Use of fertility services in Australian lesbian, bisexual and queer women's pathways to parenthood.
It is estimated that up to one in three lesbian, bisexual or queer (LBQ) women in Australia have children. In the past decade, it has become common for LBQ women to pursue pregnancy using clinic-acquired donor sperm. The aims of this paper are to explore pathways to parenthood among Australian LBQ women in the context of increased access to fertility clinics and identify the type of clinical fertility services being used. This paper reports on female LBQ parents and expectant/prospective parents who participated in a 2016/2017 online survey of Australian lesbian, gay, bisexual, transgender and queer (LGBTQ) adults exploring reproductive choices, pathways to parenthood, conception method and use of clinical fertility services. More than half the children reported on by current parents (52%) had been conceived using clinical fertility services. When asked what factors influenced a parent respondent's decision to use fertility services: 80% indicated access to donor sperm, 41% indicated fertility problems. Of respondents who had accessed donor sperm, over half (57%) had used in vitro fertilisation (IVF) services. These findings indicate that use of fertility clinics to access donor sperm is common for LBQ women, including those with no known fertility problems, and that most women who access donor sperm conceive using IVF rather than intrauterine insemination. More needs to be known about the context and reasons for this, including factors that influence LBQ women's decision making on their pathway to parenthood.


Renal cyclooxygenase-2 (COX-2). Physiological, pathophysiological, and clinical implications.
The role of COX-2 for renal function during renal development, for physiology and pathophysiology of renal diseases and the side effects of available COX-2 inhibitors, has gained increasing interest. We aimed therefore to review the respective role of renal COX-2. Review of relevant recent publications in the field, and in addition of in part unpublished data obtained in our laboratories. COX-2 is 'constitutively' localized in the kidney i.e. in macula densa, TALH, interstitial cells, and is of utmost importance for normal renal development. Renal COX-2 is regulated by for example sodium and volume intake, angiotensin II, glucocorticoids often involving specific COX-2 promotor response elements. COX-2 derived prostanoids are required for preservation of renal blood flow and glomerular filtration especially in states of fluid deficit, they promote natriuresis, and furthermore may stimulate renin secretion during low-sodium intake/loop diuretic use. Conversely, COX-2 inhibitors decrease glomerular filtration, and renal perfusion, sometimes even causing acute renal failure. In addition, COX-2 inhibitors cause sodium retention, edema formation, cardiac failure and hypertension. The role of COX-2 derived prostanoids in renal inflammation or failure including diabetic nephropathy and renal transplantation remains at present controversial. COX-2 is one of the major players in renal physiology and pathophysiology. One focus of future work should be placed on COX-2 in primary renal diseases.


MHC class I, beta2 microglobulin, and the INF-gamma receptor are upregulated in aged motoneurons.
During aging, spinal cord motoneurons show characteristic changes including the loss of afferent boutons, a selective process that associates with gliosis and behavioral motor impairment. Evidence suggests that the major histocompatibility complex Class I (MHC I) system may be involved in synaptic plasticity of neurons during development and regeneration. In search of a mechanism governing senescent changes in synaptic connectivity, we report evidence for increased expression of MHC I and beta2 microglobulin (beta2M) in motoneurons and glial-like profiles of 30-month-old rats. The regulatory signal(s) for MHC I expression in normal neurons remains unresolved but among tentative molecules are cytokines such as interferon-gamma (INF-gamma) and tumor necrosis factor alpha (TNF-alpha). Interestingly, aged motoneurons, overlapping with those showing increased levels of MHC I, contained increased levels of INF-gamma receptor message. INF-gamma mRNA was detected at low levels in most (8/9) of the aged spinal cords but only infrequently (2/9) in young adult spinal cords; however, the cellular localization of INF-gamma mRNA could not be determined. Our data also indicates that TNF-alpha is upregulated in the senescent spinal cord but that TNF-alpha immunoreactive protein does not associate with motoneurons. We report evidence for an increased expression of MHC I and beta2M in senescent spinal motoneurons and discuss the possibility that this regulation associates with INF-gamma or changes in neurotrophin signaling and neuron activity in senescence.


Application of ammonium to a N limited arable soil enriches a succession of bacteria typically found in the rhizosphere.
Crop residue management and tillage are known to affect the soil bacterial community, but when and which bacterial groups are enriched by application of ammonium in soil under different agricultural practices from a semi-arid ecosystem is still poorly understood. Soil was sampled from a long-term agronomic experiment with conventional tilled beds and crop residue retention (CT treatment), permanent beds with crop residue burned (PBB treatment) or retained (PBC) left unfertilized or fertilized with 300 kg urea-N ha-1 and cultivated with wheat (Triticum durum L.)/maize (Zea mays L.) rotation. Soil samples, fertilized or unfertilized, were amended or not (control) with a solution of (NH4)2SO4 (300 kg N ha-1) and were incubated aerobically at 25 ± 2 °C for 56 days, while CO2 emission, mineral N and the bacterial community were monitored. Application of NH4+ significantly increased the C mineralization independent of tillage-residue management or N fertilizer. Oxidation of NH4+ and NO2- was faster in the fertilized soil than in the unfertilized soil. The relative abundance of Nitrosovibrio, the sole ammonium oxidizer detected, was higher in the fertilized than in the unfertilized soil; and similarly, that of Nitrospira, the sole nitrite oxidizer. Application of NH4+ enriched Pseudomonas, Flavisolibacter, Enterobacter and Pseudoxanthomonas in the first week and Rheinheimera, Acinetobacter and Achromobacter between day 7 and 28. The application of ammonium to a soil cultivated with wheat and maize enriched a sequence of bacterial genera characterized as rhizospheric and/or endophytic independent of the application of urea, retention or burning of the crop residue, or tillage.


Seasonality in the dung beetle community in a Brazilian tropical dry forest: Do small changes make a difference?
Dung beetle (Coleoptera: Scarabaeoidea: Scarabaeinae) activity is influenced by rainfall seasonality. We hypothesized that rainfall might also play a major role in regulating the community structure of this group. In this study, we describe seasonal changes in the richness, composition, and structure of the Scarabaeinae community in a Brazilian tropical dry forest. A fragment of arboreal Caatinga was sampled using baited pitfall traps during the early dry season (EDS), late dry season (LDS), early wet season (EWS), and middle wet season (MWS). We compared the dung beetle community in each season in relationship to species richness, rank-dominance, curves, and composition. We collected 1352 Scarabaeinae individuals , belonging to 15 species. Dichotomius aff. laevicollis Felsche (Coleoptera: Scarabaeidae) was the dominant species, representing 73.89% of the individuals. There were no seasonal changes in the rank dominance curves; all had a single dominant species and a few species with low abundance, typical for arid areas. Estimated richness was highest in MWS, followed by EWS. Dry-season samples (EDS and LDS) had lower richness, with no significant difference between the dry seasons. Although species richness increased as the habitat became wetter, the difference between the wet and dry seasons was small, which differs completely from the findings of other studies in Neotropical dry forests, where almost all species cease activities in the dry season. Species composition changes were found in non-metric multidimensional scaling and sustained by analysis of similarity. All the seasons had pairwise differences in composition, with the exception of EDS and MWS, which indicates that the dung beetle community in this fragment requires more than three months of drought to trigger changes in species composition; this is probably due to small changes in the forest canopy. There was no difference in composition between EDS and MWS. As in other tropical dry forests, although to a lesser extent, the dung beetle community of this fragment responded to rainfall seasonality with changes in species composition and reduced species richness. Such responses, even to this lesser extent, may occur because of small changes in tree cover and minor microclimate changes.


The evolving role of direct thrombin inhibitors in acute coronary syndromes.
The central role of thrombin in the initiation and propagation of intravascular thrombus provides a strong rationale for direct thrombin inhibitors in acute coronary syndromes (ACS). Direct thrombin inhibitors are theoretically likely to be more effective than indirect thrombin inhibitors, such as unfractionated heparin or low-molecular-weight heparin, because the heparins block only circulating thrombin, whereas direct thrombin inhibitors block both circulating and clot-bound thrombin. Several initial phase 3 trials did not demonstrate a convincing benefit of direct thrombin inhibitors over unfractionated heparin. However, the Direct Thrombin Inhibitor Trialists' Collaboration meta-analysis confirms the superiority of direct thrombin inhibitors, particularly hirudin and bivalirudin, over unfractionated heparin for the prevention of death or myocardial infarction (MI) during treatment in patients with ACS, primarily due to a reduction in MI (odds ratio, 0.80; 95% confidence interval, 0.70 to 0.91) with little impact on death. The absolute risk reduction in the composite of death or MI at the end of treatment (0.8%) was similar at 30 days (0.7%), indicating no loss of benefit after cessation of therapy. Supportive evidence for the superiority of direct thrombin inhibitors over heparin derives from the recently reported Hirulog and Early Reperfusion or Occlusion (HERO)-2 randomized trial with ST-segment elevation ACS, which demonstrated a similar benefit of bivalirudin over heparin for the prevention of death or MI at 30 days (absolute risk reduction 1.0%), again primarily due to a reduction in MI during treatment (odds ratio, 0.70; 95% confidence interval, 0.56 to 0.87), with little impact on death. Further evaluation of hirudin and bivalirudin in the antithrombotic management of patients with ACS is warranted.


Sensing and reacting to dangers by caspases: Caspase activation via inflammasomes.
Caspases are well known as mediators of programmed cell death, or apoptosis, in which their functions are highly conserved throughout evolution. In addition to inducing apoptosis, caspases have important roles in immune reactions. As part of a cell's response to pathogens or alarm (cellular danger) signals from damaged cells, caspase-1 is activated by forming an inflammatory complex with apoptosisassociated speck like protein containing a caspase recruitment domain (ASC) and nucleotide-binding oligomerization domain like receptor (NLR) family proteins. The activated caspase-1 then cleaves and promotes the maturation of cytokines, such as IL-1β, IL-18, and IL-33. Although it has long been unclear how hosts recognize diverse stresses, including injury and pathogen infection, and react appropriately, recent analyses have revealed many details about the sensing mechanisms provided by NLRs. Members of the NLR family are activated and yield different outcomes depending on the stimulus. For example, the NLR member cryopyrin/NALP3 induces cytokine secretion and lipid synthesis in response to viral dsRNA and K+ efflux, while another NLR, IPAF, induces IL-1β? in response to the virulence protein, flagellin. Cryopyrin/NALP3-mediated caspase-1 activation is involved not only in the immune response to pathogens but also in the stress response to UV irradiation in human skin. In this review, we focus on the stress responses that particularly involve inflammatory caspases. Since host reactions to stresses have been studied in invertebrates as well as in mammals, we also review the caspase-mediated immune responses that have been identified in the fruit fly Drosophila melanogaster, and suggest that the contribution of caspases to general stress responses is evolutionally conserved.


Antagonism of the cardiac effects of leukotriene C4 by compound SKF 88046: dissociation of effects on contractility and coronary flow.
In the present study, we evaluated the properties of an imidodisulfamide derivative, compound SKF 88046, as an antagonist of the cardiac effects of leukotrienes (LTs). LTC4 (0.1-100 ng) caused dose-related decreases in the contractile force and coronary flow rate of the isolated guinea pig heart. SKF 88046 and the prototypic anti-SRS (anti-slow reacting substance) compound FPL 55712 (4.8 X 10(-7) M) were equieffective in antagonizing the LTC4-induced decrease in coronary flow. On the other hand, SKF 88046 was more potent than FPL 55712 in antagonizing the negative inotropic effect of LTC4. Our findings demonstrate that SKF 88046 is an effective antagonist of the coronary constricting and myocardial depressant effects of LTC4, but that SKF 88046 preferentially antagonizes the negative inotropic effect of LTC4. This favors the hypothesis formulated by others that LT effects may be mediated by multiple receptors.


Fluoride in Ceylon tea and its implications to dental health.
The purpose of this study was to assess the fluoride content of Ceylon Tea, which is a popular beverage throughout the world. The fluoride content of tea infusions prepared from different grades of tea leaves collected from different parts of the tea-growing regions (25 samples) of Sri Lanka was measured using a fluoride-selective electrode. Fluoride leaching was found to vary from 0.32 to 1.69 mg F/l, but there were no significant differences in terms of fluoride leaching between tea from different tea-growing regions or between tea of different grades. Dental fluorosis is widespread throughout the dry zone of Sri Lanka, and drinking water has traditionally been considered to be the main contributory factor to the development of fluorosis. However, diet, the consumption of tea in particular, may also contribute to the manifestation of dental diseases.


Sequence and structural characteristics of the trypsin-resistant T6 surface protein of group A streptococci.
The gene for the trypsin-resistant surface T6 protein of Streptococcus pyogenes D471 (M type 6) was cloned and expressed in Escherichia coli. The complete nucleotide sequence of the gene (tee6) and its flanking regions was determined and found to include only one major open reading frame coding for a protein of 537 amino acids (Mr, 57,675). The N terminus of the deduced protein sequence exhibits features of a typical signal sequence, and the C-terminal segment was found to have a high degree of homology with the membrane anchor region of other gram-positive surface proteins, such as streptococcal M protein, wapA protein from Streptococcus mutans and staphylococcal protein A. A hexapeptide having the consensus sequence LPSTGE and located immediately upstream of the C-terminal hydrophobic segment showed the highest degree of conservation at both the protein and DNA levels, with nearly all reported surface proteins from gram-positive cocci. The amino acid composition of the T6 protein revealed 21% serine and threonine residues distributed nearly regularly throughout the molecule, and analysis of the secondary structure predicted a conformation composed of greater than 70% beta-sheet potential interrupted by beta-turns or random coils. Localization experiments in E. coli show very little T6 protein in the periplasmic space. When found here, however, this T6 protein had a molecular mass of 55 kilodaltons, similar to that extracted from the streptococci by nonionic detergent. Most of the T6 protein was found localized in the membrane fraction, where it was composed of a triple band of 60, 58, and 57 kilodaltons. The coexistence of streptococcal surface proteins which are either resistant (T protein) or sensitive (M protein) to proteolytic enzymes may offer a new dimension to the modulation of these antigens under specific biological conditions.


Bayesian regression analysis of data with random effects covariates from nonlinear longitudinal measurements.
Joint models for a wide class of response variables and longitudinal measurements consist on a mixed-effects model to fit longitudinal trajectories whose random effects enter as covariates in a generalized linear model for the primary response. They provide a useful way to assess association between these two kinds of data, which in clinical studies are often collected jointly on a series of individuals and may help understanding, for instance, the mechanisms of recovery of a certain disease or the efficacy of a given therapy. When a nonlinear mixed-effects model is used to fit the longitudinal trajectories, the existing estimation strategies based on likelihood approximations have been shown to exhibit some computational efficiency problems (De la Cruz et al., 2011). In this article we consider a Bayesian estimation procedure for the joint model with a nonlinear mixed-effects model for the longitudinal data and a generalized linear model for the primary response. The proposed prior structure allows for the implementation of an MCMC sampler. Moreover, we consider that the errors in the longitudinal model may be correlated. We apply our method to the analysis of hormone levels measured at the early stages of pregnancy that can be used to predict normal versus abnormal pregnancy outcomes. We also conduct a simulation study to assess the importance of modelling correlated errors and quantify the consequences of model misspecification.


Reduced level of DNA cross-links and sister chromatid exchanges in 1,3-bis(2-chloroethyl)-1-nitrosourea-resistant rat brain tumor cells.
We found that 9L-2 cells, a cell line derived from the in vivo 9L rat brain tumor model, are approximately 8-fold more resistant to the cytotoxic effect of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) than are sensitive 9L cells. Treatment with BCNU induces sister chromatid exchanges in both lines, but to produce similar levels of exchanges, 9L-2 cells must be treated with a 14-fold higher concentration of BCNU. The extent of DNA methylation was the same in both cell lines after a 1-hr treatment with 100 microM methylnitrosourea. While the levels of the alkylation products N-7-methylguanine and N-3-methyladenine were similar in both lines, the level of O6-methylguanine was 20% lower in 9L-2 than in 9L cells, which implies that 9L-2 cells repair O6-alkylguanine derivatives more efficiently than do 9L cells. The number of DNA interstrand cross-links formed in 9L-2 cells after treatment with BCNU was approximately 50% of the number formed in 9L cells. These results suggest that the repair of O6-alkylguanine derivatives formed in BCNU-treated 9L-2 cells may be related to the reduced number of DNA interstrand cross-links formed and may have a role in the mechanism of cellular resistance of 9L-2 cells to BCNU. However, our results indicate that, in itself, the reduction in the number of DNA cross-links may not be sufficient to account entirely for the cellular resistance of 9L-2 cells to BCNU and suggest that additional mechanisms may be involved in cellular resistance of 9L-2 cells to BCNU treatment.


Delayed-Onset Psychosis Secondary to Tacrolimus Neurotoxicity After Lung Transplant: A Case Report and Systematic Review.
Tacrolimus is the most common immunosuppressant used after transplant, yet it can result in moderate-to-severe neurotoxicity in up to 32% of patients. Signs of neurotoxicity can vary from mild (tremor or headache) to severe (posterior reversible encephalopathy syndrome or psychosis. Prompt recognition and management is needed to lead to symptom resolution. The objective of this study is to describe the clinical presentation of tacrolimus-induced psychosis, a type of tacrolimus-inducted neurotoxicity, and distinguish it from other central nervous system disturbances, including delirium. We present a case of delayed onset tacrolimus-induced psychosis with focus on unique clinical features and management strategies. We conducted a systematic review of cases of tacrolimus-induced psychosis using the PubMed database and included 15 manuscripts in our review. Tacrolimus-induced psychosis is a unique presentation of tacrolimus-related neurotoxicity and can present without the cardinal symptoms of delirium. The data on isolated psychotic symptoms are limited with current literature focusing on more common presentations of tacrolimus-induced neurotoxicity, such as delirium and tremor. Development of psychosis can occur later in the treatment course and at normal tacrolimus serum levels. It can improve with antipsychotic therapies, but primary management should include cross-titration to an alternate immunosuppressant regimen.


Development of a Pathway for Multidisciplinary Neurodevelopmental Assessment and Diagnosis in Children and Young People.
There is a variable standard of access to quality neurodevelopmental assessment and diagnosis. People may have negative experiences, encountering lengthy waiting times, and inconsistent practices. Practitioners need guidance on standards and practices for assessment and diagnosis matched to new ways of working. In this paper, we present a new pathway and recommendations for multidisciplinary neurodevelopmental assessment and diagnosis for children and young people (<19 years), developed by the Scottish Government funded National Autism Implementation Team (NAIT). Our research used the Medical Research Council guidance for the development of complex interventions and included several iterative stages. Stage 1: n = 44 stakeholders attended an event on developing new practices for diagnosis and assessment. Stage 2: a literature synthesis was completed by the research team of clinical guidelines and diagnosis and assessment tools. Stage 3: an event with n = 127 stakeholders included discussion and debate of the data from stages 1 and 2. Recommendations and a draft pathway were written. Stage 4: successive drafts of recommendations and the pathway documentation were circulated among an advisory group, including multidisciplinary clinical experts and people with lived experience, until the final pathway was agreed upon. The finalised pathway includes guidance on terminology, assessment, diagnosis, triage, time standards and engagement of people with lived experience. The new pathway has been adopted by the Scottish Government. The pathway and associated documentation are freely available online for use by others.


A method for description and classification of patients with urolithiasis.
A method for description and classification of patients with renal stone disease is presented. The system which has been used in the clinical routine during several years, summarizes information on the current stone situation, previous surgical procedures, the presence of anatomical abnormalities and the result of stone analysis. This system of classification provides a basis for surgical and medical decisions.


Impacts of regulatory processes on the experiences of carers of people in LGBTQ communities living with mental illness or experiencing a mental health crisis.
This article presents the findings of exploratory research on the mental health and community services experiences of informal/family carers of people from LGBTQ communities living with mental illness, or experiencing a mental health crisis. The aim of the research is to explore the experiences of carers in relation to provisions for carers and people from LGBTIQ communities in the mental health legislation, policy and practice standards in the state of Victoria in Australia. Data were collected from online surveys and in-depth interviews and analysed according to the alignment of the stated intent of these documents and the actual experiences of carers.


Recessive lethal mutations in Anopheles albimanus.
Six recessive lethal mutants of Anopheles albimanus are described. Homozygotes for three of the autosomal mutants, viz., bar eye, dot eye and hairy, die during the last larval or early pupal stages; complete linkage data are lacking for bar eye and hairy but dot eye is tightly linked to red eye on the right arm of chromosome 2. Larval and pupal mortality is high for homozygotes of the other two autosomal mutants, diseased larva and lunate. Survival to the adult stage of the lunate type is about 60% for both sexes, and for diseased larva the rates differed according to sex, 15% for males and 3% for females. A general lack of vitality of the surviving adults has prevented the establishment of homozygous stocks. From analyses of linkage data, diseased larva and lunate were assigned to chromosome 2, most probably on the left arm. The mutant, bubble head, is on the X chromosome, and therefore is expressed only in the hemizygous male, which usually dies during the early pupal stage.


Identification of serum proteins as prognostic and predictive markers of colorectal cancer using surface enhanced laser desorption ionization-time of flight mass spectrometry.
Colorectal cancer (CRC) is the second most common cause of cancer related death. Prognosis is highly dependent on stage at diagnosis making early detection mandatory. This study aimed to identify novel disease specific biomarkers of CRC, validate our previously identified biomarkers of CRC and identify serum biomarkers predicting treatment response and for monitoring. Serum of patients with metastatic CRC was collected, according to a predefined schedule, prior to start of standard first-line chemotherapy with oxaliplatin and capecitabine and serially before each 3 weekly treatment cycle and analyzed for proteomic profile by standardized SELDI-TOF MS. Serum proteomic mass spectrometry data of all subjects were processed using the tbimass R-package and proteomic profiles of CRC patients were compared with those of matched normal control subjects. Furthermore, changes in proteomic profiles during the course of chemotherapy were recorded according to treatment response. In total, 42 patients with advanced CRC were treated and mean follow-up was 13.5 months. The response rate was 50% and the median overall survival 19.5 months (95% CI: 16-23). By comparing CRC patients and healthy controls we identified 13 potential biomarkers of CRC (m/z 2.0-31.9 kDa) whereas two proteins, m/z 14060 and 28100 Da (apolipoprotein A-I), were highly significant (p<0.0001). Comparison of responding and non-responding patients identified 6 proteins potentially predicting response, where of m/z 3330 Da was significant (p=0.007). Serial analysis identified 2 proteins, m/z 2022 and 28100 Da, that changed during chemotherapy in accordance with response. We identified 13 m/z values discriminating between CRC patients and healthy controls, including the previously identified apolipoprotein A-I as a candidate biomarker for CRC and treatment monitoring.


Protease-deficient mutants of Pseudomonas aeruginosa: pleiotropic changes in activity of other extracellular enzymes.
Mutants of Pseudomonas aeruginosa strain PAKS-I which are defective in the formation of extracellular protease activity have been characterized. The mutants produced between approximately 1 and 25% of the protease activity of the wild type and no strains completely lacking extracellular protease were found, even after repeated mutagen treatment. Most mutants also had changed activities of extracellular staphylolytic enzyme, lipase and lecithinase. Four of 13 mutants were unable to release alkaline phosphatase and staphylolytic enzyme into the medium in contrast to the wild type. Serotype, phage type and biochemical reactions were essentially unchanged. The results indicate that some of the mutations affected the cell envelope structure of function leading to decreased ability to release extracellular proteins, and that other mutations possibly affected a common regulatory mechanism for extracellular enzymes.


Intergenerational transmission of chronic pain-related disability: the explanatory effects of depressive symptoms.
Parents with chronic pain have a higher likelihood of having depression and anxiety and more often have children with these conditions. Depressive and anxious symptoms in children worsen pain-related disability and may be derived from exposure to their parents' symptoms. We assessed a model of intergenerational chronic pain-related disability that relies upon depressive and anxious symptoms of a mother and their child. Adolescents in grades 5 to 10 from 5 schools, and their mothers, completed standardized electronic questionnaires about pain. In maternal-offspring dyads (n = 1179), the mean offspring age was 12.7 years (SD = 1.7, range = 10-17) and 51% were girls. Logistic regression was used to investigate mother-offspring associations of chronic pain presence, and mediation models using multiple linear regression were used to investigate the proposed model. Adolescents of mothers with chronic pain had 1.67 (95% confidence interval [CI] = 1.29-2.16) times increased odds of chronic pain, with each year of exposure to maternal chronic pain associated with a 5% (odds ratio 95% CI = 1.01-1.10) increased likelihood of offspring chronic pain. Worse maternal pain-related disability was associated with worse offspring pain-related disability (β = 0.20, 95% CI = 0.06-0.34). The mediation model indicated maternal and adolescent offspring symptoms of depression explained 36% of the relationship between maternal and offspring pain-related disability, with 11% explained by the intergenerational transmission of depression (serial mediation). We conclude that worse pain-related disability is associated between parent and child, and that depressive symptoms common to both mother and child play a key role in this relationship.


Nogo-a regulates neural precursor migration in the embryonic mouse cortex.
Although Nogo-A has been intensively studied for its inhibitory effect on axonal regeneration in the adult central nervous system, little is known about its function during brain development. In the embryonic mouse cortex, Nogo-A is expressed by radial precursor/glial cells and by tangentially migrating as well as postmigratory neurons. We studied radially migrating neuroblasts in wild-type and Nogo-A knockout (KO) mouse embryos. In vitro analysis showed that Nogo-A and its receptor components NgR, Lingo-1, TROY, and p75 are expressed in cells emigrating from embryonic forebrain-derived neurospheres. Live imaging revealed an increased cell motility when Nogo-A was knocked out or blocked with antibodies. Antibodies blocking NgR or Lingo-1 showed the same motility-enhancing effect supporting a direct role of surface Nogo-A on migration. Bromodeoxyuridine (BrdU) labeling of embryonic day (E)15.5 embryos demonstrated that Nogo-A influences the radial migration of neuronal precursors. At E17.5, the normal transient accumulation of radially migrating precursors within the subventricular zone was not detectable in the Nogo-A KO mouse cortex. At E19, migration to the upper cortical layers was disturbed. These findings suggest that Nogo-A and its receptor complex play a role in the interplay of adhesive and repulsive cell interactions in radial migration during cortical development.


Nuclear trafficking, histone cleavage and induction of apoptosis by the meningococcal App and MspA autotransporters.
Neisseria meningitidis, a major cause of bacterial meningitis and septicaemia, secretes multiple virulence factors, including the adhesion and penetration protein (App) and meningococcal serine protease A (MspA). Both are conserved, immunogenic, type Va autotransporters harbouring S6-family serine endopeptidase domains. Previous work suggested that both could mediate adherence to human cells, but their precise contribution to meningococcal pathogenesis was unclear. Here, we confirm that App and MspA are in vivo virulence factors since human CD46-expressing transgenic mice infected with meningococcal mutants lacking App, MspA or both had improved survival rates compared with mice infected with wild type. Confocal imaging showed that App and MspA were internalized by human cells and trafficked to the nucleus. Cross-linking and enzyme-linked immuno assay (ELISA) confirmed that mannose receptor (MR), transferrin receptor 1 (TfR1) and histones interact with MspA and App. Dendritic cell (DC) uptake could be blocked using mannan and transferrin, the specific physiological ligands for MR and TfR1, whereas in vitro clipping assays confirmed the ability of both proteins to proteolytically cleave the core histone H3. Finally, we show that App and MspA induce a dose-dependent increase in DC death via caspase-dependent apoptosis. Our data provide novel insights into the roles of App and MspA in meningococcal infection.


"A Question of Trust" and "a Leap of Faith"-Study Participants' Perspectives on Consent, Privacy, and Trust in Smart Home Research: Qualitative Study.
Ubiquitous, smart technology has the potential to assist humans in numerous ways, including with health and social care. COVID-19 has notably hastened the move to remotely delivering many health services. A variety of stakeholders are involved in the process of developing technology. Where stakeholders are research participants, this poses practical and ethical challenges, particularly if the research is conducted in people's homes. Researchers must observe prima facie ethical obligations linked to participants' interests in having their autonomy and privacy respected. This study aims to explore the ethical considerations around consent, privacy, anonymization, and data sharing with participants involved in SPHERE (Sensor Platform for Healthcare in a Residential Environment), a project for developing smart technology for monitoring health behaviors at home. Participants' unique insights from being part of this unusual experiment offer valuable perspectives on how to properly approach informed consent for similar smart home research in the future. Semistructured qualitative interviews were conducted with 7 households (16 individual participants) recruited from SPHERE. Purposive sampling was used to invite participants from a range of household types and ages. Interviews were conducted in participants' homes or on-site at the University of Bristol. Interviews were digitally recorded, transcribed verbatim, and analyzed using an inductive thematic approach. Four themes were identified-motivation for participating; transparency, understanding, and consent; privacy, anonymity, and data use; and trust in research. Motivations to participate in SPHERE stemmed from an altruistic desire to support research directed toward the public good. Participants were satisfied with the consent process despite reporting some difficulties-recalling and understanding the information received, the timing and amount of information provision, and sometimes finding the information to be abstract. Participants were satisfied that privacy was assured and judged that the goals of the research compensated for threats to privacy. Participants trusted SPHERE. The factors that were relevant to developing and maintaining this trust were the trustworthiness of the research team, the provision of necessary information, participants' control over their participation, and positive prior experiences of research involvement. This study offers valuable insights into the perspectives of participants in smart home research on important ethical considerations around consent and privacy. The findings may have practical implications for future research regarding the types of information researchers should convey, the extent to which anonymity can be assured, and the long-term duty of care owed to the participants who place trust in researchers not only on the basis of this information but also because of their institutional affiliation. This study highlights important ethical implications. Although autonomy matters, trust appears to matter the most. Therefore, researchers should be alert to the need to foster and maintain trust, particularly as failing to do so might have deleterious effects on future research.


Clinical study of epileptic children with history of febrile convulsion.
Clinically, some epileptic syndromes have been linked to febrile convulsions (FC), but the exact relationship between FC and later epilepsy remains a mystery. Detailed histories of 81 Chinese children among 1950 pediatric epileptics with a history of FC were obtained retrospectively. The clinical courses and risk factors were analyzed. According to their epileptic patterns, the children were divided into a generalized group (Group G, 45/81), a partial group (Group P, 30/81) and those with severe myoclonic epilepsy in infancy (6/81). Patients of Group P had an earlier age of onset of FC with a larger number of risk factors than those of Group G (p < 0.01), and patients of Group G had a shorter interval from the last FC to later epilepsy than those of Group P (p < 0.01). More risk factors of FC were present in children of Group P; these included especially focal seizures, prolonged duration and retarded psychomotor development (p < 0.01). For group of epileptics in this study, genetic factors might predispose for the expression of FC and later epilepsy, and anticonvulsant prophylaxis for FC seemed to be unnecessary.


A critical review of the protracted domestication model for Near-Eastern founder crops: linear regression, long-distance gene flow, archaeological, and archaeobotanical evidence.
The recent review by Fuller et al. (2012a) in this journal is part of a series of papers maintaining that plant domestication in the Near East was a slow process lasting circa 4000 years and occurring independently in different locations across the Fertile Crescent. Their protracted domestication scenario is based entirely on linear regression derived from the percentage of domesticated plant remains at specific archaeological sites and the age of these sites themselves. This paper discusses why estimates like haldanes and darwins cannot be applied to the seven founder crops in the Near East (einkorn and emmer wheat, barley, peas, chickpeas, lentils, and bitter vetch). All of these crops are self-fertilizing plants and for this reason they do not fulfil the requirements for performing calculations of this kind. In addition, the percentage of domesticates at any site may be the result of factors other than those that affect the selection for domesticates growing in the surrounding area. These factors are unlikely to have been similar across prehistoric sites of habitation, societies, and millennia. The conclusion here is that single crop analyses are necessary rather than general reviews drawing on regression analyses based on erroneous assumptions. The fact that all seven of these founder crops are self-fertilizers should be incorporated into a comprehensive domestication scenario for the Near East, as self-fertilization naturally isolates domesticates from their wild progenitors.


Hirudotherapy (medicinal leeches) for treatment of upper airway obstruction in a dog.
To describe upper airway obstruction (UAO) in a dog treated with medicinal leeches (hirudotherapy) as an ancillary therapy to hasten recovery. A 10-month-old neutered female Mastiff presented for acute respiratory distress. On admission, the dog was tachycardic, cyanotic, and orthopneic; stridor was audible. A 10-cm soft tissue swelling in the right ventral cervical region and bruising around the rostral mandible were noted. At the time of endotracheal intubation, the trachea was deviated to the right as a consequence of severe soft tissue swelling that was contiguous with the sublingual hematoma and cervical region, causing loss of visualization of the arytenoids. A computed tomography with contrast scan of the head, neck, and thorax was performed, showing severe soft tissue swelling of the tongue, obliteration of the common pharyngeal/laryngeal regions from suspected hemorrhage, and rightward displacement of pharynx, larynx, and proximal trachea. Marked diffuse bronchial/bronchiolar thickening associated with bronchiolectasis and diffuse opacification of the pulmonary parenchyma with regions of consolidation were noted. The dog was minimally hypercoagulable on thromboelastography. The imaging results together with results of bronchoalveolar lavage cytology supported a comorbidity of eosinophilic bronchopneumopathy. Intubation was maintained with infusions of propofol and fentanyl, with minimal changes in oropharyngeal swelling within the first 18 hours of treatment. Medicinal leeches were then applied to the sublingual and cervical regions. There was continued slow bleeding from the sites of leech detachment, and the dog was able to be extubated at 44 hours, followed by hospital discharge. Leeches are utilized in human medicine for treatment of UAO. Although UAO from hemorrhage has been described in dogs, this is the first report of medicinal leeches (Hirudo verbana) as complementary treatment for sublingual hematoma that contributed to UAO.


Electrophysiologic testing aids diagnosis and subtyping of myoclonus.
To determine the contribution of electrophysiologic testing in the diagnosis and anatomical classification of myoclonus. Participants with a clinical diagnosis of myoclonus were prospectively recruited, each undergoing a videotaped clinical examination and battery of electrophysiologic tests. The diagnosis of myoclonus and its subtype was reviewed after 6 months in the context of the electrophysiologic findings and specialist review of the videotaped clinical examination. Seventy-two patients with myoclonus were recruited. Initial clinical anatomical classification included 25 patients with cortical myoclonus, 7 with subcortical myoclonus, 2 with spinal myoclonus, and 15 with functional myoclonic jerks. In 23 cases, clinical anatomical classification was not possible because of the complexity of the movement disorder. Electrophysiologic testing was completed in 66, with agreement of myoclonus in 60 (91%) and its subtype in 28 (47%) cases. Subsequent clinical review by a movement disorder specialist agreed with the electrophysiologic findings in 52 of 60; in the remaining 8, electrophysiologic testing was inconclusive. Electrophysiologic testing is an important additional tool in the diagnosis and anatomical classification of myoclonus, also aiding in decision-making regarding therapeutic management. Further development of testing criteria is necessary to optimize its use in clinical practice.


Serious Choices: A Systematic Environmental Scan of Decision Aids and Their Use for Seriously Ill People Near Death.
Seriously ill people near death face difficult decisions about life-sustaining treatments such as cardiopulmonary resuscitation and mechanical ventilation. Patient decision aids may improve alignment between patients' preferences and the care they receive, but the quantity, quality, and routine use of these tools are unknown. We conducted a systematic environmental scan to identify all decision aids for seriously ill people at high risk of death facing choices about life-sustaining treatments, assess their quality, and explore their use in clinical settings. We searched MEDLINE, Google, and mobile application stores and surveyed experts. We included 27 decision aids in our scan. Concerning content, 14 of 27 decision aids for seriously ill people near death were for people with specific diseases and conditions (ie, advanced cancer or kidney disease); 11 concerned individual life-sustaining treatment decisions (ie, cardiopulmonary resuscitation or mechanical ventilation). Only two focused on more general care pathways (ie, life-sustaining intervention, palliative care, and hospice). Twenty-four of 27 decision aids presented options in a balanced way; 23 identified funding sources, and 19 of 27 reported their publication date. Just 11 used plain language. A minority, 11 of 27, listed evidence sources, five documented rigorous evidence-synthesis methods, six disclosed competing interests, and three offered update policies. Preliminary results suggest that few health systems use decision aids in routine patient care. Although many decision aids exist for life-sustaining treatment decisions during serious illness, the tools are deficient in some key quality areas.


Risk of secondary progressive multiple sclerosis after early worsening of disability.
Whether progression independent of relapse activity (PIRA) heralds earlier onset of secondary progressive multiple sclerosis (SPMS) and more rapid accumulation of disability during SPMS remains to be determined. We investigated the association between early PIRA, relapse-associated worsening (RAW) of disability and time to SPMS, subsequent disability progression and their response to therapy. This observational cohort study included patients with relapsing-remitting multiple sclerosis (RRMS) from the MSBase international registry across 146 centres and 39 countries. Associations between the number of PIRA and RAW during early multiple sclerosis (MS) (the initial 5 years of MS onset) were analysed with respect to: time to SPMS using Cox proportional hazards models adjusted for disease characteristics; and disability progression during SPMS, calculated as the change of Multiple Sclerosis Severity Scores over time, using multivariable linear regression. 10 692 patients met the inclusion criteria: 3125 (29%) were men and the mean MS onset age was 32.2 years. A higher number of early PIRA (HR=1.50, 95% CI 1.28 to 1.76, p<0.001) and RAW (HR=2.53, 95% CI 2.25 to 2.85, p<0.001) signalled a higher risk of SPMS. A higher proportion of early disease-modifying therapy exposure (per 10%) reduced the effect of early RAW (HR=0.94, 95% CI 0.89 to 1.00, p=0.041) but not PIRA (HR=0.97, 95% CI 0.91 to 1.05, p=0.49) on SPMS risk. No association between early PIRA/RAW and disability progression during SPMS was found. Early disability increase during RRMS is associated with a greater risk of SPMS but not the rate of disability progression during SPMS. The deterioration associated with early relapses represents a potentially treatable risk factor of SPMS. Australian New Zealand Clinical Trials Registry (ACTRN12605000455662).


Randomised controlled trial of atenolol and pindolol in human pregnancy: effects on fetal haemodynamics.
To compare the effects of uteroplacental circulation of two beta adrenoceptor blockers, atenolol (cardioselective) and pindolol (non-selective with intrinsic sympathomimetic activity). Controlled double blind double dummy study. Departments of obstetrics and gynaecology in two Swedish university hospitals. 29 women with pregnancy induced hypertension in the third trimester, 13 randomised to atenolol and 16 to pindolol. Pulsatility index in fetal aorta, umbilical artery, and maternal arcuate artery. Volumetric blood flow in fetal aorta and umbilical vein. Mean arterial blood pressure decreased by 9.0 (95% confidence interval -13.0 to -5.0) mm Hg in the atenolol group and by 7.8 (-11.4 to -4.2) mm Hg in the pindolol group. During atenolol treatment the pulsatility index increased significantly from 1.82 (SD 0.20) to 2.07 (0.32) in the fetal thoracic descending aorta, from 1.44 (0.28) to 1.79 (0.27) in the abdominal aorta, and from 0.93 (0.17) to 1.05 (0.19) in the umbilical artery; the volumetric blood flow in the umbilical vein decreased from 106 (28.8) to 84 (22.6) ml/min/kg. No such changes were seen after treatment with pindolol. Birth weight was similar in the two groups but placental weight was significantly different (529 (122) g in atenolol group v 653 (136) g in pindolol group; p = 0.03). The hypotensive effect was similar with both drugs, but only the beta 1 blocker atenolol had significant effects on fetal haemodynamics, although within normal ranges. The implications of these findings can be only speculative, but negative fetal consequences of beta 1 adrenoceptor blockade cannot be excluded.


[The treatment of posttraumatic hemothorax].
A high procoagulative activity of monocytes, a low procoagulative activity of pulmonary macrophages, and decreased proteolytic activity of leukocytes and monocytes are predominant in patients with coagulated hemothorax. The proteolytic activity of leukocytes of the pleural exudate was higher in these patients than in their blood leukocytes and lower than that of blood leukocytes from healthy donors. Differential correction of phagocytic functional activity in the pleural exudate in terms of the type of hemothorax, its stage, procoagulative and proteolytic activities of phagocytes improve the outcome of the disease.


Cis-element mutated in GATA2-dependent immunodeficiency governs hematopoiesis and vascular integrity.
Haploinsufficiency for GATA2 causes human immunodeficiency syndromes characterized by mycobacterial infection, myelodysplasia, lymphedema, or aplastic anemia that progress to myeloid leukemia. GATA2 encodes a master regulator of hematopoiesis that is also linked to endothelial biology. Though the disease-causing mutations commonly occur in the GATA-2 DNA binding domain, we identified a patient with mycobacterial infection and myelodysplasia who had an uncharacterized heterozygous deletion in a GATA2 cis-element consisting of an E-box and a GATA motif. Targeted deletion of the equivalent murine element to yield homozygous mutant mice revealed embryonic lethality later than occurred with global Gata2 knockout, hematopoietic stem/progenitor cell depletion, and impaired vascular integrity. Heterozygous mutant mice were viable, but embryos exhibited deficits in definitive, but not primitive, hematopoietic stem/progenitor activity and reduced expression of Gata2 and its target genes. Mechanistic analysis revealed disruption of the endothelial cell transcriptome and loss of vascular integrity. Thus, the composite element disrupted in a human immunodeficiency is essential for establishment of the murine hematopoietic stem/progenitor cell compartment in the fetal liver and for essential vascular processes.


A novel method of measuring the concentration of anaesthetic vapours using a dew-point hygrometer.
The Antoine equation relates the saturated vapour pressure of a volatile substance, such as an anaesthetic agent, to the temperature. The measurement of the 'dew-point' of a dry gas mixture containing a volatile anaesthetic agent by a dew-point hygrometer permits the determination of the partial pressure of the anaesthetic agent. The accuracy of this technique is limited only by the accuracy of the Antoine coefficients and of the temperature measurement. Comparing measurements by the dew-point method with measurements by refractometry showed systematic discrepancies up to 0.2% and random discrepancies with SDS up to 0.07% concentration in the 1% to 5% range for three volatile anaesthetics. The systematic discrepancies may be due to errors in available data for the vapour pressures and/or the refractive indices of the anaesthetics.


A new touchscreen test of pattern separation: effect of hippocampal lesions.
Researchers are becoming increasingly interested in the role of the hippocampus in pattern separation, a process which keeps items distinct in memory. In this study, we develop and test a new automated touchscreen-based method for studying pattern separation in rodents. Rats were trained to discriminate locations on a computer screen that varied in their similarity, that is, their distance apart on the screen. Animals with lesions of the dorsal hippocampus were impaired when the locations discriminated were close together but not when they were far apart, indicating impaired pattern separation. This test provides an automated test of pattern separation, which adds to an expanding battery of cognitive tests that can be carried out using the touchscreen testing method.


Research in the clinical radiology department.
Researchers often feel tangled in a web of bureaucracy when attempting to conduct their research. However, it is vital that researchers get involved and develop review processes such as those described above, which facilitate animal research yet address the important ethical, legal, and other related issues raised by hospital administrators and the public. As we do so, it is vital that we communicate directly with the public. Without this participation, we will find more and more hospital radiology departments closing their doors to animal-based research.


Influence of foot-stretcher height on rowing technique and performance.
Strength, technique, and coordination are crucial to rowing performance, but external interventions such as foot-stretcher set-up can fine-tune technique and optimise power output. For the same resultant force, raising the height of foot-stretchers on a rowing ergometer theoretically alters the orientation of the resultant force vector in favour of the horizontal component. This study modified foot-stretcher heights and examined their instantaneous effect on foot forces and rowing technique. Ten male participants rowed at four foot-stretcher heights on an ergometer that measured handle force, stroke length, and vertical and horizontal foot forces. Rowers were instrumented with motion sensors to measure ankle, knee, hip, and lumbar-pelvic kinematics. Key resultant effects of increased foot-stretcher heights included progressive reductions in horizontal foot force, stroke length, and pelvis range of motion. Raising foot-stretcher height did not increase the horizontal component of foot force as previously speculated. The reduced ability to anteriorly rotate the pelvis at the front of the stroke may be a key obstacle in gaining benefits from raised foot-stretcher heights. This study shows that small changes in athlete set-up can influence ergometer rowing technique, and rowers must individually fine-tune their foot-stretcher height to optimise power transfer through the rowing stroke on an ergometer.


Localized delivery of curcumin into brain with polysorbate 80-modified cerasomes by ultrasound-targeted microbubble destruction for improved Parkinson's disease therapy.
Rationale: Treatment for Parkinson's disease (PD) is challenged by the presence of the blood-brain barrier (BBB) that significantly limits the effective drug concentration in a patient's brain for therapeutic response throughout various stages of PD. Curcumin holds the potential for α-synuclein clearance to treat PD; however, its applications are still limited due to its low bioavailability and poor permeability through the BBB in a free form. Methods: Herein, this paper fabricated curcumin-loaded polysorbate 80-modified cerasome (CPC) nanoparticles (NPs) with a mean diameter of ~110 nm for enhancing the localized curcumin delivery into the targeted brain nuclei via effective BBB opening in combination with ultrasound-targeted microbubble destruction (UTMD). Results: The liposomal nanohybrid cerasome exhibited superior stability towards PS 80 surfactant solubilization and longer circulation lifetime (t1/2 = 6.22 h), much longer than free curcumin (t1/2 = 0.76 h). The permeation was found to be 1.7-fold higher than that of CPC treatment only at 6 h after the systemic administration of CPC NPs. Notably, motor behaviors, dopamine (DA) level and tyrosine hydroxylase (TH) expression all returned to normal, thanks to α-synuclein (AS) removal mediated by efficient curcumin delivery to the striatum. Most importantly, the animal experiment demonstrated that the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice had notably improved behavior disorder and dopamine depletion during two-week post-observation after treatment with CPC NPs (15 mg curcumin/kg) coupled with UTMD. Conclusion: This novel CPC-UTMD formulation approach could be an effective, safe and amenable choice with higher therapeutic relevance and fewer unwanted complications than conventional chemotherapeutics delivery systems for PD treatment in the near future.


Disruption of Rxra gene in thymocytes and T lymphocytes modestly alters lymphocyte frequencies, proliferation, survival and T helper type 1/type 2 balance.
Retinoid X receptor (RXR) agonists, including the vitamin A metabolite 9-cis retinoic acid, decrease T-lymphocyte apoptosis and promote T helper type 2 (Th2) development ex vivo. To examine the in vivo role of RXR-alpha in T-lymphocyte development and function, we disrupted the Rxra gene in thymocytes and T lymphocytes using cyclization recombinase (Cre)-loxP-mediated excision of Rxra exon 4. Expression of Cre was targeted to these cells using the Lck promoter. Successful disruption of exon 4 was seen in thymus and T lymphocytes. Mice were healthy and the thymus, spleen and lymph nodes appeared normal. However, knockout mice had a lower percentage of double-positive (CD4(+) CD8(+)) and a higher percentage of double-negative thymocytes than wild-type mice. The percentage of splenic B lymphocytes was lower in unimmunized and ovalbumin-immunized knockout mice and the percentage of T lymphocytes was lower in immunized knockout mice. Ex vivo proliferation was decreased and apoptosis was increased in T lymphocytes from knockout mice. Memory CD4(+) T lymphocytes from knockout mice produced more interferon-gamma and interleukin-2 (IL-2) and less IL-5 and IL-10 than memory cells from wild-type mice, indicating a Th1 bias in vivo. However, Rxra disruption did not similarly bias ex vivo differentiation of naive CD4(+) T lymphocytes, nor did Rxra disruption alter the serum immunoglobulin G1/immunoglobulin G2a response to immunization. In summary, disruption of Rxra altered the percentages of T and B lymphocytes, produced a Th1 bias in vivo, and altered T-lymphocyte proliferation and apoptosis ex vivo. These differences were modest in magnitude and their impact on disease resistance is yet to be examined.


Uveal melanoma: From diagnosis to treatment and the science in between.
Melanomas of the choroid, ciliary body, and iris of the eye are collectively known as uveal melanomas. These cancers represent 5% of all melanoma diagnoses in the United States, and their age-adjusted risk is 5 per 1 million population. These less frequent melanomas are dissimilar to their more common cutaneous melanoma relative, with differing risk factors, primary treatment, anatomic spread, molecular changes, and responses to systemic therapy. Once uveal melanoma becomes metastatic, therapy options are limited and are often extrapolated from cutaneous melanoma therapies despite the routine exclusion of patients with uveal melanoma from clinical trials. Clinical trials directed at uveal melanoma have been completed or are in progress, and data from these well designed investigations will help guide future directions in this orphan disease. Cancer 2016;122:2299-2312. © 2016 American Cancer Society.


An Autonomous Microfluidic Device for Generating Volume-Defined Dried Plasma Spots.
Obtaining plasma from a blood sample and preparing it for subsequent analysis is currently a laborious process involving experienced health-care professionals and centrifugation. We circumvent this by utilizing capillary forces and microfluidic engineering to develop an autonomous plasma sampling device that filters and stores an exact amount of plasma as a dried plasma spot (DPS) from a whole blood sample in less than 6 min. We tested 24 prototype devices with whole blood from 10 volunteers, various input volumes (40-80 μL), and different hematocrit levels (39-45%). The resulting mean plasma volume, assessed gravimetrically, was 11.6 μL with a relative standard deviation similar to manual pipetting (3.0% vs 1.4%). LC-MS/MS analysis of caffeine concentrations in the generated DPS (12 duplicates) showed a strong correlation ( R2 = 0.99) to, but no equivalence with, concentrations prepared from corresponding plasma obtained by centrifugation. The presented autonomous DPS device may enable patient-centric plasma sampling through minimally invasive finger-pricking and allow generatation of volume-defined DPS for quantitative blood analysis.


Appropriateness of Computed Tomography Scanning in the Diagnosis of Craniosynostosis.
Although physicians from a variety of specialties encounter infants with possible craniosynostosis, judicious use of computed tomography (CT) imaging is important to avoid unnecessary radiation exposure and healthcare expense. The present study seeks to determine whether differences in specialty of ordering physician affects frequency of resulting diagnostic confirmations requiring operative intervention. Radiology databases from 2 institutions were queried for CT reports or indications that included "craniosynostosis" or "plagiocephaly." Patient demographics, specialty of ordering physician, confirmed diagnosis, and operative interventions were recorded. Cost analysis was performed using the fixed unit cost for a head CT to calculate the expense before 1 study led to operative intervention. Three hundred eighty-two patients were included. 184 (48.2%) CT scans were ordered by craniofacial surgeons, 71 (18.6%) were ordered by neurosurgeons, and 127 (33.3%) were ordered by pediatricians. One hundred four (27.2%) patients received a diagnosis of craniosynostosis requiring operative intervention. Craniofacial surgeons and neurosurgeons were more likely than pediatricians to order CT scans that resulted in a diagnosis of craniosynostosis requiring operative intervention (P < 0.001), with no difference between craniofacial surgeons and neurosurgeons (P = 1.0). The estimated cost of obtaining an impact CT scan when ordered by neurosurgeons or craniofacial surgeons as compared to pediatricians was $2369.69 versus $13,493.75. Clinicians who more frequently encounter craniosynostosis (craniofacial and neurosurgeons) had a higher likelihood of ordering CT images that resulted in a diagnosis of craniosynostosis requiring operative intervention. This study should prompt multi-disciplinary interventions aimed at improving evaluation of pretest probability before CT imaging.


Comparative study of treatment dose plans after the refinement of Leksell Gamma Knife single-beam dose profiles.
We investigated the amplification of discrepancy when using multiple shots of the same collimator size helmet, by comparing dose plans in the Leksell GammaPlan employing the default single-beam dose profiles and the Monte Carlo generated single-beam profiles. Four collimator helmets were studied. The results show that the largest amplification of discrepancy with multiple shots was found with the 8 mm collimator because of the largest discrepancy of its single-beam dose profile. The amplification of discrepancy is significant when tumor volumes increase but insignificant when the tumor volumes are in an elongated shape. Using close shot overlapping strategy (i.e., more shots close packed together) shows no observable increase in the amplification of discrepancy. For the best quality of Leksell Gamma Knife radiosurgery, it is suggested that the single-beam dose profiles should be refined, especially the 8 mm collimator, to prevent error amplification when using multiple collimator shots.


Management of atrial fibrillation-flutter: uptodate guideline paper on the current evidence.
The term 'flutter' and 'fibrillation' were first coined to differentiate the differences between fast, regular contractions in Atrial Flutter (AFLUT) with irregular, vermiform contractions of Atrial Fibrillation (AFIB). Management of these two diseases has been a challenge for physicians. Rate control (along with rhythm control) is the first line of management for symptomatic AFIB/AFLUT with Rapid Ventricular Rate (RVR). In some situations, atrial rhythms may not be well controlled by these anti-arrhythmic drugs, making cardioversion to sinus rhythm necessary. Anti-coagulation therapy in both the disease population is essential. Catheter ablation is an effective treatment option in certain patients that have AFIB/AFLUT refractory to medical management. Newer techniques like left atrial appendage (LAA) has been developed and is a highly attractive concept for the future in the management of AFIB/AFLUT. Newer novel drugs targeting specific ion channels are approaching the stages of clinical investigation. However, while advances in technologies have helped elucidate many aspects of these diseases, many mysteries still remain. This literature review serves as one of the guideline papers for current up-to-date management on both AFIB and AFLUT.


Construct conversions caused by simultaneous co-transfection: "GFP-walking".
Several GFP variants have been developedfor multicolor labeling in vivo. Here we report that simultaneous co-transfection of fluorescent protein chimeras can give false-positive results caused by the conversion of spectral properties. Under standard transfection conditions, approximately 8% of cells produce false-positive results, but, depending on the conditions, up to 26% of the cells permanently express altered fusion proteins. This compromises the interpretation of the results. The conversion is independent of transfection methods or cell types. Our results show that the effect is based on homologous recombination/repair/replication process events that occur between the nucleotide sequences of the fluorescent proteins. Consecutive transfection or low sequence similarities avoided recombination. The appearance of conversion facilitates exchanges of spectral properties infusion proteins, the creation of libraries, or the assembly of DNA fusion constructs in vivo. The detailed quantification of the conversion rate allows the investigation of recombination/repair/replication processes in general.


Grounding the Work of Grassroots MCH Leaders in Storytelling.
Our Grassroots Maternal and Child Health (MCH) Initiative works to build the capacity of individuals and organizations in zip codes with persistently high infant mortality rates to bring about systems change that will improve maternal and child health (MCH) outcomes. Foundational to the Initiative is the training and mentoring of local women to become Grassroots MCH Leaders. We greatly honor that these women possess community expertise, essential to the Initiative's success. Our training equips them with strategies they can use to bring about changes in social, economic, political, and/or cultural systems that underlie poor birth outcomes. One impactful strategy they learn is the use of critical narrative intervention (CNI). This approach, grounded in the crafting and sharing of stories, complements statistical, behavioral, and medical approaches to improve MCH outcomes. This article describes the impact of CNI within the Grassroots MCH Initiative. Drawing from 14 Grassroots MCH Leaders' narratives, we present five significant maternal traumas and influential supports in their surrounding contexts. We explore the leaders' reflections on the impact of story development and dissemination. Our findings reveal that situating CNI within the context of a grassroots initiative provides opportunities for leaders to use their stories to advocate for systems change. Personal MCH narratives provide a powerful and respectful approach to public health promotion, as they highlight important systems-level failures that need to be addressed to sustainability improve MCH outcomes.


Lack of correlation between the promastigote back-transformation assay and miltefosine treatment outcome.
Widespread antimony resistance in the Indian subcontinent has enforced a therapy shift in visceral leishmaniasis treatment primarily towards miltefosine and secondarily also towards paromomycin. In vitro selection of miltefosine resistance in Leishmania donovani turned out to be quite challenging. Although no increase in IC50 was detected in the standard intracellular amastigote susceptibility assay, promastigote back-transformation remained positive at high miltefosine concentrations, suggesting a more 'resistant' phenotype. This observation was explored in a large set of Nepalese clinical isolates from miltefosine cure and relapse patients to assess its predictive value for patient treatment outcome. The predictive value of the promastigote back-transformation for treatment outcome of a set of Nepalese L. donovani field isolates (n = 17) derived from miltefosine cure and relapse patients was compared with the standard susceptibility assays on promastigotes and intracellular amastigotes. In-depth phenotypic analysis of the clinical isolates revealed no correlation between the different susceptibility assays, nor any clear link to the actual treatment outcome. In addition, the clinical isolates proved to be phenotypically heterogeneous, as reflected by the large variation in drug susceptibility among the established clones. This in vitro laboratory study shows that miltefosine treatment outcome is not necessarily exclusively linked with the susceptibility profile of pre-treatment isolates, as determined in standard susceptibility assays. The true nature of miltefosine treatment failures still remains ill defined.


INFLUENCE OF OVERWEIGHT AND OBESITY IN CHILDREN ON ANESTHESIOLOGICAL COMPLICATIONS APPEARANCE DURING ADENOIDECTOMY AND ADENOTONSILLECTOMY.
Obesity in children is becoming from year to year enormous medical and socio-epidemilogical problem according to increasing number of overweight and obese children. Overweight and obesity in children mostly affects on cardiovascular, respiratory and endocrine system disturbances. Adenoidectomy and adenotonsillectomy belong to group of most often done operation in children population. Anesthesiology complications during adenodecotomy and adenotonsillectomy in children are known as very disturbing and dramatic. Retrospective-prospective study includes 162 children, both genders, 3 to 12 years old, who are hospitalized and operated (adenoidectomies and adenotonsillectomies) on Otorihinolaryngolic clinic of University clinical centre Tuzla in the four year period. Purpose of the study is to show the influence of overweight in children on appearance of anesthesiology complications such as difficult intubation, bronchospasm and laryngospasm. Body mass index (BMI), which is used as universal measure, is adapted with gender specific scales of National statistic centre of United States of America. All children with BMI over 25 are referred as overweight and those over 30 as obese. These children categories were compared to those with normal BMI according to anesthesiology complications incidence. Overweight in operated children is noticed in 21%, and 11% of children was obese and there wasn't distinction between boys and girls. Anesthesiology complications are evaluated in 12 of them (7.4%). Total analyzed sample show significant connection and influence of overweight with appearance of anesthesiology complications. Separate comparison for two types of operations is indicating that during adenoidectomies there hasn't been noticed connection between overweight and anestehesiological complications, while in case of adenotonsillectomies direct and significant correlation is proven. According to increased risk of anesthesiology complications in overweight and obese children during adenodectomies and adenotonsillectomies it is important for anesthesiologists to do much serious preoperative evaluation of obese children, and to be more prepared for every of possible unwished supersize during perioperative period.


Host-parasite and genotype-by-environment interactions: temperature modifies potential for selection by a sterilizing pathogen.
Parasite-mediated selection is potentially of great importance in modulating genetic diversity. Genetic variation for resistance, the fuel for natural selection, appears to be common in host-parasite interactions, but responses to selection are rarely observed. In the present study, we tested whether environmental variation could mediate infection and determine evolutionary outcomes. Temperature was shown to dramatically alter the potential for parasite-mediated selection in two independent laboratory infection experiments at four temperatures. The bacterial parasite, Pasteuria ramosa, was extremely virulent at 20 degrees C and 25 degrees C, sterilizing its host, Daphnia magna, so that females often never produced a single brood. However, at 10 degrees C and 15 degrees C, the host-parasite interaction was much more benign, as nearly all females produced broods before becoming sterile. This association between virulence and temperature alone could stabilize coexistence and lead to the maintenance of diversity, because it would weaken parasite-mediated selection during parts of the season. Additionally, highly significant genotype-by-environment interactions were found, with changes in clone rank order for infection rates at different temperatures. Our results clearly show that the outcome of parasite-mediated selection in this system is strongly context dependent.


The abiotic and biotic drivers of rapid diversification in Andean bellflowers (Campanulaceae).
The tropical Andes of South America, the world's richest biodiversity hotspot, are home to many rapid radiations. While geological, climatic, and ecological processes collectively explain such radiations, their relative contributions are seldom examined within a single clade. We explore the contribution of these factors by applying a series of diversification models that incorporate mountain building, climate change, and trait evolution to the first dated phylogeny of Andean bellflowers (Campanulaceae: Lobelioideae). Our framework is novel for its direct incorporation of geological data on Andean uplift into a macroevolutionary model. We show that speciation and extinction are differentially influenced by abiotic factors: speciation rates rose concurrently with Andean elevation, while extinction rates decreased during global cooling. Pollination syndrome and fruit type, both biotic traits known to facilitate mutualisms, played an additional role in driving diversification. These abiotic and biotic factors resulted in one of the fastest radiations reported to date: the centropogonids, whose 550 species arose in the last 5 million yr. Our study represents a significant advance in our understanding of plant evolution in Andean cloud forests. It further highlights the power of combining phylogenetic and Earth science models to explore the interplay of geology, climate, and ecology in generating the world's biodiversity.


Tempo of Degeneration Across Independently Evolved Nonrecombining Regions.
Recombination is beneficial over the long term, allowing more effective selection. Despite long-term advantages of recombination, local recombination suppression can evolve and lead to genomic degeneration, in particular on sex chromosomes. Here, we investigated the tempo of degeneration in nonrecombining regions, that is, the function curve for the accumulation of deleterious mutations over time, leveraging on 22 independent events of recombination suppression identified on mating-type chromosomes of anther-smut fungi, including newly identified ones. Using previously available and newly generated high-quality genome assemblies of alternative mating types of 13 Microbotryum species, we estimated degeneration levels in terms of accumulation of nonoptimal codons and nonsynonymous substitutions in nonrecombining regions. We found a reduced frequency of optimal codons in the nonrecombining regions compared with autosomes, that was not due to less frequent GC-biased gene conversion or lower ancestral expression levels compared with recombining regions. The frequency of optimal codons rapidly decreased following recombination suppression and reached an asymptote after ca. 3 Ma. The strength of purifying selection remained virtually constant at dN/dS = 0.55, that is, at an intermediate level between purifying selection and neutral evolution. Accordingly, nonsynonymous differences between mating-type chromosomes increased linearly with stratum age, at a rate of 0.015 per My. We thus develop a method for disentangling effects of reduced selection efficacy from GC-biased gene conversion in the evolution of codon usage and we quantify the tempo of degeneration in nonrecombining regions, which is important for our knowledge on genomic evolution and on the maintenance of regions without recombination.


Sparsely correlated hidden Markov models with application to genome-wide location studies.
Multiply correlated datasets have become increasingly common in genome-wide location analysis of regulatory proteins and epigenetic modifications. Their correlation can be directly incorporated into a statistical model to capture underlying biological interactions, but such modeling quickly becomes computationally intractable. We present sparsely correlated hidden Markov models (scHMM), a novel method for performing simultaneous hidden Markov model (HMM) inference for multiple genomic datasets. In scHMM, a single HMM is assumed for each series, but the transition probability in each series depends on not only its own hidden states but also the hidden states of other related series. For each series, scHMM uses penalized regression to select a subset of the other data series and estimate their effects on the odds of each transition in the given series. Following this, hidden states are inferred using a standard forward-backward algorithm, with the transition probabilities adjusted by the model at each position, which helps retain the order of computation close to fitting independent HMMs (iHMM). Hence, scHMM is a collection of inter-dependent non-homogeneous HMMs, capable of giving a close approximation to a fully multivariate HMM fit. A simulation study shows that scHMM achieves comparable sensitivity to the multivariate HMM fit at a much lower computational cost. The method was demonstrated in the joint analysis of 39 histone modifications, CTCF and RNA polymerase II in human CD4+ T cells. scHMM reported fewer high-confidence regions than iHMM in this dataset, but scHMM could recover previously characterized histone modifications in relevant genomic regions better than iHMM. In addition, the resulting combinatorial patterns from scHMM could be better mapped to the 51 states reported by the multivariate HMM method of Ernst and Kellis. The scHMM package can be freely downloaded from http://sourceforge.net/p/schmm/ and is recommended for use in a linux environment.


The changing role of school nurses--one state's experience.
The purpose of this study was to identify the scope of management responsibilities, health education, and early education for handicapped children, as well as clinical and program dimensions of the school nurse role. Changes in responsibilities over the last five years were explored in one state by utilizing a questionnaire aimed at providing a profile of the school nurse's perceived behavioral patterns. In every dimension of the school nurse role included in this study, the responsibilities of the school nurse had either increased or stayed the same on an overall basis.


Perinatal Depression Among HIV-Infected Women in KwaZulu-Natal South Africa: Prenatal Depression Predicts Lower Rates of Exclusive Breastfeeding.
Exclusive breastfeeding (EBF) provides infants with optimal nutrition, and together with appropriate antiretroviral therapy has also been shown to decrease mother-to-child transmission of HIV from 45 to less than 1 %. However, rates of EBF are particularly low in South Africa, where rates of HIV are some of the highest in the world. Although perinatal depression has been identified as a potential barrier to EBF, little is known about its impact on EBF among HIV-infected women. A cohort study was conducted as part of a pilot randomized controlled trial (RCT) examining the effect of an Information, Motivation and Behavioral skills-based intervention promoting EBF among South African women living with HIV in their third trimester (28-42 weeks) of pregnancy. At baseline and follow-up, participants were interviewed on depression symptoms (PHQ-9), and breastfeeding intentions and behavior. Multivariate logistic regressions were conducted to determine predictors of EBF at 6-weeks postpartum. A total of 68 women were enrolled and 58 women completed both baseline and follow-up assessments. Most (80.9 %) of the sample reported at least some symptoms of depression prenatally. Rates of depression were lower postpartum (47.1 %). In multivariate models, higher prenatal depression scores significantly predicted lower likelihood of EBF at 6-weeks postpartum after adjusting for demographics, condition, and intentions (AOR = 0.68, p < 0.05). Postpartum depression was not a significant predictor of EBF rates (AOR = 0.99, p = 0.96). These findings demonstrate the negative impact of prenatal depression on breastfeeding behavior. Future interventions focused on depression are warranted to identify those at risk for sub-optimal EBF. Improving maternal psychosocial well-being could be a new frontier to improving infant and young child feeding and reducing pre/postnatal transmission.


A restrained locally enhanced sampling method (RLES) for finding free energy minima in complex systems.
We present an extension of the locally enhanced sampling method. A restraint potential is introduced to drive the many-replica system to the canonical ensemble corresponding to the physical, single-replica system. Convergence properties are demonstrated using a model rugged two-dimensional potential, for which sampling by conventional equilibrium molecular dynamics is inefficient. Restrained locally enhanced sampling (RLES) is found to explore the space of configurations with an efficiency comparable to that of temperature replica exchange. To demonstrate the potential of RLES for realistic applications, the method is used to fold the 12-residue tryptophan zipper miniprotein in explicit solvent. The RLES algorithm can be incorporated into existing LES implementations with minor code modifications.


Heteromorpha trifoliata (Dombwe) accelerates acetic acid-induced peptic ulcers: a preliminary study in the rat.
To investigate the effect of H. trifoliata on: (a) acetic acid-induced ulcers, (b) food intake, (c) water intake, (d) weight gain, (e) gastric acid secretion in rats. Comparative study. Laboratory. 20 female Sprague Dawley rats (220 to 250 g) with acetic acid-induced peptic ulcers randomly assigned to test and control groups (n = 10). The test rats were allowed water and normal rat diet comprising 20% H. trifoliata ('Dombwe) and 'Imfe nkulu' in Shona and Ndebele respectively) for 17 days after ulceration while control rats were allowed water and normal rat diet for 17 days after ulceration. Thirty six other rats were prepared to study the effect of H. trifoliata on gastric and acid secretion stimulated by histamine, gastrin and carbachol. Photographs of the gross anatomy and histology of test and control rat stomachs were taken. Daily food and water intake, weekly weight gain and gastric acid secretion were measured in the test and control rats. 17 days following the consumption of the H. trifoliata containing diet, macroscopically, no ulcers were found on the outer surface of the stomach walls of test rats. However, histological examination revealed traces of ulcer at the sites where ulcers were induced previously. In contrast, 70% of the control rats still had ulcers on the surface of their stomach walls. Histological examination showed massive denuded mucosa and submucosa at the ulcer sites which are signs of severe ulceration. Food intake in both groups was not significantly different except during the first three days when test rats consumed significantly less food (p < 0.01) than control rats. Daily water intake and weekly weight gain were also not significantly different in the test and control groups. H. trifoliata had no significant effect on gastric acid secretion stimulated by histamine, gastrin and carbachol. H. trifoliata does not affect daily food and water intake and weekly weight gain in rats. It also does not affect histamine, gastrin and carbachol-stimulated acid secretion in rats. However, H. trifoliata accelerates the healing of acetic acid-induced peptic ulcer in rats. This may validate the use of H. trifoliata in the treatment of peptic ulcer in humans.


Climate-Driven Variability and Trends in Plant Productivity Over Recent Decades Based on Three Global Products.
Variability in climate exerts a strong influence on vegetation productivity (gross primary productivity; GPP), and therefore has a large impact on the land carbon sink. However, no direct observations of global GPP exist, and estimates rely on models that are constrained by observations at various spatial and temporal scales. Here, we assess the consistency in GPP from global products which extend for more than three decades; two observation-based approaches, the upscaling of FLUXNET site observations (FLUXCOM) and a remote sensing derived light use efficiency model (RS-LUE), and from a suite of terrestrial biosphere models (TRENDYv6). At local scales, we find high correlations in annual GPP among the products, with exceptions in tropical and high northern latitudes. On longer time scales, the products agree on the direction of trends over 58% of the land, with large increases across northern latitudes driven by warming trends. Further, tropical regions exhibit the largest interannual variability in GPP, with both rainforests and savannas contributing substantially. Variability in savanna GPP is likely predominantly driven by water availability, although temperature could play a role via soil moisture-atmosphere feedbacks. There is, however, no consensus on the magnitude and driver of variability of tropical forests, which suggest uncertainties in process representations and underlying observations remain. These results emphasize the need for more direct long-term observations of GPP along with an extension of in situ networks in underrepresented regions (e.g., tropical forests). Such capabilities would support efforts to better validate relevant processes in models, to more accurately estimate GPP.


Amine oxidases and monooxygenases in the in vivo metabolism of xenobiotic amines in humans: has the involvement of amine oxidases been neglected?
In this review, the major enzyme systems involved in vivo in the oxidative metabolism of xenobiotic amines in humans are discussed, i.e. the monooxygenases [cytochrome P450 system (CYPs) and flavin-containing monooxygenases (FMOs)] and the amine oxidases (AOs). Concerning the metabolism of xenobiotic amines (drugs in particular) by monoamine oxidases (MAOs), this aspect has been largely neglected in the past. An exception is the extensive investigation carried out on the inhibition of the metabolism of tyramine, when tyramine-containing food is ingested by subjects taking inhibitors of MAO A or of both MAO A and B. Moreover, investigations in humans on the metabolism of drug amines on the market by AOs, such as semicarbazide-sensitive amine oxidases (SSAOs) and polyamine oxidases (PAOs), are practically nonexistent, with the exception of amlodipine. In contrast to MAOs, monooxygenases (CYP isoenzymes more than FMOs) have been extensively investigated concerning their involvement in the metabolism of xenobiotics. It is possible that the contribution of AOs to the overall metabolism of xenobiotic amines in humans is underestimated or erroneously estimated, as most investigations of drug metabolism are performed using in vitro test systems optimized for CYP activity, such as liver microsomes, and most investigations of drug metabolism in vivo in humans carry out only the identification of the final, stable metabolites. However, for some drugs on the market, the involvement of MAOs in their in vivo metabolism in humans has been demonstrated recently, among these drugs citalopram, sertraline and the triptans are examples that can be mentioned.


Ischemic preconditioning for prevention of contrast medium-induced nephropathy: randomized pilot RenPro Trial (Renal Protection Trial).
Contrast medium-induced acute kidney injury is associated with substantial morbidity and mortality. The underlying mechanism has been attributed in part to ischemic kidney injury. The aim of this randomized, double-blind, sham-controlled trial was to assess the impact of remote ischemic preconditioning on contrast medium-induced acute kidney injury. Patients with impaired renal function (serum creatinine >1.4 mg/dL or estimated glomerular filtration rate <60 mL · min(-1) · 1.73 m(-2)) undergoing elective coronary angiography were randomized in a 1:1 ratio to standard care with (n=50) or without ischemic preconditioning (n=50; intermittent arm ischemia through 4 cycles of 5-minute inflation and 5-minute deflation of a blood pressure cuff). Overall, both study groups were at high risk of developing contrast medium-induced acute kidney injury according to the Mehran risk score. The primary end point was the incidence of contrast medium-induced kidney injury, defined as an increase in serum creatinine ≥25% or ≥0.5 mg/dL above baseline at 48 hours after contrast medium exposure. Contrast medium-induced acute kidney injury occurred in 26 patients (26%), 20 (40%) in the control group and 6 (12%) in the remote ischemic preconditioning group (odds ratio, 0.21; 95% confidence interval, 0.07-0.57; P=0.002). No major adverse events were related to remote ischemic preconditioning. Remote ischemic preconditioning before contrast medium use prevents contrast medium-induced acute kidney injury in high-risk patients. Our findings merit a larger trial to establish the effect of remote ischemic preconditioning on clinical outcomes. URL: http://www.germanctr.de. Unique identifier: U1111-1118-8098.


[Flowmetry in the evaluation of hemodynamics of the lower limbs in chronic ischemia].
Regional hemodynamics in the lower limbs was studied in 250 patients (480 lower limbs) with obliterative lesions of the abdominal aorta and lower limb arteries. Six levels of blood circulation were examined: the iliac segment, the femoral segment, the popliteal and tibial segments, the circulatory channels of the foot and toes. The suggested complex method of ultrasonic measurement of the blood flow in the lower limbs makes it possible to evaluate the hemodynamic significance of the collaterals and the adverse effect of the pathologically changed arterial segment on the regional hemodynamics. The conducted noninvasive study of hemodynamics allows the initial stages of the lesion to be detected (which physical examination fails to do in some cases) and adequate tactics of stage-by-stage treatment by surgery to be elaborated. The outcome of the reconstructive operation can be prognosed by determining the patency of the arterial arch of the foot and the leg arteries.


Chemical composition, cytotoxicity and mutagenicity of smoke from US commercial and reference cigarettes smoked under two sets of machine smoking conditions.
Eight blended US market cigarettes, two blended reference cigarettes, one Bright tobacco only reference cigarette and an electrically heated prototype cigarette (EHC) were smoked under US Federal Trade Commission (FTC)/International Organisation for Standardisation (ISO) conditions and under Massachusetts Department of Public Health (MDPH) conditions. Smoke was analysed for chemical composition and in vitro toxicity. Yields (quantity/cigarette) of smoke constituents were higher under MDPH conditions compared to FTC/ISO conditions (market and reference average approximately 2.5 times; EHC approximately 1.6 times). Consistent with the higher yields, in vitro toxicity per cigarette was also higher under MDPH conditions. Concentrations (quantity/mg TPM) of nearly all smoke constituents measured decreased with increasing total particulate matter (TPM) yields as regression analyses indicated. Higher TPM yields also tended to be associated with slightly less cytotoxic and mutagenic activity per milligram TPM. Blended reference cigarettes tracked market cigarettes with similar TPM yield. The Bright cigarette displayed high cytotoxicity but low mutagenicity, while in vitro activity of the EHC was remarkably low. The TPM-dependent decreases for the market range of 5-20 mg TPM/cigarette were about 20%, irrespective of whether the increased yields were due to smoking conditions or cigarette construction. At the same TPM yield, the smoke constituent concentrations and in vitro toxicity were similar for low- and high-yield cigarettes.


The LAMMER Kinase, LkhA, Affects Aspergillus fumigatus Pathogenicity by Modulating Reproduction and Biosynthesis of Cell Wall PAMPs.
The LAMMER kinase in eukaryotes is a well-conserved dual-specificity kinase. Aspergillus species cause a wide spectrum of diseases called aspergillosis in humans, depending on the underlying immune status of the host, such as allergy, aspergilloma, and invasive aspergillosis. Aspergillus fumigatus is the most common opportunistic fungal pathogen that causes invasive aspergillosis. Although LAMMER kinase has various functions in morphology, development, and cell cycle regulation in yeast and filamentous fungi, its function in A. fumigatus is not known. We performed molecular studies on the function of the A. fumigatus LAMMER kinase, AfLkhA, and reported its involvement in multiple cellular processes, including development and virulence. Deletion of AflkhA resulted in defects in colonial growth, production of conidia, and sexual development. Transcription and genetic analyses indicated that AfLkhA modulates the expression of key developmental regulatory genes. The AflkhA-deletion strain showed increased production of gliotoxins and protease activity. When conidia were challenged with alveolar macrophages, enodocytosis of conidia by macrophages was increased in the AflkhA-deletion strain, resulting from changes in expression of the cell wall genes and thus content of cell wall pathogen-associated molecular patterns, including β-1,3-glucan and GM. While T cell-deficient zebrafish larvae were significantly susceptible to wild-type A. fumigatus infection, AflkhA-deletion conidia infection reduced host mortality. A. fumigatus AfLkhA is required for the establishment of virulence factors, including conidial production, mycotoxin synthesis, protease activity, and interaction with macrophages, which ultimately affect pathogenicity at the organismal level.


Replication study confirms link between TSPAN18 mutation and schizophrenia in Han Chinese.
Schizophrenia (SCZ) is a severe psychiatric disorder associated with many different risk factors, both genetic and environmental. A recent genome-wide association study (GWAS) of Han Chinese identified three single-nucleotide polymorphisms (SNPs rs11038167, rs11038172, and rs835784) in the tetraspanins gene TSPAN18 as possible susceptibility loci for schizophrenia. Hoping to validate these findings, we conducted a case-control study of Han Chinese with 1093 schizophrenia cases and 1022 healthy controls. Using the LDR-PCR method to genotype polymorphisms in TSPAN18, we found no significant differences (P>0.05) between patients and controls in either the allele or genotype frequency of the SNPs rs11038167 and rs11038172. We did find, however, that the frequency of the 'A' allele of SNP rs835784 is significantly higher in patients than in controls. We further observed a significant association (OR= 1.197, 95%CI= 1.047-1.369) between risk for SCZ and this 'A' allele. These results confirm the significant association, in Han Chinese populations, of increased SCZ risk and the variant of the TSPAN18 gene containing the 'A' allele of SNP rs835784.


[Hepatitis B virus genotype E infection in Turkey: the detection of the first case].
Hepatitis B virus (HBV) infection is a global major health problem. Currently, 10 genotypes (A-J) of hepatitis B virus (HBV) are identified based on the nucleic acid sequence heterogeneity, and these genotypes have been shown to have distinct geographic distribution. Reports of the previous studies indicated that the genotype D is the predominant type among hepatitis B patients in different regions of Turkey. However, recent studies indicated that other HBV genotypes are also seen with an increasing rate. Although epidemiological and clinical information on genotype E infection is currently limited, it is known that genotype E infection is common in West and Central Africa. In this report, the first case of HBV genotype E infection in Turkey was presented. A 22-year-old Nigerian male employee who resided in Manisa for five years was admitted to Celal Bayar University Hospital Manisa, Turkey, for his routine check-up. Since HBsAg was found positive, other HBV markers were tested with a repeated serum sample. Laboratory findings were as follows; HBsAg (+), anti-HBs (-), HBeAg (-), anti-HBe (+), anti-HBc (+), anti-HCV (-), anti-HIV (-), ALT: 44 U/L and AST: 45 U/L. HBV-DNA level was detected as 700 IU/ml by real-time PCR (Artus HBV QS RGQ Qiagen, Germany). HBV-DNA isolated from the serum sample of the patient was amplified by PCR and polymerase gene segment of HBV was directly sequenced. UPGMA method was used for phylogenetic analysis and Inno-LIPA HBV genotyping method (Innogenetics, Belgium) was performed to determine multiple HBV genotype infection. On the basis of those methods the genotype of the virus was identified as genotype E. The partial sequences of the HBV polymerase gene were loaded to the international DNA data bank (GenBank) for contribution to the global HBV surveillance. This report emphasized that besides genotype D the other HBV genotypes could be found in Turkey. Since the patient was an inactive HBsAg carrier before his residence in Turkey, this case was regarded as an imported HBV genotype E case. In conclusion, detection of different HBV genotypes, their epidemiology and molecular characteristics are important for both national and global HBV surveillance and better clinical approach.