Cancer Registry and matched to California birth certificates. Control children (n = 15 513 718) included all other children born in California during the same period. Maternal birthplace and ethnic ancestry were identified from the birth certificate. Maternal race/ethnicity and birthplace. We used Cox proportional hazards modeling to estimate hazard ratios (HRs) of childhood cancer. Included in the study were 4 246 295 children of non-Hispanic white mothers (51.3% male), 2 548 822 children of US-born Hispanic mothers (51.0% male), and 4 397 703 children of non-US-born Hispanic mothers (51.0% male). Compared with children of non-Hispanic white mothers, the children of non-US-born Hispanic mothers had a reduced risk for glioma (HR, 0.50; 95% CI, 0.44-0.58), astrocytoma (HR, 0.43; 95% CI, 0.36-0.51), neuroblastoma (HR, 0.47; 95% CI, 0.40-0.54), and Wilms tumor (HR, 0.70; 95% CI, 0.59-0.82). For these cancer types, the risk estimates for children of US-born Hispanic mothers fell between those of the children of US-born white and non-US-born Hispanic mothers. Children of Mexican-born mothers had a higher risk of yolk sac tumors (HR, 1.46; 95% CI, 0.99-2.17), while children of US-born Hispanic mothers with ancestry from countries other than Mexico had a higher risk for unilateral retinoblastoma (HR, 2.03; 95% CI, 1.33-3.11). For several cancers, we observed differential risk by maternal place of birth. Examining the differences in health behaviors and environment between Hispanic groups may shed light on childhood cancer etiology.


Liquid-phase non-thermal plasma-prepared N-doped TiO(2) for azo dye degradation with the catalyst separation system by ceramic membranes.
This study strived to improve the photocatalytic activity by using liquid-phase non-thermal plasma (LPNTP) technology for preparing N-doping TiO(2) as well as to separate/recover the N-dope TiO(2) particles by using ceramic ultrafiltration membrane process. The yellow color N-doped TiO(2) photocatalysts, obtained through the LPNTP process, were characterized with UV-Vis spectroscopy, X-ray diffraction (XRD), and electron spectroscopy for chemical analysis (ESCA). The UV-Vis spectrum of N-doped TiO(2) showed that the absorption band was shifted to 439 nm and the band gap was reduced to 2.82 eV. The structure analysis of XRD spectra showed that the peak positions and the crystal structure remained unchanged as anatase after plasma-treating at 13.5 W for 40 min. The photocatalytic activity of N-doped TiO(2) was evaluated by azo dyes under visible light, and 63% of them was degraded after 16 hours in a continuous-flow photocatalytic system. For membrane separation/recover system, the recovery efficiency reached 99.5% after the ultrafiltration had been carried out for 90 min, and the result indicated that the photocatalyst was able to be separated/recovered completely.


Marine and inland fishes of St. Croix, U. S. Virgin Islands: an annotated checklist.
An historical account is given for the ichthyological research at St. Croix, U. S. Virgin Islands, followed by an annotated list of 544 species of mostly marine shore fishes known or reported from the island to depths of 200 m. Color photographs are included for 103 of these species. Collections made at Buck Island Reef National Monument with the ichthyocide rotenone in 2001 and 2005 increased the known ichthyofauna by about 80 species. The rational for inclusion of each species in the checklist is given, with remarks for those species for which additional documentation or voucher specimens are needed. Reports of species known or presumed to have been based on misidentifications are discussed. Of the total marine fish fauna of the island, 404 species (75%) are restricted to the western Atlantic Ocean, (223 of these species are essentially Caribbean endemics that do not occur south of the Amazon River outflow), and no St. Croix endemic species are known. An additional 17 species (3.2%) also occur at mid-Atlantic islands, 57 species (10.6 %) are limited to both sides of the Atlantic Ocean, and 40 species (7.4%) have circumtropical distributions. The four most species-rich families are the Gobiidae (47 species), Serranidae (groupers and sea basses, 41), Labridae (wrasses and parrotfishes, 31), and Labrisomidae (scaly blennies, 27). Literature reports of Mosquitofish, Gambusia sp., from St. Croix apparently were based on misidentifications of a different introduced poeciliid genus. Four species of the amphidromus goby genus Sicydium occur in St. Croix inland waters, together with three established introduced species (one cichlid and two poeciliids). Also included are one catfish (Ictaluridae) and three sunfishes (Centrarchidae) known only from ponds. The Lionfish, Pterois volitans, the only introduced marine species, was first reported from St. Croix in 2008 and is now common despite control efforts.


Chromosome conformation capture-on-chip analysis of long-range cis-interactions of the SOX9 promoter.
Evolutionarily conserved transcription factor SOX9 is essential for the differentiation of chondrocytes and the development of testes. Heterozygous point mutations and genomic deletions involving SOX9 lead to campomelic dysplasia (CD), a skeletal malformation syndrome often associated with sex reversal. Chromosomal rearrangements with breakpoints mapping up to 1.6 Mb up- and downstream to SOX9, and likely disrupting its distant cis-regulatory elements, have been described in patients with milder forms of CD. Based on the location of these aberration breakpoints, four clusters upstream of SOX9 have been defined. Interestingly, we found that each of these intervals overlaps a gene encoding long noncoding RNA (lncRNA), suggesting that lncRNAs may contribute to long-range regulation of SOX9 expression. One of the four upstream regions, RevSex (517-595 kb 5' to SOX9), is associated with sex reversal, and was suggested to harbor a testis-specific and sex-determining enhancer. Another sex-determining interval was mapped to a gene desert >1.3 Mb downstream of SOX9. We have performed chromosome conformation capture-on-chip (4C) analysis in Sertoli cells and lymphoblasts to verify the proposed long-range interactions of the SOX9 promoter and to identify potential novel regulatory elements that might be responsible for sex reversal in patients with CD. We identified several novel potentially cis-interacting regions both up- and downstream to SOX9, with some of them overlapping lncRNA genes. Our data point to lncRNAs as likely mediators of some of these regulatory interactions.


What home healthcare nurses should know about fraud and abuse.
Home care nurses provide a critical linh in all services provided by a home health agency. This article outlines basic information nurses can use to understand fraud and abuse regulations, see the importance of corporate compliance programs, and recognize the potential impact a focus on fraud and abuse has on their practice.


Advances in nanotechnology and asthma.
According to the World Health Organization, Asthma is the fastest-growing disease in the world alongside HIV/AIDS, and its socioeconomic burden exceeds the sum of HIV/AIDS and tuberculosis. Its high disability and mortality rates have become serious social and public health concerns. Asthma is a heterogeneous disease in which genetic polymorphisms interact with the environmental factors. While no specific treatment has been available for asthma due to its complex pathogenesis, the advances in nanotechnology have brought new hope for the early diagnosis, treatment, and prevention of asthma. Nanotechnology can achieve targeted delivery of drugs or genes, reduce toxic effects, and improve drug bioavailability. The nano-modifications of drugs and the development of new nano-drugs have become new research directions. Studies have demonstrated the safety and effectiveness of nanocarriers. However, many challenges still need to be overcome before nanotherapy can be applied in clinical practice. In this article we review the new research highlights in this area, with an attempt to explore the great potential and feasibility of nanotechnology in treating asthma.


A 7-year retrospective review of the technical success of the "low-profile" hangman technique for complicated inferior vena cava (IVC) filter retrievals.
We aimed to assess the safety and effectiveness of a modified low-profile hangman technique. We performed a retrospective review of all filter retrieval procedures performed at a major trauma center, from 2012 to 2019. Records were reviewed for patient demographics, device type, device dwell time, device tilt, embedded hook, success of device retrieval, evidence of caval injury and occurrence of complications. From 2012 to 2019 there were 473 filter retrieval attempts. An advanced technique was documented in 66 (14%). The low-profile hangman technique alone was documented in 23 procedures (5% of all procedures, 35% of advanced technique procedures). Average screening time was 28 minutes. At the time of retrieval attempt, 9 patients (41%) were anticoagulated. The hangman technique was employed as isolated maneuver in 23 patients and was successful on initial attempt in 22 cases (96%). The average dwell time of filters retrieved by the hangman technique was 228 days (range, 40-903 days; median, 196 days). No procedure-related complications occurred. The retrieval of IVC filters is an important part of offering an IVC filter service. Advanced techniques to retrieve caval filters are multiple, and the risk of complications is increased in these cases. We demonstrate the safety and effectiveness of a new modified and lower-profile hangman technique. This new technique could be performed with only an 11 French venous access sheath using off-the-shelf equipment and it remains a cost-effective approach to complex filter retrieval.


Systemic Use of Antibiotics in Dental Implant Surgeries in Immunocompetent Patients: A Blind Randomized Controlled Trial.
To evaluate two pharmacologic antibiotic prophylaxis regimens and a control group of immunocompetent patients undergoing two-stage dental implant placement in a triple-blind randomized controlled clinical trial. From a group of 61 immunocompetent patients, 21 were randomly allocated into group 1 (G1) without antibiotic prophylaxis (control), 20 in group 2 (G2) with preoperative antibiotic prophylaxis (1 g amoxicillin 1 hour before the procedure), and 20 in group 3 (G3) with preoperative (1 g amoxicillin) and postoperative (500 mg every 8 hours for 5 days) antibiotic prophylaxis. Pain was assessed with the visual analog scale (VAS) and by considering the number of painkillers patients used. Infection was identified via the presence of pus and fistula. Patients were evaluated after 7, 14, 30, and 120 days. Implant failure (defined as mobility upon the application of manual torque) was evaluated after 120 days during the second surgical stage. At the 7-day follow-up, pain intensity was less severe in the patients who had received antibiotics, with the G3 patients experiencing the least pain (P < .05). Infection was present in groups G1 (2 cases) and G3 (2 cases), but there was no statistically significant intergroup difference. Two implants failed, one in G1 and the other in G3. Based on the results of the present study, although the use of antibiotics reduced pain in the immediate postoperative period, it did not reduce infection rates and implant failure in immunocompetent patients.


Genetic control of the immune response to Trichinella spiralis: recognition of muscle larval antigens.
Host antibody recognition of muscle larval (ML) antigens of Trichinella spiralis was examined. Monoclonal antibodies (MoAbs) to known host protective ML antigens have been produced in order to aid this examination. Eleven strains of mice with independent MHC haplotypes and seventeen T. spiralis infected human patients were all found to recognize the same three major antigens as the monoclonal antibodies; i.e., of mw 41, 46 and 55 kD. However all serum samples tested also recognized further ML antigens and this recognition varied with the individual or strain. This variation in antigen recognition also applied to the MoAb. Mutual inhibition studies demonstrated that even where the MoAb apparently recognized the same antigens, specific epitope recognition was disparate. Hence some of the major antigens recognized by hosts of T. spiralis, regardless of whether vaccinated or infected, correspond with antigens which have considerable host protective properties. There also appear to be a number of epitopes upon these antigens and the biological implications of this are discussed.


Water quality in drinking water reservoirs of a megacity, istanbul.
Providing clean water at relevant quality and quantity is a challenge that regulatory authorities have to face in metropolitan cities that seem to develop at their limits of sustainability. Istanbul strives to face such a challenge for its population of over 10 million, through six surface water resources. Two approaches of classification for the reservoirs are presented, one based on current regulations and an alternative based on a more detailed classification. The results have shown that nutrient control is the primary issue, and one of the reservoirs has already exceeded the limits of being eutrophic, one is at mesotrophic conditions, and the remaining four are at the limit of being eutrophic, indicating the significance of making the correct decision and taking pertinent measures for management and control. It has been observed that the only mesotrophic resource, which also has the best general quality class, has no industry and a very low population density, whereas the one that is already eutrophic is also the one with the lowest quality class, has the highest population density, and has the greatest percentage of urban land use within its watershed.


UDP glucuronosyltransferase (UGT) 1A6 pharmacogenetics: II. Functional impact of the three most common nonsynonymous UGT1A6 polymorphisms (S7A, T181A, and R184S).
The objective of this study was to use recombinant enzymes and human liver microsomes (HLMs) to comprehensively evaluate the functional impact of the three most common nonsynonymous polymorphisms (S7A, T181A, and R184S) identified in the human UDP glucuronosyltransferase (UGT) 1A6 gene. In addition to the known allozymes, other possible amino acid variants were expressed in human embryonic kidney (HEK)293 cells to enable structure-function analysis. Initial studies using different substrates (serotonin, 5-hydroxytryptophol, 4-nitrophenol, acetaminophen, and valproic acid) showed similar results with 2-fold higher glucuronidation by UGT1A6(*)2 (S7A/T181A/R184S) compared with UGT1A6(*)1 (reference), and intermediate activities for other variants. Enzyme kinetic analyses with the UGT1A6-specific substrate (serotonin) showed 50% lower K(m) values for all R184S variants and 2-fold higher V(max) values for both S7A/T181A variants compared with UGT1A6(*)1. Furthermore, intrinsic clearance (V(max)/K(m)) values were highest for the UGT1A6(*)2 allozyme (2.3-fold over UGT1A6(*)1), resulting from additive effects of higher enzyme affinity and activity. As expected, K(m) values of (*)1/(*)1 genotyped HLMs (5.4 +/- 0.2 mM) were similar to recombinant UGT1A6(*)1 (5.8 +/- 0.6 mM). Conversely, (*)2/(*)2 HLMs showed higher K(m) values (7.0 +/- 0.3 mM) rather than the lower K(m) values displayed by recombinant UGT1A6(*)2 (3.6 +/- 0.3 mM), suggesting that this allozyme may display different enzyme kinetic behavior in HLMs compared with HEK293 cells. At best, these polymorphisms were predicted to account for 15 to 20% of the observed 13-fold variability in glucuronidation of UGT1A6 substrates by HLMs, indicating that there are likely other genetic or environmental factors responsible for the majority of this variation.


The origin and consequences of concentration dependence in gel chromatography.
Concentration dependence of elution volume was determined for Blue Dextran 2000, Dextran 500, Dextran sulphate 500 and bovine serum albumin on columns of Sephadex G-100 equilibrated with sodium phosphate buffer, I 0.1, pH6.8. From the results for Dextran 500, it was shown that a linear relation exists between elution volume and the corresponding osmotic pressure calculated for the same concentration and incorporating the term containing the second virial coefficient. This relationship was used to predict the concentration dependence of elution volume for bovine serum albumin and myoglobin, proteins that partially penetrate Sephadex G-100. Possible consequences of osmotic effects are considered in relation to various types of column experiments, including differential chromatography.


Recognition of microclimate zones through radon mapping, Lechuguilla Cave, Carlsbad Caverns National Park, New Mexico.
Radon concentrations range from less than 185 to 3,515 Bq m-3 throughout Lechuguilla Cave, Carlsbad Caverns National Park, New Mexico. Concentrations in the entrance passages and areas immediately adjacent to these passages are controlled by outside air temperature and barometric pressure, similar to other Type 2 caves. Most of the cave is developed in three geographic branches beneath the entrance passages; these areas maintain Rn levels independent of surface effects, an indication that Rn levels in deep, complex caves or mines cannot be simply estimated by outside atmospheric parameters. These deeper, more isolated areas are subject to convective ventilation driven by temperature differences along the 477-m vertical extent of the cave. Radon concentrations are used to delineate six microclimate zones (air circulation cells) throughout the cave in conjunction with observed airflow data. Suspected surface connections contribute fresh air to remote cave areas demonstrated by anomalous Rn lows surrounded by higher values, the presence of mammalian skeletal remains, CO2 concentrations and temperatures lower than the cave mean, and associated surficial karst features.


Functional and structural characterization of Francisella tularensis O-antigen antibodies at the low end of antigen reactivity.
The O-antigen (OAg) of the Gram-negative bacterium Francisella tularensis (Ft), which is both a capsular polysaccharide and a component of lipopolysaccharide, is comprised of tetrasaccharide repeats and induces antibodies mainly against repeating internal epitopes. We previously reported on several BALB/c mouse monoclonal antibodies (MAbs) that bind to internal Ft OAg epitopes and are protective in mouse models of respiratory tularemia. We now characterize three new internal Ft OAg IgG2a MAbs, N203, N77, and N24, with 10- to 100-fold lower binding potency than previously characterized internal-OAg IgG2a MAbs, despite sharing one or more variable region germline genes with some of them. In a mouse model of respiratory tularemia with the highly virulent Ft type A strain SchuS4, the three new MAbs reduced blood bacterial burden with potencies that mirror their antigen-binding strength; the best binder of the new MAbs, N203, prolonged survival in a dose-dependent manner, but was at least 10-fold less potent than the best previously characterized IgG2a MAb, Ab52. X-ray crystallographic studies of N203 Fab showed a flexible binding site in the form of a partitioned groove, which cannot provide as many contacts to OAg as does the Ab52 binding site. These results reveal structural features of antibodies at the low end of reactivity with multi-repeat microbial carbohydrates and demonstrate that such antibodies still have substantial protective effects against infection.


Dietary factors and the risks of oesophageal adenocarcinoma and Barrett's oesophagus.
Incidence rates for oesophageal adenocarcinoma have increased by over 500% during the past few decades without clear reasons. Gastro-oesophageal reflux disease, obesity and smoking have been identified as risk factors, although the demographic distribution of these risk factors is not consistent with the demographic distribution of oesophageal adenocarcinoma, which is substantially more common among whites and males than any other demographic groups. Numerous epidemiological studies have suggested associations between dietary factors and the risks of oesophageal adenocarcinoma and its precursor, Barrett's oesophagus, though a comprehensive review is lacking. The main aim of the present review is to consider the evidence linking dietary factors with the risks of oesophageal adenocarcinoma, Barrett's oesophagus, and the progression from Barrett's oesophagus to oesophageal adenocarcinoma. The existing epidemiological evidence is strongest for an inverse relationship between intake of vitamin C, β-carotene, fruits and vegetables, particularly raw fruits and vegetables and dark green, leafy and cruciferous vegetables, carbohydrates, fibre and Fe and the risk of oesophageal adenocarcinoma and Barrett's oesophagus. Patients at higher risk for Barrett's oesophagus and oesophageal adenocarcinoma may benefit from increasing their consumption of fruits and vegetables and reducing their intake of red meat and other processed food items. Further research is needed to evaluate the relationship between diet and the progression of Barrett's oesophagus to oesophageal adenocarcinoma. Evidence from cohort studies will help determine whether randomised chemoprevention trials are warranted for the primary prevention of Barrett's oesophagus or its progression to cancer.


Comparison of the Postoperative Liver Function Between Total Intravenous Anesthesia and Inhalation Anesthesia in Patients with Preoperatively Elevated Liver Transaminase Levels: A Retrospective Cohort Study.
Anesthesia and surgery may deteriorate liver function in patients with elevated liver enzyme levels; therefore, in these patients, choosing anesthetics with less hepatotoxicity is important. This retrospective study investigated the effect of total intravenous anesthesia (TIVA) versus inhalation anesthesia (INHA) on the postoperative liver function in patients with preoperatively elevated liver enzyme levels (aspartate transaminase [AST] or alanine transaminase [ALT] >40 U/L) who underwent non-hepatic surgery under general anesthesia. We compared the changes in enzyme levels within 24 hrs before and after surgery. In 730 patients (TIVA: n=138; INHA: n=592), the baseline characteristics were comparable, except for higher comorbidity rates in the TIVA group. The median anesthesia and operation times were significantly longer in the TIVA group because approximately 50% of the TIVA group (vs 19.7% of the INHA group) underwent neurosurgery, which had a relatively longer operation time than other surgeries. Intraoperative hypotensive events and vasopressor use were more frequent in the TIVA group. After 1:4 propensity score matching (TIVA: n=94; INHA: n=376), the baseline characteristics and surgical variables were comparable, except for longer anesthesia time. Before matching, postoperative AST and ALT changes were significantly lower in the TIVA group than in the INHA group. After matching, only the ALT change was significantly lower after TIVA than after INHA [median (interquartile range), -16.7 (-32 to -4) % vs -12.0 (-28.6-6.5) %, P=0.025]. TIVA may be safer for patients with preoperatively elevated liver transaminase levels.


A bidirectional network for appetite control in larval zebrafish.
Medial and lateral hypothalamic loci are known to suppress and enhance appetite, respectively, but the dynamics and functional significance of their interaction have yet to be explored. Here we report that, in larval zebrafish, primarily serotonergic neurons of the ventromedial caudal hypothalamus (cH) become increasingly active during food deprivation, whereas activity in the lateral hypothalamus (LH) is reduced. Exposure to food sensory and consummatory cues reverses the activity patterns of these two nuclei, consistent with their representation of opposing internal hunger states. Baseline activity is restored as food-deprived animals return to satiety via voracious feeding. The antagonistic relationship and functional importance of cH and LH activity patterns were confirmed by targeted stimulation and ablation of cH neurons. Collectively, the data allow us to propose a model in which these hypothalamic nuclei regulate different phases of hunger and satiety and coordinate energy balance via antagonistic control of distinct behavioral outputs.


Interaction between transcription factors Iroquois proteins 4 and 5 controls cardiac potassium channel Kv4.2 gene transcription.
The homeobox transcription factor, Iroquois protein 5 (Irx5), plays an essential role in the generation of region-selective expression of Kv4.2 gene across the left ventricular wall of rodent hearts. Here, we analyse molecular mechanisms underlying the Irx5-induced regulation of the rat Kv4.2 promoter. The mRNA levels for Irx members in various heart regions were assessed by RT-PCR. A luciferase reporter gene with the rat Kv4.2 promoter was used to test the effects of Irx members on channel promoter activity. Irx3 and Irx5 mRNAs were differentially distributed across the left ventricular wall, whereas Irx4 message was equally abundant in various ventricular regions. Irx5, but not Irx3 or Irx4, increased Kv4.2 promoter activity in 10T1/2 fibroblasts, whereas the transcription factor decreased promoter activity in neonatal ventricular myocytes. These effects were mediated by the C-terminal portion of Irx5. Irx4 appeared to inhibit the Irx5-induced increase in channel promoter activity in 10T1/2 cells. The N-terminal region of Irx4 was necessary and sufficient for this inhibition. Furthermore, when endogenous Irx4 expression was suppressed with siRNA, Irx5 increased channel promoter activity in neonatal myocytes. These results indicate that Irx5 possesses the ability to activate the Kv4.2 promoter. The abundant Irx4 expression throughout the rat ventricle may play a role in the inverse relationship between Irx5 and Kv4.2 levels across the left ventricular wall.


Growth characteristics of infantile hemangiomas: implications for management.
Infantile hemangiomas often are inapparent at birth and have a period of rapid growth during early infancy followed by gradual involution. More precise information on growth could help predict short-term outcomes and make decisions about when referral or intervention, if needed, should be initiated. The objective of this study was to describe growth characteristics of infantile hemangioma and compare growth with infantile hemangioma referral patterns. A prospective cohort study involving 7 tertiary care pediatric dermatology practices was conducted. Growth data were available for a subset of 526 infantile hemangiomas in 433 patients from a cohort study of 1096 children. Inclusion criteria were age younger than 18 months at time of enrollment and presence of at least 1 infantile hemangioma. Growth stage and rate were compared with clinical characteristics and timing of referrals. Eighty percent of hemangioma size was reached during the early proliferative stage at a mean age of 3 months. Differences in growth between hemangioma subtypes included that deep hemangiomas tend to grow later and longer than superficial hemangiomas and that segmental hemangiomas tended to exhibit more continued growth after 3 months of age. The mean age of first visit was 5 months. Factors that predicted need for follow-up included ongoing proliferation, larger size, deep component, and segmental and indeterminate morphologic subtypes. Most infantile hemangioma growth occurs before 5 months, yet 5 months was also the mean age at first visit to a specialist. Recognition of growth characteristics and factors that predict the need for follow-up could help aid in clinical decision-making. The first few weeks to months of life are a critical time in hemangioma growth. Infants with hemangiomas need close observation during this period, and those who need specialty care should be referred and seen as early as possible within this critical growth period.


Projected benefits of active surveillance for vancomycin-resistant enterococci in intensive care units.
Hospitals use many strategies to control nosocomial transmission of vancomycin-resistant enterococci (VRE). Strategies include "passive surveillance," with isolation of patients with known previous or current VRE colonization or infection, and "active surveillance," which uses admission cultures, with subsequent isolation of patients who are found to be colonized with VRE. We created a mathematical model of VRE transmission in an intensive care unit (ICU) using data from an existing active surveillance program; we used the model to generate the estimated benefits associated with active surveillance. Simulations predicted that active surveillance in a 10-bed ICU would result in a 39% reduction in the annual incidence of VRE colonization when compared with no surveillance. Initial isolation of all patients, with withdrawal of isolation if the results of surveillance cultures are negative, was predicted to result in a 65% reduction. Passive surveillance was minimally effective. Using the best available data, active surveillance is projected to be effective for reducing VRE transmission in ICU settings.


Capsaicin as an amphipathic modulator of NaV1.5 mechanosensitivity.
SCN5A-encoded NaV1.5 is a voltage-gated Na+ channel that drives the electrical excitability of cardiac myocytes and contributes to slow waves of the human gastrointestinal smooth muscle cells. NaV1.5 is mechanosensitive: mechanical force modulates several facets of NaV1.5's voltage-gated function, and some NaV1.5 channelopathies are associated with abnormal NaV1.5 mechanosensitivity (MS). A class of membrane-active drugs, known as amphiphiles, therapeutically target NaV1.5's voltage-gated function and produce off-target effects including alteration of MS. Amphiphiles may provide a novel option for therapeutic modulation of NaV1.5's mechanosensitive operation. To more selectively target NaV1.5 MS, we searched for a membrane-partitioning amphipathic agent that would inhibit MS with minimal closed-state inhibition of voltage-gated currents. Among the amphiphiles tested, we selected capsaicin for further study. We used two methods to assess the effects of capsaicin on NaV1.5 MS: (1) membrane suction in cell-attached macroscopic patches and (2) fluid shear stress on whole cells. We tested the effect of capsaicin on NaV1.5 MS by examining macro-patch and whole-cell Na+ current parameters with and without force. Capsaicin abolished the pressure- and shear-mediated peak current increase and acceleration; and the mechanosensitive shifts in the voltage-dependence of activation (shear) and inactivation (pressure and shear). Exploring the recovery from inactivation and use-dependent entry into inactivation, we found divergent stimulus-dependent effects that could potentiate or mitigate the effect of capsaicin, suggesting that mechanical stimuli may differentially modulate NaV1.5 MS. We conclude that selective modulation of NaV1.5 MS makes capsaicin a promising candidate for therapeutic interventions targeting MS.


Identification of kinases and regulatory proteins required for cell migration using a transfected cell-microarray system.
Cell migration plays a major role in a variety of normal biological processes, and a detailed understanding of the associated mechanisms should lead to advances in the medical sciences in areas such as cancer therapy. Previously, we developed a simple chip, based on transfected-cell microarray (TCM) technology, for the identification of genes related to cell migration. In the present study, we used the TCM chip for high-throughput screening (HTS) of a kinome siRNA library to identify genes involved in the motility of highly invasive NBT-L2b cells. We performed HTS using TCM coupled with a programmed image tracer to capture time-lapse fluorescence images of siRNA-transfected cells and calculated speeds of cell movement. This first screening allowed us to identify 52 genes. After quantitative PCR (qPCR) and a second screening by a conventional transfection method, we confirmed that 32 of these genes were associated with the migration of NBT-L2b cells. We investigated the subcellular localization of proteins and levels of expression of these 32 genes, and then we used our results and databases of protein-protein interactions (PPIs) to construct a hypothetic but comprehensive signal network for cell migration. The genes that we identified belonged to several functional categories, and our pathway analysis suggested that some of the encoded proteins functioned as the hubs of networks required for cell migration. Our signal pathways suggest that epidermal growth factor receptor (EGFR) is an upstream regulator in the network, while Src and GRB2 seem to represent nodes for control of respective the downstream proteins that are required to coordinate the many cellular events that are involved in migration. Our microarray appears to be a useful tool for the analysis of protein networks and signal pathways related to cancer metastasis.


Effects of insomnia on risky driving behavior among bus drivers: The mediating effect of mental health.
Crashes caused by problems with bus drivers' physical and mental health have increased in frequency in recent years. Insomnia, a common type of sleep problem, has significant positive relationships with both crash risk and mental health problems, especially anxiety and depression, which are themselves associated with driving behavior. However, few studies have conducted analysis on sleep-related problems and mental health exclusively on bus drivers, nor on how these problems influence driving performance. Thus, this study explored the effect of insomnia and mental health on bus drivers' risky driving behavior and evaluated the interaction of four variables: insomnia, anxiety, depression, and risky driving behavior. The survey-based investigation was conducted in a bus company in Suzhou, China, with 1,295 bus drivers participating. Insomnia, anxiety, and depression were self-reported based on professional mental health scales and risky driving behaviors were measured by the Driver Behavior Questionnaire. Two mediation models and a chain mediation model were developed to examine relationships among the bus drivers' insomnia, anxiety, depression, and risky driving behavior. Results revealed that (a) bus drivers less than 31 years old, drivers with more than 11 years' experience driving buses, and those with crash and violation involvement within three years demonstrated more severe degrees of insomnia, anxiety, depression, and risky driving behavior; (b) there were significant positive correlations and interactions among the four variables. Results specifically related to the interaction among variables include findings that (a) anxiety mediated between insomnia and risky driving behavior; (b) depression mediated between insomnia and risky driving behavior; and (c) anxiety affected bus drivers' risky driving behavior primarily though depression. The findings in this study indicate the importance of regular physical and mental health examination of bus drivers and suggest that interventions focused on insomnia and mental health problems may be helpful to reduce risky driving behaviors of bus drivers both directly and indirectly.


Consequences of light spectra for pigment composition and gene expression in the cryptophyte Rhodomonas salina.
Algae with a more diverse suite of pigments can, in principle, exploit a broader swath of the light spectrum through chromatic acclimation, the ability to maximize light capture via plasticity of pigment composition. We grew Rhodomonas salina in wide-spectrum, red, green, and blue environments and measured how pigment composition differed. We also measured expression of key light-capture and photosynthesis-related genes and performed a transcriptome-wide expression analysis. We observed the highest concentration of phycoerythrin in green light, consistent with chromatic acclimation. Other pigments showed trends inconsistent with chromatic acclimation, possibly due to feedback loops among pigments or high-energy light acclimation. Expression of some photosynthesis-related genes was sensitive to spectrum, although expression of most was not. The phycoerythrin α-subunit was expressed two-orders of magnitude greater than the β-subunit even though the peptides are needed in an equimolar ratio. Expression of genes related to chlorophyll-binding and phycoerythrin concentration were correlated, indicating a potential synthesis relationship. Pigment concentrations and expression of related genes were generally uncorrelated, implying post-transcriptional regulation of pigments. Overall, most differentially expressed genes were not related to photosynthesis; thus, examining associations between light spectrum and other organismal functions, including sexual reproduction and glycolysis, may be important.


The YSIRK-G/S motif of staphylococcal protein A and its role in efficiency of signal peptide processing.
Many surface proteins of pathogenic gram-positive bacteria are linked to the cell wall envelope by a mechanism requiring a C-terminal sorting signal with an LPXTG motif. Surface proteins of Streptococcus pneumoniae harbor another motif, YSIRK-G/S, which is positioned within signal peptides. The signal peptides of some, but not all, of the 20 surface proteins of Staphylococcus aureus carry a YSIRK-G/S motif, whereas those of surface proteins of Listeria monocytogenes and Bacillus anthracis do not. To determine whether the YSIRK-G/S motif is required for the secretion or cell wall anchoring of surface proteins, we analyzed variants of staphylococcal protein A, an immunoglobulin binding protein with an LPXTG sorting signal. Deletion of the YSIR sequence or replacement of G or S significantly reduced the rate of signal peptide processing of protein A precursors. In contrast, cell wall anchoring or the functional display of protein A was not affected. The fusion of cell wall sorting signals to reporter proteins bearing N-terminal signal peptides with or without the YSIRK-G/S motif resulted in hybrid proteins that were anchored in a manner similar to that of wild-type protein A. The requirement of the YSIRK-G/S motif for efficient secretion implies the existence of a specialized mode of substrate recognition by the secretion pathway of gram-positive cocci. It seems, however, that this mechanism is not essential for surface protein anchoring to the cell wall envelope.


Intraepidermal nerve fiber expression of calcitonin gene-related peptide, vasoactive intestinal peptide and substance P in psoriasis.
In order to evaluate more fully the role of neuropeptides in the pathogenesis of psoriasis, skin biopsies were obtained from 36 patients with psoriasis to identify substance P (SP), vasoactive intestinal peptide (VIP) and calcitonin gene-related peptide (CGRP). Lesional and nonlesional skin was examined from these biopsies and the results compared with those from biopsies taken from patients with a variety of other inflammatory dermatoses, including lichen planus, lichen simplex chronicus, spongiotic dermatitis, and seborrheic dermatitis. Also studied was a series of nine biopsies taken from patients with no known skin disorders. We found an increase in the number of SP-positive nerve fibers within the epidermis in biopsies from lesional skin of psoriasis patients (8.4 nerves per 3-mm biopsy) compared with nonlesional psoriatic skin (2.6 nerves per 3-mm biopsy) and normal skin (2.0 nerves per 3 mm biopsy). Other inflammatory disorders also demonstrated fewer SP-positive nerves than lesional psoriatic skin; lichen planus (0 nerves per 3 mm biopsy) and lichen simplex chronicus (1.3 nerves per 3 mm biopsy). The difference in SP-positive nerve expression between lesional psoriatic skin and the group comprising nonlesional skin, normal skin, lichen planus, and lichen simplex chronicus attained statistical significance (P < 0.013). SP-positive intraepidermal nerve fibers in lesional psoriatic specimens were fewer than in spongiotic dermatitis (17.4 nerves per 3 mm biopsy). There was no significant difference in numbers of VIP- or CGRP-immunopositive intraepidermal nerve fibers between psoriatic skin and the group comprising all other material tested. However, in five patients with psoriasis, there was a marked increase in the expression of intraepidermal CGRP (up to 10.7 nerves per 3-mm biopsy) and VIP (up to 8.3 nerves per 3-mm biopsy) which was not observed in control groups. These findings suggest that neuropeptides SP, CGRP, and VIP play a role in the pathogenesis of psoriasis.


Laparoscopic radical hysterectomy in cervical cancer as total mesometrial resection (L-TMMR): a multicentric experience.
To analyze the feasibility of total mesometrial resection by laparoscopy (L-TMMR) in a multicentric series of early stage cervical cancer. We prospectively evaluated a consecutive series of cervical cancer patients with pre-operative FIGO stages IA2-IB1 at the Catholic University in Rome and in Campobasso and the Charitè University in Berlin. All cases were assessed at pre-operative MRI scan and clinically confirmed by investigation under anesthesia, adhering strictly to the FIGO criteria. The surgical and post-surgical data were collected. 104 women with cervical cancer were admitted between July 2013 and August 2014 and among them 71 patients with pre-operative FIGO stages IA2-IB1 were treated with L-TMMR. One laparotomic conversion was registered. The median operative time was 260min (120-670min), estimated blood loss was 100cm(3) (25-900cm(3)), and the median length of hospital stay was 6days (2-26days). We observed 8 intra-operative complications including a vascular injury of the left internal iliac vein that caused conversion, 6 vesical injuries and 1 ureteral injury managed laparoscopically. Two vescico-vaginal fistula and one hemoperitoneum were observed as major post-operative complications (4.2%). L-TMMR can be safely performed in selected cervical cancer patients. Further larger prospective trials are needed to evaluate the oncological outcome of patients undergoing this surgical procedure.


Improving Medication Management by Understanding Patient and Caregiver Preferences for Medication Packaging.
OBJECTIVE: To assess older adults' perceptions and preferences when comparing multi-medication packaging products.
 DESIGN: Qualitative study involving focus group interviews (FGIs) and key informant interviews (KIIs).
 SETTING: Interviews were conducted in multiple cities within the United States during June-July 2019.
 PATIENTS, PARTICIPANTS: FGI participants (N=36) included community dwelling adults, 65 years of age or older, who took 5+ chronic medications, or their caregivers. KII participants (N=15) included health care professionals caring for similar populations.
 INTERVENTIONS: Participants were given samples of blister packs and pouches and asked about medication management and appearance and usability of medication packaging. Interviews were audio-recorded with participants' consent, then transcribed and coded using Atlas. ti. Recurrent and emergent themes were identified, and selected quotes served as examples of identified themes.
 MAIN OUTCOME MEASURE: Participants' perceptions regarding medication packaging.
 RESULTS: Participants' preferences varied for different multi-medication packaging systems. Similarly, most FGI participants did not communicate a strong attitude for or against their existing management systems. However, many FGI participants perceived a need for larger font size than seen on the either of the multimedication packaging samples. KII participants also preferred a larger font size on both packagings. KII participants thought the blister packs offered better visual organization and enabled caregivers to quickly assess adherence. However, KII participants expressed concern about integrating as-needed and short-term use medications and noted difficulty opening both types of packages.
 CONCLUSION: Visual appearance is important to both patients and health care providers. Continued research in this area is vital for tailoring packaging types and technology to patients.


Prescribing medications and nutritional supplements for athletes.
Athletes in the Caribbean depend heavily on their medical personnel to advise on the correct use of medications for their illnesses. Doctors, pharmacists and paramedical personnel that accompany or treat athletes must be knowledgeable of which commonly prescribed substances are banned in sport in order to correctly advise and treat the athletes under their care. The objective is to review the classes of banned substances, using common examples of medications, as defined by the World Anti-Doping Agency (WADA) in a simplistic manner in order to allow treating medical personnel to prescribe medications to athletes with the confidence of not violating doping regulations. The concept of Therapeutic Use Exemption (TUE) is introduced. Upper respiratory tract infections and asthma are discussed as they are both common in athletes. The use of corticosteroids and nutritional supplements are also discussed.


Geometric and dosimetric evaluations of an online image-guidance strategy for 3D-CRT of prostate cancer.
To evaluate an online image-guidance strategy for conformal treatment of prostate cancer and to estimate margin-reduction benefits. Twenty-eight patients with at least 16 helical computed tomography scans were each used in this study. Two prostate soft-tissue registration methods, including sagittal rotation, were evaluated. Setup errors and rigid organ motion were corrected online; non-rigid and intrafraction motion were included in offline analysis. Various clinical target volume-planning target volume (CTV-PTV) margins were applied. Geometrical evaluations included analyses of isocenter shifts and rotations and overlap index. Dosimetric evaluations included minimum dose and equivalent uniform dose (EUD) for prostate and gEUD for rectum. Average isocenter shift and rotation were (dX,dY,dZ,theta) = (0.0 +/- 0.7,-1.1 +/- 4.0,-0.1 +/- 2.5,0.7 degrees +/- 2.0 degrees ) mm. Prostate motion in anterior-posterior (AP) direction was significantly higher than superior-inferior and left-right (LR) directions. This observation was confirmed by isocenter shift in perspectives AP (1.8 +/- 1.8 mm) and RL (3.7 +/- 3.0 mm). Organ motion degrades target coverage and reduces doses to rectum. If 2% dose reduction on prostate D(99) is allowed for 90% patients, then minimum 3 mm margins are necessary with ideal image registration. Significant margin reduction can be achieved through online image guidance. Certain margins are still required for nonrigid and intrafraction motion. To further reduce margin, a strategy that combines online geometric intervention and offline dose replanning is necessary.


Disseminated nocardiosis caused by Nocardia abscessus in a dog.
A 4-year-old female spayed Bichon Frise dog that had been receiving cyclosporine A per os 3 times per week for 2 months to control allergic dermatitis developed lethargy, anorexia, fever, and multiple firm subcutaneous masses. Pyogranulomatous inflammation with branching nonseptate filamentous organisms approximately 2 μm in diameter, presumptively fungal organisms, was diagnosed by cytologic evaluation of fine-needle aspirates from several masses. A partially acid-fast actinomycete was cultured from 2 of the masses. The organism was identified as Nocardia abscessus (formerly Nocardia asteroides type 1) based on 16S ribosomal DNA sequencing of samples extracted from cultures and unstained cytologic smears. Immunosuppression caused by long-term administration of cyclosporine A likely predisposed the dog to disseminated infection. To our knowledge, this is the first report of N. abscessus infection in a dog. This case demonstrates that N. abscessus may be mistaken for a fungal organism based on its cytologic appearance and underscores the importance of using molecular techniques for the diagnosis of suspected fungal diseases.


A Clinical Study on Microwave Ablation in Combination with Chemotherapy in Treating Peripheral IIIB-IV Non-Small Cell Lung Cancer.
Background: This study investigated the efficacy and complications of microwave ablation in combination with chemotherapy in treating peripheral IIIB-IV non-small cell lung cancer (NSCLC). Materials and Methods: A total of 100 patients with peripheral IIIB-IV NSCLC were randomly divided into two groups: combination group (n = 52) and chemotherapy group (n = 48). Patients in the combination group were treated with microwave ablation, radiotherapy, and chemotherapy, whereas the patients in the chemotherapy group were treated with pemetrexed disodium or gemcitabine hydrochloride, cisplatin chemotherapy, and conventional radiotherapy. Results: The effectiveness and disease control rates were significantly higher in the combination group than in the chemotherapy group (p < 0.05). The second- and third-year survival rates were significantly higher in the combination group than in the chemotherapy group (p < 0.05). However, patients in the combination group had no serious complications, and there were no intraoperative and perioperative deaths. Conclusions: Microwave ablation is safe and effective. Combination chemotherapy is superior to chemotherapy in treating peripheral IIIB-IV NSCLC in terms of effectiveness rate, disease control rate, and extended patient survival time.


Novel expression and transcriptional regulation of FoxJ1 during oro-facial morphogenesis.
Axenfeld-Rieger syndrome (ARS) patients with PITX2 point mutations exhibit a wide range of clinical features including mild craniofacial dysmorphism and dental anomalies. Identifying new PITX2 targets and transcriptional mechanisms are important to understand the molecular basis of these anomalies. Chromatin immunoprecipitation assays demonstrate PITX2 binding to the FoxJ1 promoter and PITX2C transgenic mouse fibroblasts and PITX2-transfected cells have increased endogenous FoxJ1 expression. FoxJ1 is expressed at embryonic day 14.5 (E14.5) in early tooth germs, then down-regulated from E15.5-E17.5 and re-expressed in the inner enamel epithelium, oral epithelium, tongue epithelium, sub-mandibular salivary gland and hair follicles during E18.5 and neonate day 1. FoxJ1 and Pitx2 exhibit overlapping expression patterns in the dental and oral epithelium. PITX2 activates the FoxJ1 promoter and, Lef-1 and beta-catenin interact with PITX2 to synergistically regulate the FoxJ1 promoter. FoxJ1 physically interacts with the PITX2 homeodomain to synergistically regulate FoxJ1, providing a positive feedback mechanism for FoxJ1 expression. Furthermore, FoxJ1, PITX2, Lef-1 and beta-catenin act in concert to activate the FoxJ1 promoter. The PITX2 T68P ARS mutant protein physically interacts with FoxJ1; however, it cannot activate the FoxJ1 promoter. These data indicate a mechanism for the activity of the ARS mutant proteins in specific cell types and provides a basis for craniofacial/ tooth anomalies observed in these patients. These data reveal novel transcriptional mechanisms of FoxJ1 and demonstrate a new role of FoxJ1 in oro-facial morphogenesis.


HFE and transferrin directly compete for transferrin receptor in solution and at the cell surface.
Transferrin receptor (TfR) is a dimeric cell surface protein that binds both the serum iron transport protein transferrin (Fe-Tf) and HFE, the protein mutated in patients with the iron overload disorder hereditary hemochromatosis. HFE and Fe-Tf can bind simultaneously to TfR to form a ternary complex, but HFE binding to TfR lowers the apparent affinity of the Fe-Tf/TfR interaction. This apparent affinity reduction could result from direct competition between HFE and Fe-Tf for their overlapping binding sites on each TfR polypeptide chain, from negative cooperativity, or from a combination of both. To explore the mechanism of the affinity reduction, we constructed a heterodimeric TfR that contains mutations such that one TfR chain binds only HFE and the other binds only Fe-Tf. Binding studies using a heterodimeric form of soluble TfR demonstrate that TfR does not exhibit cooperativity in heterotropic ligand binding, suggesting that some or all of the effects of HFE on iron homeostasis result from competition with Fe-Tf for TfR binding. Experiments using transfected cell lines demonstrate a physiological role for this competition in altering HFE trafficking patterns.


Drugs and nutrition: how side effects can influence nutritional intake.
There are many factors that can influence nutritional intake. Food availability, physical capability, appetite, presence of gastrointestinal symptoms and perception of food are examples. Drug therapy can negatively influence nutritional intake through their effect on these factors, predominantly due to side effects. This review aims to give a brief overview of each of these factors and how drug therapy can affect them. Specific examples are given for each section and an indication of the impact on nutritional status. This article aims to assist the clinician in the identification of the effects of drug therapy on nutritional intake and provides advice on appropriate intervention. A drug history and side effect review should form an integral part of nutritional assessment. Early identification and effective therapeutic use of alternative drug therapy can also positively influence nutritional intake.


Author Correction: Nuclear ignorance.
An amendment to this paper has been published and can be accessed via a link at the top of the paper.


Assessment of small-intestine permeability in healthy Nigerian children is altered by urinary volume and voiding status.
This study aimed to uncover the effect of voided urinary volume on small intestine permeability ratios in healthy children. We assessed small intestine permeability in 155 apparently healthy children, aged 3-5 years old, without any visible symptoms of disease, in a rural, malaria-endemic setting in Nigeria, using a multi-sugar test solution, comprising lactulose, sucrose, mannitol, and rhamnose. Children were categorized into low urinary volume (LV) and high urinary volume (HV), based on the volume of urine voided per kg body weight per hour. LV children voided less than 25th percentile of the total population, while HV children voided greater than 75th percentile of the total population. Urinary volume excreted over a 90-minute period after administration of the test solution was measured, and differences in sugar ratios were compared between children with high (HV) and low urinary volumes (LV), as well as between children who voided (VC) or who were not able to void (NVC) before administration of the test solution. Urinary mannitol and rhamnose recovery were 44% (p = 0.002) and 77% (p<0.001) higher in HV children compared to LV children respectively, while urinary lactulose recovery was 34% lower (p = 0.071). There was no difference in urinary sucrose recovery between groups (p = 0.74). Lactulose-mannitol ratio, lactulose-rhamnose ratio and sucrose-rhamnose ratio were all significantly higher in children in the LV group compared to children in the HV group (p<0.001). In a multiple regression analysis, urinary volume and voiding status combined, explained 13%, 23% and 7% of the variation observed in lactulose-mannitol, lactulose-rhamnose and sucrose-rhamnose ratios, respectively. Sugar permeability ratios vary significantly with total urinary volume in multi-sugar small-intestine permeability tests. Voiding status before sugar administration appears to influence lactulose recovery, lactulose-rhamnose and sucrose-rhamnose ratios independently of total urinary volume. Evidence from this study suggests the need to take urinary volume into account when conducting multi-sugar small-intestine permeability tests.


A comparative evaluation of biological activities and bioactive compounds of the seagrasses Zostera marina and Zostera noltei from southern Portugal.
This work assessed the antioxidant potential, acetylcholinesterase (AChE) inhibition and the in vitro cytotoxic activity of extracts of the seagrasses Zostera marina and Zostera noltei collected from southern Portugal. The total phenolic contents (TPCs), the rosmarinic acid (RA) concentration (HPLC/DAD) and the fatty acid (FA) profile (GC/MS) are also described. Z. marina had the highest TPC, radical scavenging activity against DPPH radicals and copper chelating activity. Z. noltei had metal chelation capacity to copper and iron ions. None of the species was able to inhibit AChE. Both seagrasses had high levels of polyunsaturated FAs. Z. marina significantly and selectively reduced the viability of tumorous neuronal cells. Z. noltei was highly toxic for the three cell lines tested and was selective against hepatocarcinoma cells at the concentration of 100 μg/mL. RA was the main compound identified in Z. marina, but not in Z. noltei.


The impact of different volumetric thresholds to determine progressive disease in patients with recurrent glioblastoma treated with bevacizumab.
The optimal volumetric threshold for determining progressive disease (PD) in recurrent glioblastoma is yet to be determined. We investigated a range of thresholds in association with overall survival (OS). First recurrent glioblastoma patients treated with bevacizumab and/or lomustine were included from the phase II BELOB and phase III EORTC26101 trials. Enhancing and nonenhancing tumor volumes were measured at baseline, first (6 weeks), and second (12 weeks) follow-up. Hazard ratios (HRs) for the appearance of new lesions and several thresholds for tumor volume increase were calculated using cox regression analysis. Results were corrected in a multivariate analysis for well-established prognostic factors. At first and second follow-up, 138 and 94 patients respectively, were deemed eligible for analysis of enhancing volumes, while 89 patients were included in the analysis of nonenhancing volumes at first follow-up. New lesions were associated with a significantly worse OS (3.2 versus 11.2 months, HR = 7.03, P < .001). At first follow-up a threshold of enhancing volume increase of ≥20% provided the highest HR (5.55, p = .001. At second follow-up, any increase in enhancing volume (≥0%) provided the highest HR (9.00, p < .001). When measuring nonenhancing volume at first follow-up, only 6 additional patients were scored as PD with the highest HR of ≥25% increase in volume (HR=3.25, p = .008). Early appearing new lesions were associated with poor OS. Lowering the volumetric threshold for PD at both first and second follow-up improved survival prediction. However, the additional number of patients categorized as PD by lowering the threshold was very low. The per-RANO added change in nonenhancing volumes to the analyses was of limited value.


An explorative multiverse study for extracting differences in P3 latencies between young and old adults.
It is well established that P3 latencies increase with age. Investigating these age-related differences requires numerous methodological decisions, resulting in pipelines of great variation. The aim of the present work was to investigate the effects of different analytical pipelines on the age-related differences in P3 latencies in real data. Therefore, we conducted an explorative multiverse study and varied the low-pass filter (4 Hz, 8 Hz, 16 Hz, 32 Hz, and no filter), the latency type (area vs. peak), the level of event-related potential analysis (single participant vs. jackknifing), and the extraction method (manual vs. automated). Thirty young (18-21 years) and 30 old (50-60 years) participants completed three tasks (Nback task, Switching task, Flanker task), while an EEG was recorded. The results show that different analysis strategies can have a tremendous impact on the detection and magnitude of the age effect, with effect sizes ranging from 0% to 88% explained variance. Likewise, regarding the psychometric properties of P3 latencies, we found that the reliabilities fluctuated between rtt = .20 and 1.00, while the homogeneities ranged from rh = -.12 to .90. Based on predefined criteria, we found that the most effective pipelines relied on a manual extraction based on a single participant's data. For peak latencies, manual extraction performed well for all filters except for 4 Hz, while for area latencies, filters above 8 Hz produced desirable results. Furthermore, our findings add to the evidence that jackknifing combined with peak latencies can lead to inconclusive results.


Aggressive mimicry in photuris fireflies: signal repertoires by femmes fatales.
Females of Photuris versicolor prey on males of other species by mimicking the flash responses of the prey's own females. They adjust their responses according to the male pattern, and attract males of four species with distinctively different flashed responses. The capabilities of the firefly brain are more complex than previously suspected. The mimicry is quite effective, and females seldom answered more than ten males without catching one.


Review: The genetics of Alzheimer's disease; putting flesh on the bones.
For two decades the search for genes involved in Alzheimer's disease brought little reward; it was not until the advent of genome-wide association studies (GWAS) that genetic associations started to be revealed. Since 2009 increasingly large GWAS have revealed 20 loci, which in itself is a substantial increase in our understanding, but perhaps the more important feature is that these studies have highlighted novel pathways that are potentially involved in the disease process. This commentary assembles our latest knowledge while acknowledging that the casual functional variants, and undoubtedly, other genes are still yet to be discovered. This is the challenge that remains and the promise of next-generation sequencing is anticipated as there are a number of large initiatives which themselves should start to yield information before long.


Reported Behavioural Differences between Geldings and Mares Challenge Sex-Driven Stereotypes in Ridden Equine Behaviour.
Horse trainers and riders may have preconceived ideas of horse temperament based solely on the sex of the horse. A study (n = 1233) of horse enthusiasts (75% of whom had more than 8 years of riding experience) revealed that riders prefer geldings over mares and stallions. While these data may reflect different sex preferences in horses used for sport, they may also reduce the chances of some horses reaching their performance potential. Further, an unfounded sex prejudice is likely to contribute to unconscious bias when perceiving unwanted behaviours, simplistically attributing them to demographic characteristics rather than more complex legacies of training and prior learning. The current study analysed reported sex-related behavioural differences in ridden and non-ridden horses using data from responses to the pilot study of the Equine Behaviour Assessment and Research Questionnaire (E-BARQ) survey. Respondents (n = 1233) reported on the behaviour of their horse using a 151-item questionnaire. Data were searched for responses relating to mares and geldings, and 110 traits with the greatest percentage difference scores between mares and geldings were selected were tested for univariate significance at p < 0.2. Multivariable modelling of the effect of sex (mare or gelding) on remaining traits was assessed by ordinal logistic regression, using a cumulative proportional log odds model. Results revealed mares were significantly more likely to move away when being caught compared to geldings (p = 0.003). Geldings were significantly more likely to chew on lead ropes when tied (p = 0.003) and to chew on rugs (p = 0.024). However, despite sex-related differences in these non-ridden behaviours, there was no evidence of any significant sex-related differences in the behaviours of the horses when ridden. This finding suggests that ridden horse behaviour is not sexually dimorphic or that particular horse sports variously favour one sex over another.


Natural sagittal spino-pelvic alignment in boys and girls before, at and after the adolescent growth spurt.
Adolescent idiopathic scoliosis occurs far more often in girls than in boys, and its initiation and progression normally takes place around the adolescent growth spurt. Despite extensive research into the topic, no solid explanation for both well-known phenomena has been offered. The sagittal profile of the growing spine has been demonstrated previously to play an important role in the spine's rotational stiffness. Changes in this sagittal alignment around the growth spurt can be inferred to play an important role in the spine's propensity to develop a rotatory deformity, i.e. scoliosis. The aim of this study was to quantify sagittal spino-pelvic alignment and orientation in space of each individual vertebra in normal boys and girls in the beginning, at the peak and at the end of pubertal growth. Standardized lateral radiographs of the spine of boys (n = 57) and girls (n = 99) between the age of seven and eighteen who underwent screening for scoliosis, but had a normal spine were enrolled in this study. Children with spino-pelvic pathology at initial screening or during follow-up were excluded. According to Dimeglio's data, subjects were classified into three groups: before, at and after the peak growth spurt. Seven regional sagittal spino-pelvic parameters, as well as the inclination angles of each individual vertebra between C7 and L5 compared to the gravity line, were measured semi-automatically using in-house developed software. In all subjects, the posteriorly tilted segment was longer, vertebrae T1-T8 were more posteriorly inclined and thoracic kyphosis, pelvic incidence and pelvic tilt were lower before as well as during the peak of the growth spurt, when compared to after the growth spurt (P ≤ 0.023). Furthermore, in girls, thoracic kyphosis was smaller (P = 0.023), the posteriorly inclined segment was longer (P < 0.001) and T1 as well as levels T3-T11 were more posteriorly inclined (P < 0.05) compared to boys at all stages of development. At the peak of the growth spurt, girls had more posterior inclination of upper thoracic vertebrae and lower values for thoracic kyphosis than boys (P = 0.005). These results imply that the spines of girls during the growth spurt are more posteriorly inclined, and thus rotationally less stable, compared to boys at the same stage of development, as well as compared to girls after the growth spurt. This may explain why initiation and progression of adolescent idiopathic scoliosis are more prevalent in girls around puberty.


Infancy problem behaviors.
The goal of pediatric health supervision is to promote the optimal growth and development of children. Parent-infant interaction and parental attitudes toward their infant are important determinants of child development. Anticipatory guidance during child health supervision enables the pediatric provider to discuss developmental stages and demystify common stage-related behaviors, such as fussing, night-waking, repetitive movements, and clinging. Anticipating the emergence of such behaviors and issues may lessen parental anxiety and concern. When behavioral problems such as colic or sleep difficulties do arise, a consideration of developmental stage is helpful in suggesting specific management strategies. The successful implementation of developmentally-oriented approaches has benefits for the family and pediatric provider, including increased parental self-confidence, enhanced family functioning, and increased parental confidence in the pediatrician. Furthermore, by encouraging developmentally-oriented approaches, parents will be less inclined to adopt inappropriate or ineffectual behavioral management strategies.


GII.4 Norovirus Protease Shows pH-Sensitive Proteolysis with a Unique Arg-His Pairing in the Catalytic Site.
Human noroviruses (NoVs) are the main cause of epidemic and sporadic gastroenteritis. Phylogenetically, noroviruses are divided into seven genogroups, with each divided into multiple genotypes. NoVs belonging to genogroup II and genotype 4 (GII.4) are globally most prevalent. Genetic diversity among the NoVs and the periodic emergence of novel strains present a challenge for the development of vaccines and antivirals to treat NoV infection. NoV protease is essential for viral replication and is an attractive target for the development of antivirals. The available structure of GI.1 protease provided a basis for the design of inhibitors targeting the active site of the protease. These inhibitors, although potent against the GI proteases, poorly inhibit the GII proteases, for which structural information is lacking. To elucidate the structural basis for this difference in the inhibitor efficiency, we determined the crystal structure of a GII.4 protease. The structure revealed significant changes in the S2 substrate-binding pocket, making it noticeably smaller, and in the active site, with the catalytic triad residues showing conformational changes. Furthermore, a conserved arginine is found inserted into the active site, interacting with the catalytic histidine and restricting substrate/inhibitor access to the S2 pocket. This interaction alters the relationships between the catalytic residues and may allow for a pH-dependent regulation of protease activity. The changes we observed in the GII.4 protease structure may explain the reduced potency of the GI-specific inhibitors against the GII protease and therefore must be taken into account when designing broadly cross-reactive antivirals against NoVs.IMPORTANCE Human noroviruses (NoVs) cause sporadic and epidemic gastroenteritis worldwide. They are divided into seven genogroups (GI to GVII), with each genogroup further divided into several genotypes. Human NoVs belonging to genogroup II and genotype 4 (GII.4) are the most prevalent. Currently, there are no vaccines or antiviral drugs available for NoV infection. The protease encoded by NoV is considered a valuable target because of its essential role in replication. NoV protease structures have only been determined for the GI genogroup. We show here that the structure of the GII.4 protease exhibits several significant changes from GI proteases, including a unique pairing of an arginine with the catalytic histidine that makes the proteolytic activity of GII.4 protease pH sensitive. A comparative analysis of NoV protease structures may provide a rational framework for structure-based drug design of broadly cross-reactive inhibitors targeting NoVs.


Analysis of the Association between Galectin-3 Concentration in Tears and the Severity of Dry Eye Disease: A Case-Control Study.
This study aimed to investigate the relationship between the severity of dry eye disease (DED) and galectin-3 concentration (gal-3) and its cleavage (gal-3C) in tear fluid. Twenty-eight DED patients and 14 controls were recruited at Keio University Hospital. The lissamine green conjunctival staining (LG) score, fluorescein corneal staining (FL) score, tear film break-up time (TBUT), Schirmer's test, and ocular symptoms questionnaire score (dry eye questionnaire score, DEQS) were evaluated. Furthermore, the correlation between these parameters and the concentrations of gal-3 in tears (ng/µg) and the detection rate of gal-3C (%) were analyzed. Gal-3 concentration in tears was positively correlated with the LG score (R = 0.60, p < 0.01), FL score (R = 0.49, p < 0.01), and DEQS (R = 0.45, p < 0.01), and negatively correlated with the TBUT score (R = -0.40, p < 0.01) and Schirmer's I value (R = -0.36, p < 0.01). The detection rate of gal-3C in tears was significantly associated with the severity of DED, especially with the LG (p < 0.01) and FL (p < 0.01) scores. Therefore, the concentration of gal-3 and the detection rate of gal-3C in tears had a significant relationship with the severity of ocular surface barrier disruption.


High tidal volume ventilation activates Smad2 and upregulates expression of connective tissue growth factor in newborn rat lung.
High tidal volume (V(T)) ventilation plays a key role in ventilator induced lung injury and bronchopulmonary dysplasia. However, little is known about the effect of high V(T) on expression of growth factors that are critical to lung development. In a previous study, we demonstrated that connective tissue growth factor (CTGF) inhibits branching morphogenesis. In this study, we investigated the effect of high V(T) on CTGF expression in newborn rat lungs. Newborn rats were ventilated with normal V(T) (10 mL/kg) or high V(T) (25 mL/kg) for 6 h. Nonventilated animals served as controls. We found that high V(T) upregulated CTGF expression. To identify the potential signaling pathways mediating high V(T) induction of CTGF, newborn rats were ventilated with high V(T) for 1 or 3 h. Temporal expression of TGF-betas, p-Smad2, Smad7, and CTGF was analyzed. High V(T) ventilation did not change gene expression of TGF-betas and Smad7 but induced rapid and sustained expression of p-Smad2 that precedes increased CTGF expression. CTGF and p-Smad2 were localized in bronchiolar epithelial cells, alveolar walls and septa. These data suggest that high V(t) ventilation activates the Smad2 pathway, which may be responsible for downstream induction of CTGF expression in newborn rat lungs.


Isolation of methicillin-resistant coagulase-negative staphylococci from chickens.
Methicillin-resistant coagulase-negative staphylococci were isolated from the nares and skin of 1- to 8-week-old healthy chickens in three flocks from a farm. Isolation of methicillin-resistant coagulase-negative staphylococci was positive for 72 (25.7%) of the 280 chickens tested, with the frequency varying from 2.2 to 100% according to flock. A total of 45 appropriate isolates were selected and subjected to identification. Of the 45 methicillin-resistant coagulase-negative staphylococcal isolates selected, 37 were identified as Staphylococcus sciuri, 5 were identified as Staphylococcus epidermidis, and 3 were identified as Staphylococcus saprophyticus. The distribution of the species was different among the flocks. Comparative analysis of the SmaI-digested chromosomal DNA by pulsed-field gel electrophoresis revealed that the isolates could have originated from a single clone of each of S. sciuri and S. saprophyticus and three clones of S. epidermidis. By two methods based on the PCR technique, the mecA gene was detected in all five representative isolates of each methicillin-resistant coagulase-negative staphylococcal clone. The nucleotide sequence of a PCR fragment obtained from an isolate of S. sciuri was completely identical to the corresponding region of mecA genes reported in human methicillin-resistant Staphylococcus aureus isolates and Staphylococcus epidermidis isolates. The representative methicillin-resistant coagulase-negative staphylococcal isolates were resistant to many beta-lactam antibiotics, and some isolates were also resistant to macrolide and aminoglycoside antibiotics. This is the first evidence of the existence of methicillin-resistant coagulase-negative staphylococci from animals possessing the mecA gene.