Dynamic evolving spiking neural networks for on-line spatio- and spectro-temporal pattern recognition.
On-line learning and recognition of spatio- and spectro-temporal data (SSTD) is a very challenging task and an important one for the future development of autonomous machine learning systems with broad applications. Models based on spiking neural networks (SNN) have already proved their potential in capturing spatial and temporal data. One class of them, the evolving SNN (eSNN), uses a one-pass rank-order learning mechanism and a strategy to evolve a new spiking neuron and new connections to learn new patterns from incoming data. So far these networks have been mainly used for fast image and speech frame-based recognition. Alternative spike-time learning methods, such as Spike-Timing Dependent Plasticity (STDP) and its variant Spike Driven Synaptic Plasticity (SDSP), can also be used to learn spatio-temporal representations, but they usually require many iterations in an unsupervised or semi-supervised mode of learning. This paper introduces a new class of eSNN, dynamic eSNN, that utilise both rank-order learning and dynamic synapses to learn SSTD in a fast, on-line mode. The paper also introduces a new model called deSNN, that utilises rank-order learning and SDSP spike-time learning in unsupervised, supervised, or semi-supervised modes. The SDSP learning is used to evolve dynamically the network changing connection weights that capture spatio-temporal spike data clusters both during training and during recall. The new deSNN model is first illustrated on simple examples and then applied on two case study applications: (1) moving object recognition using address-event representation (AER) with data collected using a silicon retina device; (2) EEG SSTD recognition for brain-computer interfaces. The deSNN models resulted in a superior performance in terms of accuracy and speed when compared with other SNN models that use either rank-order or STDP learning. The reason is that the deSNN makes use of both the information contained in the order of the first input spikes (which information is explicitly present in input data streams and would be crucial to consider in some tasks) and of the information contained in the timing of the following spikes that is learned by the dynamic synapses as a whole spatio-temporal pattern.


Home-based neurologic music therapy for upper limb rehabilitation with stroke patients at community rehabilitation stage-a feasibility study protocol.
Impairment of upper limb function following stroke is more common than lower limb impairment and is also more resistant to treatment. Several lab-based studies with stroke patients have produced statistically significant gains in upper limb function when using musical instrument playing and techniques where rhythm acts as an external time-keeper for the priming and timing of upper limb movements. For this feasibility study a small sample size of 14 participants (3-60 months post stroke) has been determined through clinical discussion between the researcher and study host in order to test for management, feasibility and effects, before planning a larger trial determined through power analysis. A cross-over design with five repeated measures will be used, whereby participants will be randomized into either a treatment (n = 7) or wait list control (n = 7) group. Intervention will take place twice weekly over 6 weeks. The ARAT and 9HPT will be used to measure for quantitative gains in arm function and finger dexterity, pre/post treatment interviews will serve to investigate treatment compliance and tolerance. A lab based EEG case comparison study will be undertaken to explore audio-motor coupling, brain connectivity and neural reorganization with this intervention, as evidenced in similar studies. Before evaluating the effectiveness of a home-based intervention in a larger scale study, it is important to assess whether implementation of the trial methodology is feasible. This study investigates the feasibility, efficacy and patient experience of a music therapy treatment protocol comprising a chart of 12 different instrumental exercises and variations, which aims at promoting measurable changes in upper limb function in hemiparetic stroke patients. The study proposes to examine several new aspects including home-based treatment and dosage, and will provide data on recruitment, adherence and variability of outcomes.


Presenting native-like trimeric HIV-1 antigens with self-assembling nanoparticles.
Structures of BG505 SOSIP.664 trimer in complex with broadly neutralizing antibodies (bNAbs) have revealed the critical role of trimeric context for immune recognition of HIV-1. Presentation of trimeric HIV-1 antigens on nanoparticles may thus provide promising vaccine candidates. Here we report the rational design, structural analysis and antigenic evaluation of HIV-1 trimer-presenting nanoparticles. We first demonstrate that both V1V2 and gp120 can be presented in native-like trimeric conformations on nanoparticles. We then design nanoparticles presenting various forms of stabilized gp140 trimer based on ferritin and a large, 60-meric E2p that displays 20 spikes mimicking virus-like particles (VLPs). Particle assembly is confirmed by electron microscopy (EM), while antigenic profiles are generated using representative bNAbs and non-NAbs. Lastly, we demonstrate high-yield gp140 nanoparticle production and robust stimulation of B cells carrying cognate VRC01 receptors by gp120 and gp140 nanoparticles. Together, our study provides an arsenal of multivalent immunogens for HIV-1 vaccine development.


Naturally acquired antibodies to Bacillus anthracis protective antigen in vultures of southern Africa.
Sera from 19 wild caught vultures in northern Namibia and 15 (12 wild caught and three captive bred but with minimal histories) in North West Province, South Africa, were examined by an enzyme-linked immunosorbent assay (ELISA) for antibodies to the Bacillus anthracis toxin protective antigen (PA). As assessed from the baseline established with a control group of ten captive reared vultures with well-documented histories, elevated titres were found in 12 of the 19 (63%) wild caught Namibian birds as compared with none of the 15 South African ones. There was a highly significant difference between the Namibian group as a whole and the other groups (P < 0.001) and no significant difference between the South African and control groups (P > 0.05). Numbers in the Namibian group were too small to determine any significances in species-, sex- or age-related differences within the raw data showing elevated titres in four out of six Cape Vultures, Gyps coprotheres, six out of ten White-backed Vultures, Gyps africanus, and one out of three Lappet-faced Vultures, Aegypius tracheliotus, or in five of six males versus three of seven females, and ten of 15 adults versus one of four juveniles. The results are in line with the available data on the incidence of anthrax in northern Namibia and South Africa and the likely contact of the vultures tested with anthrax carcasses. It is not known whether elevated titre indicates infection per se in vultures or absorption of incompletely digested epitopes of the toxin or both. The results are discussed in relation to distances travelled by vultures as determined by new tracking techniques, how serology can reveal anthrax activity in an area and the issue of the role of vultures in transmission of anthrax.


Pediatric chronic kidney disease: blood cell count indexes as inflammation markers.
Chronic kidney disease (CKD) is defined as a progressive decline of kidney functions. In childhood, the main triggering factors are congenital anomalies of the kidneys and urinary tract (CAKUT) and glomerulopathies. Inflammatory responses present challenges for diagnosis and staging, which justifies studies on biomarkers/indexes. To define blood cell count indexes and verify their association with pediatric CKD etiology and staging. The included indexes were: Neutrophil-Lymphocyte Ratio (NLR), Derived Neutrophil-Lymphocyte Ratio (dNLR), Lymphocyte-Monocyte Ratio (LMR), Systemic Inflammation Response Index (SIRI), Aggregate Index of Systemic Inflammation (AISI), and Systemic Immune-Inflammation Index (SII). We determined the indexes in 52 pediatric CKD patients and 33 healthy controls by mathematical calculation. CKD patients were separated in five groups based on the etiology and staging: Group IA: glomerulopathies at stage 1 or 2; IB: glomerulopathies at stage 3 or 4; IIA: CAKUT at stage 1 or 2; IIB: CAKUT at stage 3 or 4; and III: stages 3 or 4 of other etiologies. In addition, we combined all patients with CKD in one group (IV). Group V was a healthy control group. Lower values of LMR were observed for groups IB and IIB compared to group V (p = 0.047, p = 0.031, respectively). Increased values of SIRI were found for group III versus group V (p = 0.030). There was no difference for other indexes when the groups were compared two by two. The LMR and SIRI indexes showed promising results in the evaluation of inflammation, as they correlated with CKD etiologies and specially staging in these patients.


The effect of particle properties on the depth profile of buoyant plastics in the ocean.
Most studies on buoyant microplastics in the marine environment rely on sea surface sampling. Consequently, microplastic amounts can be underestimated, as turbulence leads to vertical mixing. Models that correct for vertical mixing are based on limited data. In this study we report measurements of the depth profile of buoyant microplastics in the North Atlantic subtropical gyre, from 0 to 5 m depth. Microplastics were separated into size classes (0.5-1.5 and 1.5-5.0 mm) and types ('fragments' and 'lines'), and associated with a sea state. Microplastic concentrations decreased exponentially with depth, with both sea state and particle properties affecting the steepness of the decrease. Concentrations approached zero within 5 m depth, indicating that most buoyant microplastics are present on or near the surface. Plastic rise velocities were also measured, and were found to differ significantly for different sizes and shapes. Our results suggest that (1) surface samplers such as manta trawls underestimate total buoyant microplastic amounts by a factor of 1.04-30.0 and (2) estimations of depth-integrated buoyant plastic concentrations should be done across different particle sizes and types. Our findings can assist with improving buoyant ocean plastic vertical mixing models, mass balance exercises, impact assessments and mitigation strategies.


Multidrug resistance is common in Escherichia coli associated with ileal Crohn's disease.
Escherichia coli is increasingly implicated in the pathogenesis of ileal Crohn's disease (ICD), offering a potential therapeutic target for disease management. Empirical antimicrobial targeting of ileal E. coli has advantages of economy and speed of implementation, but relies on uniform susceptibility of E. coli to routinely selected antimicrobials to avoid apparent treatment failure. Therefore, we examined the susceptibility of ileal E. coli to such antimicrobials. E. coli from 32 patients with ICD and 28 with normal ileum (NI) were characterized by phylogroup, pathotype, antimicrobial susceptibility, and presence of antimicrobial resistance genes. In all, 17/32 ICD and 12/28 NI patients harbored ≥ 1 E. coli strain; 10/24 E. coli strains from ICD and 2/14 from NI were nonsuscepti-ble to ≥ 1 antimicrobial in ≥ 3 categories (multidrug-resistant). Resistance to amoxicillin/clavulanic-acid, cefoxitin, chloramphenicol, ciprofloxa-cin, gentamicin, and rifaximin was restricted to ICD, with 10/24 strains from 8/17 patients resistant to ciprofloxacin or rifaximin (P < 0.01). Adherent-invasive E. coli (AIEC) were isolated from 8/32 ICD and 5/28 NI, and accounted for 54% and 43% of E. coli strains in these groups. In all, 8/13 AIEC strains from ICD (6/8 patients) versus 2/6 NI (2/5 patients) showed resistance to the macrophage-penetrating antimicrobials ciprofloxacin, clarithromycin, rifampicin, tetracycline, and trimethoprim/sulfamethoxazole. Resistance was associated with tetA, tetB, tetC, bla-(TEM), bla(oxa)-1, sulI, sulII, dhfrI, dhfrVII, ant(3″)-Ia, and catI genes and prior use of rifaximin (P < 0.01). ICD-associated E. coli frequently manifest resistance to commonly used antimicrobials. Clinical trials of antimicrobials against E. coli in ICD that are informed by susceptibility testing, rather than empirical selection, are more likely to demonstrate valid outcomes of such therapy.


Evolution of Caulanthus amplexicaulis var. barbarae (Brassicaceae), a rare serpentine endemic plant: a molecular phylogenetic perspective.
Intra- and interspecific phylogenetic relationships of the rare serpentine endemic taxon Caulanthus amplexicaulus var. barbarae and related taxa in the "Streptanthoid Complex" of genera (Streptanthus, Caulanthus, Guillenia) were examined using nuclear ribosomal internal transcribed spacer (ITS) and chloroplast trnL intron sequences. Phylogenetic hypotheses generated from 81 variable ITS nucleotide sites and six variable trnL nucleotide sites indicate that Streptanthus and Caulanthus are nonmonophyletic groups. Caulanthus amplexicaulis var. barbarae and its more widespread nonserpentine sister taxon Caulanthus amplexicaulis var. amplexicaulis formed a distinct monophyletic group. Among the taxa in our study, C. amplexicaulis was most closely related to Streptanthus tortuosus. The ITS sequences supported monophyly of subgenus Euclesia, which includes the bulk of the serpentine endemics in the Streptanthoid Complex. The serpentine taxa were nonmonophyletic, occurring in at least three distinct clades, suggesting that tolerance to serpentine may be gained or lost through relatively few genetic changes. Intraspecific ITS1 and ITS2 sequence divergence within C. amplexicaulis (1.3-1.8%) was higher than in comparable species (0.0-0.3%); implications of this genetic differentiation for the conservation status of C. amplexicaulis var. barbarae are discussed. Evidence is presented that supports a "biotype depletion" model for the origin of this rare endemic taxon.


Human sperm ion channel (dys)function: implications for fertilization.
Intensive research on sperm ion channels has identified members of several ion channel families in both mouse and human sperm. Gene knock-out studies have unequivocally demonstrated the importance of the calcium and potassium conductances in sperm for fertility. In both species, the calcium current is carried by the highly complex cation channel of sperm (CatSper). In mouse sperm, the potassium current has been conclusively shown to be carried by a channel consisting of the pore forming subunit SLO3 and auxiliary subunit leucine-rich repeat-containing 52 (LRRC52). However, in human sperm it is controversial whether the pore forming subunit of the channel is composed of SLO3 and/or SLO1. Deciphering the role of the proton-specific Hv1 channel is more challenging as it is only expressed in human sperm. However, definitive evidence for a role in, and importance for, human fertility can only be determined through studies using clinical samples. This review aims to provide insight into the role of sperm ion channels in human fertilization as evidenced from recent studies of sperm from infertile men. We also summarize the key discoveries from mouse ion channel knock-out models and contrast the properties of mouse and human CatSper and potassium currents. We detail the evidence for, and consequences of, defective ion channels in human sperm and discuss hypotheses to explain how defects arise and why affected sperm have impaired fertilization potential. Relevant studies were identified using PubMed and were limited to ion channels that have been characterized in mouse and human sperm. Additional notable examples from other species are included as appropriate. There are now well-documented fundamental differences between the properties of CatSper and potassium channel currents in mouse and human sperm. However, in both species, sperm lacking either channel cannot fertilize in vivo and CatSper-null sperm also fail to fertilize at IVF. Sperm-lacking potassium currents are capable of fertilizing at IVF, albeit at a much lower rate. However, additional complex and heterogeneous ion channel dysfunction has been reported in sperm from infertile men, the causes of which are unknown. Similarly, the nature of the functional impairment of affected patient sperm remains elusive. There are no reports of studies of Hv1 in human sperm from infertile men. Recent studies using sperm from infertile men have given new insight and critical evidence supporting the supposition that calcium and potassium conductances are essential for human fertility. However, it should be highlighted that many fundamental questions remain regarding the nature of molecular and functional defects in sperm with dysfunctional ion channels. The development and application of advanced technologies remains a necessity to progress basic and clinical research in this area, with the aim of providing effective screening methodologies to identify and develop treatments for affected men in order to help prevent failed ART cycles. Conversely, development of drugs that block calcium and/or potassium conductances in sperm is a plausible strategy for producing sperm-specific contraceptives.


Epidemic dengue and dengue hemorrhagic fever at the Texas-Mexico border: results of a household-based seroepidemiologic survey, December 2005.
A dengue-2 epidemic causing dengue hemorrhagic fever (DHF) occurred in the contiguous border cities of Matamoros, Tamaulipas (Mexico), and Brownsville, TX, in 2005. In December, we conducted a household-based epidemiologic survey to determine the incidence and seroprevalence of dengue infection among Matamoros and Brownsville residents and to identify risk factors associated with infection. Antibodies to dengue were measured in 273 individuals. The estimated incidence of recent dengue infection was 32% and 4% among Matamoros and Brownsville participants, respectively. The estimated prevalence of past dengue infection was 77% and 39% among Matamoros and Brownsville participants, respectively. The Breteau index was 28 in Matamoros and 16 in Brownsville, reflecting an abundant winter population of Aedes mosquitoes. Discarded waste tires and buckets were the two largest categories of infested containers found in both cities. Our results underscore the risk for epidemic dengue and DHF in the Texas-Mexico border region.


Is the resulting phenotype of an embryo with balanced X-autosome translocation, obtained by means of preimplantation genetic diagnosis, linked to the X inactivation pattern?
To examine if a balanced female embryo with X-autosome translocation could, during its subsequent development, express an abnormal phenotype. Preimplantation genetic diagnosis (PGD) analysis on two female carriers with maternal inherited X-autosome translocations. Infertility center and genetic laboratory in a public hospital. Two female patients carriers undergoing PGD for a balanced X-autosome translocations: patient 1 with 46,X,t(X;2)(q27;p15) and patient 2 with 46,X,t(X;22)(q28;q12.3). PGD for balanced X-autosome translocations. PGD outcomes, fluorescence in situ hybridization in biopsied embryos and meiotic segregation patterns analysis of embryos providing from X-autosome translocation carriers. Controlled ovarian stimulation facilitated retrieval of a correct number of oocytes. One balanced embryo per patient was transferred and one developed, but the patient miscarried after 6 weeks of amenorrhea. In X-autosome translocation carriers, balanced Y-bearing embryos are most often phenotypically normal and viable. An ambiguous phenotype exists in balanced X-bearing embryos owing to the X inactivation mechanism. In 46,XX embryos issued from an alternate segregation, der(X) may be inactivated and partially spread transcriptional silencing into a translocated autosomal segment. Thus, the structural unbalanced genotype could be turned into a viable functional balanced one. It is relevant that a discontinuous silencing is observed with a partial and unpredictable inactivation of autosomal regions. Consequently, the resulting phenotype remains a mystery and is considered to be at risk of being an abnormal phenotype in the field of PGD. It is necessary to be cautious regarding to PGD management for this type of translocation, particularly in transferred female embryos.


First Report of Groundnut bud necrosis virus in Tomato in Bangladesh.
An unusual disease of tomato characterized by leaf mottling and necrotic streaks on veins, shortened internodes, necrosis of terminal buds, and concentric rings on fruits was observed during 2010 to 2011 surveys in tomato growing regions of Godagari Upzila, Rajshahi district, Bangladesh. Disease incidence in popularly grown F1 hybrid cultivars, which include Sobal, Abhiruchi, Salamat, Bangobir, and BARI hybrid tomato-5 and -6 in about 40 commercial fields, ranged from 40 to 90%. Extracts from the field samples (n = 10) reacted with polyclonal antiserum to Groundnut bud necrosis virus (GBNV) in direct antigen coated ELISA, suggesting the association of a tospovirus antigenically related to serogroup IV topsovirus (1). To identify whether the tospovirus was a distinct virus species, ELISA-positive samples were subjected to total RNA extraction with an RNeasy Plant Mini Kit (Qiagen, Chatsworth, CA) followed by reverse transcription (RT)-PCR with tospovirus-specific primers (5'-ATGGTTGAAAAGAGCAAGAATGATGC-3') and degenerate primer (5'-CTTCTTATGAAGTGTACTCACCATAAGTCATCC-3') derived from the conserved sequences of GBNV, Watermelon bud necrosis virus (WBNV), and Capsicum chlorosis virus (CaCV) (2). The RT-PCR product was cloned into pGEM-T Easy vector (Promega, Madison, WI) and sequenced at Department of Biochemistry, University of Delhi, South Campus, Delhi, India (GenBank Accession No. JQ692083). The sequences of cloned fragments were assembled. Analysis of the 477-bp region of the nucleocapsid protein (N) gene revealed that the tomato tospovirus shared maximum identity both at the nucleotide (96%) and amino acid (97%) levels with the corresponding region of GBNV. In contrast, only 78 to 81% and 85 to 87% identity at nucleotide and amino acid levels, respectively, was observed with the corresponding region of the N genes of CaCV, WBNV, and Watermelon silver mottle virus. These results suggested the association of GBNV with the diseased tomato samples. To our knowledge, this is the first report of GBNV infecting tomato in Bangladesh and regular surveys are necessary to ascertain the prevalence and incidence of GBNV in other crops. References: (1) R. K. Jain et al. J. Virol. Methods 130:162, 2005. (2) M. Tsompana and J. W. Moyer. Tospovirus. Page 157 in: Encyclopedia of Virology. Academic Press, New York, 2009.


Consumer reporting of adverse events following immunization.
Surveillance of adverse events following immunisation (AEFI) is an essential component of vaccine safety monitoring. The most commonly utilized passive surveillance systems rely predominantly on reporting by health care providers (HCP). We reviewed adverse event reports received in Victoria, Australia since surveillance commencement in July 2007, to June 2013 (6 years) to ascertain the contribution of consumer (vaccinee or their parent/guardian) reporting to vaccine safety monitoring and to inform future surveillance system development directions. Categorical data included were: reporter type; serious and non-serious AEFI category; and, vaccinee age group. Chi-square test and 2-sample test of proportions were used to compare categories; trend changes were assessed using linear regression. Consumer reporting increased over the 6 years, reaching 21% of reports received in 2013 (P<0.001), most commonly for children aged less than 7 years. Consumer reports were 5% more likely to describe serious AEFI than HCP (P=0.018) and 10% more likely to result in specialist clinic attendance (P<0.001). Although online reporting increased to 32% of all report since its introduction in 2010, 85% of consumers continued to report by phone. Consumer reporting of AEFI is a valuable component of vaccine safety surveillance in addition to HCP reporting. Changes are required to AEFI reporting systems to implement efficient consumer AEFI reporting, but may be justified for their potential impact on signal detection sensitivity.


Studying the Thenar Eminence of Amateur cooKs (STEAK) study: a double-blinded, cross-sectional study.
To evaluate the reliability of using the thenar eminence to determine steak doneness. Double-blinded, cross-sectional study. Various home kitchens in Melbourne, Australia. Amateur/home cooks. The accuracy of the finger test (the tenseness of the thenar eminence in different hand positions) for determining how well a random beef steak has been cooked (rare v medium-rare v medium v well-done). We also examined whether participants improved with practice and whether the accuracy of the finger test was correlated with age, sex, cooking experience or self-rated steak-cooking ability. Twenty-six participants completed the study, and showed that they could accurately determine the doneness of a steak with the finger test better than chance (χ2[1, n = 156] = 9.88; P < 0.01). Their overall accuracy, however, was low (36%). There was no correlation between accuracy in application of the finger test with the other collected participant and steak variables. The finger test can be used by amateur cooks to determine beef steak doneness. However, the low overall accuracy of the test suggests that more invasive tests are to be recommended for determining steak doneness for its health benefits.


Clinical factors related to the aqueous levels of vascular endothelial growth factor and hepatocyte growth factor in proliferative diabetic retinopathy.
To investigate clinical factors related to the aqueous humor levels of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in patients with proliferative diabetic retinopathy (PDR). Undiluted aqueous humor was obtained during ocular surgery from 46 eyes of 46 patients and the levels of growth factors were measured using enzyme-linked immunosorbent assays. VEGF and HGF levels were compared with the number of photocoagulation. VEGF and HGF levels in patient groups stratified according to the existence of vitreous hemorrhage, retinal detachment, and fibrovascular membrane were analyzed. And clinical parameters associated with the growth factors were determined by multiple regression analysis. The levels of VEGF decreased significantly as the extent of photocoagulation increased and showed significant positive correlation with the existence of vitreous hemorrhage. There was no significant correlation between VEGF levels and the existence of fibrovascular membrane and traction retinal detachment. The levels of HGF also decreased significantly as the extent of photocoagulation increased, but increased significantly when fibrovascular membrane existed. There were no significant correlations between HGF levels and the existence of vitreous hemorrhage and traction retinal detachment. Concerning systemic conditions, each growth factor has no significant correlation with duration and type of diabetes mellitus, the treatment regimen, the control of hemoglobin A1C, and the existence of hypertension or renal dysfunction. The therapeutic effect of panretinal photocoagulation on PDR might be partly exerted by reduction of the levels of VEGF and HGF in ocular fluid. Since the clinical parameters associated with VEGF were different from those associated with HGF, these growth factors might influence the progression of retinopathy in different ways.


[A survey on drug-related service by homehelper in the Japanese home care system].
The purposes of this study are a) to determine whether homehelpers attend to drug-related service of elder care-recipients at home and b) to determine what cooperating human resources were utilized. A structured questionnaire survey was conducted in 1997 with 403 homehelpers who provided in home care to dependent elderly person. Of the total, 19% subjects did deal with care recipients' medication. Regarding the type of service, the highest proportion of subjects had assisted by picking up medicine from pharmacy and talking it to the care recipients' home. Results showed that physicians and home visiting nurses were the most depended upon human resources in the home health care system among health, medical and welfare facilities. Results also suggested that many homehelpers are not aware that pharmacists are readily available resources for providing home health care. Hence we conclude that the respondents tend to rely on physicians or home visiting nurses to respond to care recipients care, and pharmacists should be made aware of the necessity of providing the appropriate drug-related information to physicians or home visiting nurses.


Variability of the needle essential oils of Juniperus deltoides R.P.ADAMS from different populations in Serbia and Croatia.
The essential-oil compositions of one Croatian and three Serbian populations of Juniperus deltoides R.P.ADAMS have been determined by GC/MS analysis. In total, 147 compounds were identified, representing 97.3-98.3% of the oil composition. The oils were dominated by monoterpenes, which are characteristic components for the species of the section Juniperus. Two monoterpenes, α-pinene and limonene, were the dominant constituents, with a summed-up average content of 49.45%. Statistical methods were used to determine the diversity of the terpene classes and the common terpenes between the newly described J. deltoides populations from Serbia and Croatia. Only reports on several specimens from this species have been reported so far, and there are no studies that treat population diversity. Cluster analysis of the oil contents of 21 terpenes showed high correlation with the geographical distribution of the populations, separating the Croatian from the Serbian populations. The comparison of the essential-oil compositions obtained in the present study with literature data, showed the separation of J. deltoides and J. oxycedrus ssp. oxycedrus from the western Mediterranean region.


Upregulation of Long Non-Coding RNA PlncRNA-1 Promotes Metastasis and Induces Epithelial-Mesenchymal Transition in Hepatocellular Carcinoma.
PlncRNA-1 has been demonstrated to promote malignancy in various cancers. The present study aims to investigate the expression pattern, prognosis value and the function of PlncRNA-1 in human hepatocellular carcinoma (HCC). The expression of PlncRNA-1 in 84 pairs of HCC and their matched normal tissues was examined by quantitative real-time polymerase chain reaction (qRT-PCR). The correlations of PlncRNA-1 expression and clinicopathological characteristics and prognosis were also analyzed. The biological role of PlncRNA-1 in cell proliferation, migration and invasion was examined in vitro and in vivo. The results showed that the level of PlncRNA-1 expression was significantly increased in HCC tissues and significantly correlated with tumor size, vascular invasion and advanced TNM stage. Moreover, patients with high levels of PlncRNA-1 expression had relatively poor prognostic outcomes, serving as an independent prognostic factor for HCC. In vitro functional assays indicated that knockdown of PlncRNA-1 expression significantly reduced cell proliferation, migration and invasion by inhibiting the epithelial-mesenchymal transition (EMT) signaling. Animal model experiments confirmed the ability of PlncRNA-1 to promote tumor growth in vivo. Taken together, our findings suggest that PlncRNA-1 may serve as an oncogene in HCC progression and represent a valuable prognostic marker and potential therapeutic target for HCC.


Bcl-2 overexpression attenuates resveratrol-induced apoptosis in U937 cells by inhibition of caspase-3 activity.
Resveratrol has been shown to induce anti-proliferation and apoptosis of human cancer cell lines. In the present study, we determined the effect of high intracellular levels of the anti-apoptosis protein Bcl-2 on caspase-3 activation, PLC-gamma1 degradation and cytochrome c release during resveratrol-induced apoptosis. For this, we used U937/vector and U937/Bcl-2 cells, which were generated by transfection of the cDNA of the Bcl-2 gene. As compared with U937/vector, U937/Bcl-2 cells exhibited a 4-fold greater expression of Bcl-2. Treatment with 60 or 100 microM resveratrol for 24 h produced morphological features of apoptosis and DNA fragmentation in U937/vector cells, respectively. This was associated with caspase-3 activation and PLC-gamma1 degradation. In contrast, resveratrol-induced caspase-3 activation and PLC-gamma1 degradation and apoptosis were significantly inhibited in U937/Bcl-2 cells. Bcl-2 overexpressing cells exhibited less cytochrome c release and sustained expression levels of the IAP proteins during resveratrol-induced apoptosis. In addition, these findings indicate that Bcl-2 inhibits resveratrol-induced apoptosis by a mechanism that interferes with cytochrome c release and activity of caspase-3 that is involved in the execution of apoptosis.


Reducing discrimination against job seekers with and without employment gaps.
Past research shows that decision-makers discriminate against applicants with career breaks. Career breaks are common due to caring responsibilities, especially for working mothers, thereby leaving job seekers with employment gaps on their résumés. In a preregistered audit field experiment in the United Kingdom (n = 9,022), we show that rewriting a résumé so that previously held jobs are listed with the number of years worked (instead of employment dates) increases callbacks from real employers compared to résumés without employment gaps by approximately 8%, and with employment gaps by 15%. A series of lab studies (an online pilot and two preregistered experiments; n = 2,650) shows that this effect holds for both female and male applicants-even when compared to applicants without employment gaps-as well as and for applicants with less and more total job experience. The effect is driven by making the applicant's job experience salient, not as a result of novelty or ease of reading.


Oligonucleotide typing reveals association of type I psoriasis with the HLA-DRB1*0701/2, -DQA1*0201, -DQB1*0303 extended haplotype.
Although the pathogenesis of psoriasis is still a matter of debate, there are several lines of evidence supporting the concept of this disease being immunologically mediated with T cells playing a crucial role. Because a considerable portion of the cellular infiltrate in psoriasis consists of activated T-helper cells, expression of HLA class II antigens might be of particular importance for the understanding of its pathogenesis. Therefore, we investigated the HLA type of patients with type I (early onset, positive family history) and type II (late onset, no family history) psoriasis by means of serology (n = 89) and genotyping using sequence-specific oligonucleotide probes (n = 64). Serologic analysis of class I documented the association of type I psoriasis with HLA-Cw6, -B13, and -B57, whereas type II psoriasis showed a weaker correlation with HLA-Cw2 and -B27. Genotyping using SSO for class II detected the elevation of the HLA-DRB1*0701/2 allele frequency from 13% in normal population to 36% in type I, but only to 15% in type II psoriatics. Moreover, positive correlations with type I psoriasis were detected for HLA-DQA1*0201 and HLA-DQB1*0303. The HLA-DRB1*0701/2, -DQA1*0201, -DQB1*0303 extended haplotype was found exclusively in type I psoriasis. This is the first report documenting the association of distinct HLA class II alleles with type I psoriasis as detected on the DNA level, an approach both more specific and more sensitive when compared to serology.


Daclatasvir plus peginterferon alfa and ribavirin for treatment-naive chronic hepatitis C genotype 1 or 4 infection: a randomised study.
To evaluate the safety and efficacy of daclatasvir, an HCV NS5A inhibitor with pangenotypic activity, administered with peginterferon-alfa-2a/ribavirin. In this Phase 2b double-blind, placebo-controlled study, treatment-naive adults with HCV genotype 1 (N=365) or 4 (N=30) infection were randomly assigned (2:2:1) to daclatasvir 20 mg or 60 mg, or placebo once daily plus weekly peginterferon-alfa-2a and twice-daily ribavirin. Daclatasvir recipients achieving protocol-defined response (PDR; HCV-RNA<lower limit of quantitation at Week 4 and undetectable at Week 10) were rerandomised at Week 12 to continue daclatasvir/peginterferon-alfa-2a/ribavirin for 24 weeks total duration or to placebo/peginterferon-alfa-2a/ribavirin for another 12 weeks. Patients without PDR and placebo patients continued peginterferon-alfa/ribavirin through Week 48. Primary efficacy endpoints were undetectable HCV-RNA at Weeks 4 and 12 (extended rapid virologic response, eRVR) and at 24 weeks post-treatment (sustained virologic response, SVR24) among genotype 1-infected patients. Overall, eRVR was achieved by 54.4% (80/147) of genotype 1-infected patients receiving daclatasvir 20 mg, 54.1% (79/146) receiving 60 mg versus 13.9% (10/72) receiving placebo. SVR24 was achieved among 87 (59.2%), 87 (59.6%), and 27 (37.5%) patients in these groups, respectively. Higher proportions of genotype 4-infected patients receiving daclatasvir 20 mg (66.7%; 8/12) or 60 mg (100.0%; 12/12) achieved SVR24 versus placebo (50.0%; 3/6). A majority of daclatasvir-treated patients achieved PDR and experienced less virologic failure and higher SVR24 rates with a shortened 24-week treatment duration. Adverse events occurred with similar frequency across all treatment groups. The combination of daclatasvir/peginterferon-alfa/ribavirin was generally well tolerated and achieved higher SVR24 rates compared with placebo/peginterferon-alfa/ribavirin among patients infected with HCV genotype 1 or 4. NCT01125189.


[Psychopathologic reactions in orthopedic patients].
The idea to monitor and research psychopathological responses of physically injured persons in a more systematic manner has come from our observation of huge differences in patient behavior, whose psychological responses were noticeably changed and often inappropriate. The behavior aberrations were all the more striking because we treated war-time injuries in addition to peacetime ones. Our sample had 175 patient subjects, of both sexes, different ages, marital status and professions. A group of 70 patients treated in the Institute for Orthopedic Surgery and Traumatology were divided into two subgroups. The first experimental subgroup (E1) consisted of 26 (37.1%) patients physically injured in combat. The second subgroup (E2) had 44 (62.9%) patients physically injured in peacetime circumstances (car accidents, work accidents, etc). The physical injuries encompassed injuries to spinal column and extremities. The control (K) consisted of 105 subjects without physical injuries. The clinical picture and psychological reactions of the patients were examined by means of 4 instruments--PTSD-10 scale or posttraumatic symptoms scale [1], Family Homogeneity Index/FHI/with 19 variables, applied to measure the relation between the family system homogeneity and accident effects [2], Short Eysenck's Personality Inventory applied to investigate neuroticism and extroversion and introversion traits [3], Late Effects of Accidental Injury Questionnaire [4]. Our observations of psychological responses of patients in our ward (insomnia, sedatives intake) were mostly confirmed by tests conducted with the above instruments. In the group of the wartime injured (E1), as well as in the control (K), Eysenck's scale proved a significantly higher degree of neuroticism in comparison to the peacetime injured. Such results indicated that the wartime injured would most probably develop the picture of Posttraumatic Stress Disorder. Such a conclusion was related not only to the seriousness of injuries but also to the circumstances of their occurrence. The proneness to develop PTSD symptoms was not in correlation with the preparedness for accident, it being much poorer in peace-time injuries, as opposed to wartime patients, who had been prepared to the possibility of injury occurrence. The highest value of family homogeneity (FHI) was established in the wartime injured, which led us to conclude that the injury contributed to the cohesion of the family from which the patient came. By extracting some questions related to psychopathological entities such as insomnia, depression, somatization, anxiety, and cognitive disorders, the following results were obtained. Depression was the most frequent in both groups of injuries. Anxiety was also present in the control group; and insomnia and somatization, that is, conversion symptoms, were present in both groups of the injured. By examining narrower psychological characteristics of the wartime injured revealed dissociation problems--derangement to be the most frequent. Then follow the symptoms of depression, which occur significantly more frequently in the wartime injured in comparison to the peacetime injured. The phenomenological symptoms of derangement and depression proved to be reliable parameters of physical trauma. It is also significant that the three characteristics showed correlation to psychopathological responses: severity of surgery, paralysis, and acute injury.


A delivery system specifically approaching bone resorption surfaces to facilitate therapeutic modulation of microRNAs in osteoclasts.
Dysregulated microRNAs in osteoclasts could cause many skeletal diseases. The therapeutic manipulation of these pathogenic microRNAs necessitates novel, efficient delivery systems to facilitate microRNAs modulators targeting osteoclasts with minimal off-target effects. Bone resorption surfaces characterized by highly crystallized hydroxyapatite are dominantly occupied by osteoclasts. Considering that the eight repeating sequences of aspartate (D-Asp8) could preferably bind to highly crystallized hydroxyapatite, we developed a targeting system by conjugating D-Asp8 peptide with liposome for delivering microRNA modulators specifically to bone resorption surfaces and subsequently encapsulated antagomir-148a (a microRNA modulator suppressing the osteoclastogenic miR-148a), i.e. (D-Asp8)-liposome-antagomir-148a. Our results demonstrated that D-Asp8 could facilitate the enrichment of antagomir-148a and the subsequent down-regulation of miR-148a in osteoclasts in vivo, resulting in reduced bone resorption and attenuated deterioration of trabecular architecture in osteoporotic mice. Mechanistically, the osteoclast-targeted delivery depended on the interaction between bone resorption surfaces and D-Asp8. No detectable liver and kidney toxicity was found in mice after single/multiple dose(s) treatment of (D-Asp8)-liposome-antagomir-148a. These results indicated that (D-Asp8)-liposome as a promising osteoclast-targeting delivery system could facilitate clinical translation of microRNA modulators in treating those osteoclast-dysfunction-induced skeletal diseases.


HST1, a new member of the SIR2 family of genes.
A novel Saccharomyces cerevisiae gene, HST1, was identified from among anonymous cDNAs and the complete corresponding genomic clone was isolated and sequenced. HST1 is very closely related to SIR2, showing 71% sequence identity over 84% of its length. Polymerase chain reaction with degenerate primers on S. cerevisiae DNA identified three additional SIR2-related genes designated HST2, HST3 and HST4. The sequences of HST2, HST3 and HST4 correspond to sequences previously released by the S. cerevisiae genome sequencing project as U33335, NCBI gi:965078; X87331, NCBI gi:829135; and Z48784, YD9346.03, respectively. Disruption of HST1 has shown no phenotype with respect to mechanisms in which SIR2 has a role, namely, regional silencing of HML alpha, or in rDNA recombination.


Rare inherited coagulation disorders in young children in Oman.
Background: Rare coagulation disorders represent 3-5% of all inherited coagulation deficiencies and are usually inherited as autosomal recessive. Oman has high rate of consanguineous marriages; we aimed to study the prevalence, presentation and management in affected Omani children. Materials and Methods: Retrospective study in pediatric patients with rare coagulation disorders in a tertiary hospital in Oman from 2009 to 2020. Results: Rare coagulation disorders were diagnosed in 79 patients (39 males/40 females), aged 1 day to 13 years, accounting for 24.7% (79/319) of all children with inherited coagulation disorders; remainder included patients with hemophilia and von Willebrand disease. FXI deficiency was most common with prevalence of 39.2%, followed by fibrinogen disorders 32.9%, FVII 18.9%, FV 5%, FXIII 2.5%, and FX deficiencies 1.2%. Manifestations ranged from mild to serious to rare/atypical; presentation at birth, ruptured-hemorrhagic ovarian cyst, splenic laceration-rupture, and sight-threatening retrobulbar-intraocular hemorrhage. Intracranial hemorrhage (ICH) occurred in 9/79 patients, it was initial mode of presentation in seven of them. Global developmental delay as a complication occurred in three. Standardized treatment strategies were used with prophylaxis initiation early in life in severely affected children. Conclusions: This ethnic group demonstrated unique features in terms of: heterogenous/atypical presentations; severe manifestations in moderate phenotype hypofibrinogenemia; clinical severity and laboratory phenotype correlation in FV deficiency; poor association between factor activity level and bleeding severity in FVII deficiency and severe bleeding tendency despite moderate laboratory phenotype in FXIII deficiency. We recommend multicenter collaboration to identify the genotype-phenotype correlation and therapeutic options of such rare, yet serious disorders.


Integrated micro-optical light guide plate.
In this paper, we propose an integrated micro-optical light guide plate (MOLGP), of which the top surface is designed as aspheric semi-cylindrical micro-concentrator structure (ASCMCS) arrays and the bottom surface is fused with micro-prism arrays coated with a high-reflective film. And we also present the optimized structural parameters and distribution pattern of the MOLGP. By the simulation of the professional optical software Lighttools, it's verified that the integrated MOLGP we proposed can achieve the functions of five complex-structure films in current typical backlight module (BLM), and the Five Parameters (light energy utilization efficiency, average illuminance and luminance, uniformity of illuminance and uniformity of luminance) in the BLM with integrated MOLGP are respectively 1.49, 1.40, 1.07, 0.91 and 0.97 times than those in the typical BLM. Obviously, the performance parameters of the MOLGP exceed the traditional design. Moreover, we design two sets of four-step masks of the ASCMCS by the graphical user interface (GUI). At last, we fabricate a 1.8 inch integrated MOLGP sample. Comparative experiments show that the Five Parameters of the fabricated MOLGP sample are respectively 1.43, 1.43, 0.97, 0.89 and 0.70 times than those of the typical BLM. The experimental results verify the feasibility of the concept of the integrated MOLGP proposed in this paper.


Long term outcomes of antiretroviral therapy in a large HIV/AIDS care clinic in urban South Africa: a prospective cohort study.
Clinical, immunologic and virologic outcomes at large HIV/AIDS care clinics in resource poor settings are poorly described beyond the first year of highly active antiretroviral treatment (HAART). We aimed to prospectively evaluate long-term treatment outcomes at a large scale HIV/AIDS care clinic in South Africa. Cohort study of patients initiating HAART between April 1, 2004 and March 13, 2007, and followed up until April 1, 2008 at a public HIV/AIDS care clinic in Johannesburg, South Africa. We performed time to event analysis on key treatment outcomes and program impact parameters including mortality, retention in care, CD4 count gain, virologic success and first line regimen durability. 7583 HIV-infected patients initiated care and contributed to 161,000 person months follow up. Overall mortality rate was low (2.9 deaths per 100 person years, 95% CI 2.6-3.2), but high in the first three months of HAART (8.4 per 100 person years, 95% CI 7.2-9.9). Long-term on-site retention in care was relatively high (74.4% at 4 years, 95%CI 73.2-75.6). CD4 count was above 200 cells/mm(3 )after 6 months of treatment in almost all patients. By the fourth year of HAART, the majority (59.6%, 95%CI 57.8-61.4) of patients had at least one first line drug (mainly stavudine) substituted. Women were twice as likely to experience drug substitution (OR 1.97, 95% CI 1.80-2.16). By 6 months of HAART, 90.8% suppressed virus below 400 copies. Among those with initial viral suppression, 9.4% (95% CI 8.5-10.3%) had viral rebound within one year of viral suppression, 16.8% (95% CI 15.5-18.1) within 2 years, and 20.6% (95% CI 18.9-22.4) within 3 years of initial suppression. Only 10% of women and 13% of men initiated second line HAART. Despite advanced disease presentation and a very large-scale program, high quality care was achieved as indicated by good long-term clinical, immunologic and virologic outcomes and a low rate of second line HAART initiation. High rates of single drug substitution suggest that the public health approach to HAART could be further improved by the use of a more durable first line regimen.


Dendritic cell modification of neutrophil responses to infection after burn injury.
Burn patients are highly susceptible to infections due to increased exposure through wounds and impairments in a number of immune functions. Dendritic cells (DCs) are important in activation of numerous immune responses that are essential for the clearance of infections. We have found that prophylactic treatment of burn-injured mice with the DC growth factor FLT3 ligand (FL) significantly increases resistance to burn wound infections in a DC-dependent manner that is correlated closely with enhanced bacterial clearance. However, as DCs are not typically microbicidal, the mechanisms by which DC modulation enhances bacterial clearance are not known. Due to the rapid response of neutrophils to cutaneous wounds, and the reported interactions between DCs and neutrophils, we investigated the role of neutrophils in FL-mediated resistance to burn wound infection. This was examined both in vivo and in vitro through neutrophil depletion, supplementation of neutrophils, and assessment of neutrophil chemotaxis following FL treatment. To test the involvement of DCs, CD11c-diphtheria toxin receptor transgenic mice were used to deplete DCs during FL treatment. Studies revealed that neutrophils do play a critical role in FL-mediated resistance to a burn wound infection. Additionally, treatment with FL after a burn injury enhances neutrophil-mediated control of bacterial spread, neutrophil migratory capacity, and myeloperoxidase production in a DC-dependent manner. The results of this study provide new insight into immunological mechanisms that can offer protection against infection after burn injury.


Malaria vector control practices in an irrigated rice agro-ecosystem in central Kenya and implications for malaria control.
Malaria transmission in most agricultural ecosystems is complex and hence the need for developing a holistic malaria control strategy with adequate consideration of socio-economic factors driving transmission at community level. A cross-sectional household survey was conducted in an irrigated ecosystem with the aim of investigating vector control practices applied and factors affecting their application both at household and community level. Four villages representing the socio-economic, demographic and geographical diversity within the study area were purposefully selected. A total of 400 households were randomly sampled from the four study villages. Both semi-structured questionnaires and focus group discussions were used to gather both qualitative and quantitative data. The results showed that malaria was perceived to be a major public health problem in the area and the role of the vector Anopheles mosquitoes in malaria transmission was generally recognized. More than 80% of respondents were aware of the major breeding sites of the vector. Reported personal protection methods applied to prevent mosquito bites included; use of treated bed nets (57%), untreated bed nets (35%), insecticide coils (21%), traditional methods such as burning of cow dung (8%), insecticide sprays (6%), and use of skin repellents (2%). However, 39% of respondents could not apply some of the known vector control methods due to unaffordability (50.5%), side effects (19.9%), perceived lack of effectiveness (16%), and lack of time to apply (2.6%). Lack of time was the main reason (56.3%) reported for non-application of environmental management practices, such as draining of stagnant water (77%) and clearing of vegetations along water canals (67%). The study provides relevant information necessary for the management, prevention and control of malaria in irrigated agro-ecosystems, where vectors of malaria are abundant and disease transmission is stable.


Hypermethylation of FHIT as a prognostic marker in nonsmall cell lung carcinoma.
Methylation of CpG islands in the promoter and upstream coding regions has been identified as a mechanism for transcriptional inactivation of tumor suppressor genes. The purpose of the current study was to determine the correlation between the aberrant promoter methylation of multiple genes and survival in patients with nonsmall cell lung carcinoma (NSCLC). The methylation status of nine genes was determined in 124 surgically resected NSCLC cases using methylation-specific polymerase chain reaction. The methylation frequencies of the genes tested in NSCLC specimens were 52% for E-cadherin (CDH1), 41% for RAS association domain family protein (RASSF1A), 38% for fragile histidine triad (FHIT) and adenomatous polyposis coli (APC), 27% for retinoic acid receptor beta (RARbeta) and H-cadherin (CDH13), 20% for p16INK4A, 0.8% for O6-methylguanine-DNA-methyltransferase (MGMT), and 0% for glutathione S-transferase P1 (GSTP1). The survival of the patients with FHIT methylation-positive tumors was found to be significantly shorter than that for those patients with methylation-negative tumors (P=0.03), even in those patients with International Union Against Cancer TNM Stage I or Stage II disease (P=0.007). In contrast, there were no significant survival differences noted between the methylation-positive and methylation-negative tumors for the other genes tested. In addition, based on multivariate analyses, FHIT methylation-positive status was found to be independently associated with poor survival (P=0.046) and disease stage (P<0.0001). The results of the current study suggest that methylation of FHIT is a useful biomarker of biologically aggressive disease in patients with NSCLC.


Mesodermal Wnt2b signalling positively regulates liver specification.
Endodermal organs such as the lung, liver and pancreas emerge at precise locations along the primitive gut tube. Although several signalling pathways have been implicated in liver formation, so far no single gene has been identified that exclusively regulates liver specification. In zebrafish, the onset of liver specification is marked by the localized endodermal expression of hhex and prox1 at 22 hours post fertilization. Here we used a screen for mutations affecting endodermal organ morphogenesis to identify a unique phenotype: prometheus (prt) mutants exhibit profound, though transient, defects in liver specification. Positional cloning reveals that prt encodes a previously unidentified Wnt2b homologue. prt/wnt2bb is expressed in restricted bilateral domains in the lateral plate mesoderm directly adjacent to the liver-forming endoderm. Mosaic analyses show the requirement for Prt/Wnt2bb in the lateral plate mesoderm, in agreement with the inductive properties of Wnt signalling. Taken together, these data reveal an unexpected positive role for Wnt signalling in liver specification, and indicate a possible common theme for the localized formation of endodermal organs along the gut tube.


Expanding Student Knowledge and Confidence on Dietary Supplements Through Mock Patient Consultations.
As dietary supplements are widely used in the United States, student pharmacists should be prepared to assess their appropriateness for self-care. The purpose of this project was to assess the impact of mock patient consults regarding common dietary supplements on second-year (P2) Doctor of Pharmacy (PharmD) students. This activity was part of a required course, Self-Care I. Twenty-four groups of 4 to 5 students were created, with each assigned a unique patient vignette. Students had 10 minutes to speak on the phone with their "patient" to obtain needed information in order to make an appropriate recommendation in the form of a 2 to 3-minute recorded oral response. Anonymous, voluntary pre- and post-project surveys assessing perceived dietary supplement knowledge, patient counseling skills, and attitudes about the activity were conducted during class through Google Forms. The Wilcoxon Signed-Rank Test was used to determine differences in mean 10-point Likert scale score between pre- and post-test for each survey question, with significance if p < 0.05. Significant differences were found between pre- and post-survey Likert scale means. Reported confidence in using the QuEST/SCHOLAR-MAC approaches to self-care counseling increased by 45% from baseline. Perceived student knowledge on dietary supplements increased by 44%. Self-rated counseling abilities of students increased by 87% for glucosamine/chondroitin, 28% for melatonin, 39% for red yeast rice, 38% for fish oil, and 42% for cranberry regarding their use in particular cases. The activity provided students with realistic exposure to questions about dietary supplements that patients ask community pharmacists.


Depression and suicide on Gotland. An intensive study of all suicides before and after a depression-training programme for general practitioners.
In 1983 and 1984, the Swedish Committee for the Prevention and Treatment of Depression (PTD) organised a postgraduate training programme on the diagnosis and treatment to all the general practitioners on Gotland, Sweden. In the following years, the frequency of suicide and inpatient care for depression decreased significantly, as well as the frequency of sick leave for depression. The results of the Gotland study have provided evidence for the view that early recognition and adequate treatment of depression is one essential method of suicide prevention (Rutz et al., 1989; Rutz et al., 1992). A detailed retrospective clinical analysis, of all 115 consecutive suicide victims on Gotland between 1981 and 1992 presented in this study, showed that male gender and violent methods were overrepresented. 50 suicides had a DSM-III-R axis I diagnosis and half of them (n = 25) had primary major depression. Bipolar II disorder was relatively overrepresented in this sample. After the PTD programme, the proportion of depressive suicides was significantly lower than before. This finding strongly suggests that the significant decrease in the suicide rate after the PTD programme is a direct result of the robust decrease in depressive suicides of the area served by trained GPs. The practical importance of this finding is briefly discussed.


Pressure-induced molten globule state of human acetylcholinesterase: structural and dynamical changes monitored by neutron scattering.
We used small-angle neutron scattering (SANS) to study the effects of high hydrostatic pressure on the structure of human acetylcholinesterase (hAChE). At atmospheric pressure, our SANS results obtained on D11 at ILL (Grenoble, France) give a radius of gyration close to that calculated for a mixture of monomers, dimers and tetramers of the enzyme, suggesting a good agreement between hAChE crystal structure and its conformation in solution. Applying high pressure to the sample we found a global compression of about 11% of the enzyme up to a pressure of 900 bar and then again an extension up to 2.1 kbar indicating unfolding of the tertiary structure due to a molten globule (MG) state. On the other hand, we studied the influence of pressure up to 6 kbar on the dynamics of this enzyme, on the backscattering spectrometer IN13 at ILL. For the first time, we used elastic incoherent neutron scattering (EINS) to probe the differences between hAChE in its folded state (N), its high-pressure induced MG state and its unfolded state (U). Especially around the MG state at 1750 bar we found a significant increase in the dynamics, indicating a partial unfolding. A four-step-model is suggested to describe the changes in the protein.


E-readers and visual fatigue.
The mass digitization of books is changing the way information is created, disseminated and displayed. Electronic book readers (e-readers) generally refer to two main display technologies: the electronic ink (E-ink) and the liquid crystal display (LCD). Both technologies have advantages and disadvantages, but the question whether one or the other triggers less visual fatigue is still open. The aim of the present research was to study the effects of the display technology on visual fatigue. To this end, participants performed a longitudinal study in which two last generation e-readers (LCD, E-ink) and paper book were tested in three different prolonged reading sessions separated by--on average--ten days. Results from both objective (Blinks per second) and subjective (Visual Fatigue Scale) measures suggested that reading on the LCD (Kindle Fire HD) triggers higher visual fatigue with respect to both the E-ink (Kindle Paperwhite) and the paper book. The absence of differences between E-ink and paper suggests that, concerning visual fatigue, the E-ink is indeed very similar to the paper.


Overexpression of the natural inhibitor of cysteine peptidases in Leishmania mexicana leads to reduced virulence and a Th1 response.
Leishmania mexicana cysteine peptidases (CPs) have been identified as important parasite virulence factors. More recently, a natural inhibitor of CPs (ICP) from L. mexicana has been characterized, and ICP mutants have been created. Infection of BALB/c mice with ICP null mutants or ICP reexpressing mutants resulted in nonhealing, progressively growing lesions albeit slightly attenuated compared with the growth of lesions produced by wild-type parasites. In contrast, BALB/c mice infected with mutants overexpressing ICP were able to significantly control lesion growth or heal. While BALB/c mice infected with wild-type parasites, ICP null mutants, or ICP reexpressing mutants produced significant antibody responses, including immunoglobulin E (IgE), no Th1 response, as indicated by antigen-induced splenocyte gamma interferon (IFN-gamma) production, could be demonstrated. In contrast, BALB/c mice infected with mutants overexpressing ICP produced significantly less antibody, particularly IgE, as well as significantly reduced splenocyte interleukin-4 and enhanced IFN-gamma production. BALB/c mice were able to resolve infection following infection with one ICP overexpressing clone, which was subsequently used for vaccination studies with BALB/c mice. However, no protection was afforded these mice when they were challenged with wild-type parasites. Nevertheless, two other mouse strains susceptible to L. mexicana, C3H and C57BL/6, vaccinated with overexpressing ICP mutants were able to control challenge infection associated with an enhanced Th1 response. This study confirms that L. mexicana CPs are virulence factors and that ICPs have therapeutic potential.


Sex-specific effect of IL9 polymorphisms on lung function and polysensitization.
Sex differences in asthma-associated phenotypes are well known but the genetic factors that may account for these differences have received little attention. This study aimed to characterize sex-specific and pleiotropic genetic factors underlying four quantitative phenotypes involved in the main asthma physiopathological pathways: immunoglobulin E levels, a measure of polysensitization (SPTQ), eosinophil counts and a measure of lung function FEV(1)/H(2) (forced expiratory volume in one second divided by height square). Sex-stratified univariate and bivariate linkage analyses were conducted in 295 families from the Epidemiological study on the Genetics and Environment of Asthma study. We found genome-wide significant evidence for a male-specific pleiotropic QTL (quantitative trait loci) on 5q31 (P=7 x 10(-9)) influencing both FEV(1)/H(2) and SPTQ and for a female-specific pleiotropic QTL on 11q23 underlying SPTQ and immunoglobulin E (P=2 x 10(-5)). Three other sex-specific regions of linkage were detected for eosinophil: 4q24 and 22q13 in females, and 3p25 in males. Further, bivariate association analysis of FEV(1)/H(2) and SPTQ with 5q31 candidate genes in males showed a significant association with two single-nucleotide polymorphisms within IL9 gene, rs2069885 and rs2069882 (P=0.02 and P=0.002, respectively, after Bonferroni's correction). This study underlies the importance of taking into account complex mechanisms, such as heterogeneity according to sex and pleiotropy to unravel the genes involved in asthma phenotypes.


Nutrient intakes and the common mental disorders in women.
There is an increasing recognition of the role of nutrition in depression and anxiety. Magnesium, folate and zinc have all been implicated in depressive illness, however there are few data on these nutrients in anxiety disorders and the data from population-studies are limited. In a large, randomly-selected, population-based sample of women, this study aimed to examine the relationship between the dietary intakes of these three micronutrients and clinically determined depressive and anxiety disorders and symptoms. Nutrient intakes were determined using a validated food frequency questionnaire. The General Health Questionnaire-12 measured psychological symptoms, and a clinical interview (Structured Clinical Interview for DSM-IV-TR, non-patient edition) assessed current depressive and anxiety disorders. After adjustments for energy intake, each standard deviation increase in the intake of zinc, magnesium and folate was associated with reduced odds ratio (OR) for major depression/dysthymia (zinc: OR=0.52, 95% confidence interval (CI) 0.31 to 0.88; magnesium: OR=0.60, 95% CI 0.37 to 0.96; folate: OR=0.66, 95% CI 0.45 to 0.97). There was also an inverse association between the intake of magnesium and zinc and GHQ-12 scores (zinc: zβ=-0.16, 95% CI -0.29 to -0.04; magnesium: -0.14, 95% CI -0.26 to -0.03). These relationships were not confounded by age, socioeconomic status, education or other health behaviours. There was no relationship observed between any nutrient and anxiety disorders. These results demonstrate an association between the dietary intakes of magnesium, folate and zinc and depressive illnesses, although reverse causality and/or confounding cannot be ruled out as explanations.


Effects of olive maturation and stoning on quality indices and antioxidant content of extra virgin oils (cv. Coratina) during storage.
Quality indices, antioxidant compounds, and antioxidant activities of extra-virgin oils from Coratina olives were evaluated during a 12-mo storage. Whole and stoned olives, picked at 2 different maturation index (MI), were submitted to malaxation for 45 min and extracted by a 3-phase continuous system. A 90-min malaxation trial was also performed for the stoned olives. The following parameters were monitored: free acidity, peroxide value, K(232) and K(270) indices, sensory profile, total phenolic content (TPC), phenolic profiles, tocopherol compounds, and antioxidant activity (AA). The highest TPC, AA, and sensory score were found for the oils obtained by olives picked at low MI and by stoned olives. After 12 mo, all the oils were still included into the "extra-virgin" category, and those deriving from whole olives picked at the lowest MI showed the best sensory characteristics due to high fruity and well-balanced pungent and bitter tastes. This study could represent a helpful tool for oil-makers to improve the marketing of extra-virgin olive oils produced from cultivars with very high phenolic contents, such as Coratina, generally not adequately appreciated by consumers because of their excessive bitterness and pungent taste. These oils, when extracted from whole olives, are generally consumed after a certain period of time (at least 6 mo) during which a decrease in the phenolic content occurs. The results of the present work demonstrate that oils extracted from olives picked at low maturation index can be marketed immediately after production if subjected to stoning and malaxed for a short time. This procedure allows to adjust the phenolic content and to obtain a high flavor and a well-balanced taste.


Size-Dependent Consequences of Exogenous Cortisol Manipulation on Overwinter Survival and Condition of Largemouth Bass.
Little is known about the size-dependent consequences of stressors on wild animals, which is particularly relevant during winter where size-specific trends in survival are common. Here, exogenous cortisol manipulation was used to investigate the effect of a physiological challenge on overwinter mortality and spring condition of largemouth bass (Micropterus salmoides) across a range of body sizes. Fish were wild-caught in the fall, assigned into either control or cortisol manipulated treatments, and held in replicated experimental ponds. For bass that survived the winter, length, mass, and health metrics (e.g., gonadosomatic index [GSI], hepatosomatic index [HSI], and water content) were determined in the spring. Winter survival was marginally lower for cortisol treated bass; however, there was no influence of initial length, mass, or condition on overwinter survival. When bass were grouped by size, survival was significantly higher for bass 300-350 mm in length compared to those <200 mm. The treatment did not strongly influence spring health metrics, suggesting that largemouth bass that survived the winter were able to recover from the effects of the cortisol elevation. Initial size and sex were linked to some spring health metrics, with large females having the highest GSI and HSI scores. Overall, results from this study do not support the notion that there are size-dependent responses to cortisol manipulation in a teleost fish. Rather, this type of physiological challenge may modulate the natural rates of winter mortality that are primarily driven by starvation and predation, independent of body size, in subadult and adult largemouth bass.


Protection of human participants in health research - a comparison of some US Federal Regulations and South African Research Ethics guidelines.
In response to criticism of ethical review of a South African clinical trial, we contrast aspects of the United States Common Rule with South African research ethics requirements. In the USA the Common Rule does not apply to all health research and allows many exemptions from ethics review and waivers of informed consent. At a structural level research ethics review in South Africa is in many cases equivalent to the US institutional review board (IRB) and Office for Human Research Protections (OHRP) oversight system, is wider reaching, and has no exclusions.


Intracellular inclusion bodies in 14 patients with B cell lymphoproliferative disorders.
Two types of intracytoplasmic inclusion were detected by immunofluorescence microscopy in 12 patients with chronic lymphocytic leukaemia and two patients with a leukaemic phase of well differentiated lymphocytic lymphoma. Further analysis with light- and electron microscopy, showed that most inclusion bodies were rod-like crystalline structures. However, in three patients they consisted of amorphous vesicular precipitates. Immunological studies revealed the presence of immunoglobulins of the same class and type at the cell surface as well as in the inclusion bodies. The monoclonal immunoglobulins were all of lambda type except in two cases. The origin of immunoglobulin inclusion bodies in B cell malignancies is discussed in relation to published data and our own observation in one patient followed during treatment.


Occupant Kinematics in Laboratory Rollover Tests: ATD Response and Biofidelity.
Rollover crashes are a serious public health problem in United States, with one third of traffic fatalities occurring in crashes where rollover occurred. While it has been shown that occupant kinematics affect the injury risk in rollover crashes, no anthropomorphic test device (ATD) has yet demonstrated kinematic biofidelity in rollover crashes. Therefore, the primary goal of this study was to assess the kinematic response biofidelity of six ATDs (Hybrid III, Hybrid III Pedestrian, Hybrid III with Pedestrian Pelvis, WorldSID, Polar II and THOR) by comparing them to post mortem human surrogate (PMHS) kinematic response targets published concurrently; and the secondary goal was to evaluate and compare the kinematic response differences among these ATDs. Trajectories (head, T1, T4, T10, L1 and sacrum), spinal segment (head-to-T1, T1-to-T4, T4-T10, T10-L1, and L1-to-sacrum) rotations relative to the rollover buck, and spinal segment extension/compression were calculated from the collected kinematics data from an optical motion tracking system. Response differences among the ATDs were observed mainly due to the different lateral bending stiffness of the spine from their varied architecture, while the additional thoracic joint in Polar II and THOR did not seem to provide more flexion/extension compliance than the other ATDs. In addition, the ATD response data were compared to PMHS response corridors developed from similar tests for assessing ATD biofidelity. All of the ATDs, generally, drifted outboard and upward during the tests similar to the PMHS. However, accompanied with this upward and outward motion, the ATD head and upper torso pitched forward (~10 degrees) while the PMHS' head and upper torso pitching rearward (~10 to ~15 degrees), due to the absence of flexion/extension compliance in the ATD spine. The differences in these pitch motions resulted in a difference of 130 mm to 160 mm in the longitudinal position of the head at 195 degrees of roll angle. Finally, substantially less lateral spinal bending was also observed in the ATDs compared to the PMHS. The results of the current study suggests there is greater upper spine flexion/extension, and lateral bending stiffness in all of the ATDs in comparison to the PMHS, and provided information for improvement of ATD biofidelity in future for rollover crashes.


The fingerprint of the summer 2018 drought in Europe on ground-based atmospheric CO2 measurements.
During the summer of 2018, a widespread drought developed over Northern and Central Europe. The increase in temperature and the reduction of soil moisture have influenced carbon dioxide (CO2) exchange between the atmosphere and terrestrial ecosystems in various ways, such as a reduction of photosynthesis, changes in ecosystem respiration, or allowing more frequent fires. In this study, we characterize the resulting perturbation of the atmospheric CO2 seasonal cycles. 2018 has a good coverage of European regions affected by drought, allowing the investigation of how ecosystem flux anomalies impacted spatial CO2 gradients between stations. This density of stations is unprecedented compared to previous drought events in 2003 and 2015, particularly thanks to the deployment of the Integrated Carbon Observation System (ICOS) network of atmospheric greenhouse gas monitoring stations in recent years. Seasonal CO2 cycles from 48 European stations were available for 2017 and 2018. Earlier data were retrieved for comparison from international databases or national networks. Here, we show that the usual summer minimum in CO2 due to the surface carbon uptake was reduced by 1.4 ppm in 2018 for the 10 stations located in the area most affected by the temperature anomaly, mostly in Northern Europe. Notwithstanding, the CO2 transition phases before and after July were slower in 2018 compared to 2017, suggesting an extension of the growing season, with either continued CO2 uptake by photosynthesis and/or a reduction in respiration driven by the depletion of substrate for respiration inherited from the previous months due to the drought. For stations with sufficiently long time series, the CO2 anomaly observed in 2018 was compared to previous European droughts in 2003 and 2015. Considering the areas most affected by the temperature anomalies, we found a higher CO2 anomaly in 2003 (+3 ppm averaged over 4 sites), and a smaller anomaly in 2015 (+1 ppm averaged over 11 sites) compared to 2018. This article is part of the theme issue 'Impacts of the 2018 severe drought and heatwave in Europe: from site to continental scale'.


Water flattens graphene wrinkles: laser shock wrapping of graphene onto substrate-supported crystalline plasmonic nanoparticle arrays.
Hot electron injection into an exceptionally high mobility material can be realized in graphene-plasmonic nanoantenna hybrid nanosystems, which can be exploited for several front-edge applications including photovoltaics, plasmonic waveguiding and molecular sensing at trace levels. Wrinkling instabilities of graphene on these plasmonic nanostructures, however, would cause reactive oxygen or sulfur species to diffuse and react with the materials, decrease charge transfer rates and block intense hot-spots. No ex situ graphene wrapping technique has been explored so far to control these wrinkles. Here, we present a method to generate seamless integration by using water as a flyer to transfer the laser shock pressure to wrap graphene onto plasmonic nanocrystals. This technique decreases the interfacial gap between graphene and the covered substrate-supported plasmonic nanoparticle arrays by exploiting a shock pressure generated by the laser ablation of graphite and the water impermeable nature of graphene. Graphene wrapping of chemically synthesized crystalline gold nanospheres, nanorods and bipyramids with different field confinement capabilities is investigated. A combined experimental and computational method, including SEM and AFM morphological investigation, molecular dynamics simulation, and Raman spectroscopy characterization, is used to demonstrate the effectiveness of this technique. Graphene covered gold bipyramid exhibits the best result among the hybrid nanosystems studied. We have shown that the hybrid system fabricated by laser shock can be used for enhanced molecular sensing. The technique developed has the characteristics of tight integration, and chemical/thermal stability, is instantaneous in nature, possesses a large scale and room temperature processing capability, and can be further extended to integrate other 2D materials with various 0-3D nanomaterials.


The effects of early anesthesia on neurodevelopment: A systematic review.
There is growing concern regarding the impact of general anesthesia on neurodevelopment in children. Pre-clinical animal studies have linked anesthetic exposure to abnormal central nervous system development, but it is unclear whether these results translate into humans. The purpose of this systematic review from the American Pediatric Surgical Association (APSA) Outcomes and Evidence-Based Practice (OEBP) Committee was to review, summarize, and evaluate the evidence regarding the neurodevelopmental impact of general anesthesia on children and identify factors that may affect the risk of neurotoxicity. Medline, Cochrane, Embase, Web of Science, and Scopus databases were queried for articles published up to and including December 2017 using the search terms "general anesthesia and neurodevelopment" as well as specific anesthetic agents. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used to screen manuscripts for inclusion in the review. A consensus statement of recommendations in response to each study question was synthesized based upon the best available evidence. In total, 493 titles were initially identified, with 56 articles selected for full analysis and 44 included for review. Based on currently available developmental assessment tools, a single exposure to general anesthesia does not appear to have a significant effect on general neurodevelopment, although prolonged or multiple anesthetic exposures may have some adverse effects. Exposure to general anesthesia may affect different domains of development at different ages. Regional anesthetic techniques with the addition of dexmedetomidine and/or some intravenous agents may mitigate the risks of neurotoxicity. This approach may be performed safely in some patients and can be considered as an option in selected short procedures. There is no conclusive evidence that a single short anesthetic in infancy has a detectable neurodevelopmental effect. Data do not support waiting until later in childhood to perform general anesthesia for single short procedures. With the complexities and nuances of different anesthetic methods, patients and procedures, the planning and execution of anesthesia for the pediatric patient is generally best accomplished by an anesthesiologist, ideally a pediatric anesthesiologist. Systematic review of level 1-4 studies. Level 1-4 (mainly level 3-4).


Cholecystokinin-mediated RhoGDI phosphorylation via PKCα promotes both RhoA and Rac1 signaling.
RhoA and Rac1 have been implicated in the mechanism of CCK-induced amylase secretion from pancreatic acini. In all cell types studied to date, inactive Rho GTPases are present in the cytosol bound to the guanine nucleotide dissociation inhibitor RhoGDI. Here, we identified the switch mechanism regulating RhoGDI1-Rho GTPase dissociation and RhoA translocation upon CCK stimulation in pancreatic acini. We found that both Gα13 and PKC, independently, regulate CCK-induced RhoA translocation and that the PKC isoform involved is PKCα. Both RhoGDI1 and RhoGDI3, but not RhoGDI2, are expressed in pancreatic acini. Cytosolic RhoA and Rac1 are associated with RhoGDI1, and CCK-stimulated PKCα activation releases the complex. Overexpression of RhoGDI1, by binding RhoA, inhibits its activation, and thereby, CCK-induced apical amylase secretion. RhoA translocation is also inhibited by RhoGDI1. Inactive Rac1 influences CCK-induced RhoA activation by preventing RhoGDI1 from binding RhoA. By mutational analysis we found that CCK-induced PKCα phosphorylation on RhoGDI1 at Ser96 releases RhoA and Rac1 from RhoGDI1 to facilitate Rho GTPases signaling.


A Comparison of Methods to Measure Fitness in Escherichia coli.
In order to characterize the dynamics of adaptation, it is important to be able to quantify how a population's mean fitness changes over time. Such measurements are especially important in experimental studies of evolution using microbes. The Long-Term Evolution Experiment (LTEE) with Escherichia coli provides one such system in which mean fitness has been measured by competing derived and ancestral populations. The traditional method used to measure fitness in the LTEE and many similar experiments, though, is subject to a potential limitation. As the relative fitness of the two competitors diverges, the measurement error increases because the less-fit population becomes increasingly small and cannot be enumerated as precisely. Here, we present and employ two alternatives to the traditional method. One is based on reducing the fitness differential between the competitors by using a common reference competitor from an intermediate generation that has intermediate fitness; the other alternative increases the initial population size of the less-fit, ancestral competitor. We performed a total of 480 competitions to compare the statistical properties of estimates obtained using these alternative methods with those obtained using the traditional method for samples taken over 50,000 generations from one of the LTEE populations. On balance, neither alternative method yielded measurements that were more precise than the traditional method.


The assessment of individual usual food intake in large-scale prospective studies.
Recent research has called into question the current practice to estimate individual usual food intake in large-scale studies. In such studies, usual food intake has been defined as diet over the past year. The aim of this review is to summarise the concepts of dietary assessment methods providing food intake data over this time period. A conceptualised framework is given to help researchers to understand the more recent developments to improve dietary assessment in large-scale prospective studies, and also to help to spot the gaps that need to be addressed in future methodological research. The conceptual framework illustrates the current options for the assessment of an individual's food consumption over 1 year. Ideally, a person's food intake on each day of this year should be assessed. Due to participants' burden, and organisational and financial constraints, however, the options are limited to directly requesting the long-term average (e.g. food frequency questionnaires), or selecting a few days with detailed food consumption measurements (e.g. 24-hour dietary recalls) or using snapshot techniques (e.g. barcode scanning of purchases). It seems necessary and important to further evaluate the performance of statistical modelling of the individual usual food intake from all available sources. Future dietary assessment might profit from the growing prominence of internet and telecommunication technologies to further enhance the available data on food consumption for each study participant. Research is crucial to investigate the performance of innovative assessment tools. However, the self-reported nature of the data itself will always lead to bias.


Early Blindness Shapes Cortical Representations of Auditory Frequency within Auditory Cortex.
Early loss of vision is classically linked to large-scale cross-modal plasticity within occipital cortex. Much less is known about the effects of early blindness on auditory cortex. Here, we examine the effects of early blindness on the cortical representation of auditory frequency within human primary and secondary auditory areas using fMRI. We observe that 4 individuals with early blindness (2 females), and a group of 5 individuals with anophthalmia (1 female), a condition in which both eyes fail to develop, have lower response amplitudes and narrower voxelwise tuning bandwidths compared with a group of typically sighted individuals. These results provide some of the first evidence in human participants for compensatory plasticity within nondeprived sensory areas as a result of sensory loss.SIGNIFICANCE STATEMENT Early blindness has been linked to enhanced perception of the auditory world, including auditory localization and pitch perception. Here we used fMRI to compare neural responses with auditory stimuli within auditory cortex across sighted, early blind, and anophthalmic individuals, in whom both eyes fail to develop. We find more refined frequency tuning in blind subjects, providing some of the first evidence in human subjects for compensation within nondeprived primary sensory areas as a result of blindness early in life.


Associations between cigarette smoking, obesity, sociodemographic characteristics and remote-sensing-derived estimates of ambient PM2.5: results from a Canadian population-based survey.
Long-term exposure to ambient fine particles (PM2.)) has been shown to increase mortality. Variables measured on the same spatial scales of air pollution may confound associations, and so the authors' objectives were to evaluate the associations between PM2.5 and individual-level measures of smoking, obesity and sociodemographic status. The authors present an approach to evaluate the impact that uncontrolled confounding from smoking may have on associations between PM2.5 and mortality. Individual-level behavioural and sociodemographic data were obtained from a 2003 national survey of 122,548 Canadians. Estimates of ground-level PM2.5 at a resolution of 10×10 km between 2001 and 2006 were derived from satellite remote sensing. Exposures were assigned to the residence of the participants at the time of the survey. Differences in the prevalence of smoking across concentrations of PM2.5 and RRs drawn from the literature were used to model the bias on rate ratios. Participants in areas with higher concentrations of PM2.5 had a higher income and educational attainment, smoked less and were more likely immigrants. Smoking had a negative confounding effect on the associations between PM2.5) and mortality. To compensate for this bias, for a 10 μg/m3 increase in PM2.5, mortality from lung cancer and heart disease in the referent exposure group needed to be increased by 6.9% and 3.2%, respectively. Associations were found between sociodemographic and lifestyle characteristics and PM2.5 at a resolution of 10×10 km. The authors present a model to adjust for uncontrolled confounding of smoking that can be readily adapted to exposures measured at different spatial resolutions.


Computer Kinesiology: New Diagnostic and Therapeutic Tool for Lower Back Pain Treatment (Pilot Study).
The aim of this study was to demonstrate the effectiveness of the diagnostic and therapeutic medical information system Computer Kinesiology in physiotherapy in patients with low back pain who were not responding to conventional therapy. Computer Kinesiology is primarily intended for the diagnostics and therapy of functional disorders of the locomotor system. This pilot study population included 55 patients (Group 1) with acute and chronic back pain and 51 persons (Group 2) without back pain. The third group was a control group of 67 healthy volunteers with no evidence of musculoskeletal pathologies and no back pain. All 173 subjects were examined three times by the diagnostic part of the Computer Kinesiology method. Groups 1 and 2 were treated after every diagnostics. Group 3 was not treated. The effect was evaluated by H score. Improvements after therapy were defined by reducing the H score by at least 1 point. In Group 1, the H score decreased by at least 1 point in 87.3% (95% CI: 75.5-94.7) and in Group 2 in 78.4% (95% CI: 64.7-88.7). There was no change of distribution of H Score grade in Group 3. The improvement neither depended on gender, age, and BMI nor was it influenced by the length of the therapy. This study demonstrated a high therapeutic efficacy of the Computer Kinesiology system in patients with back pain (Group 1) and in persons without back pain (Group 2) who used the Computer Kinesiology system for primary and secondary prevention of back pain.


[Three cases of fungemia caused by Blastoschizomyces capitatus].
Blastoschizomyces capitatus is a rare fungal pathogen that may lead to severe and fatal systemic infections especially in immunosuppressive individuals. B.capitatus strains have also been reported as the cause of hospital-acquired infections and outbreaks. In this report, three fungemia cases caused by B.capitatus with hematologic malignancies have been presented. The first case was a 20-year-old female with acute lymphoblastic leukemia, the second was a 26-year-old female with B-cell malignant lymphoma and the third was a 7-year-old male with B-cell acute lymphoblastic leukemia. All of the patients have been receiving chemotherapy, and treated with antibacterial and antifungal agents due to neutropenia. The blood cultures obtained from the second and third patients yielded B.capitatus although they were under empirical caspofungin therapy. Those patients have been treated with voriconazole and amphotericin B after the identification of B.capitatus, and clinical improvement were noted during their follow-up. However the first patient who was also under caspofungin therapy had died just before the isolation of B.capitatus from her blood culture. Conventional mycological methods [macroscopic and microscopic morphology, germ tube test, urea hydrolysis, carbohydrate assimilation tests (API 20C AUX; BioMerieux, France), growth temperature, cycloheximide sensitivity] were used for the identification of the isolates. The strains were identified as B.capitatus with the characteristics of annelloconidia formation, urease negativity, carbohydrate utilization, growth at 45°C and resistance to cycloheximide. Antifungal susceptibilities of isolates were determined by using microdilution method (for amphotericin B, fluconazole, itraconazole, voriconazole, ketoconazole) and E-test (for caspofungin). Minimum inhibitory concentration (MIC) values of the three B.capitatus strains were detected as 0.25, 0.125, 0.032 µg/ml for amphotericin B; 2, 2, 16 µg/ml for fluconazole; 0.064, 0.032, 0.032 µg/ml for itraconazole and 0.125, 0.064, 0.064 µg/ml for ketoconazole, respectively, while MIC values of all strains were 0.032 µg/ml for voriconazole and > 32 µg/ml for caspofungin. Since B.capitatus strains were isolated from the cases within about 15 days -sequentially-, the genotypes of the isolates were determined by repetitive sequence-based PCR (DiversiLab System; BioMerieux, France) to investigate the similarity rates. The results of analysis indicated 97% similarity between two (case 1 and 2) strains and 94.9% similarity in one strain (case 3) of B.capitatus, however the transmission route could not be clarified due to the absence of environmental sampling. In conclusion, B.capitatus should also be considered as a cause of systemic fungal infections in immunocompromised patients. Determination of the in vitro antifungal susceptibilities of clinical B.capitatus strains may contribute to the therapeutic approaches and epidemiological data.


Stage-specific expression of mucosal addressin cell adhesion molecule-1 during embryogenesis in rats.
Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is essential for lymphocyte trafficking to gut-associated lymphoid tissues and is implicated in inflammatory disorders in the gut and pancreatic islets. In this study, we examined the functional role of MAdCAM-1 during rat ontogeny using newly generated specific mAb. As previously observed in mice and humans, MAdCAM-1 was preferentially expressed in high endothelial venules (HEV) in gut-associated lymphoid tissues and venules of lamina propria in adult rats. Lymphocyte rolling and adhesion on HEV in Peyer's patches (PP) were completely abrogated with neutralizing anti-MAdCAM-1 mAb, in agreement with the notion that MAdCAM-1 is the principal HEV ligand for lymphocyte rolling and adhesion in adult PP. In the developing gastrointestinal tract, MAdCAM-1 was widely expressed in the venules of the lamina propria of fetal rats. In addition, MAdCAM-1 was also expressed in follicular dendritic cells in the neonatal PP. Interestingly, MAdCAM-1 expression was found also in nonmucosal tissues during ontogeny. MAdCAM-1 was transiently expressed in blood vascular endothelial cells in the fetal skin and neonatal thymus. Notably, MAdCAM-1-positive blood vessels were localized mainly in the cortico-medullary junction in the neonatal thymus and about 10-20% of thymocytes, most of which were either CD4, CD8 double positive or single positive specifically reacted with soluble MAdCAM-1 via integrin alpha4beta7. After birth, MAdCAM-1 expression in thymus blood vessels disappeared and concomitantly, the soluble MAdCAM-1-reactive thymocytes were rapidly down-regulated. Our results suggest that MAdCAM-1 functions as a vascular addressin in not only mucosal, but also nonmucosal lymphoid tissues during ontogeny.


Combined treatment with vitamin E and vitamin C decreases oxidative stress and improves fetal outcome in experimental diabetic pregnancy.
The aim was to investigate whether dietary supplementation of a combination of the two antioxidants, vitamin E and vitamin C, would protect the fetus in diabetic rat pregnancy at a lower dose than previously used. Normal and streptozotocin-induced diabetic rats were mated and given standard food or food supplemented with either 0.5% vitamin E + 1% vitamin C or 2% vitamin E + 4% vitamin C. At gestational d 20, gross morphology and weights of fetuses were evaluated. Vitamins E and C and thiobarbituric acid reactive substances were measured in maternal and fetal compartments. In addition, protein carbonylation was estimated in fetal liver. Maternal diabetes increased the rate of malformation and resorption in the offspring. High-dose antioxidant supplementation decreased fetal dysmorphogenesis to near normal levels. The low-dose group showed malformations and resorptions at an intermediate rate between the untreated and the high-dose groups. Thiobarbituric acid reactive substances were increased in fetal livers of diabetic rats and reduced to normal levels already by low-dose antioxidative treatment. Protein carbonylation rate was also increased in fetal liver of diabetic rats; it was normalized by high-dose treatment but only partially reduced by low-dose antioxidants. We conclude that combined antioxidative treatment with vitamins E and C decreases fetal malformation rate and diminishes oxygen radical-related tissue damage. However, no synergistic effect between the two antioxidants was noted, a result that may influence future attempts to design antiteratogenic treatments in diabetic pregnancy. Oxidatively modified proteins may be teratogenically important mediators in diabetic embryopathy.