The right location? Experiences of refugee adolescents seen by school-based mental health services.
Access to needed mental health services can be particularly difficult for newly arrived refugee and asylum-seeking adolescents, although many attend school. This study examined young refugees' impressions and experience of mental health services integrated within the school system. Semi-structured interviews were conducted with 40 adolescent refugees discharged by three school-based mental health services across the United Kingdom. Two-thirds preferred to be seen at school. Rumination and worry about insecurity in the asylum process had a negative impact particularly on the adolescents' social functioning and ability to focus at school. The important role played by teachers in supporting and mediating contact with mental health services was valued by those interviewed. The study confirms that schools offer an important location for mental health services for adolescent refugees and provide an important portal for integration of services.


Theranostic Imaging May Vaccinate against the Therapeutic Benefit of Long Circulating PEGylated Liposomes and Change Cargo Pharmacokinetics.
The enhanced permeability and retention (EPR) effect increases tumor accumulation of liposomal chemotherapy and should, in theory, increase anticancer effects and lower toxicity. Unfortunately, liposomal chemotherapy has generally not met the expected potential, perhaps because the EPR effect is not ubiquitous. PET imaging using radiolabeled liposomes can identify cancers positive for the EPR effect. In the current study, we show in clinical canine cancer patients that repeated imaging with radiolabeled liposomes (64Cu-liposome) induces the accelerated blood clearance (ABC) phenomenon. This was observed even with very long intervals between PEGylated liposome injections, which contradict previous reporting in experimental animal models. The induction of ABC may be devastating for the theranostic use of liposomal imaging, as this could vaccinate patients against therapeutic efficacy. To investigate and solve this important problem, an additional study part was designed in which rats were subjected to repeated liposomal administrations, including stealth 64Cu-liposome PET imaging and Caelyx chemotherapy. Most importantly, it was found that, by increasing the lipid dose at the first injection or by supplying a small predose before the second 64Cu-liposome injection, ABC could be prevented. Importantly, signs of liposome tracer breakdown with subsequent renal excretion were observed. These findings highlight the importance of the ABC phenomenon for liposomal predictive imaging in a clinically relevant setting and show that carefully planned application is central to avoid potential detrimental effects on patient benefit.


Nivolumab for Newly Diagnosed Advanced-Stage Classic Hodgkin Lymphoma: Safety and Efficacy in the Phase II CheckMate 205 Study.
Nivolumab, an anti-programmed death-1 monoclonal antibody, has demonstrated frequent and durable responses in relapsed/refractory classic Hodgkin lymphoma (cHL). We report results from Cohort D of the CheckMate 205 trial, which assessed nivolumab monotherapy followed by nivolumab plus doxorubicin, vinblastine, and dacarbazine (N-AVD) for newly diagnosed cHL. Patients 18 years of age or older with untreated, advanced-stage (defined as III to IV and IIB with unfavorable risk factors) cHL were eligible for Cohort D of this multicenter, noncomparative, phase II trial. Patients received nivolumab monotherapy for four doses, followed by 12 doses of N-AVD; all doses were every 2 weeks, and nivolumab was administered at 240 mg intravenously. The primary end point was safety. Efficacy end points included objective response rate and modified progression-free survival, defined as time to disease progression/relapse, death, or next therapy. Chromosome 9p24.1 alterations and programmed death-ligand 1 expression were assessed in Hodgkin Reed-Sternberg cells in evaluable patients. A total of 51 patients were enrolled and treated. At diagnosis, 49% of patients had an International Prognostic Score of 3 or greater. Overall, 59% experienced a grade 3 to 4 treatment-related adverse event. Treatment-related febrile neutropenia was reported in 10% of patients. Endocrine immune-mediated adverse events were all grade 1 to 2 and did not require high-dose corticosteroids; all nonendocrine immune-mediated adverse events resolved (most commonly, rash; 5.9%). At the end of therapy, the objective response rate (95% CI) per independent radiology review committee was 84% (71% to 93%), with 67% (52% to 79%), achieving complete remission (five patients [10%] were nonevaluable and counted as nonresponders). With a minimum follow-up of 9.4 months, 9-month modified progression-free survival was 92%. Patients with higher-level Hodgkin Reed-Sternberg programmed death-ligand 1 expression had more favorable responses to N-AVD (P = .041). Nivolumab followed by N-AVD was associated with promising efficacy and safety profiles for newly diagnosed, advanced-stage cHL.


Estimation-induced correlations of the Zernike coefficients of the eye aberration.
The statistical properties of the estimated eye aberrations differ in general from the actual ones owing to the cross coupling and aliasing generated in the estimation process. In particular, the estimated Zernike aberration coefficients may show fictitious correlations that are not present in the incoming wavefronts. This fact should be taken into account when analyzing estimated aberration datasets, searching for correlations related to physiological eye features. We give an analytical model for this effect and evaluate its magnitude for a particular example, assuming that the true aberration statistics follows a Kolmogorov power law.


Rice production threatened by coupled stresses of climate and soil arsenic.
Projections of global rice yields account for climate change. They do not, however, consider the coupled stresses of impending climate change and arsenic in paddy soils. Here, we show in a greenhouse study that future conditions cause a greater proportion of pore-water arsenite, the more toxic form of arsenic, in the rhizosphere of Californian Oryza sativa L. variety M206, grown on Californian paddy soil. As a result, grain yields decrease by 39% compared to yields at today's arsenic soil concentrations. In addition, future climatic conditions cause a nearly twofold increase of grain inorganic arsenic concentrations. Our findings indicate that climate-induced changes in soil arsenic behaviour and plant response will lead to currently unforeseen losses in rice grain productivity and quality. Pursuing rice varieties and crop management practices that alleviate the coupled stresses of soil arsenic and change in climatic factors are needed to overcome the currently impending food crisis.


Femoral fracture during non-cemented total hip arthroplasty.
A study of the data on 1,318 consecutive non-cemented total hip-replacement arthroplasties revealed thirty-nine intraoperative fractures of the femur (3 per cent), only half of which were diagnosed intraoperatively. The fractures occurred in the proximal region of the femur or at the tip of the stem of the prosthesis. Most were incomplete and minimally displaced, and they did not jeopardize the stability of the femoral component. All complete proximal fractures were stabilized with a four-fifths-coated or fully coated prosthesis to provide distal fixation, and, when diagnosed intraoperatively, were fixed with cerclage wiring. When an incomplete fracture near the tip of the stem was discovered postoperatively and the posterior part of the femoral cortex was intact, a spica cast was applied, and the patient was instructed in protected weight-bearing. For a complete fracture at the tip of the stem, we recommend open reduction and internal fixation. No statistical difference was found with respect to residual pain, the score for walking, or the stability of the implant when we compared the results for the patients who had a fracture with those for the patients who did not. Modifications in surgical technique resulted in a decrease in the incidence of fractures (p less than 0.05).


Expression patterns of Ephs and ephrins throughout retinotectal development in Xenopus laevis.
The Eph family of receptor tyrosine kinases and their ligands the ephrins play an essential role in the targeting of retinal ganglion cell axons to topographically correct locations in the optic tectum during visual system development. The African claw-toed frog Xenopus laevis is a popular animal model for the study of retinotectal development because of its amenability to live imaging and electrophysiology. Its visual system undergoes protracted growth continuing beyond metamorphosis, yet little is known about ephrin and Eph expression patterns beyond stage 39 when retinal axons first arrive in the tectum. We used alkaline phosphatase fusion proteins of EphA3, ephrin-A5, EphB2, and ephrin-B1 as affinity probes to reveal the expression patterns of ephrin-As, EphAs, ephrin-Bs, and EphBs, respectively. Analysis of brains from stage 40 to adult frog revealed that ephrins and Eph receptors are expressed throughout development. As observed in other species, staining for ephrin-As displayed a high caudal to low rostral expression pattern across the tectum, roughly complementary to the expression of EphAs. In contrast with the prevailing model, EphBs were found to be expressed in the tectum in a high dorsal to low ventral gradient in young animals. In animals with induced binocular tectal innervation, ocular dominance bands of alternating input from the two eyes formed in the tectum; however, ephrin-A and EphA expression patterns were unmodulated and similar to those in normal frogs, confirming that the segregation of axons into eye-specific stripes is not the consequence of a respecification of molecular guidance cues in the tectum.


Can Deep Learning Improve Genomic Prediction of Complex Human Traits?
The genetic analysis of complex traits does not escape the current excitement around artificial intelligence, including a renewed interest in "deep learning" (DL) techniques such as Multilayer Perceptrons (MLPs) and Convolutional Neural Networks (CNNs). However, the performance of DL for genomic prediction of complex human traits has not been comprehensively tested. To provide an evaluation of MLPs and CNNs, we used data from distantly related white Caucasian individuals (n ∼100k individuals, m ∼500k SNPs, and k = 1000) of the interim release of the UK Biobank. We analyzed a total of five phenotypes: height, bone heel mineral density, body mass index, systolic blood pressure, and waist-hip ratio, with genomic heritabilities ranging from ∼0.20 to 0.70. After hyperparameter optimization using a genetic algorithm, we considered several configurations, from shallow to deep learners, and compared the predictive performance of MLPs and CNNs with that of Bayesian linear regressions across sets of SNPs (from 10k to 50k) that were preselected using single-marker regression analyses. For height, a highly heritable phenotype, all methods performed similarly, although CNNs were slightly but consistently worse. For the rest of the phenotypes, the performance of some CNNs was comparable or slightly better than linear methods. Performance of MLPs was highly dependent on SNP set and phenotype. In all, over the range of traits evaluated in this study, CNN performance was competitive to linear models, but we did not find any case where DL outperformed the linear model by a sizable margin. We suggest that more research is needed to adapt CNN methodology, originally motivated by image analysis, to genetic-based problems in order for CNNs to be competitive with linear models.


The variegated mutants lacking chloroplastic FtsHs are defective in D1 degradation and accumulate reactive oxygen species.
In the photosynthetic apparatus, a major target of photodamage is the D1 reaction center protein of photosystem II (PSII). Photosynthetic organisms have developed a PSII repair cycle in which photodamaged D1 is selectively degraded. A thylakoid membrane-bound metalloprotease, FtsH, was shown to play a critical role in this process. Here, the effect of FtsHs in D1 degradation was investigated in Arabidopsis (Arabidopsis thaliana) mutants lacking FtsH2 (yellow variegated2 [var2]) or FtsH5 (var1). Because these mutants are characterized by variegated leaves that sometimes complicate biochemical studies, we employed another mutation, fu-gaeri1 (fug1), that suppresses leaf variegation in var1 and var2 to examine D1 degradation. Two-dimensional blue native PAGE showed that var2 has less PSII supercomplex and more PSII intermediate lacking CP43, termed RC47, than the wild type under normal growth light. Moreover, our histochemical and quantitative analyses revealed that chloroplasts in var2 accumulate significant levels of reactive oxygen species, such as superoxide radical and hydrogen peroxide. These results indicate that the lack of FtsH2 leads to impaired D1 degradation at the step of RC47 formation in PSII repair and to photooxidative stress even under nonphotoinhibitory conditions. Our in vivo D1 degradation assays, carried out by nonvariegated var2 fug1 and var1 fug1 leaves, demonstrated that D1 degradation was impaired in different light conditions. Taken together, our results suggest the important role of chloroplastic FtsHs, which was not precisely examined in vivo. Attenuated D1 degradation in the nonvariegated mutants also suggests that leaf variegation seems to be independent of the PSII repair.


Understanding differences in past year psychiatric disorders for Latinos living in the US.
This study seeks to identify risk factors for psychiatric disorders that may explain differences in nativity effects among adult Latinos in the USA. We evaluate whether factors related to the processes of acculturation and enculturation, immigration factors, family stressors and supports, contextual factors, and social status in the US account for differences in 12-month prevalence of psychiatric disorders for eight subgroups of Latinos. We report results that differentiate Latino respondents by country of origin and age at immigration (whether they were US-born or arrived before age 6: In-US-as-Child [IUSC]; or whether they arrived after age 6: later-arrival immigrants [LAI]). After age and gender adjustments, LAI Mexicans and IUSC Cubans reported a significantly lower prevalence of depressive disorders than IUSC Mexicans. Once we adjust for differences in family stressors, contextual factors and social status factors, these differences are no longer significant. The risk for anxiety disorders appears no different for LAI compared to IUSC Latinos, after age and gender adjustments. For substance use disorders, family factors do not offset the elevated risk of early exposure to neighborhood disadvantage, but coming to the US after age 25 does offset it. Family conflict and burden were consistently related to the risk of mood disorders. Our findings suggest that successful adaptation into the US is a multidimensional process that includes maintenance of family harmony, integration in advantageous US neighborhoods, and positive perceptions of social standing. Our results uncover that nativity may be a less important independent risk factor for current psychiatric morbidity than originally thought.


Factors associated with smoking cessation.
OBJECTIVE To analyze the prevalence and factors associated with smoking abstinence among patients who were treated in a reference unit for smoking cessation. METHODS This cross-sectional study examined the medical records of 532 patients treated in a reference unit for smoking cessation in Belém, PA, Northern Brazil, between January 2010 and June 2012. Sociodemographic variables and those related to smoking history and treatment were analyzed. Statistical significance was set at p < 0.05. RESULTS The mean age of the participants was 50 years; 57.0% of the patients were women. The mean tobacco load was 30 packs/year, and the mean smoking duration was approximately 32 years. Most patients remained in treatment for four months. The rate of smoking abstinence was 75.0%. Regression analysis indicated that maintenance therapy, absence of relapse triggers, and lower chemical dependence were significantly associated with smoking cessation. CONCLUSIONS The smoking abstinence rate observed was 75.0%. The cessation process was associated with several aspects, including the degree of chemical dependence, symptoms of withdrawal, and period of patient follow-up in a multidisciplinary treatment program. Studies of this nature contribute to the collection of consistent epidemiological data and are essential for the implementation of effective smoking prevention and cessation strategies.


Sodium/hydrogen exchanger NHA2 is critical for insulin secretion in β-cells.
NHA2 is a sodium/hydrogen exchanger with unknown physiological function. Here we show that NHA2 is present in rodent and human β-cells, as well as β-cell lines. In vivo, two different strains of NHA2-deficient mice displayed a pathological glucose tolerance with impaired insulin secretion but normal peripheral insulin sensitivity. In vitro, islets of NHA2-deficient and heterozygous mice, NHA2-depleted Min6 cells, or islets treated with an NHA2 inhibitor exhibited reduced sulfonylurea- and secretagogue-induced insulin secretion. The secretory deficit could be rescued by overexpression of a wild-type, but not a functionally dead, NHA2 transporter. NHA2 deficiency did not affect insulin synthesis or maturation and had no impact on basal or glucose-induced intracellular Ca(2+) homeostasis in islets. Subcellular fractionation and imaging studies demonstrated that NHA2 resides in transferrin-positive endosomes and synaptic-like microvesicles but not in insulin-containing large dense core vesicles in β-cells. Loss of NHA2 inhibited clathrin-dependent, but not clathrin-independent, endocytosis in Min6 and primary β-cells, suggesting defective endo-exocytosis coupling as the underlying mechanism for the secretory deficit. Collectively, our in vitro and in vivo studies reveal the sodium/proton exchanger NHA2 as a critical player for insulin secretion in the β-cell. In addition, our study sheds light on the biological function of a member of this recently cloned family of transporters.


Deficiency in the metabolite receptor SUCNR1 (GPR91) leads to outer retinal lesions.
Age-related macular degeneration (AMD) is a prominent cause of blindness in the Western world. To date, its molecular pathogenesis as well as the sequence of events leading to retinal degeneration remain largely ill-defined. While the invasion of choroidal neovessels in the retina is the primary mechanism that precipitates loss of sight, an earlier dry form precedes it. Here we provide the first evidence for the protective role of the Retinal Pigment Epithelium (RPE)-resident metabolite receptor, succinate receptor 1 (SUCNR1; G-Protein coupled Receptor-91 (GPR91), in preventing dry AMD-like lesions of the outer retina. Genetic analysis of 925 patients with geographic atrophy and 1199 AMD-free peers revealed an increased risk of developing geographic atrophy associated with intronic variants in theSUCNR1 gene. In mice, outer retinal expression of SUCNR1 is observed in the RPE as well as microglial cells and decreases progressively with age. Accordingly, Sucnr1-/- mice show signs of premature sub-retinal dystrophy with accumulation of oxidized-LDL, abnormal thickening of Bruch's membrane and a buildup of subretinal microglia. The accumulation of microglia in Sucnr1-deficient mice is likely triggered by the inefficient clearance of oxidized lipids by the RPE as bone marrow transfer of wild-type microglia into Sucnr1-/- mice did not salvage the patho-phenotype and systemic lipolysis was equivalent between wild-type and control mice. Our findings suggest that deficiency in SUCNR1 is a possible contributing factor to the pathogenesis of dry AMD and thus broaden our understanding of this clinically unmet need.


Enhanced anti-obesity effects of complex of resistant starch and chitosan in high fat diet fed rats.
This study investigated the interventional effect of resistant starch (RS), chitosan (CS) and chitosan-starch complexes (CL) on blood glucose, lipid composition and oxidative stress in high-fat diet fed rats. Compared with RS or CS alone, CL administration performed more efficiently in controlling body weight and adipose tissue mass, together with an increase in HDL-C concentration, oxidative stress suppression by increasing body antioxidant capacity. Gene expression analysis demonstrated the fatty acid and triglyceride synthesis and metabolism gene SREBP-1, adipocyte differentiation gene PPARγ, cholesterol synthesis gene HMGCR, gluconeogenesis gene GAPDH, were significantly down-regulated, whilst lipid oxidation gene Acox1 and liver functional genes Gstm2, Gclc were up-regulated following CL consumption compared with single RS or CS treatment. Hypolipidemic effects were observed by CL administration and oxidative stress suppression by CL appeared to be associated with elevated antioxidant enzyme activity, increased lipid oxidation, as well as improved fatty acid and cholesterol homeostasis.


An Evaluation of Alternatives for Providing Care to Veterans.
In 2014, a whistleblower reported that many U.S. veterans died while waiting for care at the Phoenix VHA. Problems with veteran's care through 2018 reveal ongoing and systematic problem. In March 2018, the VA Inspector General identified critical deficiencies at the Washington, DC VA Medical Center including failures to track patient safety events accurately, ineffective sterile processing and more than 10 thousand open or pending prosthetic/sensory aid consults. The VHA clearly has problems with access and quality in a budget-constrained environment. In this policy analysis, four separate interventions that address the gap between the magnitude as well as the use of the VHA's fixed budget versus access and cost expectations are explored. These policy interventions include maintaining the status quo, returning to a "VHA-only" option, transitioning to a CMS central payer system and consolidating care under the DoD TRICARE insurance plans. An objective evaluation suggests that extending TRICARE to veterans during the phasing out the VHA's care responsibilities, while politically unpalatable, would likely provide the best of four possible solutions under various criterion weighting schemes. A central payer solution under the CMS would also be a viable consideration. Results suggest that TRICARE patient perceptions of quality are superior to VHA and non-VHA/non-DoD, that access provided by the TRICARE program is ranked second in terms of venue acceptance only to the CMS solution set based on primary provider acceptance and that the cost per beneficiary of a TRICARE solution ($6.5 K/beneficiary) is far better than a VHA-only solution ($14.0 K/beneficiary), the CMS central payer solution ($12.2 K/beneficiary), or the status quo (between $12.2 K and $14.0 K/beneficiary). The intent of this paper is to provoke thoughtful consideration of solutions for providing access to high-quality healthcare for veterans within or outside of the VHA.


Inhibitors of protein kinase signaling pathways: emerging therapies for cardiovascular disease.
Protein kinases are enzymes that covalently modify proteins by attaching phosphate groups (from ATP) to serine, threonine, and/or tyrosine residues. In so doing, the functional properties of the protein kinase's substrates are modified. Protein kinases transduce signals from the cell membrane into the interior of the cell. Such signals include not only those arising from ligand-receptor interactions but also environmental perturbations such as when the membrane undergoes mechanical deformation (ie, cell stretch or shear stress). Ultimately, the activation of signaling pathways that use protein kinases often culminates in the reprogramming of gene expression through the direct regulation of transcription factors or through the regulation of mRNA stability or protein translation. Protein kinases regulate most aspects of normal cellular function. The pathophysiological dysfunction of protein kinase signaling pathways underlies the molecular basis of many cancers and of several manifestations of cardiovascular disease, such as hypertrophy and other types of left ventricular remodeling, ischemia/reperfusion injury, angiogenesis, and atherogenesis. Given their roles in such a wide variety of disease states, protein kinases are rapidly becoming extremely attractive targets for drug discovery, probably second only to heterotrimeric G protein-coupled receptors (eg, angiotensin II). Here, we will review the reasons for this explosion in interest in inhibitors of protein kinases and will describe the process of identifying novel drugs directed against kinases. We will specifically focus on disease states for which drug development has proceeded to the point of clinical or advanced preclinical studies.


Review of the Clinical Evidences of Modulated Electro-Hyperthermia (mEHT) Method: An Update for the Practicing Oncologist.
Background: Modulated electro-hyperthermia (mEHT) is a variation of the conventional hyperthermia which selectively targets the malignant cell membranes in order to heat the malignant tissue and sensitize the tissue to oncology treatments. Although widely applied, the formulation of guidelines for the use thereof is still in progress for many tumors. Aim: In this paper we review the literature on the effects of mEHT in cancer patients on local disease control and survival. Methodology: Our review on data presents the collected experience with capacitive hyperthermia treatments with the EHY-2000+ device (OncoTherm Ltd., Germany). A literature search was conducted in Pubmed and articles were grouped and discussed according to: trial type, animal studies, in vitro studies, and reviews. Search results from Conference Abstracts; Trial Registries; Thesis and Dissertations and the Oncothermia Journal were included in the discussions. Results: Modulated electro-hyperthermia is a safe form of hyperthermia which has shown to effectively sensitizes deep tumors, regardless of the thickness of the adipose layers. The technology has demonstrated equal benefits compared to other forms of hyperthermia for a variety of tumors. Given the effective heating ability to moderate temperatures, the improved tumor perfusion, and ability to increase drug absorption, mEHT is a safe and effective heating technology which can be easily applied to sensitize tumors which have demonstrated benefits with the addition of hyperthermia. Modulated electro-hyperthermia also appears to improve local control and survival rates and appears to induce an abscopal (systemic) response to ionizing radiation. Conclusion: Based on clinical studies, the method mEHT is a feasible hyperthermia technology for oncological applications. Concomitant utilization of mEHT is supported by the preclinical and clinical data.


Localization of anti-endometrial antibody binding in women with endometriosis using a double-labelling immunohistochemical method.
Anti-endometrial antibody binding was localized using a double-labelling immunohistochemical method on frozen sections of endometrium taken from a woman without pelvic disease. Serum from 40 women with endometriosis was tested and, as controls, serum samples from 20 adult males and 20 umbilical cords. The method allowed compensation for endogenous immunoglobulins in endometrium and accurate localization of anti-endometrial antibody binding in the cytoplasm of the glandular epithelium. Significantly more women with endometriosis (14/40) were found to have anti-endometrial antibodies than controls (1/40) (P less than 0.001; chi 2). There was no correlation between disease severity and the presence of anti-endometrial antibodies or the intensity of staining.


Evidence of increased brain amyloid in severe TBI survivors at 1, 12, and 24 months after injury: report of 2 cases.
Traumatic brain injury (TBI) is a major risk factor for Alzheimer's disease. With respect to amyloid deposition, there are no published serial data regarding the deposition rate of amyloid throughout the brain after TBI. The authors conducted serial (18)F-AV-45 (florbetapir F18) positron emission tomography (PET) imaging in 2 patients with severe TBI at 1, 12, and 24 months after injury. A total of 12 brain regions were surveyed for changes in amyloid levels. Case 1 involved a 50-year-old man who experienced a severe TBI. Compared with the 1-month time point, of the 12 brain regions that were surveyed, a decrease in amyloid (as indicated by standard uptake value ratios) was only observed in the hippocampus (-16%, left; -12%, right) and caudate nucleus (-18%, left; -18%, right), suggesting that initial amyloid accumulation in the brain was cleared between time points 1 and 12 months after injury. Compared to the scan at 1 year, a greater increase in amyloid (+15%) was observed in the right hippocampus at the 24-month time point. The patient in Case 2 was a 37-year-old man who suffered severe trauma to the head and a subsequent stroke; he had poor cognitive/functional outcomes and underwent 1.5 years of rehabilitation. Due to a large infarct area on the injured side of the brain (right side), the authors focused primarily on brain regions affected within the left hemisphere. Compared with the 1-month scan, they only found an increase in brain amyloid within the left anterior putamen (+11%) at 12 months after injury. In contrast, decreased amyloid burden was detected in the left caudate nucleus (-48%), occipital cortex (-21%), and precuneus (-19%) brain regions at the 12-month time point, which is indicative of early accumulation and subsequent clearance. In comparison with 12-month values, more clearance was observed, since a reduction in amyloid was found at 24 months after trauma within the left anterior putamen (-12%) and occipital cortex (-15%). Also, by 24 months, most of the amyloid had been cleared and the patient demonstrated improved results on the Rivermead symptom questionnaire, Glasgow Outcome Scale-Extended, and Disability Rating Scale. With respect to APOE status, the patient in Case 1 had two ε3 alleles and the patient in Case 2 had one ε2 and one ε3 allele. In comparison to the findings of the initial scan at 1 month after TBI, by 12 and 24 months after injury amyloid was cleared in some brain regions and increased in others. Serial imaging conducted here suggests that florbetapir F18 PET imaging may be useful in monitoring amyloid dynamics within specific brain regions following severe TBI and may be predictive of cognitive deficits.


Stress distributions in maxillary bone surrounding overdenture implants with different overdenture attachments.
In this study, effects of different overdenture attachments on the stress distributions in the maxillary bone surrounding the overdenture implants are studied. Four different types of attachment are considered. They are rigid Dalbo Stud, movable Dalbo Stress Broken, movable Dalro, and movable O-ring attachments. Three-dimensional finite element analysis was conducted with commercial package to obtain the stress distributions in the maxillary bone. Varying the attachment types and angle of inclination of load, the stress distributions in the portions of compact bone and trabecular bone were monitored separately. The analysis was conducted by assuming two different boundary conditions at the interface between cap and overdenture abutment in order to evaluate influence of interface boundary condition on stress distribution in the maxillary bone. They were perfect bonding condition and contact with friction at the interfaces. However, it is preferable to assume perfect bond condition at the interface for rigid type attachment systems and contact with friction at the interface for movable type attachment systems. From the numerical results, it was found that the load transfer mechanism of the implant system is altered significantly by the types of the overdenture attachment and also special care must be taken to assign proper boundary conditions at the interface for the analysis. The movable type Dalro attachment generated the highest maximum effective stress in the maxillary bone among the models under the same inclined loading condition for contact with friction. The rigid type Dalbo Stud attachment generated the smallest maximum effective stress in the maxillary bone among the models under the same inclined loading condition for perfect bonding condition.


Chlamydial cervical infection in jailed women.
The prevalence of Chlamydia trachomatis cervical infection in incarcerated adult women has not been reported. To develop a policy for testing and treatment, we determined the prevalence of and risk factors for chlamydial infection in women in a New York City jail. Interviews and cervical cultures for C trachomatis were obtained from 101 consenting female inmates. Positive cultures for C trachomatis were found in 27% of the participants. Mucopurulent cervical discharge and education of 8 years or less were two independent risk factors for infection, but only 63% of the infected women had one or both of these factors. If pelvic tenderness were considered as a third factor, an additional 7% of the infected women would have been identified. The prevalence of chlamydial infection in this population was as high as that in populations for which presumptive treatment is recommended. Although the optimal policy for detection and treatment of chlamydial infection may vary depending on practical considerations, we suggest that women entering correctional facilities should be screened or offered presumptive therapy for C trachomatis infection.


Differences in Routine Laboratory Ordering Between a Teaching Service and a Hospitalist Service at a Single Academic Medical Center.
Studies have shown that the overutilization of laboratory tests ("labs") for hospitalized patients is common and can cause adverse health outcomes. Our objective was to compare the ordering tendencies for routine complete blood counts (CBC) and chemistry panels by internal medicine residents and hospitalists. This observational study included a survey of medicine residents and hospitalists and a retrospective analysis of labs ordering data. The retrospective data analysis comprised patients admitted to either the teaching service or nonteaching hospitalist service at a single hospital during 2014. The survey asked residents and hospitalists about their practices and preferences on labs ordering. The frequency and timing of one-time and daily CBC and basic chemistry panel ordering for teaching service and hospitalist patients were obtained from our data warehouse. The average number of CBCs per patient per day and chemistry panels per patient per day was calculated for both services and multivariate regression was performed to control for patient characteristics. Forty-four of 120 (37%) residents and 41 of 53 (77%) hospitalists responded to the survey. Forty-four (100%) residents reported ordering a daily CBC and chemistry panel rather than one-time labs at patient admission compared with 22 (54%) hospitalists (P < 0.001). For CBCs, teaching service patients averaged 1.72/day and hospitalist service patients averaged 1.43/day (P < 0.001). For basic chemistry panels, teaching service patients averaged 1.96/day and hospitalist service patients averaged 1.78/day (P < 0.001). Results were similar in multivariate regression models adjusting for patient characteristics. Residents' self-reported and actual use of CBCs and chemistry panels is significantly higher than that of hospitalists in the same hospital. Our results reveal an opportunity for greater supervision and improved instruction of cost-conscious ordering practices.


Vascular endothelial cell-specific NF-kappaB suppression attenuates hypertension-induced renal damage.
Nuclear factor kappa B (NF-kappaB) participates in hypertension-induced vascular and target-organ damage. We tested whether or not endothelial cell-specific NF-kappaB suppression would be ameliorative. We generated Cre/lox transgenic mice with endothelial cell-restricted NF-kappaB super-repressor IkappaBalphaDeltaN (Tie-1-DeltaN mice) overexpression. We confirmed cell-specific IkappaBalphaDeltaN expression and reduced NF-kappaB activity after TNF-alpha stimulation in primary endothelial cell culture. To induce hypertension with target-organ damage, we fed mice a high-salt diet and N(omega)-nitro-l-arginine-methyl-ester (L-NAME) and infused angiotensin (Ang) II. This treatment caused a 40-mm Hg blood pressure increase in both Tie-1-DeltaN and control mice. In contrast to control mice, Tie-1-DeltaN mice developed a milder renal injury, reduced inflammation, and less albuminuria. RT-PCR showed significantly reduced expression of the NF-kappaB targets VCAM-1 and ICAM-1, compared with control mice. Thus, the data demonstrate a causal link between endothelial NF-kappaB activation and hypertension-induced renal damage. We conclude that in vivo NF-kappaB suppression in endothelial cells stops a signaling cascade leading to reduced hypertension-induced renal damage despite high blood pressure.


Early graft function after heart-lung transplantation.
Sixty patients underwent heart-lung transplantation at our institution between April 1984 and March 1989. The first five donor organs were removed in an adjacent operating room. Subsequently, organs were removed from distant centers. The method of preservation consisted of cold crystalloid cardioplegic arrest of the heart followed by a cold colloid pulmonary artery flush of a perfusate developed at Papworth Hospital. The lung perfusate is preceded by an infusion of prostacyclin into the pulmonary artery, during preliminary dissection of the donor organs. The total ischemic time ranged from 48 to 51 minutes (mean, 49.6 minutes) for the near-procurement group and from 70 to 249 minutes (mean, 157.6 minutes) for the distant-procurement group. Function of the lungs was assessed by gas exchange, pulmonary function tests, extubation, and survival data. Serial x-ray films were used to monitor graft performance in the postoperative period. We record our clinical experience of early graft function after heart-lung transplantation.


Intravenous iron supplementation may protect against acute mountain sickness: a randomized, double-blinded, placebo-controlled trial.
Acute mountain sickness (AMS) is a common and disabling condition that occurs in healthy individuals ascending to high altitude. Based on the ability of iron to influence cellular oxygen sensing pathways, we hypothesized that iron supplementation would protect against AMS. To examine this hypothesis, 24 healthy sea-level residents were randomized to receive either intravenous iron(III)-hydroxide sucrose (200 mg) or saline placebo, before ascending rapidly to Cerro de Pasco, Peru (4340 m). The Lake Louise scoring system was used to assess incidence and severity of AMS at sea level and on the first full day at altitude. No significant difference in absolute AMS score was detected between the two groups either at baseline or at high altitude. However, the mean increase in AMS score was 65% smaller in the iron group than in the saline group (p<0.05), and the change in AMS score correlated negatively with the change in ferritin (R=-0.43; p<0.05). Hematocrit and arterial oxygen saturation were unaffected by iron. In conclusion, this preliminary randomized, double-blinded, placebo-controlled trial suggests that intravenous iron supplementation may protect against the symptoms of AMS in healthy volunteers.


Differential effect of temperature on histamine- and carbachol-stimulated inositol phospholipid breakdown in slices of guinea-pig cerebral cortex.
Slices of guinea-pig cerebral cortex were incubated with [3H]-inositol at 37 degrees C before exposure to histamine or carbachol at 37 degrees C or 25 degrees C. Histamine-stimulated accumulation of [3H]-inositol 1-phosphate ([3H]-IP1) at 25 degrees C was only 5-7% of that at 37 degrees C, whereas for carbachol the response at 25 degrees C was 45-49% of that at 37 degrees C. The affinity of benzilylcholine, obtained from inhibition of carbachol-induced accumulation of [3H]-IP1 was similar at 25 degrees C and 37 degrees C, but the EC50 for carbachol was lower at 25 degrees C (20 +/- 2 microM) than at 37 degrees C (42 +/- 2 microM). The IC50 for histamine inhibition of [3H]-mepyramine binding to homogenates of guinea-pig cerebral cortex did not differ significantly at 25 degrees C and 37 degrees C. Histamine-induced accumulations of [3H]-IP2 and [3H]-IP3 at 25 degrees C, expressed as a percentage of the accumulation at 37 degrees C, were also much less than the corresponding value for carbachol. These observations imply that the locus or pathway(s) of agonist-induced formation of [3H]-IP1 are not the same for histamine and carbachol.


MicroRNA profiling of patient plasma for clinical trials using bioinformatics and biostatistical approaches.
MicroRNAs (miRNAs) are short noncoding RNAs that function to repress translation of mRNA transcripts and contribute to the development of cancer. We hypothesized that miRNA array-based technologies work best for miRNA profiling of patient-derived plasma samples when the techniques and patient populations are precisely defined. Plasma samples were obtained from five sources: melanoma clinical trial of interferon and bortezomib (12), purchased normal donor plasma samples (four), gastrointestinal tumor bank (nine), melanoma tumor bank (ten), or aged-matched normal donors (eight) for the tumor bank samples. Plasma samples were purified for miRNAs and quantified using NanoString® arrays or by the company Exiqon. Standard biostatistical array approaches were utilized for data analysis and compared to a rank-based analytical approach. With the prospectively collected samples, fewer plasma samples demonstrated visible hemolysis due to increased attention to eliminating factors, such as increased pressure during phlebotomy, small gauge needles, and multiple punctures. Cancer patients enrolled in a melanoma clinical study exhibited the clearest pattern of miRNA expression as compared to normal donors in both the rank-based analytical method and standard biostatistical array approaches. For the patients from the tumor banks, fewer miRNAs (<5) were found to be differentially expressed and the false positive rate was relatively high. In order to obtain consistent results for NanoString miRNA arrays, it is imperative that patient cohorts have similar clinical characteristics with a uniform sample preparation procedure. A clinical workflow has been optimized to collect patient samples to study plasma miRNAs.


Modelling the national scrapie eradication programme in the UK.
In accordance with a policy to eliminate all transmissible spongiform encephalopathies from the food chain, a national untargeted ram breeding programme to eliminate scrapie in the UK is in the final stages of planning. Here we formulate a model of flock-to-flock scrapie transmission, in order to consider the effect of a targeted breeding programme which is in the early stages of consideration. We estimate the size of the susceptible flock population, and discuss implications for potential control programmes. Targeting all rams and ewes in highly susceptible flocks rather than rams in all flocks will eradicate scrapie more quickly, and so is likely to be beneficial as long as suitable penalties or incentives are available to facilitate their identification. A more restricted programme aimed only at highly affected flocks would be much easier to implement and crucially will eradicate scrapie just as quickly. This will leave behind a residue population of susceptible sheep, which could then be gradually removed by a more general breeding programme.


The value of preserving the anal sphincter in operations for ulcerative colitis and polyposis: a review of 22 mucosal proctectomies.
Ulcerative colitis and polyposis are both diseases of the mucosa. They can be cured by colectomy combined with selective mucosal proctectomy, without sacrifice of teh anal sphincters or damage to bladder or sexual function. Terminal ileum, either as a straight tube or in the form of a pouch, is drawn down through the denuded tube of anorectal muscle and anastomosed to the mid-anal canal. A temporary defunctioning ileostomy is always used. Caecum has also been used as a neorectum after mucosal proctectomy, but without long term success. Twenty-two patients, 20 with ulcerative colitis and 2 with polyposis, have been treated by mucosal proctectomy in the past 4 years, with no mortality. The caeco-anal procedure proved a failure because of recurrence of colitis, although the early functional results were good. After ileo-anal anastomosis, continence was perfect by day, but 2 patients had occasional lapses at night. The disadvantage of straight ileo-anal anastomosis is frequency of bowel action (6-9 times a day), even with codeine medication, although the patients considered the operation a success. Some form of pelvic reservoir is therefore desirable and our early experience with the triplicated ileal pouch is encouraging.


Model system to evaluate the effect of ampD mutations on AmpC-mediated beta-lactam resistance.
Mutations within the structural gene of ampD can lead to AmpC overproduction and increases in beta-lactam MICs in organisms with an inducible ampC. However, identification of mutations alone cannot predict the impact that those mutations have on AmpD function. Therefore, a model system was designed to determine the effect of ampD mutations on ceftazidime MICs using an AmpD(-) mutant Escherichia coli strain which produced an inducible plasmid-encoded AmpC. ampD genes were amplified by PCR from strains of E. coli, Citrobacter freundii, and Pseudomonas aeruginosa. Also, carboxy-terminal truncations of C. freundii ampD genes were constructed representing deletions of 10, 21, or 25 codons. Amplified ampD products were cloned into pACYC184 containing inducible bla(ACT-1)-ampR. Plasmids were transformed into E. coli strains JRG582 (AmpD(-)) and K-12 259 (AmpD(+)). The strains were evaluated for a derepressed phenotype using ceftazidime MICs. Some mutated ampD genes, including the ampD gene of a derepressed C. freundii isolate, resulted in substantial decreases in ceftazidime MICs (from >256 microg/ml to 12 to 24 microg/ml) for the AmpD(-) strain, indicating no role for these mutations in derepressed phenotypes. However, ampD truncation products and ampD from a partially derepressed P. aeruginosa strain resulted in ceftazidime MICs of >256 microg/ml, indicating a role for these gene modifications in derepressed phenotypes. The use of this model system indicated that alternative mechanisms were involved in the derepressed phenotype observed in strains of C. freundii and P. aeruginosa. The alternative mechanism involved in the derepressed phenotype of the C. freundii isolate was downregulation of ampD transcription.


Prognostic factors for recurrence-free survival in patients with HER2-positive early-stage breast cancer treated with adjuvant trastuzumab.
The objective of this study was to identify prognostic factors affecting the recurrence-free survival (RFS) in patients who received a 52-week trastuzumab therapy for HER2-positive early stage breast cancer (EBC). The medical records of all patients with EBC from 10 centers were analyzed. Pathologic and clinical tumor characteristics were evaluated in 424 female patients who received 52 weeks of adjuvant trastuzumab for HER2-positive EBC. Survival was estimated using the Kaplan-Meier method. Univariate analyses of RFS were performed with the log-rank test. Independent prognostic and predictive factors affecting RFS were assessed by Cox regression analysis. Median follow-up time was 33.1 months (range 9.2-75.9 months). 3-year RFS and overall survival were 87 and 97%, respectively. In multivariate analysis, patients aged 70 years or over (p = 0.017, relative risk (RR) 2.7, 95% confidence interval (CI) 1.19-6.13), patients with > 9 positive lymph nodes (p = 0.001, RR 2.52, 95% CI 1.42-4.46), and those with progesterone receptor-negative tumors (p = 0.006, RR 2.33, 95% CI 1.27-4.27) had worse RFS. In spite of a 52-week adjuvant trastuzumab treatment, classic poor prognostic factors for invasive EBC remained as such in patients with HER2-positive EBC.


Fabrication of the funnel-shaped three-dimensional plasmonic tip arrays by directional photofluidization lithography.
Plasmonics allow localization of an electromagnetic (EM) field into nanoscale "hotspots", a feature that is of technological significance due to potential applications related to spectroscopic sensing and nanofocusing. In relation to this, many researchers have sought to fabricate metallic nanostructures with sharp edges, as they provide much higher EM field enhancement compared with rounded structures. However, a fabrication method satisfying stringent requirements for the efficient EM field enhancement including three-dimensionality, vertical orientation, large-area fabrication, and tunability of structural features, which are of practical importance for efficient plasmonic light enhancement at hotspots, has yet to be achieved. Herein, we fabricate large-area, vertically aligned three-dimensional plasmonic tip (i.e., nanofunnel) arrays with unprecedented flexibility in the control of the structural features by directional photofluidization lithography. Using this approach, the structural features of nanofunnel tips including the sharpness, shape, and orientation were precisely controlled in a scalable and deterministic manner. The effects of the structural features of the nanofunnel on the EM field enhancement were systematically investigated and analyzed, and the optimum tip features for maximum EM field enhancement were thereupon identified. The suggested nanofabrication technique and resulting structures will be of practical importance in spectroscopic and nanophotonic applications.


Validity, reliability, and measurement invariance of an adapted short version of the HIV stigma scale among perinatally HIV infected adolescents at the Kenyan coast.
There is a dearth of instruments that have been developed and validated for use with children living with HIV under the age of 17 years in the Kenyan context. We examined the psychometric properties and measurement invariance of a short version of the Berger HIV stigma scale administered to perinatally HIV-infected adolescents in a rural setting on the Kenyan coast. A cross-sectional study was conducted among 201 perinatally HIV-infected adolescents aged 12-17 years between November 2017 and October 2018. A short version of the Berger HIV stigma scale (HSS-40) containing twelve items (HSS-12) covering the four dimensions of stigma was evaluated. The psychometric assessment included exploratory factor analysis, confirmatory factor analysis (CFA), and multi-group CFA. Additionally, scale reliability was evaluated as internal consistency by calculating Cronbach's alpha. Evaluation of the reliability and construct validity of the HSS-12 indicated insufficient reliability on three of the four subscales. Consequently, Exploratory Factor Analysis (EFA) was conducted to identify problematic items and determine ways to enhance the scale's reliability. Based on the EFA results, two items were dropped. The Swahili version of this new 10-item HIV stigma scale (HSS-10) demonstrated excellent internal consistency with a Cronbach alpha of 0.86 (95% confidence interval (CI) 0.84-0.89). Confirmatory Factor Analysis indicated that a unidimensional model best fitted the data. The HSS-10 presented a good fit (overall Comparative Fit Index = 0.976, Tucker Lewis Index = 0.969, Root Mean Square Error of Approximation = 0.040, Standardised Root Mean Residual = 0.045). Additionally, multi-group CFA indicated measurement invariance across gender and age groups at the strict invariance level as ΔCFI was ≤ 0.01. Our findings indicate that the HSS-10 has good psychometric properties and is appropriate for evaluating HIV stigma among perinatally HIV-infected adolescents on the Kenyan coast. Further, study results support the unidimensional model and measurement invariance across gender and age groups of the HSS-10 measure.


Active learning for convenient annotation and classification of secondary ion mass spectrometry images.
Digital staining for the automated annotation of mass spectrometry imaging (MSI) data has previously been achieved using state-of-the-art classifiers such as random forests or support vector machines (SVMs). However, the training of such classifiers requires an expert to label exemplary data in advance. This process is time-consuming and hence costly, especially if the tissue is heterogeneous. In theory, it may be sufficient to only label a few highly representative pixels of an MS image, but it is not known a priori which pixels to select. This motivates active learning strategies in which the algorithm itself queries the expert by automatically suggesting promising candidate pixels of an MS image for labeling. Given a suitable querying strategy, the number of required training labels can be significantly reduced while maintaining classification accuracy. In this work, we propose active learning for convenient annotation of MSI data. We generalize a recently proposed active learning method to the multiclass case and combine it with the random forest classifier. Its superior performance over random sampling is demonstrated on secondary ion mass spectrometry data, making it an interesting approach for the classification of MS images.


The history of neurosurgical treatment of sports concussion.
Concussion has a long and interesting history spanning at least the 5 millennia of written medical record and closely mirrors the development of surgery and neurosurgery. Not surprisingly, much of the past and present experimental head injury and concussion work has been performed within neurosurgically driven laboratories or by several surgically oriented neurologists. This historical review chronicles the key aspects of neurosurgical involvement in sports concussion as related to the diagnosis, treatment, mitigation, and prevention of injury using the example of American football. In addition, we briefly trace the developments that led to our current understanding of the biomechanical and neurophysiological basis of concussion.


Influence of Cardiovascular Risk Communication Tools and Presentation Formats on Patient Perceptions and Preferences.
Practice guidelines recommend that clinicians engage patients in treatment decisions and explain atherosclerotic cardiovascular disease (ASCVD) risk but do not describe how to communicate this risk most effectively. To determine how the ASCVD risk time horizon, outcome, and presentation format influence risk perceptions and treatment preferences. From May 27, 2015, through November 12, 2015, participants from the Patient and Provider Assessment of Lipid Management Registry at 140 US cardiology, primary care, and endocrinology practices were presented 3 independent scenarios (representing the same hypothetical patient) and asked to rate their perceived risk and willingness to take medication to lower risk in light of (1) a 15% 10-year ASCVD event risk, (2) a 4% 10-year cardiovascular disease (CVD) death risk, and (3) a 50% lifetime ASCVD event risk. Participants were randomized to receive risk estimates using numbers only, a bar graph, or a face pictogram. Of 3566 eligible participants, 2708 (76.9%) responded (median age, 67 years [interquartile range, 61-76 years]; 280 [10.3%] African American; 1491 men [55.1%]). When shown the lifetime ASCVD risk, respondents were more likely to consider the risk "high to very high" than when presented the 10-year ASCVD risk or the CVD death risk (70.1% vs 31.4% vs 25.7%, respectively; both P < .001). Treatment willingness was also the highest for lifetime ASCVD risk (77.9% very willing) followed by 10-year ASCVD risk (68.1%) and 10-year CVD death risk (63.1%; both P < .001). Compared with participants who were shown a bar graph or no graphic, those who were shown the risk information with a pictogram had the lowest perception of disease severity and the lowest willingness to consider therapy. These findings were robust across demographic and socioeconomic subgroups. The format, time horizon, and outcome used for risk estimation influence patient perceptions and should be considered when designing risk communication tools. When shown lifetime risk estimates, patients had higher risk perception and willingness for therapy than when shown 10-year estimates. Pictogram risk displays may decrease risk perception and consideration for treatment.


Is there a need for a '100 questions exercise' to enhance fisheries and aquatic conservation, policy, management and research? Lessons from a global 100 questions exercise on conservation of biodiversity.
Recent global and regional exercises have been undertaken to identify 100 questions of relevance to policy makers that, if answered, would improve decision making and conservation actions. These were intentionally broad, but all included themes and questions of relevance to aquatic and fisheries professionals (e.g. exploitation, habitat alteration, effectiveness of protected areas, migratory connectivity and environmental effects of aquaculture). Here, the content of the global 100 question exercise relevant to aquatic and fisheries issues is summarized and a critical analysis is provided. Many of the questions addressed in apparently unrelated themes and topics (e.g. terrestrial, agriculture and energy policy) have potential relevance to fisheries and aquatic habitats, which underlines the connectivity between terrestrial and aquatic realms. Given the intimate link between aquatic environmental problems and human activities (including culture and economics), greater understanding of the human dimension is required to inform decision making. Stakeholder perspectives need to be included as a core component of the fisheries management triangle (i.e. managing fish, habitat and people). The benefits and risks of conducting a global 100 questions exercise with an exclusive focus on questions of relevance to fisheries and aquatic practitioners are also considered. There is no question that evidence-based approaches to conservation are essential for addressing the many threats that face aquatic ecosystems and reverse the imperilment trends among ichthyofauna. It is still unclear, however, as to the extent to which 100 questions exercises will help to achieve conservation and management targets for aquatic resources. A global 100 questions exercise that focused on fisheries and aquatic issues would certainly help to generate interest and awareness sufficient to justify such an exercise.


Prenatal Allospecific NK Cell Tolerance Hinges on Instructive Allorecognition through the Activating Receptor during Development.
Little is known about how the prenatal interaction between NK cells and alloantigens shapes the developing NK cell repertoire toward tolerance or immunity. Specifically, the effect on NK cell education arising from developmental corecognition of alloantigens by activating and inhibitory receptors with shared specificity is uncharacterized. Using a murine prenatal transplantation model, we examined the manner in which this seemingly conflicting input affects NK cell licensing and repertoire formation in mixed hematopoietic chimeras. We found that prenatal NK cell tolerance arose from the elimination of phenotypically hostile NK cells that express an allospecific activating receptor without coexpressing any allospecific inhibitory receptors. Importantly, the checkpoint for the system appeared to occur centrally within the bone marrow during the final stage of NK cell maturation and hinged on the instructive recognition of allogeneic ligand by the activating receptor rather than through the inhibitory receptor as classically proposed. Residual nondeleted hostile NK cells expressing only the activating receptor exhibited an immature, anergic phenotype, but retained the capacity to upregulate inhibitory receptor expression in peripheral sites. However, the potential for this adaptive change to occur was lost in developmentally mature chimeras. Collectively, these findings illuminate the intrinsic process in which developmental allorecognition through the activating receptor regulates the emergence of durable NK cell tolerance and establishes a new paradigm to fundamentally guide future investigations of prenatal NK cell-allospecific education.


Effects of estrogen receptor alpha- and beta-selective substances in the metaphysis of the tibia and on serum parameters of bone and fat tissue metabolism of ovariectomized rats.
The functions of estrogen receptors (ER) alpha and beta (ER-alpha and beta) in bone and fat tissue are not precisely described. Therefore we studied the effects of a specific ERalpha and ERbeta agonist in bone and fat of ovariectomized (ovx) rats and compared them with the effects of estradiol (E2). Animals were s.c. injected for 4-weeks with 3 doses of the ERalpha agonist 16alpha-LE2 or the ERbeta agonist 8beta-VE2 or with E2. The intermediate doses were antagonized by an additional daily treatment with ICI (1.53mg). Bone and fat parameters were evaluated by quantitative computer tomography (qCT). Estrogen regulated hormones were also measured. Uterine weights were stimulated; serum LH and leptin levels suppressed E2 and the ERalpha agonist. Density of the cancellous metaphyseal structures of the tibia was reduced in the controls which was prevented by E2 and the ERalpha agonist. Endosteal surface, endosteal, periosteal circumferences and fat depots were largest in the controls and the ERbeta treated animals and lowest in the E2 and the 16alpha-LE2 injected ovx rats. Osteocalcin and the CrossLaps were highest in the ovx controls and reduced by E2 and the ERalpha agonist. Serum osteocalcin was stimulated by the ERbeta agonist. The strain strength index (SSI) in relation to the bodyweight - an indicator of bone elasticity - was lowest in controls and increased dose dependently in the E2 and in the ERalpha treated animals. Most effects in the uterus, serum and bone were antagonized by ICI. Most effects in the bone and fat were exerted by mechanisms involving the ERalpha but the ERbeta agonist appears to stimulate osteoblasts.


Transcranial ultrasound stimulation to human middle temporal complex improves visual motion detection and modulates electrophysiological responses.
Transcranial ultrasound stimulation (TUS) holds promise as a novel technology for non-invasive neuromodulation, with greater spatial precision than other available methods and the ability to target deep brain structures. However, its safety and efficacy for behavioural and electrophysiological modulation remains controversial and it is not yet clear whether it can be used to manipulate the neural mechanisms supporting higher cognitive function in humans. Moreover, concerns have been raised about a potential TUS-induced auditory confound. We aimed to investigate whether TUS can be used to modulate higher-order visual function in humans in an anatomically-specific way whilst controlling for auditory confounds. We used participant-specific skull maps, functional localisation of brain targets, acoustic modelling and neuronavigation to guide TUS delivery to human visual motion processing cortex (hMT+) whilst participants performed a visual motion detection task. We compared the effects of hMT+ stimulation with sham and control site stimulation and examined EEG data for modulation of task-specific event-related potentials. An auditory mask was applied which prevented participants from distinguishing between stimulation and sham trials. Compared with sham and control site stimulation, TUS to hMT+ improved accuracy and reduced response times of visual motion detection. TUS also led to modulation of the task-specific event-related EEG potential. The amplitude of this modulation correlated with the performance benefit induced by TUS. No pathological changes were observed comparing structural MRI obtained before and after stimulation. The results demonstrate for the first time the precision, efficacy and safety of TUS for stimulation of higher-order cortex and cognitive function in humans whilst controlling for auditory confounds.


Aptamer-targeted inhibition of mTOR in T cells enhances antitumor immunity.
Recent studies have underscored the importance of memory T cells in mediating protective immunity against pathogens and cancer. Pharmacological inhibition of regulators that mediate T cell differentiation promotes the differentiation of activated CD8(+) T cells into memory cells. Nonetheless, pharmacological agents have broad targets and can induce undesirable immunosuppressive effects. Here, we tested the hypothesis that aptamer-targeted siRNA inhibition of mTOR complex 1 (mTORC1) function in CD8(+) T cells can enhance their differentiation into memory T cells and potentiate antitumor immunity more effectively than the pharmacologic inhibitor rapamycin. To specifically target activated cells, we conjugated an siRNA targeting the mTORC1 component raptor to an aptamer that binds 4-1BB, a costimulatory molecule that is expressed on CD8(+) T cells following TCR stimulation. We found that systemic administration of the 4-1BB aptamer-raptor siRNA to mice downregulated mTORC1 activity in the majority of CD8(+) T cells, leading to the generation of a potent memory response that exhibited cytotoxic effector functions and enhanced vaccine-induced protective immunity in tumor-bearing mice. In contrast, while treatment with the general mTORC1 inhibitor rapamycin also enhanced antigen-activated CD8(+) T cell persistence, the cytotoxic effector functions of the reactivated memory cells were reduced and the alloreactivity of DCs was diminished. Consistent with the immunological findings, mice treated with rapamycin, but not with 4-1BB aptamer-raptor siRNA, failed to reject a subsequent tumor challenge.


Effects of energy density and portion size on development of acquired flavour liking and learned satiety.
The concept of learned satiety (LS) suggests that associations between the sensory quality and post-ingestive effects of foods may lead to acquired control of meal-size. Although a recent study appeared to support LS since participants learned to eat more of a flavoured cereal with lower energy density (ED) after repeated experience, suggesting that they adjusted voluntary intake to ensure adequate energy was consumed, the large serving portion used in training may have lead to over-satiation. To investigate this further, groups of 12 men were assigned to one of four conditions based on the trained serving portion (150 or 300 g) and presence or absence of cues to differentiate high and low ED versions. In the absence of sensory cues, neither mass consumed nor rated pleasantness differed between high and low ED conditions either before or after training, resulting in greater energy intake in the high ED condition. When sensory cues differentiated ED, intake increased significantly post-training in both the high ED condition trained with the small portion and low ED condition trained with the large portion, and flavour pleasantness changed similarly. Moreover hunger increased significantly after the food was tasted in both conditions where intake increased. These data provide further evidence that learning can moderate meal-size dependent on energy content, but suggest that these changes are driven by changes in flavour liking rather than LS.


HLA and killer cell immunoglobulin-like receptor (KIRs) genotyping in patients with acute viral encephalitis.
The HLA genes, as well as the innate immune KIR genes, are considered relevant determinants of viral outcomes but no study, to our knowledge, has evaluated their role in the clinical setting of acute viral encephalitis. Subjects with acute viral encephalitis in comparison to subjects without acute viral encephalitis showed a significantly higher frequency of 2DL1 KIR gene and AA KIR haplotypes and of HLA-C2 and HLA-A-Bw4 alleles. Subjects without acute viral encephalitis showed a higher frequency of interaction between KIR2DL2 and HLAC1. Multiple logistic regression analysis showed the detrimental effect of HLA-A haplotype and HLA-C1, HLA-A-BW4 HLA-B-BW4T alleles, whereas multiple logistic regression showed a protective effect of AB+BB KIR haplotype and a detrimental effect of interaction between KIR3DL1 and HLA-A-Bw4. Our findings of a lower frequency of activating receptors in patients with acute encephalitis compared to controls could result in a less efficient response of NK cells. This finding could represent a possible pathogenetic explanation of susceptibility to acute symptomatic encephalitis in patients with viral infection from potentially responsible viruses such as Herpes virus. 30 Consecutive patients with symptomatic acute viral encephalitis and as controls, 36 consecutive subjects without acute encephalitis were analyzed. The following KIR genes were analyzed, KIR2DL1, 2DL2, 2DL3, 2DL5, 3DL1, 3DL2, 3DL3, 2DL4, 2DS1, 2DS2, 2DS3, 2DS4, 2DS5, 3DS1, 2 pseudogenes (2DP1 and 3DP1) and the common variants of KIR2DL5 (KIR2DL5A, KIR2DL5B).


Transcriptomic Analysis of Orange Fruit Treated with Pomegranate Peel Extract (PGE).
A Pomegranate Peel Extract (PGE) has been proposed as a natural antifungal substance with a wide range of activity against plant diseases. Previous studies showed that the extract has a direct antimicrobial activity and can elicit resistance responses in plant host tissues. In the present study, the transcriptomic response of orange fruit toward PGE treatments was evaluated. RNA-seq analyses, conducted on wounded fruits 0, 6, and 24 h after PGE applications, showed a significantly different transcriptome in treated oranges as compared to control samples. The majority (273) of the deferentially expressed genes (DEGs) were highly up-regulated compared to only 8 genes that were down-regulated. Gene Ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis showed the involvement of 1233 gene ontology (GO) terms and 35 KEGG metabolic pathways. Among these, important defense pathways were induced and antibiotic biosynthesis was the most enriched one. These findings may explain the underlying preventive and curative activity of PGE against plant diseases.


Management of Radiation Injuries by Panax ginseng Extract.
Chemical radiation protection is an important strategy to protect living beings against the deleterious effects of radiation. In the present study, the radioprotective effect of hydro-alcoholic extract of Panax ginseng extract (PGR-HAE) was studied on radiation-induced deleterious alterations in Swiss albino mice. Oral administration of such extract (25 mg/kg b wt/day/animal) for 5 consecutive days, half an h. before whole-body exposure to 6 Gy gamma radiation, enhanced the 30 days survival and also inhibited the radiogenic sickness, weight loss and life shortening. PGR-HAE ameliorated radiation induced depletion in blood constituents at different necropsy intervals between 12 h to 30 d, and significantly increased the number of femoral spleen colony forming units that survived after irradiation. Furthermore, it checked depletion of glutathione and antioxidant enzymes (superoxide dismutase, catalase, and glutathione S-transferase) as well as elevation of lipid peroxidation (LPO) level in blood and liver. The significant reduction in the yield of LPO demonstrates that PGR-HAE protects the membranes against radiation-induced oxidative damage. These findings conclude that such plant extract provides significant radioprotection, and it may be potentially valuable in the prevention of injuries caused during planned and unplanned radiation exposure.


Plasma cell disorders in HIV-infected patients: epidemiology and molecular mechanisms.
Highly active antiretroviral therapy (HAART) has significantly improved the outcome and survival of human immunodeficiency virus (HIV)-infected patients. Subsequently, long-term morbidities including cancer have become of major public health and clinical interest for this patient population. Plasma cell disorders occur at higher incidence in HIV-infected patients; however, the molecular mechanisms driving the plasma cell disease process and the optimal management for these patients remain to be defined. This article provides an up-to-date review of the characteristics and management of HIV-infected patients with plasma cell disorders. We first present 3 cases of plasma cell disorders in HIV-infected patients, ranging from polyclonal hypergammaglobulinemia to symptomatic multiple myeloma. We then discuss the epidemiology, clinical presentation, and management of each of these plasma cell disorders, with an emphasis on the molecular events underlying the progression of plasma cell diseases from monoclonal gammopathy to symptomatic multiple myeloma. We propose a three-step hypothesis for the development of multiple myeloma. Finally, we discuss the use of high dose chemotherapy and autologous hematopoietic stem cell transplantation in the treatment of HIV-infected patients with multiple myeloma. Our review includes the care of HIV-infected patients with plasma cell disorders in the current era of HAART and novel agents available for the treatment of multiple myeloma.


Visualization and analysis of blood flow and oxygen consumption in hepatic microcirculation: application to an acute hepatitis model.
There is a considerable discrepancy between oxygen supply and demand in the liver because hepatic oxygen consumption is relatively high but about 70% of the hepatic blood supply is poorly oxygenated portal vein blood derived from the gastrointestinal tract and spleen. Oxygen is delivered to hepatocytes by blood flowing from a terminal branch of the portal vein to a central venule via sinusoids, and this makes an oxygen gradient in hepatic lobules. The oxygen gradient is an important physical parameter that involves the expression of enzymes upstream and downstream in hepatic microcirculation, but the lack of techniques for measuring oxygen consumption in the hepatic microcirculation has delayed the elucidation of mechanisms relating to oxygen metabolism in liver. We therefore used FITC-labeled erythrocytes to visualize the hepatic microcirculation and used laser-assisted phosphorimetry to measure the partial pressure of oxygen in the microvessels there. Noncontact and continuous optical measurement can quantify blood flow velocities, vessel diameters, and oxygen gradients related to oxygen consumption in the liver. In an acute hepatitis model we made by administering acetaminophen to mice we observed increased oxygen pressure in both portal and central venules but a decreased oxygen gradient in the sinusoids, indicating that hepatocyte necrosis in the pericentral zone could shift the oxygen pressure up and affect enzyme expression in the periportal zone. In conclusion, our optical methods for measuring hepatic hemodynamics and oxygen consumption can reveal mechanisms related to hepatic disease.


Solvothermal synthesis, stirring-assisted assembly and photoelectric performance of Te nanowires.
Tellurium nanowires (NWs) are attractive one-dimensional materials for many applications, yet most synthesis processes require hazardous chemical reducing agents and extreme operating conditions. Here we described a solvothermal synthesis of Te NWs using a non-toxic reducing agent, ascorbic acid. Then the Te NWs were assembled into a well-aligned film through a stirring-assisted oil-water-air interface assembly method and a Te NWs photodetector was fabricated which is sensitive to infrared radiation. The photodetector based on the well-aligned Te NWs film had a series of more excellent photoelectric properties than that based on those being randomly oriented. For example, the photoresponsivity of the former is 103 times larger, and the response time is 1.15 × 103 times shorter, than those of the latter.


A three arm cluster randomised controlled trial to test the effectiveness and cost-effectiveness of the SMART Work & Life intervention for reducing daily sitting time in office workers: study protocol.
Office-based workers typically spend 70-85% of working hours, and a large proportion of leisure time, sitting. High levels of sitting have been linked to poor health. There is a need for fully powered randomised controlled trials (RCTs) with long-term follow-up to test the effectiveness of interventions to reduce sitting. This paper describes the methodology of a three-arm cluster RCT designed to determine the effectiveness and cost-effectiveness of the SMART Work & Life intervention, delivered with and without a height-adjustable desk, for reducing daily sitting. A three-arm cluster RCT of 33 clusters (660 council workers) will be conducted in three areas in England (Leicester; Manchester; Liverpool). Office groups (clusters) will be randomised to the SMART Work & Life intervention delivered with (group 1) or without (group 2) a height-adjustable desk or a control group (group 3). SMART Work & Life includes organisational (e.g., management buy-in, provision/support for standing meetings), environmental (e.g., relocating waste bins, printers), and group/individual (education, action planning, goal setting, addressing barriers, coaching, self-monitoring, social support) level behaviour change strategies, with strategies driven by workplace champions. Baseline, 3, 12 and 24 month measures will be taken. Objectively measured daily sitting time (activPAL3). objectively measured sitting, standing, stepping, prolonged sitting and moderate-to-vigorous physical activity time and number of steps at work and daily; objectively measured sleep (wrist accelerometry). Adiposity, blood pressure, fasting glucose, glycated haemoglobin, cholesterol (total, HDL, LDL) and triglycerides will be assessed from capillary blood samples. Questionnaires will examine dietary intake, fatigue, musculoskeletal issues, job performance and satisfaction, work engagement, occupational and general fatigue, stress, presenteeism, anxiety and depression and sickness absence (organisational records). Quality of life and resources used (e.g. GP visits, outpatient attendances) will also be assessed. We will conduct a full process evaluation and cost-effectiveness analysis. The results of this RCT will 1) help to understand how effective an important simple, yet relatively expensive environmental change is for reducing sitting, 2) provide evidence on changing behaviour across all waking hours, and 3) provide evidence for policy guidelines around population and workplace health and well-being. ISRCTN11618007 . Registered on 21 January 2018.


Framework negotiations: diagnostic insights among alternative medical practitioners participating in integrative medicine case conferences.
Medical anthropology concerns itself with cultural interpretations of health and illness in complex pluralistic societies whose members incorporate multiple strategies to address health issues. This research explored the variety of complementary and alternative medicine (CAM) topics introduced into biomedically structured clinical evaluation. A field study of routine case conferences held within a clinical fellowship program in integrative medicine (IM) provided the ideal setting to explore contrasting conceptualizations of disease. Study results yielded five core sources of information sought by CAM practitioners, typically not addressed in biomedicine: social relations history within family of origin, emotional health, energetic health, spiritual health, and in-depth nutritional evaluation.


Factors affecting weight and body composition in childhood cancer survivors-cross-sectional study.
Due to improved efficacy of antitumour treatment in the general population, there are increasingly more childhood cancer survivors. However, some of these survivors are at risk of distant complications including cardiovascular disease. We aimed to examine the risk of overweight/obesity and abnormal body composition in a large group of patients from our paediatric oncology centre. We used anthropometric methods and electrical bioimpedance to assess these features, and then determined their association with disease and treatment. We found patients treated for leukaemia/lymphoma (especially boys) had significantly higher rates of overweight/obesity compared to the other patient groups. On the contrary, overweight/obesity was more common in girls among patients treated for solid tumours. Patients treated for leukaemia/lymphoma were characterised by a higher body fat content compared to those treated for solid tumours and controls. During treatment for cancer, patients had a higher percentage of muscle mass deficiency compared to those in the control group. Our regression analysis showed time from completion of treatment, gender and type of therapy (radiotherapy, megachemotherapy) were associated with body weight and body composition including fat and muscle content. We recommend paediatricians and general practitioners should actively try to detect and prevent cardiovascular disease among childhood cancer survivors.


BEME Guide No. 1: Best Evidence Medical Education.
There is a need to move from opinion-based education to evidence-based education. Best evidence medical education (BEME) is the implementation, by teachers in their practice, of methods and approaches to education based on the best evidence available. It involves a professional judgement by the teacher about his/her teaching taking into account a number of factors-the QUESTS dimensions. The Quality of the research evidence available-how reliable is the evidence? the Utility of the evidence-can the methods be transferred and adopted without modification, the Extent of the evidence, the Strength of the evidence, the Target or outcomes measured-how valid is the evidence? and the Setting or context-how relevant is the evidence? The evidence available can be graded on each of the six dimensions. In the ideal situation the evidence is high on all six dimensions, but this is rarely found. Usually the evidence may be good in some respects, but poor in others.The teacher has to balance the different dimensions and come to a decision on a course of action based on his or her professional judgement.The QUESTS dimensions highlight a number of tensions with regard to the evidence in medical education: quality vs. relevance; quality vs. validity; and utility vs. the setting or context. The different dimensions reflect the nature of research and innovation. Best Evidence Medical Education encourages a culture or ethos in which decision making takes place in this context.


Interplay between Ca2+ cycling and mitochondrial permeability transition pores promotes reperfusion-induced injury of cardiac myocytes.
Uncontrolled release of Ca(2+) from the sarcoplasmic reticulum (SR) contributes to the reperfusion-induced cardiomyocyte injury, e.g. hypercontracture and necrosis. To find out the underlying cellular mechanisms of this phenomenon, we investigated whether the opening of mitochondrial permeability transition pores (MPTP), resulting in ATP depletion and reactive oxygen species (ROS) formation, may be involved. For this purpose, isolated cardiac myocytes from adult rats were subjected to simulated ischemia and reperfusion. MPTP opening was detected by calcein release and by monitoring the ΔΨ(m). Fura-2 was used to monitor cytosolic [Ca(2+)](i) or mitochondrial calcium [Ca(2+)](m), after quenching the cytosolic compartment with MnCl(2). Mitochondrial ROS [ROS](m) production was detected with MitoSOX Red and mag-fura-2 was used to monitor Mg(2+) concentration, which reflects changes in cellular ATP. Necrosis was determined by propidium iodide staining. Reperfusion led to a calcein release from mitochondria, ΔΨ(m) collapse and disturbance of ATP recovery. Simultaneously, Ca(2+) oscillations occurred, [Ca(2+)](m) and [ROS](m) increased, cells developed hypercontracture and underwent necrosis. Inhibition of the SR-driven Ca(2+) cycling with thapsigargine or ryanodine prevented mitochondrial dysfunction, ROS formation and MPTP opening. Suppression of the mitochondrial Ca(2+) uptake (Ru360) or MPTP (cyclosporine A) significantly attenuated Ca(2+) cycling, hypercontracture and necrosis. ROS scavengers (2-mercaptopropionyl glycine or N-acetylcysteine) had no effect on these parameters, but reduced [ROS](m). In conclusion, MPTP opening occurs early during reperfusion and is due to the Ca(2+) oscillations originating primarily from the SR and supported by MPTP. The interplay between Ca(2+) cycling and MPTP promotes the reperfusion-induced cardiomyocyte hypercontracture and necrosis. Mitochondrial ROS formation is a result rather than a cause of MPTP opening.


STRING v9.1: protein-protein interaction networks, with increased coverage and integration.
Complete knowledge of all direct and indirect interactions between proteins in a given cell would represent an important milestone towards a comprehensive description of cellular mechanisms and functions. Although this goal is still elusive, considerable progress has been made-particularly for certain model organisms and functional systems. Currently, protein interactions and associations are annotated at various levels of detail in online resources, ranging from raw data repositories to highly formalized pathway databases. For many applications, a global view of all the available interaction data is desirable, including lower-quality data and/or computational predictions. The STRING database (http://string-db.org/) aims to provide such a global perspective for as many organisms as feasible. Known and predicted associations are scored and integrated, resulting in comprehensive protein networks covering >1100 organisms. Here, we describe the update to version 9.1 of STRING, introducing several improvements: (i) we extend the automated mining of scientific texts for interaction information, to now also include full-text articles; (ii) we entirely re-designed the algorithm for transferring interactions from one model organism to the other; and (iii) we provide users with statistical information on any functional enrichment observed in their networks.


Expression of CD44 on bile ducts in primary sclerosing cholangitis and primary biliary cirrhosis.
To examine expression of CD44, a transmembrane glycoprotein involved in lymphocyte homing and activation, in inflammatory liver diseases. Formalin fixed, paraffin embedded tissues were obtained from normal, uninvolved liver from patients undergoing partial hepatectomy for metastatic carcinoma (9) and transplant hepatectomy specimens from patients with primary biliary cirrhosis (12), primary sclerosing cholangitis (8), autoimmune hepatitis (3), hepatitis C (3), and secondary sclerosing cholangitis (1). Expression of CD44 (using antibodies to three core epitopes), HLA-DR, and lymphocyte phenotypic markers was studied by immunohistochemistry. CD44 expression was not detected in either hepatocytes or biliary epithelial cells in normal livers. In sections from all 27 transplant hepatectomy specimens, CD44 was positive in bile duct epithelial cells but not in hepatocytes. The proportion of CD44+ ducts was much higher in biliary disease than in chronic hepatitis. By contrast, expression of HLA-DR was detected in a relatively small percentage of bile ducts. Activated, memory phenotype CD4+ T lymphocytes were increased in the parenchyma of all diseased livers and an infiltrate of activated CD8+ cells within the biliary epithelium was evident in inflammatory biliary disease. CD44 appears to play an important role in the development of autoimmune biliary disease by promoting lymphoepithelial interactions, whereas HLA-DR may be involved in the subsequent progression of these conditions.


Ostracism via virtual chat room-Effects on basic needs, anger and pain.
Ostracism is characterized by a social pain provoked by being excluded and ignored. In order to address the effects of social ostracism in virtual non-physical interactions, we developed a more realistic paradigm as an alternative to Cyberball and assessed its effects on participant's expression of basic social needs, emotional experience and painful feeling. The chat room consisted of controlled social dialogue interactions between participants and two other (confederate) chat room partners. Exclusion was manipulated by varying the number of messages a participant received (15% and 33% in exclusion and inclusion, respectively). Analysis of participant (N = 54) responses revealed that exclusion induced a lower experience of basic-need states and greater anger, compared with included participants. In addition, excluded participants reported higher levels of two specific self-pain feelings, namely tortured and hurt. Our findings suggest that this procedure is effective in inducing social ostracism in a realistic and yet highly controlled experimental procedure.


Recommendations for occupational radiation protection in interventional cardiology.
The radiation dose received by cardiologists during percutaneous coronary interventions, electrophysiology procedures and other interventional cardiology procedures can vary by more than an order of magnitude for the same type of procedure and for similar patient doses. There is particular concern regarding occupational dose to the lens of the eye. This document provides recommendations for occupational radiation protection for physicians and other staff in the interventional suite. Simple methods for reducing or minimizing occupational radiation dose include: minimizing fluoroscopy time and the number of acquired images; using available patient dose reduction technologies; using good imaging-chain geometry; collimating; avoiding high-scatter areas; using protective shielding; using imaging equipment whose performance is controlled through a quality assurance programme; and wearing personal dosimeters so that you know your dose. Effective use of these methods requires both appropriate education and training in radiation protection for all interventional cardiology personnel, and the availability of appropriate protective tools and equipment. Regular review and investigation of personnel monitoring results, accompanied as appropriate by changes in how procedures are performed and equipment used, will ensure continual improvement in the practice of radiation protection in the interventional suite. These recommendations for occupational radiation protection in interventional cardiology and electrophysiology have been endorsed by the Asian Pacific Society of Interventional Cardiology, the European Association of Percutaneous Cardiovascular Interventions, the Latin American Society of Interventional Cardiology, and the Society for Cardiovascular Angiography and Interventions.


Evolution of a cluster of innate immune genes (beta-defensins) along the ancestral lines of chicken and zebra finch.
Avian beta-defensins (AvBDs) represent a group of innate immune genes with broad antimicrobial activity. Within the chicken genome, previous work identified 14 AvBDs in a cluster on chromosome three. The release of a second bird genome, the zebra finch, allows us to study the comparative evolutionary history of these gene clusters between from two species that shared a common ancestor about 100 million years ago. A phylogenetic analysis of the beta-defensin gene clusters in the chicken and the zebra finch identified several cases of gene duplication and gene loss along their ancestral lines. In the zebra finch genome a cluster of 22 AvBD genes were identified, all located within 125 Kbp on chromosome three. Ten of the 22 genes were found to be highly conserved with orthologous genes in the chicken genome. The remaining 12 genes were all located within a cluster of 58 Kbp and are suggested to be a result of recent gene duplication events that occurred after the galliformes- passeriformes split (G-P split). Within the chicken genome, AvBD6 was found to be a duplication of AvBD7, whereas the gene AvDB14 seems to have been lost along the ancestral line of the zebra finch. The duplicated beta-defensin genes have had a significantly higher accumulation of non-synonymous over synonymous substitutions compared to the genes that have not undergone duplication since the G-P split. The expression patterns of avian beta-defensin genes seem to be well conserved between chicken and zebra finch. The genomic comparisons of the beta-defensins gene clusters of the chicken and zebra finch illuminate the evolutionary history of this gene complex. Along their ancestral lines, several gene duplication events have occurred in the passerine line after the galliformes-passeriformes split giving rise to 12 novel genes compared to a single duplication event in the galliformes line. After the duplication events, the duplicated genes have been subject to a relaxed selection pressure compared to the non-duplicated genes, thus supporting models of evolution by gene duplication.


Expression and biological activity of genetic fusions between MalE, the maltose binding protein from Escherichia coli and portions of CD4, the T-cell receptor of the AIDS virus.
Hybrid molecules between MalE, the periplasmic maltose binding protein of Escherichia coli, and CD4, the human T-lymphocyte receptor for the AIDS virus HIV, have been constructed and purified. We show that CD4 can be fused as multiple repeats to both ends of a single MalE molecule. Hybrid proteins are exported into the periplasm of bacteria, bind monoclonal antibodies directed against CD4, bind HIV gp160, and inhibit HIV binding to CD4+ cells. MalE has been used as a scaffold to graft portions of CD4. Deletion analysis allowed to define a minimal structural domain which folds in a way which is compatible with its biological activity. This minimal part was used to design compact hybrid molecules in which CD4 was inserted internally into MalE.


Certain biominerals in leaves function as light scatterers.
Cystoliths are amorphous calcium carbonate bodies that form in the leaves of some plant families. Cystoliths are regularly distributed in the epidermis and protrude into the photosynthetic tissue, the mesophyll. The photosynthetic pigments generate a steep light gradient in the leaf. Under most illumination regimes the outer mesophyll is light saturated, thus the photosynthetic apparatus is kinetically unable to use the excess light for photochemistry. Here we use micro-scale modulated fluorometry to demonstrate that light scattered by the cystoliths is distributed from the photosynthetically inefficient upper tissue to the efficient, but light deprived, lower tissue. The results prove that the presence of light scatterers reduces the steep light gradient, thus enabling the leaf to use the incoming light flux more efficiently. MicroCT and electron microscopy confirm that the spatial distribution of the minerals is compatible with their optical function. During the study we encountered large calcium oxalate druses in the same anatomical location as the cystoliths. These druses proved to have similar light scattering functions as the cystoliths. This study shows that certain minerals in the leaves of different plants distribute the light flux more evenly inside the leaf.


Plant adaptive radiation mediated by polyploid plasticity in transcriptomes.
The habitats of polyploid species are generally distinct from their parental species. Stebbins described polyploids as 'general purpose genotypes', which can tolerate a wide range of environmental conditions. However, little is known about its molecular basis because of the complexity of polyploid genomes. We hypothesized that allopolyploid species might utilize the expression patterns of both parents depending on environments (polyploid plasticity hypothesis). We focused on hydrological niche segregation along fine-scale soil moisture and waterlogging gradients. Two diploid species, Cardamine amara and Cardamine hirsuta, grew best in submerged and unsubmerged conditions, respectively, consistent with their natural habitats. Interestingly, the allotetraploid Cardamine flexuosa derived from them grew similarly in fluctuating as well as submerged and unsubmerged conditions, consistent with its wide environmental tolerance. A similar pattern was found in another species trio: allotetraploid Cardamine scutata and its parents. Using the close relatedness of Cardamine and Arabidopsis, we quantified genomewide expression patterns following dry and wet treatments using an Arabidopsis microarray. Hierarchical clustering analysis revealed that the expression pattern of C. flexuosa clustered with C. hirsuta in the dry condition and with C. amara in the wet condition, supporting our hypothesis. Furthermore, the induction levels of most genes in the allopolyploid were lower than in a specialist diploid species. This reflects a disadvantage of being allopolyploid arising from fixed heterozygosity. We propose that recurrent allopolyploid speciation along soil moisture and waterlogging gradients confers niche differentiation and reproductive isolation simultaneously and serves as a model for studying the molecular basis of ecological speciation and adaptive radiation.