Strain-driven mound formation of substrate under epitaxial nanoparticles.
We observe the growth of crystalline SiC nanoparticles on Si(001) at 900 °C using in situ electron microscopy. Following nucleation and growth of the SiC, there is a massive migration of Si, forming a crystalline Si mound underneath each nanoparticle that lifts it 4-5 nm above the initial growth surface. The volume of the Si mounds is roughly five to seven times the volume of the SiC nanoparticles. We propose that relaxation of strain drives the mound formation. This new mechanism for relieving interfacial strain, which involves a dramatic restructuring of the substrate, is in striking contrast to the familiar scenario in which only the deposited material restructures to relieve strain.


Monocyte subpopulations from pre-eclamptic patients are abnormally skewed and exhibit exaggerated responses to Toll-like receptor ligands.
The leading cause of pregnancy-associated mortality and morbidity is pre-eclampsia (PE). Although information regarding the etiology of this disease is scant, its pathophysiology is characterized by abnormal placentation, endothelial dysfunction as well as an exaggerated inflammatory response. Clinical evidence also indicates that the abundance of many immune cells at the feto-maternal interface and in the circulation of PE patients is abnormal, when compared with normal pregnant (NP) controls. In addition, the phenotype and function of some of these cells is altered. To further characterize the systemic effects of PE on circulating cells, we analyzed monocytic subpopulations in NP and PE patients by flow cytometry. We found that non-classical CD14(low)CD16(+) monocytes are significantly increased in women with PE and they display irregular expression of several chemokine receptors and antigen presentation molecules. The most striking phenotypic difference among the cell surface molecules was the marked upregulation of TLR4 expression, where both CD14(high)CD16(+) and CD14(low)CD16(+) monocytes demonstrated higher levels than their NP counterparts. Stimulation of PE monocytes with TLR ligands resulted in profound secretion of various cytokines in comparison with NP controls. These data suggest that PE monocytes are hyper-responsive to TLR ligands and this may contribute to exacerbation of the disease.


Genetic Diversity of Theileria equi From Horses In Different Regions of Brazil Based On the 18S rRNA Gene.
Equine piroplasmosis stands out among the diseases that affect Equidae in Brazil and the world. It is caused by the protozoa Theileria equi and Babesia caballi. The objective of the present study was to carry out the molecular characterization of T. equi using equine blood samples collected in the 5 geographic regions of Brazil. Samples from all over the country were tested for the presence of T. equi by real-time PCR. The 18S rRNA sequences (∼1,600 bp) obtained from 23 samples taken from naturally infected horses were characterized by sequencing and analyzed to identify the genotypes and the possible sites of genetic variability. Thirteen different T. equi 18S rRNA sequences were identified, and 2 different genotypes were demonstrated to be in circulation in Brazil. Alignment entropy analysis demonstrated the existence of three hypervariable regions (V2, V4, and V8) within the 18S rRNA sequence of T. equi. The V2 region is located between nucleotides 63 and 75, V4 is located between nucleotides 524 and 586, and V8 is located between nucleotides 1,208 and 1,226. The hypervariable region V4 demonstrated the greatest variation within the 18S rRNA sequence of T. equi. Phylogenetic analysis based on the 18S rRNA sequences revealed the formation of 3 distinct clades (A, B, and C). The Brazilian samples belonged to 2 clades (A and C). The present study describes the characterization and heterogeneity of the circulating T. equi 18S rRNA sequences in Brazil. The results confirm that the country is an endemic area for the disease, and they indicate that at least 2 distinct T. equi genotypes are naturally infecting equines in Brazil.


From portable dialysis to a bioengineered kidney.
Since the advent of peritoneal dialysis (PD) in the 1970s, the principles of dialysis have changed little. In the coming decades, several major breakthroughs are expected. Novel wearable and portable dialysis devices for both hemodialysis (HD) and PD are expected first. The HD devices could facilitate more frequent and longer dialysis outside of the hospital, while improving patient's mobility and autonomy. The PD devices could enhance blood purification and increase technique survival of PD. Further away from clinical application is the bioartificial kidney, containing renal cells. Initially, the bioartificial kidney could be applied for extracorporeal treatment, to partly replace renal tubular endocrine, metabolic, immunoregulatory and secretory functions. Subsequently, intracorporeal treatment may become possible. Key factors for successful implementation of miniature dialysis devices are patient attitudes and cost-effectiveness. A well-functioning and safe extracorporeal blood circuit is required for HD. For PD, a double lumen PD catheter would optimize performance. Future research should focus on further miniaturization of the urea removal strategy. For the bio-artificial kidney (BAK), cost effectiveness should be determined and a general set of functional requirements should be defined for future studies. For intracorporeal application, water reabsorption will become a major challenge.


Extracorporeal membrane oxygenation in severe influenza infection with respiratory failure: A systematic review and meta-analysis.
Extracorporeal membrane oxygenation (ECMO) has been extensively used for potentially reversible acute respiratory failure associated with severe influenza A (H1N1) pneumonia; however, it remains an expensive, resource-intensive therapy, with a high associated mortality. This systematic review and meta-analysis aims to summarize and pool outcomes data available in the published literature to guide clinical decision-making and further research. We conducted a systematic search of MEDLINE (1966 to April 15, 2015), EMBASE (1980 to April 15, 2015), CENTRAL, and Google Scholar for patients with severe H1N1 pneumonia and respiratory failure who received ECMO. The study validity was appraised by Newcastle-Ottawa Scale. The primary outcome was all-cause mortality. The secondary outcomes were duration of ECMO therapy, mechanical ventilation, and Intensive Care Unit (ICU) length of stay. Of 698 abstracts screened and 142 full-text articles reviewed, we included 13 studies with a total of 494 patients receiving ECMO in our final review and meta-analysis. The study validity was satisfactory. The overall mortality was 37.1% (95% confidence interval: 30-45%) limited by underlying heterogeneity (I2 = 65%, P value of Q statistic = 0.006). The median duration for ECMO was 10 days, mechanical ventilation was 19 days, and ICU length of stay was 33 days. Exploratory meta-regression did not identify any statistically significant moderator of mortality (P < 0.05), except for the duration of pre-ECMO mechanical ventilation in days (coefficient 0.19, standard error: 0.09, Z = 2.01, P < 0.04, R2 = 0.16). The visual inspection of funnel plots did not suggest the presence of publication bias. ECMO therapy may be used as an adjunct or salvage therapy for severe H1N1 pneumonia with respiratory failure. It is associated with a prolonged duration of ventilator support, ICU length of stay, and high mortality. Initiating ECMO early once the patient has been instituted on mechanical ventilation may result in improved survival.


Redesigning community mental health services for urban children: Supporting schooling to promote mental health.
This study examined a school- and home-based mental health service model, Links to Learning, focused on empirical predictors of learning as primary goals for services in high-poverty urban communities. Teacher key opinion leaders were identified through sociometric surveys and trained, with mental health providers and parent advocates, on evidence-based practices to enhance children's learning. Teacher key opinion leaders and mental health providers cofacilitated professional development sessions for classroom teachers to disseminate 2 universal (Good Behavior Game, peer-assisted learning) and 2 targeted (Good News Notes, Daily Report Card) interventions. Group-based and home-based family education and support were delivered by mental health providers and parent advocates for children in kindergarten through 4th grade diagnosed with 1 or more disruptive behavior disorders. Services were Medicaid-funded through 4 social service agencies (N = 17 providers) in 7 schools (N = 136 teachers, 171 children) in a 2 (Links to Learning vs. services as usual) × 6 (pre- and posttests for 3 years) longitudinal design with random assignment of schools to conditions. Services as usual consisted of supported referral to a nearby social service agency. Mixed effects regression models indicated significant positive effects of Links to Learning on mental health service use, classroom observations of academic engagement, teacher report of academic competence and social skills, and parent report of social skills. Nonsignificant between-groups effects were found on teacher and parent report of problem behaviors, daily hassles, and curriculum-based measures. Effects were strongest for young children, girls, and children with fewer symptoms. Community mental health services targeting empirical predictors of learning can improve school and home behavior for children living in high-poverty urban communities.


Summit on medical school education in sexual health: report of an expert consultation.
INTRODUCTION.: Medical education in sexual health in the United States and Canada is lacking. Medical students and practicing physicians report being underprepared to adequately address their patients' sexual health needs. Recent studies have shown little instruction on sexual health in medical schools and little consensus around the type of material medical students should learn. To address and manage sexual health issues, medical students need improved education and training. AIM.: This meeting report aims to present findings from a summit on the current state of medical school education in sexual health and provides recommended strategies to better train physicians to address sexual health. METHODS.: To catalyze improvements in sexual health education in medical schools, the summit brought together key U.S. and Canadian medical school educators, sexual health educators, and other experts. Attendees reviewed and discussed relevant data and potential recommendations in plenary sessions and then developed key recommendations in smaller breakout groups. RESULTS.: Findings presented at the summit demonstrate that the United States and Canada have high rates of poor sexual health outcomes and that sexual health education in medical schools is variable and in some settings diminished. To address these issues, government, professional, and student organizations are working on efforts to promote sexual health. Several universities already have sexual health curricula in place. Evaluation mechanisms will be essential for developing and refining sexual health education. CONCLUSIONS.: To be effective, sexual health curricula need to be integrated longitudinally throughout medical training. Identifying faculty champions and supporting student efforts are strategies to increase sexual health education. Sexual health requires a multidisciplinary approach, and cross-sector interaction between various public and private entities can help facilitate change. Areas important to address include: core content and placement in the curriculum; interprofessional education and training for integrated care; evaluation mechanisms; faculty development and cooperative strategies. Initial recommendations were drafted for each.


Three-dimensional micro-computed tomographic evaluation of periodontal regeneration: a human report of intrabony defects treated with Bio-Oss collagen.
This study utilized three-dimensional micro-computed tomography (micro-CT) to evaluate the regenerative response to Bio-Oss Collagen when used alone or in combination with a Bio-Gide bilayer collagen membrane for the treatment of four intrabony defects (5 to 7 mm) around single-rooted teeth. The micro-CT observations are compared to the clinical, radiographic, and histologic results, which have been previously reported. After reflecting a full-thickness flap, thorough degranulation and root planing were accomplished. Bio-Oss Collagen was then used to fill the defects, and in two cases a Bio-Gide membrane was placed over the filled defect. Radiographs, clinical probing depths, and attachment levels were obtained before treatment and immediately preceding en bloc resection of teeth and surrounding tissues 9 months later. A mean pocket depth reduction of 5.75 mm and mean clinical attachment level gain of 5.25 mm were recorded. The histologic evaluation demonstrated the formation of a complete new attachment apparatus with new cementum, periodontal ligament, and alveolar bone at the level of and coronal to the calculus reference notch. Micro-CT evaluation confirmed the histologic results and demonstrated the absence of ankylosis or root resorption for all specimens. This human histologic study demonstrated that Bio-Oss Collagen has the capacity to facilitate regeneration of the periodontal attachment apparatus when placed in intrabony defects. Micro-CT observations confirmed the histologic results and enhanced the three-dimensional understanding of periodontal wound healing. The results indicate that micro-CT may be useful for three-dimensional evaluation of periodontal regenerative procedures.


First record of the Miocene hominoid Sivapithecus from Kutch, Gujarat state, western India.
Hominoid remains from Miocene deposits in India and Pakistan have played a pivotal role in understanding the evolution of great apes and humans since they were first described in the 19th Century. We describe here a hominoid maxillary fragment preserving the canine and cheek teeth collected in 2011 from the Kutch (= Kachchh) basin in the Kutch district, Gujarat state, western India. A basal Late Miocene age is proposed based on the associated faunal assemblage that includes Hipparion and other age-diagnostic mammalian taxa. Miocene Hominoidea are known previously from several areas of the Siwalik Group in the outer western Himalayas of India, Pakistan, and Nepal. This is the first record of a hominoid from the Neogene of the Kutch Basin and represents a significant southern range extension of Miocene hominoids in the Indian peninsula. The specimen is assigned to the Genus Sivapithecus, species unspecified.


Long-term results of cemented total hip arthroplasty in patients younger than 30 years and the outcome of subsequent revisions.
The number of total hip arthroplasties in patients under 30 years is increasing over the years. Almost all of them will face at least one or more future revisions in their life. Therefore, the implant used should have a high survival rate, and needs to be easily revisable resulting in a low re-revision rate. Several studies have evaluated the outcome of total hip arthroplasties in patients under 30 years. However, only a few reported on the follow-up outcome of 10 years or more. In addition, none of these reports published data of the subsequent revisions of these implants within their original report. We studied historically prospective collected data of 48 consecutive patients (69 hips) younger than 30 years, treated with a cemented primary total hip prosthesis between 1988 and 2004. Since the last evaluation of this cohort, two patients were lost to follow-up. For all hip revisions in this cohort, again cemented implants were used, mostly in combination with bone impaction grafting. Kaplan-Meier survival curves at 10- and 15 years for the primary total hip arthroplasties and revisions were determined. The mean age at time of primary surgery was 25 years (range, 16 to 29 years). Mean follow-up of the primary hips was 11.5 years (range, 7 to 23 years). During follow-up 13 revisions were performed; in 3 cases a two-stage total revision was performed for septic loosening and 9 cups were revised for aseptic loosening. There were no aseptic stem revisions. The 10 and 15-year survival rates with endpoint revision for aseptic loosening of the primary total hip were 90% (95% CI: 79 to 96) and 82% (95% CI: 65 to 92) respectively. None of our 13 subsequent revisions needed a re-revision within 10 years after re-implantation. Cemented total hip implants in patients under 30 years have an encouraging outcome at 10 and 15 years after surgery in these young patients. The 13 revised hips, treated with bone grafting and the third generation cement technique, were performing well with no re-revisions within ten years after surgery.


Effects of land use change on soil carbon storage and water consumption in an oasis-desert ecotone.
Land use and ecosystem services need to be assessed simultaneously to better understand the relevant factors in sustainable land management. This paper analyzed land use changes in the middle reach of the arid Heihe River Basin in northwest China over the last two decades and their impacts on water resources and soil organic carbon (SOC) storage. The results indicated that from 1986 to 2007: (1) cropland and human settlements expanded by 45.0 and 17.6%, respectively, at the expense of 70.1, 35.7, and 4.1% shrinkage on woodland, grassland, and semi-shrubby desert; (2) irrigation water use was dominant and increased (with fluctuations) at an average rate of 8.2%, while basic human water consumption increased monotonically over a longer period from 1981 to 2011 at a rate of 58%; and (3) cropland expansion or continuous cultivation led to a significant reduction of SOC, while the land use transition from grassland to semi-shrubby desert and the progressive succession of natural ecosystems such as semi-shrubby desert and grassland, in contrast, can bring about significant carbon sequestration benefits. The increased water consumption and decreased SOC pool associated with some observed land use changes may induce and aggravate potential ecological risks for both local and downstream ecosystems, including water resource shortages, soil quality declines, and degeneration of natural vegetation. Therefore, it is necessary to balance socioeconomic wellbeing and ecosystem services in land use planning and management for the sustainability of socio-ecological systems across spatiotemporal scales, especially in resource-poor arid environments.


Inside the structure of a nanocomposite electrolyte membrane: how hybrid particles get along with the polymer matrix.
Hybrid materials remain the target for a fruitful range of investigations, especially for energy devices. A number of hybrid electrolyte membranes consisting of inorganic and organic phases were then synthesized. Mechanical, solvent uptake and ionic transport properties were studied with the key point being the characteristic length scale of the interaction between the phases. A group of nanocomposite membranes made of polystyrenesulfonic acid-grafted silica particles embedded in a Poly(Vinylidene Fluoride-co-HexaFluoroPropene) (PVdF-HFP) matrix was studied by combining neutron and X-ray scatterings on the nanometer to angstrom scale. This approach allows for the variation in the morphology and structure as a function of particle loading to be described. These studies showed that the particles aggregate with increasing particle loading and these aggregates swell, creating a physical interaction with the polymer matrix. Particle loadings lower than 30 wt% induce a slight strain between both of the subphases, namely the polymer matrix and the particles. This strain is decreased with particle loading between 20 and 30 wt% conjointly with the beginning of proton conduction. Then the percolation of the aggregates is the beginning of a significant increase of the conduction without any strain. This new insight can give information on the variation in other important intrinsic properties.


The Developmental Profile Inventory: Constructing a Clinically Useful Self-Report for Levels of Psychodynamic Personality Functioning.
The Developmental Profile Inventory (DPI) was constructed to assess psychodynamic personality functioning by self-report. On the basis of the frame of reference of the Development Profile interview method, a self-report was developed covering 3 domains, self, interpersonal functioning, and problem-solving strategies, which represent 6 maladaptive and 3 adaptive developmental levels of psychodynamic functioning. The DPI was administered to patients with personality disorders who were receiving psychotherapy (N=179) and to normal controls (N=228). The internal reliabilities of the subscales were in general in the fair to good range in the patient sample, (α=0.67 to 0.88, ωh=0.52 to 0.87) and adequate to good in the healthy controls (α=0.71 to 0.91, ωh=0.71 to 0.90). Mean item-rest correlations were adequate (0.30 to 0.50). Test-retest reliability was good (intraclass correlation=0.73 to 0.91). The hypothesized factorial structure of the DPI with 9 subscales organized in 3 clusters was partly confirmed by confirmatory factor analysis χ/df=2.37, root mean square error of approximation=0.060, root mean residual square=0.078, and comparative fit index=0.630, with each factor showing over 80% standardized loadings >0.30, and at least 75% loadings >0.40. The DPI discriminated patients and healthy controls in a meaningful way. Correlations among the DPI and other self-report measures of global personality pathology and psychological complaints showed satisfactory convergent and discriminant validity. The DPI is a promising self-report measure for assessing both adaptive and maladaptive patterns of psychodynamic personality functioning. The appropriate initial psychometric properties justify proceeding with more formal tests of construct validity and predictive performance in broader mental health settings.


Medical University admission test: a confirmatory factor analysis of the results.
The Graz Admission Test has been applied since the academic year 2006/2007. The validity of the Test was demonstrated by a significant improvement of study success and a significant reduction of dropout rate. The purpose of this study was a detailed analysis of the internal correlation structure of the various components of the Graz Admission Test. In particular, the question investigated was whether or not the various test parts constitute a suitable construct which might be designated as "Basic Knowledge in Natural Science." This study is an observational investigation, analyzing the results of the Graz Admission Test for the study of human medicine and dentistry. A total of 4741 applicants were included in the analysis. Principal component factor analysis (PCFA) as well as techniques from structural equation modeling, specifically confirmatory factor analysis (CFA), were employed to detect potential underlying latent variables governing the behavior of the measured variables. PCFA showed good clustering of the science test parts, including also text comprehension. A putative latent variable "Basic Knowledge in Natural Science," investigated by CFA, was indeed shown to govern the response behavior of the applicants in biology, chemistry, physics, and mathematics as well as text comprehension. The analysis of the correlation structure of the various test parts confirmed that the science test parts together with text comprehension constitute a satisfactory instrument for measuring a latent construct variable "Basic Knowledge in Natural Science." The present results suggest the fundamental importance of basic science knowledge for results obtained in the framework of the admission process for medical universities.


Community-based approaches and partnerships: innovations in health-service delivery in Bangladesh.
In Bangladesh, rapid advancements in coverage of many health interventions have coincided with impressive reductions in fertility and rates of maternal, infant, and childhood mortality. These advances, which have taken place despite such challenges as widespread poverty, political instability, and frequent natural disasters, warrant careful analysis of Bangladesh's approach to health-service delivery in the past four decades. With reference to success stories, we explore strategies in health-service delivery that have maximised reach and improved health outcomes. We identify three distinctive features that have enabled Bangladesh to improve health-service coverage and health outcomes: (1) experimentation with, and widespread application of, large-scale community-based approaches, especially investment in community health workers using a doorstep delivery approach; (2) experimentation with informal and contractual partnership arrangements that capitalise on the ability of non-governmental organisations to generate community trust, reach the most deprived populations, and address service gaps; and (3) rapid adoption of context-specific innovative technologies and policies that identify country-specific systems and mechanisms. Continued development of innovative, community-based strategies of health-service delivery, and adaptation of new technologies, are needed to address neglected and emerging health challenges, such as increasing access to skilled birth attendance, improvement of coverage of antenatal care and of nutritional status, the effects of climate change, and chronic disease. Past experience should guide future efforts to address rising public health concerns for Bangladesh and other underdeveloped countries.


The association of genomic lesions and PD-1/PD-L1 expression in resected triple-negative breast cancers.
Elevated PD-L1 expression on tumor cells, a context associated with an adaptive immune response, has been linked to the total burden of copy number variants (CNVs) in aneuploid tumors, to microsatellite instability (MSI), and to specific genomic driver lesions, including loss of PTEN, MYC amplification, and activating mutations in driver oncogenes such as KRAS and PIK3CA. Triple-negative breast cancers (TNBCs) typically have high levels of CNVs and diverse driver lesions in their genomes. Thus, there is significant interest in exploiting genomic data to develop predictive immunotherapy biomarkers for patients with TNBC. Whole tissue samples from 55 resected TNBCs were screened by immunohistochemistry (IHC) for PD-1 and PD-L1 by using validated antibodies and established scoring methods for staining of tumor and non-tumor cells. In parallel, we interrogated biopsies from each resection with DNA content flow cytometry and sorted the nuclei of diploid, tetraploid, and aneuploid cell populations. CNVs were mapped with CNV oligonucleotide arrays by using purified (>95%) tumor populations. We generated whole exome data for 12 sorted tumor samples to increase the resolution within loci of interest and to incorporate somatic mutations into our genomic signatures. PD-L1 staining was detected on tumor cells in 29 out of 54 (54%) evaluable cases and was associated with increased overall survival (P = 0.0024). High levels of PD-1 and PD-L1 (IHC ≥4) were present in 11 out of 54 (20%) and 20 out of 54 (37%) cases with staining of PD-L1 primarily on tumor cells for 17 out of 20 (85%) cases. The latter included tumors with both high (>50) and low (<20) numbers of CNVs. Notably, homozygous deletion of PTEN (n = 6) or activating mutation in PIK3CA (n = 1) was not associated with increased expression of either immune checkpoint activator in TNBC. In contrast, two treatment-naïve cases with EGFR driver amplicons had high PD-L1 tumor staining. High mutational load and predicted neoepitopes were observed in MSI+ and high CNV burden TNBCs but were not associated with high PD-L1 expression on tumor cells. Our results challenge current models of genomic-based immunotherapy signatures yet suggest that discrete genomic lesions may complement existing biomarkers to advance immune checkpoint therapies for patients with TNBC.


Acceptable risks and burdens for children in research without direct benefit: a systematic analysis of the decisions made by the Dutch Central Committee.
To evaluate whether the requirement of "minimal risk and burden" for paediatric research without direct benefit to the subjects compromises the ability to obtain data necessary for improving paediatric care. To provide evidence-based reflections on the EU recommendation that allows for a higher level of risk. Systematic analysis of the approval/rejection decisions made by the Dutch Central Committee on Research involving Human Subjects (CCMO). The analysis included 165 proposals for paediatric research without direct benefit that were reviewed by the CCMO between January, 2000, and July, 2007. A separate, in-depth analysis of all drug studies included 18 early phase drug studies and nine other drug studies without direct benefit. 11 out of 165 studies were definitively rejected because the CCMO did not regard the risk and/or burden to be minimal. In three of these 11 cases (including two early phase drug studies) the requirement of minimal risk and burden was cited as the only reason for rejection. Four other early phase drug studies also involved risks and/or burdens that were not regarded to be minimal but were nevertheless approved. The requirement of minimal risk and burden, aiming to protect research subjects, occasionally leads to rejection of protocols. Early phase drug studies relatively often do not comply with the requirement. Committees may find ways to approve important studies that formally should be rejected, but that is not a desirable solution. The regulatory framework should be revised to make such occasional exceptions to the requirement legitimate and transparent.


Modeling variation in tumors in vivo.
Transgenic mice that allow mutant cells to be visualized in situ were used to study variation in tumors. These mice carry the G11 placental alkaline phosphatase (PLAP) transgene, a mutant allele rendered incapable of producing its enzyme product by a frameshift caused by insertion of a tract of G:C base pairs in a coding region. Spontaneous deletion of one G:C base pair from this tract restores gene function, and cells with PLAP activity can be detected histochemically. To study tumors, the G11 PLAP transgene was introduced into the polyoma virus middle T antigen mammary tumor model. Tumors in these mice exhibited up to 300 times more PLAP+ cells than normal tissues. PLAP+ cells were located throughout each tumor. Many of the PLAP+ cells were singlets, but clusters also were common, with one cluster containing >30,000 cells. Comparison of these data to simulations produced by computer models suggested that multiple factors were involved in generating mutant cells in tumors. Although genetic instability appeared to have occurred in most tumors, large clusters were much more common than expected based on instability alone.


Combined multispectroscopic and molecular docking investigation on the interaction between strictosamide and human serum albumin.
The interaction between strictosamide (STM) and human serum albumin (HSA) was investigated by fluorescence spectroscopy, synchronous fluorescence spectroscopy, three-dimensional fluorescence spectroscopy, ultraviolet-visible absorption spectroscopy, circular dichroism spectroscopy and molecular modeling under physiological pH 7.4. STM effectively quenched the intrinsic fluorescence of HSA via static quenching. The binding site number n and apparent binding constant K(a) were determined at different temperatures by fluorescence quenching. The thermodynamic parameters, enthalpy change (ΔH) and entropy change (ΔS) for the reaction were calculated as -3.01 kJ/mol and 77.75 J/mol per K, respectively, which suggested that the hydrophobic force played major roles in stabilizing the HSA-STM complex. The distance r between donor and acceptor was obtained to be 4.10 nm according to Förster's theory. After the addition of STM, the synchronous fluorescence and three-dimensional fluorescence spectral results showed that the hydrophobicity of amino acid residues increased and the circular dichroism spectral results showed that the α-helix content of HSA decreased (from 61.48% to 57.73%). These revealed that the microenvironment and conformation of HSA were changed in the binding reaction. Furthermore, the study of molecular modeling indicated that STM could bind to site I of HSA and the hydrophobic interaction was the major acting force, which was in agreement with the binding mode study.


Mechanobiological implications of articular cartilage crystals.
Calcium crystals exist in both pathological and normal articular cartilage. The prevalence of these crystals dramatically increases with age, and crystals are typically found in osteoarthritic cartilage and synovial fluid. Relatively few studies have examined the effects of crystals on cartilage biomechanics or chondrocyte mechanotransduction. The purpose of this review is to describe how crystals could influence cartilage biomechanics and mechanotransduction in osteoarthritis. Crystals are found in both loaded and unloaded regions of articular cartilage. Exogenous crystals, in combination with joint motion, result in substantial joint inflammation. Articular cartilage vesicles promote crystal formation, and these vesicles are found near the periphery of chondrocytes. Crystallographic studies report monoclinic symmetry for synthetic crystals, suggesting that crystals will have a large stiffness compared with the cartilage extracellular matrix, the pericellular matrix, or the chondrocyte. This stiffness imbalance may cause crystal-induced dysregulation of chondrocyte mechanotransduction promoting both aging and osteoarthritis chondrocyte phenotypes. Because of their high stiffness compared with cartilage matrix, crystals likely alter chondrocyte mechanotransduction, and high concentrations of crystals within cartilage may alter macroscale biomechanics. Future studies should focus on understanding the mechanical properties of joint crystals and developing methods to understand how crystals affect chondrocyte mechanotransduction.


Evidence for involvement of opioid receptors in ischemic preconditioning in rat hearts.
The purpose of the present study was to investigate a possible role of opioid receptors in ischemic preconditioning (PC). To test this hypothesis, anesthetized, open-chest, male Wistar rats were subjected to five different protocols. In group I, the control group was subjected to 30 min of left coronary artery occlusion and 2 h of reperfusion. In group II, ischemic PC was elicited by three 5-min occlusion periods interspersed with 5 min of reperfusion. In group III, naloxone (NL, 3 mg/kg iv), a nonselective opioid antagonist, was given to nonpreconditioned rats 10 min before the 30-min occlusion period. Finally, NL was administered 10 min before preconditioning (NL + PC, group IV) or immediately after the last 5-min preconditioning period (PC + NL, group V). Infarct size (IS) as a percentage of the area at risk (AAR) (IS/AAR) was determined by 2,3,5-triphenyltetrazolium chloride staining. PC resulted in a marked reduction in myocardial IS from 45 +/- 5 to 8 +/- 1 (P < 0.05). NL treatment before or immediately after PC abolished this protective effect; however, NL had no effect on IS in non-PC rats. These results are the first to support the hypothesis that activation of opioid receptors may play an important role in ischemic PC in the rat myocardium.


Endangering safe motherhood in Mozambique: prenatal care as pregnancy risk.
Despite high infant and maternal mortality rates, many Mozambican women with access to prenatal services delay prenatal clinic consultations, limiting opportunity for prevention and treatment of preventable pregnancy complications. Ethnographic research, interviews with health providers and longitudinal pregnancy case studies with 83 women were conducted in Central Mozambique to examine pregnant women's underutilization of clinic-based prenatal services. The study found that pregnancy beliefs and prenatal practices reflect women's attempts to influence reproduction under conditions of vulnerability at multiple levels. Women reported high maternal reproductive morbidity, frequent pregnancy wastage, and immense pressure to bear children throughout their reproductive years. Reproductive vulnerability is intensified by poverty and an intense burden placed on poor, peri-urban women farmers for family subsistence and continuous fertility in a period of economic austerity, land shortages, and increasing social conflict and inequality. In this environment of economic insecurity exacerbated by congested living conditions, women report competing for scarce resources, including male support and income. This vulnerability heightens women's perceptions that they and their unborn infants will be targets of witchcraft or sorcery by jealous neighbors and kin. They respond by hiding pregnancy and delaying prenatal care. Within the context of women's perceived reproductive risks, delayed prenatal care can be seen as a strategy to protect pregnancy from purposeful human and spirit harm. Women mobilized limited resources to acquire prenatal care outside the formal clinic setting. It is concluded that provision of clinical prenatal services is insufficient to reduce reproductive risks for the most socially and economically marginal since it is their vulnerability that prevents women from using available services. Confidential maternity services and social safety nets for greater economic security are recommended.


The adolescent HIV executive function and drumming (AHEAD) study, a feasibility trial of a group drumming intervention amongst adolescents with HIV.
AHEAD feasibility trial assessed the feasibility and acceptability of an 8-session group drumming programme aiming to improve executive function, depression and anxiety symptoms, and perceived social support in adolescents living with HIV in a rural low-income South African setting. Sixty-eight 12- to 19-year-old adolescents participated. They were individually randomised. The intervention arm (n = 34) received weekly hour-long group drumming sessions. Controls (n = 34) received no intervention. Feasibility and acceptability were assessed using rates of: enrolment; retention; attendance; logistical problems; adolescent-reported acceptability. Secondary measures included: five Oxford Cognitive Screen-Executive Function (OCS-EF) tasks; two Rapid Assessment of Cognitive and Emotional Regulation (RACER) tasks; the Self-Reporting Questionnaire-20 (SRQ-20) measuring depression and anxiety symptoms; the Multidimensional Scale of Perceived Social Support (MSPSS). All feasibility criteria were within green progression limits. Enrolment, retention, and acceptability were high. There was a positive effect on adolescent depressed mood with signal for a working memory effect. There were no significant effects on executive function or socio-emotional scales. Qualitative findings suggested socio-emotional benefits including: group belonging; decreased internalised stigma; improved mood; decreased anxiety. Group drumming is a feasible and acceptable intervention amongst adolescents living with HIV in rural South Africa. A full-scale trial is recommended.


A phase I, first-in-human, randomized dose-escalation study of anti-activated factor XII monoclonal antibody garadacimab.
Factor XII (FXII) is the principal initiator of the plasma contact system and has proinflammatory and prothrombotic activities. This single-center, first-in-human phase I study aimed to assess the safety and tolerability of single escalating doses of garadacimab, a monoclonal antibody that specifically inhibits activated FXII (FXIIa), in healthy male volunteers. Volunteers were randomized to eight cohorts, with intravenous (i.v.) doses of 0.1, 0.3, 1, 3, and 10 mg/kg and subcutaneous (s.c.) doses of 1, 3, and 10 mg/kg. Six volunteers in each cohort received garadacimab or placebo in a ratio of 2:1. Follow-up for safety lasted 85 days after dosing. Blood samples were collected throughout for pharmacokinetic/pharmacodynamic analysis. Forty-eight volunteers were enrolled: 32 received garadacimab and 16 received placebo. Most volunteers experienced at least one treatment-emergent adverse event (TEAE), predominantly grade 1. No serious TEAEs, deaths, or TEAEs leading to discontinuation were reported. No volunteers tested positive for garadacimab antidrug antibodies. Garadacimab plasma concentrations increased in a dose-dependent manner. Sustained inhibition of FXIIa-mediated kallikrein activity beyond day 28 resulted from 3 and 10 mg/kg garadacimab (i.v. and s.c.). A dose-dependent increase in activated partial thromboplastin time with no change in prothrombin time was demonstrated. Garadacimab (single-dose i.v. and s.c.) was well-tolerated in healthy volunteers. Dose-dependent increases in plasma concentration and pharmacodynamic effects in relevant kinin and coagulation pathways were observed. These results support the clinical development of garadacimab, including in phase II studies in hereditary angioedema and coronavirus disease 2019 (COVID-19).


Histidine decarboxylase but not histamine receptor 1 or 2 deficiency protects from K/BxN serum-induced arthritis.
Serum transfer from arthritic K/BxN mice into naive animals results in arthritis. Mast cells have been shown to be essential since mice lacking these cell type do not develop arthritis upon serum injection. Mast cell function depends on the release of granules filled with mediators such as histamine. Mice deficient in histidine decarboxylase (HDC(-/-)) that do not produce histamine and mice deficient for histamine receptor 1 (H1R(-/-)) or histamine receptor 2 (H2R(-/-)) were injected with arthritogenic sera from the K/BxN mice, and the progression of arthritis was observed through the next 2 weeks. HDC(-/-) mice that are histamine free developed a milder form of arthritis in comparison with the wild-type controls. In both receptor-deficient mice as well as in wild-type controls, the onset and severity of clinical arthritis and ankle thickening occurred during day 1 to 3. These results indicate that histamine is required but not indispensable for the development of serum-induced arthritis and histamine receptors other than those studied here may be involved.


Stasis and adaptation.
Many of our most pressing societal challenges arise from our inability to move on from present practices and structures and do what is needed. Healthcare struggles to improve safety and quality. It resists adoption of best practices and persists in high levels of unwarranted variation in care delivery, and clings to financially unsustainable models of care. One explanation for this state of affairs is not a lack of will, but that we are experiencing system inertia--a consequence of the increasing complexity of our human systems. In this paper I explore three possible system level interventions that may help design systems that are less likely to approach inertia, as well as help change our current systems so that they again become adaptive, and move to the outcomes we desire. Firstly, I question our religious belief in the power of standards, an intervention designed to minimise adaptation and almost from first principles designed to lead to inertia. Next I explore the power of apoptosis, a process that sees existing structures and practices programmatically removed to free up resource for adaptation. Finally I explore a flexible but controversial approach to system management called market-based control. Whether any of these, together or in tandem, are a way out of inertia is an open question. However, it is time for us to engage with the challenge of system inertia, and find a way out.


Obesity considerations during the COVID-19 outbreak.
The worldwide population is facing a double burden of epidemic, the COVID-19 and obesity. This is even more alarming as obesity increases the COVID-19 severity. However, the relationship between obesity and COVID-19 severity is more complex than a simple association with BMI. In particular, obesity has been associated with low death rates in patients with acute respiratory distress syndrome, a fatal comorbidity to COVID-19, possibly due to the obesity paradox. Also, visceral adiposity could be a major risk factor for COVID-19 severity, due to its immune activation component, release of angiotensin-converting enzyme 2 and involvement in the cytokine storm, hypercoagulability and embolism. A poor antioxidant nutritional status also weakens the immune system, increasing inflammation and infection risk. Moreover, the COVID-19 lockdown might impact lifestyle patterns, mental health and weight bias, worsening the obesity then COIVD-19 situation. On the other hand, health care expenses and productivity loss are expected to increase during the concomitant epidemics. The co-occurrence of obesity and COVID-19 is a major challenge at both public health and economic levels that should urgently be taken into consideration. The identification of COVID-19 weight related risk factors and the development of appropriate weight management programs are needed to tackle the concomitant epidemics.


Molecular phylogeny of the scincid lizards of New Caledonia and adjacent areas: evidence for a single origin of the endemic skinks of Tasmantis.
We use approximately 1900bp of mitochondrial (ND2) and nuclear (c-mos and Rag-1) DNA sequence data to recover phylogenetic relationships among 58 species and 26 genera of Eugongylus group scincid lizards from New Caledonia, Lord Howe Island, New Zealand, Australia and New Guinea. Taxon sampling for New Caledonian forms was nearly complete. We find that the endemic skink genera occurring on New Caledonia, New Zealand and Lord Howe Island, which make up the Gondwanan continental block Tasmantis, form a monophyletic group. Within this group New Zealand and New Zealand+Lord Howe Island form monophyletic clades. These clades are nested within the radiation of skinks in New Caledonia. All of the New Caledonian genera are monophyletic, except Lioscincus. The Australian and New Guinean species form a largely unresolved polytomy with the Tasmantis clade. New Caledonian representatives of the more widespread genera Emoia and Cryptoblepharus are more closely related to the non-Tasmantis taxa than to the endemic New Caledonian genera. Using ND2 sequences and the calibration estimated for the agamid Laudakia, we estimate that the diversification of the Tasmantis lineage began at least 12.7 million years ago. However, using combined ND2 and c-mos data and the calibration estimated for pygopod lizards suggests the lineage is 35.4-40.74 million years old. Our results support the hypothesis that skinks colonized Tasmantis by over-water dispersal initially to New Caledonia, then to Lord Howe Island, and finally to New Zealand.


Review article: dose optimisation of infliximab for acute severe ulcerative colitis.
Although optimal medical management of acute severe ulcerative colitis (UC) is ill-defined, infliximab has become a standard of care. Accumulating evidence suggests an increased rate of infliximab clearance in patients with acute severe UC and a reduced colectomy rate with an intensified infliximab induction regimen. To assess the strength of the current evidence for the relationship between infliximab pharmacokinetics, dosing strategies and disease behaviour in patients with acute severe UC. We systematically searched MEDLINE and conference proceedings from 2000 to 2016 for relevant articles describing the pharmacokinetics of infliximab in acute severe UC and/or infliximab dose intensification strategies in acute severe UC. Eligible articles described randomised controlled trials, and cohort, cross-sectional, and case-controlled studies. Of 400 citations identified, 76 studies were eligible. Increased infliximab clearance occurs in patients with acute severe UC, and is driven by the total inflammatory burden and leakage of drug into the colonic lumen. Several cohort studies suggest that infliximab dose intensification is beneficial to at least 50% of acute severe UC patients and the results of case-controlled studies indicate that an intensified infliximab dosing regimen with 1-2 additional infusions in the first 3 weeks of treatment could reduce the early (3-month) colectomy rate by up to 80%, although these data require prospective validation. Uncontrolled studies suggest a benefit for infliximab dose optimisation in patients with acute severe UC. A randomised controlled trial in acute severe UC patients comparing a personalised infliximab dose-optimisation strategy with conventional dosing is a research priority.


A protein profile of visceral adipose tissues linked to early pathogenesis of type 2 diabetes mellitus.
Adipose tissue is increasingly recognized as an endocrine organ playing important pathophysiological roles in metabolic abnormalities, such as obesity, cardiovascular disease, and type 2 diabetes mellitus (T2DM). In particular, visceral adipose tissue (VAT), as opposed to subcutaneous adipose tissue, is closely linked to the pathogenesis of insulin resistance and T2DM. Despite the importance of VAT, its molecular signatures related to the pathogenesis of T2DM have not been systematically explored. Here, we present comprehensive proteomic analysis of VATs in drug-naïve early T2DM patients and subjects with normal glucose tolerance. A total of 4,707 proteins were identified in LC-MS/MS experiments. Among them, 444 increased in abundance in T2DM and 328 decreased. They are involved in T2DM-related processes including inflammatory responses, peroxisome proliferator-activated receptor signaling, oxidative phosphorylation, fatty acid oxidation, and glucose metabolism. Of these proteins, we selected 11 VAT proteins that can represent alteration in early T2DM patients. Among them, up-regulation of FABP4, C1QA, S100A8, and SORBS1 and down-regulation of ACADL and PLIN4 were confirmed in VAT samples of independent early T2DM patients using Western blot. In summary, our profiling provided a comprehensive basis for understanding the link of a protein profile of VAT to early pathogenesis of T2DM.


Health care provider advice for African American adults not meeting health behavior recommendations.
Poor dietary habits and sedentary lifestyle contribute to excessive morbidity and mortality. Healthy People 2010 goals are for 85% of physicians to counsel their patients about physical activity and for 75% of physician office visits made by patients with cardiovascular disease, diabetes, or dyslipidemia to include dietary counseling. The purpose of this study was to 1) determine the rate of participant-reported health care provider advice for healthy lifestyle changes among African Americans who do not meet recommendations for physical activity, fruit and vegetable consumption, and healthy weight; 2) examine correlates of provider advice; and 3) assess the association between provider advice and stage of readiness for change for each of these health behaviors. Data for this study were collected as part of a statewide faith-based physical activity program for African Americans. A stratified random sample of 20 African Methodist Episcopal churches in South Carolina was selected to participate in a telephone survey of members aged 18 years and older. The telephone survey, conducted over a 5-month period, asked participants a series of questions about sociodemographics, health status, physical activity, and nutrition. Analyses for moderate to vigorous physical activity, fruit and vegetable consumption, and weight loss were conducted separately. For each of these behaviors, logistic regression analyses were performed to examine the independent association of sex, age, body mass index, education, number of diagnosed diseases, perceived health, and stage of change with health care provider advice for health behaviors. A total of 572 church members (407 women, 165 men; mean age, 53.9 years; range, 18-102 years) completed the survey. Overall, participant-reported provider advice for lifestyle changes was 47.0% for physical activity, 38.7% for fruit and vegetable consumption, and 39.7% for weight. A greater number of diagnosed diseases and higher body mass index were independently associated with receiving advice to increase physical activity. A more advanced stage of change and a greater number of diagnosed diseases were independently associated with receiving advice for fruit and vegetable consumption. Body mass index, stage of change, and poorer perceived health were independently associated with receiving advice about weight. Health care provider advice appears to be based predominantly on comorbidities. Because of the preventive benefit of physical activity, fruit and vegetable consumption, and healthy weight, all health care providers are urged to increase counseling for all patients not meeting health behavior recommendations.


Examining evidence for behavioural mimicry of parental eating by adolescent females. An observational study.
Behavioural mimicry is a potential mechanism explaining why adolescents appear to be influenced by their parents' eating behaviour. In the current study we examined whether there is evidence that adolescent females mimic their parents when eating. Videos of thirty-eight parent and female adolescent dyads eating a lunchtime meal together were examined. We tested whether a parent placing a food item into their mouth was associated with an increased likelihood that their adolescent child would place any food item (non-specific mimicry) or the same item (specific mimicry) in their mouth at three different time frames, namely, during the same second or within the next fifteen seconds (+15), five seconds (+5) or two second (+2) period. Parents and adolescents' overall food intake was positively correlated, whereby a parent eating a larger amount of food was associated with the adolescent eating a larger meal. Across all of the three time frames adolescents were more likely to place a food item in their mouth if their parent had recently placed that same food item in their mouth (specific food item mimicry); however, there was no evidence of non-specific mimicry. This observational study suggests that when eating in a social context there is evidence that adolescent females may mimic their parental eating behaviour, selecting and eating more of a food item if their parent has just started to eat that food.


Phylogeny and phylogenetic classification of the antbirds, ovenbirds, woodcreepers, and allies (Aves: Passeriformes: infraorder Furnariides).
The infraorder Furnariides is a diverse group of suboscine passerine birds comprising a substantial component of the Neotropical avifauna. The included species encompass a broad array of morphologies and behaviours, making them appealing for evolutionary studies, but the size of the group (ca. 600 species) has limited well-sampled higher-level phylogenetic studies. Using DNA sequence data from the nuclear RAG-1 and RAG-2 exons, we undertook a phylogenetic analysis of the Furnariides sampling 124 (more than 88%) of the genera. Basal relationships among family-level taxa differed depending on phylogenetic method, but all topologies had little nodal support, mirroring the results from earlier studies in which discerning relationships at the base of the radiation was also difficult. In contrast, branch support for family-rank taxa and for many relationships within those clades was generally high. Our results support the Melanopareidae and Grallariidae as distinct from the Rhinocryptidae and Formicariidae, respectively. Within the Furnariides our data contradict some recent phylogenetic hypotheses and suggest that further study is needed to resolve these discrepancies. Of the few genera represented by multiple species, several were not monophyletic, indicating that additional systematic work remains within furnariine families and must include dense taxon sampling. We use this study as a basis for proposing a new phylogenetic classification for the group and in the process erect new family-group names for clades having high branch support across methods.


Welfare reform and female headship.
While much of the focus of recent welfare reforms has been on moving recipients from welfare to work, many reforms were also directed at decisions regarding living arrangements, pregnancy, marriage, and cohabitation. This article assesses the impact of welfare reform waivers and Temporary Assistance for Needy Families (TANF) programs on women's decisions to become unmarried heads of families, controlling for confounding influences from local economic and social conditions. We pooled data from the 1990, 1992, 1993, and 1996 panels of the Survey of Income and Program Participation, which span the period when many states began to adopt welfare waivers and to implement TANF, and estimated logit models of the incidence of female headship and state-stratified, Cox proportional hazard models of the rates of entry into and exit from headship. We found little consistent evidence that waivers affected female headship of families.


Identification of single-stranded-DNA-binding proteins that interact with muscle gene elements.
A sequence-specific DNA-binding protein from skeletal-muscle extracts that binds to probes of three muscle gene DNA elements is identified. This protein, referred to as muscle factor 3, forms the predominant nucleoprotein complex with the MCAT gene sequence motif in an electrophoretic mobility shift assay. This protein also binds to the skeletal actin muscle regulatory element, which contains the conserved CArG motif, and to a creatine kinase enhancer probe, which contains the E-box motif, a MyoD-binding site. Muscle factor 3 has a potent sequence-specific, single-stranded-DNA-binding activity. The specificity of this interaction was demonstrated by sequence-specific competition and by mutations that diminished or eliminated detectable complex formation. MyoD, a myogenic determination factor that is distinct from muscle factor 3, also bound to single-stranded-DNA probes in a sequence-specific manner, but other transcription factors did not. Multiple copies of the MCAT motif activated the expression of a heterologous promoter, and a mutation that eliminated expression was correlated with diminished factor binding. Muscle factor 3 and MyoD may be members of a class of DNA-binding proteins that modulate gene expression by their abilities to recognize DNA with unusual secondary structure in addition to specific sequence.


Biological and Immunogenicity Property of IgY Anti S. mutans ComD.
This study aims to elucidate the effect of IgY anti ComD on the biological properties of Streptococcus mutans. (S. mutans) ComD is an interspecies quorum-sensing signaling receptor that plays an important role in biofilm formation by S. mutans. Egg yolk IgY was produced by the immunization of chickens with a DNA vaccine containing the ComD DNA coding region. We evaluated the effect of the antibody on biofilm formation by S. mutans isolated from subjects with or without dental caries. We also assessed the immunoreactivity of the antibody against all isolates, and analyzed the protein profile of S. mutans by SDS-PAGE. The ComD antibody was successfully induced in the hens' eggs. It inhibited biofilm formation by all S. mutans isolates. In addition, the expression of some protein bands was affected after exposure to the antibody. IgY anti-S. mutans ComD reduces biofilm formation by this bacterium and alters the protein profile of S. mutans.


Flaxseed reduces the pro-carcinogenic micro-environment in the ovaries of normal hens by altering the PG and oestrogen pathways in a dose-dependent manner.
The objective of the present study was to find the optimum dose of flaxseed that would decrease PG and alter oestrogen pathway endpoints implicated in ovarian cancer. In the study, four groups of fifty 1.5-year-old chickens were fed different amounts of flaxseed (0, 5, 10 or 15% of their total diet) for 4 months and were then killed to collect blood and tissues. Levels of flaxseed lignan metabolites, Enterolactone (EL) and Enterodiol (ED) were measured in the serum, liver and ovaries by liquid chromatography-MS/MS, and n-3 and n-6 fatty acid (FA) levels were measured by GC. The effects of the varied flaxseed doses were assessed by measuring levels of PGE2 and oestrogen metabolites (16-hydroxyestrone (16-OHE1) and 2-hydroxyestrone (2-OHE1)) as well as by analysing the expression of the oestradiol metabolising enzymes CYP3A4 (cytochrome p450, family 3, subfamily A, polypeptide 4), CYP1B1 (cytochrome p450, family 1, subfamily B, polypeptide 1) and CYP1A1 (cytochrome p450, family 1, subfamily A, polypeptide 1) and that of oestrogen receptor α (ERα) in the ovaries. The ratio of n-3:n-FA increased with an increase in flaxseed supplementation and corresponded to a dose-dependent decrease in cyclo-oxygenase-2 protein and PGE2 levels. EL and ED increased in the serum, liver and ovaries with increased concentrations of flaxseed. Flaxseed decreased the expression of ERα in the ovaries. The ratio of 2-OHE1:16-OHE1 in the serum increased significantly in the 15% flaxseed diet, and there was a corresponding increase in CYP1A1 in the liver and decrease in CYP3A4 in the ovaries. CYP1B1 mRNA also decreased with flaxseed diet in the ovaries. The 15% flaxseed-supplemented diet significantly decreased inflammatory PGE2, ERα, CYP3A4, CYP1B1 and 16-OHE1, but it increased CYP1A1 and 2-OHE1, which thus reduced the inflammatory and pro-carcinogenic micro-environment of the ovaries.


Secondary immune response to hepatitis B virus vaccine in alcoholics.
The efficacy of full vaccination against hepatitis B virus (i.e., including the 1-year booster injection) was evaluated in 28 alcoholic patients with minimal liver disease. Although such patients are reportedly poor responders, the proportion of those protected (anti-HBs titer > = 10 mlU/ml) rose from 42.8% after primary immunization to 82% after the booster. The mean anti-HBs titer, which remained low in the overall group, was significantly lower in the subjects who resumed drinking during the follow-up period than in those who did not. This suggests a direct influence of alcohol itself on the response, because none of our patients had cirrhosis and none were clearly malnourished. Among the 17 patients for whom the 2-year post-booster anti-HBs titer could be determined, all those with a 1-month postbooster titer above 1000 mlU/ml still had a high anti-HBs level (> 100), whereas 80% of those with a 1-month postbooster titer < 1000 had 2 years later only a low (< 100) or even an unprotective anti-HBs level; this means that only the latter should be considered for a new booster injection. Our data indicate that protection against hepatitis B virus can be achieved in a good proportion of alcoholics with a full vaccination protocol. We suggest that efficacy should be evaluated 1 month after the booster, and that patients with low postbooster anti-HBs titers should be tested at regular intervals, because they can also be protected provided an adapted schedule of further injections is conducted.


First Report of Leptosphaeria biglobosa as a Stem Canker Pathogen of Brassicas in New Zealand.
Phoma black leg or stem canker, caused by Leptosphaeria maculans or L. biglobosa, is an important disease of brassicas, causing significant crop losses in areas such as Europe, Australia, and North America (1). Samples collected in 2011 from canola and forage brassica (swede, kale, and turnip) crops in the main New Zealand growing regions (Southland, Central Otago, Canterbury, Hawkes Bay, and Manawatu) to identify the causal agent(s) of the characteristic stem cankers, found many isolates of L. maculans, which has been reported previously in New Zealand (2), and three isolates identified by colony characteristics as L. biglobosa. Of the latter, two isolates were from canola (Brassica napus) stem cankers from Darfield and Lincoln, Canterbury, and one was from a kale (B. oleracea) stem canker from Lincoln. An isolate (ICMP10665) of similar morphology, from the International Collection of Microorganisms from Plants (ICMP), obtained from a basal rot lesion on a cauliflower (B. oleracea var. botrytis) plant in Levin, New Zealand in 1979, was also evaluated. The initial, incorrect identification of the latter isolate as L. maculans predates the reclassification of L. maculans group B isolates as a new species, L. biglobosa (1). These four isolates produced fluffy white mycelium and a yellow pigment on potato dextrose agar (PDA) after 5 days' growth, and abundant black-brown, globose pycnidia containing cylindrical hyaline conidia after 7 days. In contrast, L. maculans isolates had slower growth and no pigment production (4). Amplification of genomic DNA using species-specific primers LmacR, LmacF, and LbigF (1) generated a PCR product of 444 bp that is typical of L. biglobosa isolates. Sequencing of the PCR product from each of the four isolates showed they were 100% identical to a sequence of L. biglobosa 'brassicae' in GenBank (JF740198). To confirm the species identity of the isolates, the rDNA, actin, and β-tubulin gene regions were amplified (1,3). Sequences for the rDNA (568 bp), actin (941 bp), and β-tubulin (410 bp) gene regions were 99% identical to sequences of the same regions of isolates in GenBank for L. biglobosa 'brassicae' (AY48997, AY748949.1, and AY748997.1, respectively). The four L. biglobosa isolates were tested for pathogenicity on a canola cultivar commonly grown in New Zealand (Flash). Cotyledons of 10-day-old seedlings (n = 12 seedlings/isolate or control treatment) grown in a potting mix in pots were pricked with a sewing needle, and each wound inoculated with 10 μl of the appropriate conidial suspension (106 conidia/ml) or 10 μl sterilized distilled water for the control treatment. Leaf lesions that developed on the inoculated cotyledons were characteristic of those caused by L. biglobosa, i.e., small and dark with a distinct margin. No pycnidia were produced on the lesions. No lesions developed on the cotyledons of the non-inoculated control plants. The causal agents were confirmed as L. biglobosa by the colony morphology of isolates that grew from surface-sterilized, inoculated leaf lesions plated on PDA amended with 100 μg/ml ampicillin. The fungus was not isolated from control leaf tissue. To our knowledge, this is the first report of L. biglobosa as a pathogen of canola and kale in New Zealand. This finding shows that both causal agents of black leg are present in New Zealand's brassica cropping areas. References: (1) S. Y. Liu et al. Plant Pathol. 55:401, 2006. (2) H. C. Smith and B. C. Sutton. Trans. Brit. Mycol. Soc. 47:159, 1964. (3) L. Vincenot et al. Phytopathology 98:321, 2008. (4) R. H. Williams and B. D. L. Fitt. Plant Pathol. 48:161, 1999.


Hereditary periodic fever and reactive amyloidosis.
Hereditary periodic fever syndromes (HPF) are a group of diseases characterised by recurrences of fever and inflammation separated by symptom-free intervals. Familial Mediterranean fever (FMF) is the most frequent entity within this group of disorders which further consists of hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS), tumour necrosis factor receptor-associated periodic syndrome (TRAPS) and cryopyrin-associated periodic syndrome (CAPS). In recent years the causative genes have been identified. Reactive amyloidosis is a severe complication of HPFs. This is caused by deposition of fibrils that consist of the proteolytically cleaved acutephase protein serum amyloid A (SAA). Several factors have been identified that modulate the risk for developing amyloidosis, including SAA concentrations, polymorphisms in the SAA gene and ethnic origin. Furthermore, the risk of developing amyloidosis varies widely between the different HPFs. Colchicine is the cornerstone in the management of FMF, as it reduces the severity and frequency of attacks and is also effective in preventing amyloidosis. In the other HPFs, the introduction of anticytokine-based therapies is a promising new option in treating these inflammatory conditions and they potentially can prevent amyloidosis.


Real-time binding kinetic analyses of the interaction of the dietary stain orange II with dentin matrix.
Dietary stains can be adsorbed into the dentin of teeth. Using Orange II as a model dietary stain, this study investigated the strength of its interaction with the mineral and protein components of dentin matrix and how hydrogen peroxide (H2O2) treatment influences this interaction. Dentin slices were prepared from human teeth and were either deproteinized (5.6% sodium hypochlorite, 12 days), demineralised (0.5 M EDTA, 3 days) or left as intact control samples. Samples were stained with Orange II for 1-168 h, during which staining intensity was quantified by image analysis. Similarly, uptake of stain by deproteinized / demineralized samples treated with 10 or 30% H2O2 was investigated. Using surface plasmon resonance technology, real-time binding kinetics were determined assessing the interaction of Orange II with the dentin matrix protein constituents, collagen type I, biglycan, decorin, dentin sialoprotein and osteopontin. Deproteinization of dentin matrix reduced the uptake of the Orange II compared to the intact control. Conversely, demineralization of dentin samples increased the uptake of the dye. Treatment of samples for 48 h with H2O2 reduced subsequent uptake of the Orange II. Real-time kinetic analysis indicated moderate strength of binding for Orange II with collagen type I, weak binding with decorin and biglycan and negligible binding with dentine sialoprotein and osteopontin. These results indicate a predominant role for collagen type I, which accounts for 90% of the organic protein matrix of teeth, for attracting dietary stains. Binding analyses indicate that the interaction is highly dissociable, and further binding is reduced following H2O2 treatment. This study provides new information regarding adsorption of dietary stains into tooth dentin, suggesting that they are attracted and moderately bound to the collagen type I matrix. This study also contributes valuable information for discussion for considering the effect of H2O2 on bleaching teeth and its influence on subsequent uptake of dietary stains following whitening treatments.


Partners in health? A systematic review of the impact of organizational partnerships on public health outcomes in England between 1997 and 2008.
To systematically review the available evidence on the impact of organizational partnerships on public health outcomes (health improvement and/or a reduction in health inequalities) in England between 1997 and 2008. Systematic review of quantitative (longitudinal before and after) and qualitative studies (1997-2008) reporting on the health (and health inequalities) effects of public health partnerships in England. Eighteen electronic databases (medical, social science and economic), websites, bibliographies and expert contacts. Only 15 studies, relating to six different interventions, met the review criteria and most of these studies were not designed specifically to assess the impact of partnership working on public health outcomes. Of the studies reviewed, only four included a quantitative element and they produced a mixed picture in terms of the impacts of partnership working. Qualitative studies suggested that some partnerships increased the profile of health inequalities on local policy agendas. Both the design of partnership interventions and of the studies evaluating them meant it was difficult to assess the extent to which identifiable successes and failures were attributable to partnership working. This systematic review suggests that there is not yet any clear evidence of the effects of public health partnerships on health outcomes. More appropriately designed and timed studies are required to establish whether, and how, partnerships are effective.


The planarian P2X homolog in the regulation of asexual reproduction.
The growth in size of freshwater planarians in response to nutrient intake is limited by the eventual separation of tail and body fragments in a process called fission. The resulting tail fragment regenerates the entire body as an artificially amputated tail fragment would do, and the body fragment regenerates a tail, resulting in two whole planarians. This regenerative ability is supported by pluripotent somatic stem cells, called neoblasts, which are distributed throughout almost the entire body of the planarian. Neoblasts are the only planarian cells with the ability to continuously proliferate and give rise to all types of cells during regeneration, asexual reproduction, homeostasis, and growth. In order to investigate the molecular characteristics of neoblasts, we conducted an extensive search for neoblast-specific genes using the High Coverage Expression Profiling (HiCEP) method, and tested the function of the resulting candidates by RNAi. Disruption of the expression of one candidate gene, DjP2X-A (Dugesia japonica membrane protein P2X homologue), resulted in a unique phenotype. DjP2X-A RNAi leads to an increase of fission events upon feeding. We confirmed by immunohistochemistry that DjP2X-A is a membrane protein, and elucidated its role in regulating neoblast proliferation, thereby explaining its unique phenotype. We found that DjP2X-A decreases the burst of neoblast proliferation that normally occurs after feeding. We also found that DjP2X-A is required for normal proliferation in starved animals. We propose that DjP2X-A modulates stem cell proliferation in response to the nutritional condition.


Low back pain and the social determinants of health: a systematic review and narrative synthesis.
The social determinants of health (SDH) are known to differentially impact outcomes from many noncommunicable diseases; however, their potential role in low back pain (LBP) is poorly defined. This review endeavours to comprehensively inform the field of their relevance. Our research question was: "How do the broad range of SDH and chronic LBP (CLBP) relate?" The primary aim of this review was to synthesise evidence of relationships between SDH and the frequency or severity of CLBP. Secondary aims were to identify relationships between SDH and LBP-related disability, work absenteeism, and opioid prescription. We included studies involving adult participants that evaluated relationships between one or more of the SDH and CLBP frequency or LBP outcomes (beyond 3 months). Two reviewers screened studies, extracted data, and assessed risk of bias. We synthesized the results narratively and applied PROGRESS to organise our findings. Database searches identified 7018 records. Forty-one studies were included, containing data from 2,161,617 adults from 17 countries. Twenty-four percent and 19% of the relationships included were classified as having a high risk of bias due to confounding and missing data, respectively. We reported 166 relationships representing the majority of the PROGRESS domains. An array of independent and interdependent relationships between the SDH and CLBP were identified with the strongest evidence for associations related to educational attainment and socioeconomic status. Our findings suggest that greater recognition of the contribution of SDH to disparities in LBP outcomes is warranted and this has the potential to usefully inform strategies to impact burden.


A study on the wetting properties of broccoli leaf surfaces and their time dependent self-healing after mechanical damage.
Plants are protected from the elements by a complex hierarchical epicuticular wax layer which has inspired the creation of super-hydrophobic and self-cleaning surfaces. Although many studies have been conducted on different plant wax systems to determine the mechanisms of water repulsion hardly any have studied the recovery of the epicuticular wax layer. In the current study the wetting properties and crystallographic nature of the wax surface of Brassica oleracea var. italica (broccoli) has been studied, as well as the time-dependent recovery of the surface after mechanical damage. It was found that the surface of the broccoli leaves is not only super-repulsive and self-cleaning in regards to water but also in regards to glycerol and formamide, both of which have considerably lower surface tension values. Furthermore, it was shown that the surface properties do indeed recover after damage and that this recovery is multi-stepped and strongly dependent on the recovery of the roughness of the surface.


Mapping of Lymph Node Metastasis From Esophagogastric Junction Tumors: A Prospective Nationwide Multicenter Study.
The aim of the study was to determine the optimal extent of lymph node dissection for the 2 histological types of esophagogastric junction (EGJ) tumors based on the incidence of metastasis in a prospective nationwide multicenter study. Because most previous studies were retrospective, the optimal surgical procedure for EGJ tumors has not been standardized. Patients with cT2-T4 adenocarcinoma or squamous cell carcinoma located within 2.0 cm of the EGJ were enrolled before surgery. Surgeons dissected all lymph nodes prespecified in the protocol, using either the abdominal transhiatal or right transthoracic approach. The primary endpoint was the metastasis rate of each lymph node. Lymph nodes were classified according to metastasis rate, as follows: category-1 (strongly recommended for dissection), rate more than 10%; category-2 (weakly recommended for dissection), rate from 5% to 10%; and category-3 (not recommended for dissection), rate less than 5%. Between 2014 and 2017, 1065 patients with EGJ tumor were screened, and 371 were enrolled. Among 358 patients who underwent surgical resection, category-1 nodes included abdominal stations 1, 2, 3, 7, 9, and 11p, whereas category-2 nodes included abdominal stations 8a, 19, and lower mediastinal station 110. If esophageal involvement exceeded 2.0 cm, station 110 was assigned to category-1. Among 98 patients who had either adenocarcinoma with esophageal involvement over 3.0 cm or squamous cell carcinoma, there were no category-1 nodes in the upper/middle mediastinal field, whereas category-2 nodes included upper mediastinal station 106recR and middle mediastinal station 108. When esophageal involvement exceeded 4.0 cm, station 106recR was assigned to category-1. The study accurately identified the distribution of lymph node metastases from EGJ tumors and the optimal extent of subsequent lymph node dissection.


Humanized neuronal chimeric mouse brain generated by neonatally engrafted human iPSC-derived primitive neural progenitor cells.
The creation of a humanized chimeric mouse nervous system permits the study of human neural development and disease pathogenesis using human cells in vivo. Humanized glial chimeric mice with the brain and spinal cord being colonized by human glial cells have been successfully generated. However, generation of humanized chimeric mouse brains repopulated by human neurons to possess a high degree of chimerism have not been well studied. Here we created humanized neuronal chimeric mouse brains by neonatally engrafting the distinct and highly neurogenic human induced pluripotent stem cell (hiPSC)-derived rosette-type primitive neural progenitors. These neural progenitors predominantly differentiate to neurons, which disperse widely throughout the mouse brain with infiltration of the cerebral cortex and hippocampus at 6 and 13 months after transplantation. Building upon the hiPSC technology, we propose that this potentially unique humanized neuronal chimeric mouse model will provide profound opportunities to define the structure, function, and plasticity of neural networks containing human neurons derived from a broad variety of neurological disorders.


Thickness-profile measurement of transparent thin-film layers by white-light scanning interferometry.
White-light scanning interferometry is increasingly used for precision profile metrology of engineering surfaces, but its current applications are limited primarily to opaque surfaces with relatively simple optical reflection behavior. A new attempt is made to extend the interferometric method to the thickness-profile measurement of transparent thin-film layers. An extensive frequency-domain analysis of multiple reflection is performed to allow both the top and the bottom interfaces of a thin-film layer to be measured independently at the same time by the nonlinear least-squares technique. This rigorous approach provides not only point-by-point thickness probing but also complete volumetric film profiles digitized in three dimensions.


Cross-comparison of diet quality indices for predicting chronic disease risk: findings from the Observation of Cardiovascular Risk Factors in Luxembourg (ORISCAV-LUX) study.
The scientific community has become increasingly interested in the overall quality of diets rather than in single food-based or single nutrient-based approaches to examine diet-disease relationships. Despite the plethora of indices used to measure diet quality, there still exist questions as to which of these can best predict health outcomes. The present study aimed to compare the ability of five diet quality indices, namely the Recommendation Compliance Index (RCI), Diet Quality Index-International (DQI-I), Dietary Approaches to Stop Hypertension (DASH), Mediterranean Diet Score (MDS), and Dietary Inflammatory Index (DII), to detect changes in chronic disease risk biomarkers. Nutritional data from 1352 participants, aged 18-69 years, of the Luxembourg nationwide cross-sectional ORISCAV-LUX (Observation of Cardiovascular Risk Factors in Luxembourg) study, 2007-8, were used to calculate adherence to the diet quality index. General linear modelling was performed to assess trends in biomarkers according to adherence to different dietary patterns, after adjustment for age, sex, education level, smoking status, physical activity and energy intake. Among the five selected diet quality indices, the MDS exhibited the best ability to detect changes in numerous risk markers and was significantly associated with lower levels of LDL-cholesterol, apo B, diastolic blood pressure, renal function indicators (creatinine and uric acid) and liver enzymes (serum γ-glutamyl-transpeptidase and glutamate-pyruvate transaminase). Compared with other dietary patterns, higher adherence to the Mediterranean diet is associated with a favourable cardiometabolic, hepatic and renal risk profile. Diets congruent with current universally accepted guidelines may be insufficient to prevent chronic diseases. Clinicians and public health decision makers should be aware of needs to improve the current dietary guidelines.


Analysis of wavefront errors introduced by encoding computer-generated holograms.
The fabrication of computer-generated holograms (CGH) by e-beam or laser-writing machine specifically requires using polygon segments to approximate the continuously smooth fringe pattern of an ideal CGH. Wavefront phase errors introduced in this process depend on the size of the polygon segments and the shape of the fringes. In this paper, we propose a method for estimating the wavefront error and its spatial frequency, allowing optimization of the polygon sizes for required measurement accuracy. This method is validated with computer simulation and direct measurements from an interferometer.


Feasibility and safety of home exercise training in children with sickle cell anemia.
Exercise guidelines do not exist for individuals with sickle cell anemia (SCA) despite the impact of disease-related complications on physical functioning. Thirteen subjects (mean 15.1 ± 2.8 years old) with SCA were prescribed three exercise sessions/week for 12 weeks on a stationary bicycle placed at home. In total, 77% of subjects completed 89% of prescribed sessions without exercise-related adverse events, thus meeting feasibility and safety criteria. Adherence to prescribed duration and target heart rate during training decreased during the second half of the study. Future trials are warranted to further evaluate training benefits associated with regular exercise in children with SCA.


Regulation of beta-catenin signaling by the B56 subunit of protein phosphatase 2A.
Dysregulation of Wnt-beta-catenin signaling disrupts axis formation in vertebrate embryos and underlies multiple human malignancies. The adenomatous polyposis coli (APC) protein, axin, and glycogen synthase kinase 3beta form a Wnt-regulated signaling complex that mediates the phosphorylation-dependent degradation of beta-catenin. A protein phosphatase 2A (PP2A) regulatory subunit, B56, interacted with APC in the yeast two-hybrid system. Expression of B56 reduced the abundance of beta-catenin and inhibited transcription of beta-catenin target genes in mammalian cells and Xenopus embryo explants. The B56-dependent decrease in beta-catenin was blocked by oncogenic mutations in beta-catenin or APC, and by proteasome inhibitors. B56 may direct PP2A to dephosphorylate specific components of the APC-dependent signaling complex and thereby inhibit Wnt signaling.


Does Symptom Severity Moderate the Relationship Between Body Mass Index and Motor Competence in Children With Autism Spectrum Disorders? An Exploratory Study.
To date, there has been little research considering both autism spectrum disorder (ASD) symptom severity and motor impairment simultaneously when investigating their associations with obesity. This study was designed to identify the moderating role of symptom severity in the relationship between motor competence and overweight/obesity for children with ASD. Seventy-eight children with a clinical diagnosis were recruited from a large autism rehabilitation center in Wuhan, China. Chi-square, partial correlation, and moderation regression analyses revealed that the prevalence of overweight and obesity was similar regardless of symptom severity. Balance was the only motor skill that correlated with body mass index. Furthermore, symptom severity significantly moderated the correlation. Children with low autism severity might be more likely to demonstrate the relationship between balance and body mass index than those with high autism severity. Combating obesity by enhancing motor competence should cautiously consider personal and environment factors such as individual severity of ASD.


Non-ablative fractional laser assists cutaneous delivery of small- and macro-molecules with minimal bacterial infection risk.
Use of the ablative laser has been approved to enhance topical drug penetration. Investigation into the usefulness of the non-ablative laser for assisting drug delivery is very limited. In this study, we explored the safety and efficacy of the non-ablative fractional erbium:glass (Er:glass) laser as an enhancement approach to promote drug permeation. Both pig and nude mouse skins were employed as transport barriers. We histologically examined the skin structure after laser exposure. The permeants of 5-aminolevulinic acid (ALA), imiquimod, tretinoin, peptide, dextrans and quantum dots (QD) were used to evaluate in vitro and in vivo skin passage. The fractional laser selectively created an array of photothermal dots deep into the dermis with the preservation of the stratum corneum and epidermis. The barrier function of the skin could be recovered 8-60h post-irradiation depending on the laser spot densities. The application of the laser caused no local infection of Staphylococcus aureus and Pseudomonas aeruginosa. Compared to intact skin, ALA flux was enhanced up to 1200-fold after laser exposure. The penetration enhancement level by the laser was decreased following the increase of permeant lipophilicity. The skin accumulation of tretinoin, an extremely lipophilic drug, showed only a 2-fold elevation by laser irradiation. The laser promoted peptide penetration 10-fold compared to the control skin. Skin delivery of dextrans with a molecular weight (MW) of at least 40kDa could be achieved with the Er:glass laser. QD with a diameter of 20nm penetrated into the skin with the assistance of the non-ablative laser. The confocal microscopic images indicated the perpendicular and lateral diffusions of dextrans and nanoparticles via laser-created microscopic thermal zones. Controlled Er:glass laser irradiation offers a valid enhancement strategy to topically administer the permeants with a wide MW and lipophilicity range.


Ethical Issues Regarding Nonsubjective Psychedelics as Standard of Care.
Evidence suggests that psychedelics bring about their therapeutic outcomes in part through the subjective or qualitative effects they engender and how the individual interprets the resulting experiences. However, psychedelics are contraindicated for individuals who have been diagnosed with certain mental illnesses, on the grounds that these subjective effects may be disturbing or otherwise counter-therapeutic. Substantial resources are therefore currently being devoted to creating psychedelic substances that produce many of the same biological changes as psychedelics, but without their characteristic subjective effects. In this article, we consider ethical issues arising from the prospect of such potential "nonsubjective" psychedelics. We are broadly supportive of efforts to produce such substances for both scientific and clinical reasons. However, we argue that such nonsubjective psychedelics should be reserved for those special cases in which the subjective effects of psychedelics are specifically contraindicated, whereas classic psychedelics that affect subjective experience should be considered the default and standard of care. After reviewing evidence regarding the subjective effects of psychedelics, we raise a number of ethical concerns around the prospect of withholding such typically positive, meaningful, and therapeutic experiences from most patients.


Physiological, morphological and allocational plasticity in understory deciduous trees: importance of plant size and light availability.
In a 4-year study, we investigated changes in leaf physiology, crown morphology and whole-tree biomass allocation in seedlings and saplings of shade-tolerant sugar maple (Acer saccharum Marsh.) and intermediate shade-tolerant yellow birch (Betula alleghaniensis Britt.) growing in natural understory light (0.5 to 35% of full sunlight) or in understory light reduced by 50% with shade nets to simulate the effect of gap closure. Leaf physiological parameters were mainly influenced by the light gradient, whereas crown morphological and whole-tree allocational parameters were mainly influenced by tree size. No single physiological, morphological or allocational trait was identified that could explain the difference in shade tolerance between the species. Yellow birch had higher growth rates, biomass allocation to branches and leaf physiological plasticity and lower crown morphological plasticity in unmodified understory light than sugar maple. Sugar maple did not display significant physiological plasticity, but showed variation with tree size in both crown morphology and whole-tree biomass allocation. When sugar maple was small, a greater proportion of whole-tree biomass was allocated to roots. However, physiological differences between the species decreased with decreasing light and most morphological and allocational differences tended to disappear with increasing tree size, suggesting that many species differences in shade-tolerance are expressed mainly during the seedling stage. Understory trees of both species survived for 4 years under shade nets, possibly because of higher plasticity when small and the use of stored reserves when taller.


Bypass mechanisms of resistance to receptor tyrosine kinase inhibition in lung cancer.
Receptor tyrosine kinases (RTKs) are activated by somatic genetic alterations in a subset of cancers, and such cancers are often sensitive to specific inhibitors of the activated kinase. Two well-established examples of this paradigm include lung cancers with either EGFR mutations or ALK translocations. In these cancers, inhibition of the corresponding RTK leads to suppression of key downstream signaling pathways, such as the PI3K (phosphatidylinositol 3-kinase)/AKT and MEK (mitogen-activated protein kinase kinase)/ERK (extracellular signal-regulated kinase) pathways, resulting in cell growth arrest and death. Despite the initial clinical efficacy of ALK (anaplastic lymphoma kinase) and EGFR (epidermal growth factor receptor) inhibitors in these cancers, resistance invariably develops, typically within 1 to 2 years. Over the past several years, multiple molecular mechanisms of resistance have been identified, and some common themes have emerged. One is the development of resistance mutations in the drug target that prevent the drug from effectively inhibiting the respective RTK. A second is activation of alternative RTKs that maintain the signaling of key downstream pathways despite sustained inhibition of the original drug target. Indeed, several different RTKs have been implicated in promoting resistance to EGFR and ALK inhibitors in both laboratory studies and patient samples. In this mini-review, we summarize the concepts underlying RTK-mediated resistance, the specific examples known to date, and the challenges of applying this knowledge to develop improved therapeutic strategies to prevent or overcome resistance.


Epidemiologic investigations of Yersinia enterocolitica and related species: sources, frequency, and serogroup distribution.
During an 11-year period (1978 to 1989), over 300 strains of Yersinia spp. (excluding Y. pestis and Y. pseudotuberculosis) were recovered from a variety of gastrointestinal and extraintestinal sites in patients in California. Over the 11-year period, Y. enterocolitica serogroup O:3 predominated, although a shift in the relative frequency of this serogroup was observed during this interval, increasing dramatically during the years 1984 to 1989. Of the remaining Y. enterocolitica isolates, over 40% were identified as belonging to serogroups generally considered to be nonpathogenic, although many of these isolates were recovered in association with milder cases of gastroenteritis. The results suggest a changing and expanding spectrum of Y. enterocolitica serogroups associated with various gastrointestinal and systemic infections.


Multiple roles for astrocytes as effectors of cytokines and inflammatory mediators.
Astrocytes are increasingly recognized as exerting complex functions essential for normal neural activity in the healthy central nervous system (CNS). Because astrocytes also respond to all forms of CNS injury or disease, there is growing interest in how reactive astrogliosis might alter astrocyte functions and thereby affect neural functions. Reactive astrogliosis is heterogeneous and regulated in a context specific manner by different molecular signals. Prominent among astrocyte signaling mechanisms is the ability to respond to, as well as to produce, many different cytokines and inflammatory mediators. These signaling mechanisms enable astrocytes to interact with diverse cell types in ways that may contribute to crosstalk between immune/inflammatory and neural systems. Consistent with this notion is the increasing evidence that cytokines and inflammatory mediators modulate astrocyte signaling not only to influence immune and inflammatory activities in the CNS, but also to influence synaptic and neural functions in ways that may affect complex behaviors such as sickness behavior, pain, appetite, sleep, and mood.


Emergency tracheal intubation immediately following traumatic injury: an Eastern Association for the Surgery of Trauma practice management guideline.
The ABCs of trauma resuscitation begin with the airway evaluation, and effective airway management is imperative in the care of a patient with critical injury. The Eastern Association for the Surgery of Trauma Practice Management Guidelines committee aimed to update the guidelines for emergency tracheal intubation (ETI) published in 2002. These guidelines were made to assist clinicians with decisions regarding airway management for patients immediately following traumatic injury. The goals of the work group were to develop evidence-based guidelines to (1) characterize patients in need of ETI and (2) delineate the most appropriate procedure for patients undergoing ETI. A search of the National Library of Medicine and the National Institutes of Health MEDLINE database was performed using PubMed (www.pubmed.gov). The search retrieved English-language articles published from 2000 to 2012 involving patients who had sustained blunt trauma, penetrating trauma, or heat-related injury and had developed respiratory system insufficiency or required ETI in the immediate period after injury (first 2 hours after injury). Sixty-nine articles were used to construct this set of practice management guidelines. The data supported the formation of six Level 1 recommendations, four Level 2 recommendations, and two Level 3 recommendations. In summary, the decision to intubate a patient following traumatic injury is based on multiple factors, including the need for oxygenation and ventilation, the extent and mechanism of injury, predicted operative need, or progression of disease. Rapid sequence intubation with direct laryngoscopy continues to be the recommended method for ETI, although the use of airway adjuncts such as blind insertion supraglottic devices and video laryngoscopy may be useful in facilitating successful ETI and may be preferred in certain patient populations. There is no pharmacologic induction agent of choice for ETI; however, succinylcholine is the neuromuscular blockade agent recommended for rapid sequence intubation.