Alternatives to continuous social housing.
Although social housing is desirable for social species of nonhuman primates, circumstances arise whereby social housing is precluded (for example, certain kinds of infectious disease or toxicologic research, when the health of the animal(s) would be compromised by social housing, and animals which respond behaviorally in an inappropriate manner to social housing). Nonsocial alternatives that provide increased environmental complexity to the home cage should then be considered. Nonsocial "environmental enrichment" schemes can be designed to enhance the expression of an individually housed nonhuman primate's locomotive/postural, manipulative, and foraging behaviors. In this way, nonsocial, but species-typical, behaviors can be promoted in the single cage housing condition.


The Phenotypic variability of 16p11.2 distal BP2-BP3 deletion in a transgenerational family and in neurodevelopmentally ascertained samples.
We present genomic and phenotypic findings of a transgenerational family consisting of three male offspring, each with a maternally inherited distal 220 kb deletion at locus 16p11.2 (BP2-BP3). Genomic analysis of all family members was prompted by a diagnosis of autism spectrum disorder (ASD) in the eldest child, who also presented with a low body mass index. All male offspring underwent extensive neuropsychiatric evaluation. Both parents were also assessed for social functioning and cognition. The family underwent whole-genome sequencing. Further data curation was undertaken from samples ascertained for neurodevelopmental disorders and congenital abnormalities. On medical examination, both the second and third-born male offspring presented with obesity. The second-born male offspring met research diagnostic criteria for ASD at 8 years of age and presented with mild attention deficits. The third-born male offspring was only noted as having motor deficits and received a diagnosis of developmental coordination disorder. Other than the 16p11.2 distal deletion, no additional contributing variants of clinical significance were observed. The mother was clinically evaluated and noted as having a broader autism phenotype. In this family, the phenotypes observed are most likely caused by the 16p11.2 distal deletion. The lack of other overt pathogenic mutations identified by genomic sequencing reinforces the variable expressivity that should be heeded in a clinical setting. Importantly, distal 16p11.2 deletions can present with a highly variable phenotype even within a single family. Our additional data curation provides further evidence on the variable clinical presentation among those with pathogenetic 16p11.2 (BP2-BP3) mutations.


[CpRu((R)-Binop-F)(H2O)][SbF6], a new fluxional chiral Lewis acid catalyst: synthesis, dynamic nmr, asymmetric catalysis, and theoretical studies.
The C(2)-symmetric electron-poor ligand (R)-BINOP-F (4) was prepared by reaction of (R)-BINOL with bis(pentafluorophenyl)-phosphorus bromide in the presence of triethylamine. The iodo complex [CpRu((R)-BINOP-F)(I)] ((R)-6) was obtained by substitution of two carbonyl ligands by (R)-4 in the in situ-prepared [CpRu(CO)(2)H] complex followed by reaction with iodoform. Complex 6 was reacted with [Ag(SbF(6))] in acetone to yield [CpRu((R)-BINOP-F)(acetone)][SbF(6)] ((R)-7). X-ray structures were obtained for both (R)-6 and (R)-7. The chiral one-point binding Lewis acid [CpRu((R)-BINOP-F)][SbF(6)] derived from either (R)-7 or the corresponding aquo complex (R)-8 activates methacrolein and catalyzes the Diels-Alder reaction with cyclopentadiene to give the [4 + 2] cycloadduct with an exo/endo ratio of 99:1 and an ee of 92% of the exo product. Addition occurs predominantly to the methacrolein C(alpha)-Re face. In solution, water in (R)-8 exchanges readily. Moreover, a second exchange process renders the diastereotopic BINOP-F phosphorus atoms equivalent. These processes were studied by the application of variable-temperature (1)H, (31)P, and (17)O NMR spectroscopy, variable-pressure (31)P and(17)O NMR spectroscopy, and, using a simpler model complex, density functional theory (DFT) calculations. The results point to a dissociative mechanism of the aquo ligand and a pendular motion of the BINOP-F ligand. NMR experiments show an energy barrier of 50.7 kJ mol(-1) (12.2 kcal mol(-1)) for the inversion of the pseudo-chirality at the ruthenium center.


Belarusian Healthcare Professionals' Views on Monkeypox and Vaccine Hesitancy.
Despite the low transmission risk of Monkeypox (mpox) in Belarus, this study is vital as it contributes to our understanding of vaccine hesitancy among healthcare professionals (HCPs). It aims to assess vaccination perceptions and evaluate the willingness to pay for the vaccine among Belarusian HCPs, thereby enhancing pandemic preparedness. in October 2022, a cross-sectional survey-based study was conducted among Belarusian HCPs using a self-administered questionnaire (SAQ). Invitations were disseminated via social media platforms using a snowball sampling method. The SAQ encompassed various categories, including sociodemographic details, medical history, sources of mpox information, perceived and factual mpox knowledge, and perceptions of the mpox vaccine according to the health belief model (HBM), mpox vaccine acceptance and willingness to pay (WTP). while a large proportion of respondents had good knowledge of mpox epidemiology and its clinical manifestations, their awareness of available vaccines and treatment options was limited. Consequently, a significant correlation was found between the history of influenza vaccination and mpox-related knowledge. Furthermore, the study showed that just over half of the participants (51.4%) were willing to receive the mpox vaccine if offered for free, safely, and effectively, with their decision largely influenced by perceived benefits (Spearman's rho = 0.451) and cues to action (Spearman's rho = 0.349). However, a considerable degree of hesitancy (30.6%) and resistance (18.1%) towards the mpox vaccine was observed, underscoring the need for targeted interventions to address these issues. this study highlights a significant knowledge gap among Belarusian HCPs about mpox vaccines and treatments, despite a general awareness of the disease's epidemiology and symptoms, and it underscores the need for targeted interventions to enhance mpox knowledge and vaccine acceptance.


Haptic Neurorehabilitation and Virtual Reality for Upper Limb Paralysis: A Review.
Motor and sensory loss or dysfunction affects the quality of life for thousands of individuals daily. The upper limb, and especially the hand, are important for a person's ability to complete activities of daily living. Traditional therapy methods focus on motor recovery, but future methods should include sensory recovery and should promote the use of the affected limb(s) at home. In this review, we highlight the current state-of-art robotic devices for the upper limb, and we discuss benefits of including haptic feedback and virtual reality environments during neurorehabilitation. Robotic devices, such as end-effector devices, grounded and ungrounded exoskeletons, have been developed to assist with various functions including individual finger, whole hand, and shoulder movements. Many robots highlighted in this paper are inexpensive and are small enough to be in a patient's home, or allow for telerehabilitation. Virtual reality creates safe environments for patients to practice motor movements and interactive games improve enjoyment of therapy. Haptic feedback creates more immersive virtual reality, and contributes to the recovery of sensory function. Physiological studies conducted after brain trauma and with robotic devices contribute to the understanding of brain plasticity, and illustrate the efficacy of these technologies. We conclude by addressing the future direction of neurorehabilitation research.


Non-Destructive Testing of Materials in Civil Engineering.
This issue was proposed and organized as a means to present recent developments in the field of non-destructive testing of materials in civil engineering. For this reason, the articles highlighted in this editorial relate to different aspects of non-destructive testing of different materials in civil engineering, from building materials to building structures. The current trend in the development of non-destructive testing of materials in civil engineering is mainly concerned with the detection of flaws and defects in concrete elements and structures, and acoustic methods predominate in this field. As in medicine, the trend is towards designing test equipment that allows one to obtain a picture of the inside of the tested element and materials. Interesting results with significance for building practices were obtained.


Phytoremediation of toxic aromatic pollutants from soil.
The enormous growth of industrialization, and the use of numerous aromatic compounds in dyestuffs, explosives, pesticides and pharmaceuticals has resulted in serious environmental pollution and has attracted considerable attention continuously over the last two decades. Many aromatic hydrocarbons, nitroaromatic compounds, polycyclic aromatic hydrocarbons, polychlorinated biphenyls, diauxins and their derivatives are highly toxic, mutagenic and/or carcinogenic to natural microflora as well as to higher systems including humans. The increasing costs and limited efficiency of traditional physicochemical treatments of soil have spurred the development of new remediation technologies. Phytoremediation is emerging as an efficient treatment technology that uses plants to bioremediate pollutants from soil environments. Various modern tools and analytical devices have provided insight into the selection and optimization of remediation processes by various plant species. Sites heavily polluted with organic contaminants require hyperaccumulators, which could be developed by genetic engineering approaches. However, efficient hyperaccumulation by naturally occurring plants is also feasible and can be made practical by improving their nutritional and environmental requirements. Thus, phytoremediation of organics appears a very promising technology for the removal of contaminants from polluted soil. In this review, certain aspects of plant metabolism associated with phytoremediation of organic contaminants and their relevant phytoremediation efforts are discussed.


Ramifications of risk measures in implementing quantitative performance assessment for the proposed radioactive waste repository at Yucca Mountain, Nevada, USA.
As part of its preparation to review a potential license application from the U.S. Department of Energy (DOE), the U.S. Nuclear Regulatory Commission (NRC) is examining the performance of the proposed Yucca Mountain nuclear waste repository. In this regard, we evaluated postclosure repository performance using Monte Carlo analyses with an NRC-developed system model that has 950 input parameters, of which 330 are sampled to represent system uncertainties. The quantitative compliance criterion for dose was established by NRC to protect inhabitants who might be exposed to any releases from the repository. The NRC criterion limits the peak-of-the-mean dose, which in our analysis is estimated by averaging the potential exposure at any instant in time for all Monte Carlo realizations, and then determining the maximum value of the mean curve within 10000 years, the compliance period. This procedure contrasts in important ways with a more common measure of risk based on the mean of the ensemble of peaks from each Monte Carlo realization. The NRC chose the former (peak-of-the-mean) because it more correctly represents the risk to an exposed individual. Procedures for calculating risk in the expected case of slow repository degradation differ from those for low-probability cases of disruption by external forces such as volcanism. We also explored the possibility of risk dilution (i.e., lower calculated risk) that could result from arbitrarily defining wide probability distributions for certain parameters. Finally, our sensitivity analyses to identify influential parameters used two approaches: (1). the ensemble of doses from each Monte Carlo realization at the time of the peak risk (i.e., peak-of-the-mean) and (2). the ensemble of peak doses calculated from each realization within 10000 years. The latter measure appears to have more discriminatory power than the former for many parameters (based on the greater magnitude of the sensitivity coefficient), but can yield different rankings, especially for parameters that influence the timing of releases.


Study of cognitive function among the Adult Health Study (AHS) population in Hiroshima and Nagasaki.
Although neuropsychological dysfunction is found among A-bomb survivors exposed in utero as it is among patients who receive central nervous system radiotherapy, neuropsychological examinations have not been conducted on the survivors. Its prevalence may be increased as a result of the increased rate of strokes reported among those exposed to a high radiation dose. In this study, we examined the effects of radiation exposure on cognitive function among adult survivors in the Adult Health Study (AHS). The study subjects were men and women born prior to September 1932 who had undergone biennial examinations during the period 1992-1996 in Hiroshima or 1993-1998 in Nagasaki. We evaluated cognitive performance for 3,113 subjects with the Cognitive Abilities Screening Instrument (CASI), and we examined the relationship between cognitive performance and potentially related factors (sex, age, city where the subjects were exposed, years of education, and radiation dose). In contrast to exposure to radiotherapy, exposure to atomic bomb radiation had no apparent effect on cognitive function. Factors that did affect cognitive function were age, sex, city and years of education. Further investigation, including examination of other neurological functions, is required before a final conclusion regarding radiation-induced neurological dysfunction can be reached.


Longitudinal cohort study of the impact of specialist cancer services for teenagers and young adults on quality of life: outcomes from the BRIGHTLIGHT study.
In England, healthcare policy advocates specialised age-appropriate services for teenagers and young adults (TYA), those aged 13 to 24 years at diagnosis. Specialist Principal Treatment Centres (PTC) provide enhanced TYA age-specific care, although many still receive care in adult or children's cancer services. We present the first prospective structured analysis of quality of life (QOL) associated with the amount of care received in a TYA-PTC DESIGN: Longitudinal cohort study. Hospitals delivering inpatient cancer care in England. 1114 young people aged 13 to 24 years newly diagnosed with cancer. Exposure to the TYA-PTC defined as patients receiving NO-TYA-PTC care with those receiving ALL-TYA-PTC and SOME-TYA-PTC care. Quality of life measured at five time points: 6, 12, 18, 24 and 36 months after diagnosis. Group mean total QOL improved over time for all patients, but for those receiving NO-TYA-PTC was an average of 5.63 points higher (95% CI 2.77 to 8.49) than in young people receiving SOME-TYA-PTC care, and 4·17 points higher (95% CI 1.07 to 7.28) compared with ALL-TYA-PTC care. Differences were greatest 6 months after diagnosis, reduced over time and did not meet the 8-point level that is proposed to be clinically significant. Young people receiving NO-TYA-PTC care were more likely to have been offered a choice of place of care, be older, from more deprived areas, in work and have less severe disease. However, analyses adjusting for confounding factors did not explain the differences between TYA groups. Receipt of some or all care in a TYA-PTC was associated with lower QOL shortly after cancer diagnosis. The NO-TYA-PTC group had higher QOL 3 years after diagnosis, however those receiving all or some care in a TYA-PTC experienced more rapid QOL improvements. Receipt of some care in a TYA-PTC requires further study.


Alkyne activation and polyhedral reorganization in benzothiazolate-capped osmium clusters on reaction with diethyl acetylenedicarboxylate (DEAD) and ethyl propiolate.
The reactivity of the face-capped benzothiazolate clusters HOs3(CO)9[μ3-C7H3(R)NS] (1a, R = H; 1b, R = 2-CH3) with alkynes has been investigated. 1a reacts with DEAD at 67 °C to furnish the isomeric alkenyl clusters Os3(CO)9(μ-C7H4NS)(μ3-EtO2CCCHCO2Et) (2a and 3a). X-ray crystallographic analyses of 2a and 3a have confirmed the stereoisomeric relationship of these products and the regiospecific polyhedral expansion that follows the formal transfer of the hydride to the coordinated alkyne ligand in HOs3(CO)9(μ-C7H4NS)(η2-DEAD). The significant structural differences between the two isomers, as revealed by the solid-state structures, derives from the regiospecific cleavage of one of the three Os-Os bonds in the intermediate alkenyl cluster Os3(CO)9(μ-C7H4NS)(η1-EtO2CCCHCO2Et), which follows hydride transfer to the coordinated alkyne ligand in the pi compound HOs3(CO)9(μ-C7H4NS)(η2-DEAD). Control experiments confirm the reversibility of the reaction leading to the formation of 2a and 3a. Whereas heating either isomer in refluxing THF or benzene affords a binary mixture containing 2a and 3a, thermolysis in refluxing toluene leads to the activation of the alkenyl ligand and formation of the new cluster Os3(CO)9(μ-C7H4NS)(μ3-EtO2CCCH2) (4). 4 was independently synthesized from 1a and ethyl propiolate at room temperature. The computed mechanisms that account for the formation of 2a and 3a are presented, along with the mechanism for the reaction of 1a with ethyl propiolate to give 4.


Improved gene transfer into canine hematopoietic repopulating cells using CD34-enriched marrow cells in combination with a gibbon ape leukemia virus-pseudotype retroviral vector.
We have used dogs to study gene transfer into hematopoietic stem cells, because of the applicability of results in dogs to human transplantation and the availability of canine disease models that mimic human diseases. Previously we reported successful gene transfer into canine marrow repopulating cells, however, gene transfer efficiency was low, usually below 0.1% (Kiem et al, Hum Gene Ther 1996; 7: 89). In this study we have used CD34-enriched marrow cells to study different retroviral pseudotypes for their ability to transduce canine hematopoietic repopulating cells. Cells were divided into two equal fractions that were cocultivated for 72 h with irradiated packaging cells producing vector with different retroviral pseudotypes (GALV, amphotropic or 10A1). The vectors used contained small sequence differences to allow differentiation of cells genetically marked by the different vectors. Nonadherent and adherent cells from the cultures were infused into four dogs after a myeloablative dose of 920 cGy total body irradiation. Polymerase chain reaction (PCR) analysis of DNA from peripheral blood and marrow after transplant showed that the highest gene transfer rates (up to 10%) were obtained with the GALV-pseudotype vector. Gene transfer levels have remained stable now for more than 18 months. Southern blot analysis confirmed the high gene transfer rate. Interference studies on canine D17 cells revealed that 10A1 virus behaved like an amphotropic virus and was not able to use the GALV receptor. In summary, our results show improved gene transfer into canine hematopoietic repopulating cells when CD34-enriched cells are transduced by cocultivation on a GALV-pseudotype packaging cell line in combination with a GALV-pseudotype vector. Furthermore, these results demonstrate that the monoclonal antibody to canine CD34 used in this study is able to enrich for hematopoietic repopulating cells.


Metabolic engineering strategies for optimizing acetate reduction, ethanol yield and osmotolerance in Saccharomyces cerevisiae.
Glycerol, whose formation contributes to cellular redox balancing and osmoregulation in Saccharomyces cerevisiae, is an important by-product of yeast-based bioethanol production. Replacing the glycerol pathway by an engineered pathway for NAD+-dependent acetate reduction has been shown to improve ethanol yields and contribute to detoxification of acetate-containing media. However, the osmosensitivity of glycerol non-producing strains limits their applicability in high-osmolarity industrial processes. This study explores engineering strategies for minimizing glycerol production by acetate-reducing strains, while retaining osmotolerance. GPD2 encodes one of two S. cerevisiae isoenzymes of NAD+-dependent glycerol-3-phosphate dehydrogenase (G3PDH). Its deletion in an acetate-reducing strain yielded a fourfold lower glycerol production in anaerobic, low-osmolarity cultures but hardly affected glycerol production at high osmolarity. Replacement of both native G3PDHs by an archaeal NADP+-preferring enzyme, combined with deletion of ALD6, yielded an acetate-reducing strain the phenotype of which resembled that of a glycerol-negative gpd1Δ gpd2Δ strain in low-osmolarity cultures. This strain grew anaerobically at high osmolarity (1 mol L-1 glucose), while consuming acetate and producing virtually no extracellular glycerol. Its ethanol yield in high-osmolarity cultures was 13% higher than that of an acetate-reducing strain expressing the native glycerol pathway. Deletion of GPD2 provides an attractive strategy for improving product yields of acetate-reducing S. cerevisiae strains in low, but not in high-osmolarity media. Replacement of the native yeast G3PDHs by a heterologous NADP+-preferring enzyme, combined with deletion of ALD6, virtually eliminated glycerol production in high-osmolarity cultures while enabling efficient reduction of acetate to ethanol. After further optimization of growth kinetics, this strategy for uncoupling the roles of glycerol formation in redox homeostasis and osmotolerance can be applicable for improving performance of industrial strains in high-gravity acetate-containing processes.


Ideal body shape in young Japanese women and assessment of excessive leanness based on allometry.
The present study is aimed to clarify the degree of leanness desired by contemporary young Japanese women using questionnaires and to use allometry to define the body weight boundary between the excessively lean and the others for a given height. Questionnaires on ideal body shape were distributed to female college students living in Akita and the suburbs of Tokyo. Data for 578 respondents, aged 18 to 21 years-old, were analyzed. The questionnaire asked the subjects to report their current and ideal body shape and to make a qualitative self-assessment of their weight. On average, the perceived ideal weight was 5.2 kg lower than the current weight. The results also revealed that young women have a tendency to misunderstand their body shape and to regard themselves as heavier than they really were. Meanwhile, we defined leanness as a state of insufficient lean body mass (LBM, kg) in relation to height (Ht, cm). Allometric equation of LBM on Ht and the standard error of estimate (SEE) were calculated as LBM=3.87 x 10(-3) x Ht(1.826) and 1.09, respectively. The LBM boundary between the excessively lean and the others was determined using these values according to a statistical procedure comparing normal and abnormal values. The corresponding total body weight was estimated from the boundary LBM in the literature. Subsequently the body weight boundary for each height was tabulated in order to make young women reconsider weight control. The subjects were asked to assess the body weight boundary for their own height. The boundary values were found to be consistent with the sense of the subjects.


[Interrelations of lysosomal enzymes of leukocytes in patients with cicatricial stenosis of the larynx].
Activities of acid and alkaline phosphatases, cathepsin B, leucine aminopeptidase, N-acetyl-beta-D-hexosaminidases, beta-D-galactosidase and beta-D-glucuronidase were studied in leukocytes of two groups of patients with normal and pathological healing of wounds after surgical treatment of scar stenosis of larynx. Analysis of the enzymatic activity, calculated by means of Student's test using the data of a single estimation of the activity in leukocytes before surgical treatment, did not exhibit any distinct differences in these two groups of patients. The study of interrelationship between the activities of individual enzymes by means of principles of regression analysis enabled to show that the enzymes studied were in the positive regressive relation. Pattern of enzymatic activity in leukocytes of patients with pathological wound healing was distinctly different from that of patients with normal healing in the shape of regression and, especially, in relaxation of the interrelations between phosphatases and other enzymes. The principle of regression enabled to evaluate the prognosis of postoperative development of wound healing using the preliminary estimation of enzymatic activity in leukocytes of patients with scar stenosis of larynx.


Relation between diet cost and Healthy Eating Index 2010 scores among adults in the United States 2007-2010.
Food prices may be one reason for the growing socioeconomic disparities in diet quality. To evaluate the association between diet costs and the Healthy Eating Index-2010 (HEI-2010). Cross-sectional study based on 11,181 adults from the 2007-2010 National Health and Nutrition Examination Survey, analyzed in spring 2014. Diet cost was estimated by linking dietary data with a national food price database. The HEI-2010, a measure of adherence to the dietary guidelines, was the outcome. The population ratio method was used to estimate the average HEI-2010 scores by quintile of energy-adjusted diet cost. Additional analyses evaluated the association between cost and HEI-2010 components. There was a strong positive association between lower energy-adjusted diet costs and lower HEI-2010 scores. The association was stronger among women (p-interaction=0.003). Lower diet costs were associated with lower consumption of vegetables, fruits, whole grains, and seafood, and higher consumption of refined grains and solid fat, alcohol and added sugars. Lower energy-adjusted diet costs were associated with lower-quality diets. Future efforts to improve the nutritional status of the US public should take food prices and diet costs into account.


[Osteoarthrosis in patients with type 2 diabetes mellitus].
To estimate the frequency of a comorbidity of type 2 diabetes mellitus (DM) and osteoarthrosis (OA) in relation to patient age and to identify risk factors for degenerative and dystrophic changes in the joints. 160 patients with type 2 diabetes (23 men and 137 women at the age of 44 to 82 years; body mass index 33 +/- 5 kg/m2 were examined. A control group consisted of 112 age- and gender-matched subjects without type 2 DM. Degenerative and dystrophic changes in the joints were found in 60% of the patients with type 2 DM, which exceeded the similar values in the control subjects (42.9%; p < 0.05). Moreover, OA developed earlier in the patients with DM than in the general population, but the difference became leveled after the age 60 years. The development of OA was found to be associated with lipid metabolic disturbances: the incidence of obesity, hypercholesterolemia, and triglyceridemia was higher in the group of type 2 DM patients with OA (p < 0.05). The patients with type 2 DM showed the higher incidence of OA, the age of disease manifestation is less than in the general population. DM and overweight are risk factors for OA.


The relationship between prevention of mother to child transmission of HIV and stakeholder decision making in Uganda: implications for health policy.
To explore a selection of stakeholders' use of evidence and other reasons in the relative ranking of the prevention of mother to child HIV transmission with nevirapine in a setting of extreme resource scarcity. Group interviews using nominal group technique with provision of evidence. One rural and one urban district in Uganda. People living with HIV/AIDS, people from the general population, planners, health workers and people with hypertension. relative ranking of prevention of vertical HIV transmission with nevirapine compared to nine other interventions for different conditions and evaluation of participants' use of evidence in the ranking. In the overall final ranking, prevention of vertical HIV transmission with nevirapine was ranked as number five compared to the other eight conditions. Treatment for childhood diseases and highly active anti retroviral treatment (HAART) for HIV/AIDS were ranked higher. Group specific ranking followed the same pattern, although the people living with HIV-group ranked HAART consistently as number one. Stakeholders seem to rank prevention of vertical HIV transmission lower than treatment for malaria, pneumonia and diarrhoea. Policies considering prevention of vertical transmission of HIV should consider its implications. This study shows that stakeholders are open to considering evidence in assessing the relative priority of different interventions competing for scarce resources. More research is needed to develop methods that can involve representative stakeholders, including the public, in good and legitimate decisions on priorities.


Polyploidy can drive rapid adaptation in yeast.
Polyploidy is observed across the tree of life, yet its influence on evolution remains incompletely understood. Polyploidy, usually whole-genome duplication, is proposed to alter the rate of evolutionary adaptation. This could occur through complex effects on the frequency or fitness of beneficial mutations. For example, in diverse cell types and organisms, immediately after a whole-genome duplication, newly formed polyploids missegregate chromosomes and undergo genetic instability. The instability following whole-genome duplications is thought to provide adaptive mutations in microorganisms and can promote tumorigenesis in mammalian cells. Polyploidy may also affect adaptation independently of beneficial mutations through ploidy-specific changes in cell physiology. Here we perform in vitro evolution experiments to test directly whether polyploidy can accelerate evolutionary adaptation. Compared with haploids and diploids, tetraploids undergo significantly faster adaptation. Mathematical modelling suggests that rapid adaptation of tetraploids is driven by higher rates of beneficial mutations with stronger fitness effects, which is supported by whole-genome sequencing and phenotypic analyses of evolved clones. Chromosome aneuploidy, concerted chromosome loss, and point mutations all provide large fitness gains. We identify several mutations whose beneficial effects are manifest specifically in the tetraploid strains. Together, these results provide direct quantitative evidence that in some environments polyploidy can accelerate evolutionary adaptation.


Deficiency of the transcription factor c-fos increases lipopolysaccharide-induced macrophage interleukin 12 production.
Interleukin 12 (IL-12) p70 is a heterodimeric protein (p35, p40 subunits) that promotes T-helper TH1-type cytokine response. In critically ill patients, after severe trauma or sepsis, IL-12 production is markedly impaired. We tested the hypothesis that deficiency of the transcription factor c-fos will increase macrophage IL-12 production. We harvested adherent peritoneal macrophages harvested from wild-type (WT), heterozygous c-fos knockout (Hetero KO), or homozygous c-fos knockout (Homo KO) mice and investigated lipopolysaccharide (LPS)-induced IL-12 p70 protein synthesis (by enzyme-linked immunosorbent assay), IL-12 p35 and IL-12 p40 messenger RNA accumulation (mRNA) (by reverse transcriptase-polymerase chain reaction), and the transcription rate (by nuclear runoff). (1) LPS treatment compared with vehicle increases c-fos mRNA accumulation 5-fold and AP-1 DNA protein binding (electrophoretic mobility shift assay), which precedes either IL-12 p35 or IL-12 p40 mRNA accumulation. (2) LPS induces a significant increase in IL-12 p70 protein, IL-12 p40 mRNA, and the transcription rate in the Homo KO group compared with either the Hetero KO or WT groups. (3) Compared with vehicle control, we demonstrate that interferon gamma priming increases LPS-stimulated macrophage IL-12 p70 protein in the Hetero KO or WT groups to the level of the Homo KO group but has no significant effect on the Homo KO group. These data suggest that deficiency of the transcription factor c-fos increases LPS-induced macrophage IL-12 production, possibly by simulating the effect of interferon gamma priming.


Nanosegregation and Structuring in the Bulk and at the Surface of Ionic-Liquid Mixtures.
Ionic-liquid (IL) mixtures hold great promise, as they allow liquids with a wide range of properties to be formed by mixing two common components rather than by synthesizing a large array of pure ILs with different chemical structures. In addition, these mixtures can exhibit a range of properties and structural organization that depend on their composition, which opens up new possibilities for the composition-dependent control of IL properties for particular applications. However, the fundamental properties, structure, and dynamics of IL mixtures are currently poorly understood, which limits their more widespread application. This article presents the first comprehensive investigation into the bulk and surface properties of IL mixtures formed from two commonly encountered ILs: 1-ethyl-3-methylimidazolium and 1-dodecyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([C2mim][Tf2N] and [C12mim][Tf2N]). Physical property measurements (viscosity, conductivity, and density) reveal that these IL mixtures are not well described by simple mixing laws, implying that their structure and dynamics are strongly composition dependent. Small-angle X-ray and neutron scattering measurements, alongside molecular dynamics (MD) simulations, show that at low mole fractions of [C12mim][Tf2N], the bulk of the IL is composed of small aggregates of [C12mim]+ ions in a [C2mim][Tf2N] matrix, which is driven by nanosegregation of the long alkyl chains and the polar parts of the IL. As the proportion of [C12mim][Tf2N] in the mixtures increases, the size and number of aggregates increases until the C12 alkyl chains percolate through the system and a bicontinuous network of polar and nonpolar domains is formed. Reactive atom scattering-laser-induced fluorescence experiments, also supported by MD simulations, have been used to probe the surface structure of these mixtures. It is found that the vacuum-IL interface is enriched significantly in C12 alkyl chains, even in mixtures low in the long-chain component. These data show, in contrast to previous suggestions, that the [C12mim]+ ion is surface active in this binary IL mixture. However, the surface does not become saturated in C12 chains as its proportion in the mixtures increases and remains unsaturated in pure [C12mim][Tf2N].


Emergency Hartmann's Procedure and Its Reversal: A Totally Laparoscopic 2-Step Surgery for the Treatment of Hinchey III and IV Diverticulitis.
Hartmann's procedure (HP) followed by reversal restoration is the first choice for treatment of diffuse diverticular peritonitis. There is no unanimous consensus regarding the use of laparoscopy to treat the same condition. Data from 60 patients with diverticular diffuse peritonitis who underwent urgent HP followed by laparoscopic reversal were retrospectively analyzed. Patients were divided into 2 groups according to the open or laparoscopic HP (OHP, 24 patients; LHP, 36 patients). Outcomes were measured in terms of functional recovery, morbidity, mortality, and length of hospital stay. HPs showed no differences among the groups in terms of operative time, blood loss, and length of intensive care unit stay. Overall morbidity was significantly lower in LHP than in OHP, corresponding to 33.3% and 66.7% respectively ( P = .018). The incidence of both surgical and medical complications was higher in OHP than in LHP (41.7% vs 22.2% [ P = .044] and 45.8% vs 24.3% [ P = .023], respectively). Mortality was 16.6% for each group. LHP showed a faster return to bowel movements and a shorter hospital stay than OHP. The secondary intestinal reversal was possible in 92% of cases, successfully completed laparoscopically in 91.3%. No patients of LHP group required a conversion to open intestinal reversal. LHP for treatment of diverticular diffuse peritonitis showed significantly lower morbidity, faster recovery, shorter hospital stay, and higher rates of successful laparoscopic reversal when compared with OHP.


Changes of myoplasmic calcium concentration during fatigue in single mouse muscle fibers.
Measurements of the intracellular free concentration of Ca2+ ([Ca2+]i) were performed during fatiguing stimulation of intact, single muscle fibers, which were dissected from a mouse foot muscle and loaded with fura-2. Fatigue, which was produced by repeated 100-Hz tetani, generally occurred in three phases. Initially, tension declined rapidly to approximately 90% of the original tension (0.9 Po) and during this period the tetanic [Ca2+]i increased significantly (phase 1). Then followed a lengthy period of almost stable tension production and tetanic [Ca2+]i (phase 2). Finally, both the tetanic [Ca2+]i and tension fell relatively fast (phase 3). The resting [Ca2+]i rose continuously throughout the stimulation period. A 10-s rest period during phase 3 resulted in a significant increase of both tetanic [Ca2+]i and tension, whereas a 10-s pause during phase 2 did not have any marked effect. Application of caffeine under control conditions and early during phase 2 resulted in a substantial increase of the tetanic [Ca2+]i but no marked tension increase, whereas caffeine applied at the end of fatiguing stimulation (tension depressed to approximately 0.3 Po) gave a marked increase of both tetanic [Ca2+]i and tension. The tetanic [Ca2+]i for a given tension was generally higher during fatiguing stimulation than under control conditions. Fatigue developed more rapidly in fibers exposed to cyanide. In these fibers there was no increase of tetanic [Ca2+]i during phase 1 and the increase of the resting [Ca2+]i during fatiguing stimulation was markedly larger. The present results indicate that fatigue produced by repeated tetani is caused by a combination of reduced maximum tension-generating capacity, reduced myofibrillar Ca2+ sensitivity, and reduced Ca2+ release from the sarcoplasmic reticulum. The depression of maximum tension-generating capacity develops early during fatiguing stimulation and it is of greatest importance for the force decline at early stages of fatigue. As fatigue gets more severe, reduced Ca2+ sensitivity and reduced Ca2+ release become quantitatively more important for the tension decline.


Ataxia telangiectasia-related protein is involved in the phosphorylation of BRCA1 following deoxyribonucleic acid damage.
The breast/ovarian cancer susceptibility gene BRCA1 exerts its tumor suppressor function, at least in part, by participating in DNA repair and/or DNA damage-responsive pathways. BRCA1 protein is hyperphosphorylated following various DNA-damaging events. Here, we report that the ataxia telangiectasia mutated protein-related protein kinase (ATR) is involved in the phosphorylation of BRCA1 following gamma radiation and hydroxyurea treatment. We have shown that ATR can phosphorylate several BRCA1 fragments in vitro and that a kinase-inactive mutant of ATR interacts with BRCA1 in vivo. Taken together, these results suggest that ATR directly phosphorylates BRCA1 following DNA damage.


What can genetics tell us about population connectivity?
Genetic data are often used to assess 'population connectivity' because it is difficult to measure dispersal directly at large spatial scales. Genetic connectivity, however, depends primarily on the absolute number of dispersers among populations, whereas demographic connectivity depends on the relative contributions to population growth rates of dispersal vs. local recruitment (i.e. survival and reproduction of residents). Although many questions are best answered with data on genetic connectivity, genetic data alone provide little information on demographic connectivity. The importance of demographic connectivity is clear when the elimination of immigration results in a shift from stable or positive population growth to negative population growth. Otherwise, the amount of dispersal required for demographic connectivity depends on the context (e.g. conservation or harvest management), and even high dispersal rates may not indicate demographic interdependence. Therefore, it is risky to infer the importance of demographic connectivity without information on local demographic rates and how those rates vary over time. Genetic methods can provide insight on demographic connectivity when combined with these local demographic rates, data on movement behaviour, or estimates of reproductive success of immigrants and residents. We also consider the strengths and limitations of genetic measures of connectivity and discuss three concepts of genetic connectivity that depend upon the evolutionary criteria of interest: inbreeding connectivity, drift connectivity, and adaptive connectivity. To conclude, we describe alternative approaches for assessing population connectivity, highlighting the value of combining genetic data with capture-mark-recapture methods or other direct measures of movement to elucidate the complex role of dispersal in natural populations.


Cross-protective efficacy of HPV-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by non-vaccine oncogenic HPV types: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial.
We evaluated the efficacy of the human papillomavirus HPV-16/18 AS04-adjuvanted vaccine against non-vaccine oncogenic HPV types in the end-of-study analysis after 4 years of follow-up in PATRICIA (PApilloma TRIal against Cancer In young Adults). Healthy women aged 15-25 years with no more than six lifetime sexual partners were included in PATRICIA irrespective of their baseline HPV DNA status, HPV-16 or HPV-18 serostatus, or cytology. Women were randomly assigned (1:1) to HPV-16/18 vaccine or a control hepatitis A vaccine, via an internet-based central randomisation system using a minimisation algorithm to account for age ranges and study sites. The study was double-blind. The primary endpoint of PATRICIA has been reported previously; the present analysis evaluates cross-protective vaccine efficacy against non-vaccine oncogenic HPV types in the end-of-study analysis. Analyses were done for three cohorts: the according-to-protocol cohort for efficacy (ATP-E; vaccine n=8067, control n=8047), total vaccinated HPV-naive cohort (TVC-naive; no evidence of infection with 14 oncogenic HPV types at baseline, approximating young adolescents before sexual debut; vaccine n=5824, control n=5820), and the total vaccinated cohort (TVC; all women who received at least one vaccine dose, approximating catch-up populations that include sexually active women; vaccine n=9319, control=9325). Vaccine efficacy was evaluated against 6-month persistent infection, cervical intraepithelial neoplasia grade 2 or greater (CIN2+) associated with 12 non-vaccine HPV types (individually or as composite endpoints), and CIN3+ associated with the composite of 12 non-vaccine HPV types. This study is registered with ClinicalTrials.gov, number NCT00122681. Consistent vaccine efficacy against persistent infection and CIN2+ (with or without HPV-16/18 co-infection) was seen across cohorts for HPV-33, HPV-31, HPV-45, and HPV-51. In the most conservative analysis of vaccine efficacy against CIN2+, where all cases co-infected with HPV-16/18 were removed, vaccine efficacy was noted for HPV-33 in all cohorts, and for HPV-31 in the ATP-E and TVC-naive. Vaccine efficacy against CIN2+ associated with the composite of 12 non-vaccine HPV types (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68), with or without HPV-16/18 co-infection, was 46·8% (95% CI 30·7-59·4) in the ATP-E, 56·2% (37·2-69·9) in the TVC-naive, and 34·2% (20·4-45·8) in the TVC. Corresponding values for CIN3+ were 73·8% (48·3-87·9), 91·4% (65·0-99·0), and 47·5% (22·8-64·8). Data from the end-of-study analysis of PATRICIA show cross-protective efficacy of the HPV-16/18 vaccine against four oncogenic non-vaccine HPV types-HPV-33, HPV-31, HPV-45, and HPV-51-in different trial cohorts representing diverse groups of women. GlaxoSmithKline Biologicals.


Proteomic Signature and mRNA Expression in Hippocampus of SAMP8 and SAMR1 Mice during Aging.
Aging is a complex process often accompanied by cognitive decline that represents a risk factor for many neurodegenerative disorders including Alzheimer's and Parkinson's disease. The molecular mechanisms involved in age-related cognitive decline are not yet fully understood, although increased neuroinflammation is considered to play a significant role. In this study, we characterized a proteomic view of the hippocampus of the senescence-accelerated mouse prone-8 (SAMP8), a model of enhanced senescence, in comparison with the senescence-accelerated-resistant mouse (SAMR1), a model of normal aging. We additionally investigated inflammatory cytokines and cholinergic components gene expression during aging in the mouse brain tissues. Proteomic data defined the expression of key proteins involved in metabolic and cellular processes in neuronal and glial cells of the hippocampus. Gene Ontology revealed that most of the differentially expressed proteins are involved in the cytoskeleton and cell motility regulation. Molecular analysis results showed that both inflammatory cytokines and cholinergic components are differentially expressed during aging, with a downward trend of cholinergic receptors and esterase enzymes expression, in contrast to an upward trend of inflammatory cytokines in the hippocampus of SAMP8. Together, our results support the important role of the cholinergic and cytokine systems in the aging of the murine brain.


Scanning electron microscopy of fungiform papillae on the tongue of man and monkey.
The surface topography of the fungiform papillae of homo and monkey was studied by scanning electron microscopy. Different methods of specimen preparation were tried. Satisfactory preservation was obtained with fixation in formaldehyde, or in glutaraldehyde with postfixation in OSO4, followed by critical point drying. Taste pores were found in nearly half of the fungiform papillae. Up to 3 pores, located in the dorsal surface, were observed in a single papilla. Most taste pores opened in the form of a rounded crater with a diameter of about 5-7 mum, elevated slightly above the surface of the papilla. Microvilli could be observed in large-bore pores.


Demonstration of T lymphocytes in cerebrospinal fluid.
Cerebrospinal fluid (CSF) was allowed to drop straight into Hanks's balanced salt solution. After centrifugation the pellet was resuspended and mixed with sheep erythrocytes. The mixture was further handled as in the E-rosette test with peripheral blood lymphocytes. CSF from 20 individuals were investigated, and rosette-forming cells (RFC) were found in all. Six patients with normal fluid had between 46% and 83% RFC. Four patients with multiple sclerosis had increased numbers of RFC (94%-96%). Low numbers of RFC were found in one patient with cerebellar ataxia and in one of two patients with acute viral meningitis. With this technique RFC can be counted even in normal CSF with a 3-ml sample.


Impact of Optimal Medical Therapy in the Dual Antiplatelet Therapy Study.
Continued dual antiplatelet therapy and optimal medical therapy (OMT) improve outcomes in selected patient populations with established coronary heart disease, but whether OMT modifies the treatment effect of dual antiplatelet therapy is unknown. The DAPT (Dual Antiplatelet Therapy) Study, a double-blind trial, randomly assigned 11 648 patients who had undergone coronary stenting and completed 1 year of dual antiplatelet therapy without major bleeding or ischemic events to an additional 18 months of continued thienopyridine or placebo. OMT was defined as a combination of statin, β-blocker, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use in patients with an American College of Cardiology/American Heart Association class I indication for each medication. Per protocol, all patients were treated with 75 to 325 mg aspirin daily. End points included myocardial infarction, major adverse cardiovascular and cerebrovascular events, and Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries moderate or severe bleeding events. Of 11 643 randomly assigned patients with complete medication data, 63% were on OMT. Between 12 and 30 months, continued thienopyridine reduced myocardial infarction in comparison with placebo in both groups (on OMT 2.1% versus 3.3%, hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.48-0.86; P=0.003; off OMT 2.2% versus 5.2%, HR, 0.41; CI, 0.29-0.58; P<0.001; interaction P=0.103). Comparing continued thienopyridine versus placebo, rates of major adverse cardiovascular and cerebrovascular events were 4.2% versus 5.0% among patients on OMT (HR, 0.82; CI, 0.66-1.02; P=0.077) and 4.5% versus 7.0% among those off OMT (HR, 0.63; CI, 0.49-0.82; P<0.001; interaction P=0.250); rates of bleeding for thienopyridine versus placebo in patients on OMT were 2.2% versus 1.0% (HR, 2.13; CI, 1.43-3.17; P<0.001), and in patients off OMT were 2.8% versus 2.2% (HR, 1.30; CI, 0.88-1.92; P=0.189; interaction P=0.073). Overall, patients on OMT had lower rates of myocardial infarction (2.7% versus 3.7%, P=0.003), major adverse cardiovascular and cerebrovascular events (4.6% versus 5.7%, P=0.007), and bleeding (1.6% versus 2.5%, P<0.001) in comparison with patients off OMT. Rates of stent thrombosis (0.8% versus 1.0%, P=0.171) and death (1.6% versus 1.9%, P=0.155) did not differ. Continued thienopyridine therapy reduced the rate of myocardial infarction regardless of OMT status and had consistent effects on reduction in major adverse cardiovascular and cerebrovascular events and increased bleeding. URL: http://clinicaltrials.gov. Unique identifier: NCT00977938.


Prolonged mechanical ventilation as a consequence of acute illness.
To determine why acutely ill children become dependent upon mechanical ventilation and what happens to them. A retrospective medical record study of all patients aged between 1 month and 16 years from 1983 to 1996 who required ventilation for more than 28 days. Forty children were ventilated for between 36 and 180 days before discharge or death. Before their presenting illness, 13 (33%) were normal, 15 (37%) had documented predisposing conditions such as bronchopulmonary dysplasia, and the remaining 12 (30%) had diagnoses made after admission. The cause of respiratory failure was central in four patients (10%), spinal cord in eight (20%), neuromuscular in 11 (28%), and pulmonary in 17 (42%). Severe nosocomial infection requiring treatment with intravenous antibiotics occurred in 22. To date, 16 children (40%) have died, and 10 (25%) remain ventilator dependent. Of the 24 survivors, seven (29%) have severe residual neurological deficit. Increasingly, children are surviving intensive care only to remain ventilator dependent and at risk of significant comorbidity. This study should inform further debate on why such children remain ventilator dependent, and how and where they are managed.


Principles of safety, efficacy and stability in gene therapy--review.
Somatic gene therapy based on nonviral and viral vectors is an attractive approach for treatment of human diseases. It has developed from preliminary animal experiments to clinical trials. Vectors and target genes used in gene therapy are mainly focused on viral, nonviral vector and single target gene or monogene and each vector system has a series of advantages and limitations. However, the application of gene therapy to human disease is currently hampered by potential hazards of methods of gene delivery, the relatively low efficiency and intracellular stability of target gene. Safety, efficacy and stability are three problems that people often met and also three principles that people should be followed in gene therapy.


Effects of irrigation solutions on the surface of ProTaper instruments: a microscopy study.
The aim of this study was to evaluate the effects of sodium hypochlorite (NaOCl), chlorhexidine digluconate (CHX), and mixture of tetracycline, citric acid, and detergent (MTAD) solutions on the surfaces of nickel titanium (NiTi) rotary files with scanning electron microscopy (SEM) and atomic force microscopy (AFM). Irrigation solutions including 2.5% NaOCl, 5% NaOCl, 2% CHX, and MTAD were used. Four new ProTaper rotary NiTi files (F3) were immersed in each four irrigation solutions for 10 min, separately. One untreated NiTi file was used as a control specimen. The surface analysis was performed with SEM and AFM. The surface analysis in AFM was performed on 12 different regions located between first and second millimeters from the tip. SEM images were taken with different magnifications. No surface alteration was recorded under SEM evaluation. AFM revealed that the root mean square (RMS) values of all treated specimens were statistically higher than the control sample (P < 0.05). The sample which was treated with CHX showed lowest RMS values in test groups. All tested solutions caused surface alterations. CHX demonstrated limited surface alterations when compared to the other tested solutions.


Microbial control of phosphate in the nutrient-depleted North Atlantic subtropical gyre.
Little is known about the dynamics of dissolved phosphate in oligotrophic areas of the world's oceans, where concentrations are typically in the nanomolar range. Here, we have budgeted phosphate uptake by the dominant microbial groups in order to assess the effect of the microbial control of this depleted nutrient in the North Atlantic gyre. Low concentrations (2.2 +/- 1.2 nM) and rapid microbial uptake (2.1 +/- 2.4 nM day(-1)) of bioavailable phosphate were repeatedly determined in surface waters of the North Atlantic oligotrophic gyre during spring and autumn research cruises, using a radiotracer dilution bioassay technique. Upper estimates of the concentration of bioavailable phosphate were 7-55% of the dissolved mineral phosphate suggesting that a considerable part of the chemically measured nanomolar phosphate was in a form unavailable for direct microbial uptake. A 1:1 relationship (r(2) = 0.96, P < 0.0001) was observed between the bioavailable total phosphate uptake and the phosphate uptake of all the flow sorted bacterioplankton cells, demonstrating that bacterioplankton were the main consumers of phosphate. Within the bacterioplankton a group of heterotrophic bacteria and Prochlorococcus phototrophic cyanobacteria, were the two major competing groups for bioavailable phosphate. These heterotrophic bacteria had low nucleic acid content and 60% of them comprised of SAR11 clade cells based on the results of fluorescence in situ hybridization. Each of the two competing bacterial groups was responsible for an average of 45% of the phosphate uptake, while Synechococcus cyanobacteria (7%) and picoplanktonic algae (0.3%) played minor roles in direct phosphate uptake. We have demonstrated that phosphate uptake in the oligotrophic gyre is rapid and dominated by two bacterial groups rather than by algae.


Genetic Counselling, BRCA1/2 Status and Clinico-pathologic Characteristics of Patients with Ovarian Cancer before 50 Years of Age.
In Slovenia like in other countries, till recently, personal history of epithelial ovarian cancer (EOC) has not been included among indications for genetic counselling. Recent studies reported up to 17% rate of germinal BRCA1/2 mutation (gBRCA1/2m) within the age group under 50 years at diagnosis. The original aim of this study was to invite to the genetic counselling still living patients with EOC under 45 years, to offer gBRCA1/2m testing and to perform analysis of gBRCA1/2m rate and of clinico-pathologic characteristics. Later, we added also the data of previously genetically tested patients with EOC aged 45 to 49 years. All clinical data have to be interpreted in the light of many changes happened in the field of EOC just in the last few years: new hystology stage classification (FIGO), new hystology types and differentiation grades classification, new therapeutic possibilities (PARP inhibitors available, also in Slovenia) and new guidelines for genetic counselling of EOC patients (National Comprehensive Cancer Network, NCCN), together with next-generation sequencing possibilities. Compliance rate at the invitation was 43.1%. In the group of 27 invited or previously tested patients with EOC diagnosed before the age of 45 years, five gBRCA1/2 mutations were found. The gBRCA1/2m detection rate within the group was 18.5%. There were 4 gBRCA1 and 1 gBRCA2 mutations detected. In the extended group of 42 tested patients with EOC diagnosed before the age of 50 years, 14 gBRCA1/2 mutations were found. The gBRCA1/2m detection rate within this extended, partially selected group was 33.3%. There were 11 gBRCA1 and 3 gBRCA2 mutations detected. The rate of gBRCA1/2 mutation in tested unselected EOC patients under the age of 50 years was higher than 10%, namely 18.5%. Considering also a direct therapeuthic benefit of PARP inhibitors for BRCA positive patients, there is a double reason to offer genetic testing to all EOC patients younger than 50 years. Regarding clinical data, it is important to perform their re-interpretation in everyday clinical practice, because this may influence therapeutic possibilities to be offered.


An international study of the relation between somatic symptoms and depression.
Patients with depression, particularly those seen by primary care physicians, may report somatic symptoms, such as headache, constipation, weakness, or back pain. Some previous studies have suggested that patients in non-Western countries are more likely to report somatic symptoms than are patients in Western countries. We used data from the World Health Organization's study of psychological problems in general health care to examine the relation between somatic symptoms and depression. The study, conducted in 1991 and 1992, screened 25,916 patients at 15 primary care centers in 14 countries on 5 continents. Of the patients in the original sample, 5447 underwent a structured assessment of depressive and somatoform disorders. A total of 1146 patients (weighted prevalence, 10.1 percent) met the criteria for major depression. The range of patients with depression who reported only somatic symptoms was 45 to 95 percent (overall prevalence, 69 percent; P=0.002 for the comparison among centers). A somatic presentation was more common at centers where patients lacked an ongoing relationship with a primary care physician than at centers where most patients had a personal physician (odds ratio, 1.8; 95 percent confidence interval, 1.2 to 2.7). Half the depressed patients reported multiple unexplained somatic symptoms, and 11 percent denied psychological symptoms of depression on direct questioning. Neither of these proportions varied significantly among the centers. Although the overall prevalence of depressive symptoms varied markedly among the centers, the frequencies of psychological and physical symptoms were similar. Somatic symptoms of depression are common in many countries, but their frequency varies depending on how somatization is defined. There is substantial variation in how frequently patients with depression present with strictly somatic symptoms. In part, this variation may reflect characteristics of physicians and health care systems, as well as cultural differences among patients.


Lateral and axial resolution criteria in incoherent and coherent optics and holography, near- and far-field regimes.
This work presents an overview of spatial resolution criteria in classical optics, digital optics, and holography. Although the classical Abbe and Rayleigh resolution criteria have been thoroughly discussed in the literature, there are a few issues that still need to be addressed, e.g., the axial resolution criteria for coherent and incoherent radiation (which is a crucial parameter in 3D imaging), the resolution criteria in the Fresnel regime, and the lateral and the axial resolution criteria in digital optics and holography. This work discusses these issues and provides a simple guide on which resolution criteria should be applied for a particular imaging scheme: coherent/incoherent, far- and near-field, lateral and axial resolution. Different resolution criteria such as two-points resolution and the resolution obtained from the image spectrum (diffraction pattern) are compared and demonstrated with simulated examples. It is shown that, for coherent light, the classical Abbe and Rayleigh resolution criteria do not provide accurate estimation of the lateral and axial resolution. The lateral and axial resolution criteria based on the evaluation of the spectrum of the diffracted wave provide more precise estimation of the resolution for coherent and incoherent light. It is also shown that the resolution criteria derived in approximation of the far-field can be applied for the near-field (Fresnel) imaging regime.


The morphology of the interfacial tissue between bighorn sheep horn and bony horncore increases contact surface to enhance strength and facilitate load transfer from the horn to the horncore.
The horns of bighorn sheep rams are permanent cranial appendages used for high energy head-to-head impacts during interspecific combat. The horns attach to the underlying bony horncore by a layer of interfacial tissue that facilitates load transfer between the impacted horn and underlying horncore, which has been shown to absorb substantial energy during head impact. However, the morphology and mechanical properties of the interfacial tissue were previously unknown. Histomorphometry was used to quantify the interfacial tissue composition and morphology and lap-shear testing was used to quantify its mechanical properties. Histological analyses revealed the interfacial tissue is a complex network of collagen and keratin fibers, with collagen being the most abundant protein. Sharpey's fibers provide strong attachment between the interfacial tissue and horncore bone. The inner horn surface displayed microscopic porosity and branching digitations which increased the contact surface with the interfacial tissue by approximately 3-fold. Horn-horncore samples tested by lap-shear loading failed primarily at the horn surface, and the interfacial tissue displayed non-linear strain hardening behavior similar to other soft tissues. The elastic properties of the interfacial tissue (i.e., low- and high-strain shear moduli) were comparable to previously measured values for the equine laminar junction. The interfacial tissue contact surface was positively correlated with the interfacial tissue shear strength (1.23 ± 0.21 MPa), high-strain shear modulus (4.5 ± 0.7 MPa), and strain energy density (0.38 ± 0.07 MJ/m3). STATEMENT OF SIGNIFICANCE: : The bony horncore in bighorn sheep rams absorbs energy to reduce brain cavity accelerations and mitigate brain injury during head butting. The horn-horncore interface transfers energy from the impacted horn to the energy absorbing horncore but has been largely neglected in previous models of bighorn sheep ramming since interface properties were previously unknown. This study quantified the morphology and mechanical properties of the horn-horncore interface to better understand structure-property relationships that contribute to energy transfer during ramming. Results from this study will improve models of bighorn sheep ramming used to study mechanisms of brain injury mitigation and may inspire novel materials and structures for brain injury prevention in humans.


Sparsity-enforced slice-selective MRI RF excitation pulse design.
We introduce a novel algorithm for the design of fast slice-selective spatially-tailored magnetic resonance imaging (MRI) excitation pulses. This method, based on sparse approximation theory, uses a second-order cone optimization to place and modulate a small number of slice-selective sinc-like radio-frequency (RF) pulse segments ("spokes") in excitation k-space, enforcing sparsity on the number of spokes allowed while simultaneously encouraging those that remain to be placed and modulated in a way that best forms a user-defined in-plane target magnetization. Pulses are designed to mitigate B(1) inhomogeneity in a water phantom at 7 T and to produce highly-structured excitations in an oil phantom on an eight-channel parallel excitation system at 3 T. In each experiment, pulses generated by the sparsity-enforced method outperform those created via conventional Fourier-based techniques, e.g., when attempting to produce a uniform magnetization in the presence of severe B(1) inhomogeneity, a 5.7-ms 15-spoke pulse generated by the sparsity-enforced method produces an excitation with 1.28 times lower root mean square error than conventionally-designed 15-spoke pulses. To achieve this same level of uniformity, the conventional methods need to use 29-spoke pulses that are 7.8 ms long.


Differences in titin segmental elongation between passive and active stretch in skeletal muscle.
Since the 1950s, muscle contraction has been explained using a two-filament system in which actin and myosin exclusively dictate active force in muscle sarcomeres. Decades later, a third filament called titin was discovered. This titin filament has recently been identified as an important regulator of active force, but has yet to be incorporated into contemporary theories of muscle contraction. When sarcomeres are actively stretched, a substantial and rapid increase in force occurs, which has been suggested to arise in part from titin-actin binding that is absent in passively stretched sarcomeres. However, there is currently no direct evidence for such binding within muscle sarcomeres. Therefore, we aimed to determine whether titin binds to actin in actively but not in passively stretched sarcomeres by observing length changes of proximal and distal titin segments in the presence and absence of calcium. We labeled I-band titin with fluorescent F146 antibody in rabbit psoas myofibrils and tracked segmental elongations during passive (no calcium) and active (high calcium) stretch. Without calcium, proximal and distal segments of titin elongated as expected based on their free spring properties. In contrast, active stretch differed statistically from passive stretch, demonstrating that calcium activation increases titin segment stiffness, but not in an actin-dependent manner. The consistent elongation of the proximal segment was contrary to what was expected if titin's proximal segment was attached to actin. This rapid calcium-dependent change in titin stiffness likely contributes to active muscle force regulation in addition to actin and myosin.


Spatial structure of lemming populations (Dicrostonyx groenlandicus) fluctuating in density.
The pattern and scale of the genetic structure of populations provides valuable information for the understanding of the spatial ecology of populations, including the spatial aspects of density fluctuations. In the present paper, the genetic structure of periodically fluctuating lemmings (Dicrostonyx groenlandicus) in the Canadian Arctic was analysed using mitochondrial DNA (mtDNA) control region sequences and four nuclear microsatellite loci. Low genetic variability was found in mtDNA, while microsatellite loci were highly variable in all localities, including localities on isolated small islands. For both genetic markers the genetic differentiation was clear among geographical regions but weaker among localities within regions. Such a pattern implies gene flow within regions. Based on theoretical calculations and population census data from a snap-trapping survey, we argue that the observed genetic variability on small islands and the low level of differentiation among these islands cannot be explained without invoking long distance dispersal of lemmings over the sea ice. Such dispersal is unlikely to occur only during population density peaks.


Human endothelial cells are activated by interferon-gamma plus tumour necrosis factor-alpha to kill intracellular Pseudomonas aeruginosa.
Proinflammatory cytokines have been shown to activate endothelial cells. To investigate the effect of cytokines on the interaction of human umbilical vein endothelial cells (HUVEC) with Pseudomonas aeruginosa, cells were treated with interferon-gamma (IFN-gamma) plus tumour necrosis factor-alpha (TNF-alpha) for 24 hr and exposed to P. aeruginosa suspension for 1 hr. Light microscopy showed that activated cells internalized significantly more bacteria than control cells. To ascertain the effect of cytokines on the microbicidal activity of HUVEC, the concentrations of viable intracellular (IC) bacteria in control and activated cells were determined, at 1 and 5 hr postinfection, by the gentamicin exclusion assay. In control cells, no significant decrease in the concentration of bacteria was detected 5 hr postinfection. In contrast, in activated cells the concentration of viable bacteria at 5 hr was significantly lower. Concentrations of superoxide and hydrogen peroxide detected in supernatants of activated cells were significantly higher than in control cell supernatants. HUVEC anti-P. aeruginosa activity was insensitive to the antioxidants superoxide dismutase, dimethylthiourea and allopurinol as well as to the L-arginine analogues aminoguanidine and NG-monomethyl-L-arginine (L-NMMA), but was significantly inhibited by catalase. Our results indicate that HUVEC can be activated by IFN-gamma plus TNF-alpha to kill IC P. aeruginosa and suggest a role for reactive oxygen radicals, notably hydrogen peroxide, in HUVEC antibacterial activity.


Protection from chemotherapy- and antibiotic-mediated dysbiosis of the gut microbiota by a probiotic with digestive enzymes supplement.
There are numerous downstream consequences of marketed drugs like antineoplastic agents on the gut microbiome, an effect that is suggested to contribute to adverse event profiles and may also influence drug responses. In cancer, progress is needed toward modulation of the host microbiome to prevent off-target side effects of drugs such as gastrointestinal mucositis that result from gut dysbiosis. The objective of this study was evaluation of the bioactivity of a supplement consisting of capsules with a blend of 9 probiotic organisms of the genera Lactobacillus and Bifidobacterium plus 10 digestive enzymes, in protecting the human gastrointestinal tract from chemotherapy and an antibiotic. We used the Simulator of Human Intestinal Microbial Ecosystem (SHIME) model, an in vitro model of a stable colon microbiota, and introduced 5-fluorouracil (5-FU) and vancomycin as microbiome-disrupting drugs. The probiotic with digestive enzymes supplement, added in capsules at in vivo doses, improved fermentation activity in the colon reactors and accelerated the recovery of microbial populations following 5-FU/vancomycin treatment. The supplement restored the Bacteroidetes to Firmicutes ratios in the colon reactors, increased the diversity of microbiota, and induced the production of microbial metabolites that elicited anti-inflammatory cytokines in an in vitro model of intestinal inflammation. In the proximal colon, preventative administration of the supplement resulted in full recovery of the gut microbial community after cessation of 5-FU and vancomycin treatment. These results identify a probiotic with digestive enzymes formulation that protects against drug-induced gut dysbiosis, highlighting its potential utility as a component of routine cancer care.


MATT-DDI: Predicting multi-type drug-drug interactions via heterogeneous attention mechanisms.
The joint use of multiple drugs can result in adverse drug-drug interactions (DDIs) and side effects that harm the body. Accurate identification of DDIs is crucial for avoiding accidental drug side effects and understanding potential mechanisms underlying DDIs. Several computational methods have been proposed for multi-type DDI prediction, but most rely on the similarity profiles of drugs as the drug feature vectors, which may result in information leakage and overoptimistic performance when predicting interactions between new drugs. To address this issue, we propose a novel method, MATT-DDI, for predicting multi-type DDIs based on the original feature vectors of drugs and multiple attention mechanisms. MATT-DDI consists of three main modules: the top k most similar drug pair selection module, heterogeneous attention mechanism module and multi‑type DDI prediction module. Firstly, based on the feature vector of the input drug pair (IDP), k drug pairs that are most similar to the input drug pair from the training dataset are selected according to cosine similarity between drug pairs. Then, the vectors of k selected drug pairs are averaged to obtain a new drug pair (NDP). Next, IDP and NDP are fed into heterogeneous attention modules, including scaled dot product attention and bilinear attention, to extract latent feature vectors. Finally, these latent feature vectors are taken as input of the classification module to predict DDI types. We evaluated MATT-DDI on three different tasks. The experimental results show that MATT-DDI provides better or comparable performance compared to several state-of-the-art methods, and its feasibility is supported by case studies. MATT-DDI is a robust model for predicting multi-type DDIs with excellent performance and no information leakage.


The global burden of conduct disorder and attention-deficit/hyperactivity disorder in 2010.
The Global Burden of Disease Study 2010 (GBD 2010) is the first to include conduct disorder (CD) and attention-deficit/hyperactivity disorder (ADHD) for burden quantification. A previous systematic review pooled the available epidemiological data for CD and ADHD, and predicted prevalence by country, region, age and sex for each disorder. Prevalence was then multiplied by a disability weight to calculate years lived with disability (YLDs). As no evidence of deaths resulting directly from either CD or ADHD was found, no years of life lost (YLLs) were calculated. Therefore, the number of disability-adjusted life years (DALYs) was equal to that of YLDs. Globally, CD was responsible for 5.75 million YLDs/DALYs with ADHD responsible for a further 491,500. Collectively, CD and ADHD accounted for 0.80% of total global YLDs and 0.25% of total global DALYs. In terms of global DALYs, CD was the 72nd leading contributor and among the 15 leading causes in children aged 5-19 years. Between 1990 and 2010, global DALYs attributable to CD and ADHD remained stable after accounting for population growth and ageing. The global burden of CD and ADHD is significant, particularly in male children. Appropriate allocation of resources to address the high morbidity associated with CD and ADHD is necessary to reduce global burden. However, burden estimation was limited by data lacking for all four epidemiological parameters and by methodological challenges in quantifying disability. Future studies need to address these limitations in order to increase the accuracy of burden quantification.


Developing an HbA(1c)-based equation to estimate blood glucose in maintenance hemodialysis patients.
Hemoglobin A1c (HbA(1c)) has been widely used as a clinically important assessment tool for outcome analyses related to glycemic control. However, because of special conditions in dialysis patients, including the uremic milieu, there is no HbA(1c) blood glucose (BG) equation specific for patients on dialysis. In this study, we sought to develop HbA(1c)-BG equation models for hemodialysis patients. We examined associations between HbA(1c) and random serum BG over time in a contemporary cohort of diabetic patients with hemodialysis treated in DaVita dialysis clinics. We identified 11,986 patients (63 ± 12 years old and 49% male) with 69,764 paired measurements of HbA(1c) and BG over the course of 5 years (2001-2006). Bootstrapping method was used to estimate average BG and corresponding HbA(1c) levels. The association was adjusted by patient factors using linear regression. Linear regression analyses yielded the following three regression equations: BG = 59.2 + 29.4 × HbA(1c) - 20.8 × Alb (R(2) = 0.483); BG = 104.8 + 29.7 × HbA(1c) - 18.4 × Alb - 4.7 × Hb (R(2) = 0.486); and BG = 82.9 + 30.7 × HbA(1c) - 16.5 × Alb - 5.4 × Hb + 0.3 × age + race (R(2) = 0.491). All our models showed stronger association than previous equation models (R(2) = 0.468 in the Diabetes Control and Complications Trial and A1c-Derived Average Glucose equations). The association between HbA(1c) and BG in hemodialysis patients is different than that of patients with normal kidney function. Our analysis suggests that equations including serum albumin or hemoglobin are better for hemodialysis patients.


Regioselective Iridium-Catalyzed Asymmetric Monohydrogenation of 1,4-Dienes.
A highly efficient regio- and enantioselective monohydrogenation of 1,4-dienes has been realized using an iridium catalyst with a chiral N,P-ligand under mild conditions. The substrate scope was studied and included both unfunctionalized as well as functionalized substituents on the meta- or para-position. Substrates having substituents with functionalities such as silyl protected alcohols or ketals were monohydrogenated in high regioselectivity and high enantiomeric excess (up to 98% ee).


Alignment of Rutaceae Genomes Reveals Lower Genome Fractionation Level Than Eudicot Genomes Affected by Extra Polyploidization.
Owing to their nutritional and commercial values, the genomes of several citrus plants have been sequenced, and the genome of one close relative in the Rutaceae family, atalantia (Atalantia buxifolia), has also been sequenced. Here, we show a family-level comparative analysis of Rutaceae genomes. By using grape as the outgroup and checking cross-genome gene collinearity, we systematically performed a hierarchical and event-related alignment of Rutaceae genomes, and produced a gene list defining homologous regions based on ancestral polyploidization or speciation. We characterized genome fractionation resulting from gene loss or relocation, and found that erosion of gene collinearity could largely be described by a geometric distribution. Moreover, we found that well-assembled Rutaceae genomes retained significantly more genes (65-82%) than other eudicots affected by recursive polyploidization. Additionally, we showed divergent evolutionary rates among Rutaceae plants, with sweet orange evolving faster than others, and by performing evolutionary rate correction, re-dated major evolutionary events during their evolution. We deduced that the divergence between the Rutaceae family and grape occurred about 81.15-91.74 million years ago (mya), while the split between citrus and atalantia plants occurred <10 mya. In addition, we showed that polyploidization led to a copy number expansion of key gene families contributing to the biosynthesis of vitamin C. Overall, the present effort provides an important comparative genomics resource and lays a foundation to understand the evolution and functional innovation of Rutaceae genomes.


Criteria for the safety evaluation of flavoring substances. The Expert Panel of the Flavor and Extract Manufacturers Association.
The current status of the GRAS evaluation program of flavoring substances operated by the Expert Panel of FEMA is discussed. The Panel maintains a rigorous rotating 10-year program of continuous review of scientific data related to the safety evaluation of flavoring substances. The Panel concluded a comprehensive review of the GRAS (GRASa) status of flavors in 1985 and began a second comprehensive review of the same substances and any recently GRAS materials in 1994. This second re-evaluation program of chemical groups of flavor ingredients, recognized as the GRAS reaffirmation (GRASr) program, is scheduled to be completed in 2005. The evaluation criteria used by the Panel during the GRASr program reflects the significant impact of advances in biochemistry, molecular biology and toxicology that have allowed for a more complete understanding of the molecular events associated with toxicity. The interpretation of novel data on the relationship of dose to metabolic fate, formation of protein and DNA adducts, enzyme induction, and the cascade of cellular events leading to toxicity provides a more comprehensive basis upon which to evaluate the safety of the intake of flavor ingredients under conditions of intended use. The interpretation of genotoxicity data is evaluated in the context of other data such as in vivo animal metabolism and lifetime animal feeding studies that are more closely related to actual human experience. Data are not viewed in isolation, but comprise one component that is factored into the Panel's overall safety assessment. The convergence of different methodologies that assess intake of flavoring substances provides a greater degree of confidence in the estimated intake of flavor ingredients. When these intakes are compared to dose levels that in some cases result in related chemical and biological effects and the subsequent toxicity, it is clear that exposure to these substances through flavor use presents no significant human health risk.


Life after Stroke: Coping mechanisms among African Caribbean Women.
In the UK, stroke is the third most common cause of death for women and the incidence in African Caribbean women is higher than that in the general population. Stroke burden has major consequences for the physical, mental and social health of African Caribbean women. In order to adjust to life after stroke, individuals affected employ a range of strategies which may include personal, religious (church) or spiritual support (i.e. prayer), individual motivation or resignation to life with a disability. This study explored these areas through the coping mechanisms that African Caribbean women utilised post stroke in the context of stroke recovery and lifestyle modification efforts needed to promote healthy living post stroke. A qualitative approach using interpretative phenomenological analysis was adopted. Seven women were recruited into the study. Semi-structured, in-depth interviews were audio recorded and were transcribed verbatim. Data were analysed using a four-stage framework: familiarisation, sense making, developing themes, and data refinement and analysis. Three main themes on coping emerged: the need to follow medical rules to manage stroke, strength and determination, and the use of religion and faith to cope with life after stroke. These findings illustrate both a tension between religious beliefs and the medical approach to stroke and highlight the potential benefits that religion and the church can play in stroke recovery. Implications for practice include acknowledgement and inclusion of religion- and church-based health promotion in post-stroke recovery.


Turning it inside out: The organization of human septin heterooligomers.
Septin family proteins are quite similar to each other both within and between eukaryotic species. Typically, multiple discrete septins co-assemble into linear heterooligomers (usually hexameric or octameric rods) with a variety of cellular functions. We know little about how incorporation of different septins confers different properties to such complexes. This issue is especially acute in human cells where 13 separate septin gene products (often produced in multiple forms arising from alternative start codons and differential splicing) are expressed in a tissue-specific manner. Based on sequence alignments and phylogenetic criteria, human septins fall into four distinct groups predictive of their interactions, that is, members of the same group appear to occupy the same position within oligomeric septin protomers, which are "palindromic" (have twofold rotational symmetry about a central homodimeric pair). Many such protomers are capable of end-to-end polymerization, generating filaments. Over a decade ago, a study using X-ray crystallography and single-particle electron microscopy deduced the arrangement within recombinant heterohexamers comprising representatives of three human septin groups-SEPT2, SEPT6, and SEPT7. This model greatly influenced subsequent studies of human and other septin complexes, including how incorporating a septin from a fourth group forms heterooctamers, as first observed in budding yeast. Two recent studies, including one in this issue of Cytoskeleton, provide clear evidence that, in fact, the organization of subunits within human septin heterohexamers and heterooctamers is inverted relative to the original model. These findings are discussed here in a broader context, including possible causes for the initial confusion.


The relations of family members' unique and shared perspectives of family dysfunction to dyad adjustment.
Among a community sample of families (N = 128), this study examined how family members' shared and unique perspectives of family dysfunction relate to dyad members' shared views of dyad adjustment within adolescent-mother, adolescent-father, and mother-father dyads. Independent of a family's family perspective (shared perspective of family dysfunction), the adolescent's unique perspective was associated with lower security and higher conflict with both mother and father; the father's unique perspective was associated with lower security and higher conflict with the adolescent, as well as lower marital quality with mother; and the mother unique perspective was associated with lower marital quality with the father. Moreover, for adolescent-parent dyads, compared with the parent unique perspective, the adolescent unique perspective was more strongly associated with dyad adjustment. These findings indicate that both shared and unique views of the family system-the adolescent's unique view in particular-independently relate to the health of family subsystems. They also suggest that research, as well as therapeutic interventions, that focus on just the shared view of the family may miss important elements of family dysfunction.


Immunoglobulin light chain amyloidosis: 2022 update on diagnosis, prognosis, and treatment.
Immunoglobulin light chain amyloidosis is a clonal, nonproliferative plasma cell disorder in which fragments of immunoglobulin light or heavy chain are deposited in tissues. Clinical features depend on organs involved but can include heart failure with preserved ejection fraction, nephrotic syndrome, hepatic dysfunction, peripheral/autonomic neuropathy, and "atypical smoldering multiple myeloma or monoclonal gammopathy of undetermined significance (MGUS)." Tissue biopsy stained with Congo red demonstrating amyloid deposits with apple-green birefringence is required for the diagnosis of AL amyloidosis. Invasive organ biopsy is not required in 85% of patients. Verification that amyloid is composed of immunoglobulin light chains is mandatory. The gold standard is laser capture mass spectroscopy. N-terminal pro-brain natriuretic peptide (NT-proBNP or BNP), serum troponin T (or I), and difference between involved and uninvolved immunoglobulin free light chain values are used to classify patients into four groups of similar size; median survivals are 73, 35, 15, and 5 months. All patients with a systemic amyloid syndrome require therapy to prevent deposition of amyloid in other organs and prevent progressive organ failure. Current first-line therapy with the best outcome is daratumumab, bortezomib, cyclophosphamide, and dexamethasone. The goal of therapy is a complete response (CR). In patients failing to achieve this depth of response options for consolidation include pomalidomide, stem cell transplantation, venetoclax, and bendamustine. Delayed diagnosis remains a major obstacle to initiating effective therapy prior to the development of end-stage organ failure. Trials of antibodies to catabolize deposited fibrils are underway.


The last resort? Staff and client perspectives on physical intervention.
This study provides feedback from research with staff and clients of a medium secure learning disability service in north-west England. Participants were asked about incidents which required the use of physical intervention, using unstructured interviews within a participatory research framework. The article explores clients' and staff accounts of aggressive incidents and the consequences of physical intervention. Clients cited other clients and the ward atmosphere as the main reasons for aggressive behaviour. Some clients said that the use of physical intervention made them more frustrated and brought back memories of frightening experiences. Staff reported that incidents of aggression and the use of physical intervention were upsetting and traumatic, causing feelings of guilt and self-reproach. Staff said that they always used physical intervention as a last resort, although clients often reported otherwise. Time out and post-incident discussions were valued by both groups, as were strong staff/client relationships.


Ventricular arrhythmias, Part II: Special concerns in evaluation.
In the initial installment of this series, the prevalence, significance, and indications for treatment of ventricular arrhythmias were discussed. In this section, we address special concerns in the evaluation of patients with ventricular arrhythmias including the importance of extracardiac and exacerbating factors, the likely role of silent myocardial ischemia, benefits and drawbacks of monitoring methods, proarrhythmic effect, and torsades de pointes. Treatment considerations and discussion of pitfalls in management will follow in the final two installments of this series.


Activation of 5-HT1A Receptors Promotes Retinal Ganglion Cell Function by Inhibiting the cAMP-PKA Pathway to Modulate Presynaptic GABA Release in Chronic Glaucoma.
Serotonin (5-hydroxytryptamine, 5-HT) receptor agonists are neuroprotective in CNS injury models. However, the neuroprotective functional implications and synaptic mechanism of 8-hydroxy-2- (di-n-propylamino) tetralin (8-OH-DPAT), a serotonin receptor (5-HT1A) agonist, in an adult male Wistar rat model of chronic glaucoma model remain unknown. We found that ocular hypertension decreased 5-HT1A receptor expression in rat retinas because the number of retinal ganglion cells (RGCs) was significantly reduced in rats with induced ocular hypertension relative to that in control retinas and 8-OH-DPAT enhanced the RGC viability. The protective effects of 8-OH-DPAT were blocked by intravitreal administration of the selective 5-HT1A antagonist WAY-100635 or the selective GABAA receptor antagonist SR95531. Using patch-clamp techniques, spontaneous and miniature GABAergic IPSCs (sIPSCs and mIPSCs, respectively) of RGCs in rat retinal slices were recorded. 8-OH-DPAT significantly increased the frequency and amplitude of GABAergic sIPSCs and mIPSCs in ON- and OFF-type RGCs. Among the signaling cascades mediated by the 5-HT1A receptor, the role of cAMP-protein kinase A (PKA) signaling was investigated. The 8-OH-DPAT-induced changes at the synaptic level were enhanced by PKA inhibition by H-89 and blocked by PKA activation with bucladesine. Furthermore, the density of phosphorylated PKA (p-PKA)/PKA was significantly increased in glaucomatous retinas and 8-OH-DPAT significantly decreased p-PKA/PKA expression, which led to the inhibition of PKA phosphorylation upon relieving neurotransmitter GABA release. These results showed that the activation of 5-HT1A receptors in retinas facilitated presynaptic GABA release functions by suppressing cAMP-PKA signaling and decreasing PKA phosphorylation, which could lead to the de-excitation of RGC circuits and suppress excitotoxic processes in glaucoma.SIGNIFICANCE STATEMENT We found that serotonin (5-HT) receptors in the retina (5-HT1A receptors) were downregulated after intraocular pressure elevation. Patch-clamp recordings demonstrated differences in the frequencies of miniature GABAergic IPSCs (mIPSCs) in ON- and OFF-type retinal ganglion cells (RGCs) and RGCs in normal and glaucomatous retinal slices. Therefore, phosphorylated protein kinase A (PKA) inhibition upon release of the neurotransmitter GABA was eliminated by 8-hydroxy-2- (di-n-propylamino) tetralin (8-OH-DPAT), which led to increased levels of GABAergic mIPSCs in ON- and OFF-type RGCs, thus enhancing RGC viability and function. These protective effects were blocked by the GABAA receptor antagonist SR95531 or the 5-HT1A antagonist WAY-100635. This study identified a novel mechanism by which activation of 5-HT1A receptors protects damaged RGCs via the cAMP-PKA signaling pathway that modulates GABAergic presynaptic activity.


Improved protocol for Bst polymerase and reverse transcriptase production and application to a point-of-care diagnostics system.
The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has raised awareness in the scientific community about the importance of being prepared for sanitary emergencies. Many measures implemented during the COVID pandemic are now being expanded to other applications. In the field of molecular and immunological diagnostics, the need to massively test the population worldwide resulted in the application of a variety of methods to detect viral infection. Besides gold standard reverse transcription quantitative polymerase chain reaction (RT-qPCR), the use of reverse transcription loop-mediated isothermal amplification (RT-LAMP) arose as an alternative and sensitive method to amplify and detect viral genetic material. We have used openly available protocols and have improved the protein production of RT-LAMP enzymes Bst polymerase and HIV-reverse transcriptase. To optimize enzyme production, we tested different protein tags, and we shortened the protein purification protocol, resulting in reduced processing time and handling of the enzymes and, thus, preserved the protein activity with high purity. The enzymes showed significant stability at 4 °C and 25 °C, over 60 days, and were highly reliable when used as a one-step RT-LAMP reaction in a portable point-of-care device with clinical samples. The enzymes and the reaction setup can be further expanded to detect other infectious diseases agents.


[Protective effects and their mechanisms of cobalt on soybean seedling's leaf under drought stress].
This paper studied the effects of cobalt on the polyamine content, reactive oxygen level, anti-oxidative enzyme activity, and cell membrane permeability of soybean seedling's leaf under drought stress, and discussed the mechanisms of these effects. The results showed that under drought stress, cobalt at its concentration of 30 micromol x L(-1) could significantly inhibit the production of ethylene. This concentration of cobalt had no significant effects on the contents of MDA and chlorophyll when the drought stress lasted 0 to approximately 12 days, but significantly restrained the increase of reactive oxygen level, hampered the decline of putrescine, spermidine and spermine contents and anti-oxidative enzyme activities,and thus,inhibited the accumulation of MDA and alleviated the reduction of chlorophyll content when the stress lasted 15 to approximately 21 days. It could be concluded that when soybean seedling's leaf was deeply stressed and damaged under drought stress, cobalt could alleviate the decline of polyamine content and anti-oxidative enzyme activity,and hence, alleviate the increment of reactive oxygen level and cell membrane's damage degree through inhibiting the production of ethylene, and exerted its protective effects on the soybean seedling's leaf under drought stress.


Large Bulk Photovoltaic Effect and Spontaneous Polarization of Single-Layer Monochalcogenides.
We use a first-principles density functional theory approach to calculate the shift current and linear absorption of uniformly illuminated single-layer Ge and Sn monochalcogenides. We predict strong absorption in the visible spectrum and a large effective three-dimensional shift current (∼100 μA/V^{2}), larger than has been previously observed in other polar systems. Moreover, we show that the integral of the shift-current tensor is correlated to the large spontaneous effective three-dimensional electric polarization (∼1.9 C/m^{2}). Our calculations indicate that the shift current will be largest in the visible spectrum, suggesting that these monochalcogenides may be promising for polar optoelectronic devices. A Rice-Mele tight-binding model is used to rationalize the shift-current response for these systems, and its dependence on polarization, in general terms with implications for other polar materials.


Modelling accelerated degradation data using Wiener diffusion with a time scale transformation.
Engineering degradation tests allow industry to assess the potential life span of long-life products that do not fail readily under accelerated conditions in life tests. A general statistical model is presented here for performance degradation of an item of equipment. The degradation process in the model is taken to be a Wiener diffusion process with a time scale transformation. The model incorporates Arrhenius extrapolation for high stress testing. The lifetime of an item is defined as the time until performance deteriorates to a specified failure threshold. The model can be used to predict the lifetime of an item or the extent of degradation of an item at a specified future time. Inference methods for the model parameters, based on accelerated degradation test data, are presented. The model and inference methods are illustrated with a case application involving self-regulating heating cables. The paper also discusses a number of practical issues encountered in applications.