How to increase chlamydia testing in primary care: a qualitative exploration with young people and application of a meta-theoretical model.
The objective of this study was to explore young people's perspectives barriers to chlamydia testing in general practice and potential intervention functions and implementation strategies to overcome identified barriers, using a meta-theoretical framework (the Behaviour Change Wheel (BCW)). Twenty-eight semistructured individual interviews were conducted with 16-24 year olds from across the UK. Purposive and convenience sampling methods were used (eg, youth organisations, charities, online platforms and chain-referrals). An inductive thematic analysis was first conducted, followed by thematic categorisation using the BCW. Participants identified several barriers to testing: conducting self-sampling inaccurately (physical capability); lack of information and awareness (psychological capability); testing not seen as a priority and perceived low risk (reflective motivation); embarrassment, fear and guilt (automatic motivation); the UK primary care context and location of toilets (physical opportunity) and stigma (social opportunity). Potential intervention functions raised by participants included education (eg, increase awareness of chlamydia); persuasion (eg, use of imagery/data to alter beliefs); environmental restructuring (eg, alternative sampling methods) and modelling (eg, credible sources such as celebrities). Potential implementation strategies and policy categories discussed were communication and marketing (eg, social media); service provision (eg, introduction of a young person's health-check) and guidelines (eg, standard questions for healthcare providers). The BCW provided a useful framework for conceptually exploring the wide range of barriers to testing identified and possible intervention functions and policy categories to overcome said barriers. While greater education and awareness and expanded opportunities for testing were considered important, this alone will not bring about dramatic increases in testing. A societal and structural shift towards the normalisation of chlamydia testing is needed, alongside approaches which recognise the heterogeneity of this population. To ensure optimal and inclusive healthcare, researchers, clinicians and policy makers alike must consider patient diversity and the wider health issues affecting all young people.


Text-mining network analysis of the response to osmotic stimuli in the intervertebral disc.
Intervertebral disc cells experience a broad range of physical stimuli under physiologic conditions, including alterations in their osmotic environment. The purpose of this study was to construct a text-mining network of the genes induced during the response to osmotic stimuli in the intervertebral disc. We obtained a gene expression profile of human intervertebral disc cells from the National Center for Biotechnology Information, after culture under hyper- and hypo-osmotic conditions compared to iso-osmotic conditions, and we identified 65 differentially expressed genes of intervertebral disc cells. We constructed a text-mining network using Biblio-MetReS between the differentially expressed genes and other genes that were included in the same document as the differentially expressed genes. Then, we performed pathway-enrichment analysis to identify the most relevant pathways for the response to osmotic stimuli in intervertebral disc cells. Our data provide a comprehensive bioinformatics analysis of genes and pathways that may be involved in the response to osmotic stimuli in the intervertebral disc.


Coral larvae suppress heat stress response during the onset of symbiosis decreasing their odds of survival.
The endosymbiosis between most corals and their photosynthetic dinoflagellate partners begins early in the host life history, when corals are larvae or juvenile polyps. The capacity of coral larvae to buffer climate-induced stress while in the process of symbiont acquisition could come with physiological trade-offs that alter behaviour, development, settlement and survivorship. Here we examined the joint effects of thermal stress and symbiosis onset on colonization dynamics, survival, metamorphosis and host gene expression of Acropora digitifera larvae. We found that thermal stress decreased symbiont colonization of hosts by 50% and symbiont density by 98.5% over 2 weeks. Temperature and colonization also influenced larval survival and metamorphosis in an additive manner, where colonized larvae fared worse or prematurely metamorphosed more often than noncolonized larvae under thermal stress. Transcriptomic responses to colonization and thermal stress treatments were largely independent, while the interaction of these treatments revealed contrasting expression profiles of genes that function in the stress response, immunity, inflammation and cell cycle regulation. The combined treatment either cancelled or lowered the magnitude of expression of heat-stress responsive genes in the presence of symbionts, revealing a physiological cost to acquiring symbionts at the larval stage with elevated temperatures. In addition, host immune suppression, a hallmark of symbiosis onset under ambient temperature, turned to immune activation under heat stress. Thus, by integrating the physical environment and biotic pressures that mediate presettlement event in corals, our results suggest that colonization may hinder larval survival and recruitment under projected climate scenarios.


The Separation Power of Highly Porous 3D Nanofiber Sponges.
Sponges formed by the self-assembly of nanofiber building blocks are versatile materials used in various fields such as filtration, thermal insulation, scaffolding or sound absorption. Their potential seems to be constantly expanding given the variety of possible fiber materials, from bio-based to fossil polymers to inorganic nanofibers. In general, nanofiber sponges - also called nanofiber aerogels - are flexible, have low density, and a large specific surface area thanks to their tunable open-porous nanofiber based architecture. The latter property makes nanofiber sponges an interesting material for separation problems, as recently demonstrated for a variety of mixtures such as aerosols, emulsions, dispersions, solutions or two-phase systems. Due to their highly porous structure, they generally exhibit high filtration efficiency, flow rate and capacity. This article reviews the state of the art in the application of 3D nanofiber sponges for the different classes of mixtures. We will discuss on a mechanistic basis why nanofiber sponges are particularly well suited for separation applications. Finally, their performance in terms of efficiency, flow rate, capacity and regeneration will be compared to other fiber-based filter media.


Mouse strains to study cold-inducible beige progenitors and beige adipocyte formation and function.
Cold temperatures induce formation of beige adipocytes, which convert glucose and fatty acids to heat, and may increase energy expenditure, reduce adiposity and lower blood glucose. This therapeutic potential is unrealized, hindered by a dearth of genetic tools to fate map, track and manipulate beige progenitors and 'beiging'. Here we examined 12 Cre/inducible Cre mouse strains that mark adipocyte, muscle and mural lineages, three proposed beige origins. Among these mouse strains, only those that marked perivascular mural cells tracked the cold-induced beige lineage. Two SMA-based strains, SMA-Cre(ERT2) and SMA-rtTA, fate mapped into the majority of cold-induced beige adipocytes and SMA-marked progenitors appeared essential for beiging. Disruption of the potential of the SMA-tracked progenitors to form beige adipocytes was accompanied by an inability to maintain body temperature and by hyperglycaemia. Thus, SMA-engineered mice may be useful to track and manipulate beige progenitors, beige adipocyte formation and function.


Efficacy of Synthetic Peptide Corresponding to the ACTH-Like Sequence of Human Immunoglobulin G1 in Experimental Autoimmune Encephalomyelitis.
Peptide immunocortin sequence corresponds to the amino acid residues 11-20 of the variable part of human immunoglobulin G1 (IgG1) heavy chain. Since immunocortin was shown previously to inhibit phagocytosis in peritoneal macrophages and ConA-induced T-lymphocytes proliferation in culture, we suggested that immunocortin administering may be of use for patients with self-immune syndrome. Immunocortin in concentration 10 μM inhibited proliferation of both antigen (myelin)-induced and ConA-induced LN lymphocytes isolated from the lymph nodes of Dark Agouti (DA) rats immunized with chorda shear. The biological trials of the synthetic immunocortin were carried out on the DA rats with induced experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. These in vivo experiments have shown that intraperitoneal injections of immunocortin in a daily dosage 100 μg per animal reduced symptoms of EAE in DA rats.


Primitive synteny of vertebrate major histocompatibility complex class I and class II genes.
Major histocompatibility complex (MHC) class I and class II molecules bind to and display peptidic antigens acquired from pathogens that are recognized by lymphocytes coordinating and executing adaptive immune responses. The two classes of MHC proteins have nearly identical tertiary structures and were derived from a common ancestor that probably existed not long before the emergence of the cartilaginous fish. Class I and class II genes are genetically linked in tetrapods but are not syntenic in teleost fish, a phylogenetic taxon derived from the oldest vertebrate ancestor examined to date. Cartilaginous fish (sharks, skates, and rays) are in the oldest taxon of extant jawed vertebrates; we have carried out segregation analyses in two families of nurse sharks and one family of the banded houndshark that revealed a close linkage of class IIalpha and beta genes both with each other and with the classical class I (class Ia) gene. These results strongly suggest that the primordial duplication giving rise to classical class I and class II occurred in cis, and the close linkage between these two classes of genes has been maintained for at least 460 million years in representatives of most vertebrate taxa.


Study of DNA methylation by tobacco-specific N-nitrosamines.
An enzyme-linked immunosorbent assay (BA-ELISA) involving use of biotin-labeled anti-rabbit IgG and avidin-labeled horseradish peroxidase was developed for the measurement of O6-methyl-2'-deoxyguanosine (O6-MedGuo). Up to 5 micrograms of methylated DNA was enzymatically hydrolyzed, and the extent of inhibition of binding of immobilized O6-MedGuo-bovine serum albumin to rabbit anti-O6-MedGuo was measured. Fifty percent inhibition of antigen-antibody binding was achieved with 2.5 pmole of of O6-MedGuo. Separation of O6-MedGuo from unmodified nucleosides by high-performance liquid chromatography (HPLC-BA-ELISA) allowed detection of 700 fmole O6-MedGuo in 1 mg of DNA. Among the tobacco-related carcinogens, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is one of the most potent. In F344 rats it induces nasal cavity, lung and liver tumors. Four hours after a single IV injection of NNK to F344 rats (87 mg/kg body weight), O6-MedGuo was present in target organs (mumole O6-MedGuo/mole dGuo) (nasal mucosa, 219; lung, 13.2; and liver, 34.5) but was not detectable in nontarget organs. F344 rats receiving daily IP injections of NNK (40 mg/kg body weight) for 14 days were sacrificed 24 hr after the last injection. The levels of (O6-Medguo/dGuo) were 7.9 and 11.4 mumole/mole in the nasal mucosa and lung, respectively. In the liver no O6-MedGuo was detected, but 1050 mumole of 7-MeGua/mole Gua was measured by HPLC-fluorimetry. No DNA methylation was observed in the nasal mucosa or liver of F344 rats treated with the nicotine-derived carcinogen N'-nitrosonornicotine.(ABSTRACT TRUNCATED AT 250 WORDS)


Impact of COVID-19 on gynecologic cancer treatment in Japan: a nationwide survey by the Japan Society of Gynecologic Oncology (JSGO).
As coronavirus disease 2019 (COVID-19) rages on, it is a challenging task to balance resources for treatment of COVID-19 and malignancy-based treatment. For the development of optimal strategies, assessing the conditions and constrains in treatment during the COVID-19 pandemic is pertinent. This study reported about a nationwide survey conducted by the Japan Society of Gynecologic Oncology. We interviewed 265 designated training facilities about the state of their clinical practice from the time period between March and December 2020. We asked the facility doctors in charge to fill a web-based questionnaire. A total of 232 facilities (87.5%) responded. A decrease in the number of outpatient visits was reported, and the major reason attributed was reluctance of patients to visit hospitals rather than facility restrictions. The actual number of surgeries decreased by 3.9%, compared to 2019. There was a significant difference when the variable of "Prefectures operating under special safety precautions" or not was introduced. There was no increase in the rate of advanced stages in the three cancer types studied. However, 34.1% participants perceived COVID-19 affected management and prognosis. Refraining from visiting hospitals based on the patient's judgment may be expected to be an issue in the future. No significant decrease in surgeries was observed, and it would seem that there were few forced changes in treatment plans, but "the State of Emergency" had an impact. There was no increase in the rate of advanced cancers, but this will need to be monitored.


Patients' experiences with routine outcome monitoring and clinical feedback systems: A systematic review and synthesis of qualitative empirical literature.
Routine outcome monitoring (ROM) and clinical feedback (CF) systems have become important tools for psychological therapies, but there are challenges for their successful implementation. To overcome these challenges, a greater understanding is needed about how patients experience the use of ROM/CF. We conducted a systematic literature search of qualitative studies on patient experiences with the use of ROM/CF in mental health services. The findings from 16 studies were synthesized, resulting in four meta-themes: (1) Suspicion towards service providers, (2) Flexibility and support to capture complexity, (3) Empowering patients, and (4) Developing collaborative practice. We discuss the implications of these meta-themes for further development and implementation of ROM/CF into clinical practice, acknowledging the limitations of our review and suggesting avenues for further research. Clinical or methodological significance of this article: This article provides useful and actionable knowledge about the patient perspective on ROM/CF, an important discussion on the current state of research in this area, and useful and concrete suggestions for further avenues of research.


Cardiovascular Risk Factors Associated With the Metabolically Healthy Obese (MHO) Phenotype Compared to the Metabolically Unhealthy Obese (MUO) Phenotype in Children.
Background: In pediatric age the prevalence of obesity is high. Obese children who do not have other risk factors than excess weight have been defined as "metabolically healthy obese" (MHO). Aim: The aim of this study is to evaluate, in a population of obese children, the prevalence of the MHO and "metabolically unhealthy obese" (MUO) phenotype. Furthermore, we evaluated the distribution of Uric Acid, HOMA index and Waist-Height ratio (W-Hr) in the MHO and MUO sub-groups and the impact of these non-traditional risk factors on the probability to be MUO. Methods: In 1201 obese children and adolescents [54% males, age (±SD) 11.9 (±3.0) years] weight, height, waist circumference, systolic (SBP) and diastolic (DBP) blood pressure, pubertal status, glucose, insulin, HDL cholesterol, triglycerides and Uric Acid serum values were assessed. MUO phenotype was defined as the presence of at least one of the following risk factors: SBP or DBP ≥ 90th percentile, glycaemia ≥ 100 mg/dl, HDL cholesterol <40 mg/dl, triglycerides ≥100 mg/dl (children <10 years) or ≥130 mg/dl (children ≥10 years). A multivariate logistic regression analysis was used to estimate the association between MUO phenotype and non-traditional cardiovascular risk factors. Results: The prevalence of the MUO status was high (61%). MUO subjects were more often male, older and pubertal (p < 0.001). The levels of the three non-traditional risk factors were significantly higher in MUO children compared to MHO children (p < 0.001) and all of them were independent predictors of the fact of being MUO [OR 1.41 (95% CI 1.24-1.69); 1.15 (95% CI 1.06-1.23) and 1.03 (95% CI1.01-1.05) for Uric Acid, HOMA index and W-Hr, respectively]. About 15% of MHO subjects had serum Uric Acid, HOMA index and W-Hr values within the highest quartile of the study population. Conclusion: The prevalence of MUO subjects in a large pediatric population is high and serum Uric Acid, HOMA index and W-Hr values are independent predictors of the probability of being MUO. A non-negligible percentage of subjects MHO has high values of all three non-traditional risk factors.


"Coming from the place of walking with the youth -- that feeds everything": A mixed methods case study of a runaway and homeless youth organization.
Organizations for runaway and homeless youth (RHY) provide essential services to highly vulnerable youth who have a wide variety of basic needs and complex psychosocial challenges. We present a mixed-methods case study of an RHY organization to identify the specific mechanisms and processes by the organization successfully promotes engagement and positive development of the youth they serve. We analyzed the qualitative and quantitative data separately and then integrated these two strands of data. Our findings indicate a consistent convergence of responses across the data sources, in both the qualitative and quantitative strands, that consistently reflect the organization's youth-centered approach. Primary among these policies and practices is the emphasis on building and maintaining empathic relationships with youth, the promotion of youths' autonomy, and an institutional culture of continuous evaluation of how the organization is meeting their mission to provide services that reflect best practices.


Serological studies in bullous pemphigoid: a literature review of antibody titers at presentation and in clinical remission.
Bullous pemphigoid is associated with antibodies to a 230 kDa and a 180 kDa protein. In a literature review we investigated the role of auto-antibodies as detected by different serological assays. Nine reports containing data on 143 patients were analyzed. Pre-treatment data showed that indirect immunofluorescence, enzyme-linked immunosorbent assay (ELISA) and immunoblotting offer an 82.2% or greater probability of being positive. At the end of the study period, all patients had clinically improved, whether or not they were on therapy. Auto-antibodies were present in 29% of patients evaluated by monkey esophagus immunofluorescence and 75% of those evaluated by human skin immunofluorescence. Positive titers were also reported in 67.6% of patients evaluated by ELISA. In 100% of patients in whom immunoblotting was performed the titers became negative. In 3 patients (5.3%) using human skin immunofluorescence and in one patient (1.4%) using ELISA the titers were increased at the end of the study period. The correlation between anti-basement membrane zone antibodies and the clinical course of bullous pemphigoid requires further and long-term studies.


A new strategy for using historical imbalanced yield data to conduct genome-wide association studies and develop genomic prediction models for wheat breeding.
Using imbalanced historical yield data to predict performance and select new lines is an arduous breeding task. Genome-wide association studies (GWAS) and high throughput genotyping based on sequencing techniques can increase prediction accuracy. An association mapping panel of 227 Texas elite (TXE) wheat breeding lines was used for GWAS and a training population to develop prediction models for grain yield selection. An imbalanced set of yield data collected from 102 environments (year-by-location) over 10 years, through testing yield in 40-66 lines each year at 6-14 locations with 38-41 lines repeated in the test in any two consecutive years, was used. Based on correlations among data from different environments within two adjacent years and heritability estimated in each environment, yield data from 87 environments were selected and assigned to two correlation-based groups. The yield best linear unbiased estimation (BLUE) from each group, along with reaction to greenbug and Hessian fly in each line, was used for GWAS to reveal genomic regions associated with yield and insect resistance. A total of 74 genomic regions were associated with grain yield and two of them were commonly detected in both correlation-based groups. Greenbug resistance in TXE lines was mainly controlled by Gb3 on chromosome 7DL in addition to two novel regions on 3DL and 6DS, and Hessian fly resistance was conferred by the region on 1AS. Genomic prediction models developed in two correlation-based groups were validated using a set of 105 new advanced breeding lines and the model from correlation-based group G2 was more reliable for prediction. This research not only identified genomic regions associated with yield and insect resistance but also established the method of using historical imbalanced breeding data to develop a genomic prediction model for crop improvement. The online version contains supplementary material available at 10.1007/s11032-022-01287-8.


Brief alcohol intervention--where to from here? Challenges remain for research and practice.
Brief intervention (BI) is intended as an early intervention for non-treatment-seeking, non-alcohol-dependent, hazardous and harmful drinkers. This text provides a brief summary of key BI research findings from the last three decades and discusses a number of knowledge gaps that need to be addressed. Five areas are described: patient intervention efficacy and effectiveness; barriers to BI implementation by health professionals; individual-level factors that impact on BI implementation; organization-level factors that impact on BI implementation; and society-level factors that impact on BI implementation. BI research has focused largely upon the individual patient and health professional levels, with the main focus upon primary health care research, and studies are lacking in other settings. However, research must, to a larger degree, take into account the organizational and wider context in which BI occurs, as well as interaction between factors at different levels, in order to advance the understanding of how wider implementation of BI can be achieved in various settings and how different population groups can be reached. It is also important to expand BI research beyond its current parameters to investigate more ambitious long-term educational programmes and new organizational models. More widespread implementation of BI will require many different interventions (efforts, actions, initiatives, etc.) at different interlinked levels, from implementation interventions targeting individual health professionals' knowledge, skills, attitudes and behaviours concerning alcohol issues, BI and behaviour change counselling to efforts at the organizational and societal levels that influence the conditions for delivering BI as part of routine health care.


Regulation of Pseudomonas aeruginosa chemotaxis by the nitrogen source.
The regulation of amino acid chemotaxis by nitrogen was investigated in the gram-negative bacterium Pseudomonas aeruginosa. The quantitative capillary tube technique was used to measure chemotactic responses of bacteria to spatial gradients of amino acids and other attractants. Chemotaxis toward serine, arginine, and alpha-aminoisobutyrate was sharply dependent on the form in which nitrogen was presented to the bacteria. Bacteria grown on mineral salts-succinate with potassium nitrate gave responses to amino acids that were 2 to 3 times those of cells grown on ammonium sulfate and 10 to 20 times those of cells grown in mineral salts-succinate with Casamino Acids as the nitrogen source. A combination of ammonium sulfate and glutamate was as effective as Casamino Acids in depressing serine taxis. The threshold concentration for alpha-aminoisobutyrate taxis was consistently lower in nitrate-grown bacteria than in ammonia-grown bacteria. Responsiveness to sodium succinate, however, was not subject to regulation by nitrogen, and glucose chemotaxis was inhibited, rather than enhanced, in nitrate-grown bacteria. These results indicate that chemotaxis of P. aeruginosa toward amino acids is subject to regulation by nitrogen and that this regulation probably is expressed at the level of the chemoreceptors or transducers.


Intracerebroventricular infusion of angiotensin AT2 receptor agonist novokinin aggravates some diabetes-mellitus-induced alterations in Wistar rats.
Cumulative data suggest the significant role of the renin-angiotensin system in the development of the pathological consequences of diabetes mellitus (DM). Newly synthesized AT2 receptor agonists gained importance as a target for creating new antihypertensives. The aim of the present work was to study the effects of peptide AT2 agonist novokinin, infused intracerebroventricularly, on the consequences of the streptozotocin-induced type 1 DM (T1DM) in Wistar rats. Food and water consumption, body mass, urine excretion (metabolic cages), motor activity (open-field test), anxiety (elevated plus maze), nociception (paw pressure analgesimeter test), spatial memory (T-maze alternation test), and plasma levels of glucose and corticosterone (ELISA) were assessed 2 weeks after the T1DM induction. Novokinin increased water and food consumption, as well as urine output, and reduced mass gain in the control rats. Diabetic rats demonstrated hyperalgesia, increased level of plasma corticosterone, decreased motor and exploratory activity, and impaired spatial memory. Novokinin infusion increased water intake, diuresis, and mortality rate, decreased food intake, exacerbated diabetes-induced hyperalgesia, and provoked anxiety-like behavior but improved spatial memory in diabetic rats. These initial data suggest that angiotensin AT2 receptors participate in the pathogenesis of T1DM-induced complications in the function of the nervous system.


Triple combination of HAIC-FO plus tyrosine kinase inhibitors and immune checkpoint inhibitors for advanced hepatocellular carcinoma: A systematic review and meta-analysis.
The triple combination of hepatic arterial infusion chemotherapy (HAIC) with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) plus tyrosine kinase inhibitor (TKI) and immune checkpoint inhibitors (ICIs) is expected to have a synergistic anticancer effect in HCC. We conducted this meta-analysis to evaluate the efficacy and safety of the triple combination treatment in advanced HCC patients. PubMed, Embase, Cochrane Library, Web of Science databases were systematically searched for relevant studies from the inception of each database to May 10, 2023. All articles focusing the triple combination treatment of HAIC-FO plus TKI and ICIs for advanced HCC were eligible. The meta-analysis was conducted following the PRISMA guidelines. The risk of bias was assessed using the Joanna Briggs Institute (JBI) for case series and Newcastle-Ottawa Scale (NOS) for cohort studies. The primary outcomes were overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR). The secondary results were adverse events. Further meta-analysis of control studies demonstrated the superiority of the triple combination modality to TKI plus ICIs, and TKI alone. Nine articles (four cohort studies and five one-arm studies) involving 777 advanced HCC patients were included in this meta-analysis. In terms of survival analysis, the pooled median PFS was 11 months (95% CI: 10.1-12.0 months) with low heterogeneity (I2 = 0%, p = 0.97). With regard to tumor response, the pooled ORR and DCR was 61.6% (I2=0%, p = 0.71) and 87.9% (I2 = 13%, p = 0.33) with low heterogeneity, respectively. As compared with TKIs plus ICIs, and TKIs alone, the triple combination thrapy was associated with improved median OS (HR=0.51, 95%CI 0.41-0.62) with low heterogeneity across studies (I2 = 0%, p = 0.47), median PFS (HR=0.51, 95%CI 0.41-0.64) with low heterogeneity across studies (I2 = 0%, p = 0.41), ORR (RR = 0.56, 95% CI: 0.42-0.74) with high heterogeneity across studies (I2 = 69%, p = 0.02), and DCR (RR = 0.38, 95%CI 0.27-0.54) with low heterogeneity across studies (I2 = 14%, p = 0.32). The most common 3/4 AEs were elevated ALT and AST, thrombocytopenia, hypertension, nausea and vomiting in this meta-analysis. The triple combination therapy of HAIC-FO plus TKI and ICIs showed promising efficacy and safety in patients with advanced HCC. The protocol was registered with PROSPERO (ID:CRD42023424281).


One-step, aid-mediated method for modification of glass surfaces with N-hydroxysuccinimide esters and its application to the construction of microarrays for studies of biomolecular interactions.
Microarray technologies have received considerable attention owing to the fact that they serve as powerful tools for the high-throughput analysis of biomolecular interactions and the identification of bioactive substances that bind to biomolecules. Most of the current methods used to construct microarrays rely on the immobilization of substances on properly derivatized surfaces. Among various functional groups used for this purpose, the N-hydroxysuccinimide (NHS) ester group has been largely employed because it can be readily reacted with amine or hydrazide functionalities in substances of interest. However, the NHS ester group is usually introduced onto the surface of a glass slide by employing inconvenient and time-consuming multistep processes. In recent studies, we have developed an efficient, single step method for derivatization of glass surfaces with NHS ester groups that takes advantage of an acid-mediated reaction of NHS ester functionalized dimethallylsilanes with silanols on the glass surface. Conditions for the surface modification procedure that utilize TfOH rather than Sc(OTf)(3) were found to be superior. Protein and RNA-binding experiments show that glass surfaces modified by employing this method are suitable for efficient immobilization of various substances that are appended by amine, hydrazide, and alcohol functionalities. The microarrays, generated in this way, are applicable to procedures for rapid analysis of protein-protein, protein-glycan, protein-small molecule, and peptide-RNA interactions, as well as for profiling enzyme activities. The newly developed acid-mediated, glass surface modification method should be generally applicable to the preparation of various functional group-modified surfaces.


Treatment with docosahexaenoic acid, but not eicosapentaenoic acid, delays Ca2+-induced mitochondria permeability transition in normal and hypertrophied myocardium.
Intake of fish oil containing docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) prevents heart failure; however, the mechanisms are unclear. Mitochondrial permeability transition pore (MPTP) opening contributes to myocardial pathology in cardiac hypertrophy and heart failure, and treatment with DHA + EPA delays MPTP opening. Here, we assessed: 1) whether supplementation with both DHA and EPA is needed for optimal prevention of MPTP opening, and 2) whether this benefit occurs in hypertrophied myocardium. Rats with either normal myocardium or cardiac hypertrophy induced by 8 weeks of abdominal aortic banding were fed one of four diets: control diet without DHA or EPA or diets enriched with either DHA, EPA, or DHA + EPA (1:1 ratio) at 2.5% of energy intake for 17 weeks. Aortic banding caused a 27% increase in left ventricular mass and 25% depletion in DHA in mitochondrial phospholipids in rats fed the control diet. DHA supplementation raised DHA in phospholipids ∼2-fold in both normal and hypertrophied hearts and increased EPA. DHA + EPA supplementation also increased DHA, but to a lesser extent than DHA alone. EPA supplementation increased EPA, but did not affect DHA compared with the control diet. Ca(2+)-induced MPTP opening was delayed by DHA and DHA + EPA supplementation in both normal and hypertrophied hearts, but EPA had no effect on MPTP opening. These results show that supplementation with DHA alone effectively increases both DHA and EPA in cardiac mitochondrial phospholipids and delays MPTP and suggest that treatment with DHA + EPA offers no advantage over DHA alone.


8-chloro-cAMP enhances the growth inhibitory effect of cytotoxic drugs in human colon cancer cells.
8-Cl-cAMP is a novel agent able to inhibit the growth of a wide variety of cancer cell types in vitro and in vivo by interfering with the protein kinase A type I (PKAI), a protein directly involved in mitogenic signalling and neoplastic transformation. In a recent phase I study conducted in cancer patients we have demonstrated that 8-Cl-cAMP, at doses devoid of toxicity, may achieve plasma concentrations in a range previously shown effective for cancer cell growth inhibition. In the present study we have investigated the effect of 8-Cl-cAMP in association with cytotoxic drugs acting by different mechanisms of action on the growth of LS174T and GEO human colon cancer cells. We here demonstrate that 8-Cl-cAMP administered after the cytotoxic drugs does not interfere with their growth inhibitory effect but rather is additive with most of them. Moreover, a synergistic effect was observed when 8-Cl-cAMP was administered after cisplatin or paclitaxel. The sequence of treatment seems to be important since pretreatment with 8-Cl-cAMP interferes with the effect of the cytoxic drugs. These results demonstrate that 8-Cl-cAMP is not only able to induce cell growth inhibition when used alone but also exhibit the capacity to enhance the efficacy of different cytotoxic drugs.


Lasing Supraparticles Self-Assembled from Nanocrystals.
One of the most attractive commercial applications of semiconductor nanocrystals (NCs) is their use in lasers. Thanks to their high quantum yield, tunable optical properties, photostability, and wet-chemical processability, NCs have arisen as promising gain materials. Most of these applications, however, rely on incorporation of NCs in lasing cavities separately produced using sophisticated fabrication methods and often difficult to manipulate. Here, we present whispering gallery mode lasing in supraparticles (SPs) of self-assembled NCs. The SPs composed of NCs act as both lasing medium and cavity. Moreover, the synthesis of the SPs, based on an in-flow microfluidic device, allows precise control of the dimensions of the SPs, i.e. the size of the cavity, in the micrometer range with polydispersity as low as several percent. The SPs presented here show whispering gallery mode resonances with quality factors up to 320. Whispering gallery mode lasing is evidenced by a clear threshold behavior, coherent emission, and emission lifetime shortening due to the stimulation process.


An Innovative System to Facilitate Extension Osteotomy in the Prone Position for Chin-on-Chest Deformity of Ankylosing Spondylitis.
In the presence of chin-on-chest deformity of ankylosing spondylitis, positioning for extension osteotomy of the spine is a challenging endeavor. Conventional prone positioning equipment cannot safely accommodate all patients with advanced deformity where the chin brow angle approaches or exceeds 90°. Issues such as inability to accommodate the head and associated equipment while providing operative stability and venous congestion of the head represent significant perioperative risks. The sitting position has been advocated as an alternative but is suboptimal for surgical access and anesthetic care. We present a technical note for a positioning system developed to facilitate extension osteotomy in the prone position. A positioning device was designed to accommodate patients with advanced deformity. A series of patients with chin brow angles of up to 89° were positioned using our new system. We were able to facilitate safe extension osteotomy in the prone position, for procedures lasting up to 14 hours. All our patients were discharged home without significant complication. Our device is simply constructed and may be easily replicated in other institutions engaging in complex spine surgery. We hope our system provides clinicians with greater freedom to provide optimal perioperative care to their patients.


Pharmacodynamic modelling of β-lactam/β-lactamase inhibitor checkerboard data: illustration with aztreonam-avibactam.
Checkerboard experiments followed by fractional inhibitory concentration (FIC) index determinations are commonly used to assess in vitro pharmacodynamic interactions between combined antibiotics, but FIC index cannot be determined in case of antibiotic/non-active compound combinations. The aim of this study was to use a simple modelling approach to quantify the in vitro activity of aztreonam-avibactam, a new β-lactam-β-lactamase inhibitor combination. MIC checkerboard experiments were performed with 12 Enterobacteriaceae with diverse β-lactamases profiles. Aztreonam MICs in the absence and presence of avibactam at different concentrations (ranging from 0.0625 to 4 mg/L) were determined. Aztreonam MIC versus avibactam concentrations were fitted by an inhibitory Emax model with a baseline effect parameter. A concentration-dependent relationship was observed with a steep initial reduction of aztreonam MIC at low avibactam concentrations and reaching a maximum at higher avibactam concentrations that was adequately fitted by the model. Maximum avibactam effect was characterized by the ratio of aztreonam MICs in the absence of avibactam (MIC0) and when avibactam concentration tends toward infinity (MIC∞), and this ratio ranged between 90 and 10 068 depending on the strain. Avibactam potency was characterized by avibactam concentrations corresponding to 50% of the maximum effect (IC50 values between 0.00022 and 0.053 mg/L). An inhibitory Emax model with a baseline effect could quantify maximum avibactam effect and potency among various strains. This simple modelling approach can be used to compare the activity of other combinations of antibiotics with non-antibiotic drugs when FIC index is inappropriate.


Sorption and high dynamics of micropollutants in sewers.
Down-the-drain household chemicals are mostly discharged intermittently (i.e. with water pulses, e.g. pharmaceuticals from toilet flushing) and well soluble micropollutants can, therefore, be subject to significantly high short-term fluctuations. It is not known how these fluctuations are attenuated by sorption to sewer sediments or biofilm. First, we investigated in this paper the effect of sorption for substances with high, medium and low affinity to particulate matter based on computational experiments. For substances with high K(oc) we found that the additional attenuation of a load pattern due to sorption is in the same order of magnitude as caused by dispersion in a typical main sewer. The mass flux between wastewater and the first biofilm layer was identified as the most sensitive parameter. Furthermore, the interplay of systematic, slow diurnal variations does not affect short-term fluctuations. Second, during rain events partial erosion of the biofilm can lead to increased micropollutant loads for substances with high K(oc). This increase is in the same order of magnitude as diurnal variations of the loads in the liquid phase and the TSS.


Adrenal-permissive HSD3B1 genetic inheritance and risk of estrogen-driven postmenopausal breast cancer.
BACKGROUNDGenetics of estrogen synthesis and breast cancer risk has been elusive. The 1245A→C missense-encoding polymorphism in HSD3B1, which is common in White populations, is functionally adrenal permissive and increases synthesis of the aromatase substrate androstenedione. We hypothesized that homozygous inheritance of the adrenal-permissive HSD3B1(1245C) is associated with postmenopausal estrogen receptor-positive (ER-positive) breast cancer.METHODSA prospective study of postmenopausal ER-driven breast cancer was done for determination of HSD3B1 and circulating steroids. Validation was performed in 2 other cohorts. Adrenal-permissive genotype frequency was compared between postmenopausal ER-positive breast cancer, the general population, and postmenopausal ER-negative breast cancer.RESULTSProspective and validation studies had 157 and 538 patients, respectively, for the primary analysis of genotype frequency by ER status in White female breast cancer patients who were postmenopausal at diagnosis. The adrenal-permissive genotype frequency in postmenopausal White women with estrogen-driven breast cancer in the prospective cohort was 17.5% (21/120) compared with 5.4% (2/37) for ER-negative breast cancer (P = 0.108) and 9.6% (429/4451) in the general population (P = 0.0077). Adrenal-permissive genotype frequency for estrogen-driven postmenopausal breast cancer was validated using Cambridge and The Cancer Genome Atlas data sets: 14.4% (56/389) compared with 6.0% (9/149) for ER-negative breast cancer (P = 0.007) and the general population (P = 0.005). Circulating androstenedione concentration was higher with the adrenal-permissive genotype (P = 0.03).CONCLUSIONAdrenal-permissive genotype is associated with estrogen-driven postmenopausal breast cancer. These findings link genetic inheritance of endogenous estrogen exposure to estrogen-driven breast cancer.FUNDINGNational Cancer Institute, NIH (R01CA236780, R01CA172382, and P30-CA008748); and Prostate Cancer Foundation Challenge Award.


A systematic approach to CT evaluation of orbital trauma.
Computed tomography (CT) is widely used in the initial evaluation of patients with craniofacial trauma. Due to anatomical proximity, craniofacial trauma often involves concomitant injury to the eye and orbit. These injuries may have devastating consequences to vision, ocular motility, and cosmesis. CT imaging provides a rapid and detailed evaluation of bony structures and soft tissues of the orbit, is sensitive in detection of orbital foreign bodies, and often guides clinical and surgical management decisions in orbital trauma. For this reason, radiologists should be prepared to rapidly recognize common orbital fracture patterns, accurately describe soft tissue injuries of the orbit, detect and localize retained foreign bodies within the globe and orbit, and recognize abnormalities of the contents and integrity of the globe. In this review, we present a systematic approach to assist radiologists in the rapid evaluation of orbital trauma using the "BALPINE" mnemonic-bones, anterior chamber, lens, posterior globe structures, intraconal orbit, neurovascular structures, and extraocular muscles/extraconal orbit. Using this approach, we describe common traumatic findings within each of these spaces, and present common postsurgical appearances that can mimic findings of acute trauma.


[Variations in position and place of formation of appendix vermiformis found in the course of open appendectomy].
This paper describes variations of the appendix vermiformis, found in the course of open appendectomy. Investigations involved surgeries performed in 2008 year in the Regional Hospital TeSanj. Variations in the site of formation and position of appendix vermiformis were established. Dominantly, appendix vermiformis is placed in the pelvic position in 57.71% of cases. In the smallest number of cases (2), or 3.07% lateral (paracecal) position was found. Variations of position of ostium appendicis vermiformis were registered as well. Two types of ostium appendicis vermiformis were found: dorso-medial wall of intestinum caecum below ostium ileocaecale (35.39%), dorso-lateral medial wall of intestinum caecum (30.7%) and lower pole of intestinum caecum (64.61%). Results of this research indicate very large variability of appendix vermiformis anatomy, which together with other factors (age, sex, phase in which is patient at the moment of examination) form a clinical picture of the acute appendicitis.


Social networks, support and early psychosis: a systematic review.
Background. There is strong evidence that those with a long-standing psychotic disorder have fewer social contacts and less social support than comparison groups. There is less research on the extent of social contacts and support prior to or at the onset of psychosis. In the light of recent evidence implicating a range of social experiences and contexts at the onset of psychosis, it is relevant to establish whether social networks and support diminished before or at the time of onset and whether the absence of such supports might contribute to risk, either directly or indirectly. We, therefore, conducted a systematic review of this literature to establish what is currently known about the relationship between social networks, support and early psychosis. Methods. We identified all studies investigating social networks and support in first episode psychosis samples and in general population samples with measures of psychotic experiences or schizotype by conducting systematic searches of electronic databases using pre-defined search terms and criteria. Findings were synthesized using non-quantitative approaches. Results. Thirty-eight papers were identified that met inclusion criteria. There was marked methodological heterogeneity, which limits the capacity to draw direct comparisons. Nonetheless, the existing literature suggests social networks (particularly close friends) and support diminished both among first episode samples and among non-clinical samples reporting psychotic experiences or with schizotype traits, compared with varying comparison groups. These differences may be more marked for men and for those from minority ethnic populations. Conclusions. Tentatively, reduced social networks and support appear to pre-date onset of psychotic disorder. However, the substantial methodological heterogeneity among the existing studies makes comparisons difficult and suggests a need for more robust and comparable studies on networks, support and early psychosis.


Genetically engineered and enucleated human mesenchymal stromal cells for the targeted delivery of therapeutics to diseased tissue.
Targeting the delivery of therapeutics specifically to diseased tissue enhances their efficacy and decreases their side effects. Here we show that mesenchymal stromal cells with their nuclei removed by density-gradient centrifugation following the genetic modification of the cells for their display of chemoattractant receptors and endothelial-cell-binding molecules are effective vehicles for the targeted delivery of therapeutics. The enucleated cells neither proliferate nor permanently engraft in the host, yet retain the organelles for energy and protein production, undergo integrin-regulated adhesion to inflamed endothelial cells, and actively home to chemokine gradients established by diseased tissues. In mouse models of acute inflammation and of pancreatitis, systemically administered enucleated cells expressing two types of chemokine receptor and an endothelial adhesion molecule enhanced the delivery of an anti-inflammatory cytokine to diseased tissue (with respect to unmodified stromal cells and to exosomes derived from bone-marrow-derived stromal cells), attenuating inflammation and ameliorating disease pathology. Enucleated cells retain most of the cells' functionality, yet acquire the cargo-carrying characteristics of cell-free delivery systems, and hence represent a versatile delivery vehicle and therapeutic system.


Invasiveness and malignant potential of pulmonary lesions presenting as pure ground-glass opacities.
We retrospectively investigated the pathological diagnoses of pulmonary lesions presenting as pure ground-glass opacities (GGOs) to evaluate the risk of invasive malignancy. We examined 191 GGO lesions, including 114 pure GGO and 77 mixed lesions, in 160 patients who underwent resection between January 2008 and December 2010. Of the 114 pure GGO lesions, 14 (12%) were diagnosed as invasive lung cancer and 16 (14%) as minimally invasive adenocarcinoma. Twenty-one lesions exhibited pleural indentation on high-resolution computed tomography (HRCT), and 5 of these were diagnosed as invasive cancer, indicating an invasive tendency of pure GGO lesions with pleural indentation (odds ratio, 2.64). Of 14 pure GGO lesions positive on positron emission tomography (PET), 8 were diagnosed as invasive lung cancer, indicating an invasive tendency of pure GGO lesions with PET positivity (odds ratio, 16.0; p <0.001; sensitivity, 67%; specificity, 89%). Invasive lung cancer accounted for 12% of the pure GGO lesions. Pure GGO lesions should be carefully monitored by periodic chest computed tomography, and surgical resection is recommended when they exhibit pleural indentation on HRCT or positivity on PET.


Salivary Proteome and Intact N-Glycopeptides Analysis Reveal Specific Signatures in Periodontitis.
Periodontitis is a prevalent oral inflammatory disease that can result in tooth loss and is closely linked to type 2 diabetes (T2D). In this study, we analyzed the salivary proteome and intact N-glycopeptides (IGPs) of individuals with mild-moderate, severe, aggressive periodontitis, and periodontitis with T2D, including those treated with antidiabetic drugs, to identify specific signatures associated with the disease. Our results revealed that salivary proteins and glycoproteins were altered in all periodontitis groups (PRIDE ID: 1-20230612-72345), with fucose- and sialic acid-containing N-glycans showing the greatest increase. Additionally, differentially expressed proteins were classified into 9 clusters, including those that were increased in all periodontitis groups and those that were only altered in certain types of periodontitis. Interestingly, treatment with antidiabetic drugs reversed many of the changes observed in the salivary proteome and IGPs in T2D-related periodontitis, suggesting a potential therapeutic approach for managing periodontitis in patients with T2D. Consistent with MS/MS results, the expression of salivary IGHA2 and Fucα1-3/6GlcNAc (AAL) was significantly increased in MP. These findings provide new insights into the pathogenesis of periodontitis and highlight the potential of salivary biomarkers for diagnosis, prognosis, and monitoring of disease progression and treatment response.


A non-contact technique for evaluation of elastic structures at large stand-off distances: applications to classification of fluids in steel vessels.
A novel technique for non-contact evaluation of structures in air at large stand-off distances (on the order of several meters) has been developed. It utilizes a recently constructed air-coupled, parametric acoustic array to excite the resonance vibrations of elastic, fluid-filled vessels. The parametric array is advantageous for NDE applications in that it is capable of producing a much narrower beamwidth and broader bandwidth than typical devices that operate under linear acoustic principles. In the present experiments, the array operates at a carrier frequency of 217 kHz, and the sound field several meters from the source is described spectrally by the envelope of the drive voltage. An operating bandwidth of more than 25 kHz at a center frequency of 15 kHz is demonstrated. For the present application, the array is used to excite vibrations of fluid-filled, steel containers at stand-off distances of greater than 3 m. The vibratory response of a container is detected with a laser vibrometer in a monostatic configuration with the acoustic source. By analyzing the change in the response of the lowest order, antisymmetric Lamb wave as the interior fluid loading conditions of the container are changed, the fluid contained within the steel vessel is classified.


Analysis of two Aspergillus nidulans genes encoding extracellular proteases.
Characterization of prtADelta mutants, generated by gene disruption, showed that the prtA gene is responsible for the majority of extracellular protease activity secreted by Aspergillus nidulans at both neutral and acid pH. The prtA delta mutation was used to map the prtA gene to chromosome V. Though aspartic protease activity has never been reported in A. nidulans and the prtADelta mutants appear to lack detectable acid protease activity, a gene (prtB) encoding a putative aspartic protease was isolated from this species. Comparison of the deduced amino acid sequence of PrtB to the sequence of other aspergillopepsins suggests that the putative prtB gene product contains an eight-amino-acid deletion prior to the second active site Asp residue of the protease. RT-PCR experiments showed that the prtB gene is expressed, albeit at a low level.


Speakers exhibit a multimodal Lombard effect in noise.
In everyday conversation, we are often challenged with communicating in non-ideal settings, such as in noise. Increased speech intensity and larger mouth movements are used to overcome noise in constrained settings (the Lombard effect). How we adapt to noise in face-to-face interaction, the natural environment of human language use, where manual gestures are ubiquitous, is currently unknown. We asked Dutch adults to wear headphones with varying levels of multi-talker babble while attempting to communicate action verbs to one another. Using quantitative motion capture and acoustic analyses, we found that (1) noise is associated with increased speech intensity and enhanced gesture kinematics and mouth movements, and (2) acoustic modulation only occurs when gestures are not present, while kinematic modulation occurs regardless of co-occurring speech. Thus, in face-to-face encounters the Lombard effect is not constrained to speech but is a multimodal phenomenon where the visual channel carries most of the communicative burden.


[STAT3 activation by hypoxia in in vitro models of cervix cancer and endothelial cells].
The biological behavior of cancer cells is influenced by the tumor microenvironment in which they develop. In this context, stressor stimuli such as hypoxia are considered critical for tumor development and therapeutic management. Cellular response to various stimuli is evidenced in the activation of intracellular signaling pathways such as JAK/STAT, which is one of the most important for its effects in differentiation and cell proliferation. To evaluate the condition of the JAK/STAT pathway through the expression/activation of the STAT3 protein in cervix cancer cells (HeLa) and endothelial cells (EA.hy926) subjected to hypoxia. Cell lines were subjected to physical (1% O2) or chemical (deferoxamine, DFO, 100 μM) hypoxia for 2, 6 and 24 hours. Changes in the expression and activation of STAT3, and its subcellular localization by indirect immunofluorescence, were determined by western blot. Hypoxia was evidenced by the activation and translocation to the nucleus of HIF-1. Neither physical nor chemical hypoxia altered STAT3 expression, but it did affect its activation, as seen in its phosphorylation and translocation to the nucleus in the two models under study. The present study highlights the importance of hypoxia as a stimulus that modifies the activation of the STAT3 protein in HeLa and EA.hy926 cells, which makes it an important factor in the design of therapeutic strategies against cancer.


SEROEPIDEMIOLOGY OF HBV ANTIGEN AND ANTI-HCV AMONG GENERAL POPULATION IN A RURAL LOCAL IN BAUCHI STATE, NIGERIA.
HBV and HCV infections are a significant public health issue in developing countries with weak healthcare systems, high poverty rates, illiteracy, low HBV immunization coverage, and low public health education. A study assessed the sero epidemiology of HBV antigen, anti- HCV markers, biochemical and heamatological indices of 559 participants in Dambam local government during hepatitis day. A structured questionnaire was administered to assess demographic information and risk factors. Rapid latex immunochromtographic kits were used for HBV, HCV, and HBV Combo serological markers, with positive and negative control included in each batch analysis. Descriptive statistics analysis was conducted on the data. The 559 study participants, had a mean age of 35.5+10.9years, majority within the age- group, 18-39years 279(49.04%), female accounted for 291(52.1%) compared to male 268(47.9), educational background, tertiary 244(43.6%), married, 356(68.7%) and student were 254(45.4%). Seroprevalence of HBsAg was 10.7%, serological markers as follows, HbsAb 1.7%, HbeAg 13.3%, HbeAb 60.0% HbcAb 95.0% and Anti-HCV of 3.4%. Gender breakdown(M vs F) of HBV(13.4% vs 8.2%) and HCV(3.0% vs 3.8%). Significant association was observed in the seroprevalence of HBV and HCV with age-group, gender, marital status and occupation(<0.05). No significant difference was observed with the risk factors of HBV and HCV. Biochemical and heamatological indices showed a significant difference between seropositive and negative study participants(<0.05). The study's findings affirmed the endemicity of HBV infection and the increasing trend of HCV infection in Bauchi state, posing serious public health concerns. HBV serological markers suggest a low HBV immunization coverage rate and exposure of participants to the viral etiology in the community. Strengthening immunization coverage and population-based surveillance is strategic in the prevention and control of viral hepatitis in Bauchi state.


Conodont affinity and chordate phylogeny.
Current information on the conodonts Clydagnathus windsorensis (Globensky) and Promissum pulchrum Kovács-Endrödy, together with the latest interpretations of conodont hard tissues, are reviewed and it is concluded that sufficient evidence exists to justify interpretation of the conodonts on a chordate model. A new phylogenetic analysis is undertaken, consisting of 17 chordate taxa and 103 morphological, physiological and biochemical characters; conodonts are included as a primary taxon. Various experiments with character coding, taxon deletion and the use of constraint trees are carried out. We conclude that conodonts are cladistically more derived than either hagfishes or lampreys because they possess a mineralised dermal skeleton and that they are the most plesiomorphic member of the total group Gnathostomata. We discuss the evolution of the nervous and sensory systems and the skeleton in the context of our optimal phylogenetic tree. There appears to be no simple evolution of free to canal-enclosed neuromasts; organised neuromasts within canals appear to have arisen at least three times from free neuromasts or neuromasts arranged within grooves. The mineralised vertebrate skeleton first appeared as odontodes of dentine or dentine plus enamel in the paraconodont/euconodont feeding apparatus. Bone appeared later, co-ordinate with the development of a dermal skeleton, and it appears to have been primitively acellular. Atubular dentine is more primitive than tubular dentine. However, the subsequent distribution of the different types of dentine (e.g. mesodentine, orthodentine), suggests that these tissue types are homoplastic. The topology of relationships and known stratigraphic ranges of taxa in our phylogeny predict the existence of myxinoids and petromyzontids in the Cambrian.


High-throughput screening for human lysosomal beta-N-Acetyl hexosaminidase inhibitors acting as pharmacological chaperones.
The adult forms of Tay-Sachs and Sandhoff diseases result when the activity of beta-hexosaminidase A (Hex) falls below approximately 10% of normal due to decreased transport of the destabilized mutant enzyme to the lysosome. Carbohydrate-based competitive inhibitors of Hex act as pharmacological chaperones (PC) in patient cells, facilitating exit of the enzyme from the endoplasmic reticulum, thereby increasing the mutant Hex protein and activity levels in the lysosome 3- to 6-fold. To identify drug-like PC candidates, we developed a fluorescence-based real-time enzyme assay and screened the Maybridge library of 50,000 compounds for inhibitors of purified Hex. Three structurally distinct micromolar competitive inhibitors, a bisnaphthalimide, nitro-indan-1-one, and pyrrolo[3,4-d]pyridazin-1-one were identified that specifically increased lysosomal Hex protein and activity levels in patient fibroblasts. These results validate screening for inhibitory compounds as an approach to identifying PCs.


Home Visiting and the Health of Preterm Infants.
The results of home visiting programs which target medically fragile low-birth-weight preterm infants (LBWPT) have been inconsistent. We provided nurse/social worker home visits to families of LBWPT infants on a regular schedule. Teams were trained in approaches to improve the health and development of the infants. The completion of immunization series was sigmificantly higher and the infant mortality rates of the home visits childen were significanly lower compared to national and state rates. We used state Medicaid data and examined frequency of hospitalization, emergency department visits, routine and nonscheduled visits to primary care physician, and pharmacy use of the home-visited subjects compared with a propensity-matched group. The home-visited group had more routine and nonscheduled visits but no more hospitalizations or E.D. visits. Home visiting teams improved important markers of child health, including completed immunizations and mortality rate, perhaps by the careful monitoring of health status and assuring health care when needed.


Pain and inflammatory response following off-pump coronary artery bypass grafting.
Inflammation and pain are two common clinical issues following cardiac surgery, which are important to patient outcomes. This article reviews the literature regarding inflammation and pain following cardiac surgery with special emphasis on off-pump cardiac surgery. Off-pump surgery is associated with decreased intraoperative inflammatory response compared with procedures using cardiopulmonary bypass; however, the postoperative pattern of inflammatory response is similar to on-pump procedures. Multimodal analgesic regimens and protocol-based approaches to pain management improve analgesia compared to conventional approaches. Off-pump cardiac surgeries although known to decrease the inflammatory burden do not appear to impact the overall patient outcomes. Recent evidence indicates the prothrombotic tendency following off-pump procedures, which could be related to the time course of inflammation following off-pump cardiac surgery. There might be some benefit of off-pump procedures regarding neurological and renal function that needs further studies. Pain management following off-pump procedures is similar to that of patients undergoing on-pump cardiac surgery. Better caregiver and patient education is crucial for improving pain control following cardiac surgery. Analgesic regimens need to consider adjuvants and regional analgesic techniques and patient-controlled modalities while providing care.


Chagas disease transmission in periurban communities of Arequipa, Peru.
Chagas disease, caused by Trypanosoma cruzi infection, is an urban problem in Arequipa, Peru, and the epidemiology of Chagas disease is likely to be quite different in this area, compared with in rural zones. We conducted a serosurvey of 1615 children <18 years old in periurban districts that included hillside shantytowns and slightly more affluent low-lying communities. In addition, 639 adult residents of 1 shantytown were surveyed to provide data across the age spectrum for this community. Of 1615 children, 75 (4.7%) were infected with Trypanosoma cruzi. Infection risk increased by 12% per year of age, and children living in hillside shantytowns were 2.5 times as likely to be infected as were those living in lower-lying communities. However, age-prevalence data from 1 shantytown demonstrated that adults were no more likely to be seropositive than were teenagers; the results of maximum likelihood modeling suggest that T. cruzi transmission began in this community <20 years ago. The problem of Chagas disease in periurban settings, such as those around Arequipa, must be addressed to achieve elimination of vector-borne T. cruzi transmission. Identification of infected children, vector-control efforts, and education to avoid modifiable risk factors are necessary to decrease the burden of Chagas disease.


Cervical cancer in sub-Saharan Africa: an emerging and preventable disease associated with oncogenic human papillomavirus.
Highly oncogenic human papillomavirus (HPV) infections are responsible for 7.7 % of cancers in developing countries, mainly cervical cancer. The incidence of this emerging cancer is steadily increasing in sub-Saharan Africa, with more than 75,000 new cases and close to 50,000 deaths a year, a toll further increased by HIV infection. According to the World Health Organization, cervical cancer will kill more than 443,000 women per year worldwide by 2030, nearly 90 % of them in sub-Saharan Africa. This increase in cervical cancer incidence in Africa is now counteracting the progress made by African women in reducing maternal mortality and increasing longevity. Nevertheless, cervical cancer is a potentially preventable noncommunicable disease that can be averted or halted by primary (vaccination), secondary (early diagnosis of situations at risk), and tertiary (early diagnosis of proven cases of cervical neoplasia) prevention. The close links between HIV and HPV justify linking cervical cancer prevention, screening, and management programs with AIDS programs as part of the "90-90-90" initiative of the UNAIDS, both nationally and regionally. Innovative strategies based on effective, rapid, inexpensive, and mobile screening tools, including at best molecular biology as well as vaccination and awareness programs, should be rapidly implemented and evaluated in sub-Saharan Africa.


Word comprehension in temporal cortex and Wernicke area: A PPA perspective.
To explore atrophy-deficit correlations of word comprehension and repetition in temporoparietal cortices encompassing the Wernicke area, based on patients with primary progressive aphasia (PPA). Cortical thickness in regions within and outside the classical Wernicke area, measured by FreeSurfer, was correlated with repetition and single word comprehension scores in 73 right-handed patients at mild to moderate stages of PPA. Atrophy in the Wernicke area was correlated with repetition (r = 0.42, p = 0.001) but not single word comprehension (r = -0.072, p = 0.553). Correlations with word comprehension were confined to more anterior parts of the temporal lobe, especially its anterior third (r = 0.60, p < 0.001). A single case with postmortem autopsy illustrated preservation of word comprehension but not repetition 6 months prior to death despite nearly 50% loss of cortical volume and severe neurofibrillary degeneration in core components of the Wernicke area. Temporoparietal cortices containing the Wernicke area are critical for language repetition. Contrary to the formulations of classic aphasiology, their role in word and sentence comprehension is ancillary rather than critical. Thus, the Wernicke area is not sufficient to sustain word comprehension if the anterior temporal lobe is damaged. Traditional models of the role of the Wernicke area in comprehension are based almost entirely on patients with cerebrovascular lesions. Such lesions also cause deep white matter destruction and acute network diaschisis, whereas progressive neurodegenerative diseases associated with PPA do not. Conceptualizations of the Wernicke area that appear to conflict, therefore, can be reconciled by considering the hodologic and physiologic differences of the underlying lesions.


In vivo mutational analysis of the mupirocin gene cluster reveals labile points in the biosynthetic pathway: the "leaky hosepipe" mechanism.
A common feature of the mupirocin and other gene clusters of the AT-less polyketide synthase (PKS) family of metabolites is the introduction of carbon branches by a gene cassette that contains a beta-hydroxy-beta-methylglutaryl CoA synthase (HMC) homologue and acyl carrier protein (ACP), ketosynthase (KS) and two crotonase superfamily homologues. In vivo studies of Pseudomonas fluorescens strains in which any of these components have been mutated reveal a common phenotype in which the two major isolable metabolites are the truncated hexaketide mupirocin H and the tetraketide mupiric acid. The structure of the latter has been confirmed by stereoselective synthesis. Mupiric acid is also the major metabolite arising from inactivation of the ketoreductase (KR) domain of module 4 of the modular PKS. A number of other mutations in the tailoring region of the mupirocin gene cluster also result in production of both mupirocin H and mupiric acid. To explain this common phenotype we propose a mechanistic rationale in which both mupirocin H and mupiric acid represent the products of selective and spontaneous release from labile points in the pathway that occur at significant levels when mutations block the pathway either close to or distant from the labile points.


Mutational analysis of the D1/E1 core helices and the conserved N-terminal region of yeast transcription factor IIB (TFIIB): identification of an N-terminal mutant that stabilizes TATA-binding protein-TFIIB-DNA complexes.
The general transcription factor IIB (TFIIB) plays an essential role in transcription of protein-coding genes by RNA polymerase II. We have used site-directed mutagenesis to assess the role of conserved amino acids in several important regions of yeast TFIIB. These include residues in the highly conserved amino-terminal region and basic residues in the D1 and E1 core domain alpha-helices. Acidic substitutions of residues K190 (D1) and K201 (E1) resulted in growth impairments in vivo, reduced basal transcriptional activity in vitro, and an inability to form stable TFIIB-TATA-binding protein-DNA (DB) complexes. Significantly, these mutants retained the ability to respond to acidic activators in vivo and to the Gal4-VP16 activator in vitro, supporting the view that these basic residues play a role in basal transcription. In addition, 14 single-amino-acid substitutions were introduced in the conserved amino-terminal region. Three of these mutants, the L50D, R64E, and R78L mutants, displayed altered growth properties in vivo and were compromised for supporting transcription in vitro. The L50D mutant was impaired for RNA polymerase II interaction, while the R64E mutant exhibited altered transcription start site selection both in vitro and in vivo and, surprisingly, was more active than the wild type in the formation of stable DB complexes. These results support the view that the amino-terminal domain is involved in the direct interaction between yeast TFIIB and RNA polymerase II and suggest that this domain may interact with DNA and/or modulate the formation of a DB complex.


Breaking the cycles of violence.
Violence begets violence and it is important to understand how cycles of violence are perpetuated if we are to find solutions to the global problems they present. A multi-disciplinary group of The International Work Group on Death, Dying and Bereavement has developed a model of the cyclical events that perpetuate violence at all levels including the family, community, nation, and world. This includes the Violent Act(s), the Perception of the Violent Act(s), the Immediate Response, Legitimising Authority, Destructive Codes, and Inflammatory/Polarising Strategies. It is possible at each point to break the cycle, examples are given and recommendations made.


Prevalence of migraine in a diverse community--electronic methods for migraine ascertainment in a large integrated health plan.
The growing availability of electronic health data provides an opportunity to ascertain diagnosis-specific cases via systematic methods for sample recruitment for clinical research and health services evaluation. We developed and implemented a migraine probability algorithm (MPA) to identify migraine from electronic health records (EHR) in an integrated health plan. We identified all migraine outpatient diagnoses and all migraine-specific prescriptions for a five-year period (April 2008-March 2013) from the Kaiser Permanente, Northern California (KPNC) EHR. We developed and evaluated the MPA in two independent samples, and derived prevalence estimates of medically-ascertained migraine in KPNC by age, sex, and race. The period prevalence of medically-ascertained migraine among KPNC adults during April 2008-March 2013 was 10.3% (women: 15.5%, men: 4.5%). Estimates peaked with age in women but remained flat for men. Prevalence among Asians was half that of whites. We demonstrate the feasibility of an EHR-based algorithm to identify cases of diagnosed migraine and determine that prevalence patterns by our methods yield results comparable to aggregate estimates of treated migraine based on direct interviews in population-based samples. This inexpensive, easily applied EHR-based algorithm provides a new opportunity for monitoring changes in migraine prevalence and identifying potential participants for research studies.


[Diagnostic features of tuberculosis in extra-pulmonary locations].
Bacteriological examination of patients with extralung tuberculosis is carried out, namely: tuberculosis of urino-genital organs, cerebral membranes and central nervous system, bones and joints, and also of peripheral lymphatic knots. Strains isolated under these diseases were examined for medical sensitivity to antibacterial drugs (ABD), their biochemical characteristics were studied. It was ascertained, that the strains of mycobacteria of tuberculosis (MBT), isolated under tuberculosis of cerebral membranes and central nervous system, tuberculosis of urino-genital organs, tuberculosis of bones and joints are characterized by the expressed high resistance to two-three antibacterial drugs of the first series.


Subcellular distribution of isocitrate dehydrogenase in early and term human placenta.
The activities of NAD-specific and NADP-specific isocitrate dehydrogenases were measured in early and term human placenta. In both tissues the activity of NADP-specific isocitrate dehydrogenase was severalfold higher than that of the NAD-dependent enzyme. Subcellular distribution of these two enzymes in the placental tissue was estimated. About 60% of the total NADP-specific isocitrate dehydrogenase activity was found in the mitochondrial fraction and about 40% in the cytosol fraction. Insignificant amounts of the total activity were bound to the microsomal fraction. The whole of the NAD-specific isocitrate dehydrogenase activity was localized in the mitochondrial fraction. The total mitochondrial NADP-specific isocitrate dehydrogenase activity in both early and term placenta was also estimated from the mitochondrial specific activity of this enzyme and the amount of mitochondrial protein in wet tissue, calculated from the activities of citrate synthase or cytochrome c oxidase assayed in the isolated mitochondrial fraction and in the tissue of early and term human placenta.


Tissue Anisotropy Modeling Using Soft Composite Materials.
Soft tissues in general exhibit anisotropic mechanical behavior, which varies in three dimensions based on the location of the tissue in the body. In the past, there have been few attempts to numerically model tissue anisotropy using composite-based formulations (involving fibers embedded within a matrix material). However, so far, tissue anisotropy has not been modeled experimentally. In the current work, novel elastomer-based soft composite materials were developed in the form of experimental test coupons, to model the macroscopic anisotropy in tissue mechanical properties. A soft elastomer matrix was fabricated, and fibers made of a stiffer elastomer material were embedded within the matrix material to generate the test coupons. The coupons were tested on a mechanical testing machine, and the resulting stress-versus-stretch responses were studied. The fiber volume fraction (FVF), fiber spacing, and orientations were varied to estimate the changes in the mechanical responses. The mechanical behavior of the soft composites was characterized using hyperelastic material models such as Mooney-Rivlin's, Humphrey's, and Veronda-Westmann's model and also compared with the anisotropic mechanical behavior of the human skin, pelvic tissues, and brain tissues. This work lays the foundation for the experimental modelling of tissue anisotropy, which combined with microscopic studies on tissues can lead to refinements in the simulation of localized fiber distribution and orientations, and enable the development of biofidelic anisotropic tissue phantom materials for various tissue engineering and testing applications.


Beneath the Retinal Pigment Epithelium: Histopathologic Findings in Metastatic Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type.
To report a case of extranodal natural killer/T-cell lymphoma (ENKTCL), nasal type metastatic to the space beneath the retinal pigment epithelium (RPE) with coincident paraneoplastic lymphoma-associated retinopathy. Findings of clinical and histopathologic examination are presented with differential diagnoses and a literature review. A 53-year-old man presented with bilateral blindness and had exudative retinal detachments overlying subretinal masses in both eyes. Flow cytometry of pericardial fluid revealed malignant T lymphocytes. After two cycles of chemotherapy, the patient was hospitalized and quickly expired. Autopsy revealed lymphoma involving the eyes, heart, right lung, and two subcarinal lymph nodes focally. Histopathologic examination of the eyes revealed intraocular metastases from ENKTCL, nasal type. Expression of CD3 and CD56, along with expression of Epstein-Barr virus by in situ hybridization, confirmed the diagnosis. Lymphomatous infiltrates were confined to the space beneath the neurosensory retina and between the RPE and the Bruch membrane, sparing the uveal tissue, similar to other metastatic T-cell lymphomas. Extensive RPE and photoreceptor loss in regions with and without underlying tumor was typical of a concurrent paraneoplastic lymphoma-associated retinopathy. Patients diagnosed with ENKTCL should be evaluated by an ophthalmologist, as ophthalmic involvement portends a poor prognosis.


Intact mAb LC-MS for drug concentration from pre-clinical studies: bioanalytical method performance and in-life samples.
Background: Antibody biotherapeutic measurement from pharmacokinetic studies has not been traditionally based on intact molecular mass as is the case for small molecules. However, recent advancements in protein capture and mass spectrometer technology have enabled intact mass detection and quantitation for dosed biotherapeutics. A bioanalytical method validation is part of the regulatory requirement for sample analysis to determine drug concentration from in-life study samples. Results/methodology: Here, an intact protein LC-MS assay is subjected to mock bioanalytical method validation, and unknown samples are compared between intact protein LC-MS and established bioanalytical assay formats: Ligand-binding assay and peptide LC-MS/MS. Discussion/conclusion: Results are presented from the intact and traditional bioanalytical method evaluations, where the in-life sample concentrations were comparable across method types with associated data analyses presented. Furthermore, for intact protein LC-MS, modification monitoring and evaluation of data processing parameters is demonstrated.


CRISPR-Cas9(D10A) nickase-based genotypic and phenotypic screening to enhance genome editing.
The RNA-guided Cas9 nuclease is being widely employed to engineer the genomes of various cells and organisms. Despite the efficient mutagenesis induced by Cas9, off-target effects have raised concerns over the system's specificity. Recently a "double-nicking" strategy using catalytic mutant Cas9(D10A) nickase has been developed to minimise off-target effects. Here, we describe a Cas9(D10A)-based screening approach that combines an All-in-One Cas9(D10A) nickase vector with fluorescence-activated cell sorting enrichment followed by high-throughput genotypic and phenotypic clonal screening strategies to generate isogenic knockouts and knock-ins highly efficiently, with minimal off-target effects. We validated this approach by targeting genes for the DNA-damage response (DDR) proteins MDC1, 53BP1, RIF1 and P53, plus the nuclear architecture proteins Lamin A/C, in three different human cell lines. We also efficiently obtained biallelic knock-in clones, using single-stranded oligodeoxynucleotides as homologous templates, for insertion of an EcoRI recognition site at the RIF1 locus and introduction of a point mutation at the histone H2AFX locus to abolish assembly of DDR factors at sites of DNA double-strand breaks. This versatile screening approach should facilitate research aimed at defining gene functions, modelling of cancers and other diseases underpinned by genetic factors, and exploring new therapeutic opportunities.


Relationships among selected measures of single-channel cochlear implant performance.
Relationships among a number of pre- and postimplant variables measured in 20 adults implanted with a single-channel cochlear implant were examined through a variety of univariate and multivariate statistical techniques. A large number of variables were analyzed to yield information on the relationships between pre- and postimplant performance, and among a variety of postimplant measures. Variables included: age; etiology and nature of deafness; type of implant worn; pre- and postimplant warble tone and speech detection thresholds; postimplant performance on the Monosyllable-Trochee-Spondee (MTS) and Environmental Sounds tests; postimplant electrical thresholds, uncomfortable loudness levels, and dynamic range; I.Q. scores; and postimplant discourse tracking performance with and without the implant. The difference score on the discourse tracking task, representing the auditory advantage over performance with lipreading alone, related substantively to a combination of variables including type of unit worn (Sigma versus Alpha), nature of deafness (progressive versus sudden), and etiology (meningitis versus nonmeningitis). Additionally, MTS and Environmental Sounds test scores were found to relate to one another and to etiology and nature of deafness.


New treatment modalities with vaccine therapy in renal cell carcinoma.
The aim of implementing vaccine therapy is to activate immune response against malignant cells by overcoming the tolerance triggered by the tumor. These treatments are effective using the immune response against cancer. Not every type of cancer is suitable for vaccine therapies. For a vaccine therapy to be implemented, cancer should be immunogenic and contain tissue-specific proteins, should have a slow progression, and treatments should be feasible. For that reason, studies regarding urological cancers are mostly focused on the kidneys and the prostate. Vaccine therapies used in renal cell carcinoma (RCC) can be categorized under the following titles: autologous tumor cells, dendritic cells, genetically modified tumor cells, and protein/peptide. Although there are old studies on the implementation of vaccine therapies in RCC, researches have only been intensified recently. In addition to their effective potential for lengthening general survival, decreasing tumor burden and cancer development in long term, vaccine treatments are especially effective in metastatic RCC patients. We think that vaccine treatments would be applied more in near future since RCC are immunogenic. In this compilation, we will discuss vaccine therapies used in RCC, which urologists are not so familiar with, in the light of the up-to-date literature.


Cangrelor: A New Route for P2Y12 Inhibition.
Antiplatelet therapy with a P2Y12 inhibitor is a key component of treatment for patients with acute coronary syndromes undergoing percutaneous coronary intervention. Before the development of cangrelor (Kengreal, The Medicines Company, Parsippany, NJ), only oral P2Y12 inhibitors were available. Cangrelor is a reversible P2Y12 inhibitor that is administered as an intravenous infusion, and its quick onset and offset make it an appealing option for antiplatelet therapy, particularly for patients who are unable to take oral medications. Although cangrelor struggled to show benefit in early trials, the positive results of the CHAMPION PHOENIX trial led to its approval for use as an adjunct to percutaneous coronary intervention to reduce the risk of periprocedural myocardial infarction, repeat coronary revascularization, and stent thrombosis in patients who have not been treated with another P2Y12 inhibitor and are not being given a glycoprotein IIb/IIIa inhibitor. Cangrelor has also been evaluated as an option for bridging therapy in patients who must discontinue their oral P2Y12 inhibitor before coronary artery bypass grafting. This review of cangrelor will discuss its mechanism of action, its pharmacodynamics and pharmacokinetics, the clinical trial experience, and its potential place in therapy.


Crystal structure of penicillin G acylase from the Bro1 mutant strain of Providencia rettgeri.
Penicillin G acylase is an important enzyme in the commercial production of semisynthetic penicillins used to combat bacterial infections. Mutant strains of Providencia rettgeri were generated from wild-type cultures subjected to nutritional selective pressure. One such mutant, Bro1, was able to use 6-bromohexanamide as its sole nitrogen source. Penicillin acylase from the Bro1 strain exhibited an altered substrate specificity consistent with the ability of the mutant to process 6-bromohexanamide. The X-ray structure determination of this enzyme was undertaken to understand its altered specificity and to help in the design of site-directed mutants with desired specificities. In this paper, the structure of the Bro1 penicillin G acylase has been solved at 2.5 A resolution by molecular replacement. The R-factor after refinement is 0.154 and R-free is 0.165. Of the 758 residues in the Bro1 penicillin acylase heterodimer (alpha-subunit, 205; beta-subunit, 553), all but the eight C-terminal residues of the alpha-subunit have been modeled based on a partial Bro1 sequence and the complete wild-type P. rettgeri sequence. A tightly bound calcium ion coordinated by one residue from the alpha-subunit and five residues from the beta-subunit has been identified. This enzyme belongs to the superfamily of Ntn hydrolases and uses Ogamma of Ser beta1 as the characteristic N-terminal nucleophile. A mutation of the wild-type Met alpha140 to Leu in the Bro1 acylase hydrophobic specificity pocket is evident from the electron density and is consistent with the observed specificity change for Bro1 acylase. The electron density for the N-terminal Gln of the alpha-subunit is best modeled by the cyclized pyroglutamate form. Examination of aligned penicillin acylase and cephalosporin acylase primary sequences, in conjunction with the P. rettgeri and Escherichia coli penicillin acylase crystal structures, suggests several mutations that could potentially allow penicillin acylase to accept charged beta-lactam R-groups and to function as a cephalosporin acylase and thus be used in the manufacture of semi-synthetic cephalosporins.


Effect of Cellulose Nanocrystals Extracted from Oil Palm Empty Fruit Bunch as Green Admixture for Mortar.
This paper aims to examine the effect of cellulose nanocrystals (CNCs) derived from oil palm empty fruit bunch fiber (EFB) incorporating cement mortar on its structural performances. Cellulose nanocrystals (CNCs) were extracted from α-cellulose extracted from EFB using an acid hydrolysis process with a concentration of acid used was 64% w/v under the temperature of 45 °C for 60 minutes. The Cellulose nanocrystals (CNCs) were mixed into the cement mortar ranging from 0 to 0.8% w/w and its mechanical properties were determined. The developed CNCs mortar was characterized for their compressive and flexural properties as well as microstructure. The influence of CNCs concentration, curing method, dispersion of CNCs on mortar's mechanical performance was thoroughly examined to find out the optimum condition. Overall results revealed that an addition of 0.4% cellulose nanocrystals has shown to increase the compressive and flexural strength to 46% and 20%, respectively cured under the wrapping method. The hydration of cementitious composites also improved significantly with the addition of CNCs by the formation of highly crystalline of portlandite observed under the XRD test. This present work demonstrates the importance of palm oil empty fruit bunch waste as a sustainable resource of cellulose nanocrystals admixture to achieve structural strength of cement mortar and promotes green technologies in construction.


[Relaparotomy in abdominal injuries].
Relaparotomies in the postoperative period were performed in 56 out of 529 patients (10,6%) operated upon for injuries of organs of the abdominal cavity. Twenty-two of them died. In most cases relaparotomies were caused by peritonitis, intraabdominal bleedings and abscesses.


Altered intracortical myelin staining in the dorsolateral prefrontal cortex in severe mental illness.
Imaging and postmortem studies into the severe mental illnesses of major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ) have revealed deficiencies in the myelination of deep white matter tracts of the brain. Recent studies have further suggested that deficits could extend to myelinated fibers running through the cortex in those illnesses. Disruptions in this intracortical myelin may underlie functional symptomology in MDD, BD, and SZ; thus, in this study, we hypothesized that individuals with these illnesses may have reduced myelin staining relative to controls in the cerebral cortex. We stained 60 sections of dorsolateral prefrontal cortex for myelin with Luxol® fast blue in four groups: 15 BD, 15 MDD, 15 SZ, and 15 controls with no psychiatric illness. We digitally measured optical tissue attenuation reflecting the amount of myelin staining across six cortical depths in the middle frontal gyrus (MFG), in superficial white matter in the crown of the MFG, and in deep white matter. We found that a diagnosis of MDD or SZ meant that optical tissue attenuation was significantly reduced in the shallowest depths of the cortex. Furthermore, there was a trend toward reduced optical tissue attenuation in all illnesses across all myelinated regions we studied. These results encourage future studies into potential reductions in intracortical myelin in severe mental illness.


A ten-step process to develop case management plans.
The use of case management plans has contained cost and improved quality of care successfully. However, the process of developing these plans remains a great challenge for healthcare executives. In this article, the author presents the answer to this challenge by discussing a 10-step format process that administrators of patient care services and case managers can adapt to their institutions. It also can be used by interdisciplinary team members as a practical guide to develop a specific case management plan. This process is applicable to any care setting (acute, ambulatory, long term, and home care), diagnosis, or procedure. It is particularly important for those organizations that currently do not have a deliberate and systematic process to develop case management plans and are struggling with how to improve the efficiency and productivity of interdisciplinary teams charged with developing case management plans.


Planned homebirths in South Australia 1976-1987.
Homebirths booked with a group of general practitioners and midwives in South Australia in 1976-1987 are described using data obtained from midwives' and hospital records. The births represented 84.7% of all births occurring at home in South Australia in 1984-1987, as assessed by official birth registrations. Of the 799 women intending to deliver at home, 136 (17.0%) required transfer to hospital before or during labour. A further 38 mothers or babies (4.8%) required transfer after delivery. The women tended to be of a relatively high socioeconomic status and older age distribution when compared with women who had hospital births as identified from the State perinatal data collection. Some had recognised pregnancy risk factors. They had lower frequencies of ultrasound examination, induced labour, epidural analgesia, episiotomy, forceps delivery and caesarean section, and a low frequency of use of oxytocics for the third stage. Their rates of postpartum haemorrhage and, in particular, perinatal mortality were higher. Potential sources of risk and difficulty in homebirth care and evaluation of this care are identified and an approach to providing an effective homebirth service is proposed.


Electronic-PRO Measures for adverse events Of Treatment In ONcology (E-PROMOTION).
Cancer patients struggle with the trauma of the disease and its treatment. PRO-CTCAE was developed to improve the recording of underreported symptomatic toxicities. We evaluated the improvement and ease in reporting symptomatic adverse events through add-on PRO-CTCAE (via a mobile application) compared to standard clinician-reported outcomes in routine clinical practice. We also evaluated changes in the health-related quality of life (HRQoL). 110 cancer patients were studied for three weeks between their first and second chemotherapy session. HRQoL was assessed using EORTC QLQ-c30. Fifty-three patients self-reported their symptomatic adverse events on the day 7th & day 14th after the first cycle of chemotherapy. For the other fifty-seven patients, recording of adverse events was done by standard clinician-reported outcomes. All the patients in the study group reported adverse events compared to only 21 % in the standard reporting group. All 15 domains of adverse events were reported in the self-reporting group compared to only 5 in the standard reporting group. The self-reporting group had a significantly better overall quality of life. Self-reporting of adverse events using mobile app-based PRO-CTCAE helps patients and clinicians with better documentation of symptomatic toxicities of chemotherapy, reducing the burden on physicians and improving patient satisfaction. Mobile app-based self-reporting empowers cancer patients undergoing treatment, improves their quality of life, and should be implemented in routine clinical practice. Wider implementation can lead to further optimised solutions.


Thirty-day results of the SAPIEN aortic Bioprosthesis European Outcome (SOURCE) Registry: A European registry of transcatheter aortic valve implantation using the Edwards SAPIEN valve.
Transcatheter aortic valve implantation was developed to mitigate the mortality and morbidity associated with high-risk traditional aortic valve replacement. The Edwards SAPIEN valve was approved for transcatheter aortic valve implantation transfemoral delivery in the European Union in November 2007 and for transapical delivery in January 2008. The SAPIEN Aortic Bioprosthesis European Outcome (SOURCE) Registry was designed to assess the initial clinical results of the Edwards SAPIEN valve in consecutive patients in Europe after commercialization. Cohort 1 consists of 1038 patients enrolled at 32 centers. Patients who were treated with the transapical approach (n=575) suffered more comorbidities than the transfemoral patients (n=463), resulting in a significantly higher logistic EuroSCORE (29.1% versus 25.7%; P<0.001). Therefore, these groups are considered different, and outcomes cannot be compared. Overall short-term procedural success was observed in 93.8%. The incidence of valve embolization was 0.3% (n=3), and coronary obstruction was reported for 0.6% (n=6 cases). Incidence of stroke was 2.5% and similar for both procedural approaches. Thirty-day mortality was 6.3% in transfemoral patients and 10.3% in transapical patients. The occurrence of vascular complications was not a predictor of <30-day mortality in the transfemoral population. Technical proficiency can be learned and adapted readily as demonstrated by the short-term procedural success rate and low 30-day mortality rates reported in the SOURCE Registry. Specific complication management and refinement of patient selection are needed to further improve outcomes.


Mis-trafficking of endosomal urokinase proteins triggers drug-induced glioma nonapoptotic cell death.
5-Benzylglycinyl-amiloride (UCD38B) is the parent molecule of a class of anticancer small molecules that kill proliferative and nonproliferative high-grade glioma cells by programmed necrosis. UCD38B intracellularly triggers endocytosis, causing 40-50% of endosomes containing proteins of the urokinase plasminogen activator system (uPAS) to relocate to perinuclear mitochondrial regions. Endosomal "mis-trafficking" caused by UCD38B in human glioma cells corresponds to mitochondrial depolarization with the release and nuclear translocation of apoptotis-inducing factor (AIF) followed by irreversible caspase-independent cell demise. High-content quantification of immunocytochemical colocalization studies identified that UCD38B treatment increased endocytosis of the urokinase plasminogen activator (uPA), its receptor (uPAR), and plasminogen activator inhibitor-1 (PAI-1) into the early and late endosomes by 4- to 5-fold prior to AIF nuclear translocation and subsequent glioma demise. PAI-1 was found to comparably relocate with a subset of early and late endosomes in four different human glioma cell lines after UCD38B treatment, followed by caspase-independent, nonapoptotic cell death. Following UCD38B treatment, the receptor guidance protein LRP-1, which is required for endosomal recycling of the uPA receptor to the plasmalemma, remained abnormally associated with PAI-1 in early and late endosomes. The resultant aberrant endosomal recycling increased the total cellular content of the uPA-PAI-1 protein complex. Reversible inhibition of cellular endocytosis demonstrated that UCD38B bypasses the plasmalemmal uPAS complex and directly acts intracellularly to alter uPAS endocytotic trafficking. UCD38B represents a class of small molecules whose anticancer cytotoxicity is a consequence of causing the mis-trafficking of early and late endosomes containing uPAS cargo and leading to AIF-mediated necrotic cell death.