Hypertension, overweight and obesity in adolescents: the CRO-KOP study.
The objective of this study was to determine the prevalence of hypertension, overweight and obesity in Croatian adolescents. In this cross-sectional survey (the sub-study of the EH-UH study) 375 boys and 381 girls (mean age 15.9 +/- 0.5 years) from four high schools in the city of Koprivnica were enrolled. Blood pressure, body height and body weight were measured according to the current ESH/ESC guidelines. Data on life style were obtained from questionnaire. Average blood pressure values were higher in boys than in girls (117/74 mmHg vs. 111/69 mmHg; p < 0.001). Significantly higher blood pressure values were obtained in overweight children compared to those with normal weight (119/76 mmHg us. 115/72 mmHg; p < 0.01). Prevalence of hypertension was 8.5% in the whole group being significantly higher in boys than in girls (11.2% vs. 5.8%; p = 0.0007). As expected, prevalence of hypertension was significantly higher in obese children than in those with normal weight (20.0% vs. 6.8%; p = 0.015). A significant correlation was found between body mass index and blood pressure (p = 0.0001). The overall prevalence of obesity was 3.54% (boys 2.2%; girls 4.9%). Our results confirmed positive relationship between overweight, obesity and hypertension starting from childhood pointing again the utmost importance of preventive measures beginning from early life.


An optimized probucol microencapsulated formulation integrating a secondary bile acid (deoxycholic acid) as a permeation enhancer.
The authors have previously designed, developed, and characterized a novel microencapsulated formulation as a platform for the targeted delivery of therapeutics in an animal model of type 2 diabetes, using the drug probucol (PB). The aim of this study was to optimize PB microcapsules by incorporating the bile acid deoxycholic acid (DCA), which has good permeation-enhancing properties, and to examine its effect on microcapsules' morphology, rheology, structural and surface characteristics, and excipients' chemical and thermal compatibilities. Microencapsulation was carried out using a BÜCHI-based microencapsulating system established in the authors' laboratory. Using the polymer sodium alginate (SA), two microencapsulated formulations were prepared: PB-SA (control) and PB-DCA-SA (test) at a constant ratio (1:30 and 1:3:30, respectively). Complete characterization of the microcapsules was carried out. The incorporation of DCA resulted in better structural and surface characteristics, uniform morphology, and stable chemical and thermal profiles, while size and rheological parameters remained similar to control. In addition, PB-DCA-SA microcapsules showed good excipients' compatibilities, which were supported by data from differential scanning calorimetry, Fourier transform infrared spectroscopy, scanning electron microscopy, and energy dispersive X-ray studies, suggesting microcapsule stability. Hence, PB-DCA-SA microcapsules have good rheological and compatibility characteristics and may be suitable for the oral delivery of PB in type 2 diabetes.


Envelope-induced cell transformation by ovine betaretroviruses.
Ovine betaretroviruses include Jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV). JSRV and ENTV represent a unique class of oncogenic retroviruses that induce tumors of the respiratory tract. JSRV and ENTV are highly related but induce different diseases. Expression of the JSRV envelope (Env) induces transformation of rodent fibroblasts in vitro and phosphorylation of Akt, a central player in the phosphatidylinositol 3-kinase (PI-3K)/Akt signal transduction pathway. However, little information is available on the molecular biology of ENTV. In this study, we initially assessed whether the ENTV Env has the same properties as the homologous JSRV protein. We performed entry and interference assays using retroviral vectors pseudotyped with either the JSRV or the ENTV Env and sheep choroid plexus cells, choroid plexus cells stably expressing the JSRV Env protein, human 293T cells, mouse NIH 3T3 cells, or NIH 3T3 cells expressing human hyaluronidase 2 (HYAL2), the cellular receptor for JSRV. The results obtained indicated that ENTV and JSRV share the same receptor in sheep cells and that they can use human HYAL2 as a cellular receptor in mouse cells. The ENTV Env induces transformation of rodent fibroblasts in vitro. As with the JSRV Env, the tyrosine at position 590 is critical for ENTV Env-induced cell transformation, and Akt is phosphorylated in ENTV Env-transformed cells but not in the parental cell lines. Thus, ovine betaretroviruses share a common mechanism of cell transformation. We further investigated the relevance of Akt activation in cells transformed by ovine betaretroviruses. A PI-3K inhibitor blocked Akt phosphorylation in JSRV Env-transformed cells, suggesting a possible involvement of PI-3K in JSRV and ENTV Env-induced cell transformation. In addition, phosphorylated Akt was detected in a cell line derived from a lung tumor of a sheep with naturally occurring ovine pulmonary adenocarcinoma.


Development and validation of the Medication Regimen Simplification Guide for Residential Aged CarE (MRS GRACE).
Residents of aged care facilities use increasingly complex medication regimens. Reducing unnecessary medication regimen complexity (eg, by consolidating the number of administration times or using alternative formulations) may benefit residents and staff. To develop and validate an implicit tool to facilitate medication regimen simplification in aged care facilities. A purposively selected multidisciplinary expert panel used modified nominal group technique to identify and prioritize factors important in determining whether a medication regimen can be simplified. The five prioritized factors were formulated as questions, pilot-tested using non-identifiable medication charts and refined by panel members. The final tool was validated by two clinical pharmacists who independently applied the tool to a random sample of 50 residents of aged care facilities to identify opportunities for medication regimen simplification. Inter-rater agreement was calculated using Cohen's kappa. The Medication Regimen Simplification Guide for Residential Aged CarE (MRS GRACE) was developed as an implicit tool comprising of five questions about 1) the resident; 2) regulatory and safety requirements; 3) drug interactions; 4) formulation; and 5) facility and follow-up considerations. Using MRS GRACE, two pharmacists independently simplified medication regimens for 29/50 and 30/50 residents (Cohen's kappa=0.38, 95% CI 0.12-0.64), respectively. Simplification was possible for all residents with five or more administration times. Changing an administration time comprised 75% of the two pharmacists' recommendations. Using MRS GRACE, two clinical pharmacists independently simplified over half of residents' medication regimens with fair agreement. MRS GRACE is a promising new tool to guide medication regimen simplification in aged care.


Specific beta-lactam antibiotics inhibit secretion of lipo-beta-lactamase in yeast.
The beta-lactam antibiotic cloxacillin can inhibit secretion of prokaryotic lipo-beta-lactamase into the periplasm of yeast. The results indicate that this phenomenon is specific with respect to both the antibiotic and the lipo-beta-lactamase whose secretion is affected, strongly suggesting that this involves an interaction between the enzyme and its substrates. The effect of the antibiotic on secretion is reversible. With different beta-lactam antibiotics, the clearest difference is observed between type A and type S penicillins; the former exert a strong inhibition of secretion whereas the latter exhibit a weak effect or no effect at all. Type A penicillins have been previously shown to cause a conformational change in various beta-lactamases. Mature lipo-beta-lactamase species in yeast were localized either to the periplasmic space or bound to the outer surface of the cytoplasmic membrane and thus exposed to periplasm. The results are consistent with the hypothesis that binding of cloxacillin to lipo-beta-lactamase induces a conformation on the protein that is unfavourable for its release from the membrane.


ASSOCIATION OF INTERLEUKIN-10 -592A>C AND -819T>C POLYMORPHISMS WITH GASTRIC CANCER RISK: A SYSTEMATIC REVIEW AND META-ANALYSIS OF 44 CASE-CONTROL STUDIES.
A series of studies have evaluated the association between -592A>C and -819T>C polymorphisms in the promoter regions of Interleukin-10 (IL-10) and gastric cancer (GC) risk. However, the results remain inconclusive. To better understand the association of the polymorphisms with GC risk, we performed a comprehensive meta-analysis. An electronic search was performed of several databases to identify relevant studies up to April 2018. A total of 44 case-control studies, including 26 studies on IL-10 -592A>C (5,332 cases and 8,272 controls) and 18 studies on IL-10 -819T>C (3,431 cases and 6,109 controls) were selected. Overall, -592A>C polymorphism was associated with the risk of GC under the heterozygote model (OR=1.153, 95% CI=1.020-1.305, p=0.023), but not -819T>C polymorphism. When stratified by ethnicity, significant association was only observed in the Asians under the allele model (OR=1.153, 95% CI=1.007-1.320, p=0.040) and the heterozygote model (OR=1.218, 95% CI=1.076-1.379, p=0.002) for -592A>C. The current meta-analysis results inconsistent with previous meta-analyses; showed that the IL-10 -592A>C polymorphism, but not -819T>C polymorphism, may be contributed to the susceptibility of GC in overall and Asian populations.


Similar associations of total adiponectin and high molecular weight adiponectin with cardio-metabolic risk factors in a population of overweight and obese postmenopausal women: a MONET study.
The aim of the study was to examine the association between total adiponectin and high molecular weight (HMW) adiponectin levels with cardio-metabolic risk factors in a population of sedentary, overweight, and obese postmenopausal women. Cross-sectional study was carried out on 55 nondiabetic sedentary overweight and obese postmenopausal women aged between 50 and 70 years. Insulin sensitivity was assessed by euglycemic-hyperinsulinemic clamp technique. Body composition and visceral fat were measured using dual X-ray absorptiometry and computed tomography, respectively. Other cardio-metabolic risk factors included: plasma lipids, hsC-reactive protein, energy expenditure (doubly labeled water), peak oxygen consumption, muscle strength (using weight training equipment) as well as total and HMW adiponectin. Correlations of total and HMW adiponectin with various cardio-metabolic risk factors were comparable. In addition, regression analysis results showed similar independent predictors of total and HMW adiponectin. Finally, the receiver operator characteristic (ROC) curves for total and HMW adiponectin to predict insulin sensitivity showed no difference between the areas under curve (AUC) (AUC total adiponectin=0.80 [95% CI: 0.66-0.95] versus AUC HMW adiponectin=0.76 [95% CI: 0.60-0.91], p=0.36). The present study indicates that HMW adiponectin does not seem to provide additional information than total adiponectin in relation to cardio-metabolic risk factors in overweight/obese postmenopausal women.


Molecular characterization of human immunodeficiency virus from Zaire: nucleotide sequence analysis identifies conserved and variable domains in the envelope gene.
To examine the genetic relatedness of human immunodeficiency viruses (HIV) from different geographic locations, we molecularly cloned the genome of HIV isolated from a Zairian AIDS patient. Restriction mapping of the recombinant clone, designated HIV-Zr6, revealed both common (as observed in other HIV isolates) and unique restriction sites. The DNA clone of HIV-Zr6, shown to give rise to infectious cytopathic virus after transfection of cultured lymphoid cells, was sequenced in several regions. The long terminal repeat (LTR), open reading frame 1 (ORF1), C-terminal envelope (env) gene domain, and ORF2 showed less than 6% difference in nucleotide sequence when compared to other HIV isolates including human T-lymphotropic virus-type III (HTLV-III) clone B10, lymphadenopathy-associated virus-1 (LAV-1), and AIDS-associated retrovirus-2 (ARV-2). About 15% difference in nucleotide sequences was noted in the N-terminal env gene domain. Alignments of env gene sequences revealed conserved, moderately variable, and hypervariable stretches in the predicted amino acid sequences. This model provides a basis for assessing the significance of sequence variation on properties controlled by the viral Env glycoproteins such as cell tropism and immunogenicity.


Acute myelogenous leukaemia presenting with mid-foot pain after an inversion injury.
The case is presented of a 5 year old boy who attended after an inversion injury. He had persistent pain despite treatment and was subsequently diagnosed with acute myelogenous leukaemia. It is well recognised that acute leukaemia commonly presents as non-traumatic limb pain. This case highlights the need to consider acute leukaemia in the differential diagnosis of any persisting bone or joint pain, even in the context of recent injury.


Mlc is a transcriptional activator with a key role in integrating cyclic AMP receptor protein and integration host factor regulation of leukotoxin RNA synthesis in Aggregatibacter actinomycetemcomitans.
Aggregatibacter actinomycetemcomitans, a periodontal pathogen, synthesizes leukotoxin (LtxA), a protein that helps the bacterium evade the host immune response. Transcription of the ltxA operon is induced during anaerobic growth. The cyclic AMP (cAMP) receptor protein (CRP) indirectly increases ltxA expression, but the intermediary regulator is unknown. Integration host factor (IHF) binds to and represses the leukotoxin promoter, but neither CRP nor IHF is responsible for the anaerobic induction of ltxA RNA synthesis. Thus, we have undertaken studies to identify other regulators of leukotoxin transcription and to demonstrate how these proteins work together to modulate leukotoxin synthesis. First, analyses of ltxA RNA expression from defined leukotoxin promoter mutations in the chromosome identify positions -69 to -35 as the key control region and indicate that an activator protein modulates leukotoxin transcription. We show that Mlc, which is a repressor in Escherichia coli, functions as a direct transcriptional activator in A. actinomycetemcomitans; an mlc deletion mutant reduces leukotoxin RNA synthesis, and recombinant Mlc protein binds specifically at the -68 to -40 region of the leukotoxin promoter. Furthermore, we show that CRP activates ltxA expression indirectly by increasing the levels of Mlc. Analyses of Δmlc, Δihf, and Δihf Δmlc strains demonstrate that Mlc can increase RNA polymerase (RNAP) activity directly and that IHF represses ltxA RNA synthesis mainly by blocking Mlc binding. Finally, a Δihf Δmlc mutant still induces ltxA during anaerobic growth, indicating that there are additional factors involved in leukotoxin transcriptional regulation. A model for the coordinated regulation of leukotoxin transcription is presented.


Synthesis and Structure-Activity Relationships of Tool Compounds Based on WAY163909, a 5-HT2C Receptor Agonist.
The development of probe molecules that can be used to investigate G protein-coupled receptor (GPCR) pharmacology, trafficking, and relationship with other GPCRs is an important and growing area of research. Here, we report the synthesis of analogues of the known selective serotonin (5-HT) 5-HT2C receptor (5-HT2CR) agonist WAY163909 which were designed to allow for the attachment of a second ligand, signaling or reporter molecules, as well as immobilization agents to the parent molecule with the maintenance of agonist activity. This goal was accomplished by the synthesis of novel molecules in which sites a-d were modified and resulting compounds were analyzed pharmacologically in vitro.


The sequence of the acidic repeat protein (arp) gene differentiates venereal from nonvenereal Treponema pallidum subspecies, and the gene has evolved under strong positive selection in the subspecies that causes syphilis.
Despite the completion of the Treponema pallidum genome project, only minor genetic differences have been found between the subspecies that cause venereal syphilis (ssp. pallidum) and the nonvenereal diseases yaws (ssp. pertenue) and bejel (ssp. endemicum). In this paper, we describe sequence variation in the arp gene which allows straightforward differentiation of ssp. pallidum from the nonvenereal subspecies. We also present evidence that this region is subject to positive selection in ssp. pallidum, consistent with pressure from the immune system. Finally, the presence of multiple, but distinct, repeat motifs in both ssp. pallidum and Treponema paraluiscuniculi (the pathogen responsible for rabbit syphilis) suggests that a diverse repertoire of repeat motifs is associated with sexual transmission. This study suggests that variations in the number and sequence of repeat motifs in the arp gene have clinical, epidemiological, and evolutionary significance.


Poly(l-alanine-co-l-threonine succinate) as a Biomimetic Cryoprotectant.
We synthesized a series of [(l-Ala)x-co-(l-Thr succinate)y] (PATs), which are analogous to natural antifreezing glycoprotein with the structure of [l-Ala-l-Ala-l-Thr disaccharide]n, by varying the composition and degree of succinylation while fixing their molecular weight (Mn) and Ala/Thr ratio at approximately 10-12 kDa and 2:1, respectively. We investigated their ice recrystallization inhibition (IRI), ice nucleation inhibition (INI), dynamic ice shaping (DIS), thermal hysteresis (TH), and protein cryopreservation activities. Both IRI and INI activities were greater for PATs with higher l-Ala content (PATs-3 and PATs-4) than those with lower l-Ala content (PATs-1 and PATs-2). DIS activity with faceted crystal growth was clearly observed in PATs-2 and PATs-4 with a high degree of succinylation. TH was small with <0.1 °C for all PATs and slightly greater for PATs with a high l-Ala content. Except for PATs-1, the protein (lactate dehydrogenase, LDH) stabilization activity was excellent for all PATs studied, maintaining LDH activity as high as that of fresh LDH even after 15 freeze-thaw cycles. To conclude, the cryo-active biomimetic PATs were synthesized by controlling the l-Ala content and degree of succinylation. Our results showed that PATs with an l-Ala content of 65-70% and degree of succinylation of 12-19% exhibited the cryo-activities of IRI, INI, and DIS, and particularly promising properties for the cryoprotection of LDH protein.


When components collide: Spatiotemporal overlap of the N400 and P600 in language comprehension.
The problem of spatiotemporal overlap between event-related potential (ERP) components is generally acknowledged in language research. However, its implications for the interpretation of experimental results are often overlooked. In a previous experiment on the functional interpretation of the N400 and P600, it was argued that a P600 effect to implausible words was largely obscured - in one of two implausible conditions - by an overlapping N400 effect of semantic association. In the present ERP study, we show that the P600 effect of implausibility is uncovered when the critical condition is tested against a proper baseline condition which elicits a similar N400 amplitude, while it is obscured when tested against a baseline condition producing an N400 effect. Our findings reveal that component overlap can result in the apparent absence or presence of an effect in the surface signal and should therefore be carefully considered when interpreting ERP patterns. Importantly, we show that, by factoring in the effects of spatiotemporal overlap between the N400 and P600 on the surface signal, which we reveal using rERP analysis, apparent inconsistencies in previous findings are easily reconciled, enabling us to draw unambiguous conclusions about the functional interpretation of the N400 and P600 components. Overall, our results provide compelling evidence that the N400 reflects lexical retrieval processes, while the P600 indexes compositional integration of word meaning into the unfolding utterance interpretation.


[Influence of genetic factors on human sexual orientation. Review].
Human sexual orientation is a complex trait, influenced by several genes, experiential and sociocultural factors. These elements interact and produce a typical pattern of sexual orientation towards the opposite sex. Some exceptions exist, like bisexuality and homosexuality, which seem to be more frequent in males than females. Traditional methods for the genetic study of behavior multifactorial characteristics consist in detecting the presence of familial aggregation. In order to identify the importance of genetic and environmental factors in this aggregation, the concordance of the trait for monozygotic and dizygotic twins and for adopted sibs, reared together and apart, is compared. These types of studies have shown that familial aggregation is stronger for male than for female homosexuality. Based on the threshold method for multifactorial traits, and varying the frequency of homosexuality in the population between 4 and 10%, heritability estimates between 0.27 and 0.76 have been obtained. In 1993, linkage between homosexuality and chromosomal region Xq28 based on molecular approaches was reported. Nevertheless, this was not confirmed in later studies. Recently, a wide search of the genome has given significant or close to significant linkage values with regions 7q36, 8p12 and 10q26, which need to be studied more closely. Deviation in the proportion of X chromosome inactivation in mothers of homosexuals seems to favor the presence of genes related with sexual orientation in this chromosome. There is still much to be known about the genetics of human homosexuality.


Cancer therapy combination: green tea and a phosphodiesterase 5 inhibitor?
The major constituent of green tea, (-)-epigallocatechin-3-O-gallate (EGCG), has been shown to have cancer-preventive and therapeutic activities. Numerous molecular targets for EGCG have been proposed, but the mechanisms of its anticancer activities are not clearly understood. In this issue of the JCI, Kumazoe et al. report that EGCG activates 67-kDa laminin receptor (67LR), elevates cGMP levels, and induces cancer cell apoptosis. Furthermore, a phosphodiesterase 5 inhibitor, vardenafil, synergizes with EGCG to induce cancer cell death. This is a provocative observation with important implications for cancer therapy. It also raises several issues for further investigation, such as the mechanism by which EGCG specifically activates 67LR.


Three dimensional structure of the anthrax toxin translocon-lethal factor complex by cryo-electron microscopy.
We have visualized by cryo-electron microscopy (cryo-EM) the complex of the anthrax protective antigen (PA) translocon and the N-terminal domain of anthrax lethal factor (LF(N) inserted into a nanodisc model lipid bilayer. We have determined the structure of this complex at a nominal resolution of 16 Å by single-particle analysis and three-dimensional reconstruction. Consistent with our previous analysis of negatively stained unliganded PA, the translocon comprises a globular structure (cap) separated from the nanodisc bilayer by a narrow stalk that terminates in a transmembrane channel (incompletely distinguished in this reconstruction). The globular cap is larger than the unliganded PA pore, probably due to distortions introduced in the previous negatively stained structures. The cap exhibits larger, more distinct radial protrusions, previously identified with PA domain three, fitted by elements of the NMFF PA prepore crystal structure. The presence of LF(N), though not distinguished due to the seven-fold averaging used in the reconstruction, contributes to the distinct protrusions on the cap rim volume distal to the membrane. Furthermore, the lumen of the cap region is less resolved than the unliganded negatively stained PA, due to the low contrast obtained in our images of this specimen. Presence of the LF(N) extended helix and N terminal unstructured regions may also contribute to this additional internal density within the interior of the cap. Initial NMFF fitting of the cryoEM-defined PA pore cap region positions the Phe clamp region of the PA pore translocon directly above an internal vestibule, consistent with its role in toxin translocation.


Effect of Calcium Carbonate Fineness on Calcium Sulfoaluminate-Belite Cement.
This study investigated the hydration characteristics and strength development of calcium sulfoaluminate-belite (CSAB) cements incorporating calcium carbonate (CC) powders with various particle size distributions and different gypsum amounts. In general, the CSAB hydration was accelerated by the CC powder, but the acceleration and resulting strength improvement were more effective with finer CC powder. Regardless of the fineness of the CC powder, it took part in the hydration of CSAB cement, forming hemicarboaluminate and monocarboaluminate phases. These hydration and nucleation effects compensated for the strength reduction from decreased cementing components (i.e., dilution effect) when finer CC powders were used, while they did not overcome the strength reduction when coarser CC powder was used. On the other hand, increasing the amount of gypsum for a given CC content improved the strength. The strength of CSAB cement had a clear inverse relationship with its total pore volume measured by mercury intrusion porosimetry (MIP). Thermodynamic modeling for CSAB cement hydration showed that the use of CC powder increased total volume of solid phases up to 6 wt % at a given amount of gypsum.


Pregnancy following repair of anal and vaginal atresia and bladder exstrophy.
Pregnancy following surgical correction of bladder exstrophy with anal and partial vaginal atresia is extremely rare. These defects, plus the absence of the pubic symphysis and anatomic deficiencies of the urogenital diaphragm, pose extraordinary obstetric and surgical problems. This report is based on the experience of a 21-year-old patient who had successful pregnancy following curative repair of these defects. Progressive uterine prolapse occurred during pregnancy to the extent that at the time of delivery the presenting part of the fetus was below the pelvic outlet. Cesarean section was performed at 36 weeks' gestation when the cervix was 4 cm dilated with a single footling breech presentation. Postpartum surgical management of the uterine and vaginal prolapse is described.


Are dietary intakes and eating behaviors related to childhood obesity? A comprehensive review of the evidence.
The purpose of this article is to comprehensively review studies that have examined the relation between diet and childhood obesity. The review specifically considers the roles of total energy intake and energy density; dietary composition; individual foods, food groups, and dietary patterns; beverage consumption; and eating behaviors. The paper also discusses methodological considerations and future research directions and concludes by summarizing the evidence presented and highlighting the ethical issues surrounding providing dietary advice.


A discussion of microplastics in soil and risks for ecosystems and food chains.
Microplastics are among the major contaminations in terrestrial and marine environments worldwide. These persistent organic contaminants composed of tiny particles are of concern due to their potential hazards to ecosystem and human health. Microplastics accumulates in the ocean and in terrestrial ecosystems, exerting effects on living organisms including microbiomes, fish and plants. While the accumulation and fate of microplastics in marine ecosystems is thoroughly studied, the distribution and biological effects in terrestrial soil call for more research. Here, we review the sources of microplastics and its effects on soil physical and chemical properties, including water holding capacity, bulk density, pH value as well as the potential effects to microorganisms and animals. In addition, we discuss the effects of microplastics in combination with other toxic environmental contaminants including heavy metals and antibiotics on plant growth and physiology, as well as human health and possible degradation and remediation methods. This reflect is an urgent need for monitoring projects that assess the toxicity of microplastics in soil and plants in various soil environments. The prospect of these future research activities should prioritize microplastics in agro-ecosystems, focusing on microbial degradation for remediation purposes of microplastics in the environment.


Performance Evaluation of Montelukast Pediatric Formulations: Part II - a PBPK Modelling Approach.
This study aimed to build a physiologically based pharmacokinetic (PBPK) model coupled with age-appropriate in vitro dissolution data to describe drug performance in adults and pediatric patients. Montelukast sodium was chosen as a model drug. Two case studies were investigated: case study 1 focused on the description of formulation performance from adults to children; case study 2 focused on the description of the impact of medicine co-administration with vehicles on drug exposure in infants. The PBPK model for adults and pediatric patients was developed in Simcyp® v18.2 informed by age-appropriate in vitro dissolution results obtained in a previous study. Oral administration of montelukast was simulated with the ADAM™ model. For case study 1, the developed PBPK model accurately described montelukast exposure in adults and children populations after the administration of montelukast chewable tablets. Two-stage dissolution testing in simulated fasted gastric to intestinal conditions resulted in the best description of in vivo drug performance in adults and children. For case study 2, a good description of in vivo drug performance in infants after medicine co-administration with vehicles was achieved by incorporating in vitro drug dissolution (under simulated fasted gastric to fed intestinal conditions) into a fed state PBPK model with consideration of the in vivo dosing conditions (mixing of formulation with applesauce or formula). The case studies presented demonstrate how a PBPK absorption modelling strategy can facilitate the description of drug performance in the pediatric population to support decision-making and biopharmaceutics understanding during pediatric drug development.


A randomized controlled field trial assessing foot and mouth disease vaccine effectiveness in Gondar Zuria district, Northwest Ethiopia.
Foot and mouth disease (FMD) is a highly transmissible viral disease of cloven-hoofed animals, which is endemic in many developing countries. Vaccination is the main tool for FMD control in resource limited endemic countries like Ethiopia. Vaccine quality, which is often questionable in developing countries, is a critical element for effective disease control. The present study was aimed at evaluating the field effectiveness of a trivalent FMD vaccine (containing serotypes O, A and SAT 2), produced and widely used in Ethiopia, in terms of preventing clinical infection and severe disease. A randomized controlled field trial design was employed in the study in which the attack rate of clinical FMD infection in vaccinated cattle was compared with the attack rate in unvaccinated controls in cattle population of 16 villages in Gondar Zuria district, Northwest Ethiopia. The vaccine was administered as a single dose course in the face of an impending FMD outbreak and the trial groups were monitored for clinical infection until the end of the outbreak. The attack rate of clinical FMD 20 days post vaccination in the vaccinated cattle (34 %) was significantly lower than the attack rate in the unvaccinated controls (49 %) (p < 0.001). However, the effectiveness of the vaccine was only 31 % (95 %CI: 20-40 %). This vaccine effectiveness increased to 52 % ((95 %CI: 33-66 %) 42 days post vaccination. The proportion of severely affected cattle in the vaccinated group (5.7 %) was significantly lower than in the unvaccinated group (9.4 %) (p < 0.001), resulting in 39 % (95 %CI: 18-55 %) vaccine effectiveness against severe disease. Generally, the observed level of vaccine effectiveness was lower than the internationally recommended 75 % plus expected percentage of protection for a standard potency 3PD50/dose FMD vaccine. Moreover, the level of effectiveness was insufficient to provide herd immunity to control the disease at the population level. Nevertheless, given the significant difference in the incidence of clinical disease and severity between vaccinated and unvaccinated cattle, it might still be worth using the current vaccine to reduce production losses associated with the disease provided it is cost effective and affordable for the farmers. Factors that cause low effectiveness of the vaccine need to be identified and addressed for effective control of the disease at population level.


Deletion of the pH sensor GPR4 decreases renal acid excretion.
Proton receptors are G protein-coupled receptors that accept protons as ligands and function as pH sensors. One of the proton receptors, GPR4, is relatively abundant in the kidney, but its potential role in acid-base homeostasis is unknown. In this study, we examined the distribution of GPR4 in the kidney, its function in kidney epithelial cells, and the effects of its deletion on acid-base homeostasis. We observed GPR4 expression in the kidney cortex, in the outer and inner medulla, in isolated kidney collecting ducts, and in cultured outer and inner medullary collecting duct cells (mOMCD1 and mIMCD3). Cultured mOMCD1 cells exhibited pH-dependent accumulation of intracellular cAMP, characteristic of GPR4 activation; GPR4 knockdown attenuated this accumulation. In vivo, deletion of GPR4 decreased net acid secretion by the kidney and resulted in a nongap metabolic acidosis, indicating that GPR4 is required to maintain acid-base homeostasis. Collectively, these findings suggest that GPR4 is a pH sensor with an important role in regulating acid secretion in the kidney collecting duct.


Early stage ovarian cancer: a randomized clinical trial comparing whole abdominal radiotherapy, melphalan, and intraperitoneal chromic phosphate: a National Cancer Institute of Canada Clinical Trials Group report.
Two hundred fifty-seven eligible patients with stage I, IIA "high risk" ovarian carcinoma and IIB, IIIO (disease confined to pelvis), were randomized to either total abdominal radiotherapy (arm A) 2,250 rad in 20 fractions (107 patients), melphalan (arm B) 8 mg/m2/d X 4 every 4 weeks X 18 courses (106 patients), or intraperitoneal chromic phosphate (arm C) 10 to 20 mCi (44 patients). All patients were initially treated with pelvic radiotherapy; arm A, 2,250 rad in ten fractions; and arms B and C, 4,500 rad in 20 fractions. Entry to arm C was discontinued early because of toxicity. In a multifactor analysis using proportional hazards models, no significant difference in survival was observed although there was a marginally significant difference in disease-free survival (P = .015) with arm B being superior to arm A. Stage (P less than .0001), grade (P less than .0001), and histology (P less than .008) were predictors of survival in the multifactor analysis. Performance status, age, and residual disease were significant predictors in the single factor analysis but were not predictive when correction was made for the effects of stage, grade, and histology. Five-year survival rates are 62% for arm A, 61% for arm B, and 66% for arm C. Median duration of follow-up is 8 years. Long-term complications of radiotherapy were seen in 19 patients on arm A, 11 on arm B, and 11 on arm C. Four patients who had received melphalan developed either a myelodysplastic syndrome or acute leukemia. Violations in covering the whole abdominal target volume were correlated with survival.


Dimer dissociation and thermosensitivity kinetics of the Saccharomyces cerevisiae and human TATA binding proteins.
A kinetic analysis of dimer dissociation, TATA DNA binding, and thermal inactivation of the yeast Saccharomyces cerevisiae and human TATA binding proteins (TBP) was conducted. We find that yeast TBP dimers, like human TBP dimers, are slow to dissociate in vitro (t(1/2) approximately 20 min). Mild mutations in the crystallographic dimer interface accelerate the rate of dimer dissociation, whereas severe mutations prevent dimerization. In the presence of excess TATA DNA, which measures the entire active TBP population, dimer dissociation represents the rate-limiting step in DNA binding. These findings provide a biochemical extension to genetic studies demonstrating that TBP dimerization prevents unregulated gene expression in yeast [Jackson-Fisher, A. J., Chitikila, C., Mitra, M., and Pugh, B. F. (1999) Mol. Cell 3, 717-727]. In the presence of vast excesses of TBP over TATA DNA, which measures only a very small fraction of the total TBP, the monomer population in a monomer/dimer equilibrium binds DNA rapidly, which is consistent with a simultaneous binding and bending of the DNA. Under conditions where other studies failed to detect dimers, yeast TBP's DNA binding activity was extremely labile in the absence of TATA DNA, even at temperatures as low as 0 degrees C. Kinetic analyses of TBP instability in the absence of DNA at 30 degrees C revealed that even under fairly stabilizing solution conditions, TBP's DNA binding activity rapidly dissipated with t(1/2) values ranging from 6 to 26 min. TBP's stability appeared to vary with the square root of the TBP concentration, suggesting that TBP dimerization helps prevent TBP inactivation.


Energy and nutrient recovery from sewage sludge via pyrolysis.
Energy recovery and nutrient reuse from sewage sludge has traditionally been achieved via anaerobic digestion/power generation with land application of the biosolids. By contrast, thermal processes such as pyrolysis have typically been used only for energy recovery. One such technology has demonstrated at commercial scale that all of the energy in sludge can be beneficially recovered and reused. No attempt was however made to recover and reuse sludge nutrients. There are many potential benefits of using pyrolysis for both energy and nutrient recovery. Firstly, unlike digestion, the principal energy product is oil, which can readily be stored and used when required, ensuring that energy recovery is maximised. Secondly is that the sludge nutrients are recovered in the pyrolysis char. Laboratory soil incubation studies using char from the Subiaco demonstration plant were conducted over an eight-week period to confirm nutrient availability. Results from this study showed that the phosphorus in the char is plant available although the nitrogen was insoluble. Based on these results it appears that there is potential to use pyrolysis as an effective means to recover and reuse both the energy and the very valuable phosphorus present in sewage sludges.


N6-methyladenosine modification of hepatitis B virus RNA differentially regulates the viral life cycle.
N6-methyladenosine (m6A) RNA methylation is the most abundant epitranscriptomic modification of eukaryotic messenger RNAs (mRNAs). Previous reports have found m6A on both cellular and viral transcripts and defined its role in regulating numerous biological processes, including viral infection. Here, we show that m6A and its associated machinery regulate the life cycle of hepatitis B virus (HBV). HBV is a DNA virus that completes its life cycle via an RNA intermediate, termed pregenomic RNA (pgRNA). Silencing of enzymes that catalyze the addition of m6A to RNA resulted in increased HBV protein expression, but overall reduced reverse transcription of the pgRNA. We mapped the m6A site in the HBV RNA and found that a conserved m6A consensus motif situated within the epsilon stem loop structure, is the site for m6A modification. The epsilon stem loop is located in the 3' terminus of all HBV mRNAs and at both the 5' and 3' termini of the pgRNA. Mutational analysis of the identified m6A site in the 5' epsilon stem loop of pgRNA revealed that m6A at this site is required for efficient reverse transcription of pgRNA, while m6A methylation of the 3' epsilon stem loop results in destabilization of all HBV transcripts, suggesting that m6A has dual regulatory function for HBV RNA. Overall, this study reveals molecular insights into how m6A regulates HBV gene expression and reverse transcription, leading to an increased level of understanding of the HBV life cycle.


Sutures versus staples in skin flap operations.
Apposition of skin edges in plastic surgical procedures can be achieved by sutures or stainless steel staples. This retrospective study reviews 45 skin falp operations and finds that 20.6% of sutured flaps are complicated by partial necrosis or slow healing. These complications occur in 62.5% of stapled flaps. It is proposed that crimping of the skin edges by the staples results in tension across the flap. This mechanism is demonstrated on cadaver skin. The efficacy of staples in closure of surgical incisions is recognised, but this study does not favour their use on skin flaps.


Study protocol of an economic evaluation of an extended implementation strategy for the treatment of low back pain in general practice: a cluster randomised controlled trial.
In Denmark, guidelines on low back pain management are currently being implemented; in association with this, a clinical trial is conducted. A health economic evaluation is carried out alongside the clinical trial to assess the cost-effectiveness of an extended implementation strategy to increase the general practitioners' adherence to the guidelines. In addition to usual dissemination, the extended implementation strategy is composed of visits from a guideline facilitator, stratification tools, and feedback on guideline adherence. The aim of this paper is to provide the considerations on the design of the health economic evaluation. The economic evaluation is carried out alongside a cluster randomised controlled trial consisting of 60 general practices in the North Denmark Region. An expected 1,200 patients between the age of 18 and 65 years with a low back pain diagnosis will be enrolled. The economic evaluation comprises both a cost-effectiveness analyses and a cost-utility analysis. Effectiveness measures include referral to secondary care, health-related quality of life measured by EQ-5D-5L, and disability measured by the Roland Morris disability questionnaire. Cost measures include all relevant additional costs of the extended implementation strategy compared to usual implementation. The economic evaluation will be performed from both a societal perspective and a health sector perspective with a 12-month time horizon. It is expected that the extended implementation strategy will reduce the number of patients referred to secondary care. It is hypothesised that the additional upfront cost of extended implementation will be counterbalanced by improvements in clinical practice and patient-related outcomes, thereby rendering the extended implementation strategy cost-effective. ClinicalTrials.gov: NCT01699256.


Neuropeptides of anterior pituitary origin. Autocrine or paracrine functions?
Several neuropeptides classically associated with the hypothalamus have been found in the anterior pituitary. The question arises whether they are locally synthesized and if they play a paracrine or autocrine role on pituitary cell functions. Using normal and tumoral human pituitaries we found neuropeptides (TRH, SRIH, GHRH) and dopamine in variable quantities according to the nature of the tissue. They were all present in normal pituitaries, while stimulatory hormones (TRH and GHRH) were predominantly found in tumoral tissue, implying an imbalance of pathophysiological importance between the stimulatory and inhibitory control of hypophyseal hormones (PRL and GH) in pituitary adenomas. Both normal and tumoral pituitaries released TRH, SRIH and GHRH in large amounts suggesting their local synthesis. The in situ synthesis was demonstrated for SRIH by the evidence of SRIH mRNA, the detection of SRIH immunoreactivity in peculiar cells and the presence of SRIH precursor. The possible role of these pituitary neuropeptides was suggested for instance by the negative correlation found in vitro between SRIH and GH secretions. Moreover, neuropeptides could interact with each other. Indeed DA stimulated TRH release while PRL secretion decrease at the same time. Pulses of TRH had differential effects on SRIH release according to the nature of the tissue as TRH inhibited SRIH release from adenoma while it stimulated SRIH release from normal pituitary. Concerning the effects of SRIH and GHRH on GH secretion, there was an endogenous regulatory pattern comparable to that observed in rat portal blood vessels. Pulses of GHRH induced GH secretion only when endogenous SRIH release was not stimulated.(ABSTRACT TRUNCATED AT 250 WORDS)


Profiles of calcium antagonists in cardiovascular disease with special reference to second-generation agents and amlodipine.
The majority of second-generation calcium antagonists are dihydropyridines, some of which show vascular selectivity. Several new dihydropyridines have been developed with comparable pharmacodynamic properties to existing calcium antagonists in this class and greatly improved kinetic half-lives. Of these agents, amlodipine has by far the longest half-life (30-40 h) allowing the benefit of once-daily administration; it has the additional property of a slow association and dissociation with the calcium channel binding site. In the treatment of hypertension and myocardial ischaemia the prolonged duration of action distinguishes amlodipine from other second-generation agents.


Sudden death in the late hospital phase of acute myocardial infarction.
Forty-seven patients died suddenly during the late hospital phase of acute myocardial infarction. Risk factors associated with late in-hospital sudden death included prior cardiovascular disease, circulatory failure while in the coronary care unit, and certain arrhythmias and conduction disturbances while in the coronary care unit. These were associated with a twofold to sixfold increase in late in-hospital phase sudden death. The most prevalent risk factor occured in 62% of the sudden-death patients; the highest incidence of sudden death with a single risk factor was 2.6%, and the greatest relative risk was 6.0. Relative risks were uniformly greater for males than females. Multiple factors were associated with a greater risk than single factors. These risk factors characterize the group of sudden-death patients as a whole but do not allow precise identification of individual patients at high risk.


Angry cognitive bias, trait aggression and impulsivity in substance users.
According to cognitive theory, people who are aggressive expect angry responses to ambiguous situations. Increased aggression has been reported a few days or weeks following use of MDMA (ecstasy). This may relate to low 5-HT release, and so a 5-HT challenge may increase cognitive bias towards anger differentially in MDMA users and non-users. To investigate whether: (1) measures of anger and aggression will correlate with processing time of angry material and with generation of aggressive responses and (2) tryptophan challenge in people abstinent from MDMA and controls will affect angry cognitive bias. Thirty-two current MDMA users abstinent for 3 weeks, 32 ex-users abstinent for longer than 1 year and 32 non-MDMA substance users were recruited. Trait measures were administered before and state measures before and 5 h after an amino acid drink, depleted or augmented with tryptophan. After the drink, subjects undertook a computer task, which involved reading ambiguous short stories. Reading times to a key sentence describing an angry or non-angry reaction were recorded and subjects wrote a continuing sentence for half the stories. Subjects were faster to process angry than non-angry reactions, indicating the presence of angry cognitive bias. Trait anger and aggression were correlated with processing time of angry relative to non-angry reactions, particularly in the current users. Impulsivity was correlated with non-specific speed of response. Subjects wrote more aggressive sentences after an angry reaction. Tryptophan depletion tended to increase aggressive content. Trait aggression was correlated with aggressive content following non-angry reactions. Evidence of angry cognitive bias was shown in this group of substance users, which was not specific to MDMA use. People high on trait aggression were more likely to expect an angry reaction to an ambiguous situation and to generate more written aggression when this did not occur.


Cheese consumption and the development and progression of dental caries.
Whereas research into the causes of dental decay has focused on the harmful relationship between dental plaque bacteria and foods, studies into the protective effects of foods have been infrequent and limited in number. Recent investigations showed that milk and cheese could reduce the effects of metabolic acids, and could help restore the enamel that is lost during eating. Postulated mechanisms involve buffering, salivary stimulation, reduction of bacterial adhesion, reduction of enamel demineralization, and/or promotion of remineralization by casein and ionizable Ca and P. Given this information, consumers may be motivated to use milk and cheese to reduce, or reverse the cariogenic effects of many other foods.


[Determination of mepiquat chloride in grape, wine and juice by liquid chromatography with electrospray tandem mass spectrometry].
A simple and rapid method was developed for the analysis of mepiquat chloride in grape, wine and juice by high-performance liquid chromatography with electrospray tandem mass spectrometry (LC/MS/MS). Mepiquat chloride was extracted with water-methanol (1:1). Extracted solution was adjusted to pH 10 with ammonia solution. A part of the extracted solution was cleaned up on a styrenedivinylbenzene (SDVB) cartridge for LC/MS/MS. The LC separation was performed on a C18 column (50 mm x 2 mm i.d.) using 0.1% IPCC-MS7-methanol (60:40) as the mobile phase at a flow rate of 0.2 mL/min. The mass spectral acquisition was done in the positive ion mode by applying selected reaction monitoring (SRM). The recoveries of mepiquat chloride from fresh grape, wine and juice fortified at 5 microg/kg and 50 microg/kg were 84.5-96.1%. The lower limit of quantification was 1 microg/kg. Fourteen fresh grape samples, 14 wines (white), 36 wines (red) and 11 juice samples were analyzed by this method. Mepiquat chloride was detected in 5 fresh grape samples, 3 wines (white) and 1 wine (red) at the level of 12.8-199 microg/kg, 5.7-47.7 microg/kg and 24.1 microg/kg, respectively.


Failure of high-dose ergocalciferol to correct vitamin D deficiency in adults with cystic fibrosis.
Treatment guidelines for vitamin D monitoring and supplementation in cystic fibrosis (CF) have recently been developed and published by a consensus committee, but have not been prospectively tested. To use these guidelines to determine the percentage of adults with CF requiring vitamin D repletion therapy and to evaluate the effectiveness of the currently recommended high-dose oral ergocalciferol repletion protocol. Prospective study of clinical outcomes after therapy with the recommended vitamin D repletion algorithm. Of 134 adults with CF, 109 (81.3%) were found to have 25-hydroxyvitamin D (25-OHD) levels below the recommended 30 ng/ml. Sixty-six of these adults completed the recommended course of 400,000 IU of oral ergocalciferol over 2 months, and only five (8%) responded with correction of their serum 25-OHD to the goal of 30 ng/ml or greater (mean change, +0.3 ng/ml; from 18.8 to 19.1 ng/ml). In the 33 adults with CF who also completed the recommended second course of 800,000 IU of ergocalciferol over 2 months, none demonstrated correction of their deficiency (mean change, -1.2 ng/ml). The results of this study demonstrate that a majority of adults with CF have serum 25-OHD levels below 30 ng/ml, and the currently recommended ergocalciferol repletion regimen often does not fully correct vitamin D deficiency and may need to be revised to include even higher dosing of ergocalciferol. Further work is needed to establish the ideal 25-OHD level for maximizing calcium absorption and bone health in CF.


ITSoneDB: a comprehensive collection of eukaryotic ribosomal RNA Internal Transcribed Spacer 1 (ITS1) sequences.
A holistic understanding of environmental communities is the new challenge of metagenomics. Accordingly, the amplicon-based or metabarcoding approach, largely applied to investigate bacterial microbiomes, is moving to the eukaryotic world too. Indeed, the analysis of metabarcoding data may provide a comprehensive assessment of both bacterial and eukaryotic composition in a variety of environments, including human body. In this respect, whereas hypervariable regions of the 16S rRNA are the de facto standard barcode for bacteria, the Internal Transcribed Spacer 1 (ITS1) of ribosomal RNA gene cluster has shown a high potential in discriminating eukaryotes at deep taxonomic levels. As metabarcoding data analysis rely on the availability of a well-curated barcode reference resource, a comprehensive collection of ITS1 sequences supplied with robust taxonomies, is highly needed. To address this issue, we created ITSoneDB (available at http://itsonedb.cloud.ba.infn.it/) which in its current version hosts 985 240 ITS1 sequences spanning over 134 000 eukaryotic species. Each ITS1 is mapped on the NCBI reference taxonomy with its start and end positions precisely annotated. ITSoneDB has been developed in agreement to the FAIR guidelines by enabling the users to query and download its content through a simple web-interface and access relevant metadata by cross-linking to European Nucleotide Archive.


The role of cytokines in cartilage matrix degeneration in osteoarthritis.
Chondrocytes are the single cellular component of hyaline cartilage. Under physiologic conditions, they show steady-state equilibrium between anabolic and catabolic activities that maintains the structural and functional integrity of the cartilage extracellular matrix. Implicit in the loss of cartilage matrix that is associated with osteoarthritis is that there is a disturbance in the regulation of synthetic (anabolic) and resorptive (catabolic) activities of the resident chondrocytes that results in a net loss of cartilage matrix components and deterioration in the structural and functional properties of the cartilage. Multiple mechanisms likely are involved in the disturbance of chondrocyte remodeling activities in OA. They include the development of acquired or age-related alterations in chondrocyte function, the effects of excessive mechanical loading, and the presence of dysregulated cytokine activities. Cytokines are soluble or cell-surface molecules that play an essential role in mediating cell-cell interactions. It is possible to classify the cytokines that regulate cartilage remodeling as catabolic, acting on target cells to increase products that enhance matrix degradation; as anticatabolic, tending to inhibit or antagonize the activity of the catabolic cytokines; and as anabolic, acting on chondrocytes to increase synthetic activity. This review will focus on the role of proinflammatory cytokines and their roles in mediating the increased matrix degradation that characterizes the osteoarthritic cartilage lesion.


A survey on what pharmacists and physicians caring for nursing home residents expect of user-friendly lists of potentially inappropriate prescribing (PIP lists).
Potentially inappropriate prescribing (PIP, including potentially inappropriate medication, PIM) is frequent. In research and practice, the use of PIP lists could optimize a patient's medication. However, they are barely used, possibly because of their limited user-friendliness. This study aimed at evaluating the opinions of pharmacists and physicians caring for nursing home residents on user-friendliness as well as knowledge and current use of PIP lists. Semi-structured telephone interviews and paper-based surveys were conducted with physicians and pharmacists who care for nursing home residents. Descriptive analysis and Fisher's exact test were performed. A total of 30 practitioners participated in the survey, eight of whom were interviewed by phone. 43 % (13/30) of the participants had already heard of PIP lists, and 46 % (6/13) of them made use of a PIP list. Less experienced professionals had more often heard of PIP lists than more experienced ones. The most important aspects of user-friendliness were: time required to use the list, electronic availability, clear structure and provision of reasons why a medication is potentially inappropriate. Physicians preferred a PIP list adapted to the Swiss drug market more often than pharmacists. Knowledge and current use of PIP lists are limited, which is partially consistent with the results of other studies. Participants with less professional experience have heard of PIP lists more frequently, opinions on user-friendliness differ between professions, and preferences seem to be, overall, highly individual. In order for PIP lists to be used more frequently, the aspects of user-friendliness should be taken into account. Personalizable PIP lists could be an interesting development.


Sonographic predictors of postnatal bowel atresia in fetal gastroschisis.
To estimate the association between antenatal bowel dilation and postnatal small-bowel atresia in fetal gastroschisis and to establish a threshold at which the risk of adverse neonatal outcome increases. This was a retrospective cohort study of singleton gestations with an antenatal diagnosis of gastroschisis seen in our ultrasound unit from 2001 to 2010. We reviewed stored images from the last ultrasound examination before delivery, blinded to postnatal diagnoses and outcomes. Fetal intra- and extra-abdominal bowel dilation (IABD and EABD, respectively) and bowel-wall thickness were measured. Previously published definitions of bowel dilation, including > 6, > 10, > 14 and > 18 mm, were evaluated for association with the primary outcome of bowel atresia. The optimal threshold to define fetal bowel dilation was determined by evaluating the significance of association as well as test performance characteristics. Of 109 consecutive patients with fetal gastroschisis, there were four cases of intrauterine fetal demise and three neonatal deaths. Of the 94 live births with complete outcome data, 39 (41.5%) had measurable IABD. There were 14 (14.9%) cases of bowel atresia. Using a threshold of > 14 mm, IABD was significantly associated with an increased risk for bowel atresia (relative risk, 3.1 (95% CI, 1.2-8.2)) with a sensitivity of 57.1%, specificity of 75.0%, positive predictive value of 28.6% and negative predictive value of 90.9%. IABD > 14 mm was also associated with a significantly longer stay in neonatal intensive care unit. There was no significant association between EABD and bowel atresia at any of the thresholds evaluated. IABD > 14 mm is associated with an increased risk for postnatal bowel atresia in fetal gastroschisis. This finding may be useful in counseling patients regarding the anticipated postnatal course for their neonate.


LIII-Edge Anomalous X-ray Scattering by Cesium Measured with Synchrotron Radiation.
Diffraction of monochromatized synchrotron radiation by crystals of cesium hydrogen tartrate has been used to measure the magnitude and phase of x-ray scattering for cesium near the LIII absorption edge. In this wavelength region the scattering amplitude of cesium is reduced by as much as 25 electrons per atom, compared to scattering of copper Kalpha x-rays. This change, which varies as a function of wavelength, affects the diffraction intensities in a manner similar to isomorphous substitution, and it is large enough to have promise for phase determination in the study of macromolecular structures. This experiment also demonstrates that accurate diffractometer measurements are possible with synchrotron radiation produced by an electron storage ring.


The role of the small airways in the clinical expression of asthma in adults.
The clinical relevance of increased ventilation heterogeneity, a marker of small-airways disease, in asthmatic patients is unclear. Ventilation heterogeneity is an independent determinant of airway hyperresponsiveness (AHR), improves with bronchodilators and inhaled corticosteroids (ICSs), and worsens during exacerbations, but its relationship to asthma control is unknown. We sought to determine the association between ventilation heterogeneity and current asthma control before and after ICS treatment. Adult subjects with asthma had lung function and asthma control (5-item Asthma Control Questionnaire [ACQ-5 score] ≥1.5 = poorly controlled, ACQ-5 score ≤0.75 = well controlled) measured at baseline. A subgroup with AHR had repeat measurements after 3 months of high-dose ICS treatment. The indices of ventilation heterogeneity in the regions of the lung where gas transport occurs predominantly through convection (ventilation heterogeneity in convection-dependent airways [Scond]) and through diffusion (ventilation heterogeneity in diffusion-dependent airways [Sacin]) were derived by using the multiple-breath nitrogen washout technique. At baseline (n = 105), subjects with poorly controlled asthma had worse FEV(1), fraction of exhaled nitric oxide measured at 200 mL/s (Feno), Scond, and Sacin values. In the treatment group (n = 50) spirometric, Feno, residual volume (RV)/total lung capacity (TLC), AHR, and Scond values significantly improved. Asthma control also improved (mean ACQ-5 score, 1.3-0.7; P < .0001). The change in ACQ-5 score correlated with changes in Feno (r(s) = 0.31, P = .03), Sacin (r(s) = 0.32, P = .02), and Scond (r(s) = 0.41, P = .003) values. The independent predictors of a change in asthma control were changes in Scond and Sacin values (model r(2) = 0.20, P = .005). Current asthma control is associated with markers of small-airways disease. Improvements in ventilation heterogeneity with anti-inflammatory therapy are associated with improvements in symptoms. Sensitive measures of small-airway function might be useful in monitoring the response to therapy in asthmatic subjects.


Integrative transcriptomic and metabolomic analyses reveal the phenylpropanoid and flavonoid biosynthesis of Prunus mume.
Prunus mume is an important medicinal plant with ornamental and edible value. Its flowers contain phenylpropanoids, flavonoids and other active components, that have important medicinal and edible value, yet their molecular regulatory mechanisms in P. mume remain unclear. In this study, the content of total flavonoid and total phenylpropanoid of P. mume at different developmental periods was measured first, and the results showed that the content of total flavonoid and total phenylpropanoid gradually decreased in three developmental periods. Then, an integrated analysis of transcriptome and metabolome was conducted on three developmental periods of P. mume to investigate the law of synthetic accumulation for P. mume metabolites, and the key enzyme genes for the biosynthesis of phenylpropanoids and flavonoids were screened out according to the differentially expressed genes (DEGs). A total of 14,332 DEGs and 38 differentially accumulate metabolites (DAMs) were obtained by transcriptomics and metabolomics analysis. The key enzyme genes and metabolites in the bud (HL) were significantly different from those in the half-opening (BK) and full-opening (QK) periods. In the phenylpropanoid and flavonoid biosynthesis pathway, the ion abundance of chlorogenic acid, naringenin, kaempferol, isoquercitrin, rutin and other metabolites decreased with the development of flowers, while the ion abundance of cinnamic acid increased. Key enzyme genes such as HCT, CCR, COMT, CHS, F3H, and FLS positively regulate the downstream metabolites, while PAL, C4H, and 4CL negatively regulate the downstream metabolites. Moreover, the key genes FLS (CL4312-2, CL4312-3, CL4312-4, CL4312-5, CL4312-6) regulating the synthesis of flavonols are highly expressed in bud samples. The dynamic changes of these metabolites were validated by determining the content of 14 phenylpropanoids and flavonoids in P. mume at different developmental periods, and the transcription expression levels of these genes were validated by real-time PCR. Our study provides new insights into the molecular mechanism of phenylpropanoid and flavonoid accumulation in P. mume.


Inpatient epidemiology and economic burden of granulomatosis with polyangiitis: a 10-year study of the national inpatient sample.
To characterize inpatient epidemiology and economic burden of granulomatosis with polyangiitis (GPA). Patients with GPA were identified from the Nationwide Inpatient Sample (NIS), the largest inpatient database in the USA consisting of over 4000 non-federal acute care hospitals, using the ICD-9 CM code. A cohort of comparators without GPA was also constructed from the same database. Data on demographics, procedures, length of stay, mortality, morbidity and total hospitalization charges were extracted. All analysed data were extracted from the database for the years 2005-2014. The inpatient prevalence of GPA was 32.6 cases per 100 000 admissions. GPA itself (38.3%), pneumonia (13.7%) and sepsis (8.4%) were the most common reasons for admission. After adjusting for potential confounders, the all-cause mortality adjusted odds ratio (aOR) of patients with GPA was significantly higher than that of patients without GPA (aOR 1.20; 95% CI: 1.41, 1.61). This was also true for several morbidities, including acute kidney injury, multi-organ failure, shock and need for intensive care unit admission. Hospitalizations of patients with GPA were associated with higher cost as demonstrated by an adjusted additional mean of $5125 (95% CI: $4719, $5531) for total hospital cost and an adjusted additional mean of $16 841 (95% CI: $15 280, $18 403) for total hospitalization charges when compared with patients without GPA. Inpatient prevalence of GPA was higher than what would be expected from prevalence in the general population. Hospitalizations of patients with GPA were associated with higher morbidity, mortality and cost.


The effects of antioxidant vitamin supplementation on resistance exercise induced lipid peroxidation in trained and untrained participants.
The theoretical benefits of using antioxidant vitamin supplements to quench oxygen free radicals appear large. High intensity aerobic-type exercise produces oxygen free radicals that can cause damage to lipid membranes (lipid peroxidation) that may lead to many problems such as the inactivation of cell membrane enzymes, the progression of degenerative diseases (cardiovascular disease and cancer) and lessening of the effectiveness of the immune system. The major function of vitamin E is to work as a chain-breaking antioxidant in a fat soluble environment. Little research has examined lipid peroxidation associated with high intensity resistance exercise or possible protective effects of antioxidant supplementation or the effects of training state. There were no significant group (trained vs untrained) or treatment (vitamin E vs placebo) effects found between the 4 groups assessed. There was only one significant difference found and that was in the main effect for time (F = 22.41, p < 0.01). The Resistance Exercise Test caused a significant increase in malondialdehyde in all 4 groups at 6 hours post exercise. There was no evidence that vitamin E supplementation was effective in reducing oxidative damage in comparison to the placebo group. As well, there was no difference between the trained and untrained groups with respect to their impact on lipid peroxidation measures.


Specific hormonal and neurochemical responses to different stressors.
The neuroendocrine and neurochemical responses of rats to 5 min of cold exposure versus 5 min of forced immobilization were determined and compared. We found that plasma hormones and brain neurochemical systems responded differently to the two different stressors. Plasma prolactin levels were elevated over 10-fold in the immolilized group, while rising only 2-fold in the cold stress group. Levels of corticosterone were significantly increased and growth hormone levels were decreased in both stressed groups as compared to controls. Levels of cyclic GMP were markedly elevated in 11 brain regions following cold exposure. Surprisingly, no elevation of cyclic GMP was found after forced immobilization. Cyclic AMP, norepinephrine, and dopamine levels throughout the 17 regions of brain examined showed no significant response to 5 min of either stressor. Lesions of the ventral medial tegmental area did not affect the cyclic GMP or neuroendocrine responses to cold stress. Lesion of the nucleus locus ceruleus did not affect the cyclic GMP response but significantly reduced growth hormone levels in the cold-stressed rats.


Timing of moderate level prenatal alcohol exposure influences gene expression of sensory processing behavior in rhesus monkeys.
Sensory processing disorder, characterized by over- or under-responsivity to non-noxious environmental stimuli, is a common but poorly understood disorder. We examined the role of prenatal alcohol exposure, serotonin transporter gene polymorphic region variation (rh5-HTTLPR), and striatal dopamine (DA) function on behavioral measures of sensory responsivity to repeated non-noxious sensory stimuli in macaque monkeys. Results indicated that early gestation alcohol exposure induced behavioral under-responsivity to environmental stimuli in monkeys carrying the short (s) rh5-HTTLPR allele compared to both early-exposed monkeys homozygous for the long (l) allele and monkeys from middle-to-late exposed pregnancies and controls, regardless of genotype. Moreover, prenatal timing of alcohol exposure altered the relationship between sensory scores and DA D(2)R availability. In early-exposed monkeys, a positive relationship was shown between sensory scores and DA D(2)R availability, with low or blunted DA function associated with under-responsive sensory function. The opposite pattern was found for the middle-to-late gestation alcohol-exposed group. These findings raise questions about how the timing of prenatal perturbation and genotype contributes to effects on neural processing and possibly alters neural connections.


EFFECTS OF FAMILIARITY AND AGE ON DRIVER SAFETY ERRORS DURING WAYFINDING.
Wayfinding is a critical skill that enables drivers to navigate from one location to another. Wayfinding abilities decline as individuals age, which may increase older driver reliance on directional cues (e.g. signs) and divert cognitive resources at the expense of vehicle control and safety. Familiarity with an environment can facilitate wayfinding due to previous knowledge of the route. This study examines the role of familiarity in driving safety errors committed during a wayfinding task. Results suggest that age-related driving difficulties can be lessened by familiarity with the environment. The results underscore the need to consider geographical license restrictions in administrative policies aimed at improving older driver safety.


Gene therapy for chronic granulomatous disease.
Identification of gene mutations responsible for leukocyte dysfunction along with the application of gene transfer technology has made genetic correction of such disorders possible. Much of the research into molecular therapy for inherited disorders of phagocytes has been focused on chronic granulomatous disease (CGD). CGD results from mutations in any one of the four genes encoding essential subunits of respiratory burst NADPH oxidase, the enzyme complex required for the production of reactive oxygen intermediates in phagocytes. The absence of phagocyte oxidants results in a predisposition to recurrent bacterial and fungal infections and inflammatory granulomas in CGD patients, associated with significant morbidity and mortality. Allogeneic bone marrow transplantation can cure CGD, but transplant-related toxicity and the limited availability of matched donors have restricted its wider application. Because the gene defects causing CGD are known, and CGD is a stem cell disorder treatable by marrow transplantation, CGD has emerged as a promising disease for somatic gene therapy targeted at the hematopoietic system. Multiple reports have demonstrated the reconstitution of NADPH oxidase activity by gene transfer to human CGD marrow and cell lines cultured in vitro. CGD mouse models have been developed by gene disruption, and preclinical studies on these animals using recombinant retroviral vectors have demonstrated reconstitution of functionally normal neutrophils and increased resistance to pathogens such as Aspergillus fumigatus, Burkholderia cepacia and Staphylococcus aureus. Although the results of these murine studies are encouraging, human phase-I clinical studies in CGD patients have yet to produce clinically beneficial numbers of corrected neutrophils for extended periods. Efforts to improve gene transfer efficiency into human hematopoietic stem cells and to increase engraftment of transduced stem cells are ongoing.


Condition assessment survey of onsite sewage disposal systems (OSDSs) in Hawaii.
Onsite sewage disposal systems (OSDSs) are the third leading cause of groundwater contamination in the USA. The existing condition of OSDSs in the State of Hawaii was investigated to determine whether a mandatory management program should be implemented. Based on observed conditions, OSDSs were differentiated into four categories: 'pass', 'sludge scum', 'potential failure' and 'fail'. Of all OSDSs inspected, approximately 68% appear to be in good working condition while the remaining 32% are failing or are in danger of failing. Homeowner interviews found that 80% of OSDSs were not being serviced in any way. About 70% of effluent samples had values of total-N and total-P greater than typical values and 40% had total suspended solids (TSS) and 5-day biochemical oxygen demand (BOD5) greater than typical values. The performance of aerobic treatment units (ATUs) was no better than septic tanks and cesspools indicating that the State's approach of requiring but not enforcing maintenance contracts for ATUs is not working. In addition, effluent samples from OSDSs located in drinking water wells estimated 2-year capture zones had higher average concentrations of TSS, BOD5, and total-P than units outside of these zones, indicating the potential for contamination. These findings suggest the need to introduce a proactive, life-cycle OSDS management program in the State of Hawaii.


Postoperative local interventions for the palate as a gingival graft donor area: a scoping review.
This scoping review aimed to systematically identify evidence-based interventions to stimulate healing or protect the harvested palate of patients undergoing gingival grafting. The study followed guidelines from the Joanna Briggs Institute and PRISMA-ScR (protocol available at osf.io/zhafn). PubMed, Embase, and seven other databases were searched on November 2022, with additional monitoring until April 2023. The inclusion criteria focused on studies evaluating outcomes related to the donor area (palate) and interventions for healing or protecting it, regardless of publication year and language. Data from the included publications was extracted and presented through narrative text, tables, and figures. Eighty-one studies (including 64 clinical trials, four case series, five theses, and eight systematic reviews) and 37 clinical trial records were included. The number of studies on this topic has significantly increased, reflecting a growing interest in the field. Thirty-six interventions with published results and 12 interventions with unpublished results from clinical trial registers were identified. Some promising interventions that showed potential for improving patient-reported outcomes include cyanoacrylate adhesive, platelet-rich fibrin (PRF), and the combination of palatal stents and healing agents. Thirty-six interventions with published results were identified for postoperative use on the harvested palate, showing varying levels of evidence and conflicting effectiveness for specific outcomes. Postoperative discomfort and pain in the palate are commonly experienced by patients undergoing grafting procedures using this region as the donor area. Awareness of the available options and their levels of evidence is crucial for informed decision-making.


Apolipoprotein E polymorphism and fertility: a study in pre-industrial populations.
Human apolipoprotein E is the most important supplier of the cholesterol precursor for steroid hormone production in steroidogenic tissues and therefore could play a role in the regulation of steroid hormone function and influence human reproduction. This hypothesis has been confirmed by studies describing a differential fertility associated with common apolipoprotein (APOE) genotypes in two European populations. In the present investigation the impact of APOE genetic variation on fertility was studied in two Ecuadorian populations, African-Ecuadorians (57 women) and Cayapa Indians (27 women). In addition some biodemographic variables concerning women's fertility were investigated (124 African-Ecuadorian women; 40 Cayapa women) to better understand the APOE-fertility relationships in these pre-industrial populations. General fertility rates in both populations were very high (6.5 and 6.2 for the African-Ecuadorians and for the Cayapa respectively). When considering only women near the end of reproductive life (>/=40 years), a more marked difference was observed between the two groups (9.1 versus 7.7, P=0.09). In both communities, the highest number of children was found to be associated with the e*4/e*3 genotype; the e*4/e*3 genotype frequency (0.50) in the African-Ecuadorian women with 9-17 children was about three times that of the women with 0-8 children (0.14) (P=0.02). The present findings are at variance with those observed in European populations, where e*3/e*3 was the genotype associated with the highest reproductive efficiency. A possible explanation for this inconsistency could be due to the different functional properties associated with the e*3 and e*4 alleles and to genotype interactions with environmental factors including reproductive strategies.


Tuning of Thermal Stability in Layered Li(NixMnyCoz)O2.
Understanding and further designing new layered Li(NixMnyCoz)O2 (NMC) (x + y + z = 1) materials with optimized thermal stability is important to rechargeable Li batteries (LIBs) for electrical vehicles (EV). Using ab initio calculations combined with experiments, we clarified how the thermal stability of NMC materials can be tuned by the most unstable oxygen, which is determined by the local coordination structure unit (LCSU) of oxygen (TM(Ni, Mn, Co)3-O-Li3-x'): each O atom bonds with three transition metals (TM) from the TM-layer and three to zero Li from fully discharged to charged states from the Li-layer. Under this model, how the lithium content, valence states of Ni, contents of Ni, Mn, and Co, and Ni/Li disorder to tune the thermal stability of NMC materials by affecting the sites, content, and the release temperature of the most unstable oxygen is proposed. The synergistic effect between Li vacancies and raised valence state of Ni during delithiation process can aggravate instability of oxygen, and oxygen coordinated with more nickel (especially with high valence state) in LSCU becomes more unstable at a fixed delithiation state. The Ni/Li mixing would decrease the thermal stability of the "Ni═Mn" group NMC materials but benefit the thermal stability of "Ni-rich" group, because the Ni in the Li layer would form 180° Ni-O-Ni super exchange chains in "Ni-rich" NMC materials. Mn and Co doping can tune the initial valence state of Ni, local coordination environment of oxygen, and the Ni/Li disorder, thus to tune the thermal stability directly.


Management of major obstetric haemorrhage.
One of the most important causes of maternal mortality is major obstetric haemorrhage. Major haemorrhage can occur in parturients either during the antepartum period, during delivery, or in the postpartum period. Early recognition and a multidisciplinary team approach in the management are the cornerstones of improving the outcome of such cases. The management consists of fluid resuscitation, administration of blood and blood products, conservative measures such as uterine cavity tamponade and sutures, and finally hysterectomy. Blood transfusion strategies have changed over the last decade with emphasis on use of fresh frozen plasma, platelets, and fibrinogen. Point-of-care testing for treating coagulopathies promptly and interventional radiological procedures have further revolutionized the management of such cases.


Omalizumab for the treatment of severe persistent allergic asthma: a systematic review and economic evaluation.
Allergic asthma is a long-term disorder of the airways resulting from overexpression of immunoglobulin E (IgE) in response to environmental allergens. Patients with poorly controlled asthma are at high risk of exacerbations requiring additional treatment, including hospitalisations. Severe exacerbations are potentially life threatening. Guidelines identify five treatment steps for both adults and children. Omalizumab (Xolair(®)) is a recombinant DNA-derived humanised monoclonal antibody indicated as an add-on therapy in patients aged ≥ 6 years with severe persistent allergic asthma uncontrolled at treatment step 4 or 5. To determine the clinical effectiveness, safety and cost-effectiveness of omalizumab, as an add-on therapy to standard care, within its licensed indication, compared with standard therapy alone for the treatment of severe persistent allergic asthma in adults and adolescents aged ≥ 12 years and children aged 6-11 years. Eleven electronic databases (including MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials) and additional sources including regulatory agency reports were searched from inception to October 2011. Additional data sources include: the manufacturer's submission (MS); two previous National Institute for Health and Care Excellence (NICE) single technology appraisal (STA) submissions; and existing reviews on the safety of omalizumab and oral corticosteroids (OCSs). Systematic reviews of the clinical effectiveness and cost-effectiveness evidence for omalizumab were performed. The primary outcome was number of clinically significant (CS) exacerbations. Other outcomes included asthma symptoms, unscheduled health-care use, asthma-related mortality, OCS use and health-related quality of life (HRQoL). Because of methodological and clinical heterogeneity between trials, a narrative synthesis was applied. Pragmatic reviews with best evidence syntheses were used to assess adverse events of omalizumab and OCSs. The cost-effectiveness of omalizumab was assessed from the perspective of the UK NHS in the two separate populations: adults and adolescents, and children, using a cohort Markov model. Costs and outcomes were discounted at 3.5% per annum. Results are presented for additional subgroup populations: (1) hospitalised for asthma in the previous year, (2) adults and adolescents on maintenance OCSs and (3) three or more exacerbations in the previous year. Eleven randomised controlled trials (RCTs) and 13 observational studies were identified, including four RCTs/subgroups in the adult licensed population and one subgroup in children. A minority of patients were on maintenance OCSs. No evidence comparing omalizumab with OCSs was identified. Omalizumab significantly reduced the incidence of CS exacerbations in both adults and children [adults: INvestigatioN of Omalizumab in seVere Asthma Trial (INNOVATE): rate ratio 0.74; 95% CI 0.55 to 1.00; children IA-05 EUP (the a priori subgroup of patients who met the European Medicines Agency license criteria) 0.66; 95% CI 0.44 to 1.00]. Significant benefits were observed for a range of other outcomes in adults. Subgroup evidence showed benefits in adults on maintenance OCSs. Evidence for an OCS-sparing effect of omalizumab was limited but consistent. Omalizumab is available as 75 mg and 150 mg prefilled syringes at prices of £128.07 and £256.15 respectively. The incremental cost-effectiveness ratio (ICER) for adults and adolescents is £83,822 per quality-adjusted life-year (QALY) gained, whereas the ICER for children is £78,009 per QALY gained. The results are similar for the subgroup population of ≥ 3 exacerbations in the previous year, whereas the ICER for the other subgroup populations are lower; £46,431 for the hospitalisation subgroup in adults and adolescents, £44,142 for the hospitalisation subgroup in children and £50,181 for the maintenance OCS subgroup. Omalizumab reduces the incidence of CS exacerbations in adults and children, with benefits on other outcomes in adults. Limited, underpowered subgroup evidence exists that omalizumab reduces exacerbations and OCS requirements in adults on OCSs. Evidence in children is weaker and more uncertain. The ICERs are above conventional NHS thresholds of cost-effectiveness. The key drivers of cost-effectiveness are asthma-related mortality risk and, to a lesser extent, HRQoL improvement and OCS-related adverse effects. An adequately powered double-blind RCT in both adults and children on maintenance OCSs and an individual patient data meta-analysis of existing trials should be considered. A registry of all patients on omalizumab should be established. The study was registered as PROSPERO CRD42011001625. This report was commissioned by the National Institute for Health Research Health Technology Assessment programme on behalf of NICE as project number HTA 10/128/01.


Recombinant human cytomegalovirus (HCMV) RL13 binds human immunoglobulin G Fc.
The human cytomegalovirus (HCMV) protein RL13 has recently been described to be present in all primary isolates but rapidly mutated in culture adapted viruses. Although these data suggest a crucial role for this gene product in HCMV primary infection, no function has so far been assigned to this protein. Working with RL13 expressed in isolation in transfected human epithelial cells, we demonstrated that recombinant RL13 from the clinical HCMV isolates TR and Merlin have selective human immunoglobulin (Ig)-binding properties towards IgG1 and IgG2 subtypes. An additional Fc binding protein, RL12, was also identified as an IgG1 and IgG2 binding protein but not further characterized. The glycoprotein RL13 trafficked to the plasma membrane where it bound and internalized exogenous IgG or its constant fragment (Fcγ). Analysis of RL13 ectodomain mutants suggested that the RL13 Ig-like domain is responsible for the Fc binding activity. Ligand-dependent internalization relied on a YxxL endocytic motif located in the C-terminal tail of RL13. Additionally, we showed that the tyrosine residue could be replaced by phenylalanine but not by alanine, indicating that the internalization signal was independent from phosphorylation events. In sum, RL13 binds human IgG and may contribute to HCMV immune evasion in the infected host, but this function does not readily explain the instability of the RL13 gene during viral propagation in cultured cells.


Associations among Parental Phubbing, Self-esteem, and Adolescents' Proactive and Reactive Aggression: A Three-Year Longitudinal Study in China.
Parental phubbing, as a new risk factor for adolescents' healthy development, has been noticed by scholars. However, few studies have clarified the associations between parental phubbing and adolescents' proactive and reactive aggression and the potential mediating mechanisms. To address the gaps, the current study explored the longitudinal associations among parental phubbing, self-esteem, and adolescents' proactive and reactive aggression by using the parallel process latent growth curve model and the cross-lagged panel model. The current study involved 2407 Chinese adolescents (girls were 1202, Mage = 12.75, SD = 0.58 at baseline, range = 11-16). Results indicated that parental phubbing significantly positively predicted adolescents' reactive aggression but not proactive aggression. Self-esteem significantly predicted the adolescents' reactive and proactive aggression. Self-esteem significantly mediated the associations between parental phubbing and adolescents' proactive and reactive aggression, respectively. These findings suggest that intervening with parental phubbing is a promising way to reduce adolescents' reactive aggression, and promoting adolescents' self-esteem is an effective approach to prevent their proactive and reactive aggression.


Lifestyle Factors Are Important Contributors to Subjective Memory Complaints among Patients without Objective Memory Impairment or Positive Neurochemical Biomarkers for Alzheimer's Disease.
Many patients presenting to a memory disorders clinic for subjective memory complaints do not show objective evidence of decline on neuropsychological data, have nonpathological biomarkers for Alzheimer's disease, and do not develop a neurodegenerative disorder. Lifestyle variables, including subjective sleep problems and stress, are factors known to affect cognition. Little is known about how these factors contribute to patients' subjective sense of memory decline. Understanding how lifestyle factors are associated with the subjective sense of failing memory that causes patients to seek a formal evaluation is important both for diagnostic workup purposes and for finding appropriate interventions and treatment for these persons, who are not likely in the early stages of a neurodegenerative disease. The current study investigated specific lifestyle variables, such as sleep and stress, to characterize those patients that are unlikely to deteriorate cognitively. Two hundred nine patients (mean age 58 years) from a university hospital memory disorders clinic were included. Sleep problems and having much to do distinguished those with subjective, but not objective, memory complaints and non-pathological biomarkers for Alzheimer's disease. Lifestyle factors including sleep and stress are useful in characterizing subjective memory complaints from objective problems. Inclusion of these variables could potentially improve health care utilization efficiency and guide interventions.


Utilization of collagenous by-products from the meat packing industry: production of single-cell protein by the continuous cultivation of Bacillus megaterium.
The conditions for continuous cultivation of Bacillus megaterium on a collagen-derived substrate (SP-100) were determined. The optimum conditions of temperature, pH, and dilution rate were 34 C, pH 7.0, and 0.25/hr, respectively. Increasing the substrate concentration in plain tap water resulted in proportional increases in the productivity of cell mass from 0.6 g per liter per hr at 1% substrate to 1.8 g per liter per hr at 10% substrate; however, the protein content of the biomass decreased from 60 to 36%, and the protein yield decreased from 91 to 50% at substrate concentrations of 1 and 10%, respectively. These effects (decreases) were reversed up to 7.5% substrate by mineral supplementation of the medium. The productivity of biomass increased from 0.6 to 1.9 per liter per hr; the protein content of the biomass, from 43 to 54%; and the protein yield, from 60 to 93%, respectively, as the substrate concentration (with mineral supplementation of the medium) was increased from 1 to 7.5%. Spent medium could be refortified and recycled as often as five times. The amino acids in the substrate protein appeared to be utilized for growth and metabolism more or less uniformly. Analysis of the B. megaterium biomass indicated considerable enrichment of the essential amino acids and reduction of proline, glycine, and hydroxyproline as compared to the collagen-derived substrate. The Protein Efficiency Ratios obtained on the collagen-derived substrate (SP-100) and on the B. megaterium biomass, expressed as percentages of the casein reference protein, were 14 and 74%, respectively. Thus, considerable improvement in nutritional value was effected by bacterial conversion of the collagen-derived substrate into single-cell protein.


Effect of intranasal dexmedetomidine on emergence agitation after sevoflurane anesthesia in children undergoing tonsillectomy and/or adenoidectomy.
Emergence agitation (EA) after sevoflurane anesthesia is common in children during recovery from general anesthesia and may result in postoperative complications. This study investigated safety and effectiveness of intranasal dexmedetomidine in reducing the incidence and severity of EA. This prospective, randomized double-blinded controlled trial included 86 patients scheduled for the tonsillectomy and/or adenoidectomy under general anesthesia with sevoflurane. They were randomly allocated into two groups. Group D received intranasal dexmedetomidine at 1 μg/kg, and Group C received intranasal saline 0.9% after the induction of general anesthesia. Four-point agitation scale and Face, Legs, Activity, Cry and Consolability (FLACC) scale for pain assessment were measured at six time points (after extubation, leaving the operating room, on arrival to postanesthesia care unit [PACU], 10, 20, and 30 min after arrival in PACU). Extubation, emergence, and discharge times were recorded in addition to any adverse effects. There was a significant difference in the incidence of EA between Groups D and C (6.98% and 58%, respectively, with P = 0.001). The median four-point agitation scales and the median scores of FLACC pain scales of Group D were significantly lower than those of Group C at the all six time points with P < 0.05. Extubation, emergence, and discharge times were comparable in both groups, and none of the subjects reported any adverse effects. This study demonstrates that a 1 μg/kg dose of intranasal dexmedetomidine administered after the induction of anesthesia reduces post-sevoflurane incidence and severity of EA in children undergone tonsillectomy and/or adenoidectomy with no adverse effects and smooth recovery profile.


Clinician views regarding early surgery for paediatric epilepsy.
Many children with lesional epilepsies progress to drug resistance, a criterion required for surgical referral. Expedited surgery may reduce exposure of the developing brain to uncontrolled seizures, improving cognitive outcomes. Designing a trial comparing early surgery with standard care necessitates input from specialist clinicians regarding feasibility and measurable outcomes, which this study investigated. Online surveys were disseminated from June-July 2022 via regional paediatric epilepsy networks and professional societies. 51 UK clinicians responded, mostly paediatricians, paediatric neurologists and epilepsy specialist nurses. Candidacy for epilepsy surgery, outcome measures and support for the proposed study were surveyed. Clinician views were compared by speciality, using Pearson's chi-squared tests to explore differences. 76-98 % of clinicians would refer children for presurgical evaluation at/before drug resistance development across four subgroups (those younger/older than two years, and those with/without a detectable lesion). Earlier referral, at/before epilepsy diagnosis, was considered mostly in those with visible lesions (53 %) and those under two years (31 %). 73 % would consider early surgery before drug resistance is established. Top outcomes to measure were seizure freedom (39 %) and quality of life (22 %). Views of paediatric neurologists and paediatricians did not differ (p > .05). Clinician opinions generally aligned with published guidance regarding epilepsy surgery referral. Some remain cautious to refer young children with lesions prior to trialling more than one antiseizure medication. Most support early surgery in appropriate patients, with seizure and quality of life outcomes rated highly. Incorporating these perspectives will aid future trial design, recruitment and clinical utility.


Cytokines in preterm parturition.
We have proposed a model in which the initiation of human parturition in the presence of infection is mediated by the host response. Systemic infections such as pyelonephritis, or localized intrauterine maternal infections such as deciduitis and cervicitis, might trigger parturition via the monocyte/macrophage system in both maternal blood and human decidua. According to this model, labor is to be considered an event that occurs when the intrauterine or maternal environment is hostile to the well-being of the fetus, as was supported by recent studies. From this point of view, the initiation of preterm labor may have survival value.


The effect of chronic mild stress on tumor-bearing rats' behavior and its mechanism.
Much evidence has demonstrated that stress and tumor interact, but the mechanisms are poorly understood. The purpose of this study is to discuss the effect of unpredictable chronic mild stress (CMS) upon the behavior of Walker 256 tumor-bearing rats and its mechanism. Observe the effects of CMS on the sucrose consumption, activities, body weight and levels of serums TNF-alpha and IL-6 of both tumor-bearing rats and non-tumor-bearing rats, and on the levels of Bcl-2 and the phosphor-ERK1/2 in their hippocampus. CMS can reduce the average sucrose consumption, behavioral scores, body weight gain, expression of Bcl-2 and p-ERK1/2 protein in hippocampus, and increase serums TNF-alpha and IL-6 of both tumor-bearing rats and non-tumor-bearing rats. The stressed tumor-bearing rats had less sucrose consumption, body weight gain and lower behavioral scores, but higher level of serum TNF-alpha than stressed non-tumor-bearing rats. A negative correlation was found between the levels of serum TNF-alpha and sucrose consumption, while a positive correlation between the expression of Bcl-2 protein in hippocampus proper and sucrose consumption. CMS can reduce the protein levels of Bcl-2 and p-ERK1/2 in the rats' hippocampus, which contributes to the changes in the rats' behavior caused by CMS. Tumor-bearing rats are prone to behave depressively after the exposure to CMS. Our findings have suggested that the tumor, by increasing the inflammatory reaction, can be taken as a stressor, affecting the hippocampus and consequently causing depression by decreasing the expression of Bcl-2 and p-ERK1/2 in hippocampus.