Negative regulation of KNOX expression in tomato leaves.
Leaves of seed plants can be described as simple, where the leaf blade is entire, or dissected, where the blade is divided into distinct leaflets. Both simple and dissected leaves are initiated at the flanks of a pluripotent structure termed the shoot apical meristem (SAM). In simple-leafed species, expression of class I KNOTTED1-like homeobox (KNOX) proteins is confined to the meristem while in many dissected leaf plants, including tomato, KNOX expression persists in leaf primordia. Elevation of KNOX expression in tomato leaves can result in increased leaflet number, indicating that tight regulation of KNOX expression may help define the degree of leaf dissection in this species. To test this hypothesis and understand the mechanisms controlling leaf dissection in tomato, we studied the clausa (clau) and tripinnate (tp) mutants both of which condition increased leaflet number phenotypes. We show that TRIPINNATE and CLAUSA act together, to restrict the expression level and domain of the KNOX genes Tkn1 and LeT6/Tkn2 during tomato leaf development. Because loss of CLAU or TP activity results in increased KNOX expression predominantly on the adaxial (upper) leaf domain, our observations indicate that CLAU and TP may participate in a domain-specific KNOX repressive system that delimits the ability of the tomato leaf to generate leaflets.


Cow's Milk Allergy: Immunomodulation by Dietary Intervention.
Cow's milk proteins cause allergic symptoms in 2% to 3% of all infants. In these individuals, the physiological mechanism of tolerance is broken with subsequent possible sensitization to antigens, which can lead eventually to allergic responses. The present review aims to provide an overview of different aspects of immune modulation by dietary intervention in cow's milk allergy (CMA). It focuses on pathogenetic mechanisms of different CMA related disorders, e.g., gastroesophageal reflux and eosinophilic esophagitis, highlighting the role of dietary management on innate and adaptive immune systems. The traditional dietary management of CMA has greatly changed in the last years, moving from a passive approach, consisting of an elimination diet to relieve symptoms, to a "proactive" one, meaning the possibility to actively modulate the immune system. Thus, new insights into the role of hydrolysates and baked milk in immunomodulation are addressed here. Additionally, nutritional components, such as pre- and probiotics, may target the immune system via microbiota, offering a possible road map for new CMA prevention and treatment strategies.


ESMO Consensus Conference on malignant lymphoma: general perspectives and recommendations for the clinical management of the elderly patient with malignant lymphoma.
The European Society for Medical Oncology (ESMO) consensus conference on mature B cell lymphomas and chronic lymphocytic leukaemia (CLL) was held on 20 June 2015 in Lugano, Switzerland, and included a multidisciplinary panel of 25 leading experts. The aim of the conference was to develop recommendations on critical subjects difficult to consider in detail in the ESMO Clinical Practice Guidelines. The following areas were identified: (1) the elderly patient, (2) prognostic factors suitable for clinical use, and (3) the 'ultra-high-risk' group. Before the conference, the expert panel was divided into three working groups; each group focused on one of these areas in order to address clinically-relevant questions relating to that topic. All relevant scientific literature, as identified by the experts, was reviewed in advance. During the consensus conference, each working group developed recommendations to address each of the four questions assigned to their group. These recommendations were presented to the entire panel and a consensus was reached. This consensus, which was further developed in continuous post-meeting discussions, formed the basis of three manuscripts, each covering one of the three key areas identified. This manuscript presents the consensus recommendations regarding the clinical management of elderly patients diagnosed with malignant lymphoma. Four clinically-relevant topics identified by the panel were: 1) how to define patient fitness, 2) assessing quality of life, 3) diagnostic work-up and 4) clinical management of elderly patients with lymphoma. Each of these key topics is addressed in the context of five different lymphoma entities, namely: CLL, follicular lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma and diffuse large B-cell lymphoma. Results, including a summary of evidence supporting each recommendation, are detailed in this manuscript.


Mammary stem cells and breast cancer--role of Notch signalling.
Adult stem cells are found in numerous tissues of the body and play a role in tissue development, replacement and repair. Evidence shows that breast stem cells are multipotent and can self renew, which are key characteristics of stem cells, and a single cell enriched with cell surface markers has the ability to grow a fully functional mammary gland in vivo. Many groups have extrapolated the cancer stem cell hypothesis from the haematopoietic system to solid cancers, where using in vitro culture techniques and in vivo transplant models have established evidence of cancer stem cells in colon, pancreas, prostate, brain and breast cancers. In the report we describe the evidence for breast cancer stem cells; studies consistently show that stem cell like and breast cancer initiating populations can be enriched using cell surface makers CD44+/CD24- and have upregulated genes which include Notch. Notch signalling has been highlighted as a pathway involved in the development of the breast and is frequently dysregulated in invasive breast cancer. We have investigated the role of Notch in a pre-invasive breast lesion, ductal carcinoma in situ (DCIS), and have found that aberrant activation of Notch signalling is an early event in breast cancer. High expression of Notch 1 intracellular domain (NICD) in DCIS also predicted a reduced time to recurrence 5 years after surgery. Using a non-adherent sphere culture technique we have grown DCIS mammospheres from primary DCIS tissue, where self-renewal capacity, measured by the number of mammosphere initiating cells, were increased from normal breast tissue. A gamma-secretase inhibitor, DAPT, which inhibits all four Notch receptors and a Notch 4 neutralising antibody were shown to reduce DCIS mammosphere formation, indicating that Notch signalling and other stem cell self-renewal pathways may represent novel therapeutic targets to prevent recurrence of pre-invasive and invasive breast cancer.


Human Eye Activity Monitoring Using Continuous Wave Doppler Radar: A Feasibility Study.
Human eye activity has been widely studied in many fields such as psychology, neuroscience, medicine, and human-computer interaction engineering. In previous studies, monitoring of human eye activity mainly depends on electrooculogram (EOG) that requires a contact sensor. This paper proposes a novel eye movement monitoring method called continuous wave doppler oculogram (cDOG). Unlike the conventional EOG-based eye movement monitoring methods, cDOG based on continuous wave doppler radar sensor (cDRS) can remotely measure human eye activity without placing electrodes on the head. To verify the feasibility of using cDOG for eye movement monitoring, we first theoretically analyzed the association between the radar signal and the corresponding eye movements measured with EOG. Afterward, we conducted an experiment to compare EOG and cDOG measurements under the conditions of eyes closure and opening. In addition, different eye movement states were considered, including right-left saccade, up-down saccade, eye-blink, and fixation. Several representative time domain and frequency domain features obtained from cDOG and from EOG were compared in these states, allowing us to demonstrate the feasibility of using cDOG for monitoring eye movements. The experimental results show that there is a correlation between cDOG and EOG in the time and frequency domain features, the average time error of single eye movement is less than 280.5 ms, and the accuracy of cDOG in eye movement detection is higher than 92.35%, when the distance between the cDRS and the face is 10 cm and eyes is facing the radar directly.


The anatomical basis of symptomatic hemidystonia.
Twenty-eight patients with focal (arm or leg) or hemidystonia due to tumour, arteriovenous malformation, infarction, haemorrhage or hemiatrophy are described. All had typical dystonic movements and/or postures, identical to those seen in idiopathic (primary) torsion dystonia. The site(s) of the lesion responsible, as defined by CT (computerized tomography) scan or pathological examination, was in the contralateral caudate nucleus, lentiform nucleus (particularly the putamen) or thalamus, or in a combination of these structures. Review of 13 other patients in the literature with hemidystonia and lesions defined by CT scan, and of 7 other patients with pathologically discrete lesions associated with hemidystonia, also indicated involvement of these structures. Dystonia may be due to abnormal input from thalamus to premotor cortex, due to lesions either of the thalamus itself, or of the striatum projecting by way of the globus pallidus to the thalamus.


CdSxSe1-x quantum dots as colouring agents of Art Nouveau and contemporary stained glass: a combined transmission electron microscopy and Raman study.
The use of cadmium chalchogenide nanoprecipitates to obtain brightly coloured glasses enormously expanded by the beginning of the twentieth century, when the production of cadmium-based pigments was already well established. Six historical stained glass pieces produced between the late 1920s and modern days have been investigated in order to delineate the average size and the elemental composition of the nanocrystals. As non-invasive conditions are now mandatory when considering objects belonging to cultural heritage, Raman spectroscopy is used to measure the (average) elemental composition of the nanoparticles. Zinc substitution is also detected by the shifting of the Raman peak position. Moreover, a tentative evaluation of size distribution and crystallinity of the nanoparticles has been performed considering those parameters that are mainly influenced by the disorder of the system, such as Raman band width, surface phonons and the ratio between second and first order band intensities. A confirmation of the above-mentioned conclusion is searched by means of transmission electron microscopy (TEM) and local elemental analysis. Raman investigations allowed identifying a different and more pronounced disorder characterizing the oldest glasses, also verified by TEM observations, suggesting a different manufacture.This article is part of the themed issue 'Raman spectroscopy in art and archaeology'.


Towards a more realistic biomechanical modelling of breast malignant tumours.
We develop a biomechanical model of an isolated stellate breast tumour under mammographic compression forces for a range of reported mechanical properties, both linear elastic and hyperelastic. We also introduce different volumes of increased density/stiffness around the tumour as well as a solid pressure effect. We show that each of these issues--well known to clinicians but ignored to date in models--has a non-negligible effect on stresses and strains/deformations.


Implantation in the baboon: endometrial responses.
Blastocyst implantation in the baboon usually occurs between 8 and 10 days post ovulation. Changes that occur within this window of receptivity and immediately following implantation can be divided into three distinct phases. The first phase, regulated by estrogen and progesterone, is characterized primarily by changes in both the luminal and glandular epithelial cells in preparation for blastocyst apposition and attachment. The second phase is the further modulation of these steroid induced changes in both epithelial and stromal cells by embryonic signals. The final phase is associated with trophoblast invasion and the remodeling of the endometrial stromal compartment. During the initial phase, the actions of estrogen and progesterone are dependent on the presence of specific receptors. Estrogen up-regulates both its own receptor (ER) and the progesterone receptor (PR), while progesterone down-regulates this expression pattern. However, the pattern of progesterone-induced down-regulation of ER and PR is confined to the epithelial cells and demonstrates a gradient effect from the functionalis to the basalis. What is most intriguing is that the loss of epithelial PR is closely correlated with the establishment of uterine receptivity. Coincident with the changes in ER and PR expression, epithelial cells undergo alterations in their cytoskeletal architecture and secretory profile. These changes can be counteracted by PR antagonist treatment during the luteal phase. Although estrogen and progesterone play a critical role in establishing the initial phase of uterine receptivity, it is becoming increasingly evident that the embryo induces functional receptivity in ruminants and rodents. In our studies in the primate, we demonstrate that chorionic gonadotrophin when infused in a manner that mimics blastocyst transit, has physiological effects on the three major cell types in the uterine endometrium. The luminal epithelium undergoes endoreplication and distinct epithelial plaques are evident. The glandular epithelium responds by inducing transcriptional and post-translational modifications in the major secretory product, glycodelin. The stromal fibroblasts initiate their differentiation process into a decidual phenotype and are characterized by the expression of actin filaments. In phase three, blastocyst attachment to the surface epithelium and subsequent implantation is associated with local remodeling of the maternal stroma, smooth muscle, and endothelium of the blood vessels by the trophoblast. In addition, there is a gradual diminution of the epithelial plaques on the luminal surface although the glandular epithelium remains highly secretory. The most dramatic effect is on the stromal fibroblasts, which in response to embryonic stimuli, differentiate into decidual cells, the major cell type of the gestational endometrium. This differentiation is characterized by the expression of insulin-like growth factor binding protein-1 (IGFBP-1) in these cells. The cytokine IL-1 beta is one possible embryonic signal. COX-2 is the rate-limiting enzyme for prostaglandin biosynthesis and transcription of this enzyme in response to the embryonic stimulus (IL-1 beta) results in an increase in prostaglandin biosynthesis in stromal fibroblasts at the site of implantation. Prostaglandins and PGE2 in particular, binds to its specific receptor (EP2 or EP4) and activates adenyl cyclase. The resulting increase in intracellular levels of cAMP can now activate IGFBP-1 gene transcription at the site of implantation. In summary, our studies have demonstrated that chorionic gonadotrophin, when infused into non-pregnant baboons during the window of uterine receptivity can induce epithelial responses that are similar to those observed in a fertile cycle. Stromal differentiation is initiated; however, decidualization requires a signal from the conceptus.


Topical bioavailability of diclofenac from locally-acting, dermatological formulations.
Assessment of the bioavailability of topically applied drugs designed to act within or beneath the skin is a challenging objective. A number of different, but potentially complementary, techniques are under evaluation. The objective of this work was to evaluate in vitro skin penetration and stratum corneum tape-stripping in vivo as tools with which to measure topical diclofenac bioavailability from three approved and commercialized products (two gels and one solution). Drug uptake into, and its subsequent clearance from, the stratum corneum of human volunteers was used to estimate the input rate of diclofenac into the viable skin layers. This flux was compared to that measured across excised porcine skin in conventional diffusion cells. Both techniques clearly demonstrated (a) the superiority in terms of drug delivery from the solution, and (b) that the two gels performed similarly. There was qualitative and, importantly, quantitative agreement between the in vitro and in vivo measurements of drug flux into and beyond the viable skin. Evidence is therefore presented to support an in vivo - in vitro correlation between methods to assess topical drug bioavailability. The potential value of the stratum corneum tape-stripping technique to quantify drug delivery into (epi)dermal and subcutaneous tissue beneath the barrier is demonstrated.


miR-4417 Targets Tripartite Motif-Containing 35 (TRIM35) and Regulates Pyruvate Kinase Muscle 2 (PKM2) Phosphorylation to Promote Proliferation and Suppress Apoptosis in Hepatocellular Carcinoma Cells.
BACKGROUND MicroRNAs (miRNAs) are a class of small non-coding RNAs that are strongly involved in various types of carcinogenesis, including hepatocellular carcinoma (HCC). This study aimed to clarify whether miR-4417 promotes HCC growth by targeting TRIM35 and regulating PKM2 phosphorylation. MATERIAL AND METHODS Online software, including TargetScan and miRanda, was used to predict the potential target of miR-4417. Real-Time PCR (qRT-PCR) and Western blot assays were performed to detect the expression levels of mRNA and protein, respectively. Cell proliferation was measured by MTT assay and apoptosis in A549 cells was examined by flow cytometry. RESULTS Bioinformatics reveal that TRIM35 mRNA contains 1 conserved target site of miR-4417. High level of miR-4417 and low levels of TRIM35 mRNA and protein were observed in HCC cells compared with a normal liver cell line. Biological function analysis showed that miR-4417 inhibitor inhibits cell proliferation and promotes apoptosis in HCC cells. Furthermore, we verified that TRIM35 is a functional target of miR-4417 by use of luciferase reporter assay, and TRIM35 overexpressing showed an elevation of proliferation and a reduction of apoptosis in HCC cells. We subsequently investigated whether miR-4417 and TRIM35 regulate HCC cell proliferation and apoptosis through PKM2 Y105 phosphorylation, and the results supported our speculation that miR-4417 targets TRIM35 and regulates the Y105 phosphorylation of PKM2 to promote hepatocarcinogenesis. CONCLUSIONS Our findings indicate that miR-4417 may function as an oncogene in HCC and is a potential alternative therapeutic target for this deadly disease.


Genetic differentiation and estimation of effective population size and migration rates in two sympatric ecotypes of the marine snail Littorina saxatilis.
On exposed rocky shores in Galicia (northwest Spain), a striking polymorphism exists between two ecotypes (RB and SU) of Littorina saxatilis that occupy different levels of the intertidal zone and exhibit an incomplete reproductive isolation. The setting has been suggested to represent ongoing sympatric speciation by ecological adaptation of the two ecotypes to their respective habitats. In this article we address whether or not the ecotypes have developed their own population structures in response to the rigors of their corresponding environments and life histories. We analyzed four to five allozymic loci from three surveys of the same sites, spanning a 14-year period. An experimental design including three localities with two transects per locality and three shore levels allowed studying temporal and spatial population structure and estimation of effective population sizes (N(e)), neighborhood sizes (N(n)), and migration rates (m). Genetic differentiation was significantly lower in RB populations (theta(ST) = 0.067) than in SU ones (theta(ST) = 0.124). Mean estimates of N(e), N(n), and m did not differ significantly between ecotypes, but local ecotype differences in migration between the two closest localities (larger migration rates in RB than in SU populations) could explain the pattern in population differentiation.


EDD mediates DNA damage-induced activation of CHK2.
EDD, the human orthologue of Drosophila melanogaster "hyperplastic discs," is overexpressed or mutated in a number of common human cancers. Although EDD has been implicated in DNA damage signaling, a definitive role has yet to be demonstrated. Here we report a novel interaction between EDD and the DNA damage checkpoint kinase CHK2. EDD and CHK2 associate through a phospho-dependent interaction involving the CHK2 Forkhead-associated domain and a region of EDD spanning a number of putative Forkhead-associated domain-binding threonines. Using RNA interference, we demonstrate a critical role for EDD upstream of CHK2 in the DNA damage signaling pathway. EDD is necessary for the efficient activating phosphorylation of CHK2 in response to DNA damage following exposure to ionizing radiation or the radiomimetic, phleomycin. Cells depleted of EDD display impaired CHK2 kinase activity and an inability to respond to DNA damage. These results identify EDD as a novel mediator in DNA damage signal transduction via CHK2 and emphasize the potential importance of EDD in cancer.


Characterization of intact glycopeptides reveals the impact of culture media on site-specific glycosylation of EPO-Fc fusion protein generated by CHO-GS cells.
With the increasing demand to provide more detailed quality attributes, more sophisticated glycan analysis tools are highly desirable for biopharmaceutical manufacturing. Here, we performed an intact glycopeptide analysis method to simultaneously analyze the site-specific N- and O-glycan profiles of the recombinant erythropoietin Fc (EPO-Fc) protein secreted from a Chinese hamster ovary glutamine synthetase stable cell line and compared the effects of two commercial culture media, EX-CELL (EX) and immediate advantage (IA) media, on the glycosylation profile of the target protein. EPO-Fc, containing the Fc region of immunoglobulin G1 (IgG1) fused to EPO, was harvested at Day 5 and 8 of a batch cell culture process followed by purification and N- and O-glycopeptide profiling. A mixed anion exchange chromatographic column was implemented to capture and enrich N-linked glycopeptides. Using intact glycopeptide characterization, the EPO-Fc was observed to maintain their individual EPO and Fc N-glycan characteristics in which the EPO region presented bi-, tri-, and tetra-branched N-glycan structures, while the Fc N-glycan displayed mostly biantennary glycans. EPO-Fc protein generated in EX medium produced more complex tetra-antennary N-glycans at each of the three EPO N-sites while IA medium resulted in a greater fraction of bi- and tri-antennary N-glycans at these same sites. Interestingly, the sialylation content decreased from sites 1-4 in both media while the fucosylation progressively increased with a maximum at the final IgG Fc site. Moreover, we observed that low amounts of Neu5Gc were detected and the content increased at the later sampling time in both EX and IA media. For O-glycopeptides, both media produced predominantly three structures, N1F1F0SOG0, N1H1F0S1G0, and N1H1F0S2G0, with lesser amounts of other structures. This intact glycopeptide method can decipher site-specific glycosylation profile and provide a more detailed characterization of N- and O-glycans present for enhanced understanding of the key product quality attributes such as media on recombinant proteins of biotechnology interest.


Improving the Delivery of Healthcare through Clinical Diagnostic Insights: A Valuation of Laboratory Medicine through "Clinical Lab 2.0".
As healthcare payment and reimbursement begin to shift from a fee-for-service to a value-based model, ancillary providers including laboratories must incorporate this into their business strategy. Laboratory medicine, while continuing to support a transactional business model, should expand efforts to include translational data analytics, proving its clinical and economic valuation. Current literature in this area is limited. This article is a summary of how laboratory medicine can support value-based healthcare. Population health management is emerging as a method to support value-based healthcare by aggregating patient information, providing data analysis, and contributing to clinical decision support. Key issues to consider with a laboratory-developed population health management model are discussed, including changing reimbursement models, the use of multidisciplinary committees, the role of specialists in data analytics and programming, and barriers to implementation. Examples of data considerations and value are given. Laboratory medicine is able to provide meaningful clinical diagnostic insights for population health initiatives that result in improved short- and long-term patient outcomes and drive cost-effective care. Opportunities include data analysis with longitudinal laboratory data, identification of patient-specific targeted interventions, and development of clinical decision support tools. Laboratories will need to leverage the skills and knowledge of their multidisciplinary staff, along with their extensive patient data sets, through innovative analytics to meet these objectives.


Opposing functions of Fbxw7 in keratinocyte growth, differentiation and skin tumorigenesis mediated through negative regulation of c-Myc and Notch.
The tumor suppressor Fbxw7 (also known as Sel-10, hCdc4, hAgo, or Fbw7) is an F-box protein that functions as the substrate-recognition subunit of an SCF ubiquitin ligase complex and targets a group of oncoproteins for degradation. We now show that Fbxw7 regulates the proliferation and differentiation of keratinocytes by mediating the degradation of c-Myc and Notch proteins. Fbxw7-deficient keratinocytes showed an increased proliferative capacity that was dependent on the accumulation of c-Myc but not on that of Notch. Fbxw7 deficiency also resulted in the premature differentiation of keratinocytes in a manner dependent on both c-Myc and Notch. Although Fbxw7-deficient keratinocytes proliferated excessively in vitro, loss of Fbxw7 did not predispose keratinocytes to the formation of squamous cell carcinoma in vivo induced by the expression of oncogenic Ras, possibly because the stem cell population of keratinocytes becomes exhausted as a result of enhanced Notch activity. Indeed, suppression of Notch signaling by additional ablation of RBP-J in Fbxw7-deficient keratinocytes conferred a more aggressive tumorigenic capacity. Collectively, these results indicate that Fbxw7 controls the proliferation and differentiation of keratinocytes, and that it exerts both inhibitory and stimulatory actions in skin carcinogenesis by counteracting the proliferation-promoting effect of c-Myc and the tumor-suppressive effect of Notch, respectively.


Slowing of the axonal transport of neurofilament proteins during development.
We examined age-dependent changes in neurofilament transport in motor axons of the rat sciatic nerve. SDS-PAGE and gel fluorography confirmed that the distribution of labeled neurofilament triplet protein coincides with the major slow component a (SCa) wave in these neurons. The velocity of neurofilament transport was calculated on the basis of the location of the 50th percentile Of radioactivity in this wave 33 days after motor neurons were labeled by the intraspinal administration of [3H]leucine and [3H]lysine. Overall, the velocity fell from 1.95 mm/day at 3 weeks of age to 1.12 mm/day at 20 weeks. Between 3 and 10 weeks, it fell at a 6-fold higher rate (0.096 mm/day/week) than between 10 and 20 weeks (0.016 mm/day/week). We also found a marked change in the shape of the slow component wave during development. It appeared to consist of several overlapping peaks moving at slightly different velocities in animals 10 weeks of age or less as compared to a single slower moving peak at 20 weeks. We propose that the velocity of slow axonal transport reflects the level of maturation of the neuron, and that the presence of several overlapping peaks Of transported radioactivity in the sciatic nerve of younger animals reflects the presence of several populations of motor axons at different stages of development. We also discuss the relationship between changes in the velocity of neurofilament transport and alterations in the composition of the cytoskeleton that occur as the axon grows in caliber during postnatal development.


Chemically mediated predator inspection behaviour in the absence of predator visual cues by a characin fish.
Animals commonly approach (i.e. 'inspect') potential predators. Glowlight tetras, Hemigrammus erythrozonus, have previously been shown to inspect the combined chemical and visual cues originating from novel predators and to modify their inspection (approach) behaviour depending upon the predator's diet. We conducted two experiments to determine whether tetras would inspect the chemical cues of injured prey or the dietary cues of a novel predator in the absence of any visual cues. Shoals of glowlight tetras were exposed to either distilled water (control) or the skin extract of swordtail (lacking ostariophysan alarm pheromones) or the skin extract of tetra (with alarm pheromones). There was no significant difference in the frequency of predator inspection behaviour towards swordtail or tetra skin extract compared to the distilled water controls. In the second experiment, we exposed shoals of tetras to either distilled water or the odour of Jack Dempsey cichlids, Cichlasoma octofasciatum, which had been food deprived, or fed a diet of swordtails or tetras. There was no significant difference in the frequency of predator inspection behaviour towards the odour of the starved cichlids and the odour of the fed cichlids in either of the two diet treatments. However, when tetras were exposed to the odour of cichlids fed tetras, they took significantly longer to initiate an inspection visit, remained further from the source of the chemical cues and inspected in smaller groups, compared with the odour of a starved cichlid or a cichlid fed swordtails. These data strongly suggest that tetras will inspect chemical cues alone, but only if the cue contains information about the predator. Copyright 2000 The Association for the Study of Animal Behaviour.


Prevalence of antimicrobial resistance among bacterial pathogens isolated from cattle in different European countries: 2002-2004.
The project "Antibiotic resistance in bacteria of animal origin - II" (ARBAO-II) was funded by the European Union (FAIR5-QLK2-2002-01146) for the period 2003-2005, with the aim to establish a continuous monitoring of antimicrobial susceptibility among veterinary laboratories in European countries based on validated and harmonised methodologies. Available summary data of the susceptibility testing of the bacterial pathogens from the different laboratories were collected. Antimicrobial susceptibility data for several bovine pathogens were obtained over a three year period (2002-2004). Each year the participating laboratories were requested to fill in excel-file templates with national summary data on the occurrence of antimicrobial resistance from different bacterial species.A proficiency test (EQAS - external quality assurance system) for antimicrobial susceptibility testing was conducted each year to test the accuracy of antimicrobial susceptibility testing in the participating laboratories. The data from this testing demonstrated that for the species included in the EQAS the results are comparable between countries. Data from 25,241 isolates were collected from 13 European countries. For Staphylococcus aureus from bovine mastitis major differences were apparent in the occurrence of resistance between countries and between the different antimicrobial agents tested. The highest frequency of resistance was observed for penicillin. For Mannheimia haemolytica resistance to ampicillin, tetracycline and trimethoprim/sulphonamide were observed in France, the Netherlands and Portugal. All isolates of Pasteurella multocida isolated in Finland and most of those from Denmark, England (and Wales), Italy and Sweden were susceptible to the majority of the antimicrobials. Streptococcus dysgalactiae and Streptococcus uberis isolates from Sweden were fully susceptible. For the other countries some resistance was observed to tetracycline, gentamicin and erythromycin. More resistance and variation of the resistance levels between countries were observed for Escherichia coli compared to the other bacterial species investigated. In general, isolates from Denmark, England (and Wales), the Netherlands, Norway, Sweden and Switzerland showed low frequencies of resistance, whereas many isolates from Belgium, France, Italy, Latvia and Spain were resistant to most antimicrobials tested. In the future, data on the prevalence of resistance should be used to develop guidelines for appropriate antimicrobial use in veterinary medicine.


Increasing prevalence of Type 2 diabetes mellitus in all ethnic groups in Mauritius.
To describe the prevalence of different stages of glucose intolerance in a population from Mauritius followed over 11 years. Population-based surveys were undertaken in the multiethnic nation of Mauritius in 1987, 1992 and 1998, with 5083, 6616, and 6291 participants, respectively. Questionnaires, anthropometric measurements, and a 2-h 75-g oral glucose tolerance test were included. Subjects aged between 25 and 75 years with classifiable data were identified; 4991, 6463 and 5392 from 1987, 1992 and 1998, respectively. Glucose tolerance was classified according to WHO 1999 criteria. The prevalence of Type 2 diabetes increased significantly during the period studied, from 12.8% in 1987, to 15.2% in 1992, and 17.9% in 1998. The increasing prevalence was seen in both men and women, and in all age groups. The prevalence of known diabetes (KDM) increased progressively, and more markedly than the increase in newly diagnosed diabetes (NDM). A diagnosis of impaired glucose tolerance (IGT) was more prevalent amongst women whereas impaired fasting glucose (IFG) was more common amongst men. The prevalences of IGT and IFG did not change markedly during the period. The prevalence of diabetes and IGT was similar for participants of Indian, Creole and Chinese background in each survey, and the increasing prevalence of diabetes was seen in all ethnic groups. In this study, we report an increasing prevalence of diabetes over an 11-year period in Mauritius. This increase was seen in both sexes, and in all age and ethnic groups, and was mainly due to an increase in the numbers of those with known diabetes.


Evaluation of low dose alpha-interferon (Roferon-A) in patients with advanced renal cell carcinoma: a Southwest Oncology Group study.
Alpha-interferon (IFN) has been shown to produce antitumor responses among patients with advanced renal cell carcinoma. While responses have been observed over a range of IFN doses and schedules, significant toxicities can be experienced from relatively high doses given three to five times weekly. Based upon the report of a pilot study indicating that low dose daily IFN could produce antitumor responses with minimal toxicity, the Southwest Oncology Group investigated this schema in a phase II trial. Patients with bidimensionally measurable disease were treated with Roferon-A 1 million units subcutaneously daily and tumor assessments were conducted on a monthly basis. There were no dose escalations and no dose reductions for toxicity. The treatment was well tolerated with only two patients withdrawing from treatment because of side effects. Among 56 eligible patients treated, there were five partial responses and one complete response for an overall response rate of 11% (95% confidence interval, 4 - 22%). However, objective antitumor responses could not be determined for 16 of the 56 patients. Among the 40 fully evaluable patients the 6 objective responses yields a response rate of 15% (95% confidence interval, 5.7-30%). It is concluded that this dose and schedule of IFN has activity against advanced renal cell carcinoma. A randomized trial would be required to determine if this low dose regimen is as effective as the higher doses which have been used traditionally.


Relating mathematical abilities to numerical skills and executive functions in informal and formal schooling.
The current evidence on an integrative role of the domain-specific early mathematical skills and number-specific executive functions (EFs) from informal to formal schooling and their effect on mathematical abilities is so far unclear. The main objectives of this study were to (i) compare the domain-specific early mathematics, the number-specific EFs, and the mathematical abilities between preschool and primary school children, and (ii) examine the relationship among the domain-specific early mathematics, the number-specific EFs, and the mathematical abilities among preschool and primary school children. The current study recruited 6- and 7-year-old children (Ntotal = 505, n6yrs = 238, and n7yrs = 267). The domain-specific early mathematics as measured by symbolic and nonsymbolic tasks, number-specific EFs tasks, and mathematics tasks between these preschool and primary school children were compared. The relationship among domain-specific early mathematics, number-specific EFs, and mathematical abilities among preschool and primary school children was examined. MANOVA and structural equation modeling (SEM) were used to test research hypotheses. The current results showed using MANOVA that primary school children were superior to preschool children over more complex tests of the domain-specific early mathematics; number-specific EFs; mathematical abilities, particularly for more sophisticated numerical knowledge; and number-specific EF components. The SEM revealed that both the domain-specific early numerical and the number-specific EFs significantly related to the mathematical abilities across age groups. Nevertheless, the number comparison test and mental number line of the domain-specific early mathematics significantly correlated with the mathematical abilities of formal school children. These results show the benefits of both the domain-specific early mathematics and the number-specific EFs in mathematical development, especially at the key stages of formal schooling. Understanding the relationship between EFs and early mathematics in improving mathematical achievements could allow a more powerful approach in improving mathematical education at this developmental stage.


Linking predator-prey interactions with exposure to a trophically transmitted parasite using PCR-based analyses.
Parasite transmission is determined by the rate of contact between a susceptible host and an infective stage and susceptibility to infection given an exposure event. Attempts to measure levels of variation in exposure in natural populations can be especially challenging. The level of exposure to a major class of parasites, trophically transmitted parasites, can be estimated by investigating the host's feeding behaviour. Since the parasites rely on the ingestion of infective intermediate hosts for transmission, the potential for exposure to infection is inherently linked to the definitive host's feeding ecology. Here, we combined epidemiological data and molecular analyses (polymerase chain reaction) of the diet of the definitive host, the white-footed mouse (Peromyscus leucopus), to investigate temporal and individual heterogeneities in exposure to infection. Our results show that the consumption of cricket intermediate hosts accounted for much of the variation in infection; mice that had consumed crickets were four times more likely to become infected than animals that tested negative for cricket DNA. In particular, pregnant female hosts were three times more likely to consume crickets, which corresponded to a threefold increase in infection compared with nonpregnant females. Interestingly, males in breeding condition had a higher rate of infection even though breeding males were just as likely to test positive for cricket consumption as nonbreeding males. These results suggest that while heterogeneity in host diet served as a strong predictor of exposure risk, differential susceptibility to infection may also play a key role, particularly among male hosts. By combining PCR analyses with epidemiological data, we revealed temporal variation in exposure through prey consumption and identified potentially important individual heterogeneities in parasite transmission.


Protein synthesis and assembly in mitochondrial disorders.
Human mitochondrial DNA (mtDNA) codes for 13 polypeptides which constitute the central core of the oxidative phosphorylation (OXPHOS) complexes. The machinery for mitochondrial protein synthesis has a dual origin: a full set of tRNAs, as well as the 12S and 16S rRNAs are encoded in the mitochondrial genome, while most factors necessary for translation are encoded by nuclear genes. The mitochondrial translation apparatus is highly specialized in expressing membrane proteins, and couples the synthesis of proteins to the insertion into the mitochondrial inner membrane. In recent years it has become clear that defects of mitochondrial translation and protein assembly cause several mitochondrial disorders. Since direct studies on protein synthesis in human mitochondria are still a relatively difficult task, we owe our current knowledge of this field to the large amount of genetic and biochemical studies performed in the yeast Saccharomyces cerevisiae. These studies have allowed the identification of several genes involved in mitochondrial protein synthesis and assembly, and have provided insights into the conserved mechanisms of mitochondrial gene expression. In the present review we will discuss the most recent advances in the understanding of the mechanisms and factors that govern mammalian mitochondrial translation/protein insertion, as well as known pathologies associated with them.


A randomized controlled trial to test the efficacy of trans-tympanic injections of a sodium thiosulfate gel to prevent cisplatin-induced ototoxicity in patients with head and neck cancer.
Cisplatin-induced hearing loss is frequent and severe. Antioxidants such as sodium thiosulfate (STS) can neutralize the effects of cisplatin. The objective of the trial was to test the efficacy of trans-tympanic injections of a STS gel to prevent cisplatin-induced ototoxicity. Eligible participants were newly diagnosed patients with stage III or IV squamous cell carcinoma of the mouth, oropharynx, hypopharynx, or larynx and scheduled to be treated by concurrent chemoradiation (CCR). Patients with asymmetric hearing were not eligible. The planed treatment included cisplatin 100 mg/m2 at days 1, 22 and 43. A baseline pre-treatment complete audiometric evaluation (pure tone at frequencies ranging from 0.5 to 14 kHz, bone conduction at 0.5-4 kHz and DPOAEs) was performed. Adverse effects were noted according to CTCAE. On the day before the beginning of CCR, eligible and consenting patients were randomized to receive a trans-tympanic injection of the gel either in the left ear or in the right ear. A final post-treatment complete audiometric evaluation was scheduled to be performed 1 month after the end of CCR by audiologists kept blind to the ear assignment. For the main outcome, the permanent threshold shift (PTS) in decibel (dB) was calculated as the difference between the final and baseline measures at all pure tone frequencies at 0.5-14 kHz for each patient and for each ear. The main outcome was assessed blindly in a mixed linear model with the PTS as the dependent variable and intervention, frequency, their interaction and radiation dose to the cochlea as independent variables. Between January 2015 and April 2016, 13 patients were randomized. The trial was stopped in June 2016 for poor accrual. The average loss of hearing over all frequencies was 1.3 dB less for treated ears compared to control ears. Although not statistically (p = 0.61) nor clinically significant, the difference was in favor of the treated ears for all frequencies between 3 and 10 kHz. Our trial suggests that STS deposited on the round window was safe for the middle and inner ears. More work is needed to improve the efficacy of trans-tympanic injections of cisplatin antidotes. ClinicalTrials.gov, NTC02281006 , Registered 3 November 2014.


Match between soaring modes of black kites and the fine-scale distribution of updrafts.
Understanding how soaring birds use updrafts at small spatial scales is important to identify ecological constraints of movement, and may help to prevent conflicts between wind-energy development and the conservation of wildlife. We combined high-frequency GPS animal tracking and fine-spatial-scale uplift modelling to establish a link between flight behaviour of soaring birds and the distribution of updrafts. We caught 21 black kites (Milvus migrans) and GPS-tracked them while flying over the Tarifa region, on the Spanish side of the Strait of Gibraltar. This region has a diverse topography and land cover, favouring a heterogeneous updraft spatial distribution. Bird tracks were segmented and classified into flight modes from motion parameters. Thermal and orographic uplift velocities were modelled from publically available remote-sensing and meteorological data. We found that birds perform circular soaring in areas of higher predicted thermal uplift and linear soaring in areas of higher predicted orographic uplift velocity. We show that updraft maps produced from publically available data can be used to predict where soaring birds will concentrate their flight paths and how they will behave in flight. We recommend the use of this methodological approach to improve environmental impact assessments of new wind-energy installations.


Children with severe or moderate obstructive sleep apnoea syndrome show a high incidence of persistence after adenotonsillectomy.
Persistent obstructive sleep apnoea syndrome (OSAS) occurs in approximately 20% of normal-weight children after adenotonsillectomy (T&A) and, in nearly 70% of them, it is caused by adenoid regrowth. Patients with severe or moderate OSAS showed a high incidence of persistent disease even after T&A. Allergic disease, severity and large adenoid size are associated with adenoid regrowth and persistent disease. To investigate factors contributing to persistent OSAS and adenoid regrowth after T&A in normal-weight children. This was a prospective, observational study at a single institute and involved 49 normal-weight children with severe or moderate OSAS (apnoea-hypopnoea index, AHI, ≥ 5) who underwent T&A. Background information, nasal endoscopic data and pre- and postoperative polysomnographic data were collected. A third polysomnography (PSG) was performed 1.5 year postoperatively in children who subsequently developed symptoms of sleep disturbance. Thirteen children (27%, 13/49) were symptomatic 1.5 years after T&A. Allergic rhinitis (38.5% vs 11.1%, p = 0.03) and allergic disease (69.2% vs 30.6%, p = 0.02) were seen more frequently in these children. A third PSG confirmed persistent disease (AHI ≥ 5) in nine children (18.4%, 9/49). Six children (12.2%, 6/49) were diagnosed as having adenoid regrowth and three (6.1%, 3/49) underwent revision adenoidectomy.


Increasing cumulative exposure to volatile anesthetic agents is associated with poorer neurodevelopmental outcomes in children with hypoplastic left heart syndrome.
Despite improved survival in children with hypoplastic left heart syndrome (HLHS), significant concern persists regarding their neurodevelopmental (ND) outcomes. Previous studies have identified patient factors, such as prematurity and genetic syndromes, to be associated with worse ND outcomes. However, no consistent relationships have been identified among modifiable management factors, including cardiopulmonary bypass strategies, and ND outcomes after cardiac surgery in infancy. Studies in immature animals, including primates, have demonstrated neurodegeneration and apoptosis in the brain after certain levels and extended durations of anesthetic exposure. Retrospective human studies have also suggested relationships between adverse ND effects and anesthetic exposure. Cumulative minimum alveolar concentration hours (MAC-hrs) of exposure to volatile anesthetic agents (VAA) (desflurane, halothane, isoflurane, and sevoflurane) were collected from an anesthetic database and medical record review for 96 patients with HLHS or variants. ND testing was performed between ages 4 and 5 years, including full-scale IQ, verbal IQ, performance IQ, and processing speed. Four generalized linear modes were hypothesized a priori and tested using a Gaussian (normal) distribution with an identity link. Cumulative VAA exposure ranged from 0 to 35.3 MAC-hrs (median 7.5 hours). Using specified covariates identified previously as significant predictors of ND outcomes, statistically significant relationships were identified between total MAC-hrs exposure and worse full-scale IQ and verbal IQ scores (P's < .05) alone and after adjusting for relevant covariates. Increased cumulative MAC-hrs exposure to VAA is associated with worse ND outcomes in certain domains in children with HLHS and variants.


Average glandular dose in digital mammography and breast tomosynthesis.
To determine the average glandular dose (AGD) in digital full-field mammography (2 D imaging mode) and in breast tomosynthesis (3 D imaging mode). Using the method described by Boone, the AGD was calculated from the exposure parameters of 2247 conventional 2 D mammograms and 984 mammograms in 3 D imaging mode of 641 patients examined with the digital mammographic system Hologic Selenia Dimensions. The breast glandular tissue content was estimated by the Hologic R2 Quantra automated volumetric breast density measurement tool for each patient from right craniocaudal (RCC) and left craniocaudal (LCC) images in 2 D imaging mode. The mean compressed breast thickness (CBT) was 52.7 mm for craniocaudal (CC) and 56.0 mm for mediolateral oblique (MLO) views. The mean percentage of breast glandular tissue content was 18.0% and 17.4% for RCC and LCC projections, respectively. The mean AGD values in 2 D imaging mode per exposure for the standard breast were 1.57 mGy and 1.66 mGy, while the mean AGD values after correction for real breast composition were 1.82 mGy and 1.94 mGy for CC and MLO views, respectively. The mean AGD values in 3 D imaging mode per exposure for the standard breast were 2.19 mGy and 2.29 mGy, while the mean AGD values after correction for the real breast composition were 2.53 mGy and 2.63 mGy for CC and MLO views, respectively. No significant relationship was found between the AGD and CBT in 2 D imaging mode and a good correlation coefficient of 0.98 in 3 D imaging mode. In this study the mean calculated AGD per exposure in 3 D imaging mode was on average 34% higher than for 2 D imaging mode for patients examined with the same CBT.


Protective Effects of Dioscorea batatas Flesh and Peel Extracts against Ethanol-Induced Gastric Ulcer in Mice.
Gastric ulcer is a major digestive disorder and provoked by multifactorial etiologies, including excessive alcohol consumption. In this study, we examined the gastroprotective effect of aqueous and ethanolic extracts of Dioscorea batatas Decne (DBD; commonly called Chinese yam) flesh or peel against acidified ethanol-induced acute gastric damage in mice. Our findings demonstrated that oral supplementation of aqueous or ethanolic extracts of DBD flesh or peel before ulcer induction was significantly effective in macroscopically and histologically alleviating ethanol-induced pathological lesions in gastric mucosa, decreasing the plasma levels of inflammatory mediators, such as nitric oxide and interleukin-6, attenuating the gastric expression of cyclooxygenase-2, and increasing the gastric content of prostaglandin E₂. In particular, pretreatment with the flesh extract prepared in 60% ethanol prominently decreased the expression of biomarkers of oxidative stress, including the plasma levels of 8-hydroxy-2-guanosine and malondialdehyde, and restored heme oxygenase-1 expression and superoxide dismutase activity in the stomach. Overall, these findings suggest that the oral supplementation with DBD extract, especially flesh ethanol extract, prior to excessive alcohol consumption, may exert a protective effect against ethanol-induced gastric mucosal damage in vivo, presumably through the activation of the antioxidant system and suppression of the inflammatory response.


Accounting for linkage disequilibrium in genome-wide association studies: A penalized regression method.
Penalized regression methods are becoming increasingly popular in genome-wide association studies (GWAS) for identifying genetic markers associated with disease. However, standard penalized methods such as LASSO do not take into account the possible linkage disequilibrium between adjacent markers. We propose a novel penalized approach for GWAS using a dense set of single nucleotide polymorphisms (SNPs). The proposed method uses the minimax concave penalty (MCP) for marker selection and incorporates linkage disequilibrium (LD) information by penalizing the difference of the genetic effects at adjacent SNPs with high correlation. A coordinate descent algorithm is derived to implement the proposed method. This algorithm is efficient in dealing with a large number of SNPs. A multi-split method is used to calculate the p-values of the selected SNPs for assessing their significance. We refer to the proposed penalty function as the smoothed MCP and the proposed approach as the SMCP method. Performance of the proposed SMCP method and its comparison with LASSO and MCP approaches are evaluated through simulation studies, which demonstrate that the proposed method is more accurate in selecting associated SNPs. Its applicability to real data is illustrated using heterogeneous stock mice data and a rheumatoid arthritis.


Management of invasive aspergillosis in patients with COPD: rational use of voriconazole.
Invasive pulmonary aspergillosis (IPA) is an important cause of mortality in patients with hematologic malignancies. The reported incidence of IPA in the context of chronic obstructive pulmonary disease (COPD) seems to increase. Approximately 1%-2% of overall fatal cases of IPA occur in COPD patients. The combination of factors such as lung immune imbalance, long-term corticosteroid use, increasing rate of bacterial exacerbations over time, and malnutrition are responsible for the emergence of IPA in these patients. The diagnosis of IPA is difficult to establish, which explains the delay in implementing accurate antifungal therapy and the high mortality rate. Persistent pneumonia nonresponsive to appropriate antibiotic treatment raises the concern of an invasive fungal infection. Definite diagnosis is obtained from tissue biopsy evidencing Aspergillus spp. on microscopic examination or in culture. Culture and microscopy of respiratory tract samples have a sensitivity and specificity of around 50%. Other diagnostic tools can be useful in documenting IPA: computed tomography (CT) scan, nonculture-based tests in serum and/or in bronchoalveolar lavage such as antibody/antigen tests for Aspergillus spp. More recent tools such as polymerase chain reaction or [1-->3]-beta-D-glucan have predictive values that need to be further investigated in COPD patients. Antifungal monotherapy using azole voriconazole is recommended as a first-line treatment of IPA. This review assesses the use of voriconazole in COPD patients.


Human immunodeficiency virus reverse transcriptase T helper epitopes identified in mice and humans: correlation with a cytotoxic T cell epitope.
T cell immunity may be critical to development of a vaccine for human immunodeficiency virus (HIV-1). T helper epitopes were identified in three predominantly conserved regions in the HIV-1 reverse transcriptase by using reverse transcriptase-immunized mice of five major histocompatibility complex haplotypes. One peptide (residues 38-52) that stimulated H-2k T cells also contained an epitope recognized by cytotoxic T cells from the same mice and from HIV-infected patients. Such concordance between helper and cytotoxic T lymphocyte epitopes, observed in four cases, may be important in vaccine development. Peptide 36-52 was recognized by interleukin-2-producing peripheral blood T cells from 9 of 17 HIV-seropositive humans studied, of multiple human leukocyte antigen-DR and -DQ types. The broad recognition of this peptide by both helper and cytotoxic T cells substantiates its potential importance in a vaccine.


Improved reperfusion and clinical outcome with enoxaparin as an adjunct to streptokinase thrombolysis in acute myocardial infarction. The AMI-SK study.
To establish whether the addition of enoxaparin (a low-molecular-weight heparin) to streptokinase therapy improves early and sustained coronary patency and clinical outcome in patients with evolving myocardial infarction. A total of 496 patients with acute myocardial infarction treated with streptokinase were randomized to an intravenous bolus (30 mg) and subcutaneous injections (1mg x kg(-1), twice daily) of enoxaparin (n=253), or placebo (n=243) for 3-8 days. The median duration of treatment in both groups was 5 days. ST-segment resolution at 90 min and 180 min measured by electrocardiogram was improved in patients receiving enoxaparin. Complete, partial and no ST-segment resolution at 180 min was observed in 36%, 44% and 19% in the enoxaparin group vs 25%, 44% and 31% in the placebo group, respectively (P=0.004). Assessment of the primary end-point revealed improved TIMI-3 flow with enoxaparin vs placebo (70% vs 58%, P=0.01). Combined TIMI-2 and -3 flow was also improved (88% vs 72%, P=0.001), as was TIMI frame count (P=0.003). The triple clinical end-point of death, reinfarction and recurrent angina at 30 days was reduced with enoxaparin (13% vs 21%, P=0.03). Streptokinase in combination with enoxaparin is associated with better ST-segment resolution and better angiographic patency at days 5-10, suggesting more effective reperfusion. This was associated with a significant reduction in clinical events, indicating less reocclusion.


Periplasmic protein related to the sn-glycerol-3-phosphate transport system of Escherichia coli.
Two-dimensional gel electrophoresis of shock fluids of Escherichia coli K-12 revealed the presence of a periplasmic protein related to sn-glycerol-3-phosphate transport (GLPT) that is under the regulation of glpR, the regulatory gene of the glp regulon. Mutants selected for their resistance to phosphonomycin and found to be defective in sn-glycerol-3-phosphate transport either did not produce GLPT or produced it in reduced amounts. Other mutations exhibited no apparent effect of GLPT. Transductions of glpT+ nalA phage P1 into these mutants and selection for growth on sn-glycerol-3-phosphate revealed a 50% cotransduction frequency to nalA. Reversion of mutants taht did not produce GLPT to growth on sn-glycerol-3-phosphate resulted in strains that produce GLPT. This suggests a close relationship of GLPT to the glpT gene and to sn-glycerol-3-phosphate transport. Attempts to demonstrate binding activity of GLPT in crude shock fluid towards sn-glycerol-3-phosphate have failed so far. However, all shock fluids, independent of their GLPT content, exhibited an enzymatic activity that hydrolyzes under the conditions of the binding assay, 30 to 60% of the sn-glycerol-3-phosphate to glycerol and inorganic orthophosphate.


Statistical investigation of the full concentration range of fasted and fed simulated intestinal fluid on the equilibrium solubility of oral drugs.
Upon oral administration the solubility of a drug in intestinal fluid is a key property influencing bioavailability. It is also recognised that simple aqueous solubility does not reflect intestinal solubility and to optimise in vitro investigations simulated intestinal media systems have been developed. Simulated intestinal media which can mimic either the fasted or fed state consists of multiple components each of which either singly or in combination may influence drug solubility, a property that can be investigated by a statistical design of experiment technique. In this study a design of experiment covering the full range from the lower limit of fasted to the upper limit of fed parameters and using a small number of experiments has been performed. The measured equilibrium solubility values are comparable with literature values for simulated fasted and fed intestinal fluids as well as human fasted and fed intestinal fluids. The equilibrium solubility data range is statistically equivalent to a combination of published fasted and fed design of experiment data in six (indomethacin, phenytoin, zafirlukast, carvedilol, fenofibrate and probucol) drugs with three (aprepitant, tadalafil and felodipine) drugs not equivalent. In addition the measured equilibrium solubility data sets were not normally distributed. Further studies will be required to determine the reasons for these results however it implies that a single solubility measurement without knowledge of the solubility distribution will be of limited value. The statistically significant media factors which promote equilibrium solubility (pH, sodium oleate and bile salt) were in agreement with published results but the number of determined significant factors and factor interactions was fewer in this study, lecithin for example did not influence solubility. This may be due to the reduction in statistical sensitivity from the lower number of experimental data points or the fact that using the full range will examine media parameters ratios that are not biorelevant. Overall the approach will provide an estimate of the solubility range and the most important media factors but will not be equivalent to larger scale focussed studies. Further investigations will be required to determine why some drugs do not produce equivalent DoE solubility distributions, for example combined fasted and fed DoE, but this simply may be due to the complexity and individuality of the interactions between a drug and the media components.


Characterization of a novel tonic gamma-aminobutyric acidA receptor-mediated inhibition in magnocellular neurosecretory neurons and its modulation by glia.
In addition to mediating conventional quantal synaptic transmission (also known as phasic inhibition), gamma-aminobutyric acidA (GABAA) receptors have been recently shown to underlie a slower, persistent form of inhibition (tonic inhibition). Using patch-clamp electrophysiology and immunohistochemistry, we addressed here whether a GABAA receptor-mediated tonic inhibition is present in supraoptic nucleus (SON) neurosecretory neurons; identified key modulatory mechanisms, including the role of glia; and determined its functional role in controlling SON neuronal excitability. Besides blocking GABAA-mediated inhibitory postsynaptic currents, the GABAA receptor blockers bicuculline and picrotoxin caused an outward shift in the holding current (I(tonic)), both in oxytocin and vasopressin neurons. Conversely, the high-affinity antagonist gabazine selectively blocked inhibitory postsynaptic currents. Under basal conditions, I(tonic) was independent on the degree of synaptic activity but was strongly modulated by the activity GABA transporters (GATs), mostly the GAT3 isoform, found here to be localized in SON glial cells/processes. Extracellular activation of GABAergic afferents evoked a small gabazine-insensitive, bicuculline-sensitive current, which was enhanced by GAT blockade. These results suggest that I(tonic) may be activated by spillover of GABA during conditions of strong and/or synchronous synaptic activity. Blockade of I(tonic) increased input resistance, induced membrane depolarization and firing activity, and enhanced the input-output function of SON neurons. In summary, our results indicate that GABAA receptors, possibly of different molecular configuration and subcellular distribution, mediate synaptic and tonic inhibition in SON neurons. The latter inhibitory modality plays a major role in modulating SON neuronal excitability, and its efficacy is modulated by the activity of glial GATs.


Pioneer farming in southeast Europe during the early sixth millennium BC: Climate-related adaptations in the exploitation of plants and animals.
The Old World farming system arose in the semi-arid Mediterranean environments of southwest Asia. Pioneer farmers settling the interior of the Balkans by the early sixth millennium BC were among the first to introduce southwest Asian-style cultivation and herding into areas with increasingly continental temperate conditions. Previous research has shown that the bioarchaeological assemblages from early farming sites in southeast Europe vary in their proportions of plant and animal taxa, but the relationship between taxonomic variation and climate has remained poorly understood. To uncover associations between multiple species and environmental factors simultaneously, we explored a dataset including altitude, five bioclimatic and 30 bioarchaeological variables (plant and animal taxa) for 57 of the earliest farming sites in southeast Europe using Canonical Correspondence Analysis (CCA). An extension of correspondence analysis, CCA is widely used in applied ecology to answer similar questions of species-environment relationships, but has not been previously applied in prehistoric archaeology to explore taxonomic and climatic variables in conjunction. The analyses reveal that the changes in plant and animal exploitation which occurred with the northward dispersal of farmers, crops and livestock correlate with south-north climate gradients, and emphasize the importance of adaptations in the animal domain for the initial establishment of farming beyond the Mediterranean areas.


Daytime and nighttime carbon balance and assimilate export in soybean leaves at different photon flux densities.
To evaluate daytime and nighttime carbon balance and assimilate export in soybean (Glycine max [L.] Merrill) leaves at different photon flux densities, rates of CO(2) exchange, specific leaf weights, and concentrations of sucrose and starch were measured at intervals in leaves of pod-bearing ;Amsoy 71' and ;Wells II' plants grown in a controlled environment room. Assimilate export was estimated from CO(2) exchange and change in specific leaf weight. Total diurnal assimilate export was similar for both cultivars. Large cultivar differences existed, however, in the partitioning of carbon into starch reserves and the relative amounts of assimilate exported during the day and the night. Total amounts of both daytime and nighttime export increased with increasing photon flux density, as did sucrose and starch concentrations, specific leaf weight, and rate of respiratory carbohydrate loss at night. Cultivar differences in nighttime rate of export were more closely related to the differences in amount of assimilate available at the end of the day than to differences in daytime rate of net CO(2) assimilation. Daytime rates of export, however, were closely related to daytime rates of net CO(2) assimilation within each cultivar. The total amount of starch depleted during the 10-hour night increased as starch concentration at the beginning of the night increased.


Tunneling Does Not Prevent Dislodgment of Epidural Catheters: A Randomized Trial.
Epidural analgesia is preferred in postoperative pain control, but dislodgment is a major factor for failure. Tunneling is well known to control displacement of catheters. In this study, we evaluated if we can depend on tunneling in preventing dislodgment of epidural catheters. The aim is to study if tunneling is effective and safe in reducing the rate of epidural catheters' dislodgment. The study was carried out at a single tertiary cancer center. The trial was parallel, simple randomized, controlled, and single blind. Allocation of treatments was generated using random number tables. Two hundred patients undergoing major surgeries were randomized. Epidural catheters were affixed to the skin through subcutaneous tunneling to a length of 5 cm or using standard adhesive tape without tunneling. Patients were on follow-up for 6 days postsurgery according to policy. Categorical variables were analyzed by Chi-square and Fisher's exact test. Student t-test was used for continuous variables. A total of 200 patients were randomized, 92 patients received tunneled catheters and 108 received nontunneled catheters. Patients were between 20 and 85 years; 63% were male. The mean days of epidural analgesia were similar in both groups (2.7 compared to 2.5 days). About 7.6% of epidurals were dislodged in the tunneled group compared to 10.2% in the nontunneled group (P = 0.699). No differences were identified in the incidence of pain or adverse events between the groups. Tunneling did not improve the rates of dislodgment in epidural catheters. There were no safety concerns associated with tunneling epidural catheters.


Genetic and epigenetic alterations during renal carcinogenesis.
Renal cell carcinoma (RCC) is not a single entity, but comprises a group of tumors including clear cell RCC, papillary RCC and chromophobe RCC, which arise from the epithelium of renal tubules. The majority of clear cell RCCs, the major histological subtype, have genetic or epigenetic inactivation of the von Hippel-Lindau (VHL) gene. Germline mutations in the MET and fumarate hydratase (FH) genes lead to the development of type 1 and type 2 papillary RCCs, respectively, and such mutations of either the TSC1 or TSC2 gene increase the risk of RCC. Genome-wide copy number alteration analysis has suggested that loss of chromosome 3p and gain of chromosomes 5q and 7 may be copy number aberrations indispensable for the development of clear cell RCC. When chromosome 1p, 4, 9, 13q or 14q is also lost, more clinicopathologically aggressive clear cell RCC may develop. Since renal carcinogenesis is associated with neither chronic inflammation nor persistent viral infection, and hardly any histological change is evident in corresponding non-tumorous renal tissue from patients with renal tumors, precancerous conditions in the kidney have been rarely described. However, regional DNA hypermethylation on C-type CpG islands has already accumulated in such non-cancerous renal tissues, suggesting that, from the viewpoint of altered DNA methylation, the presence of precancerous conditions can be recognized even in the kidney. Genome-wide DNA methylation profiles in precancerous conditions are basically inherited by the corresponding clear cell RCCs developing in individual patients: DNA methylation alterations at the precancerous stage may further predispose renal tissue to epigenetic and genetic alterations, generate more malignant cancers, and even determine patient outcome. The list of tumor-related genes silenced by DNA hypermethylation has recently been increasing. Genetic and epigenetic profiling provides an optimal means of prognostication for patients with RCCs. Recently developed high-throughput technologies for genetic and epigenetic analyses will further accelerate the identification of key molecules for use in the prevention, diagnosis and therapy of RCCs.


Social contact patterns and implications for infectious disease transmission - a systematic review and meta-analysis of contact surveys.
Transmission of respiratory pathogens such as SARS-CoV-2 depends on patterns of contact and mixing across populations. Understanding this is crucial to predict pathogen spread and the effectiveness of control efforts. Most analyses of contact patterns to date have focused on high-income settings. Here, we conduct a systematic review and individual-participant meta-analysis of surveys carried out in low- and middle-income countries and compare patterns of contact in these settings to surveys previously carried out in high-income countries. Using individual-level data from 28,503 participants and 413,069 contacts across 27 surveys, we explored how contact characteristics (number, location, duration, and whether physical) vary across income settings. Contact rates declined with age in high- and upper-middle-income settings, but not in low-income settings, where adults aged 65+ made similar numbers of contacts as younger individuals and mixed with all age groups. Across all settings, increasing household size was a key determinant of contact frequency and characteristics, with low-income settings characterised by the largest, most intergenerational households. A higher proportion of contacts were made at home in low-income settings, and work/school contacts were more frequent in high-income strata. We also observed contrasting effects of gender across income strata on the frequency, duration, and type of contacts individuals made. These differences in contact patterns between settings have material consequences for both spread of respiratory pathogens and the effectiveness of different non-pharmaceutical interventions. This work is primarily being funded by joint Centre funding from the UK Medical Research Council and DFID (MR/R015600/1).


A prospective multicentre randomized placebo-controlled superiority trial in patients with suspected bacterial endophthalmitis after cataract surgery on the adjuvant use of intravitreal dexamethasone to intravitreal antibiotics.
We aimed to determine whether intravitreal dexamethasone as an adjuvant to intravitreal antibiotics is beneficial in the treatment of suspected bacterial endophthalmitis after cataract surgery. Randomized, placebo-controlled superiority trial in three tertiary referral centres in the Netherlands. Patients with suspected bacterial endophthalmitis within 6 weeks after cataract surgery were eligible. A diagnostic vitreous biopsy was taken for culture, and patients received intravitreal injections of 400 μg dexamethasone (without preservatives) or placebo, in addition to 0.2 mg vancomycin and 0.05 mg gentamicin. The vancomycin and dexamethasone or placebo injections were repeated once at day 3 or 4. Primary outcome measure was best-corrected visual acuity (BCVA) at 1 year. Between 1 November 2004 and 1 March 2014 (excluding two interruptions totalling 20 months), 324 eligible patients presented. A total of 167 patients (81 dexamethasone, 86 placebo) were available for the intention-to-treat analysis. Biopsies of 114 patients (68%) were culture-positive. Final BCVA did not differ between the dexamethasone and the placebo group (logMAR 0.31 ± 0.58 versus 0.27 ± 0.50; p = 0.90), nor did the number of patients with final vision of no light perception (LP, 7 versus 13). Pain, corneal oedema, the absence of a red fundus reflex on presentation, LP on presentation and culture of virulent pathogens from biopsy were statistically significantly associated with an unfavourable visual outcome. Intravitreal dexamethasone without preservatives as an adjuvant to intravitreal antibiotics does not improve visual acuity (VA) in patients treated for suspected bacterial endophthalmitis after cataract surgery.


A volumetric study of parietal lobe subregions in Turner syndrome.
Turner syndrome, a genetic disorder that results from the complete or partial absence of an X chromosome in females, has been associated with specific impairment in visuospatial cognition. Previous studies have demonstrated a relationship between parietal lobe abnormalities and visuospatial deficits in Turner syndrome. We used high-resolution magnetic resonance imaging to measure parietal lobe subdivisions in 14 participants with Turner syndrome (mean age 13 years 5 months, SD 5 years) and 14 age-matched controls (mean age 13 years 5 months, SD 4 years 7 months) to localize neuroanatomical variations more closely. Scans were acquired and analyzed for 14 females with Turner syndrome. Analyses of variance were used to investigate differences in regional parietal lobes. Females with Turner syndrome showed a bilateral parietal lobe reduction, specifically in the superior parietal and postcentral gyri. Full-scale IQ scores were significantly positively correlated with postcentral tissue volume in the Turner syndrome group. Structural differences in the parietal lobe are localized specifically to the anterior and superior parietal lobe and might be related to the visuospatial and visuomotor deficits associated with Turner syndrome.


Prevalence of idiopathic hypercalciuria in children with urinary system related symptoms attending a pediatric hospital in Bandar Abbas in 2014.
Idiopathic hypercalciuria is a group of diseases which can be manifested with urinary symptoms. Its importance is due to high prevalence, recurrent infections, and stone formations which are often asymptomatic. The objective of this study was to determine the prevalence of idiopathic hypercalciuria in children with urinary system related symptoms in Bandar Abbas in 2014. This descriptive cross-sectional study was done in 2014 in a children's hospital in Bandar Abbas (southern Iran) on 321 children who were between 2 months to 14 years old. Random morning urine sample was obtained from all the patients, and calcium to creatinine ratio was assessed for all the patients for two times. Hypercalciuria is defined as urinary calcium excretion rate that is greater than 4 mg/kg per 24 hours in a child older than two years of age. Data was analyzed using IBM SPSS statistics 23.0 software and Chi-square and independent-samples t-test. Among the 321 children assessed, 153 (47.7%) had idiopathic hypercalciuria. The mean age of the children with idiopathic hypercalciuria was 55.20±43.71. Prevalence of idiopathic hypercalciuria was 48.3% in children with urinary tract infection, 54.9% and 53.6% in children with microscopic and macroscopic hematuria respectively, In children with dysuria, there were 52.1%, and 51.8% in children with frequency, 49.1% in children with kidney stone which was confirmed with sonography, 28.6% and 37.5% in children with nocturnal and daily urinary incontinency respectively. Results of this study showed no significant relationship between urinary system symptoms and idiopathic hypercalciuria (p>0.05). Hypercalciuria can be presented with different symptoms associated with urinary symptoms. Therefore, it is recommended to check the urinary calcium level in children with urinary symptoms with no definite etiology.


Nevoscopy: three-dimensional computed tomography of nevi and melanomas in situ by transillumination.
The thickness of a malignant nevus has been found to be an important prognostic factor for patients with melanoma. We have designed a new method of imaging nevi that permits their thickness to be measured in situ. Using fiber optics directed into the surrounding skin, we transilluminate the nevus. Three images are picked up by a digitizing TV camera: the vertical image (90 degrees ), a glancing image (180 degrees ), and one at 45 degrees , obtained by using two front-silvered mirrors held next to the nevus in a "nevoscope." The digitized images are used in a computed tomography algorithm to calculate approximate vertical cross sections of the nevus. The algorithm is one we recently developed to permit reconstruction from a very few projections. Our method is completely noninvasive. It may be used to check all the nevi on a patient. Without excisions, we could establish a baseline three-dimensional shape for each nevus, follow any changes in time, and obtain an early warning of increase in thickness and possible malignancy.


Neither antibody to a group B streptococcal conjugate vaccine nor the vaccine itself is teratogenic in rabbits.
Group B Streptococcus (GBS) is a leading cause of human neonatal bacterial disease, resulting in pneumonia, sepsis, meningitis and sometimes, death. Supportive preclinical studies of GBS capsular polysaccharide (CPS)-protein conjugate vaccines have led to several phase 1 and phase 2 trials in healthy, non-pregnant adults, which demonstrated that the vaccines, produced at the Channing Laboratory, were safe and immunogenic. However, evaluation of the safety and immunogenicity of a GBS conjugate vaccine administered to pregnant women demanded that it be manufactured under current good manufacturing practices (cGMP) and that it undergo developmental toxicity evaluation. In this report, we describe a GBS type III CPS-tetanus toxoid (III-TT) vaccine lot 3-1-96 manufactured and vialed under cGMP and our evaluation of the effect of this vaccine and of GBS type III CPS-specific antibody on conception and early- and late-stage fetal development in rabbits. III-TT lot 3-1-96 was compositionally similar to prototype III-TT lot 91-1, produced under non-GMP, and was potent in a mouse maternal vaccination-neonatal pup challenge model of GBS disease. Four groups of 30 female rabbits each were randomized to receive III-TT lot 3-1-96 vaccine, saline-alum, or combinations of these treatments before and after insemination. The dose of conjugated CPS on a weight basis was 1 microg/kg, mimicking the anticipated actual human dose. Based on the weight of the rabbits, this was 20- to 100-fold greater than the expected human dose. Does were pre-assigned to deliver litters naturally or have their kits delivered by Caesarean-section at gestation day 29, to assess late fetal development. Sera from does and kits were collected, and the presence of type III CPS-specific IgG was confirmed by quantitative ELISA. Based on all assessments, GBS type III-TT lot 3-1-96, nor antibody to it did not affect embryo fetal viability, sex ratio, growth or cause malformations (i.e., it was non-teratogenic). In addition, that III-TT lot 3-1-96 was found to be safe and immunogenic in two clinical studies involving healthy non-pregnant adults supports a clinical evaluation of this vaccine in pregnant women.


Mortality and health-related quality of life in prevalent dialysis patients: Comparison between 12-items and 36-items short-form health survey.
To assess health- related quality of life (HRQOL) with SF-12 and SF-36 and compare their abilities to predict mortality in chronic dialysis patients, after adjusting for traditional risk factors. The Short-Form Health Survey (SF-36) with the embedded SF-12 was applied in 301 dialysis patients cross-sectionally. Physical and mental component summary (PCS-36, MCS-36, PCS-12, and MCS-12) scores were calculated. Clinical and demographic data were collected. Mortality (followed for up to 4.5 years) was analyzed with Kaplan Meier plots and Cox proportional hazards, after censoring for renal transplantation. Exclusion factors were observation time <2 months (n = 21) and missing component summary scores (n = 10 for SF-36; n = 28 for SF-12), thus 252 patient were included in the analyses. In 252 patients (60.2 ± 15.5 years, 65.9% males, dialysis vintage 9.0, IQR 5.0-23.0 months), mortality during follow-up was 33.7%.(85 deaths). Significant correlations were observed between PCS-36 and PCS-12 (ρ = 0.93, p < 0.001) and between MCS-36 and MCS-12 (ρ = 0.95, p < 0.001). Mortality rate was highest in patients in the lowest quartile of PCS-12 (χ² = 15.3, p = 0.002) and PCS-36 (χ² = 16.7, p = 0.001). MCS was not associated with mortality. Adjusted hazard ratios for mortality were 2.5 (95% CI 1.0-6.3, PCS-12) and 2.7 (1.1 - 6.4, PCS-36) for the lowest compared with the highest ("best perceived") quartile of PCS. Compromised HRQOL is an independent predictor of poor outcome in dialysis patients. The SF-12 provided similar predictions of mortality as SF-36, and may serve as an applicable clinical tool because it requires less time to complete.


α-Lipoic acid, functional fatty acid, as a novel therapeutic alternative for central nervous system diseases: A review.
α-lipoic acid (ALA) is a natural antioxidant which acts as a cofactor of bioenergetic mitochondrial enzymes. Along with its mitochondrial action, ALA and its reduced form have many biological functions resulting in a wide variety of actions such as anti-inflammation and antioxidant protection, scavenging reactive oxygen species, regenerating other antioxidant agents, such as vitamins C and E, and cytosolic glutathione, chelating the transitional metal ions (e.g. iron and copper), and modulating the signal transduction of nuclear factor. By selecting papers from PubMed, Science Direct, EBSCO, and databases, this review discusses the biochemical properties of LA, its mechanism of action, pharmacokinetics, and its possible therapeutic role in central nervous system diseases, such as Alzheimer's disease, Parkinson's disease, Multiple sclerosis, stroke, and spinal cord injury. ALA as an antioxidant and anti-inflammation agent has therapeutical effects on central nervous system diseases, especially multiple sclerosis and PD. ALA can be considered as a potentially useful treatment in central nervous disorders.


Rab regulation by GEFs and GAPs during membrane traffic.
Rab GTPases and their regulatory proteins play a crucial role in vesicle-mediated membrane trafficking. During vesicle membrane tethering Rab GTPases are activated by GEFs (guanine nucleotide exchange factors) and then inactivated by GAPs (GTPase activating proteins). Recent evidence shows that in addition to activating and inactivating Rab GTPases, both Rab GEFs and GAPs directly contribute to membrane tethering events during vesicle traffic. Other studies have extended the range of processes, in which Rabs function, and revealed roles for Rabs and their GAPs in the regulation of autophagy. Here, we will discuss these advances and the emerging relationship between the domain architectures of Rab GEFs and vesicle coat protein complexes linked with GTPases of the Sar, ARF and Arl families in animal cells.


Exercise-Induced Neuroplasticity: A Mechanistic Model and Prospects for Promoting Plasticity.
Aerobic exercise improves cognitive and motor function by inducing neural changes detected using molecular, cellular, and systems level neuroscience techniques. This review unifies the knowledge gained across various neuroscience techniques to provide a comprehensive profile of the neural mechanisms that mediate exercise-induced neuroplasticity. Using a model of exercise-induced neuroplasticity, this review emphasizes the sequence of neural events that accompany exercise, and ultimately promote changes in human performance. This is achieved by differentiating between neuroplasticity induced by acute versus chronic aerobic exercise. Furthermore, this review emphasizes experimental considerations that influence the opportunity to observe exercise-induced neuroplasticity in humans. These include modifiable factors associated with the exercise intervention and nonmodifiable factors such as biological sex, ovarian hormones, genetic variations, and fitness level. To maximize the beneficial effects of exercise in health, disease, and following injury, future research should continue to explore the mechanisms that mediate exercise-induced neuroplasticity. This review identifies some fundamental gaps in knowledge that may serve to guide future research in this area.


Exposure-based traffic crash injury rates by mode of travel in British Columbia.
Traffic-related trauma is an important contributor to morbidity and mortality in Canada, especially among children and young adults. Comparing exposure-based injury rates between travel modes and jurisdictions is a valuable tool towards improving safety. We used injury data from the British Columbia Motor Vehicle Branch, trip diary data from the Metro Vancouver transportation authority, and population and provincial travel data from the Census to calculate crude fatality and injury rates for motor vehicle occupants, bicyclists, and pedestrians. We used three different denominators: population; person-trip; and distance travelled. Motor vehicle occupants had the lowest fatality rates using exposure-based denominators: 9.6 per 100 million person-trips and 0.97 per 100 million km. Bicyclists and pedestrians had similar fatality rates using one denominator (13.8 vs. 14.7 per 100 million person-trips, respectively), but bicyclists had a lower rate using the other (2.60 vs. 7.37 per 100 million km). For injuries, pedestrians had the lowest rate and bicyclists the highest using the person-trip denominator, whereas motor vehicle occupants had the lowest rate using the distance denominator, and bicycling and walking had similar rates. Risks of driving, walking and bicycling in British Columbia were similar to their risks in the United States. The injury and fatality rates for these three travel modes were intermediate compared to much higher rates among US motorcyclists and much lower rates among US bus passengers. Data improvements would enable transportation trauma rate calculations for Canada as a whole and for other modes of travel (transit, motorcycling).


Interaction of land management and araucaria trees in the maintenance of landscape diversity in the highlands of southern Brazil.
In the southern Brazilian highlands, pre-Columbian societies created domesticated landscapes through the use and management of forests, including nurse Araucaria angustifolia trees, a common conifer in these regions. Nowadays, local smallholders still use traditional practices, such as burning, to promote vegetation for cattle grazing in highland grasslands. Even though burning is normally of small extent and low frequency, such management can slow down natural forest expansion and contribute to the maintenance of grasslands, by opposing the facilitative effect of nurse araucaria trees. To comprehend the interplay between human cultural management, species interactions and the environment, it is important to better understand how these relations affect diversity and composition. Our goal was to investigate how land management, biotic interactions and abiotic factors affect saplings species richness, abundance and composition. We hypothesized that (1) land management would decrease sapling richness and abundance and change sapling composition, (2) nurse araucaria trees would increase species richness and abundance and change sapling composition, and (3) the interactive effect between land management and nurse araucaria trees would shape sapling richness, abundance and composition. Data were collected in unmanaged and managed conditions, both beneath araucaria crowns and in nearby treeless areas. Our results indicate that abundance and species composition are affected by land management and araucaria crown influence. The highest values of sapling abundance were found beneath crowns in unmanaged areas. Species composition changed between all assessed combinations of land management and crown influence. Our study demonstrates the major roles of land management and facilitation in structuring communities, despite the effects of rock and grass cover. Moreover, our results clarify patterns and processes that may emerge in natural highland grasslands, such as the conversion of grasslands into forests and the loss of cultural landscapes when the main local management actions are excluded.


The Ballabgarh Health and Demographic Surveillance System (CRHSP-AIIMS).
The Ballabgarh Health and Demographic Surveillance System (HDSS), also known as the Comprehensive Rural Health Services Project (CRHSP) Ballabgarh, is located in north India and was established in 1961 to develop a model for rural health-care practice in India. In addition to demographic surveillance and community-based research, CRHSP Ballabgarh provides preventive, health-promotion, and curative services to its surrounding population. The population served by CRHSP Ballabgarh in 2011 was about 90,000. The system collects data for the entire population through fortnightly visits by health workers (HWs). The system's data base is updated once every month and further updated with missing data and special morbidity surveillance data during the annual census. Since 1961, CRHSP Ballabgarh has collected demographic data, reproductive data, and health data about mothers and their children. More recently, the project began collecting data on diseases such as tuberculosis, and because of changes in life style it recently began collecting data about non-communicable diseases (NCD) and risk factors for NCDs. Nonetheless, an adverse sex ratio, with more boys than girls, and a stagnant neonatal mortality rate, remain major challenges in the population served by CRHSP Ballabgarh. The project shares data with different agencies for health-management purposes, which can be made available to bona fide researchers on receipt of a proposal (enquiries should be directed to: email@example.com); collaboration requests are welcome.


Mung bean (Phaseolus aureus) nuclease. A mechanistic investigation of the DNA-cleavage reaction using a dinucleoside phosphorothioate.
Mung-bean (Phaseolus aureus) nuclease has been found to cleave the Sp diastereoisomer of 5'-O-thymidyl 3'-O-(2'-deoxyadenosyl)phosphorothioate, (Sp)-d[Ap(S)T], in 18O-labelled water with inversion of configuration at phosphorus to give (Sp)-thymidine 5'-[16O, 18O]phosphorothioate, the stereochemistry of which was deduced by methylation to (Rp,Sp)-thymidine 5'-S-methyl-O-methyl-[16O,18O]phosphorothioate and 31P-n.m.r. analysis. This result is consistent with a mechanism involving a direct 'in-line' attack of water on DNA for the nuclease-catalysed reaction without the involvement of a covalent nucleotidylated-enzyme intermediate.


Experimental test of an analytical model of aberration in an oil-immersion objective lens used in three-dimensional light microscopy.
Oil-immersion microscope objective lenses have been designed and optimized for the study of thin, two-dimensional object sections that are mounted immediately below the coverslip in a medium that is index matched to the immersion oil. It has been demonstrated both experimentally and through geometrical- and physical-optics theory that, when the microscope is not used with the correct coverslip or immersion oil, when the detector is not located at the optimal plane in image space, or when the object does not satisfy specific conditions, aberration will degrade both the contrast and the resolution of the image. In biology the most severe aberration is introduced when an oil-immersion objective lens is used to study thick specimens, such as living cells and tissues, whose refractive indices are significantly different from that of the immersion oil. We present a model of the three-dimensional imaging properties of a fluorescence light microscope subject to such aberration and compare the imaging properties predicted by the model with those measured experimentally. The model can be used to understand and compensate for aberration introduced to a microscope system under nondesign optical conditions so that both confocal laser scanning microscopy and optical serial sectioning microscopy can be optimized.


Outbreak of measles among persons with prior evidence of immunity, New York City, 2011.
Measles was eliminated in the United States through high vaccination coverage and a public health system able to rapidly respond to measles. Measles may occur among vaccinated individuals, but secondary transmission from such individuals has not been documented. Suspected patients and contacts exposed during a measles outbreak in New York City in 2011 were investigated. Medical histories and immunization records were obtained. Cases were confirmed by detection of measles-specific immunoglobulin M and/or RNA. Tests for measles immunoglobulin G (IgG), IgG avidity, measurement of measles neutralizing antibody titers, and genotyping were performed to characterize the cases. The index patient had 2 doses of measles-containing vaccine; of 88 contacts, 4 secondary patients were confirmed who had either 2 doses of measles-containing vaccine or a past positive measles IgG antibody. All patients had laboratory confirmation of measles infection, clinical symptoms consistent with measles, and high-avidity IgG antibody characteristic of a secondary immune response. Neutralizing antibody titers of secondary patients reached >80 000 mIU/mL 3-4 days after rash onset and that of the index was <500 mIU/mL 9 days after rash onset. No additional cases of measles occurred among 231 contacts of secondary patients. This is the first report of measles transmission from a twice-vaccinated individual with documented secondary vaccine failure. The clinical presentation and laboratory data of the index patient were typical of measles in a naive individual. Secondary patients had robust anamnestic antibody responses. No tertiary cases occurred despite numerous contacts. This outbreak underscores the need for thorough epidemiologic and laboratory investigation of suspected cases of measles regardless of vaccination status.


Evaluation of the pilot phase of an Aboriginal and Torres Strait Islander Male Health Module.
This article evaluates the pilot phase of an Aboriginal and Torres Strait Islander Male Health Module. Although men experience higher levels of illness and die younger than women, educational programs to support health workers utilise a gender-based approach to increase participation of Aboriginal and Torres Strait Islander males in health care are rare and lack appropriate content. Recognising this gap in service provision, and under the guidance of a Reference Group comprising community leaders in Aboriginal and Torres Strait male health, a comprehensive and culturally appropriate Male Health Module has been developed to enhance the capacity of health workers to improve access to services for Aboriginal and Torres Strait Islander males. Methods used were: in-depth interviews with Module developers, pilot workshops for trainers and health workers, questionnaires and focus group discussions with workshop participants, and participant observations. As well as enhancing capacity to facilitate access to health services for men, the Module was deemed relevant because of its potential to promote health worker empowerment and wellbeing. Findings revealed that improving access to services for men required male and female health workers working in partnership. Despite overall enthusiasm for the Module, the findings also revealed deep fear that it would end up 'collecting dust on shelves'. Strategies to improve the Module quality and accessibility are highlighted.