SU-E-T-589: There was No Dosimetric Benefit in Sparing Bone Marrow in the Radiotherapy of Whole Pelvic Lymph Node Applying 6MV X-Ray RapidArc Plans.
To investigate the dosimetric difference in sparing bone marrow in the radiotherapy of whole pelvic node comparing 6MV and 15MV X-ray RaidArc plans. Twelve patients who had undergone radical surgery for cervical cancer and with demonstrated multiple pelvic lymph node metastases were treated with radiotherapy were selected. All pelvic bone was delineated to define the bone marrow, and the pelvic bones consisted of the hip bone, the sacrum, the vertebral body near planning target volume (PTV), and the upper parts of femur. RapidArc plans applying 6MV and 15MV X-ray with one single whole arc (counter-clockwise from 179° to 181°) were generated for each patient, and named RapidArc-6MV and RapidArc-15MV. The prescription dose was 2.0Gy/fractionx28fractions. The dosimetric differences were compared. There were no significant differences in conformity index(0.90±0.03 Vs 0.89±0.04), homogeneity index(1.08±0.01 Vs 1.08±0.02) and external volume index(0.08±0.04 Vs0. 09±0.05) between RapidArc-6MV and RapidArc-15MV(P>0.05). Neither there were no significant differences in V5 (93.6±6.4Vs92.2±7.3), V10(88.6±9.3Vs88.3±9.2), V20(76.9±12.6Vs76.9±11.2), V30 (57.9± 10.5Vs55.9±11.5), V40(35.2±10.2Vs34.9±10.9) between RapidArc-6MV and RapidArc-15MV (P>0.05). The monitor untie of RapidArc-6MV (552±40Mu) was more than RapidArc-15MV (455±44 Mu) with significant difference (P<0.05). Compared to 15MV X-ray RapidArc plans, there was no dosimetric benefit in sparing bone marrow in the radiotherapy of whole pelvic lymph node applying 6MV X-ray.


Family Presence During Resuscitation: Impact of Online Learning on Nurses' Perception and Self-confidence.
Family presence during resuscitation (FPDR) is supported by patients and their family members. Nurses, however, including critical care nurses who frequently implement resuscitative care, have mixed views. To determine the impact of online learning on critical care nurses' perception of and self-confidence with FPDR. A 2-group, random assignment, pretest and posttest quasi-experimental study was conducted with critical care nurses recruited nationally. An online learning module on FPDR was developed and administered to the intervention group. Perceptions and self-confidence for FPDR were measured by using the Family Presence Risk- Benefit Scale (FPR-BS) and the Family Presence Self-confidence Scale (FPS-CS). Two-factor, mixed-model factorial analysis of variance was used to compare mean scores. A total of 74 critical care nurses participated in the study. Mean FPR-BS and FPS-CS scores were significantly greater in the intervention group than in the control group. For the intervention group, mean scores on the FPR-BS increased from 3.63 to 4.07 (P < .001) and on the FPS-CS increased from 4.24 to 4.57 (P < .001), signifying improved perception and self-confidence. Scores did not change significantly in the control group: mean FPR-BS score increased from 3.82 to 3.88 (P = .23) and the mean FPS-CS score of 4.40 did not change (P > .99). Online learning is a feasible and effective method for educating large numbers of critical care nurses about FPDR. Online learning can improve perceptions and self-confidence related to FPDR, which may promote more widespread adoption of FPDR into practice.


A dual-tracer study of extrastriatal 6-[18F]fluoro-m-tyrosine and 6-[18F]-fluoro-L-dopa uptake in Parkinson's disease.
6-[(18)F]-Fluoro-L-dopa (FDOPA) has been widely used as a biomarker for catecholamine synthesis, storage, and metabolism--its intense uptake in the striatum, and fainter uptake in other brain regions, is correlated with the symptoms and pathophysiology of Parkinson's disease (PD). 6-[(18)F]fluoro-m-tyrosine (FMT), which also targets L-amino acid decarboxylase, has potential advantages over FDOPA as a radiotracer because it does not form catechol-O-methyltransferase (COMT) metabolites. The purpose of the present study was to compare the regional distribution of these radiotracers in the brains of PD patients. Fifteen Parkinson's patients were studied with FMT and FDOPA positron emission tomography (PET) as well as high-resolution structural magnetic resonance imaging (MRI). MRI's were automatically parcellated into neuroanatomical regions of interest (ROIs) in Freesurfer (http://surfer.nmr.mgh.harvard.edu); region-specific uptake rate constants (Kocc) were generated from coregistered PET using a Patlak graphical approach. The essential findings were as follows: (1) regional Kocc were highly correlated between the radiotracers and in agreement with a previous FDOPA studies that used different ROI selection techniques; (2) FMT Kocc were higher in extrastriatal regions of relatively large uptake such as amygdala, pallidum, brainstem, hippocampus, entorhinal cortex, and thalamus, whereas cortical Kocc were similar between radiotracers; (3) while subcortical uptake of both radiotracers was related to disease duration and severity, cortical uptake was not. These results suggest that FMT may have advantages for examining pathologic changes within allocortical loop structures, which may contribute to cognitive and emotional symptoms of PD.


Promoting the Self-Regulation of Stress in Health Care Providers: An Internet-Based Intervention.
The aim of our internet-based intervention study was to find out whether healthcare professionals can autonomously down-regulate the stress they experience at their workplace, using an established self-regulation tool called Mental Contrasting with Implementation Intentions (MCII). Applying MCII to reduce stress implied for our participants to repeatedly engage in a mental exercise that (1) required specifying a wish related to reducing stress, (2) identifying and imagining its most desired positive outcome, (3) detecting and imagining the obstacle that holds them back, and (4) coming up with an if-then plan on how to overcome it. We recruited on-line nurses employed at various health institutions all over Germany, and randomly assigned participants to one of three groups. In the MCII group (n = 33), participants were taught how to use this exercise via email and the participants were asked to engage in the exercise on a daily basis for a period of 3 weeks. As compared to two control groups, one being a no-treatment control group (n = 35) and the other a modified MCII group (n = 32), our experimental MCII group showed a reduced stress level and an enhanced work engagement. We discuss the strengths and weaknesses of the present study as well as ways to intensify MCII effects on stress reduction.


[Efficacy of an occupational group therapy in degenerative dementias: a controlled study in the nursing home setting].
We investigated the effectiveness of an occupational group therapy, tailored to dementia patients, performed regularly 6 days a week, on everyday-practical capabilities and dementia-related behavior. Fifty-six dementia patients in one nursing home in Northern Bavaria (Germany) were observed for 6 months: 28 patients in a therapy group and 28 patients in a matched controlled group. Performance tests, ADAS-kog and E-ADL-Test, were carried out blinded. Data were analyzed using adjusted mean differences for baseline and 6-months follow-up data and multiple regression analysis. The therapy leads to stabilization of everyday-practical capabilities (adjusted mean difference 4.0; 95 % CI 1.6-6.3; p = 0.002) and of dementia-related behavior (adjusted mean difference -6.8; 95 % CI -11.8--1.8; p = 0.009) compared to deterioration in the control group who received treatment as usual. The effect power (Cohen d) on everyday-practical capabilities is |0.83|. The therapy had no significant effect on cognitive capacity. An occupational therapy program directed particularly to everyday-practical activities cannot slow the progression of all dementia-related symptoms, but has a main target effect on everyday-practical capabilities.


Unexpected refacetting of palladium nanoparticles under atmospheric N2 conditions.
We demonstrate an unexpected refacetting process of Pd nanoparticles, induced by N2 under atmospheric pressure at elevated temperatures, by in situ TEM observations. The morphology changes, with a notable increase in the fraction of Pd{110} facets, were visualized by atomic-scale TEM images and further explained by theoretical calculations. Firm evidence and rational understanding revealed that the "inert" gas N2 has the ability to modify the structure of metal nanoparticles. This surprising effect should be considered seriously in vast chemical applications that use N2 as a carrier gas or protective atmosphere.


Semaphorin 3A is expressed in human osteoarthritic cartilage and antagonizes vascular endothelial growth factor 165-promoted chondrocyte migration: an implication for chondrocyte cloning.
Vascular endothelial growth factor 165 (VEGF165) and its receptors, including neuropilin 1 (NRP-1), are overexpressed in human osteoarthritic (OA) articular cartilage, although their functional roles in the cartilage are not fully understood. An axon-guidance molecule, semaphorin 3A (Sema3A), which binds to NRP-1, acts as an antagonist of VEGF signaling in endothelial cells. The aim of this study was to examine the expression of Sema3A and the functions of the VEGF165/Sema3A/NRP-1 axis in OA cartilage. The expression of Sema3A in OA and normal cartilage samples was examined by real-time polymerase chain reaction and immunohistochemical analyses. Functional analyses of VEGF165 and Sema3A were carried out using OA chondrocytes in culture. The migration activity of chondrocytes was examined in a monolayer wound assay. The effects of Sema3A on VEGF165-induced up-regulation of matrix metalloproteinases (MMPs) and intracellular signaling were also studied in cultured chondrocytes. Sema3A expression was significantly elevated in OA cartilage as compared to normal cartilage. Sema3A immunoreactivity directly correlated with the Mankin score and with chondrocyte cloning. VEGF165 promoted the migration of chondrocytes, and this activity was suppressed by VEGF receptor 2 tyrosine kinase inhibitors. Sema3A antagonized the chondrocyte migration promoted by VEGF165, and the activity was blocked by a selective inhibitor of, or small interfering RNA for, Sema3A. VEGF165-induced overexpression of MMPs and phosphorylation of ERK and focal adhesion kinase in chondrocytes were inhibited by Sema3A. Our findings provide the first evidence that Sema3A is overexpressed, with a direct correlation with cloning, in OA cartilage and that it suppresses the VEGF165-promoted migration of chondrocytes. Our findings also suggest that Sema3A plays a role in chondrocyte cloning through inhibition of cell migration in OA cartilage.


Immunologic alterations in the pancreatic cancer microenvironment of patients treated with neoadjuvant chemotherapy and radiotherapy.
Pancreatic ductal adenocarcinoma (PDAC) has dismal 5-year survival (<9%). We hypothesize that exposure of tumors to conventional therapies may preferentially modulate immune biomarkers in the tumor microenvironment in PDAC. PDAC patients who underwent upfront surgical resection or who received neoadjuvant FOLFIRINOX with or without neoadjuvant radiotherapy followed by surgical resection were selected for study. Total expression of immunologically relevant transcripts and spatially resolved expression of immunologically relevant proteins was quantitated using multiplexed methods (NanoString nCounter and GeoMX platforms). This analysis identified numerous differentially expressed transcripts associated with the type of neoadjuvant therapy received. Moreover, we identified significant alterations in the expression and/or spatial distribution of immunologically relevant proteins in different regions (tumor cell rich, immune cell rich, stromal cell rich) of the tumor microenvironment. These data provide insight into the immunological effects of clinically relevant neoadjuvant therapy for resectable/borderline-resectable PDAC by describing significant differences in the expression of key immunologic biomarkers within the PDAC microenvironment that were associated with the type of treatment patients received prior to surgical resection. This represents a comprehensive analysis of numerous biomarkers conducted on the PDAC microenvironment. This work may guide strategic new combination therapies for pancreatic cancer.


Biochemical, cellular and molecular identification of DNA polymerase α in yeast mitochondria.
DNA replication occurs in various compartments of eukaryotic cells such as the nuclei, mitochondria and chloroplasts, the latter of which is used in plants and algae. Replication appears to be simpler in the mitochondria than in the nucleus where multiple DNA polymerases, which are key enzymes for DNA synthesis, have been characterized. In mammals, only one mitochondrial DNA polymerase (pol γ) has been described to date. However, in the mitochondria of the yeast Saccharomyces cerevisiae, we have found and characterized a second DNA polymerase. To identify this enzyme, several biochemical approaches such as proteinase K treatment of sucrose gradient purified mitochondria, analysis of mitoplasts, electron microscopy and the use of mitochondrial and cytoplasmic markers for immunoblotting demonstrated that this second DNA polymerase is neither a nuclear or cytoplasmic contaminant nor a proteolytic product of pol γ. An improved purification procedure and the use of mass spectrometry allowed us to identify this enzyme as DNA polymerase α. Moreover, tagging DNA polymerase α with a fluorescent probe demonstrated that this enzyme is localized both in the nucleus and in the organelles of intact yeast cells. The presence of two replicative DNA polymerases may shed new light on the mtDNA replication process in S. cerevisiae.


Synthesis of polyhalogenated 4,4'-bipyridines via a simple dimerization procedure.
Polyhalogenated 4,4'-bipyridines were conveniently synthesized in a single step starting from dihalopyridines. A mechanism was proposed on the basis of experiments performed with 2-chloro-5-bromopyridine 1a. 2-Chloro-4-lithio-5-bromopyridine A1 was produced via ortholithiation of 1a by using either LDA or t-BuLi bases. When LDA was used, dimer 3a containing two chlorines and two bromine atoms was formed predominantly accompanied by several byproducts whose structure and mechanism of formation are discussed. In the case of t-BuLi, although the major product was 2-chloropyridine 7, a new pyridone product 8 was formed that is probably the result of the dihydropyridine intermediate hydrolysis. The dimerization procedure involving LDA was employed to prepare a large number of halogenated 4,4'-bipyridines in moderate to good yields. In some specific cases, halogenated 3,4' and 2,4'-bipyridines were obtained in lower yields and their structures were unambiguously assigned by X-ray diffraction analysis.


Breastfeeding, Mixed, or Formula Feeding at 9 Months of Age and the Prevalence of Iron Deficiency and Iron Deficiency Anemia in Two Cohorts of Infants in China.
To assess associations between breastfeeding and iron status at 9 months of age in 2 samples of Chinese infants. Associations between feeding at 9 months of age (breastfed as sole milk source, mixed fed, or formula fed) and iron deficiency anemia (IDA), iron deficiency, and iron sufficiency were determined in infants from Zhejiang (n = 142) and Hebei (n= 813) provinces. Iron deficiency was defined as body iron < 0 mg/kg, and IDA as iron deficiency + hemoglobin < 110 g/L. Multiple logistic regression assessed associations between feeding pattern and iron status. Breastfeeding was associated with iron status (P < .001). In Zhejiang, 27.5% of breastfed infants had IDA compared with 0% of formula-fed infants. The odds of iron deficiency/IDA were increased in breastfed and mixed-fed infants compared with formula-fed infants: breastfed vs formula-fed OR, 28.8 (95% CI, 3.7-226.4) and mixed-fed vs formula-fed OR, 11.0 (95% CI, 1.2-103.2). In Hebei, 44.0% of breastfed infants had IDA compared with 2.8% of formula-fed infants. With covariable adjustment, odds of IDA were increased in breastfed and mixed-fed groups: breastfed vs formula-fed OR, 78.8 (95% CI, 27.2-228.1) and mixed-fed vs formula-fed OR, 21.0 (95% CI, 7.3-60.9). In both cohorts, the odds of iron deficiency/IDA at 9 months of age were increased in breastfed and mixed-fed infants, and iron deficiency/IDA was common. Although the benefits of breastfeeding are indisputable, these findings add to the evidence that breastfeeding in later infancy identifies infants at risk for iron deficiency/IDA in many settings. Protocols for detecting and preventing iron deficiency/IDA in breastfed infants are needed. ClinicalTrials.gov: NCT00642863 and NCT00613717.


The NF-κB signaling protein Bcl10 regulates actin dynamics by controlling AP1 and OCRL-bearing vesicles.
The protein Bcl10 contributes to adaptive and innate immunity through the assembly of a signaling complex that plays a key role in antigen receptor and FcR-induced NF-κB activation. Here we demonstrate that Bcl10 has an NF-κB-independent role in actin and membrane remodeling downstream of FcR in human macrophages. Depletion of Bcl10 impaired Rac1 and PI3K activation and led to an abortive phagocytic cup rich in PI(4,5)P(2), Cdc42, and F-actin, which could be rescued with low doses of F-actin depolymerizing drugs. Unexpectedly, we found Bcl10 in a complex with the clathrin adaptors AP1 and EpsinR. In particular, Bcl10 was required to locally deliver the vesicular OCRL phosphatase that regulates PI(4,5)P(2) and F-actin turnover, both crucial for the completion of phagosome closure. Thus, we identify Bcl10 as an early coordinator of NF-κB-mediated immune response with endosomal trafficking and signaling to F-actin remodeling.


Patient-reported long-term quality of life after tisagenlecleucel in relapsed/refractory diffuse large B-cell lymphoma.
The JULIET phase 2 trial evaluated a single infusion of tisagenlecleucel in adult patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). The objective of the current analysis was to evaluate patient-reported health-related quality of life (HRQoL) with a median follow-up of 19.3 months among patients infused with a single dose of tisagenlecleucel. Patients enrolled were ≥18 years of age with r/r DLBCL after ≥2 lines of therapy and had either undergone a failed autologous stem cell transplant or were ineligible for the procedure. Two validated HRQoL instruments, Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) and Short Form-36 (SF-36) Health Survey, were used to measure HRQoL at baseline and months 3, 6, 12, and 18. At data cutoff (21 May 2018), 115 patients had received tisagenlecleucel infusion. Among the 99 patients evaluated, overall response rate was 54%, and 40% of patients achieved complete response (CR). Initially, 108 patients completed the HRQoL assessments at baseline, including 57 patients who eventually achieved CR or partial response (PR). Further, 30 and 21 patients in clinical response who completed assessments at baseline also completed assessments at months 12 and 18, respectively. Patients who achieved CR or PR sustained HRQoL improvement in all FACT scores at all time points. SF-36 instruments showed improvement above the minimal clinically important differences on 5 of 8 subscales. Long-term follow-up in the phase 2 JULIET study demonstrated that patients with r/r DLBCL who respond to tisagenlecleucel therapy had sustained, clinically meaningful improvements in HRQoL. This trial was registered at www.clinicaltrials.gov as #NCT02445248.


Ultrasound elastography for imaging tendons and muscles.
Ultrasound elastography is a recently developed ultrasound-based method which allows the qualitative or quantitative evaluation of the mechanical properties of tissue. Strain (compression) ultrasound elastography is the commonest technique performed by applying mild compression with the hand-held transducer to create real-time strain distribution maps, which are color-coded and superimposed on the B-mode images. There is increasing evidence that ultrasound elastography can be used in the investigation of muscle, tendon and soft tissue disease in the clinical practice, as a supplementary tool to conventional ultrasound examination. Based on preliminary data, potential clinical applications include early diagnosis, staging, and guiding interventions musculotendinous and neuromuscular disease as well as monitoring disease during rehabilitation. Ultrasound elastography could also be used for research into the biomechanics and pathophysiology of musculotendinous disease. Despite the great interest in the technique, there is still limited evidence in the literature and there are several technical issues which limit the reproducibility of the method, including differences in quantification methods, artefacts, limitations and variation in the application of the technique by different users. This review presents the published evidence on musculoskeletal applications of strain elastography, discusses the technical issues and future perspectives of this method and emphasizes the need for standardization and further research.


Straightforward and sensitive RT-qPCR based gene expression analysis of FFPE samples.
Fragmented RNA from formalin-fixed paraffin-embedded (FFPE) tissue is a known obstacle to gene expression analysis. In this study, the impact of RNA integrity, gene-specific reverse transcription and targeted cDNA preamplification was quantified in terms of reverse transcription polymerase chain reaction (RT-qPCR) sensitivity by measuring 48 protein coding genes on eight duplicate cultured cancer cell pellet FFPE samples and twenty cancer tissue FFPE samples. More intact RNA modestly increased gene detection sensitivity by 1.6 fold (earlier detection by 0.7 PCR cycles, 95% CI = 0.593-0.850). Application of gene-specific priming instead of whole transcriptome priming during reverse transcription further improved RT-qPCR sensitivity by a considerable 4.0 fold increase (earlier detection by 2.0 PCR cycles, 95% CI = 1.73-2.32). Targeted cDNA preamplification resulted in the strongest increase of RT-qPCR sensitivity and enabled earlier detection by an average of 172.4 fold (7.43 PCR cycles, 95% CI = 6.83-7.05). We conclude that gene-specific reverse transcription and targeted cDNA preamplification are adequate methods for accurate and sensitive RT-qPCR based gene expression analysis of FFPE material. The presented methods do not involve expensive or complex procedures and can be easily implemented in any routine RT-qPCR practice.


Plug-and-Display: decoration of Virus-Like Particles via isopeptide bonds for modular immunization.
Virus-like particles (VLPs) are non-infectious self-assembling nanoparticles, useful in medicine and nanotechnology. Their repetitive molecularly-defined architecture is attractive for engineering multivalency, notably for vaccination. However, decorating VLPs with target-antigens by genetic fusion or chemical modification is time-consuming and often leads to capsid misassembly or antigen misfolding, hindering generation of protective immunity. Here we establish a platform for irreversibly decorating VLPs simply by mixing with protein antigen. SpyCatcher is a genetically-encoded protein designed to spontaneously form a covalent bond to its peptide-partner SpyTag. We expressed in E. coli VLPs from the bacteriophage AP205 genetically fused to SpyCatcher. We demonstrated quantitative covalent coupling to SpyCatcher-VLPs after mixing with SpyTag-linked to malaria antigens, including CIDR and Pfs25. In addition, we showed coupling to the VLPs for peptides relevant to cancer from epidermal growth factor receptor and telomerase. Injecting SpyCatcher-VLPs decorated with a malarial antigen efficiently induced antibody responses after only a single immunization. This simple, efficient and modular decoration of nanoparticles should accelerate vaccine development, as well as other applications of nanoparticle devices.


Nuclear Localization of DNAJB6 Is Associated With Survival of Patients With Esophageal Cancer and Reduces AKT Signaling and Proliferation of Cancer Cells.
The DnaJ (Hsp40) homolog, subfamily B, member 6 (DNAJB6) is part of a family of proteins that regulates chaperone activities. One of its isoforms, DNAJB6a, contains a nuclear localization signal and regulates β-catenin signaling during breast cancer development. We investigated the role of DNAJB6 in the pathogenesis of esophageal squamous cell carcinoma (ESCC). We performed immunohistochemical analyses of primary ESCC samples and lymph node metastases from a cohort of 160 patients who underwent esophagectomy with no preoperative chemoradiotherapy at Hong Kong Queen Mary Hospital. Data were collected on patient outcomes over a median time of 12.1 ± 2.9 months. Retrospective survival association analyses were performed. Wild-type and mutant forms of DNAJB6a were overexpressed in cancer cell lines (KYSE510, KYSE 30TSI, KYSE140, and KYSE70TS), which were analyzed in proliferation and immunoblot assays, or injected subcutaneously into nude mice. Levels of DNAJB6 were knocked down in ESCC cell lines (KYSE450 and T.Tn), immortalized normal esophageal epithelial cell lines (NE3 and NE083), and other cells with short hairpin RNAs, or by genome engineering. Bimolecular fluorescence complementation was used to study interactions between proteins in living cells. In primary ESCC samples, patients whose tumors had high nuclear levels of DNAJB6 had longer overall survival times (19.2 ± 1.8 months; 95% confidence interval [CI], 15.6-22.8 mo) than patients whose tumors had low nuclear levels of DNAJB6 (12.6 ± 1.4 mo; 95% CI, 9.8-15.4 mo; P = .004, log-rank test). Based on Cox regression analysis, patients whose tumors had high nuclear levels of DNAJB6 had a lower risk of death than patients with low levels (hazard ratio, 0.562; 95% CI, 0.379-0.834; P = .004). Based on log-rank analysis and Cox regression analysis, the combination of the nuclear level of DNAJB6 and the presence of lymph node metastases at diagnosis could be used to stratify patients into groups with good or bad outcomes (P < .0005 for both analyses). There was a negative association between the nuclear level of DNAJB6 and the presence of lymph node metastases (P = .022; Pearson χ(2) test). Cancer cell lines that overexpressed DNAJB6a formed tumors more slowly in nude mice than control cells or cells that expressed a mutant form of DNAJB6a that did not localize to the nucleus. DNAJB6 knockdown in cancer cell lines promoted their growth as xenograft tumors in mice. A motif of histidine, proline, and aspartic acid in the J domain of DNAJB6a was required for its tumor-suppressive effects and signaling via AKT1. Loss of DNAJB6a resulted in up-regulation of AKT signaling in cancer cell lines and immortalized esophageal epithelial cells. Expression of a constitutively active form of AKT1 restored proliferation to tumor cells that overexpressed DNAJB6a, and DNAJB6a formed a complex with AKT1 in living cells. The expression of DNAJB6a reduced the sensitivity of ESCC to AKT inhibitors; the expression level of DNAJB6a affected AKT signaling in multiple cancer cell lines. Nuclear localization of DNAJB6 is associated with longer survival times of patients with ESCC. DNAJB6a reduces AKT signaling, and DNAJB6 expression in cancer cells reduces their proliferation and growth of xenograft tumors in mice. DNAJB6a might be developed as a biomarker for progression of ESCC.


A comparative analysis of risk factors for stroke in blacks and whites: the Atherosclerosis Risk in Communities study.
Previous studies have speculated that the higher stroke incidence rate (IR) in blacks compared with whites may be due, in part, to stroke risk factors exerting a more adverse effect among blacks than whites. To determine whether such racial differences exist we compared the prospective associations between novel, traditional, and emerging stroke risk factors in blacks and whites. Baseline characteristics on risk factor levels were obtained on 15,407 participants from the Atherosclerosis Risk in Communities Study. Stroke incidence was ascertained from 1987 to 2008. Adjusted Cox proportional hazard models were used to compute hazard ratios (HRs) and their 95% confidence intervals (CIs) for stroke in relation to stroke risk factor levels stratified by race. During follow-up, 988 stroke events occurred: blacks had higher stroke incident rates compared with whites with the greatest difference in those aged <60 years: 4.34, 3.24, 1.20, and 0.84 per 1000 person-years, in black men, black women, white men, and white women, respectively. Associations between risk factors with incident stroke were similar in blacks and whites excluding diabetes which was more strongly associated with the risk of stroke in blacks than in whites: HR 2.54 (95% CI: 2.03-3.18) versus 1.74 (1.37-2.21), respectively; p for race interaction=0.02. At all ages, blacks are at a considerably higher risk of incident stroke compared with whites, although the effect is most marked in younger age groups. This is most likely due to blacks having a greater burden of stroke risk factors rather than there being any substantial race differences in the associations between risk factors and stroke outcomes.


[Paget disease of bone in Chile: report of 15 cases].
Paget disease of bone (PD) is a localized disorder of bone remodeling, which leads to bone fragility and deformity. In Chile PD is uncommon. To study clinical and demographic characteristics of patients with PD seen in the Clinical Hospital of the Catholic University. Patients with typical radiological and clinical features of PD referred to our institution during the last decade were included in this review. We obtained data from 15 patients with PD (ten males, eight Chilean, six European and one Asian), eleven of them were diagnosed during the last 3 years. The mean age at diagnosis was 68.7 +/- 11.1 years old. No one had first degree relatives with PD. Bone pain was the main complaint in 13 patients and elevated total alkaline phosphatases in the other two. The average duration of the symptoms prior to diagnosis was 38.8 months. Eight patients had monostotic lesions; the most commonly involved sites were the pelvis, spine and femur. Radiological evaluation disclosed sclerotic changes in all patients as well as bone deformity and osteoarthritis in eight patients. Total alkaline phosphatases were elevated in 14 cases (mean: 4 times over the upper normal limit). When compared to series of the Northern hemisphere, PD in Chile is characterized by an older age at diagnosis, a higher frequency of symptomatic presentation, advanced radiological involvement and greater proportion of complications. PD should be suspected in every patient, Chilean or foreigner, with bone pain or elevated alkaline phosphatases.


TAP associates with a unique class I conformation, whereas calnexin associates with multiple class I forms in mouse and man.
To define the rules governing de novo assembly of the trimeric class I complex, we have identified the class I folding/assembly intermediates associated with calnexin or TAP, using both human and mouse cell lines. To better characterize the class I H chain structure associated with TAP, mouse mAb that distinguish open (64-3-7+) vs folded (30-5-7+) Ld heavy (H) chains were used. We report here that open forms of Ld are uniquely and specifically associated with TAP and that the conformational change in the class I H chain coincident with peptide binding induces TAP release. Chimeric Ld/Q10 displayed TAP association, demonstrating that soluble class I molecules can bind TAP. As previously reported, beta 2m was found to be required for H chain association with TAP. Interestingly, beta 2m was associated with TAP in the human class I-negative cell line LCL 721.221, suggesting that beta 2m can bind to TAP before class I H chain. In contrast to TAP, which binds a specific class I conformation, calnexin was detected in association with multiple forms of both mouse and human class I. Most significantly, we show for the first time that beta 2m-assembled forms of human as well as mouse class I molecules interact with calnexin. Based on these findings, we propose a model for the sequential assembly of class I heterotrimers and their respective interactions with TAP and calnexin.


Meta-Analysis and the Development of Knowledge.
With the widespread application of meta-analysis, it is important to examine the role of meta-analysis in the development of knowledge. Researchers have proposed that meta-analysis provides us with an overview of where the research field has been, summarizes and integrates extant research findings, and suggests directions for future research efforts. Some researchers further argue that meta-analysis can contribute to the accumulation of knowledge and the progress of science. In this article, these claims are examined from an epistemological perspective. Using Kuhn's (1962, 1970b) framework, the authors discuss how meta-analysis contributes to the progress of both normal science and extraordinary science and thus plays an important role in knowledge development in a field.


The association of the mitochondrial DNA OriB variant (16184-16193 polycytosine tract) with type 2 diabetes in Europid populations.
The association between the mitochondrial DNA 16181-16193 polycytosine variant (known as the OriB variant as it maps to the OriB origin of replication) and type 2 diabetes has not been reliably characterised, with studies reporting conflicting results. We report a systematic review of published literature in Europid populations, new data from the Norfolk Diabetes Case-Control Study and a meta-analysis to help quantify this association. We performed a systematic review identifying all the studies of the OriB variant and type 2 diabetes in Europid populations published before January 2013. We typed the OriB variant by pyrosequencing and sequencing in the Norfolk Diabetes Case-Control Study, which comprised 5,574 type 2 diabetes cases and 6,950 population-based controls. Overall, the meta-analysis included eight published studies plus the current new results, with a total of 11,794 type 2 diabetes cases and 14,465 controls. In the Norfolk Diabetes Case-Control Study, the OR for type 2 diabetes for the OriB variant was 1.09 (95% CI 0.96, 1.24). In a combined analysis, the relative risk for type 2 diabetes for the OriB variant in Europid populations was 1.10 (95% CI 1.01, 1.20; p = 0.03) CONCLUSIONS/INTERPRETATION: Results from this systematic review and meta-analysis suggest that the mitochondrial DNA OriB variant is modestly associated with an increased risk of type 2 diabetes in Europid populations, with an effect size comparable with that of recently identified variants from genome-wide association studies.


Eisosomes mark static sites of endocytosis.
Endocytosis functions to recycle plasma membrane components, to regulate cell-surface expression of signalling receptors and to internalize nutrients in all eukaryotic cells. Internalization of proteins, lipids and other cargo can occur by one of several pathways that have different, but often overlapping, molecular requirements. To mediate endocytosis, effectors assemble transiently underneath the plasma membrane, carry out the mechanics of membrane deformation, cargo selection and vesicle internalization, and then disassemble. The mechanism by which endocytosis initiates at particular locations on the plasma membrane has remained unknown. Sites of endocytosis might be formed randomly, induced by stochastic protein and/or lipid clustering. Alternatively, endocytosis might initiate at specific locations. Here we describe large immobile protein assemblies at the plasma membrane in the yeast Saccharomyces cerevisiae that mark endocytic sites. These structures, termed eisosomes (from the Greek 'eis', meaning into or portal, and 'soma', meaning body), are composed primarily of two cytoplasmic proteins, Pil1 and Lsp1. A plasma membrane protein, Sur7, localizes to eisosomes. These structures colocalize with sites of protein and lipid endocytosis, and their components genetically interact with known endocytic effectors. Loss of Pil1 leads to clustering of eisosome remnants and redirects endocytosis and endocytic effector proteins to these clusters.


Blood pressure during pregnancy in Canadian Inuit: community differences related to diet.
To assess a possible relation between the incidence of hypertension during pregnancy and the consumption of fatty acids found in fish and sea mammals. Retrospective survey of pregnancy-induced hypertension; prospective diet survey. Inuit women from seven communities in the Keewatin region of the Northwest Territories. All women from Arviat (formerly Eskimo Point), Baker Lake, Chesterfield Inlet, Coral Harbour, Repulse Bay, Sanikiluaq and Whale Cove who gave birth between Sept. 1, 1984, and Aug. 31, 1987. All blood pressure measurements recorded during the pregnancy, incidence of pregnancy-induced hypertension in the seven communities, harvest of country food (food obtained from the land or sea rather than bought in a store) for six of the communities, self-reported consumption of fish, sea mammals and terrestrial mammals by a subgroup of the subjects and levels of phospholipid fatty acids in cord serum samples from a subgroup of the infants. Significantly lower mean diastolic blood pressure values during the last 6 hours of pregnancy were noted for the women from the three communities with a higher consumption of fish and sea mammals (78.2 [95% confidence limits (CL) 76.6 and 79.9] mm Hg) than for those from the four communities with a lower consumption of such food (81.5 [95% CL 80.1 and 82.9] mm Hg) (p less than 0.005). The relation between community diet type and blood pressure was independent of other factors. Correspondingly, the women from communities with a lower consumption of marine food were 2.6 times more likely to be hypertensive during the pregnancy than those from communities with a higher consumption of marine food (p less than 0.007). Parity (p less than 0.05) and prepregnancy weight (p less than 0.005) were also significantly associated with pregnancy-induced hypertension; however, the relation between hypertension and community diet type remained significant in logistic regression analysis (odds ratio 2.56, p = 0.03). The differences between the community groups were substantiated by the results of the diet survey, the levels of eicosapentaenoic acid (EPA) in the cord serum phospholipids and the harvest data. Increased consumption of fish may be beneficial for women at risk for hypertension during pregnancy. A prospective randomized trial of fish or EPA supplementation during pregnancy is warranted.


Increased sensitivity of the non-human primate eye to microwave radiation following ophthalmic drug pretreatment.
Previous studies in our laboratory have established that pulsed microwaves at 2.45 GHz and 10 mW/cm2 are associated with production of corneal endothelial lesions and with disruption of the blood-aqueous barrier in the non-human primate eye. In the study reported here we examined ocular damage in monkeys (M. mulatta and M. fascicularis) following topical treatment with one of two ophthalmic drugs (timolol maleate and pilocarpine) that preceded exposure to pulsed microwaves. Anesthetized monkeys were sham exposed or exposed to pulsed, 2.45 GHz microwaves (10 microseconds, 100 pps) at average power densities of 0.2, 1, 5, 10, or 15 mW/cm2 4 h a day for 3 consecutive days (respective SARs were 0.052, 0.26, 1.3, 2.6, and 3.9 W/kg). Immediately before microwave exposure, one or both eyes were treated topically with one drop of 0.5% timolol maleate or of 2% pilocarpine. Following administration of a drug, we observed a significant reduction in the power-density threshold (from 10 to 1 mW/cm2) for induction of corneal endothelial lesions and for increased vascular permeability of the iris. Diagnostic procedures (in vivo specular microscopy and fluorescein iris angiography) were performed following each exposure protocol. In addition, increased vascular permeability was confirmed with horseradish peroxidase tracer techniques. Although we did not measure intraocular temperatures in experimental animals, the results suggest that a mechanism other than significant heating of the eye is involved. Our data indicate that pulsed microwaves at an average SAR of 0.26 W/kg, if administered after pretreatment with ophthalmic drugs, can produce significant ocular effects in the anesthetized primate.


Automatic detection of protected health information from clinic narratives.
This paper presents a natural language processing (NLP) system that was designed to participate in the 2014 i2b2 de-identification challenge. The challenge task aims to identify and classify seven main Protected Health Information (PHI) categories and 25 associated sub-categories. A hybrid model was proposed which combines machine learning techniques with keyword-based and rule-based approaches to deal with the complexity inherent in PHI categories. Our proposed approaches exploit a rich set of linguistic features, both syntactic and word surface-oriented, which are further enriched by task-specific features and regular expression template patterns to characterize the semantics of various PHI categories. Our system achieved promising accuracy on the challenge test data with an overall micro-averaged F-measure of 93.6%, which was the winner of this de-identification challenge.


Psychiatric nurses' lived experiences of working with inpatient care on a general team psychiatric ward.
To reveal the meaning of being a nurse working with inpatient care on a team psychiatric ward in Sweden, 22 psychiatric nurses were interviewed and the transcribed texts were analysed by means of latent content analysis. Three themes emerged from the analysis: developing a working relationship with the patient in everyday caregiving; encountering and handling the unforseeable in daily living; and struggling with professional independence and dependency. Developing a working relationship with the patient in everyday caregiving meant that the nurse-patient relationship was the foundation of the caregiving and included being with, as well as doing for, and with, the patient. Four different approaches in daily caregiving were revealed: networking, teaching, containing and protecting. The nurses' approaches in the nurse-patient relationship alternated between being an 'expert' and a 'collaborator'. Encountering and handling unforeseeable situations meant that the nurses were exposed to and had to be prepared for unpredictable situations where they were on their own, handling sometimes strong emotional reactions and relying on their own ability to act. Struggling with professional independence and dependency meant that the nurses seemed to lack professional confidence, although they had many responsibilities, but also less authority to decide about overall care planning. Contextual aspects such as organizational hindrance, unsatisfactory work-environment and co-operation difficulties were illuminated. The result indicates the need for a stable and predictable organizational structure if nurses are to manage the demanding nurse-patient relationships that everyday caregiving requires. A question highlighted by this study is whether multidisciplinary team organization has been effectively developed in Sweden, as uncertainty about the roles and responsibilities of nurses was apparent.


Incorporating immunizations into routine obstetric care to facilitate Health Care Practitioners in implementing maternal immunization recommendations.
Immunization against pertussis, influenza, and rubella reduces morbidity and mortality in pregnant women and their offspring. Health care professionals (HCPs) caring for women perinatally are uniquely placed to reduce maternal vaccine preventable diseases (VPDs). Despite guidelines recommending immunization during the perinatal period, maternal vaccine uptake remains low. This qualitative study explored the role of obstetricians, general practitioners, and midwives in maternal vaccine uptake. Semi-structured interviews (n = 15) were conducted with perinatal HCPs at a tertiary maternity hospital in South Australia. HCPs were asked to reflect on their knowledge, beliefs, and practice relating to immunization advice and vaccine provision. Interviews were transcribed and coded using thematic analysis. Data collection and analysis was an iterative process, with collection ceasing with theoretical saturation. Participants unanimously supported maternal vaccination as an effective way of reducing risk of disease in this vulnerable population, however only rubella immunity detection and immunization is embedded in routine care. Among these professionals, delegation of responsibility for maternal immunization was unclear and knowledge about maternal immunization was variable. Influenza and pertussis vaccine prevention measures were not included in standard pregnancy record documentation, information provision to patients was "ad hoc" and vaccinations not offered on-site. The key finding was that the incorporation of maternal vaccinations into standard care through a structured process is an important facilitator for immunization uptake. Incorporating vaccine preventable disease management measures into routine obstetric care including incorporation into the Pregnancy Record would facilitate HCPs in implementing recommendations. Rubella prevention provides a useful 'template' for other vaccines.


Targeted Structure-Activity Analysis of Endochin-like Quinolones Reveals Potent Qi and Qo Site Inhibitors of Toxoplasma gondii and Plasmodium falciparum Cytochrome bc1 and Identifies ELQ-400 as a Remarkably Effective Compound against Acute Experimental Toxoplasmosis.
Cytochrome bc1 inhibitors have been broadly studied as human and veterinary medicines and agricultural fungicides. For the most part, cytochrome bc1 inhibitors compete with ubiquinol at the ubiquinol oxidation (Qo) site or with ubiquinone at the quinone reduction (Qi) site. 4(1 H)-Quinolones with 3-position substituents may inhibit either site based on quinolone ring substituents. 4(1 H)-Quinolones that inhibit the Qi site are highly effective against toxoplasmosis, malaria, and babesiosis and do not inhibit human cytochrome bc1. We tested a series of 4(1 H)-Quinolones against wild-type and drug resistant strains of Toxoplasma gondii and Plasmodium falciparum. These experiments identified very potent compounds that inhibit T. gondii proliferation at picomolar concentrations. The most potent compounds target the Qo site, and for these compounds, an alkyl side chain confers potency against T. gondii greater than that of bulkier side chains. Our experiments also show that substituents on the quinolone ring influenced selectivity between T. gondii and P. falciparum and between Qo and Qi site-mediated activity. Comparison of the parasite cytochrome b sequences identified amino acids that are associated with drug resistance in P. falciparum that exist naturally in wild-type T. gondii. These underlying differences may influence drug susceptibility. Finally, a Qo site active 4(1 H)-quinolone-3-diarylether tested in a murine model of toxoplasmosis was superior to atovaquone, resulting in survival from Type I strain T. gondii infection. These experiments identify highly effective compounds for toxoplasmosis and provide valuable insight into the structure-activity relationship of cytochrome bc1 inhibitors.


Differentiation of Monocyte Derived Dendritic Cells in End Stage Renal Disease is Skewed Towards Accelerated Maturation.
Dendritic cells (DC) play an important role in the induction of immune responses. Patients with end stage renal disease (ESRD) suffer from chronic inflammation, leading to a secondary, uremic immunodeficiency associated with alterations in monocyte subpopulations with increased proinflammatory capacities. The aim of this study was to examine, under isolated conditions, whether alterations in monocyte subpopulations may affect in vitro maturation of dendritic cells (DC) in patients with ESRD, thus allowing us to draw conclusions for the situation in vivo. Monocytes from 30 patients undergoing hemodialysis (HD) and 15 healthy volunteers were enriched from peripheral blood leukocytes, differentiated into immature DC (iDC) in medium containing IL-4 and GM-CSF, and were induced with LPS to differentiate into mature DC (mDC). Monocyte subpopulations and DC maturation stages were phenotypically characterized using flow-cytometry. Although phenotypically indistinguishable, the number of both iDC and mDC that were generated from uremic monocytes was significantly higher compared to those from healthy controls (p=0.02 and p=0.03, respectively). This was associated with an increased number of CD14+ CD16+ monocytes (p=0.02) and by a higher maturation efficiency of mDC in patients (p=0.04). A high percentage of CD14+ CD16+ monocytes in patients with ESRD is associated with an increased propensity to differentiate into DC. This indicates that chronic inflammation may substantiate the biased consistence of monocyte subpopulations leading to profound alteration in DC generation and maturation in ESRD.


Enhancing the accuracy of next-generation sequencing for detecting rare and subclonal mutations.
Mutations, the fuel of evolution, are first manifested as rare DNA changes within a population of cells. Although next-generation sequencing (NGS) technologies have revolutionized the study of genomic variation between species and individual organisms, most have limited ability to accurately detect and quantify rare variants among the different genome copies in heterogeneous mixtures of cells or molecules. We describe the technical challenges in characterizing subclonal variants using conventional NGS protocols and the recent development of error correction strategies, both computational and experimental, including consensus sequencing of single DNA molecules. We also highlight major applications for low-frequency mutation detection in science and medicine, describe emerging methodologies and provide our vision for the future of DNA sequencing.


Estimation of stoichiometric and kinetic coefficients of ASM3 under aerobic and anoxic conditions via respirometry.
Activated Sludge Model No. 1 (ASM 1) has been used extensively for the design and simulation of biological treatment systems. Batch respirometric experiments have been described in the model for the determination of model coefficients and respirometric studies have been proved to be useful in kinetic parameter estimation and wastewater characterisation for ASM 1. Activated Sludge Model No. 3 (ASM3) has also introduced a number of kinetic and stoichiometric coefficients with the new processes defined in the model, also suggesting some default values. Recent studies on the application of ASM3 are limited to special cases in terms of parameter determination. Proper calibration of ASM3 parameters can be a difficult task without involving respirometric procedures as experimental tools. Respirometric batch tests were conveniently used in this study in order to estimate ASM3 parameters and the main kinetic and stoichiometric model coefficients were successfully and uniquely determined for aerobic and anoxic conditions for acetate.


Can molecular imprinting explain heterozygote deficiency and hybrid vigor?
Molecular imprinting, the phenomenon of differential expressions of a gene based on whether it is paternally or maternally derived, has been noted in mice, humans, and other nonmammalian organisms. Effects of differential imprinting are important not only in the study of the manifestation of deleterious genes; they have important evolutionary implications as well. It is shown here that molecular imprinting may mimic observations that are often construed to be due to hybrid vigor and/or inbreeding depression. Furthermore, if a locus undergoes differential imprinting, it also yields observed genotypic proportions which mimic heterozygote deficiency in the population without the aid of natural selection.


Advanced imaging of cardiac sarcoidosis.
Sarcoidosis is a systemic granulomatous disease of unknown etiology. Cardiac involvement may occur, leading to an adverse outcome. Although early treatment to improve morbidity and mortality is desirable, sensitive and accurate detection of cardiac sarcoidosis remains a challenge. Accordingly, interest in the use of advanced imaging such as cardiac MR and PET with (18)F-FDG is increasing in order to refine the clinical workup. Although the field is still facing challenges and uncertainties, this article presents a summary of clinical background and the current state of diagnostic modalities and treatment of cardiac sarcoidosis.


Short communication: Evaluation of vaginal discharge following treatment with a progesterone insert.
Yellowish discharge after application of intravaginal progesterone releasing inserts is frequently observed in cows. The objective of this study was to compare the bacteriological contamination of the vagina and uterus before and after a treatment with a progesterone insert in heifers. Forty-two Holstein heifers received a progesterone releasing insert [Eazi-Breed controlled internal drug release (CIDR) insert; Pfizer Animal Health, Berlin, Germany] for 7d. The protruding tail had been removed from half of the inserts (no tail group: n=21; tail group: n=21). Nine heifers from the tail group lost the insert within the 7-d treatment interval and were excluded. Heifers identified in estrus were artificially inseminated on d 9 or 10. Vaginal discharge was scored on a 4-point scale [vaginal discharge score (VDS) 0 to 3] and vaginal swabs were taken for bacteriological examination on d 0 and 7 and the day of artificial insemination (AI). Furthermore, cytological and bacteriological samples were obtained from the uterus on d 7 and the day of AI. On d 0, coliforms and Streptococcus spp. were found in vaginal swabs of 21 heifers (64%). On d 7, all heifers showed purulent vaginal discharge (VDS 2 to 3). The VDS was higher in the tail group compared with the no tail group. Arcanobacterium pyogenes, coliforms, and Streptococcus spp. were isolated from the vaginal swabs in 32 of 33 (96%) heifers on d 7. On the day of AI, VDS had improved to 0 or 1 in 96% of the heifers. However, A. pyogenes, coliforms, and Streptococcus spp. were still isolated in 17 of 33 (53%) heifers from the vagina and in 32 of 33 (96%) heifers from the endometrium. Endometrial cytology revealed polymorphonuclear neutrophils (PMN) in 11 heifers (6 to 32% PMN). Five samples exceeded the threshold of 5% PMN, and 2 samples exceeded the 10% PMN threshold, indicative of subclinical endometritis. In conclusion, pyogenic bacteria were found in the vagina and uterus on d 7 and the day of AI after intravaginal progesterone treatment. The severity of the discharge was affected by the protruding tail of the insert.


Addressing substance use disorder in primary care: The role, integration, and impact of recovery coaches.
Only 10% of people with substance use disorder (SUD) receive treatment, partially due to inadequate access to specialty SUD care and limited management within primary care. "Recovery coaches" (RCs), peers sharing the lived experience of addiction and recovery, are increasingly being integrated into primary care to help reach and treat people experiencing SUD, yet little is known about how their role should be defined or about their clinical integration and impact. Semistructured interviews with RCs (n = 5) and their patients (n = 16) were used to explore patient and RC perspectives on the RC role. Maximum variation sampling was employed to select patients who displayed diversity across gender, RC, housing status, and number of contacts with an RC. Patients were sampled until no new concepts emerged from additional interviews, and a semistructured interview guide was used for data collection. To analyze interview transcripts, the constant comparative method was used to develop and assign inductively developed codes. Two coders separately coded all transcripts and reconciled code assignments. Four core RC activities were identified: system navigation, supporting behavior change, harm reduction, and relationship building. Across these activities, benefits of the RC role emerged, including accessibility, shared experiences, motivation of behavior change, and links to social services. Challenges of the RC model were also evident: patient discomfort with asking for help, lack of clarity in RC role, and tension within the care team. These findings shed light on RCs in primary care. Many patients and coaches perceived that RCs play a valuable role within primary care, providing both tangible system navigation and intangible, social support that promote recovery and might not otherwise be available. Enhanced communication between RCs and health center leadership in defining the RC role may help resolve ambiguity and related tensions between RCs and care team members.


Involvement of dopaminergic receptor signaling in the effects of glutamatergic receptor antagonists on conditioned place aversion induced by naloxone in single-dose morphine-treated rats.
A better understanding of the neurochemical mechanisms mediating the aversive consequences of drug withdrawal is important for understanding drug addiction. We previously demonstrated that the inhibitory effect of glutamate receptor antagonists on the conditioned place aversion (CPA) induced by naloxone-precipitated withdrawal after a single morphine exposure could be blocked by dopamine receptor antagonists. Thus, a glutamatergic-dopaminergic interaction may participate in this phenomenon. The current study was undertaken to further characterize this interaction by employing both D(1) (SCH 23390) and D(2) (raclopride and eticlopride) dopamine receptor antagonists. The influence of these antagonists on the attenuation of CPA by MK-801 (NMDA receptor antagonist), GYKI 52466 (AMPA receptor antagonist), and MCPG (metabotropic glutamate receptor antagonist) was determined in rats receiving a single dose of morphine. The dopamine antagonists showed either a significant reversal or a tendency to reverse the effects of MK-801 on CPA. The effect of GYKI 52466 was also attenuated by the blockade of either D(1) or D(2) receptors. The effect of MCPG, however, was only blocked by D(2) antagonists and not by the D(1) antagonist SCH 23390. These results add evidence to the hypothesis that a glutamatergic-dopaminergic interaction may be involved in the CPA induced by naloxone-precipitated withdrawal following a single morphine exposure and suggest that both D(1) and D(2) dopamine receptor signaling mechanisms play a role in mediating the aversive aspects of acute dependence.


Benefits from membership in cancer patient associations: relations to gender and involvement.
Cancer patient associations report a growing number of members and increasing possibilities to influence health care, but knowledge about the members' views on the benefit of involvement is scarce. We therefore investigated how members (n = 1742) of Swedish patient associations for breast cancer and prostate cancer rate the benefit of membership for their physical and psychological well-being and social adjustment to cancer. Using a scoring scale, 2/3 of the members reported that membership had benefit for psychological well-being, whereas half of the members reported benefit for physical well-being and social adjustment. Individuals who had been actively involved in board work and/or contact person activities within the associations reported significantly more benefit for all three parameters. Gender differences were observed with men, represented by individuals affected by prostate cancer, reporting greater benefit for all three parameters, although especially evident for psychological well-being. Individuals who obtained membership within two years of diagnosis reported greater benefit for psychological well-being and social adjustment compared to those who became members later. In conclusion, members in patient associations for cancer report benefit particularly for their psychological well-being and actively involved members and men affected by prostate cancer perceive the greatest benefit from membership.


Evaluation of Depth Cameras for Use as an Augmented Reality Emergency Ruler.
Children are rarely affected by medical emergencies. The experience of doctors or paramedics with child emergencies is correspondingly poor. The anatomical features and individual calculations make such an emergency much more error-prone than a comparable adult emergency. Particularly in dose calculations, critical errors occur time and again. Since these calculations are based on the child's weight, which is preclinically often derived from the size of the child, the number of errors can be minimized with an assistance service that performs all calculations based on the size. Technically, it is possible to detect the size with a depth camera, which is occasionally installed in smartphones or head-mounted displays. In order to investigate to what extent these cameras provide precise results, a study with 33 children was carried out. The children were measured with both an emergency ruler and an augmented reality app with associated smartphone with depth camera. The result is that the depth camera does not provide significantly different results than an emergency ruler. This allows further research, e.g. the automatic recognition of patients with the help of machine learning or usability studies, to be tackled.


Use of the Berg Balance Test to predict falls in elderly persons.
The purpose of this study was to determine whether the Berg balance test could be used to predict an elderly person's risk of falling. Sixty-six residents of two independent life-care communities, aged 69 to 94 years (X = 79.2, SD = 6.2), participated. Subjects completed a questionnaire pertaining to their fall history and activity level. The Berg balance test, consisting of 14 functional subtests, was then administered. Six months later, subjects again completed the questionnaire. Performance of activities of daily living predicted 43% of the subjects' scores. There was a difference between the subjects who were prone to falling and those who were not prone to falling, but the test demonstrated poor sensitivity for predicting who would fall. The specificity of the test was very strong. The use of an assistive device was a strong predictor of performance on the Berg balance test. No relationship was noted between increasing age and decreasing performance on the Berg balance test. Although the Berg balance test demonstrated only 53% sensitivity, the results support the test developers' use of 45 (out of 56) as a generalized cutoff score. Older adults who scored higher than the cutoff score on the test were less likely to fall than were those adults who scored below the cutoff score. Decreased scores, however, did not predict increased frequency of falls. Results must be viewed cautiously because self-report was the sole means of documenting fall history.


DNA analysis by flow cytometry in early gastric cancer.
Flow cytometric analysis of a paraffin-embedded block of tissue provides rapid and accurate means of analyzing the DNA content of a tumor. The aim of this study was to clarify the clinical significance of flow cytometric findings in early gastric cancer(EGC). Thus we conducted this study to investigate whether DNA contents of tumor cells can correlate with known prognostic indices in patients with EGC. The flow cytometric DNA analysis was performed with paraffin-embedded specimens from tumors of 107 patients with EGC. Flow cytometric analysis was performed using a FACScan (Becton Dickinson). In constructing the histogram, 30,000 cells were scanned from each section and results were scored. The S-phase fraction was obtained according to the CellFit cell cycle analysis (Becton Dikinson). Frequencies of aneuploidy in tumors with various clinical and pathologic parameters were compared using the chi-square test. Mean SPF/PI valuse were compared by the student t-test. Diploidy pattern was observed in 80 (75%) cases while aneuploidy was seen in 27(25%) cases. Aneuploidy was more frequently detected in tumors with submucosal involvement (32.7%) and lymph node (+) group (30.8%) than in the mucosal tumor (17.3%) and lymph node (-) group (24.5%), but the differences were not significant. Frequency of aneuploidy was not affected by either the histologic type or morphologic classification. On the other hand, high proliferative activities (SPF/PI) significantly correlated with the submucosal tumor invasion (66.7% vs. 45%; p < 0.05) and lymph node metastasis (28.6% vs. 7.5%; p < 0.05). Tumor aggressiveness is not directly related to DNA aneuploidy but proliferative activities are responsible for the aggressive nature of early gastric cancer. The results of this study show that DNA analysis by flow cytometry in considered to be one method of determining the biological activity of gastric cancer cells.


An Extended-gate Type Organic FET Based Biosensor for Detecting Biogenic Amines in Aqueous Solution.
This study is the first to report on the detection of biogenic amines in an aqueous solution using an organic field-effect transistor (OFET) device with an extended gate electrode modified with a layer of diamine oxidase and a horseradish peroxidase osmium-redox polymer. The limit of detection (LOD) for histamine was estimated to be 1.2 μM. These results reveal that extended-gate type OFET devices are highly suitable enzyme-based biosensors for the detection of biogenic amine levels.


Political contexts surrounding Title X, the national family planning program, over the past four decades: oral histories with key stakeholders in Florida.
Title X, enacted in 1970, remains the only policy devoted solely to providing voluntary and confidential family planning and related preventative services to all those in need. Despite Title X's significant public health achievements, this policy continues to receive scrutiny and faces political, financial, and social challenges. This study explores key stakeholders' perceptions regarding the political contexts that have surrounded Title X over its historical maturation. Six oral histories were conducted with key stakeholders in Florida using a semi structured interview guide developed from Title X's legislative history, McPhail's Feminist Policy Analysis Framework, and the literature. Oral histories were audio recorded, transcribed, and analyzed using open, axial, and selective coding in NVivo 8. Participants identified and discussed the following political topics and controversies that they perceived have directly or indirectly affected Title X: abortion, adolescents, parental notification, school-based clinics, abstinence-only education, political administrations, and family planning methods. Participants' recollections regarding the political contexts that have surrounded Title X over the past 4 decades provided a broad yet rich description of the barriers that exist with fulfilling this policy. Such opposition hinders Title X's ability to support women's right to reproductive health. Practitioners play a key role in advocating for family planning services and should understand the political issues hindering reproductive health policies and the need to translate family planning services as a basic human right.


Negative pressure wound therapy for treating leg ulcers.
Leg ulcers are open skin wounds that occur between the ankle and the knee that can last weeks, months or even years and are a consequence of arterial or venous valvular insufficiency. Negative pressure wound therapy (NPWT) is a technology that is currently used widely in wound care and is promoted for use on wounds. NPWT involves the application of a wound dressing to the wound, to which a machine is attached. The machine applies a carefully controlled negative pressure (or vacuum), which sucks any wound and tissue fluid away from the treated area into a canister. To assess the effects of negative pressure wound therapy (NPWT) for treating leg ulcers in any care setting. For this review, in May 2015 we searched the following databases: the Cochrane Wounds Group Specialised Register (searched 21 May 2015); the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2015, Issue 4); Ovid MEDLINE (1946 to 20 May 2015); Ovid MEDLINE (In-Process & Other Non-Indexed Citations 20 May 2015); Ovid EMBASE (1974 to 20 May 2015); EBSCO CINAHL (1982 to 21 May 2015). There were no restrictions based on language or date of publication. Published or unpublished randomized controlled trials (RCTs) comparing the effects of NPWT with alternative treatments or different types of NPWT in the treatment of leg ulcers. Two review authors independently performed study selection, risk of bias assessment and data extraction. We included one study, with 60 randomized participants, in the review. The study population had a range of ulcer types that were venous arteriolosclerotic and venous/arterial in origin. Study participants had recalcitrant ulcers that had not healed after treatment over a six-month period. Participants allocated to NPWT received continuous negative pressure until they achieved 100% granulation (wound preparation stage). A punch skin-graft transplantation was conducted and the wound then exposed to further NPWT for four days followed by standard care. Participants allocated to the control arm received standard care with dressings and compression until 100% granulation was achieved. These participants also received a punch skin-graft transplant and then further treatment with standard care. All participants were treated as in-patients until healing occurred.There was low quality evidence of a difference in time to healing that favoured the NPWT group: the study reported an adjusted hazard ratio of 3.2, with 95% confidence intervals (CI) 1.7 to 6.2. The follow-up period of the study was a minimum of 12 months. There was no evidence of a difference in the total number of ulcers healed (29/30 in each group) over the follow-up period; this finding was also low quality evidence.There was low quality evidence of a difference in time to wound preparation for surgery that favoured NPWT (hazard ratio 2.4, 95% CI 1.2 to 4.7).Limited data on adverse events were collected: these provided low quality evidence of no difference in pain scores and Euroqol (EQ-5D) scores at eight weeks after surgery. There is limited rigorous RCT evidence available concerning the clinical effectiveness of NPWT in the treatment of leg ulcers. There is some evidence that the treatment may reduce time to healing as part of a treatment that includes a punch skin graft transplant, however, the applicability of this finding may be limited by the very specific context in which NPWT was evaluated. There is no RCT evidence on the effectiveness of NPWT as a primary treatment for leg ulcers.


"First, know thyself": cognition and error in medicine.
Although error is an integral part of the world of medicine, physicians have always been little inclined to take into account their own mistakes and the extraordinary technological progress observed in the last decades does not seem to have resulted in a significant reduction in the percentage of diagnostic errors. The failure in the reduction in diagnostic errors, notwithstanding the considerable investment in human and economic resources, has paved the way to new strategies which were made available by the development of cognitive psychology, the branch of psychology that aims at understanding the mechanisms of human reasoning. This new approach led us to realize that we are not fully rational agents able to take decisions on the basis of logical and probabilistically appropriate evaluations. In us, two different and mostly independent modes of reasoning coexist: a fast or non-analytical reasoning, which tends to be largely automatic and fast-reactive, and a slow or analytical reasoning, which permits to give rationally founded answers. One of the features of the fast mode of reasoning is the employment of standardized rules, termed "heuristics." Heuristics lead physicians to correct choices in a large percentage of cases. Unfortunately, cases exist wherein the heuristic triggered fails to fit the target problem, so that the fast mode of reasoning can lead us to unreflectively perform actions exposing us and others to variable degrees of risk. Cognitive errors arise as a result of these cases. Our review illustrates how cognitive errors can cause diagnostic problems in clinical practice.


Corticosteroid-binding globulin contributes to the neuroendocrine phenotype of mice selected for extremes in stress reactivity.
Increasing evidence indicates an important role of steroid-binding proteins in endocrine functions, including hypothalamic-pituitary-adrenal (HPA) axis activity and regulation, as they influence bioavailability, local delivery, and cellular signal transduction of steroid hormones. In the plasma, glucocorticoids (GCs) are mainly bound to the corticosteroid-binding globulin (CBG) and to a lesser extend to albumin. Plasma CBG levels are therefore involved in the adaptive stress response, as they determine the concentration of free, biologically active GCs. In this study, we investigated whether male mice with a genetic predisposition for high-reactivity (HR), intermediate-reactivity (IR), or low-reactivity (LR) stress-induced corticosterone (CORT) secretion present different levels of free CORT and CORT-binding proteins, basally and in response to stressors of different intensity. Our results suggest a fine control interaction between plasma CBG expression and stress-induced CORT release. Although plasma CBG levels, and therefore CBG binding capacity, were higher in HR animals, CORT secretion overloaded the CBG buffering function in response to stressors, resulting in clearly higher free CORT levels in HR compared with IR and LR mice (HR>IR>LR), resembling the pattern of total CORT increase in all three lines. Both stressors, restraint or forced swimming, did not evoke fast CBG release from the liver into the bloodstream and therefore CBG binding capacity was not altered in our three mouse lines. Thus, we confirm CBG functions in maintaining a dynamic equilibrium between CBG-bound and unbound CORT, but could not verify its role in delaying the rise of plasma free CORT immediately after stress exposure.


Heterogeneous public and local knowledge provides a qualitative indicator of coastal use by marine recreational fishers.
Marine recreational fishing (MRF) benefits individuals and economies, but can also impact fish stocks and associated ecosystems. Fish are an important resource providing direct economic benefit through commercial and recreational exploitation, and more esoteric ecosystem services. It is important to consider recreational fishing in marine spatial planning, but spatial information on coastal utilisation for MRF is frequently lacking. Public sources of local knowledge were reviewed and the frequency of unique references to sites extracted. Sites were georeferenced using a gazetteer compiled from the Ordnance Survey and United Kingdom Hydrographic Office named sea features gazetteer and local knowledge sources. Recreational fishing site densities were calculated across 2700 km of coastline and this proxy indicator of coastal utilisation validated against two independent surveys using permutative Monte Carlo sampling to control for sparse and non-independent data. Site density had fair agreement with independent surveys, but standardization by shore length reduced this agreement. Applying a 3 by 3 box filter convolution to the spatial layers improved the agreement between local knowledge derived predictions of activity and those of directed surveys, and permutation testing showed that agreement did not arise as a result of the convolution itself. High and low activity areas were more accurately predicted than areas of intermediate activity. Site density derived from heterogeneous participant and local knowledge can produce qualitative predictions of where recreational fishers fish, and applying a convolution can improve the predictive power of data so derived. However, this approach will be subject to unquantifiable bias and may fail to identify areas highly valued by marine recreational fishers. Thus it should be used in conjunction with other information in decision making and may be best suited to inform the early stage sampling design of on-site surveys or to complement other data sets in mapping areas of importance to recreational fishers.


Stress regularity or consistency? Reading aloud Italian polysyllables with different stress patterns.
Stress assignment to three- and four-syllable Italian words is not predictable by rule, but needs lexical look-up. The present study investigated whether stress assignment to low-frequency Italian words is determined by stress regularity, or by the number of words sharing the final phonological segment and the stress pattern (stress neighborhood or consistency). Experiment 1 showed an effect of stress neighborhood: words were read aloud faster and more accurately when they had a prevalence of stress "friends," irrespective of stress regularity. Moreover, when irregularly stressed words have a higher number of stress friends compared to regularly stressed words, they are read even faster (Experiment 2). In Experiment 3, using visual lexical decision, no difference related to the numerosity of stress friends was found. It is concluded that reading aloud Italian low-frequency words with different stress patterns is mainly affected by the numerosity of lexical types that share a given final sequence and the stress pattern. The phonological nature of the numerosity of lexical representations affecting reading aloud finds support in the absence of such effect in visual lexical decision. These results have implications for models of reading aloud that go beyond monosyllables.


SCN VIP Neurons Are Essential for Normal Light-Mediated Resetting of the Circadian System.
The suprachiasmatic nucleus (SCN) synchronizes circadian rhythms in behavior and physiology to the external light cycle, but the mechanisms by which this occurs are unclear. As the neuropeptide vasoactive intestinal peptide (VIP) is important for circadian light responses, we tested the hypothesis that rhythmic VIP-producing SCN neurons mediate circadian light responses in male and female mice. Using in vivo fiber photometry over multiple days, we found daily rhythms in spontaneous calcium events of SCN VIP neurons that peaked during the subjective day and were disrupted by constant light. The light-evoked calcium responses peaked around subjective dusk and were greater during the subjective night. Using novel VIP sensor cells, we found that the activity patterns in SCN VIP neurons correlated tightly with spontaneous and NMDA-evoked VIP release. Finally, in vivo hyperpolarization of VIP neurons attenuated light-induced shifts of daily rhythms in locomotion. We conclude that SCN VIP neurons exhibit circadian rhythms in spontaneous and light-responsive activity and are essential for the normal resetting of daily rhythms by environmental light.SIGNIFICANCE STATEMENT Daily rhythms in behavior and physiology, including sleep/wake and hormone release, are synchronized to local time by the master circadian pacemaker, the suprachiasmatic nucleus (SCN). The advent of artificial lighting and, consequently, light exposure at night, is associated with an increased risk of disease due to disrupted circadian rhythms. However, the mechanisms by which the SCN encodes normal and pathological light information are unclear. Here, we find that vasoactive intestinal peptide (VIP)-producing SCN neurons exhibit daily rhythms in neuronal activity and VIP release, and that blocking the activity of these neurons attenuates light-induced phase shifts. We conclude that rhythmic VIP neurons are an essential component of the circadian light transduction pathway.


Combined posterior sagittal and three-flap anoplasty in the repair of anorectal anomalies.
The aim of this study was to describe a new technique for the repair of high and intermediate imperforate anus. From 1989 to 1999, 22 children with high and intermediate imperforate anus (17 boys, 5 girls) were operated on with a combination of a posterior sagittal and 3-flap perineal anoplasty. Long-term clinical follow up (to a maximum of 10 years) was done in all patients as well as a recent phone interview with a questionnaire regarding bowel function and degree of satisfaction with the result of the surgical correction. A continence ratio (CR, patient score/maximum possible score) was obtained by a blinded interviewer. A continence survey was obtained in 19 patients. The average CR was 0.68. The CR for high anomalies was 0.62 and for intermediate anomalies was 0.78 (0.84 for girls and 0.64 for boys). Patients with sacral anomalies had a CR of 0.58. Two patients with Trisomy 21 had associated Hirschsprung's disease and were excluded from analysis. Advantages of this combined surgical approach are excellent anatomic exposure, the ability to limit rectal mobilization to a minimum, reduction of the incidence of mucosal prolapse, the new skin-lined anal canal may assist attainment of continence by providing a "sensory warning zone," and, finally, the cosmetic appearance is satisfactory.


Genomic Surveillance of 4CMenB Vaccine Antigenic Variants among Disease-Causing Neisseria meningitidis Isolates, United Kingdom, 2010-2016.
In September 2015, 4CMenB meningococcal vaccine was introduced into the United Kingdom infant immunization program without phase 3 trial information. Understanding the effect of this program requires enhanced surveillance of invasive meningococcal disease (IMD) Neisseria meningitidis isolates and comparison with prevaccination isolates. Bexsero Antigen Sequence Types (BASTs) were used to analyze whole-genome sequences of 3,073 prevaccine IMD N. meningitidis isolates obtained during 2010-2016. Isolates exhibited 803 BASTs among 31 clonal complexes. Frequencies of antigen peptide variants were factor H binding protein 1, 13.4%; Neisserial heparin-binding antigen 2, 13.8%; Neisseria adhesin A 8, 0.8%; and Porin A-VR2:P1.4,10.9%. In 2015-16, serogroup B isolates showed the highest proportion (35.7%) of exact matches to >1 Bexsero components. Serogroup W isolates showed the highest proportion (93.9%) of putatively cross-reactive variants of Bexsero antigens. Results highlighted the likely role of cross-reactive antigens. BAST surveillance of meningococcal whole-genome sequence data is rapid, scalable, and portable and enables international comparisons of isolates.


Diurnal variation, response to eccentric exercise, and association of inflammatory mediators with muscle damage variables.
This investigation determined whether inflammatory mediators 1) have diurnal variations, 2) respond to high-force eccentric exercise, and 3) associate with markers of muscle damage after high-force eccentric exercise. College-aged men and women (n = 51) completed exercise (3 x 15 maximal eccentric elbow flexor actions using 1 arm) and control conditions in random order. Blood was collected preexercise and 4, 8, 12, 24, 48, and 96 h postexercise. Additional measures included maximal isometric force and midbiceps arm circumference (to detect swelling). Serum and plasma were analyzed for soluble tumor necrosis factor receptor-1 (sTNFR1), IL-6, C-reactive protein, cortisol, and creatine kinase (CK) activity. Relative to the 7:00 AM point in the control condition, diurnal decreases were measured at 12:00 PM and 4:00 PM for IL-6 and at 12:00 PM, 4:00 PM, and 8:00 PM for sTNFR1 and cortisol. sTNFR1, IL-6, CK, swelling, and soreness were higher in the exercise compared with the control condition. The largest of the inflammatory mediator responses was measured for IL-6 8 h postexercise in the exercise (3.00 +/- 3.59 pg/ml) relative to the control condition (1.15 +/- 0.99 pg/ml). The IL-6 response (time-matched exercise--control concentration) at 8 h associated (r > 0.282) with muscle soreness at 24 and 96 h, and the cortisol response at 8 h associated (r > 0.285) with swelling at 8, 24, and 96 h. Thus soreness and swelling, but not CK and strength loss, had a low association with the inflammatory response following eccentric exercise.


Imbalanced positive selection maintains the functional divergence of duplicated DIHYDROKAEMPFEROL 4-REDUCTASE genes.
Gene duplication could be beneficial by functional division but might increase the risk of genetic load. The dynamics of duplicated paralogs number could involve recombination, positive selection, and functional divergence. Duplication of DIHYDROFLAVONOL 4-REDUCTASE (DFR) has been reported in several organisms and may have been retained by escape from adaptive conflict (EAC). In this study, we screened the angiosperm DFR gene focusing on a diversified genus Scutellaria to investigate how these duplicated genes are retained. We deduced that gene duplication involved multiple independent events in angiosperms, but the duplication of DFR was before the divergence of Scutellaria. Asymmetric positive selective pressures resulted in different evolutionary rates between the duplicates. Different numbers of regulatory elements, differential codon usages, radical amino acid changes, and differential gene expressions provide evidences of functional divergence between the two DFR duplicates in Scutellaria, implying adaptive subfunctionalization between duplicates. The discovery of pseudogenes accompanying a reduced replacement rate in one DFR paralogous gene suggested possibly leading to "loss of function" due to dosage imbalance after the transient adaptive subfunctionalization in the early stage of duplication. Notwithstanding, episodic gene duplication and functional divergence may be relevant to the diversification of ecological function of DFR gene in Scutellaria.


Neutrophil induced oxidative injury of cardiac myocytes. A compartmented system requiring CD11b/CD18-ICAM-1 adherence.
We have previously shown that cytokines and postischemic cardiac lymph induce expression of intercellular adhesion molecule-1 (ICAM-1, CD54) on canine adult cardiac myocytes. ICAM-1 expression allows adherence of activated neutrophils to myocytes that is blocked by anti-CD18 mAb, R15.7, or anti-ICAM-1 mAb, CL18/6. Interleukin 1, tumor necrosis factor-alpha, or interleukin 6-stimulated cardiac myocytes were loaded with 2',7'-dichlorofluorescin, and oxidation to the fluorescent dichlorofluorescein was monitored. Fluorescence and neutrophil/myocyte adherence followed the same time course, and both were blocked by monoclonal antibodies to CD18, CD11b, and ICAM-1, but mAb R7.1, recognizing a functional epitope on CD11a, was not inhibitory. The iron chelator, desferroxamine, and the hydroxyl radical scavenger, dimethylthiourea, did not inhibit neutrophil adherence, but completely inhibited fluorescence. In contrast, the extracellular oxygen radical scavengers superoxide dismutase and catalase, and the extracellular iron chelator, starch-immobilized desferroxamine, did not affect either fluorescence or adherence. Under the experimental conditions used, no superoxide production could be detected in the extracellular medium. Fluorescence microscopy demonstrated that fluorescence began within 5 min after neutrophil adherence to an individual myocyte, and myocyte contracture followed rapidly. Fluorescent intensity was highest initially at the site of myocyte-neutrophil adherence. When only neutrophils were loaded with 2',7'-dichlorofluorescein, fluorescence was observed only in those neutrophils adhering to the cardiac myocytes. Thus, adherence dependent on Mac-1 (CD11b/CD18) and ICAM-1 (CD54) activates the neutrophil respiratory burst resulting in a highly compartmented iron-dependent myocyte oxidative injury.


Ecology and evolution of the diaspore "burial syndrome".
Hygroscopically active awns or "bristles" have long intrigued scientists. Experimental evidence shows that they are important for diaspore burial in the correct orientation, thereby increasing successful seed germination and seedling survival. Despite these ecological advantages, 38 of the 280 species of grasses in Danthonioideae lack awns. We provide the first study of awns in a phylogenetic context and show that although the awnless state has arisen ca. 25 times independently, the ecological disadvantage of not having an awn also applies in an evolutionary context. Only in Tribolium and Schismus have awnless ancestors diversified to form a clade of primarily awnless descendents. Several of the awnless species in these genera are annual and we find a significant correlation between the evolution of awns and the evolution of life history. A suite of other diaspore traits accompany the awned or awnless states. We interpret the awn as being the visible constituent of a compound "burial syndrome," the two ecological extremes of which may explain the correlation between awns and life history and provide an explanation why awnless species in Tribolium and Schismus persist.


Ion channel activity of influenza A virus M2 protein: characterization of the amantadine block.
The influenza A virus M2 integral membrane protein has ion channel activity which can be blocked by the antiviral drug amantadine. The M2 protein transmembrane domain is highly conserved in amino acid sequence for all the human, swine, equine, and avian strains of influenza A virus, and thus, known amino acid differences could lead to altered properties of the M2 ion channel. We have expressed in oocytes of Xenopus laevis the M2 protein of human influenza virus A/Udorn/72 and the avian virus A/chicken/Germany/34 (fowl plague virus, Rostock) and derivatives of the Rostock ion channel altered in the presumed pore region. The pH of activation of the M2 ion channels and amantadine block of the M2 ion channels were investigated. The channels were found to be activated by pH in a similar manner but differed in their apparent Kis for amantadine block.


The abdominal air sac ostium of the domestic fowl: a sphincter regulated by neuro-epithelial cells?
A microscopic study of the ostium of the abdominal air sac of the domestic fowl has shown that the ostium has a sphincter-like ring of well innervated smooth muscle. Three types of neuro-epithelial cell characterised by their content of numerous large granular vesicles are found in the wall of the ostium. Type I cells are present within the submucosal nerve plexus and appear to be morphologically similar to SIF cells. Type II cells occur in the lamina propria, in clusters or cords, are often associated with fenestrated capillaries, and have synaptic contact with axonal terminals containing small agranular vesicles. The cells of Types I and II are not intra-epithelial and therefore differ from the cells which have been found elsewhere in the respiratory tract of the domestic fowl and other vertebrates. Type III cells are intra-epithelial, and some of those in the basal region of the epithelium are associated with axon terminals. Type III cells are similar in ultrastructure and location to neuro-epithelial cells found elsewhere in the major airways of the domestic fowl. They also resemble cells in neuro-epithelial bodies in amphibian, reptilian and mammalian lungs, although neuro-epithelial bodies have not been found in the lung of this species of bird. The morphology of the ostium suggests that it may have a sphincter-like function, possibly regulated by the neuro-epithelial cells. The presence of a mucociliary epithelium and defensive tissue in the lamina propria indicates that the ostium is the site of defence mechanisms.


[Coping experiences in the work environment of men living with HIV/AIDS].
The objective of this study was to understand the coping mechanisms of men living with HIV/AIDS in terms of their work environment. A qualitative study was carried out at a specialized outpatient clinic in Fortaleza-Ceará between March and June 2010, involving eleven men infected with the virus. Semi-structured and audio-recorded interviews were used. The statements were categorized through content analysis into the following categories: absence from work due to the infection; subterfuges used to hide the disease; disrespect for confidentiality in the work environment; suffering associated with the fear of rejection and prejudice; ways of coping after diagnosis of the disease; and the importance of work for personal accomplishment. In conclusion, men infected with HIV face counterproductive situations in the work environment, mainly evidenced by fear of discovery of the infection and prejudice. Associated with coping, absences for health monitoring purposes interfered with performance at work and increased the risk of losing their job.


A high-speed tunable beam splitter for feed-forward photonic quantum information processing.
We realize quantum gates for path qubits with a high-speed, polarization-independent and tunable beam splitter. Two electro-optical modulators act in a Mach-Zehnder interferometer as high-speed phase shifters and rapidly tune its splitting ratio. We test its performance with heralded single photons, observing a polarization-independent interference contrast above 95%. The switching time is about 5.6 ns, and a maximal repetition rate is 2.5 MHz. We demonstrate tunable feed-forward operations of a single-qubit gate of path-encoded qubits and a two-qubit gate via measurement-induced interaction between two photons.


Congenital osteoclast deficiency in osteopetrotic (op/op) mice is cured by injections of macrophage colony-stimulating factor.
Osteopetrotic (op/op) mice have a severe deficiency of osteoclasts, monocytes, and peritoneal macrophages because of a defect in the production of functional macrophage colony-stimulating factor (M-CSF) resulting from a mutation within the M-CSF gene. In this study, we examined whether daily 5-microgram injections of purified recombinant human M-CSF (rhM-CSF) for 14 d would cure these deficiencies in the mutant mice. Monocytes in the peripheral blood of the op/op mice were significantly increased in number after subcutaneous injections of the factor two or three times a day. In contrast, osteopetrosis in the long bones of op/op mice was completely cured by only one injection of rhM-CSF per day. Bone trabeculae in the diaphyses were removed. Many osteoclasts were detected on the surface of bone trabeculae in the metaphyses. Although development of tooth germs of uninjected op/op mice was impaired, rhM-CSF injection restored the development of molar tooth germs and led to tooth eruption as a consequence of the recovery of bone-resorbing activity. These results demonstrate that M-CSF is one of the factors responsible for the differentiation of osteoclasts and monocyte/macrophages under physiological conditions.


A monte carlo study of weak polyampholytes: stiffness and primary structure influences on titration curves and chain conformations.
The conformation and titration curves of weak polyampholytes are examined using Monte Carlo simulations with screened Coulomb potentials in the Grand Canonical ensemble. Two different types of monomers are considered. Depending on the solution pH, monomers A are weak acidic sites that can either be negatively charged or uncharged (as carboxylic groups), whereas monomers B are weak basic sites that can either be positively charged or uncharged (as amino groups). The influence of the chain stiffness, primary structure, and ionic concentration on the acid/base properties of the polyampholyte chains are systematically investigated. By adjusting the pH values, titration curves and then the fractions of positively and negatively ionized charged monomers are calculated. Stiffness influence is estimated by comparing two models of chain: a fully flexible and a rod-like polyampholyte. Different primary structures such as statistical (diblock, octablock, and alternating) and random polyampholytes are also considered. We demonstrate that the primary structure plays important roles in the acid/base properties as well as the charge distribution along the polymer backbone of a statistical rod-like polyampholyte. When flexible polyampholytes are considered, polyampholyte conformations promote the attractive electrostatic interactions between positively and negatively charged monomers, hence leading to more or less compact conformations and acid/base properties relatively different in comparison to the rod-like polyampholytes. Various conformations such as extended, globular, and pearl-necklace conformations are found in good agreement with the literature by adjusting the interaction parameter between monomers and monomer stoichiometry.


Prevalence of hypertension in healthy school children in Pakistan and its relationship with body mass index, proteinuria and hematuria.
To determine the prevalence of high blood pressure (BP) in healthy school Pakistani children and its association with high body mass index (BMI), asymptomatic hematuria and proteinuria, we studied 661 public school children and measured their body weight, height and BP and urine dipstick for hematuria performed on a single occasion. Hypertension (BP >95 th centile) and pre-hypertension (BP >90 th centile) were defined based on the US normative BP tables. Over-weight and obesity were defined according to the World Health Organization (WHO) classification of BMI. The mean age of the children was 14 ± 1.3 years. The mean BMI was 18.5 ± 4.3 kg/m 2 . The majority (81.8%) of the children were found to be normotensive (BP <90 th centile). Pre-hypertension was observed in 15% and hypertension in 3% of the children. Overweight was observed in 7.7% and obesity in 1% of the children. The independent risk factors for hypertension and pre-hypertension were age of the child (RR 1.2 95% CI 1-1.4), gender (RR 2.0 for being female 95% CI 1-4.4), BMI >25 (RR for BMI b/w 25-30 = 2.6, RR for BMI >30 = 4.3), positive urine dipstick for proteinuria (RR = 2.3 95% CI 0.7-7.7) and positive urine dipstick for hematuria (RR 1.0 95% CI 0.2-8.3). Hypertension in children is strongly correlated with obesity, asymptomatic proteinuria and hematuria. Community based screening programs for children should include BP recording, BMI assessment and urine dipsticks analysis and approach high-risk groups for early detection and lifestyle modifications.