Evaluation of prognostic factors and survival results in pancreatic carcinomas in Turkey.
The goal of this retrospective study was to evaluate patient characteristics, treatment modalities and prognostic factors in Turkish patients with pancreatic cancer. Between January 1997 and December 2012, 64 patients who presented to the Department of Radiation Oncology, Karadeniz Technical University, Faculty of Medicine with a diagnosis of pancreatic cancer were evaluated. The E/K ratio of the cases was 2.4/1 and the median age was 59.6 (32-80) years, respectively. Some 11 cases (18%) were stage 1, 21 (34.4%) were stage 2, 10 (16.4%) were stage 3, and 19 (31.1%) were metastatic. The mean follow-up time was 15.7 months (0.7-117.5) and loco-regional recurrence was noted in 11 (40.7%) who underwent surgery while metastases were observed in 41 patients (66.1%). The median overall survival (OS) was 11.2 months and the 1, 3 and 5-year OS rates were 41.7%, 9.9% and 7.9% respectively. The median disease-free survival (DFS) was 5.2 month and the1, 2 and 5 year DFS were 22.6%, 7.6% and 3.8% respectively. On univariate analysis, prognostic factors affecting OS included status of the operation (p<0.001), tumor stage (p=0.008), ECOG performance status (p=0.005) and CEA level (p=0.017).On multivariate analysis, prognostic factors affecting survival included status of the operation (p=0.033) and age (p= 0.023). In the current study, age and operation status were independent prognostic factors for overall survival with pancreatic patients. Thus, the patients early diagnosis and treatment ars essential. However, prospective studies with more patients are needed for confirmation.


Identifying evidence of effectiveness in the co-creation of research: a systematic review and meta-analysis of the international healthcare literature.
To investigate and address the evidence gap on the effectiveness of co-creation/production in international health research. An initial systematic search of previous reviews published by 22 July 2017 in Medline, Embase, PsycINFO, Scopus and Web of Science. We extracted reported aims, elements and outcomes of co-creation/production from 50 reviews; however, reviews rarely tested effectiveness against intended outcomes. We therefore checked the reference lists in 13 included systematic reviews that cited quantitative studies involving the public/patients in the design and/or implementation of research projects to conduct meta-analyses on their effectiveness using standardized mean difference (SMD). Twenty-six primary studies were included, showing moderate positive effects for community functions (SMD = 0.56, 95%CI = 0.29-0.84, n = 11) and small positive effects for physical health (SMD = 0.25, 95%CI = 0.07-0.42, n = 9), health-promoting behaviour (SMD = 0.14, 95%CI = 0.03-0.26, n = 11), self-efficacy (SMD = 0.34, 95%CI = 0.01-0.67, n = 3) and health service access/receipt (SMD = 0.36, 95%CI = 0.21-0.52, n = 12). Non-academic stakeholders that co-created more than one research stage showed significantly favourable mental health outcomes. However, co-creation was rarely extended to later stages (evaluation/dissemination), with few studies specifically with ethnic minority groups. The co-creation of research may improve several health-related outcomes and public health more broadly, but research is lacking on its longer term effects.


DHEA supplementation improves follicular microenviroment in poor responder patients.
To analyze the effect of dehydroepiandrosterone (DHEA) supplementation on follicular microenvironment and on in vitro fertilization (IVF) outcomes among poor responder patients. We enrolled 24 patients diagnosed as poor responders based on ESHRE consensus criteria. One group received 25 mg/die three times daily of DHEA supplementation for 3 months previous to IVF cycle, while the other did not receive any treatment. COH was performed with rFSH and hMG, and a GnRH antagonist was administered according to a flexible protocol. We evaluated perifollicular vascularization of recruited follicles through power Doppler blood flow analysis and follicles were graded as described by Chui et al. Follicular fluids (FF) from F3-F4 follicles were collected, and FF levels of vascular endothelial growth factor (VEGF) and hypoxic inducible factor1 (HIF1) were measured. FF levels of HIF1 were statistically significant lower in women treated with DHEA (14.76 ± 51.13 vs. 270.03 ± 262.18 pg/ml; p = 0.002). On the contrary, VEGF levels did not differ between the two groups. Concerning COH, in the DHEA-group the mean duration of treatment was significantly shorter (9.83 ± 1.85 vs. 12.09 ± 2.81; p = 0.023). Total numbers of oocytes retrieved, fertilized oocytes, good quality embryos, number of transferred embryos and clinical pregnancies tended to be higher in study group, but the results were not significant. On the other hand, considering the oocytes retrieved in selected F3-F4 follicles, there was a relation between HIF1 levels and oocytes quality. In fact, mature oocytes retrieved in selected follicles were significantly more numerous in DHEA-group (0.50 ± 0.52 vs. 0.08 ± 0.29; p = 0.018). The improvement of reproductive parameters after DHEA supplementation in poor responders may be explained through the effect that this pro-hormone exerts on follicular microenvironment.


The Ferredoxin-Like Protein FerR Regulates PrbP Activity in Liberibacter asiaticus.
In Liberibacter asiaticus, PrbP is an important transcriptional accessory protein that regulates gene expression through interactions with the RNA polymerase β-subunit and a specific sequence on the promoter region. The constitutive expression of prbP observed upon chemical inactivation of PrbP-DNA interactions in vivo indicated that the expression of prbP was not autoregulated at the level of transcription. This observation suggested that a modulatory mechanism via protein-protein interactions may be involved. In silico genome association analysis identified FerR (CLIBASIA_01505), a putative ferredoxin-like protein, as a PrbP-interacting protein. Using a bacterial two-hybrid system and immunoprecipitation assays, interactions between PrbP and FerR were confirmed. In vitro transcription assays were used to show that FerR can increase the activity of PrbP by 16-fold when present in the PrbP-RNA polymerase reaction mixture. The FerR protein-protein interaction surface was predicted by structural modeling and followed by site-directed mutagenesis. Amino acids V20, V23, and C40 were identified as the most important residues in FerR involved in the modulation of PrbP activity in vitro The regulatory mechanism of FerR abundance was examined at the transcription level. In contrast to prbP of L. asiaticus (prbPLas), mRNA levels of ferR of L. asiaticus (ferRLas) are induced by an increase in osmotic pressure. The results of this study revealed that the activity of the transcriptional activator PrbPLas is modulated via interactions with FerRLas The induction of ferRLas expression by osmolarity provides insight into the mechanisms of adjusting gene expression in response to host environmental signals in L. asiaticusIMPORTANCE The rapid spread and aggressive progression of huanglongbing (HLB) in the major citrus-producing areas have raised global recognition of and vigilance to this disease. As a result, the causative agent, Liberibacter asiaticus, has been investigated from various perspectives. However, gene expression regulatory mechanisms that are important for the survival and persistence of this intracellular pathogen remain largely unexplored. PrbP is a transcriptional accessory protein important for L. asiaticus survival in the plant host. In this study, we investigated the interactions between PrbP in L. asiaticus (PrbPLas) and a ferredoxin-like protein (FerR) in L. asiaticus, FerRLas We show that the presence of FerR stabilizes and augments the activity of PrbPLas In addition, we demonstrate that the expression of ferR is induced by increases in osmolarity in Liberibacter crescens Altogether, these results suggest that FerRLas and PrbPLas may play important roles in the regulation of gene expression in response to changing environmental signals during L. asiaticus infection in the citrus host.


Occupational exposure of healthcare and research staff to static magnetic stray fields from 1.5-7 Tesla MRI scanners is associated with reporting of transient symptoms.
Limited data is available about incidence of acute transient symptoms associated with occupational exposure to static magnetic stray fields from MRI scanners. We aimed to assess the incidence of these symptoms among healthcare and research staff working with MRI scanners, and their association with static magnetic field exposure. We performed an observational study among 361 employees of 14 clinical and research MRI facilities in The Netherlands. Each participant completed a diary during one or more work shifts inside and/or outside the MRI facility, reporting work activities and symptoms (from a list of potentially MRI-related symptoms, complemented with unrelated symptoms) experienced during a working day. We analysed 633 diaries. Exposure categories were defined by strength and type of MRI scanner, using non-MRI shifts as the reference category for statistical analysis. Non-MRI shifts originated from MRI staff who also participated on MRI days, as well as CT radiographers who never worked with MRI. Varying per exposure category, symptoms were reported during 16-39% of the MRI work shifts. We observed a positive association between scanner strength and reported symptoms among healthcare and research staff working with closed-bore MRI scanners of 1.5 Tesla (T) and higher (1.5 T OR=1.88; 3.0 T OR=2.14; 7.0 T OR=4.17). This finding was mainly driven by reporting of vertigo and metallic taste. The results suggest an exposure-response association between exposure to strong static magnetic fields (and associated motion-induced time-varying magnetic fields) and reporting of transient symptoms on the same day of exposure. 11-032/C.


Tunable slow light device using quantum dot semiconductor laser.
This investigation experimentally demonstrates a tunable slow light device using a quantum dot (QD) semiconductor laser. The QD semiconductor laser at 1.3 mum fabricated on a GaAs substrate is grown by molecular beam epitaxy. Tunable slow light can be achieved by adjusting the bias current and wavelength detuning. The slow light device operated under probe signal from 5 to 10 GHz is presented. Moreover, we also demonstrate that the tunable slow light device can be used in a subcarrier multiplexed system.


Network-based Phenome-Genome Association Prediction by Bi-Random Walk.
The availability of ontologies and systematic documentations of phenotypes and their genetic associations has enabled large-scale network-based global analyses of the association between the complete collection of phenotypes (phenome) and genes. To provide a fundamental understanding of how the network information is relevant to phenotype-gene associations, we analyze the circular bigraphs (CBGs) in OMIM human disease phenotype-gene association network and MGI mouse phentoype-gene association network, and introduce a bi-random walk (BiRW) algorithm to capture the CBG patterns in the networks for unveiling human and mouse phenome-genome association. BiRW performs separate random walk simultaneously on gene interaction network and phenotype similarity network to explore gene paths and phenotype paths in CBGs of different sizes to summarize their associations as predictions. The analysis of both OMIM and MGI associations revealed that majority of the phenotype-gene associations are covered by CBG patterns of small path lengths, and there is a clear correlation between the CBG coverage and the predictability of the phenotype-gene associations. In the experiments on recovering known associations in cross-validations on human disease phenotypes and mouse phenotypes, BiRW effectively improved prediction performance over the compared methods. The constructed global human disease phenome-genome association map also revealed interesting new predictions and phenotype-gene modules by disease classes.


Effects of endurance training and captivity on activity metabolism of lizards.
Two groups of Amphibolurus nuchalis, an Australian agamid lizard, were maintained in captivity for 8 wk. The "trained" group was given submaximal exercise at 1 km/h on a motorized treadmill, 30 min/day, 5 days/wk; the treadmill was inclined 10% for the last 5 wk. The "sedentary" group was not exercised. Endurance capacity did not change significantly in either group, but sprint speed decreased in trained lizards. The sedentary group exhibited significant decreases in maximal O2 consumption, standard metabolic rate, and heart mass, but an increase in liver mass. Trained lizards exhibited significant decreases in heart and thigh muscle masses, but significant increases in liver mass, hematocrit, liver pyruvate kinase, and heart citrate synthase activities. It is concluded that the adaptive response to endurance training, typical of mammals, does not generally occur in lizards. Moreover, levels of chronic activity that would elicit adaptive responses in mammals may be excessive for lizards and may induce pathological effects in joints and skeletal muscle. The ecological and evolutionary significance of these conclusions is discussed.


An integrated map of HIV genome-wide variation from a population perspective.
The HIV pandemic is characterized by extensive genetic variability, which has challenged the development of HIV drugs and vaccines. Although HIV genomes have been classified into different types, groups, subtypes and recombinants, a comprehensive study that maps HIV genome-wide diversity at the population level is still lacking to date. This study aims to characterize HIV genomic diversity in large-scale sequence populations, and to identify driving factors that shape HIV genome diversity. A total of 2996 full-length genomic sequences from 1705 patients infected with 16 major HIV groups, subtypes and circulating recombinant forms (CRFs) were analyzed along with structural, immunological and peptide inhibitor information. Average nucleotide diversity of HIV genomes was almost 50% between HIV-1 and HIV-2 types, 37.5% between HIV-1 groups, 14.7% between HIV-1 subtypes, 8.2% within individual HIV-1 subtypes and less than 1% within single patients. Along the HIV genome, diversity patterns and compositions of nucleotides and amino acids were highly similar across different groups, subtypes and CRFs. Current HIV-derived peptide inhibitors were predominantly derived from conserved, solvent accessible and intrinsically ordered structures in the HIV-1 subtype B genome. We identified these conserved regions in Capsid, Nucleocapsid, Protease, Integrase, Reverse transcriptase, Vpr and the GP41 N terminus as potential drug targets. In the analysis of factors that impact HIV-1 genomic diversity, we focused on protein multimerization, immunological constraints and HIV-human protein interactions. We found that amino acid diversity in monomeric proteins was higher than in multimeric proteins, and diversified positions were preferably located within human CD4 T cell and antibody epitopes. Moreover, intrinsic disorder regions in HIV-1 proteins coincided with high levels of amino acid diversity, facilitating a large number of interactions between HIV-1 and human proteins. This first large-scale analysis provided a detailed mapping of HIV genomic diversity and highlighted drug-target regions conserved across different groups, subtypes and CRFs. Our findings suggest that, in addition to the impact of protein multimerization and immune selective pressure on HIV-1 diversity, HIV-human protein interactions are facilitated by high variability within intrinsically disordered structures.


Detection of transcriptionally active high-risk HPV in patients with head and neck squamous cell carcinoma as visualized by a novel E6/E7 mRNA in situ hybridization method.
Evidence for transcriptional activation of the viral oncoproteins E6 and E7 is regarded as the gold standard for the presence of clinically relevant human papillomavirus (HPV), but detection of E6/E7 mRNA requires RNA extraction and polymerase chain reaction amplification-a challenging technique that is restricted to the research laboratory. The development of RNA in situ hybridization (ISH) probes complementary to E6/E7 mRNA permits direct visualization of viral transcripts in routinely processed tissues and has opened the door for accurate HPV detection in the clinical care setting. Tissue microarrays containing 282 head and neck squamous cell carcinomas from various anatomic subsites were tested for the presence of HPV using p16 immunohistochemistry, HPV DNA ISH, and an RNA ISH assay (RNAscope) targeting high-risk HPV E6/E7 mRNA transcripts. The E6/E7 mRNA assay was also used to test an additional 25 oropharyngeal carcinomas in which the HPV status as recorded in the surgical pathology reports was equivocal due to conflicting detection results (ie, p16 positive, DNA ISH negative). By the E6/E7 mRNA method, HPV was detected in 49 of 282 (17%) HNSCCs including 43 of 77 (56%) carcinomas from the oropharynx, 2 of 3 (67%) metastatic HNSCCs of an unknown primary site, 2 of 7 (29%) carcinomas from the sinonasal tract, and 2 of 195 (1%) carcinomas from other head and neck sites. p16 expression was strongly associated with the presence of HPV E6/E7 mRNA: 46 of 49 HPV-positive tumors exhibited p16 expression, whereas only 22 of 233 HPV-negative tumors were p16 positive (94% vs. 9%, P<0.0001). There was also a high rate of concordance (99%) between the E6/E7 mRNA method and HPV DNA ISH. For the selected group of discordant HNSCCs (p16/HPV DNA), the presence of E6/E7 transcripts was detected in 21 of 25 (84%) cases. The E6/E7 mRNA method confirmed the presence of transcriptionally active HPV-related HNSCC that has a strong predilection for the oropharynx and is strongly associated with high levels of p16 expression. Testing for HPV E6/E7 transcripts by RNA ISH is ideal because it confirms the presence of integrated and transcriptionally active virus, permits visualization of viral transcripts in tissues, and is technically feasible for routine testing in the clinical laboratory.


Evaluation of the cytotoxic effect of the monoterpene indole alkaloid echitamine in-vitro and in tumour-bearing mice.
The cytotoxic effect of various concentrations of echitamine chloride was studied in HeLa, HepG2, HL60, KB and MCF-7 cell lines in-vitro and in mice bearing Ehrlich ascites carcinoma (EAC). Exposure of various cells to different concentrations of echitamine chloride resulted in a concentration-dependent cell killing, and KB cells were found to be most sensitive amongst all the cells evaluated. EAC mice treated with 1, 2, 4, 6, 8, 12 or 16 mg kg-1 echitamine chloride showed a dose-dependent elevation in the anti-tumour activity, as evident by increased number of survivors in comparison with the non-drug treated controls. The highest dose of echitamine chloride (16 mg kg-1) caused toxicity in the recipient mice, therefore 12 mg kg-1 was considered the best cytotoxic dose for its anti-tumour effect. Administration of 12 mg kg-1 echitamine chloride resulted in an increase in the median survival time (MST) up to 30.5 days, which was 11.5 days higher than the non-drug treated control (19 days). Administration of 16 mg kg-1 echitamine chloride to EAC mice resulted in a time dependent elevation in lipid peroxidation that reached a peak at 6 h post-treatment, whereas glutathione concentration declined in a time dependent manner and a maximum decline was reported at 3 h post-treatment. Our study demonstrated that echitamine chloride possessed anti-tumour activity in-vitro and in-vivo.


Single gene variants causing deafness in Asian Indians.
Congenital deafness is one of the common disorders, with some common genes accounting for most of the cases. One in 1000 children are born with sensorineural hearing loss, and of that 50% are hereditary. In the Mediterranean Europeans, 80% of the nonsyndromic recessive deafness is due to homozygous mutation in GJB2, the 35del G allele. InWestern population, the GJB2 variation have been found in up to 30-40% cases. In Indians, the GJB2 variants have been found in up to 20% cases, mostly from central and southern India. In the present study, DNA was extracted from blood using standard methods. This was used to perform targeted gene capture using a custom capture kit. Multiple genes causing deafness were sequenced by next-generation sequencing to mean >80-100x coverage on Illumina sequencing platform. We found variants in GJB2, WFS1, FGF3, EYA4, MYO7A. and CHD7 genes. Most of these variants were pathogenic and novel, and possibly causative. Deafness is most commonly due to the autosomal dominant genes but in severe cases of early onset deafness, autosomal recessive genes may contribute in our population. In selected families of severe prelingual deafness, prenatal diagnosis can be done.


Multimodality approach to the sentinel node: an algorithm for the use of presentinel lymph node biopsy ultrasound (after lymphoscintigraphy) in conjunction with presentinel lymph node biopsy fine needle aspiration cytology.
In a recent article by Lam et al. describing the experience of the Sydney Melanoma Unit, a novel term called 'multimodality approach' to the sentinel node (SN) was applied. However, the timing of the use of the tools available in the presented cases should be discussed. An algorithm of which time to use, which tool to detect the correct SN by preoperative ultrasound (US) in combination with an US-guided fine needle aspiration cytology (FNAC) will be proposed and demonstrated using five clinical examples. All examples prove the advantage of a combined strategy to track down the correct and involved SN. A sensitive US power mode, for the amplification of even the slightest changes in vascularization, is the most important tool in our diagnostic preoperative approach. First, reliable US criteria, as recently published must consequently be applied. Second, a FNAC should be performed early enough, even when only early signs are visible. Third, a swift overnight cytology before sentinel lymph node biopsy should be available. US is a method for the early detection of clinically nonevident metastases. Using the proposed algorithm when to perform which part of the multimodality approach, we demonstrated the enormous information out of additionally performed US. In the case of a suspicious US finding, we always perform a FNAC of the node. In the event of a negative finding, the SLND will take place as scheduled. In the case of a positive finding, the patient can directly undergo completion lymph node dissection.


Detailed regulatory mechanism of the interaction between ZO-1 PDZ2 and connexin43 revealed by MD simulations.
The gap junction protein connexin43 (Cx43) binds to the second PDZ domain of Zonula occludens-1 (ZO-1) through its C-terminal tail, mediating the regulation of gap junction plaque size and dynamics. Biochemical study demonstrated that the very C-terminal 12 residues of Cx43 are necessary and sufficient for ZO-1 PDZ2 binding and phosphorylation at residues Ser (-9) and Ser (-10) of the peptide can disrupt the association. However, only a crystal structure of ZO-1 PDZ2 in complex with a shorter 9 aa peptide of connexin43 was solved experimentally. Here, the interactions between ZO-1 PDZ2 and the short, long and phosphorylated Cx43 peptides were studied using molecular dynamics (MD) simulations and free energy calculation. The short peptide bound to PDZ2 exhibits large structural variations, while the extension of three upstream residues stabilizes the peptide conformation and enhanced the interaction. Phosphorylation at Ser(-9) significantly weakens the binding and results in conformational flexibility of the peptide. Glu210 of ZO-1 PDZ2 was found to be a key regulatory point in Cx43 binding and phosphorylation induced dissociation.


A fovea for pain at the fingertips.
The spatial resolution of sensory systems is not homogeneous across their receptive surfaces. For example, tactile acuity is greatest on the fingertips, reflecting the high innervation density and small mechanoreceptive fields in this area [1, 2]. In contrast, pain is considered to lack any equivalent to the tactile fovea on the fingertips, where the density of nociceptive fibers is remarkably low [3]. Here, by combining psychophysics with histology, we show that this established notion is incorrect. By delivering small-diameter nociceptive-specific laser pulses to human volunteers, we discovered that (1) the spatial acuity for pain is higher on the fingertips than on proximal skin regions such as the hand dorsum, and (2) this distal-proximal gradient for pain is comparable to that for touch. In contrast, skin biopsies in the same participants showed that the intraepidermal nerve fiber density is lower in the fingertips than in the hand dorsum. The increased spatial acuity for pain on the fingertips therefore cannot be explained simply by peripheral innervation density. This finding is, however, consistent with the existence of fine-grained maps of nociceptive input to individual digits in the human primary somatosensory cortex [4].


Pathogenesis of defined invasion mutants of Yersinia enterocolitica in a BALB/c mouse model of infection.
It has been hypothesized for many years that the ability of Yersinia spp. to invade tissue culture cells is reflective of their ability to penetrate the intestinal epithelium and that this capacity is an important aspect of the disease process. Three different genes from Yersinia spp. that are involved in the tissue culture invasion phenotype have been identified: inv, ail, and yadA. It was previously shown that inv is necessary for efficient penetration of the intestinal epithelium by Yersinia enterocolitica. The present study was initiated to determine whether other known Yersinia invasion factors could promote uptake of the bacteria by mice in the absence of invasion. In addition, the roles of these three invasion factors in the survival of the bacteria, lethality for mice, and development of pathology were compared. We found that YadA is necessary for persistence of Y. enterocolitica in Peyer's patches, and consistent with this observation, the yadA mutant was avirulent for mice infected either orally or intraperitoneally. In addition, the inv yadA double mutant was avirulent. Histological and immunohistological examination of the Peyer's patches of infected mice indicated that despite the presence of large numbers of CFU at 24 h the yadA and ail yadA mutants cause only minimal pathology and recruitment of macrophages. At 42 h postinfection, Peyer's patches from mice infected with the inv mutant showed no pathology, despite the prediction that some of the mice by this time would be colonized. However, at 72 h, inflammation and necrosis were evident in some Peyer's patches. Together, these observations suggest that for visible pathology to develop, a threshold number of bacteria (> 10(5)) is needed and the bacteria need to persist for more than 24 h. Lastly, YadA but not Ail may play a role in the less efficient, delayed invasion of the intestinal epithelium observed for the inv mutant.


Individual, Social, and Neighborhood Associations With Sitting Time Among Veterans.
Sedentary behavior is an increasingly recognized health risk factor, independent of physical activity. Although several correlates of sedentary behavior are known, little research has identified them among U.S. veterans, a population that faces disproportionate chronic disease burden. A survey was mailed to 1997 randomly selected veterans at a large urban Veterans Affairs medical center in 2012 and remailed in 2013 to nonresponders, resulting in a 40% response rate. We examined individual-, social-, and neighborhood-level factors in association with self-reported sitting time. Factors correlated with sitting time at P < .05 were included in a multiple linear regression model. In the multivariate model, higher depression (B = 7.8), body mass index (B = 5.1), functional impairment (B = 4.2), and self-rated health (B = 68.5) were significantly associated with higher sitting time, and leisure time physical activity (B = -0.10) and being employed (B = -71.3) were significantly associated with lower sitting time. Individual-level, but not social- and neighborhood-level, variables were associated with sitting time in this population. This study identified individual-level targets for reducing sitting time and improving overall health among veterans.


Reproductive health problems in rural South African young women: risk behaviour and risk factors.
South African young women continue to be vulnerable, with high prevalence of teenage pregnancy, HIV, sexually transmitted infections (STIs) and female genital schistosomiasis (FGS). This study seeks to examine the underlying factors that may be associated with these four adverse reproductive health outcomes. In a cross-sectional study of 1413 sexually active of young women, we explored these four adverse reproductive health outcomes by considering socio-demographic factors, socio-economic factors, sexual risk behaviour, substance abuse and knowledge about reproductive health by using a questionnaire. Consenting participants were asked about previous pregnancies and were tested for HIV, STIs and FGS. Multivariable regression analyses were used to explore the factors associated with these four reproductive health outcomes. 1. Early pregnancy: Among the young women, 44.4% had already been pregnant at least once. Associated factors were hormonal contraceptives, (adjusted odds ratio (AOR): 17.94, 95% confidence interval (CI): 12.73-25.29), and sexual debut < 16 years (AOR: 3.83, 95% CI: 2.68-5.47). Living with both parents (AOR 0.37, 95% CI: 0.25-0.57) and having a steady partner (AOR: 0.43, 95% CI: 0.24-0.76) were identified as protective factors against pregnancy. 2. HIV: HIV prevalence was 17.1%. The odds of having HIV were higher in intergenerational (AOR: 2.06, 95% CI: 1.05-4.06) and intragenerational relationships (AOR: 1.51 95% CI: 1.06-2.15), compared to age-homogenous relationships. Other associated factors were: condom use (AOR: 1.60, 95% CI: 1.16-2.20), number of times treated for an STI (AOR: 1.32, 95% CI: 1.02-1.71), and total number of partners (AOR: 1.14, 95% CI: 1.03-1.28). 3. STIs: Participants who had at least one STI (40.5%) were associated with total partner number (AOR 1.17, 95% CI: 1.06-1.30), and testing HIV positive (AOR: 1.88, 95% CI 1.41-2.50). 4. FGS: FGS prevalence (19.7%) was associated with previous anti-schistosomal treatment (AOR: 2.18, 95% CI: 1.57-3.05). There is a high prevalence of pregnancy, HIV, STIs and FGS among sexually active young women in rural KwaZulu-Natal. Multidisciplinary approaches are urgently needed for educational and health literacy programs prior to sexual debut, and health care facilities, which should be made accessible for young women.


The contact-mediated response of peripheral-blood monocytes to preactivated T cells is suppressed by serum factors in rheumatoid arthritis.
Stimulation of monocytes/macrophages after cell contact with preactivated T cells has been suggested to contribute to the excessive TNF-alpha production in rheumatoid arthritis (RA). In this study, T cell-contact-dependent TNF-alpha production by peripheral-blood monocytes in vitro was investigated and found to be significantly lower in treated and untreated patients with RA than in healthy controls. This suppression was not due to a general deficiency of monocytes to respond, because responses to lipopolysaccharide were comparable in patients and controls. In agreement with the pivotal role of TNF-alpha in RA, T cell-dependent induction of TNF-alpha in synovial macrophages was fivefold to tenfold higher than in peripheral-blood monocytes from either patients or controls. The decreased response of peripheral-blood monocytes from patients with RA was found to be mediated by inhibitory serum factors, because the addition of patient sera to monocytes from healthy controls suppressed TNF-alpha response in the co-culture assay. Preincubation of monocytes from healthy controls with RA serum was sufficient to suppress the subsequent TNF-alpha response in T cell co-cultures, indicating that inhibitory factors do indeed bind to monocyte surfaces, which might represent a regulatory counter-action of the immune system to the long-standing and consuming autoimmune process in RA. There are some indications that apolipoprotein A-1 might be part of this regulatory system.


Surface chemistry, structure, and electronic properties from microns to the atomic scale of axially doped semiconductor nanowires.
Using both synchrotron-based photoemission electron microscopy/spectroscopy and scanning tunneling microscopy/spectroscopy, we obtain a complete picture of the surface composition, morphology, and electronic structure of InP nanowires. Characterization is done at all relevant length scales from micrometer to nanometer. We investigate nanowire surfaces with native oxide and molecular adsorbates resulting from exposure to ambient air. Atomic hydrogen exposure at elevated temperatures which leads to the removal of surface oxides while leaving the crystalline part of the wire intact was also studied. We show how surface chemical composition will seriously influence nanowire electronic properties. However, opposite to, for example, Ge nanowires, water or sulfur molecules adsorbed on the exterior oxidized surfaces are of less relevance. Instead, it is the final few atomic layers of the oxide which plays the most significant role by strongly negatively doping the surface. The InP nanowires in air are rather insensitive to their chemical surroundings in contrast to what is often assumed for nanowires. Our measurements allow us to draw a complete energy diagram depicting both band gap and differences in electron affinity across an axial nanowire p-n junction. Our findings thus give a robust set of quantitative values relating surface chemical composition to specific electronic properties highly relevant for simulating the performance of nanoscale devices.


Surgical treatment of a pulmonary artery vascular hamartoma in a dog.
A 6-year-old Siberian Husky-mix dog was examined for episodes of collapse. Physical examination, echocardiography, abdominal ultrasonography, ECG, and thoracic computed tomography with contrast were performed and revealed a 2.5 × 2.3 × 2.0-cm mass over the pulmonic valve leaflets, resulting in moderate pulmonic stenosis. Other abnormal findings included systemic hypertension, right bundle branch block, proteinuria, and a urinary bladder mass. Pulmonary arteriotomy was performed under inflow occlusion, and the mass was resected with transesophageal echocardiographic guidance and direct visualization. Results of histologic examination of the mass revealed a vascular hamartoma. Sequential follow-up examinations and telephone contacts (at 0.5, 5, and 15 months after surgery) revealed that the patient had been free from episodes of collapse since surgery. No regrowth of the mass was noted on follow-up echocardiograms, and the pulmonic stenosis had resolved, although mild to moderate pulmonary insufficiency later developed. The bladder mass was excised 15 months after the first surgery when hematuria developed, and results of histologic examination of this mass revealed a vascular hamartoma. The dog was eventually euthanized 31 months after the initial surgery for reasons that could not be directly linked to any recurrence of the pulmonary artery mass. Hamartomas are benign tumors that can be located in various tissues, including large arteries. Computed tomography was helpful in predicting the resectability of the intracardiac mass in this dog. Treatment with arteriotomy under inflow occlusion and mild hypothermia resulted in a favorable outcome.


Identification of a group of AML/MDS patients with a relatively favorable prognosis who have chromosome 5 and/or 7 abnormalities.
Patients with AML, RAEB-t, or RAEB and abnormalities involving chromosomes 5 and/or 7 (-5, -7) generally, but not always, have poorer prognoses than patients with a normal karyotype. Our objective was to see whether the occasional relatively favorable outcome in -5/-7 patients is a random event or, rather, reflects true heterogeneity in -5/-7. We examined 3 factors known to be prognostic in AML for their prognostic significance in 400 -5/-7 patients treated at the M.D. Anderson Cancer Center from 1980-1998 for AML or MDS. The outcome of comparative interest was survival as assessed by log-rank test. There was evidence that outcome was better in -5/-7 patients with a simple (rather than complex) karyotype, with > 1 normal metaphase (rather than only metaphases containing -5/-7), and without an antecedent hematologic disorder. More importantly, the 10% of the patients with a simple karyotype, > 1 normal metaphase, and no antecedent hematologic disorder not only had a better outcome than the other -5/-7 patients but had essentially identical outcomes to the 669 AML/MDS patients with a normal karyotype treated at M.D. Anderson during the same period. The results indicate that the -5/-7 group should not a priori be regarded as having an unfavorable prognosis, and more generally suggest the need to refine prognosis within each of the cytogenetic subsets of AML.


Inductively coupled plasma mass spectroscopy quantitation of platinum-DNA adducts in peripheral blood leukocytes of patients receiving cisplatin- or carboplatin-based chemotherapy.
Platinum-DNA adducts can be assayed in peripheral blood leukocytes by means of atomic absorption spectroscopy and ELISA, and high adduct levels have been correlated previously with favorable clinical response to platinum-based chemotherapy. Our purpose was to study adduct formation in peripheral blood leukocytes by means of a new method, inductively coupled plasma mass spectroscopy (ICP-MS), and to correlate adduct formation with clinical response and toxicity. Platinum (Pt)-DNA adducts were measured by means of ICP-MS in leukocytes of 66 patients receiving a cisplatin- or carboplatin-based chemotherapy, collected either before the beginning of treatment and incubated in vitro with cisplatin or 1 and 24 h after the administration of drug to the patient. The Pt-DNA adduct level in leukocytes from patients exposed to drug in vitro was 14.33 +/- 14.71 fmol/microgram DNA (mean +/- SD), which was not significantly different from the value of 23.4 +/- 19.53 fmol/microgram DNA observed in leukocytes from nine healthy volunteers. In samples collected after the administration of chemotherapy, Pt-DNA adducts ranged from 1.91 +/- 3.59 fmol/microgram DNA (mean +/- SD) at the 1-h time point to 2.61 +/- 3.35 fmol/microgram DNA at 24 h (P > 0.05). Adduct levels in leukocytes exposed in vitro did not correlate with adduct levels from patients treated with cisplatin-based chemotherapy (r = 0.085 and 0.011 at 1 and 24 h, respectively). At 24 h, adduct levels in patients receiving cisplatin (3.15 +/- 3.64 fmol/microgram DNA, mean +/- SD) were significantly higher (P = 0.02) than those observed in patients treated with standard dose carboplatin (0.57 +/- 0.73 fmol/microgram DNA) and also higher than those in patients receiving high-dose carboplatin (1.18 +/- 1.06 fmol/microgram DNA), although the latter difference did not reach statistical significance (P = 0.071). No differences in adduct levels (mean +/- SD) were evident between patients responsive (3.23 +/- 3.51 fmol/microgram DNA) and nonresponsive (2.34 +/- 3.01 fmol/microgram DNA) to chemotherapy. In the homogeneous group of patients treated with combination of cisplatin and 5FU, received dose intensity, hemoglobin decrease, and posttreatment creatinine could not be linked with the extent of leukocyte adduct formation. The data presented here demonstrate that ICP-MS allows the detection of adducts in patients treated with cisplatin or carboplatin and suggest that adduct formation in leukocytes is not a major determinant of response or toxicity.


Patient feelings during the preoperative period for cardiac surgery.
This qualitative study aimed to identify the feelings patients presented when confronted with the news about the need to undergo cardiac surgery and, later, during the preoperative period. Twenty male patients were interviewed. The case study methodology was adopted and the analysis process resulted in two theme categories: Feelings of apprehension (fear, worry, anxiety, suspicion and jittery) and Positive and hopeful feelings. We observed that, although both categories were present at the two moments, over time, during the preoperative period, the need for surgical intervention was accepted better and the Feelings of apprehension started to be mentioned less, while the Positive and hopeful feelings were most frequently mentioned by the patients.


Evaluating Single-Spacecraft Observations of Planetary Magnetotails With Simple Monte Carlo Simulations: 1. Spatial Distributions of the Neutral Line.
A simple Monte Carlo model is presented that considers the effects of spacecraft orbital sampling on the inferred distribution of magnetic flux ropes, generated through magnetic reconnection in the magnetotail current sheet. When generalized, the model allows the determination of the number of orbits required to constrain the underlying population of structures: It is able to quantify this as a function of the physical parameters of the structures (e.g., azimuthal extent and probability of generation). The model is shown adapted to the Hermean magnetotail, where the outputs are compared to the results of a recent survey. This comparison suggests that the center of Mercury's neutral line is located dawnward of midnight by 0 . 3 7 - 1 . 02 + 1 . 21 R M and that the flux ropes are most likely to be wide azimuthally (∼50% of the width of the Hermean tail). The downtail location of the neutral line is not self-consistent or in agreement with previous (independent) studies unless dissipation terms are included planetward of the reconnection site; potential physical explanations are discussed. In the future the model could be adapted to other environments, for example, the dayside magnetopause or other planetary magnetotails.


Potential Toxicity of α-Cypermethrin-Treated Nets on Tuta absoluta (Lepidoptera: Gelechiidae).
Insect-proof nets are thought to be effective physical barriers to protect tomato crops against several insect pests, including the invasive tomato pest, Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae). However, protected tomato crops are frequently infested by this destructive pest, and there is a higher infestation of plants closer to openings in Mediterranean greenhouses, suggesting that immigrating adults can easily walk on these protective materials and find a way to reach the crop. Laboratory bioassays were carried out to characterize the potential toxicity of α-cypermethrin-treated insect-proof nets (Agronet) against T. absoluta adults. The data showed that the net acts mainly through a variety of chronic sublethal effects rather than acute ones. Reduced longevity and, more markedly, a reduced number of laid eggs were observed after the moths were exposed to the treated net over the duration of their lifetimes. A Y-tube experiment showed that the treated net does not affect the T. absoluta olfaction cues for host location. In contrast, when the moths were given the option to choose either the treated or the untreated net in laboratory cages, they significantly preferred the untreated one. The toxicological significance and the functional implications of these subtle effects for the implementation of integrated T. absoluta management strategies are discussed.


Salmonella enterica Serovar Szentes, a Rare Serotype Causing a 9-Month Outbreak in 2013 and 2014 in Switzerland.
During the summer of 2013, an increase of Salmonella enterica ssp. enterica serovar Szentes isolates from human clinical cases was registered by the Swiss National Centre for Enteropathogenic Bacteria and Listeria. In the course of the ensuing 9 months, 18 isolates originating from 13 patients and from one food sample were collected. Of the 13 human cases, 10 (77%) were female. The patients' ages ranged from 27 to 83 years (median age 49 years). Pulsed-field gel electrophoresis (PFGE) performed with XbaI, and multilocus sequence typing (MLST) were used to type the strains. PFGE as well as MLST showed the strains as indistinguishable. The PFGE pattern and MLST sequence type (ST427) were identical to those of Salmonella enterica serovar Szentes isolated in previous years (2002-2013) from sporadic cases in Switzerland and Germany. The increased isolation frequency continued for 6 months after the detection of Salmonella Szentes in sprouts. No common food exposure could be established. Due to lack of information on the potential food source, further investigations were not possible. The outbreak of this unusual serotype was detected because of its temporal clustering.


Luminance sticker based facial expression recognition using discrete wavelet transform for physically disabled persons.
Developing tools to assist physically disabled and immobilized people through facial expression is a challenging area of research and has attracted many researchers recently. In this paper, luminance stickers based facial expression recognition is proposed. Recognition of facial expression is carried out by employing Discrete Wavelet Transform (DWT) as a feature extraction method. Different wavelet families with their different orders (db1 to db20, Coif1 to Coif 5 and Sym2 to Sym8) are utilized to investigate their performance in recognizing facial expression and to evaluate their computational time. Standard deviation is computed for the coefficients of first level of wavelet decomposition for every order of wavelet family. This standard deviation is used to form a set of feature vectors for classification. In this study, conventional validation and cross validation are performed to evaluate the efficiency of the suggested feature vectors. Three different classifiers namely Artificial Neural Network (ANN), k-Nearest Neighborhood (kNN) and Linear Discriminant Analysis (LDA) are used to classify a set of eight facial expressions. The experimental results demonstrate that the proposed method gives very promising classification accuracies.


Haemotoxicity of busulphan, doxorubicin, cisplatin and cyclophosphamide in the female BALB/c mouse using a brief regimen of drug administration.
Many anticancer drugs are myelotoxic and cause bone marrow depression; however, generally, the marrow/blood returns to normal after treatment. Nevertheless, after the administration of some anti-neoplastic agents (e.g. busulphan, BU) under conditions as yet undefined, the marrow may begin a return towards normal, but normality may not be achieved, and late-stage/residual marrow injury may be evident. The present studies were conducted to develop a short-term mouse model (a 'screen') to identify late-stage/residual marrow injury using a brief regimen of drug administration. Female BALB/c mice were treated with BU, doxorubicin (DOX), cisplatin (CISPLAT) or cyclophosphamide (CYCLOPHOS) on days 1, 3 and 5. In 'preliminary studies', a maximum tolerated dose (MTD) for each drug was determined for use in 'main studies'. In main studies, mice were treated with vehicle (control), low and high (the MTD) dose levels of each agent. Necropsies were performed, and blood parameters and femoral/humeral nucleated marrow cell counts (FNCC/HNCC) were assessed on six occasions (from days 1 to 60/61 post-dosing). Late-stage/residual changes were apparent in BU-treated mice at day 61 post-dosing: RBC, Hb and haematocrit were reduced, mean cell volume/mean cell haemoglobin were increased and platelet and FNCC counts were decreased. Mice given DOX, CISPLAT and CYCLOPHOS, in general, showed no clear late-stage/residual effects (day 60/61). It was concluded that a brief regimen of drug administration, at an MTD, with assessment at day 60/61 post-dosing was a suitable short-term method/screen in the mouse for detecting late-stage/residual marrow injury for BU, a drug shown to exhibit these effects in man.


Identifying the causal mechanisms of the quiet eye.
Scientists who have examined the gaze strategies employed by athletes have determined that longer quiet eye (QE) durations (QED) are characteristic of skilled compared to less-skilled performers. However, the cognitive mechanisms of the QE and, specifically, how the QED affects performance are not yet fully understood. We review research that has examined the functional mechanism underlying QE and discuss the neural networks that may be involved. We also highlight the limitations surrounding QE measurement and its definition and propose future research directions to address these shortcomings. Investigations into the behavioural and neural mechanisms of QE will aid the understanding of the perceptual and cognitive processes underlying expert performance and the factors that change as expertise develops.


Do health care reforms in Turkey have a significant effect in equal access to maternal and child health services in Turkey: An evidence from 20 years.
This study aimed to investigate whether there was an improvement in the equitable access to maternal and child health care services by examining the effects of socioeconomic and individual factors in Turkey from 1993 to 2013 and determine the effectiveness of health care reforms implemented mainly under the Health Transformation Program since 2003 on equitable access t;o maternal and child health care services in terms of years. The study used nationally representative 5 Turkey Demographic and Health Surveys (1993, 1998, 2003, 2008, and 2013). Prenatal care utilization rate increased from 67.0% in 1993 to 96.2% in 2013 while the rate of women giving birth at health care facilities increased from 63.8% to 98.1% in 2013. Prenatal care utilization and giving birth at health care facilities were higher among women who were under health insurance coverage, first time mothers, those staying in the western region and urban areas, and those with the highest level of wealth. The findings suggest that the issue of equity in the utilization of maternal and child health care services exists in Turkey, and the latest health care reforms under HTP are not effective in diminishing the effect of wealth.


Women's views of different models of antenatal care in Victoria, Australia.
This study assessed women's views of care in pregnancy, contrasting the experiences and satisfaction of women using different models of care in Victoria, Australia. A statewide postal survey of women who gave birth during a 2-week period in 1993 was carried out 6 to 7 months after birth. Of 1336 women, 62.5 percent responded, and of these, 62.4 percent rated their antenatal care as very good, 27.7 percent as good, 8.2 percent as mixed, and 1.8 percent as poor or very poor. Although social factors, obstetric factors, and model of care had significant associations with satisfaction in univariate analyses, only model of care, mother's country of birth, and medical risk remained significant in a multivariate analysis using logistic regression. Women were most likely to be satisfied when antenatal care was provided by an obstetrician in private practice or a birth center. When comparisons were restricted to options available to women without private health insurance, using public hospital clinics as the baseline in a multivariate analysis, women were significantly more likely to be satisfied with birth center care, and significantly less likely to be satisfied with shared care. Contributing factors were waiting times, staff seeming rushed, and lack of continuity of caregiver. The expansion of shared antenatal care has not succeeded in improving satisfaction with antenatal care for women in the public health care sector.


Effects of minority stress processes on the mental health of Latino men who have sex with men and women: a qualitative study.
Emerging literature on minority stress among sexual minority populations has described the negative consequences that multiple minority statuses may exert on mental health and well-being. This literature has tended to focus on individuals whose self-identifications reflect sexual minority sexual categories, such as gay or bisexual, and has explored the intersection of these definitions with ethnic, racial, and class statuses. Few such studies have explored mental health among men who actively deny a sexual minority sexual identity label while engaging in same-sex sexual behaviors. The present study used ethnographic interview data from 20 non-gay-identified bisexually behaving Dominican and Puerto Rican men in New York City. Participants described discovery of same sex sexual behavior as a threat to their intimate relationships, community affiliation, and counter to expectations of Latino masculinity. Recounting a wide range of information management strategies used to avoid open disclosure about their sexual lives, participants experienced the potential consequences of disclosure as extreme and even life threatening. Men anticipated social isolation, depression, self-injury, and suicidality as possible outcomes from disclosing sexual behavior with other men to their female romantic partners. This analysis provides direction for future research on minority stress processes and mental health service delivery among Latino men who have sex with men and women.


Smoke-induced signal molecules in bone marrow cells from altered low-density lipoprotein receptor-related protein 5 mice.
Mechanism underlying smoke-induced loss of bone mass is unknown. In this study, we hypothesized that protein signals induced by smoking in bone marrow may be associated with the loss of bone mass. Using a proteomics approach, we identified 38 proteins differentially expressed in bone marrow cells from low-density lipoprotein receptor-related protein 5 (Lrp5) mice exposed to cigarette smoking. Smoking effects on protein expression in bone marrow among three genotypes (Lrp5(+/+), Lrp5(G171V), and Lrp5(-/-)) varied. On the basis of the ratio of protein expression induced by smoking versus nonsmoking, smoke induced protein expression significantly in wild-type mice compared to the other two genotypes (Lrp5(G171V) and Lrp5(-/-)). These proteins include inhibitors of β-catenin and proteins associated with differentiation of osteoclasts. We observed that S100A8 and S100A9 were overexpressed in human smokers compared to nonsmokers, which confirmed the effect of smoking on the expression of two proteins in Lrp5 mice, suggesting the role of these proteins in bone remodeling. Smoke induced expression of S100A8 and S100A9 in a time-dependent fashion, which was opposite of the changes in the ratio of OPG/RANKL in bone marrow cells, suggesting that the high levels of S100A8 and S100A9 may be associated with smoke-induced bone loss by increasing bone resorption.


Lack of noggin expression by cancer cells is a determinant of the osteoblast response in bone metastases.
Prostate and mammary cancer bone metastases can be osteoblastic or osteolytic, but the mechanisms determining these features are unclear. Bone morphogenetic and Wnt proteins are osteoinductive molecules. Their activity is modulated by antagonists such as noggin and dickkopf-1. Differential expression analysis of bone morphogenetic and Wnt protein antagonists in human prostate and mammary cancer cell lines showed that osteolytic cell lines constitutively express in vitro noggin and dickkopf-1 and at least one of the osteolytic cytokines parathyroid hormone-related protein, colony-stimulating factor-1, and interleukin-8. In contrast, osteoinductive cell lines express neither noggin nor dickkopf-1 nor osteolytic cytokines in vitro. The noggin differential expression profile observed in vitro was confirmed in vivo in prostate cancer cell lines xenografted into bone and in clinical samples of bone metastasis. Forced noggin expression in an osteoinductive prostate cancer cell line abolished the osteoblast response induced in vivo by its intraosseous xenografts. Basal bone resorption and tumor growth kinetics were marginally affected. Lack of noggin and possibly dickkopf-1 expression by cancer cells may be a relevant mechanism contributing to the osteoblast response in bone metastases. Concomitant lack of osteolytic cytokines may be permissive of this effect. Noggin is a candidate drug for the adjuvant therapy of bone metastasis.


Enhanced discriminative aversive learning and amygdala responsivity in 5-HT transporter mutant mice.
Genetic variation in the human serotonin transporter (5-HTT) has been linked to altered fear learning but the data are inconsistent and the mechanism is unclear. The present study investigated conditioned aversive learning in 5-HTT knockout (KO) mice while simultaneously recording neural network activity (theta oscillations) and hemodynamic responses (tissue oxygen delivery) from the amygdala, a brain region necessary for forming fearful memories. Conditioned aversive learning was measured using a discrimination learning task in which one auditory cue was paired with foot-shock, whereas a second auditory cue was not. Compared with wild-type mice, 5-HTTKO mice exhibited faster discrimination learning. This effect was associated with stronger theta frequency oscillations and greater hemodynamic changes in the amygdala in response to both the emotionally relevant cues and the unconditioned foot-shock stimulus. Furthermore, hemodynamic responses to the unconditioned stimulus predicted behavioral discrimination performance the following day. Acute pharmacological 5-HTT blockade in wild-type mice produced a similar effect, to the extent that administration of citalopram during the fear conditioning sessions enhanced fear memory recall. Collectively, our data argue that loss of 5-HTT function enhances amygdala responsivity to aversive events and facilitates learning for emotionally relevant cues.


Hypothesis testing and earthquake prediction.
Requirements for testing include advance specification of the conditional rate density (probability per unit time, area, and magnitude) or, alternatively, probabilities for specified intervals of time, space, and magnitude. Here I consider testing fully specified hypotheses, with no parameter adjustments or arbitrary decisions allowed during the test period. Because it may take decades to validate prediction methods, it is worthwhile to formulate testable hypotheses carefully in advance. Earthquake prediction generally implies that the probability will be temporarily higher than normal. Such a statement requires knowledge of "normal behavior"--that is, it requires a null hypothesis. Hypotheses can be tested in three ways: (i) by comparing the number of actual earth-quakes to the number predicted, (ii) by comparing the likelihood score of actual earthquakes to the predicted distribution, and (iii) by comparing the likelihood ratio to that of a null hypothesis. The first two tests are purely self-consistency tests, while the third is a direct comparison of two hypotheses. Predictions made without a statement of probability are very difficult to test, and any test must be based on the ratio of earthquakes in and out of the forecast regions.


Epithelial-derived IL-18 regulates Th17 cell differentiation and Foxp3⁺ Treg cell function in the intestine.
Elevated levels of interleukin-18 (IL-18) are found in many chronic inflammatory disorders, including inflammatory bowel disease (IBD), and polymorphisms in the IL18R1-IL18RAP locus are associated with IBD susceptibility. IL-18 is an IL-1 family cytokine that has been proposed to promote barrier function in the intestine, but the effects of IL-18 on intestinal CD4(+) T cells are poorly understood. Here we demonstrate that IL-18R1 expression is enhanced on both effector and regulatory CD4(+) T cells in the intestinal lamina propria, with T helper type 17 (Th17) cells exhibiting particularly high levels. We further show that, during steady state, intestinal epithelial cells constitutively secrete IL-18 that acts directly on IL-18R1-expressing CD4(+) T cells to limit colonic Th17 cell differentiation, in part by antagonizing IL-1R1 signaling. In addition, although IL-18R1 is not required for colonic Foxp3(+) regulatory T (Treg) cell differentiation, we found that IL-18R1 signaling was critical for Foxp3(+) Treg cell-mediated control of intestinal inflammation, where it promoted the expression of key Treg effector molecules. Thus IL-18 is a key epithelial-derived cytokine that differentially regulates distinct subsets of intestinal CD4(+) T cells during both homeostatic and inflammatory conditions, a finding with potential implications for treatment of chronic inflammatory disorders.


Effects of auxiliary fiber posts on endodontically treated teeth with flared canals.
This study investigated the fracture resistance and retention of endodontically treated roots with over-flared canals restored with different post systems, including one cast metal post and four fiber posts with/without auxiliary fiber posts. One hundred endodontically treated incisor roots were experimentally flared using a tapered diamond bur. The roots were restored using one of the five post systems: Ni-Cr cast metal post (CM), D.T. Light glass fiber post (DT), Macro-Lock glass fiber post (ML), ML+2 Fibercone auxiliary fiber posts (2FC), and ML+5 Fibercone auxiliary fiber posts (5FC). After fabrication of the crowns, half of the specimens (n=50) were subjected to a fracture failure test--loading with an incremental static force at an angle of 45 degrees to the long axis of the root. The other 50 samples underwent a pull-out test. Fracture failure strength and pull-out strength were measured and analyzed using one-way analysis of variance (ANOVA) followed by Tukey's post hoc test (α=0.05). After the tests were completed, all specimens displayed oblique root fractures or cracks, initiating from the palatal cervical margin and propagating in a labial-apical direction. The order of the fracture failure strength was as follows: 5FC=CM=2FC>ML>DT. Cast metal posts demonstrated the highest pull-out strength (p<0.05). No significant differences in pull-out strength were found in the ML, 2FC, and 5FC groups. Within the limitations of this study, it was concluded that the application of an auxiliary fiber post could significantly increase the fracture resistance of over-flared roots; however, no beneficial effects in enhancing retention were observed.


Association of indoor smoke-free air laws with hospital admissions for acute myocardial infarction and stroke in three states.
To examine whether comprehensive smoke-free air laws enacted in Florida, New York, and Oregon are associated with reductions in hospital admissions for acute myocardial infarction (AMI) and stroke. Analyzed trends in county-level, age-adjusted, hospital admission rates for AMI and stroke from 1990 to 2006 (quarterly) for Florida, 1995 to 2006 (monthly) for New York, and 1998 to 2006 (monthly) for Oregon to identify any association between admission rates and passage of comprehensive smoke-free air laws. Interrupted time series analysis was used to adjust for the effects of preexisting moderate local-level laws, seasonal variation in hospital admissions, differences across counties, and a secular time trend. More than 3 years after passage of statewide comprehensive smoke-free air laws, rates of hospitalization for AMI were reduced by 18.4% (95% CI: 8.8-28.0%) in Florida and 15.5% (95% CI: 11.0-20.1%) in New York. Rates of hospitalization for stroke were reduced by 18.1% (95% CI: 9.3-30.0%) in Florida. The few local comprehensive laws in Oregon were not associated with reductions in AMI or stroke statewide. Comprehensive smoke-free air laws are an effective policy tool for reducing the burden of AMI and stroke.


A population pharmacokinetic model of piperaquine in pregnant and non-pregnant women with uncomplicated Plasmodium falciparum malaria in Sudan.
Pregnancy is associated with an increased risk of developing a malaria infection and a higher risk of developing severe malaria. The pharmacokinetic properties of many anti-malarials are also altered during pregnancy, often resulting in a decreased drug exposure. Piperaquine is a promising anti-malarial partner drug used in a fixed-dose combination with dihydroartemisinin. The aim of this study was to investigate the population pharmacokinetics of piperaquine in pregnant and non-pregnant Sudanese women with uncomplicated Plasmodium falciparum malaria. Symptomatic patients received a standard dose regimen of the fixed dose oral piperaquine-dihydroartemisinin combination treatment. Densely sampled plasma aliquots were collected and analysed using a previously described LC-MS/MS method. Data from 12 pregnant and 12 non-pregnant women were analysed using nonlinear mixed-effects modelling. A Monte Carlo Mapped Power (MCMP) analysis was conducted based on a previously published study to evaluate the power of detecting covariates in this relatively small study. A three-compartment disposition model with a transit-absorption model described the observed data well. Body weight was added as an allometric function on all clearance and volume parameters. A statistically significant decrease in estimated terminal piperaquine half-life in pregnant compared with non-pregnant women was found, but there were no differences in post-hoc estimates of total piperaquine exposure. The MCMP analysis indicated a minimum of 13 pregnant and 13 non-pregnant women were required to identify pregnancy as a covariate on relevant pharmacokinetic parameters (80% power and p=0.05). Pregnancy was, therefore, evaluated as a categorical and continuous covariate (i.e. estimate gestational age) in a full covariate approach. Using this approach pregnancy was not associated with any major change in piperaquine elimination clearance. However, a trend of increasing elimination clearance with increasing gestational age could be seen. The population pharmacokinetic properties of piperaquine were well described by a three-compartment disposition model in pregnant and non-pregnant women with uncomplicated malaria. The modelling approach showed no major difference in piperaquine exposure between the two groups and data presented here do not warrant a dose adjustment in pregnancy in this vulnerable population.


Shortsighted acts in the decapentaplegic pathway in Drosophila eye development and has homology to a mouse TGF-beta-responsive gene.
Differentiation in the Drosophila eye imaginal disc traverses the disc as a wave moving from posterior to anterior. The propagation of this wave is driven by hedgehog protein secreted by the differentiated cells in the posterior region of the disc. Hedgehog induces decapentaplegic expression at the front of differentiation, in the morphogenetic furrow. We have identified a gene, shortsighted, which is expressed in a hedgehog-dependent stripe in the undifferentiated cells just anterior to the furrow and which appears to be involved in the transmission of the differentiation-inducing signal; a reduction in shortsighted function leads to a delay in differentiation and to a loss of photoreceptors in the adult. shortsighted is also required for a morphogenetic movement in the brain that reorients the second optic lobe relative to the first. shortsighted encodes a cytoplasmic leucine zipper protein with homology to a mouse gene, TSC-22, which is transcriptionally induced in response to TGF-beta.


Completeness of hepatitis, brucellosis, syphilis, measles and HIV/AIDS surveillance in Izmir, Turkey.
According to the surveillance system in Turkey, most diseases are notified only by clinicians, without involving laboratory notification. It is assumed that a considerable inadequacy in notifications exists; however, this has not been quantified by any researcher. Our aim was to evaluate the completeness of communicable disease surveillance in the province of Izmir, Turkey for the year of 2003 by means of estimating the incidences of diseases. Data on positive laboratory results for the notifiable and serologically detectable diseases hepatitis A, B, C, brucellosis, syphilis, measles and HIV detected in 2003 in Izmir (population 3.5 million) were collected from serology laboratories according to WHO surveillance standards and compared to the notifications received by the Provincial Health Directorate. Data were checked for duplicates and matched. Incidences were estimated with the capture-recapture method. Sensitivities of both notifications and laboratory data were calculated according to these estimates. Among laboratories performing serologic tests (n = 158) in Izmir, 84.2% accepted to participate, from which 23,515 positive results were collected. Following the elimination of duplicate results as well as of cases residing outside of Izmir, the total number was 11,402. The total number of notifications was 1802. Notification rates of cases found in laboratories were 31.6% for hepatitis A, 12.1% for acute hepatitis B, 31.8% for brucellosis, 25.9% for syphilis and 100% for HIV confirmation. It was discovered that for hepatitis A, B, C, brucellosis and syphilis, there is a considerable under-notification by clinicians and that laboratory data has the potential of contributing greatly to their surveillance. The inclusion of laboratories in the surveillance system of these diseases could help to achieve completeness of reporting.


The Myotonometer: Not a Valid Measurement Tool for Active Hamstring Musculotendinous Stiffness.
Hamstring musculotendinous stiffness (MTS) is associated with lower-extremity injury risk (ie, hamstring strain, anterior cruciate ligament injury) and is commonly assessed using the damped oscillatory technique. However, despite a preponderance of studies that measure MTS reliably in laboratory settings, there are no valid clinical measurement tools. A valid clinical measurement technique is needed to assess MTS and permit identification of individuals at heightened risk of injury and track rehabilitation progress. To determine the validity and reliability of the Myotonometer for measuring active hamstring MTS. Descriptive laboratory study. Laboratory. 33 healthy participants (15 men, age 21.33 ± 2.94 y, height 172.03 ± 16.36 cm, mass 74.21 ± 16.36 kg). Hamstring MTS was assessed using the damped oscillatory technique and the Myotonometer. Intraclass correlations were used to determine the intrasession, intersession, and interrater reliability of the Myotonometer. Criterion validity was assessed via Pearson product-moment correlation between MTS measures obtained from the Myotonometer and from the damped oscillatory technique. The Myotonometer demonstrated good intrasession (ICC3,1 = .807) and interrater reliability (ICC2,k = .830) and moderate intersession reliability (ICC2,k = .693). However, it did not provide a valid measurement of MTS compared with the damped oscillatory technique (r = .346, P = .061). The Myotonometer does not provide a valid measure of active hamstring MTS. Although the Myotonometer does not measure active MTS, it possesses good reliability and portability and could be used clinically to measure tissue compliance, muscle tone, or spasticity associated with multiple musculoskeletal disorders. Future research should focus on portable and clinically applicable tools to measure active hamstring MTS in efforts to prevent and monitor injuries.


Origins and Evolutionary Patterns of the 1.688 Satellite DNA Family in Drosophila Phylogeny.
Satellite DNAs (satDNAs) are a ubiquitous feature of eukaryotic genomes and are usually the major components of constitutive heterochromatin. The 1.688 satDNA, also known as the 359 bp satellite, is one of the most abundant repetitive sequences in Drosophila melanogaster and has been linked to several different biological functions. We investigated the presence and evolution of the 1.688 satDNA in 16 Drosophila genomes. We find that the 1.688 satDNA family is much more ancient than previously appreciated, being shared among part of the melanogaster group that diverged from a common ancestor ∼27 Mya. We found that the 1.688 satDNA family has two major subfamilies spread throughout Drosophila phylogeny (∼360 bp and ∼190 bp). Phylogenetic analysis of ∼10,000 repeats extracted from 14 of the species revealed that the 1.688 satDNA family is present within heterochromatin and euchromatin. A high number of euchromatic repeats are gene proximal, suggesting the potential for local gene regulation. Notably, heterochromatic copies display concerted evolution and a species-specific pattern, whereas euchromatic repeats display a more typical evolutionary pattern, suggesting that chromatin domains may influence the evolution of these sequences. Overall, our data indicate the 1.688 satDNA as the most perduring satDNA family described in Drosophila phylogeny to date. Our study provides a strong foundation for future work on the functional roles of 1.688 satDNA across many Drosophila species.


How to build personalized multi-omics comorbidity profiles.
Multiple diseases (acute or chronic events) occur together in a patient, which refers to the disease comorbidities, because of the multi ways associations among diseases. Due to shared genetic, molecular, environmental, and lifestyle-based risk factors, many diseases are comorbid in the same patient. Methods for integrating multiple types of omics data play an important role to identify integrative biomarkers for stratification of patients into groups with different clinical outcomes. Moreover, integrated omics and clinical information may potentially improve prediction accuracy of disease comorbidities. However, there is a lack of effective and efficient bioinformatics and statistical software for true integrative data analysis. With the availability of the wide spread huge omics, phenotype and ontology information, it is becoming more and more practical to help doctors in clinical diagnostics and comorbidity prediction by providing appropriate software tool. We developed an R software POGO to compute novel estimators of the disease comorbidity risks and patient stratification. Starting from an initial diagnosis, omics and clinical data of a patient the software identifies the association risk of disease comorbidities. The input of this software is the initial diagnosis of a patient and the output provides evidence of disease comorbidities. The functions of POGO offer flexibility for diagnostic applications to predict disease comorbidities, and can be easily integrated to high-throughput and clinical data analysis pipelines. POGO is compliant with the Bioconductor standard and it is freely available at www.cl.cam.ac.uk/~mam211/POGO/.


Normalization of hemodynamics is delayed in patients with a single ventricle after pediatric heart transplantation.
The time course for hemodynamic normalization after pediatric heart transplantation has not been well characterized. We hypothesized that patients with a single ventricle would normalize later than those with dilated cardiomyopathy. Establishing the expected course based on the underlying pathophysiology will allow identification of patients who are outliers, requiring further investigation. We performed a retrospective review of patients with dilated cardiomyopathy, Glenn, and Fontan who underwent heart transplantation from January 2007 to December 31, 2017, and had 6-month and 1-year catheterization data. Hemodynamic data were examined for sustained normalization of pressures. Myocardial biopsies were reviewed for clinically significant rejection within the first year. Ninety-four patients comprised the cohort (47 dilated cardiomyopathy, 18 Glenn, 29 Fontan) with a median age of 6.8 (12) years. Patients with dilated cardiomyopathy were more likely to normalize hemodynamics by 6 months (85% vs 28% Fontan, 44% Glenn, P < .05), and 96% of patients with dilated cardiomyopathy had normalized hemodynamics by 1 year (vs 62% Fontan, 78% Glenn, P < .001). The pulmonary capillary wedge pressure at 6 months was higher in patients who underwent the Fontan and Glenn (median 12.8 [8.8] mm Hg and 11.2 [5.9] mm Hg, respectively) compared with patients with dilated cardiomyopathy (7.0 [3.3] mm Hg, P < .001). Patients with dilated cardiomyopathy demonstrated normalized hemodynamics earlier (121 ± 72 days) than patients who underwent the Fontan (329 ± 62 days) and Glenn (233 ± 11 days, P < .001). Eighteen patients (19%) experienced significant rejection, which was not increased in patients with delayed hemodynamic normalization. The 6-month pulmonary capillary wedge pressure was associated with delayed normalization (hazard ratio, 1.36; 95% confidence interval, 1.16-1.60; P < .001). Patients with a single ventricle demonstrated delayed hemodynamic normalization compared with dilated cardiomyopathy heart transplant recipients, without affecting survival or need for retransplantation.


Experimental chronic noise is related to elevated fecal corticosteroid metabolites in lekking male greater Sage-Grouse (Centrocercus urophasianus).
There is increasing evidence that individuals in many species avoid areas exposed to chronic anthropogenic noise, but the impact of noise on those who remain in these habitats is unclear. One potential impact is chronic physiological stress, which can affect disease resistance, survival and reproductive success. Previous studies have found evidence of elevated stress-related hormones (glucocorticoids) in wildlife exposed to human activities, but the impacts of noise alone are difficult to separate from confounding factors. Here we used an experimental playback study to isolate the impacts of noise from industrial activity (natural gas drilling and road noise) on glucocorticoid levels in greater sage-grouse (Centrocercus urophasianus), a species of conservation concern. We non-invasively measured immunoreactive corticosterone metabolites from fecal samples (FCMs) of males on both noise-treated and control leks (display grounds) in two breeding seasons. We found strong support for an impact of noise playback on stress levels, with 16.7% higher mean FCM levels in samples from noise leks compared with samples from paired control leks. Taken together with results from a previous study finding declines in male lek attendance in response to noise playbacks, these results suggest that chronic noise pollution can cause greater sage-grouse to avoid otherwise suitable habitat, and can cause elevated stress levels in the birds who remain in noisy areas.


Inverted hyperplastic polyposis of the colon.
To describe and evaluate two apparently unique cases of inverted hyperplastic (metaplastic) polyposis of the colon. The cases were analysed by standard histopathological, histochemical, and immunohistochemical techniques and the findings compared with those of regular hyperplastic polyps of the colorectum. Both patients were middle-aged men with concurrent adenocarcinoma of the proximal large intestine. The inverted polyps numbered 18 and 12, measured between 0.4 and 2.5 cm in diameter, and all were present in the proximal ascending colon. The polyps had characteristic macroscopic features: they were positioned on the apex of mucosal folds and demonstrated surface pitting and mucus hypersecretion. Histologically, inversion and misplacement of hyperplastic epithelium was related to lymphoglandular complexes. The polyps showed all the histochemical and immunohistochemical features of regular hyperplastic polyps. Inverted hyperplastic polyps are an unusual but distinctive polyp of the proximal colon, may be multiple, and share the phenotypic changes of regular hyperplastic polyps. The pathogenesis of epithelial inversion probably relates to misplacement of epithelium through anatomical defects in the muscularis mucosae due to mechanical forces. The polyps may mimic both adenomas and carcinomas. The neoplastic potential of inverted hyperplastic polyposis is likely to be very low: one polyp only showed adenomatous change.


Large-scale death of retinal astrocytes during normal development is non-apoptotic and implemented by microglia.
Naturally occurring cell death is a fundamental developmental mechanism for regulating cell numbers and sculpting developing organs. This is particularly true in the nervous system, where large numbers of neurons and oligodendrocytes are eliminated via apoptosis during normal development. Given the profound impact of death upon these two major cell populations, it is surprising that developmental death of another major cell type-the astrocyte-has rarely been studied. It is presently unclear whether astrocytes are subject to significant developmental death, and if so, how it occurs. Here, we address these questions using mouse retinal astrocytes as our model system. We show that the total number of retinal astrocytes declines by over 3-fold during a death period spanning postnatal days 5-14. Surprisingly, these astrocytes do not die by apoptosis, the canonical mechanism underlying the vast majority of developmental cell death. Instead, we find that microglia engulf astrocytes during the death period to promote their developmental removal. Genetic ablation of microglia inhibits astrocyte death, leading to a larger astrocyte population size at the end of the death period. However, astrocyte death is not completely blocked in the absence of microglia, apparently due to the ability of astrocytes to engulf each other. Nevertheless, mice lacking microglia showed significant anatomical changes to the retinal astrocyte network, with functional consequences for the astrocyte-associated vasculature leading to retinal hemorrhage. These results establish a novel modality for naturally occurring cell death and demonstrate its importance for the formation and integrity of the retinal gliovascular network.


Prospective randomized two-Arm controlled study to determine the efficacy of a specific intervention to improve long-term adherence to highly active antiretroviral therapy.
Nearly perfect compliance seems to be indispensable to obtain the maximum benefit from highly active antiretroviral therapy (HAART). Interventions to ensure a high level of adherence during a relatively long-term period of therapy are necessary. This is a prospective, randomized, two-arm controlled study including patients starting their first-or second-line HAART who were randomized to receive psychoeducative intervention to implement adherence (experimental group [EG]) or a usual medical follow-up (control group [CG]). We aimed to study the efficacy of a psychoeducative intervention to ensure long-term adherence to HAART, its relation with the virologic efficacy of treatment, and to determine the variables related to long-term adherence. Visits were made at weeks 0, 4, 24, and 48 for data collection. Self-reported adherence was registered at each visit and its veracity was tested by randomized blood analyses performed without previous warning to 40% of patients. Appropriate adherence was defined as the consumption of >/=95% of medication prescribed. Statistical analyses were performed both by the as treated (AT) and the intention to treat missing = failure (ITT) methods. In all, 116 patients were included. At week 48, 94% of patients in the EG versus 69% controls achieved adherence >/=95% (p =.008); 89% of patients in the EG versus 66% controls had HIV-1 RNA levels <400 copies/ml (p =.026). Overall, 85% of patients with adherence >/=95% but only 45% of those with adherence <95% had viral load (VL) <400 copies/ml (p =. 008). In multivariate analysis, variables significantly related to adherence were having received a psychoeducative intervention (odds ratio [OR], 6.58; p =.04), poor effort to take medication (OR, 5.38; p =.03), and high self-perceived capacity to follow the regimen (OR, 13.76; p =.04). Self-reported adherence and drug plasma levels coincided in 93% of cases. However, differences in adherence did not reach statistical significance in the ITT analysis although a clear tendency toward benefit was observed in EG. Specific and maintained psychoeducative interventions based on excellence on clinical practice are useful to keep high levels of adherence as well as high levels of viral suppression. There is a clear relation between high adherence levels and virologic success. Assessment of certain specific variables related to adherence may be helpful to monitor patient's compliance in the clinical setting.


Validation of a blood plasma separation system by biomarker detection.
A microfluidic system was developed for blood plasma separation at high flow rate. This system uses only hydrodynamic forces to separate plasma from whole blood. The microfluidic network features a series of constrictions and bifurcations to enhance the product yield and purity. A maximum purity efficiency of 100% is obtained on blood with entrance hematocrit level up to 30% with a flow rate of 2 mL h(-1). Flow cytometry was performed on the extracted plasma to evaluate the separation efficiency and to assess cell damage. A core target of this study was the detection of cell-free DNA from the on-chip extracted plasma. To this effect, PCR was successfully carried out off-chip on the cell-free DNA present in the plasma extracted on-chip. A house-keeping gene sequence (GAPDH) was amplified without the need for a purification after the separation, thereby showing the high quality of the plasma sample. The resulting data suggests that the system can be used as a preliminary module of a total analysis system for cell-free DNA detection in human plasma.


Laboratory reporting of hemostasis assays: the final post-analytical opportunity to reduce errors of clinical diagnosis in hemostasis?
The advent of modern instrumentation, with associated improvements in test performance and reliability, together with appropriate internal quality control (IQC) and external quality assurance (EQA) measures, has led to substantial reductions in analytical errors within hemostasis laboratories. Unfortunately, the reporting of incorrect or inappropriate test results still occurs, perhaps even as frequently as in the past. Many of these cases arise due to a variety of events largely outside the control of the laboratories performing the tests. These events are primarily preanalytical, related to sample collection and processing, but can also include post-analytical events related to the reporting and interpretation of test results. The current report provides an overview of these events, as well as guidance for prevention or minimization. In particular, we propose several strategies for the post-analytical reporting of hemostasis assays, and how this may provide the final opportunity to prevent serious clinical errors in diagnosis. This report should be of interest to both the laboratory scientists working in hemostasis and clinicians that request and attempt to interpret the test results. Laboratory scientists are ultimately responsible for these test results, and there is a duty to provide both accurate and precise results to enable clinicians to manage patients appropriately and to avoid the need to recollect and retest. Also, clinicians will not be in a position to best diagnose and manage their patient unless they gain an appreciation of these issues.


Protective role of endothelial nitric oxide synthase following pressure-induced insult to the optic nerve.
Although intracranial pressure (ICP) elevation can induce significant structural and functional changes within the central nervous system (CNS), almost complete neuronal recovery is possible if ICP and associated pathogenic factors are restored in the acute phase of the disease process. Nitric oxide synthase (NOS) isoforms have been implicated in the pathogenesis of many CNS diseases and may play an important role in the development of neuronal tolerance in the early stages of pressure elevation. In this paper we use the pig optic nerve, a typical central white matter tract, to study the time-dependent sequence of NOS isoform change following pressure elevation. The timing of NOS isoform change in relationship to structural and functional changes to axons and glial cells is also discussed. This study demonstrates that endothelial cell nitric oxide synthase (ecNOS), an enzyme that plays a protective role in the CNS, is up-regulated in a time-dependent manner after pressure elevation. ecNOS levels increase after axonal and astrocyte injury, suggesting that it might be a compensatory response that is initiated in an effort to preserve CNS function. Inducible NOS (iNOS) and neuronal NOS (nNOS), which are known to have a deleterious effect on the CNS, were not detected in this study. The increase in ecNOS demonstrated in this study is significantly different to the increase in iNOS and nNOS previously demonstrated following traumatic brain injury. Changes in ecNOS levels may therefore be important in the development of neuronal tolerance in the early stages of CNS diseases such as hydrocephalus.


Solvent-dependent properties of electrospun fibrous composites for bone tissue regeneration.
Biodegradable polymer-ceramic composite scaffolds have gained importance in recent years in the field of orthopedic biomaterials and tissue engineering scaffolds for improving the rate of degradation and limited mechanical properties of bioactive ceramics. This study sought to create composites using the electrospinning process to achieve fibrous scaffolds with uniform fiber morphologies and uniform ceramic dispersions. Composites consisting of 20% hydroxyapatite/80% beta-tricalcium phosphate (20/80 HA/TCP) and poly (epsilon-caprolactone) (PCL) were fabricated. The 20/80 HA/TCP composition was chosen as the ceramic component because of previous reports of greater bone tissue formation in comparison with HA or TCP alone. For electrospinning, PCL was dissolved in either methylene chloride (Composite-MC) or a combination of methylene chloride (80%) and dimethylformamide (20%) (Composite-MC + DMF). Composite-MC mats contained a bimodal distribution of fiber diameters with nanofibers between larger, micron-sized fibers with an average pore size of 79.6 + or - 67 microm, whereas Composite-MC + DMF fibers had uniform fiber diameters with an average pore size of 7.0 + or - 4.2 microm. Elemental mapping determined that the ceramic was distributed throughout the mat and inside the fiber for both composites. However, physical characterization using differential scanning calorimetry (DSC) and mechanical testing revealed that the ceramic in the mats produced with MC + DMF were more uniformly dispersed than the ceramic in the mats produced with MC alone. Maximum tensile stress and strain were significantly higher for Composite-MC + DMF mats compared with Composite-MC mats and were comparable with the mechanical properties of mats of PCL alone. For both composites, there was molecular interaction between the PCL and the ceramic, as demonstrated by a maximum increase of approximately 10 degrees C in the glass transition values with the addition of the ceramic, as confirmed by Fourier transform infrared analysis. In addition, the crystallization behavior of the composites suggested that the ceramic was acting as a nucleating agent. Cell viability studies using human mesenchymal stem cells (MSC) showed that both composite scaffolds supported cell growth. However, cell numbers at early time points in culture were significantly higher on mats produced from MC + DMF compared with mats prepared with MC alone. Further examination revealed that cells were able to infiltrate the pores of the Composite-MC mats, but remained on the outer surface of the Composite-MC + DMF and unfilled PCL mats during the culture period. The results of this study demonstrate that the solvent or solvent combination used in preparing the electrospun composite mats plays a critical role in determining its properties, which may, in turn, affect cell behavior.


Pathogens and indicators in United States Class B biosolids: national and historic distributions.
This paper reports on a major study of the incidence of indicator organisms and pathogens found within Class B biosolids within 21 samplings from 18 wastewater treatment plants across the United States. This is the first major study of its kind since the promulgation of the USEPA Part 503 Rule in 1993, and includes samples before and after the Part 503 Rule was promulgated. National distributions collected between 2005 and 2008 show that the incidence of bacterial and viral pathogens in Class B mesophilic, anaerobically digested biosolids were generally low with the exception of adenoviruses, which were more prevalent than enteric viruses. No Ascaris ova were detected in any sample. In contrast, indicator organism numbers were uniformly high, regardless of whether they were bacteria (fecal coliforms) or viruses (phage). Indicators were not correlated with pathogen loads. Historic distributions were collected between 1988 and 2006 at one location in Tucson, AZ. By comparing data collected before and after 1993, the influence of the USEPA Part 503 Rule on indicator and pathogen levels within Class B biosolids can be inferred. In general, the bacterial indicators total and fecal coliforms decreased from the 1980s to present. Enteric virus concentrations after 1993 are much lower than those reported in other studies in the 1980s, although our values from 1988 to 1993 are not significantly different from our values obtained from 1994 to 2006. Presumably this is due to better and more consistent treatment of the wastewater, illustrating that the Part 503 Rule has been effective in reducing public exposure to pathogens relative to 17 yr ago. The percent reduction of both indicators and pathogens during anaerobic mesophilic digestion was between 94 and 99% for all organisms, illustrating that such treatment is effective in reducing pathogen loads.


Towards an individualized management strategy for patients with chronic venous disease: Results of a Delphi consensus.
Objective To obtain consensus on management criteria for symptomatic patients with chronic venous disease (CVD; C2-C6) and superficial venous reflux. Method We used a Delphi method by means of 36 statements sent by email to experts in the field of phlebology across the world over the course of three rounds. The statements addressed criteria for different venous treatments in patients with different characteristics (e.g. extensive comorbidities, morbid obesity and peripheral arterial disease). If at least 70% of the ratings for a specific statement were between 6 and 9 (agreement) or between 1 and 3 (disagreement), experts' consensus was reached. Results Twenty-five experts were invited to participate, of whom 24 accepted and completed all three rounds. Consensus was reached in 25/32 statements (78%). However, several statements addressing UGFS, single phlebectomies, patients with extensive comorbidities and morbid obesity remained equivocal. Conclusion Considerable consensus was reached within a group of experts but also some gaps in available research were highlighted.


Spinal cord evolution in early Homo.
The discovery at Nariokotome of the Homo erectus skeleton KNM-WT 15000, with a narrow spinal canal, seemed to show that this relatively large-brained hominin retained the primitive spinal cord size of African apes and that brain size expansion preceded postcranial neurological evolution. Here we compare the size and shape of the KNM-WT 15000 spinal canal with modern and fossil taxa including H. erectus from Dmanisi, Homo antecessor, the European middle Pleistocene hominins from Sima de los Huesos, and Pan troglodytes. In terms of shape and absolute and relative size of the spinal canal, we find all of the Dmanisi and most of the vertebrae of KNM-WT 15000 are within the human range of variation except for the C7, T2, and T3 of KNM-WT 15000, which are constricted, suggesting spinal stenosis. While additional fossils might definitively indicate whether H. erectus had evolved a human-like enlarged spinal canal, the evidence from the Dmanisi spinal canal and the unaffected levels of KNM-WT 15000 show that unlike Australopithecus, H. erectus had a spinal canal size and shape equivalent to that of modern humans. Subadult status is unlikely to affect our results, as spinal canal growth is complete in both individuals. We contest the notion that vertebrae yield information about respiratory control or language evolution, but suggest that, like H. antecessor and European middle Pleistocene hominins from Sima de los Huesos, early Homo possessed a postcranial neurological endowment roughly commensurate to modern humans, with implications for neurological, structural, and vascular improvements over Pan and Australopithecus.


Myosin filament structure in vertebrate smooth muscle.
The in vivo structure of the myosin filaments in vertebrate smooth muscle is unknown. Evidence from purified smooth muscle myosin and from some studies of intact smooth muscle suggests that they may have a nonhelical, side-polar arrangement of crossbridges. However, the bipolar, helical structure characteristic of myosin filaments in striated muscle has not been disproved for smooth muscle. We have used EM to investigate this question in a functionally diverse group of smooth muscles (from the vascular, gastrointestinal, reproductive, and visual systems) from mammalian, amphibian, and avian species. Intact muscle under physiological conditions, rapidly frozen and then freeze substituted, shows many myosin filaments with a square backbone in transverse profile. Transverse sections of fixed, chemically skinned muscles also show square backbones and, in addition, reveal projections (crossbridges) on only two opposite sides of the square. Filaments gently isolated from skinned smooth muscles and observed by negative staining show crossbridges with a 14.5-nm repeat projecting in opposite directions on opposite sides of the filament. Such filaments subjected to low ionic strength conditions show bare filament ends and an antiparallel arrangement of myosin tails along the length of the filament. All of these observations are consistent with a side-polar structure and argue against a bipolar, helical crossbridge arrangement. We conclude that myosin filaments in all smooth muscles, regardless of function, are likely to be side-polar. Such a structure could be an important factor in the ability of smooth muscles to contract by large amounts.