Optical property study of FePt-C nanocomposite thin film for heat-assisted magnetic recording.
Optical properties of the FePt-C nanocomposite thin film that was synthesized by sputtering with MgO/NiTa underlayer on glass substrate have been determined by an approach combining spectroscopic ellipsometry and transmission over the wavelength range of 380 - 1700 nm. It was observed that the refractive index is larger than the extinction coefficient, indicating that free electron absorption is not the dominant optical transition in the FePt-C thin film. Compared with FePt thin film, the FePt-C thin film has smaller optical constants, which lead to better optical performance including smaller optical spot on recording media and higher transducer efficiency for heat assisted magnetic recording.


Longitudinal Models of Reading and Mathematics Achievement in Deaf and Hard of Hearing Students.
Deaf and hard of hearing (DHH) students often experience systemic barriers to academic success, especially low expectations of what they know and can do. Longitudinal data analysis is critical to understanding how academic achievement for DHH students progresses over time and where they may need additional support on their academic journey to achieve at the level of their hearing peers. This study provides an analysis of NWEA MAP® Growth™ data from grades 2 to 8 across seven reading and mathematics domains over a period of 5 years. Results indicate that both DHH and hearing students continue to build skills through this period, and that DHH students, contrary to many previously held assumptions, do not necessarily plateau in the elementary grades.


Structural equation modeling of symptoms, awareness and fear of hypoglycemia, and personality in patients with insulin-treated diabetes.
To assess the possible influence of personality on self-reported awareness, symptoms, and fear of hypoglycemia and also to identify the relationship among these self-reported measures using formal structural equation modeling. A structured questionnaire, which included questions about sociodemographic details, awareness of the onset of hypoglycemia, and a list of symptoms of hypoglycemia, was completed by 305 consecutive insulin-treated diabetic patients attending the diabetic clinic at the Royal Infirmary of Edinburgh. They also completed the Hypoglycemia Fear Survey (HFS), and personality was assessed using the short form of the shortened Eysenck Personality Questionnaire-Revised (EPQ-R). Formal structural equation modeling was performed using the following variables: awareness, autonomic symptoms, neuroglycopenic symptoms, severe hypoglycemic episodes in the last year, worry and behavior (from the HFS), and extroversion and neuroticism (from the short EPQ-R). This allowed a model to be constructed that expressed the putative causal associations among the variables that could be tested statistically. Of the 302 patients who had experienced hypoglycemia, 111 (37%) reported reduced awareness, and these patients scored higher on the worry subscale of the HFS (reduced awareness: 41 +/- 12 vs. normal awareness: 34 +/- 12, P < 0.001). The patients with reduced awareness scored higher for neuroticism than did the patients with normal awareness (reduced awareness: 6.1 +/- 3.4 vs. normal awareness: 4.9 +/- 3.3, P < 0.01) and scored lower for extroversion (reduced awareness: 5.8 +/- 3.7 vs. normal awareness: 7.1 +/- 3.7, P < 0.01). In the structural equation modeling exercise, neuroticism was a significant putative determinant of many of the other variables. Personality was the major determinant of the variance that could be accounted for in this study and influenced self-reported symptoms, awareness, and fear of hypoglycemia. Personality factors may, therefore, influence self-reports from patients, particularly when soft measures, such as symptoms, are assessed and even when using validated clinical questionnaires. This finding stresses the importance of using additional evidence, such as reports from relatives, to substantiate reports from patients of loss of hypoglycemia awareness.


Bilateral caudal superficial epigastric skin flap and perineal urethrostomy for wound reconstruction secondary to traumatic urethral rupture in a cat.
Use of a bilateral caudal superficial epigastric skin flap and perineal urethrostomy for reconstruction of a wound which occurred secondary to rupture of the distal urethra and extravasation of urine is reported. A 10-month-old male neutered Domestic Shorthaired cat was presented with a history of trauma, signs of pain of the hind quarters and anuria. Progression of the clinical signs, including anuria, lethargy, anorexia, and azotemia, prompted referral and investigation 108 hours following the initial injury. Retrograde urethrography indicated a rupture of the distal pelvic urethra with extravasation of urine subcutaneously. Development of extensive skin necrosis of the perineum and rump progressed leaving a large wound defect which was managed with wound debridement and dressing. The wound was closed using staged caudal superficial epigastric skin flaps and perineal urethrostomy as part of the reconstruction.


[Polychemotherapy of leprosy in the Central African Republic, 1987].
The Central African Republic, which once had the highest Hansen disease prevalence rate in the Central African States, had exemplary results in the control carried out on the basis of sulfonic monotherapy since 1958. In 1983, a cluster sample survey in Upper-Sangha seemed to show that the prevalence of the disease was underestimated. It then became necessary to adopt a new national strategy whose objective would be to reduce the prevalence of leprosy in the country by 50% within five years. For this, a "National Programme for the Control of Leprosy in C.A.R." has been developed; in part it foresees the setting up of polychemotherapy for patients. These treatment protocols should insure healing of paucibacillary forms within six months and of multibacillary forms within twenty-four months. The new strategy of screening and decentralized treatment required retraining personnel and combining health education at individual and collective levels. The preliminary results of a national survey for the evaluation of the prevalence of leprosy are presented.


Radical prostatectomy or watchful waiting in early prostate cancer.
Radical prostatectomy reduces mortality among men with localized prostate cancer; however, important questions regarding long-term benefit remain. Between 1989 and 1999, we randomly assigned 695 men with early prostate cancer to watchful waiting or radical prostatectomy and followed them through the end of 2012. The primary end points in the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) were death from any cause, death from prostate cancer, and the risk of metastases. Secondary end points included the initiation of androgen-deprivation therapy. During 23.2 years of follow-up, 200 of 347 men in the surgery group and 247 of the 348 men in the watchful-waiting group died. Of the deaths, 63 in the surgery group and 99 in the watchful-waiting group were due to prostate cancer; the relative risk was 0.56 (95% confidence interval [CI], 0.41 to 0.77; P=0.001), and the absolute difference was 11.0 percentage points (95% CI, 4.5 to 17.5). The number needed to treat to prevent one death was 8. One man died after surgery in the radical-prostatectomy group. Androgen-deprivation therapy was used in fewer patients who underwent prostatectomy (a difference of 25.0 percentage points; 95% CI, 17.7 to 32.3). The benefit of surgery with respect to death from prostate cancer was largest in men younger than 65 years of age (relative risk, 0.45) and in those with intermediate-risk prostate cancer (relative risk, 0.38). However, radical prostatectomy was associated with a reduced risk of metastases among older men (relative risk, 0.68; P=0.04). Extended follow-up confirmed a substantial reduction in mortality after radical prostatectomy; the number needed to treat to prevent one death continued to decrease when the treatment was modified according to age at diagnosis and tumor risk. A large proportion of long-term survivors in the watchful-waiting group have not required any palliative treatment. (Funded by the Swedish Cancer Society and others.).


Respiratory allergy in laboratory animal workers: a retrospective cohort study using pre-employment screening data.
To study the role of exposure, atopy, and smoking in the development of laboratory animal allergy (LAA) in a retrospective cohort study. Between 1977 and 1993, 225 people received a pre-employment screening when they started a job at a Dutch research institute where they were going to work with laboratory animals. After active follow up 136 of them (60.4%) could be traced and were sent a questionnaire with extensive questions on allergic symptoms, smoking habits, and job history. 122 people (89.7%) sent back a completed questionnaire. Those who were accepted for a job at the institute and did not have allergic symptoms at the start of the job were selected as cohort members. After selecting people with complete data on start and end date of jobs, exposure intensity, atopy, and smoking, the cohort consisted of 99 people with an average time of follow up of 9.7 years. LAA was defined as a positive response to a set of questions in the questionnaire. The mean number of hours a week a person was exposed to laboratory animals at entry of the cohort was used as a surrogate for exposure, and was divided into four categories. 19 cohort members (19.2%) reported LAA. More people with asthmatic symptoms were found in the high exposure categories. More atopic than non-atopic people reported asthmatic symptoms (13% v 6%). The mean time until development of symptoms of LAA was about 109 months in non-atopic people (n = 9), and 45 months in atopic people (n = 10) (t test; P < 0.05). Time until development of symptoms of LAA was shorter at a higher intensity of exposure, except for those exposed for less than two hours a week. A proportional hazard regression analysis showed that exposure and atopy were significant determinants of LAA. An increased relative risk (RR) was found for non-atopic people exposed to laboratory animal allergens for more than two hours a week. Atopic people had an even higher risk when exposed to laboratory animals for more than two hours a week (RR above 7.3). Sex, smoking, and age were not risk factors. More atopic than non-atopic people were absent from work or transferred because of allergies. This study showed that exposure and atopy are significant predictors of LAA and that the risk of developing LAA remained present for a much longer period (> 3 y) than considered before.


Barriers and facilitators to uptake of the school-based HPV vaccination programme in an ethnically diverse group of young women.
To identify the barriers and facilitators to uptake of the HPV vaccine in an ethnically diverse group of young women in the south west of England. Three school-based vaccination sessions were observed. Twenty-three young women aged 12 to 13 years, and six key informants, were interviewed between October 2012 and July 2013. Data were analysed using thematic analysis and the Framework method for data management. The priority given to preventing cervical cancer in this age group influenced whether young women received the HPV vaccine. Access could be affected by differing levels of commitment by school staff, school nurses, parents and young women to ensure parental consent forms were returned. Beliefs and values, particularly relevant to minority ethnic groups, in relation to adolescent sexual activity may affect uptake. Literacy and language difficulties undermine informed consent and may prevent vaccination. The school-based HPV vaccination programme successfully reaches the majority of young women. However, responsibility for key aspects remain unresolved which can affect delivery and prevent uptake for some groups. A multi-faceted approach, targeting appropriate levels of the socio-ecological model, is required to address procedures for consent and cultural and literacy barriers faced by minority ethnic groups, increase uptake and reduce inequalities.


Multiple Dimensions of Stigma and Health Related Factors Among Young Black Men Who Have Sex with Men.
This study is among the first to examine the association between multiple domains of HIV-related stigma and health-related correlates including viral load and medication adherence among young Black men who have sex with men (N = 92). Individual logistic regressions were done to examine the hypothesized relationships between HIV-related stigma and various health and psychosocial outcomes. In addition to examining total stigma, we also examined four domains of HIV stigma. Findings revealed the various domains of stigma had differential effects on health-related outcomes. Individuals who reported higher levels of total stigma and personalized stigma were less likely to be virally suppressed (OR 0.96, 95 % CI 0.91-1.00 and OR 0.50, 95 % CI 0.25-1.02, respectively). Concerns about public attitudes toward HIV were positively related to medication adherence (OR 2.18, 95 % CI 1.20-3.94) and psychological distress (OR 5.02, 95 % CI 1.54-16.34). The various domains of HIV stigma differentially affected health and psychosocial outcomes, and our findings suggest that some forms of HIV stigma may significantly affect viral load and medication adherence among this population. Stigma-informed approaches to care and treatment are needed, along with incorporated psychological and social supports.


Effect of ART scale-up and female migration intensity on risk of HIV acquisition: results from a population-based cohort in KwaZulu-Natal, South Africa.
Despite increased antiretroviral therapy (ART) coverage, the incidence of HIV infection among women in rural South Africa remains high. While many socio-demographic and behavioral factors have been identified, the effect of female migration intensity on the risk of HIV acquisition before and after ART scale-up has not been evaluated in the country. We followed 13,315 female participants aged 15-49 who were HIV-uninfected at baseline and recorded their migration events between 2004 and 2015. Using a Cox proportional hazard model, we estimated the time to HIV acquisition among the women, adjusting for annual migration intensity (high: ≥2 events/year, moderate = 1 event/year, and low = 0 event/year) before and after ART scale-up in 2010. 1998 (15%) new HIV-infection events were recorded during the observation period. Overall, high migration intensity was associated with an increased HIV acquisition risk among women when compared with low migration intensity (HR = 2.88, 95% CI: 1.56-5.53). Among those with high migration intensity, the risk of HIV acquisition was significantly lower in the post-ART period compared to the pre-ART period, after controlling for key socio-demographic and behavioural covariates (aHR = 0.18, 95% CI 0.04-0.83). Women who migrated frequently after ART scale-up had a significantly reduced HIV acquisition risk compared to those before its implementation. While this reduction is encouraging, women who migrate frequently remain at high risk of HIV acquisition. In the era of ART, there remains a critical need for public health interventions to reduce the risk of HIV acquisition in this highly vulnerable population.


Enhanced CD8+ T cell immune responses and protection elicited against Plasmodium berghei malaria by prime boost immunization regimens using a novel attenuated fowlpox virus.
Sterile immunity can be provided against the pre-erythrocytic stages of malaria by IFN-gamma-secreting CD8(+) T cells that recognize parasite-infected hepatocytes. In this study, we have investigated the use of attenuated fowlpox virus (FPV) strains as recombinant vaccine vectors for eliciting CD8(+) T cells against Plasmodium berghei. The gene encoding the P. berghei circumsporozoite (PbCS) protein was inserted into an FPV vaccine strain licensed for use in chickens, Webster's FPV, and the novel FPV vaccine strain FP9 by homologous recombination. The novel FP9 strain proved more potent as a vaccine for eliciting CD8(+) T cell responses against the PbCS Ag. Sequential immunization with rFP9 and recombinant modified vaccinia virus Anakara (MVA) encoding the PbCS protein, administered by clinically acceptable routes, elicited potent CD8(+) T cell responses against the PbCS protein. This immunization regimen elicited substantial protection against a stringent liver-stage challenge with P. berghei and was more immunogenic and protective than DNA/MVA prime/boost immunization. However, further improvement was not achieved by sequential (triple) immunization with a DNA vaccine, FP9, and MVA.


Oncogenic KRAS promotes malignant brain tumors in zebrafish.
Zebrafish have been used as a vertebrate model to study human cancers such as melanoma, rhabdomyosarcoma, liver cancer, and leukemia as well as for high-throughput screening of small molecules of therapeutic value. However, they are just emerging as a model for human brain tumors, which are among the most devastating and difficult to treat. In this study, we evaluated zebrafish as a brain tumor model by overexpressing a human version of oncogenic KRAS (KRAS(G12V)). Using zebrafish cytokeratin 5 (krt5) and glial fibrillary acidic protein (gfap) gene promoters, we activated Ras signaling in the zebrafish central nervous system (CNS) through transient and stable transgenic overexpression. Immunohistochemical analyses were performed to identify activated pathways in the resulting brain tumors. The effects of the MEK inhibitor U0126 on oncogenic KRAS were evaluated. We demonstrated that transient transgenic expression of KRAS(G12V) in putative neural stem and/or progenitor cells induced brain tumorigenesis. When expressed under the control of the krt5 gene promoter, KRAS(G12V) induced brain tumors in ventricular zones (VZ) at low frequency. The majority of other tumors were composed mostly of spindle and epithelioid cells, reminiscent of malignant peripheral nerve sheath tumors (MPNSTs). In contrast, when expressed under the control of the gfap gene promoter, KRAS(G12V) induced brain tumors in both VZs and brain parenchyma at higher frequency. Immunohistochemical analyses indicated prominent activation of the canonical RAS-RAF-ERK pathway, variable activation of the mTOR pathway, but no activation of the PI3K-AKT pathway. In a krt5-derived stable and inducible transgenic line, expression of oncogenic KRAS resulted in skin hyperplasia, and the MEK inhibitor U0126 effectively suppressed this pro-proliferative effects. In a gfap-derived stable and inducible line, expression of oncogenic KRAS led to significantly increased mitotic index in the spinal cord. Our studies demonstrate that zebrafish could be explored to study cellular origins and molecular mechanisms of brain tumorigenesis and could also be used as a platform for studying human oncogene function and for discovering oncogenic RAS inhibitors.


FCGR2A polymorphism is correlated with clinical outcome after immunotherapy of neuroblastoma with anti-GD2 antibody and granulocyte macrophage colony-stimulating factor.
Anti-GD2 murine IgG3 antibody 3F8 kills neuroblastoma cells by antibody-dependent cell-mediated cytotoxicity (ADCC). Granulocyte macrophage colony-stimulating factor (GM-CSF) enhances phagocyte-mediated ADCC. The differential affinity of the human FCGR polymorphic alleles for 3F8 may influence the effectiveness of antibody immunotherapy. The entire cohort of high risk neuroblastoma patients (N = 136) treated on protocol using 3F8 and GM-CSF were the subjects of this analysis. Tumor response was measured by standard clinical tools plus sensitive molecular monitoring using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Polymorphic alleles of FCGR2A and FCGR3A were determined by PCR plus direct sequencing using genomic DNA samples obtained from marrow or blood of patients. FCGR2A (R/R) genotype correlated with progression-free survival for the entire cohort (P = .049) and for the subset of patients with no history of prior relapse (P = .023). FCGR2A (R/R) also correlated with marrow remission 2.5 months after treatment initiation: by histology (P = .021 and P = .036, for the entire cohort and the subset, respectively) and by qRT-PCR (P = .052 and P = .033, respectively). The favorable outcome associated with FCGR2A (R/R) genotype is consistent with the proposed role of FCGR2A and phagocyte-mediated ADCC in 3F8 plus GM-CSF immunotherapy.


Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature in patients initially classified as idiopathic short stature.
Based on the stature observed in relatives of patients with acromesomelic dysplasia, type Maroteaux, homozygous for mutations in natriuretic peptide receptor B gene (NPR2), it has been suggested that heterozygous mutations in this gene could be responsible for the growth impairment observed in some children with idiopathic short stature (ISS). The objective of the study was to investigate the presence of NPR2 mutations in a group of patients with ISS. The NPR2 coding region was directly sequenced in 47 independent patients with ISS. The functional consequences of NPR2 nonsynonymous variations were established using in vitro cell-based assays. Three novel heterozygous NPR2 mutations were identified: c.226T>C (p.Ser76Pro), c.788G>C (p.Arg263Pro), and c.2455C>T (p.Arg819Cys). These allelic variants were not found in our controls or in the 1000 Genomes database. In silico analysis suggested that the three missense mutations are probably damaging. All of them were selected for in vitro functional evaluation. Cells transfected with the three mutants failed to produce cyclic GMP after treatment with C-type natriuretic peptide. Cells cotransfected with mutant and wild-type-NPR-B (1:1) showed a significant decrease in cGMP levels after C-type natriuretic peptide stimulation in comparison with cells cotrasnfected with empty vector and wild type, suggesting a dominant-negative effect. These three mutations segregated with short stature phenotype in an autosomal dominant pattern (height SD score ranged from -4.5 to -1.7). One of these patients and two relatives have disproportionate short stature, whereas in another patient a nonspecific skeletal abnormality was observed. All three of these patients were treated with recombinant human GH (33-50 μg/kg · d) without significant height SD score change during therapy. We identified heterozygous NPR2 mutations in 6% of patients initially classified as ISS. Affected patients have mild and variable degrees of short stature without a distinct phenotype. Heterozygous mutations in NPR2 could be an important cause of nonsyndromic familial short stature.


High altitude organic gold: The production network for Ophiocordyceps sinensis from far-western Nepal.
Ophiocordyceps sinensis (Berk.) G.H.Sung, J.M.Sung, Hywel-Jones & Spatafora, a high altitude Himalayan fungus-caterpillar product found in alpine meadows in China, Bhutan, Nepal, and India, has been used in the Traditional Chinese Medicine system for over 2000 years. Heightened demand in China over the past 15 years, coupled with limited production, has led to a price hike and increased economic importance of harvests to rural households throughout the species' range. There is, however, limited knowledge on the actors and profit distribution in the O. sinensis production network, especially from the distribution areas on the southern flanks of the Himalayas. Filling in this knowledge gap is essential to the identification and design of public interventions. To describe and quantify the O. sinensis production network originating from Darchula District in far-western Nepal. Data was collected, for fiscal year 2014-15, in spring and summer 2016 using standardized collector (n=56) and trader (n=45) questionnaires in Darchula District, and central wholesaler (n=9) questionnaires in cities of Nepal. All questionnaires contained quantitative and qualitative components focusing on key elements of the production network, i.e. value creation, enhancement, and capture; and network and territorial embeddedness. Trade is sustained and significant even at the margins of the distributional range, with 384.1 kg of O. sinensis harvested in and traded from Darchula District in 2014-15, having a collector value of approximately USD 4.7 million and constituting the dominant household-level source of income for collectors. The functioning production network is characterised by conflicts in relation to value creation, a high share of value capture by collectors, limited value enhancement, and a high degree of network and territorial embeddedness. O. sinensis income is of major economic importance for rural households at the margin of its distribution range in Nepal. Production networks operated by informal actors establishing trust-based relationships allow responses to cross-border market signals, enabling the flow of rural and remote environmental resources to urban centres of demand. There is scope for public interventions, e.g. to determine the drivers of demand.


Study protocol: a randomised controlled trial on the clinical effects of levothyroxine treatment for subclinical hypothyroidism in people aged 80 years and over.
Subclinical hypothyroidism is common in older people and its contribution to health and disease needs to be elucidated further. Observational and clinical trial data on the clinical effects of subclinical hypothyroidism in persons aged 80 years and over is inconclusive, with some studies suggesting harm and some suggesting benefits, translating into equipoise whether levothyroxine therapy provides clinical benefits. This manuscript describes the study protocol for the Institute for Evidence-Based Medicine in Old Age (IEMO) 80-plus thyroid trial to generate the necessary evidence base. The IEMO 80-plus thyroid trial was explicitly designed as an ancillary experiment to the Thyroid hormone Replacement for Untreated older adults with Subclinical hypothyroidism randomised placebo controlled Trial (TRUST) with a near identical protocol and shared research infrastructure. Outcomes will be presented separately for the IEMO and TRUST 80-plus groups, as well as a pre-planned combined analysis of the 145 participants included in the IEMO trial and the 146 participants from the TRUST thyroid trial aged 80 years and over. The IEMO 80-plus thyroid trial is a multi-centre randomised double-blind placebo-controlled parallel group trial of levothyroxine treatment in community-dwelling participants aged 80 years and over with persistent subclinical hypothyroidism (TSH ≥4.6 and ≤ 19.9 mU/L and fT4 within laboratory reference ranges). Participants are randomised to levothyroxine 25 or 50 micrograms daily or matching placebo with dose titrations according to TSH levels, for a minimum follow-up of one and a maximum of three years. Primary study endpoints: hypothyroid physical symptoms and tiredness on the thyroid-related quality of life patient-reported outcome (ThyPRO) at one year. Secondary endpoints: generic quality of life, executive cognitive function, handgrip strength, functional ability, blood pressure, weight, body mass index, and mortality. Adverse events will be recorded with specific interest on cardiovascular endpoints such as atrial fibrillation and heart failure. The combined analysis of participants in the IEMO 80-plus thyroid trial with the participants aged over 80 in the TRUST trial will provide the largest experimental evidence base on multimodal effects of levothyroxine treatment in 80-plus persons to date. Nederlands (Dutch) Trial Register: NTR3851 (12-02-2013), EudraCT: 2012-004160-22 (17-02-2013), ABR-41259.058.13 (12-02-2013).


Is there a direct role for erythrocytes in the immune response?
Erythrocytes are highly abundant circulating cells in the vertebrates, which, with the notable exception of mammals, remain nucleated throughout the entire life cycle. The major function associated with these cells is respiratory gas exchange however other functions including interaction with the immune system have been attributed to these cells. Many viral, prokaryotic and eukaryotic pathogens directly target this cell type and across the vertebrate group a significant number of related pathologies have been reported. Across the primary literature mechanisms of interaction, invasion and replication between viruses and erythrocytes have been well described however the functional response of the erythrocyte has been poorly studied. A fragmented series of reports spanning the vertebrates suggests that these cells are capable of functional responses to viral infection. In contrast, in-depth proteomic studies using human erythrocytes have strongly progressed throughout the past decade providing a rich source of information related to protein expression and potential function. Furthermore information at the gene expression level is becoming available. Here we provide a review of erythrocyte-pathogen interactions, erythrocyte functions in immunity and propose in light of recent -omics research that the nucleated erythrocytes may have a direct role in the immune response.


Pseudomonas syringae pv. tomato: the right pathogen, of the right plant, at the right time.
Abstract Pseudomonas syringae pv. tomato and the closely related pathovar P. s. pv. maculicola have been the focus of intensive research in recent years, not only because of the diseases they cause on tomato and crucifers, but because strains such as P. s. pv. tomato DC3000 and P. s. pv. maculicola ES4326 are pathogens of the model plant Arabidopsis thaliana. Consequently, both P. s. pv. tomato and P. s. pv. maculicola have been widely used to study the molecular mechanisms of host responses to infection. Analyses of the molecular basis of pathogenesis in P. s. pv. tomato reveal a complex and intimate interaction between bacteria and plant cells that depends on the coordinated expression of multiple pathogenicity and virulence factors. These include toxins, extracellular proteins and polysaccharides, and the translocation of proteins into plant cells by the type III (Hrp) secretion system. The contribution of individual virulence factors to parasitism and disease development varies significantly between strains. Application of functional genomics and cell biology to both pathogen and host within the P. s. pv. tomato/A. thaliana pathosystem provides a unique opportunity to unravel the molecular interactions underlying plant pathogenesis. Taxonomic relationship: Bacteria; Proteobacteria; gamma subdivision; Pseudomonadaceae/Moraxellaceae group; Pseudomonadaceae family; Pseudomonas genus; Pseudomonas syringae species; tomato pathovar. Microbiological properties: Gram-negative, aerobic, motile, rod-shaped, polar flagella, oxidase negative, arginine dihydrolase negative, DNA 58-60 mol% GC, elicits the hypersensitive response on tobacco. Primarily studied as the causal agent of bacterial speck of tomato and as a model pathogen of A. thaliana, although it has been isolated from a wide range of crop and weed species. Disease symptoms: Tomato (Lycopersicon esculentum): Brown-black leaf spots sometimes surrounded by chlorotic margin; dark superficial specks on green fruit; specks on ripe fruit may become sunken, and are surrounded by a zone of delayed ripening. Stunting and yield loss, particularly if young plants are infected. Reduced market value of speckled fruit. A. thaliana: Water-soaked, spreading lesions, sometimes surrounded by chlorotic margin. Seed borne. Survives as a saprophyte in plant debris, soil and on leaf surfaces. Dispersed by aerosols and rain splash. Development of disease symptoms favoured by leaf wetness and cool temperatures (55-77 degrees F/13-25 degrees C). Disease control: Pathogen-free seed and transplants. Resistant and tolerant cultivars. Sanitation, rotation, and drip irrigation to reduce leaf wetness. Some measure of control with bactericides (copper, streptomycin).


Fluidics of Single and Double Blade Guillotine Vitrectomy Probes in Balanced Salt Solution and Artificial Vitreous.
To assess the fluidics of double-vitreous cutter blade (DB) compared with single-blade (SB) guillotine with 23-, 25-, and 27-gauge vitrectomy probes. To assess flow characteristics and flow rates in viscous and viscoelastic fluids. We used Particle Image Velocimetry to measure the flow field close to the tip of each cutter probe and we derived kinematic quantities of interest, such as kinetic energy and acceleration. We performed measurements both on a balanced salt solution (BSS) and on a viscoelastic artificial vitreous (AV). The flow rate is significantly higher with DB than SB vitrectomy probes, for a given pumping pressure and cutting rate. The fluid flow observed is very different between BSS and AV tests. The DB has more efficient fluidics than SB vitrectomy probe in all tested conditions. Fluid acceleration depends on the cutting frequency, especially in the case of measurements in AV. The flow rate strongly depends on the pressure and it is little affected by the cutting frequency, in a range of clinical interest. The 27-G DB produces flow rates similar to the 23- and 25-G SB, with significantly smaller acceleration. The flow induced in the AV is different from that in BSS and oscillates at different frequencies. DB cutters prove to be more efficient in terms of lower acceleration for a given flow rate. The latter is mainly controlled by aspiration pressure and less by cut rates. The influence of vitreous rheology deserves further investigations.


Transcatheter arterial chemoembolization in unresectable cholangiocarcinoma: initial experience in a single institution.
Unresectable cholangiocarcinoma carries a dismal prognosis, with median survival times ranging from 6 to 12 months from the time of diagnosis. Palliative therapies have been disappointing and have not been shown to significantly prolong survival. Conversely, transcatheter arterial chemoembolization (TACE) has been effective in prolonging the lives of patients with hepatocellular carcinoma but has not been used against cholangiocarcinoma. Therefore, the purpose of the present study was to assess the safety and efficacy (ie, survival) of TACE in patients with unresectable intrahepatic cholangiocarcinoma. Seventeen patients with unresectable cholangiocarcinoma were treated with one or more cycles of TACE between 1995 and 2004 at our institution. Follow-up imaging was performed on all patients 4-6 weeks after each TACE procedure to determine tumor response and need for further treatment. Survival was calculated with use of the Kaplan-Meier survival curve. The median survival for 17 patients treated with TACE was 23 months. Two patients with previously unresectable disease underwent successful resection after TACE. The procedure was well tolerated by 82% of the patients, who experienced no side effects or mild side effects that quickly resolved with conservative therapy alone. Two patients had minor complications (12%), which were managed successfully, and one had a major complication that resulted in a fatal outcome. This patient had a rapidly declining course from the time of diagnosis and died shortly after TACE. The results suggest that TACE was effective at prolonging survival of patients with unresectable cholangiocarcinoma. Therefore, for these patients, TACE may be an appropriate palliative therapy.


Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3.
The propagation of embryonic stem (ES) cells in an undifferentiated pluripotent state is dependent on leukemia inhibitory factor (LIF) or related cytokines. These factors act through receptor complexes containing the signal transducer gp130. The downstream mechanisms that lead to ES cell self-renewal have not been delineated, however. In this study, chimeric receptors were introduced into ES cells. Biochemical and functional studies of transfected cells demonstrated a requirement for engagement and activation of the latent trancription factor STAT3. Detailed mutational analyses unexpectedly revealed that the four STAT3 docking sites in gp130 are not functionally equivalent. The role of STAT3 was then investigated using the dominant interfering mutant, STAT3F. ES cells that expressed this molecule constitutively could not be isolated. An episomal supertransfection strategy was therefore used to enable the consequences of STAT3F expression to be examined. In addition, an inducible STAT3F transgene was generated. In both cases, expression of STAT3F in ES cells growing in the presence of LIF specifically abrogated self-renewal and promoted differentiation. These complementary approaches establish that STAT3 plays a central role in the maintenance of the pluripotential stem cell phenotype. This contrasts with the involvement of STAT3 in the induction of differentiation in somatic cell types. Cell type-specific interpretation of STAT3 activation thus appears to be pivotal to the diverse developmental effects of the LIF family of cytokines. Identification of STAT3 as a key transcriptional determinant of ES cell self-renewal represents a first step in the molecular characterization of pluripotency.


Beyond daily dosing: clinical experience.
Osteoporosis has had a significant public health impact, with many sufferers experiencing fractures. Such fractures lead to increased disability, mortality and reduced quality of life, all of which raise healthcare costs. Oral bisphosphonates are associated with significant antifracture efficacy and have therefore become the mainstay of treatment for postmenopausal osteoporosis. Poor therapeutic adherence with daily bisphosphonates has been improved by the introduction of weekly regimens, although adherence levels remain suboptimal. Bisphosphonate regimens with dosing intervals beyond a week have therefore been developed to address this issue. Oral ibandronate, a potent nitrogen-containing bisphosphonate, has been studied using daily and intermittent regimens (between-dose interval >2 months). The initial phase II 2-year study confirmed the feasibility of the intermittent regimen, providing increases in lumbar spine bone mineral density (BMD) superior to placebo (P < 0.01) and equivalent to the daily regimen (5.64% vs. 5.54%, respectively). BONE (Oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe), a large phase III 3-year study was subsequently initiated, including 2946 women with postmenopausal osteoporosis and testing both a daily as well as an intermittent regimen with a dose-free interval of more than 2 months. Significant vertebral antifracture efficacy (the primary study endpoint) was demonstrated with daily (2.5 mg) and intermittent (20 mg every other day for 12 doses every 3 months) ibandronate in comparison with placebo (P < or = 0.0006). As a result of the study not being designed and powered to show an effect on non-vertebral fractures and the overall population being at low risk for osteoporotic fractures, differences in the incidence of non-vertebral fractures were similar between groups (8.2-9.1%) However, a post hoc analysis in a subgroup of patients with a femoral neck BMD T-score < -3.0 showed that daily ibandronate significantly reduced the risk of non-vertebral fractures (P = 0.012). Both regimens were associated with significant increases in lumbar spine and proximal femur BMD and normalization of bone turnover. As determined by adverse event incidence and laboratory evaluation, the safety profile for both ibandronate regimens was similar to that observed for placebo. The BONE study therefore confirmed that daily or intermittent ibandronate is an effective and well-tolerated treatment for postmenopausal women. Being the first study to demonstrate antifracture efficacy with an intermittent regimen, it provided "proof of concept" for beyond weekly dosing with ibandronate and prompted further development of a more convenient once-monthly regimen.


Effective emissivity of a blackbody cavity formed by two coaxial tubes.
A blackbody cavity is developed for continuously measuring the temperature of molten steel, which consists of a cylindrical outer tube with a flat bottom, a coaxial inner tube, and an aperture diaphragm. The ray-tracing approach based on the Monte Carlo method was applied to calculate the effective emissivity for the isothermal cavity with the diffuse walls. And the dependences of the effective emissivity on the inner tube relative length were calculated for various inner tube radii, outer tube lengths, and wall emissivities. Results indicate that the effective emissivity usually has a maximum corresponding to the inner tube relative length, which can be explained by the impact of the inner tube relative length on the probability of the rays absorbed after two reflections. Thus, these results are helpful to the optimal design of the blackbody cavity.


Distinct morning and evening fatigue profiles in gastrointestinal cancer during chemotherapy.
Purposes were to identify subgroups of patients with gastrointestinal cancers with distinct morning and evening fatigue severity profiles and evaluate for differences among these subgroups in demographic and clinical characteristics, co-occurring symptoms and quality of life (QOL) outcomes. Patients with gastrointestinal cancers (n=405) completed questionnaires six times over two cycles of chemotherapy. Latent profile analysis was used to identify distinct morning and evening fatigue profiles. Differences in demographic and clinical characteristics, co-occurring symptoms and QOL outcomes among the subgroups were evaluated using parametric and nonparametric tests. Two distinct mornings (ie, low and very high) and three distinct evenings (ie, low, moderate and very high) fatigue classes were identified. Common risk factors for both morning and evening fatigue included younger age, lower performance status, higher comorbidity burden and self-reported depression. Higher levels of morning fatigue were associated with being unmarried, living alone, being unemployed, having a lower income, lack of regular exercise and a self-reported diagnosis of anaemia. Higher levels of evening fatigue were associated with being women, white and having childcare responsibilities. Patients in the very high morning and evening fatigue classes reported higher levels of anxiety, depressive symptoms, sleep disturbance and pain and lower levels of attentional function and poorer QOL. Findings provide new insights into risk factors for and deleterious effects of morning and evening fatigue in patients with gastrointestinal cancers. Clinicians can use this information to identify high-risk patients and develop individualised interventions for morning and evening fatigue and other co-occurring symptoms.


Proteasome-mediated effects on amyloid precursor protein processing at the gamma-secretase site.
Abeta (beta-amyloid) peptides are found aggregated in the cortical amyloid plaques associated with Alzheimer's disease neuropathology. Inhibition of the proteasome alters the amount of Abeta produced from APP (amyloid precursor protein) by various cell lines in vitro. Proteasome activity is altered during aging, a major risk factor for Alzheimer's disease. In the present study, a human neuroblastoma cell line expressing the C-terminal 100 residues of APP (SH-SY5Y-SPA4CT) was used to determine the effect of proteasome inhibition, by lactacystin and Bz-LLL-COCHO (benzoyl-Leu-Leu-Leu-glyoxal), on APP processing at the gamma-secretase site. Proteasome inhibition caused a significant increase in Abeta peptide levels in medium conditioned by SH-SY5Y-SPA4CT cells, and was also associated with increased cell death. APP is a substrate of the apoptosis-associated caspase 3 protease, and we therefore investigated whether the increased Abeta levels could reflect caspase activation. We report that caspase activation was not required for proteasome-inhibitor-mediated effects on APP (SPA4CT) processing. Cleavage of Ac-DEVD-AMC (N-acetyl-Asp-Glu-Val-Asp-7-amino-4-methylcoumarin), a caspase substrate, was reduced following exposure of SH-SY5Y-SPA4CT cells to lactacystin, and co-treatment of cells with lactacystin and a caspase inhibitor [Z-DEVD-FMK (benzyloxycarbonyl-Val-Ala-DL-Asp-fluoromethylketone)] resulted in higher Abeta levels in medium, augmenting those seen with lactacystin alone. This study indicated that proteasome inhibition could increase APP processing specifically at the gamma-secretase site, and increase release of Abeta, in the absence of caspase activation. This indicates that the decline in proteasome function associated with aging would contribute to increased Abeta levels.


The effect of verapamil on the transport of peptides across the blood-brain barrier in rats: kinetic evidence for an apically polarized efflux mechanism.
When the blood-brain barrier (BBB) transport of a series of model peptides that varied in their physicochemical properties (lipophilicity, size and hydrogen-bonding potential) was determined using an in situ rat brain perfusion technique, an unexpected increase in flux with increasing peptide concentration was observed with one of the peptides. Further, inclusion of verapamil in the perfusion medium also increased permeability of the peptides. These observations were consistent with the presence of a polarized efflux system in the BBB that was saturable, could be competitively inhibited and showed substrate specificity. Such properties are similar to those of P-glycoprotein (P-gp), an apically localized efflux pump that has recently been reported to be present in the endothelial cells that constitute the BBB, and suggest that P-gp may be responsible for this activity. By measuring the BBB transport of the model peptides in the presence of verapamil (a P-gp inhibitor), the intrinsic BBB permeabilities (due to passive diffusion only) were obtained. The presence of verapamil caused a significant increase in the BBB permeabilities of six of the seven model peptides. When the intrinsic permeability coefficients were correlated with several physicochemical parameters, it was shown that hydrogen bonding potential rather than lipophilicity had the greatest influence on the passive diffusion of these model peptides across the BBB. From these studies it can be concluded that inhibition of P-gp, as well as reduction of the hydrogen bonding potential, can be used as strategies to increase peptide transport across the BBB.


Association Between Life's Simple 7 and Noncardiovascular Disease: The Multi-Ethnic Study of Atherosclerosis.
The American Heart Association introduced the Life's Simple 7 (LS7) metrics to assess and promote cardiovascular health. We examined the association between the LS7 metrics and noncardiovascular disease. We studied 6506 men and women aged between 45 and 84 years, enrolled in the Multi-Ethnic Study of Atherosclerosis. Median follow-up time was 10.2 years. Each component of the LS7 metrics (smoking, body mass index, physical activity, diet, total cholesterol, blood pressure, and blood glucose) was assigned points, 0 indicates "poor" category; 1, "intermediate," and 2, "ideal." The LS7 score, ranged from 0 to 14, was created from the points and categorized as optimal (11-14), average (9-10), and inadequate (0-8). Hazard ratios and event rates per 1000 person-years were calculated for outcomes based on self-reported hospitalizations with the International Classification of Diseases, 9th Revision, diagnoses of cancer, chronic kidney disease, pneumonia, deep venous thromboembolism/pulmonary embolism, chronic obstructive pulmonary disease, dementia, and hip fracture. Analyses were adjusted for age, sex, race/ethnicity, income, and education. Overall, noncardiovascular disease event rates were lower with increasing LS7 scores. With the inadequate LS7 score as reference, an optimal score was associated with a decreased risk for noncardiovascular disease events. The hazard ratio for cancer was, 0.80 (0.64-0.98); chronic kidney disease, 0.38 (0.27-0.54); pneumonia, 0.57 (0.40-0.80); deep venous thromboembolism/pulmonary embolism, 0.52 (0.33-0.82), and chronic obstructive pulmonary disease, 0.51 (0.31-0.83). The American Heart Association's LS7 score identified individuals who were vulnerable to multiple chronic nonvascular conditions. These results suggest that improving cardiovascular health will also reduce the burden of cancer and other chronic diseases.


Cerebrospinal fluid levels of iodothyronines and nerve growth factor in patients with multiple sclerosis and neuromyelitis optica.
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the human central nervous system (CNS) and a major cause of neurological disability among adults in North America and Europe. Neuromyelitis optica (NMO) is a very severe disease of inflammatory demyelination located in the optic chiasm, nerves and the spinal cord. The aim of this study is to assess thyroid hormone (TH) and nerve growth factor (NGF) levels in cerebrospinal fluid (CSF) of MS, NMO patients and controls, and investigate whether there is any correlation between TH and NGF levels in the CSF. 38 relapsing-remitting multiple sclerosis (RRMS), 10 NMO and 19 controls were investigated whether there was any correlation between TH and NGF levels in the CSF. MS and NMO patients exhibited significantly higher CSF NGF (respectively P<0.05, P<0.05), TT4 levels (P<0.001) and higher TT4/ rT3 ratio (respectively P<0.01, P<0.01) compared with the controls. Significant correlation was found between CSF NGF levels and CSF rT3 levels or TT4/ rT3 ratio in controls (respectively P<0.01, P<0.05). EDSS was significantly correlated with CSF rT3 levels and TT4/ rT3 ratio in MS patients (respectively P<0.05, P<0.001). These results indicate that an abnormal thyroid hormone may exist within the brain in the patients with MS. CSF rT3 levels and TT4/ rT3 ratio could be regarded as useful markers of underlying disease activity.


Disseminated adenovirus infection in heart and kidney transplant.
Presently described is a case of disseminated adenovirus infection in a heart-kidney transplant recipient that was successfully treated with cidofovir. There are several reports of adenovirus infections in adult solid organ transplant recipients and the prognosis is usually poor, with mortality rates of 40% to 60%. Severe disseminated adenovirus infections have been associated with increased risk of adverse transplant events, such as rejection, ventricular dysfunction, allograft vasculopathy, graft loss, and the need for re-transplantation. The patient's lack of clinical improvement, the onset of hemorrhagic cystitis and acute kidney injury were factors in our decision to temporarily discontinue administration of immunosuppressive agents and start an antiviral agent. It is important to suspect adenovirus in transplant patients when they do not respond to antibiotics and cultures are negative. Early diagnosis and treatment are critical to improving outcomes in immunocompromised patients.


Differentiation-linked leukemogenesis in lymphocytes.
Most human lymphoid malignancies preserve a pattern of gene expression reflecting their proliferative activity and the development level of clonal expansion and maturation arrest. Characteristics of leukemia and other cancer cells frequently considered to reflect aberrant differentiation may more often reflect clonal selection of cell types that are normally infrequent and transitory. The differentiation status of progenitor or mature lymphoid cells influences which genetic elements are at risk of being exploited, via mutation, recombination, or deletion, for clonal advantage. These alterations may frequently arise spontaneously as a consequence of the unique developmental and functional programs of lymphoid cells and have as a major phenotypic consequence the stabilization of transitory cellular phenotypes.


Systemic autoimmune rheumatic disease prevalence in Canada: updated analyses across 7 provinces.
To estimate systemic autoimmune rheumatic disease (SARD) prevalence across 7 Canadian provinces using population-based administrative data evaluating both regional variations and the effects of age and sex. Using provincial physician billing and hospitalization data, cases of SARD (systemic lupus erythematosus, scleroderma, primary Sjögren syndrome, polymyositis/dermatomyositis) were ascertained. Three case definitions (rheumatology billing, 2-code physician billing, and hospital diagnosis) were combined to derive a SARD prevalence estimate for each province, categorized by age, sex, and rural/urban status. A hierarchical Bayesian latent class regression model was fit to account for the imperfect sensitivity and specificity of each case definition. The model also provided sensitivity estimates of different case definition approaches. Prevalence estimates for overall SARD ranged between 2 and 5 cases per 1000 residents across provinces. Similar demographic trends were evident across provinces, with greater prevalence in women and in persons over 45 years old. SARD prevalence in women over 45 was close to 1%. Overall sensitivity was poor, but estimates for each of the 3 case definitions improved within older populations and were slightly higher for men compared to women. Our results are consistent with previous estimates and other North American findings, and provide results from coast to coast, as well as useful information about the degree of regional and demographic variations that can be seen within a single country. Our work demonstrates the usefulness of using multiple data sources, adjusting for the error in each, and providing estimates of the sensitivity of different case definition approaches.


The Ras/protein kinase A pathway acts in parallel with the Mob2/Cbk1 pathway to effect cell cycle progression and proper bud site selection.
In Saccharomyces cerevisiae, Ras proteins connect nutrient availability to cell growth through regulation of protein kinase A (PKA) activity. Ras proteins also have PKA-independent functions in mitosis and actin repolarization. We have found that mutations in MOB2 or CBK1 confer a slow-growth phenotype in a ras2Delta background. The slow-growth phenotype of mob2Delta ras2Delta cells results from a G1 delay that is accompanied by an increase in size, suggesting a G1/S role for Ras not previously described. In addition, mob2Delta strains have imprecise bud site selection, a defect exacerbated by deletion of RAS2. Mob2 and Cbk1 act to properly localize Ace2, a transcription factor that directs daughter cell-specific transcription of several genes. The growth and budding phenotypes of the double-deletion strains are Ace2 independent but are suppressed by overexpression of the PKA catalytic subunit, Tpk1. From these observations, we conclude that the PKA pathway and Mob2/Cbk1 act in parallel to determine bud site selection and promote cell cycle progression.


Single mothers in Ontario: sociodemographic, physical and mental health characteristics.
To examine the sociodemographic, physical and mental health characteristics of single mothers in Ontario. Cross-sectional. Ontario. Ontario residents aged 15 years or older who participated in the Ontario Health Supplement survey conducted between December 1990 and April 1991; of 9953 eligible participants, 1540 were mothers with at least 1 dependent child (less than 16 years of age). Prevalence rates of sociodemographic, physical and mental health characteristics. Single mothers were significantly more likely than the mothers in 2-parent families to be poor, to be 25 years of age or less, to have mental health problems (dissatisfaction with multiple aspects of life, affective disorder ever and 1 or more psychiatric disorders in the past year or ever) and to use mental health services. When compared by income level, poor single mothers had a higher prevalence of all mental health outcomes measured; the difference was significant for anxiety disorder in the past year or ever and for 1 or more psychiatric disorders in the past year or ever. In a logistic regression analysis, single-mother status was found to have the strongest independent effect on predicting mental health morbidity and utilization of mental health services; the next strongest was low income. Single mothers are more likely to be poor, to have an affective disorder and to use mental health services than mothers in 2-parent families. The risk of mental health problems is especially pronounced among poor single mothers. Further studies are needed to determine which aspects of single motherhood, apart from economic status, affect mental health outcomes.


How should we evaluate health status? A comparison of three methods in patients presenting with obstructive sleep apnoea.
The purpose of this paper is to compare three approaches to the measurement of patient-reported health status which produce summary scales of health status: the Patient-generated Index (PGI) is a measure of individual quality of life (QoL), the EuroQol is a measure of QoL the results of which are weighted by utility values gained from community surveys and the SF-36 which produces two summary scales of health status (the physical component summary (PCS) and the mental component summary (MCS) scores). A follow-up interview survey of patients with obstructive sleep apnoea (OSA) was conducted. The patients received continuous positive airways pressure therapy (CPAP) between the two administrations of the questionnaires. One hundred patients presenting with OSA and who were suitable for CPAP therapy were asked if they would take part in the study. The results on the PGI, EuroQol EQ-5D utility weighted scores and 'thermometer' scores and SF-36 physical and mental summary scores were measured. Eighty-nine respondents provided sufficient data to calculate PGI and EuroQol scores and 86 patients provided sufficient data to calculate SF-36 summary scores. The PGI indicated substantial improvement after CPAP treatment whereas the EuroQol indicated little or no improvement on either utility weighted or thermometer scores. The SF-36 PCS and MCS scores were lower than those of the general population at baseline, but had improved to the normative levels after treatment. The EuroQol provided a substantially different picture of change to either of the ones gained from the SF-36 or PGI. It is suggested that the EuroQol does not contain questions which relate to important aspects of health and well-being and may not accurately reflect the health state of individuals. Consequently, caution must be exercised to assure that an appropriate instrument has been employed when using health outcomes data to assess or prioritize available health care treatments.


Evidence for the Efficacy of Systemic Opioid-Sparing Analgesics in Pediatric Surgical Populations: A Systematic Review.
While a large number of studies has examined the efficacy of opioid-sparing analgesics in adult surgical populations, fewer studies are available to guide postoperative pain treatment in pediatric patients. We systematically reviewed available publications on the use of systemic nonopioid agents for postoperative analgesia in pediatric surgical populations. A comprehensive literature search identified meta-analyses and randomized controlled trials (RCTs) assessing the effects of systemic, nonopioid agents on postoperative narcotic requirements or pain scores in pediatric surgical populations. If a meta-analysis was located, we summarized its results and any RCTs published after it. We located and reviewed 11 acetaminophen RCTs, 1 nonsteroidal anti-inflammatory drug (NSAID) meta-analysis, 2 NSAID RCTs, 1 dexamethasone meta-analysis, 3 dexamethasone RCTs, 2 ketamine meta-analyses, 5 ketamine RCTs, 2 gabapentin RCTs, 1 clonidine meta-analysis, 3 magnesium RCTs, 2 dexmedetomidine meta-analyses, and 1 dextromethorphan RCT. No meta-analyses or RCTs were found assessing the perioperative efficacy of intravenous lidocaine, amantadine, pregabalin, esmolol, or caffeine in pediatric surgical patients. The available evidence is limited, but suggests that perioperative acetaminophen, NSAIDs, dexamethasone, ketamine, clonidine, and dexmedetomidine may decrease postoperative pain and opioid consumption in some pediatric surgical populations. Not enough, or no, data exist from which to draw conclusions on the perioperative use of gabapentin, magnesium, dextromethorphan, lidocaine, amantadine, pregabalin, esmolol, and caffeine in pediatric surgical patients. Further pharmacokinetic and pharmacodynamics studies to establish both the clinical benefit and efficacy of nonopioid analgesia in pediatric populations are needed.


In vivo protein transduction to the CNS.
Proteins and peptides are useful research and therapeutic tools, however applications are limited because delivery to the desired location is not easily achievable. There are two hurdles in protein/peptide delivery to the brain: the blood-brain barrier and intracellular penetration. Penetration to both brain and the intracellular space can be achieved by adjusting hydrophilicity, and small molecule pharmacological agents have been successfully developed using this approach. But with proteins and peptides, it is difficult to modify the hydrophilicity without influencing biological functions. Trans-acting factor protein from the human immunodeficiency virus contains a highly conserved cationic peptide sequence necessary for transduction across the cell membrane. While trans-acting factor peptide has been used for in vitro protein transduction, its in vivo application is very limited because it is rapidly degraded by proteolysis. Polyethylenimine is a chemically synthesized small molecule cationization agent; the charge density is greater than a peptide-based cationic cluster such as trans-acting factor, and it is resistant to proteolysis in vivo. We first tested intracellular protein transduction following direct brain injection in mice using polyethylenimine-conjugated green fluorescence protein and beta-galactosidase (molecular weights 29 and 540 kDa, respectively). Polyethylenimine-conjugates penetrated to the intracellular space immediately surrounding the injection site within one hour. We further tested polyethylenimine-mediated protein transduction following intranasal administration, which bypasses the blood-brain barrier. Polyethylenimine-conjugates in pH 7.5 solution did not reach the brain, probably because the polyethylenimine-conjugates penetrated into the intracellular space where first exposed to the tissue, i.e. at the nasal mucosae. We temporarily reduced the electrostatic interaction between cationized polyethylenimine-conjugates and cellular surfaces by adjusting the pH to 4.5; solution rapidly reached the brain and penetrated to the intracellular space. This study suggests that polyethylenimine is a useful protein transduction agent in the brain in vivo, and adjusting cationic charge interaction can determine the extent of brain penetration.


Anti-nociceptive effect of patchouli alcohol: Involving attenuation of cyclooxygenase 2 and modulation of mu-opioid receptor.
To explore the anti-nociceptive effect of patchouli alcohol (PA), the essential oil isolated from Pogostemon cablin (Blanco) Bent, and determine the mechanism in molecular levels. The acetic acid-induced writhing test and formalin-induced plantar injection test in mice were employed to confirm the effect in vivo. Intracellular calcium ion was imaged to verify PA on mu-opioid receptor (MOR). Cyclooxygenase 2 (COX2) and MOR of mouse brain were expressed for determination of PA's target. Cellular experiments were carried out to find out COX2 and MOR expression induced by PA. PA significantly reduced latency period of visceral pain and writhing induced by acetic acid saline solution (P<0.01) and allodynia after intra-plantar formalin (P<0.01) in mice. PA also up-regulated COX2 mRNA and protein (P<0.05) with a down-regulation of MOR (P<0.05) both in in vivo and in vitro experiments, which devote to the analgesic effect of PA. A decrease in the intracellular calcium level (P<0.05) induced by PA may play an important role in its anti-nociceptive effect. PA showed the characters of enhancing the MOR expression and reducing the intracellular calcium ion similar to opioid effect. Both COX2 and MOR are involved in the mechanism of PA's anti-nociceptive effect, and the up-regulation of the receptor expression and the inhibition of intracellular calcium are a new perspective to PA's effect on MOR.


Maternal postnatal care in Bangladesh: a closer look at specific content and coverage by different types of providers.
The first 48 hours after birth is a critical window of time for the survival for both mothers and their newborns. Timely and adequate postnatal care (PNC) is being promoted as a strategy to reduce both maternal and newborn mortality. Whether or not a woman has received a postnatal check within 48 hours has been well studied, however, specific content and type of provider are also important for understanding the quality of the check. The objective of this paper is to understand who receives specific PNC interventions by type of provider in Bangladesh. Data from the 2014 Bangladesh Demographic and Health Survey (DHS) were used to study receipt of specific PNC interventions - breast exam, vaginal discharge exam, temperature check and counseling on danger signs - within 2 days of birth. Descriptive bivariate analyses and regression analyses using generalized estimating equations (GEE) were used to understand if receipt of an intervention differed by socio-economic and health-related factors. A key factor studied was the type of provider of the PNC. The proportion of women receiving specific interventions during maternal PNC was mostly low (41.81% for breast exam, 39.72% for vaginal discharge, 82.22% for temperature check, 55.56% for counseling on danger signs and 16.95% for all four interventions). Findings from the regression analyses indicated that compared to having postnatal contact with formal providers (doctors, nurses, midwives and paramedics), having postnatal contact with village doctors was significantly associated with lower probabilities of receiving a breast exam, vaginal discharge exam and receiving all four interventions. PNC provided by NGO workers and other community attendants was significantly associated with a lower probability of receiving a vaginal discharge exam but a higher probability of receiving counseling on danger signs. During PNC, women were much more likely to receive a temperature check than counseling on danger signs, breast exams or vaginal discharge exams. Very few women received all four interventions. In the situation where Bangladesh is experiencing a shortage of high-level providers, training more types of providers, particularly informal village doctors, may be an important strategy for improving the quality of PNC.


Effect of Salicylic Acid on the Membrane Proteome and Virulence of Pseudomonas aeruginosa.
This study aimed to determine the effect of salicylic acid on the membrane proteome, sensitivity to antibiotics, and production of microbial keratitis by Pseudomonas aeruginosa. P. aeruginosa 6294 was grown in the presence or absence of 30 mM salicylic acid. Bacterial membrane proteins were extracted in carbonate buffer, separated using two-dimensional gel electrophoresis and identified by mass spectrometry. The minimum inhibitory concentration (MIC) of various antibiotics was determined using P. aeruginosa 6294 grown in presence or absence of salicylic acid. The scratch mouse model of microbial keratitis was used to determine whether treatment with 30 mM salicylic acid could improve the outcome of infection. Growth in salicylic acid altered the membrane proteome of P. aeruginosa 6294. Eighteen proteins, including OprF, OprD, MexA, OprG, PilQ, and flagellin-type A protein, were downregulated, six proteins, including OprM and OprB, were upregulated, and nine proteins were unaffected by growth in salicylic acid. Growth in salicylic acid slightly increased the resistance to carbapenem antibiotics but did not affect MICs of the other antibiotics tested. Salicylic acid treatment significantly reduced the clinical score of eyes and bacterial load in eyes during microbial keratitis but had no effect on numbers of infiltrating neutrophils. Salicylic acid altered the membrane proteins of P. aeruginosa, slightly increased the resistance of the bacterium to carbapenem antibiotics only, and was able to reduce the pathogenicity associated with P. aeruginosa infection of mouse corneas. Salicylic acid may be useful as an antimicrobial agent in the treatment of Pseudomonas keratitis.


Exercise prevention of unloading-induced bone and muscle loss in adult mice.
Skeletal unloading causes bone and muscle loss that may be reversed by post-unloading exercise. This study examines the effects of unloading and exercise, using tail-suspension for 14 days combined with a week of post-suspension cage wheel running in mice. Twenty-four adult, male, C57BL/6J mice were divided into four groups (n = 6 mice/group); unsuspended non-running, tail-suspended non-running, unsuspended running, and tail-suspended running. At sacrifice, the calf (soleus, gastrocnemeius and plantaris complex), heart, tibia and femur were collected and weighed. The femora and tibiae were cleaned of non-osseous tissue, subjected to 3-point bending (femurs only), and weighed for dry (105 degrees C; 24h) and ash mass (800 degrees C; 24h). The mean calf mass from the tail-suspended groups (157.13 +/- 2.83 mg) was significantly less than in the unsuspended groups (167.33 +/- 2.83 mg; p = 0.019), with no significant effect of cage wheel running. The mean heart mass in running groups (166.58 +/- 4.78 mg) was significantly greater than the non-running groups (148.17 +/- 4.78 mg; p = 0.013), with no effect of hindlimb suspension. The mean femur ash mass from tail-suspended groups (24.02 +/- 0.38 mg) were significantly less than the unsuspended groups (25.11 +/- 0.34 mg; p = 0.050), and the running groups (25.13 +/- 0.38 mg) were significantly greater than the non-running groups (24.00 +/- 0.34 mg; p = 0.043). No effect was observed for the femur dry mass or percent mineralization. Measurements of mechanical length tended to be lower in tail-suspension, with no significant affects do to cage wheel running. This study suggests that tail-suspension in adult mice significantly decreases skeletal muscle and bone mass, with no change in percent mineralization. Furthermore, one week of running does not reverse the effects on the skeletal muscle and bone mass.


Minimum convex hull mass estimations of complete mounted skeletons.
Body mass is a critical parameter used to constrain biomechanical and physiological traits of organisms. Volumetric methods are becoming more common as techniques for estimating the body masses of fossil vertebrates. However, they are often accused of excessive subjective input when estimating the thickness of missing soft tissue. Here, we demonstrate an alternative approach where a minimum convex hull is derived mathematically from the point cloud generated by laser-scanning mounted skeletons. This has the advantage of requiring minimal user intervention and is thus more objective and far quicker. We test this method on 14 relatively large-bodied mammalian skeletons and demonstrate that it consistently underestimates body mass by 21 per cent with minimal scatter around the regression line. We therefore suggest that it is a robust method of estimating body mass where a mounted skeletal reconstruction is available and demonstrate its usage to predict the body mass of one of the largest, relatively complete sauropod dinosaurs: Giraffatitan brancai (previously Brachiosaurus) as 23200 kg.


Association of Preceding Antithrombotic Treatment With Acute Ischemic Stroke Severity and In-Hospital Outcomes Among Patients With Atrial Fibrillation.
Antithrombotic therapies are known to prevent stroke for patients with atrial fibrillation (AF) but are often underused in community practice. To examine the prevalence of patients with acute ischemic stroke with known history of AF who were not receiving guideline-recommended antithrombotic treatment before stroke and to determine the association of preceding antithrombotic therapy with stroke severity and in-hospital outcomes. Retrospective observational study of 94 474 patients with acute ischemic stroke and known history of AF admitted from October 2012 through March 2015 to 1622 hospitals participating in the Get With the Guidelines-Stroke program. Antithrombotic therapy before stroke. Stroke severity as measured by the National Institutes of Health Stroke Scale (NIHSS; range of 0-42, with a higher score indicating greater stroke severity and a score ≥16 indicating moderate or severe stroke), and in-hospital mortality. Of 94 474 patients (mean [SD] age, 79.9 [11.0] years; 57.0% women), 7176 (7.6%) were receiving therapeutic warfarin (international normalized ratio [INR] ≥2) and 8290 (8.8%) were receiving non-vitamin K antagonist oral anticoagulants (NOACs) preceding the stroke. A total of 79 008 patients (83.6%) were not receiving therapeutic anticoagulation; 12 751 (13.5%) had subtherapeutic warfarin anticoagulation (INR <2) at the time of stroke, 37 674 (39.9%) were receiving antiplatelet therapy only, and 28 583 (30.3%) were not receiving any antithrombotic treatment. Among 91 155 high-risk patients (prestroke CHA2DS2-VASc score ≥2), 76 071 (83.5%) were not receiving therapeutic warfarin or NOACs before stroke. The unadjusted rates of moderate or severe stroke were lower among patients receiving therapeutic warfarin (15.8% [95% CI, 14.8%-16.7%]) and NOACs (17.5% [95% CI, 16.6%-18.4%]) than among those receiving no antithrombotic therapy (27.1% [95% CI, 26.6%-27.7%]), antiplatelet therapy only (24.8% [95% CI, 24.3%-25.3%]), or subtherapeutic warfarin (25.8% [95% CI, 25.0%-26.6%]); unadjusted rates of in-hospital mortality also were lower for those receiving therapeutic warfarin (6.4% [95% CI, 5.8%-7.0%]) and NOACs (6.3% [95% CI, 5.7%-6.8%]) compared with those receiving no antithrombotic therapy (9.3% [95% CI, 8.9%-9.6%]), antiplatelet therapy only (8.1% [95% CI, 7.8%-8.3%]), or subtherapeutic warfarin (8.8% [95% CI, 8.3%-9.3%]). After adjusting for potential confounders, compared with no antithrombotic treatment, preceding use of therapeutic warfarin, NOACs, or antiplatelet therapy was associated with lower odds of moderate or severe stroke (adjusted odds ratio [95% CI], 0.56 [0.51-0.60], 0.65 [0.61-0.71], and 0.88 [0.84-0.92], respectively) and in-hospital mortality (adjusted odds ratio [95% CI], 0.75 [0.67-0.85], 0.79 [0.72-0.88], and 0.83 [0.78-0.88], respectively). Among patients with atrial fibrillation who had experienced an acute ischemic stroke, inadequate therapeutic anticoagulation preceding the stroke was prevalent. Therapeutic anticoagulation was associated with lower odds of moderate or severe stroke and lower odds of in-hospital mortality.


Description of the third-order optical aberrations of near-circular pupil optical systems without symmetry.
Many authors, dating back to at least the 1950s, have presented mathematical expansions of the wave-front aberration function for optical systems without symmetry, typically based on limiting assumptions and simplifications, with some of the most recent work being done by Howard and Stone [Appl. Opt. 39, 3232 (2000)]. This paper reveals that in fact there are no new aberrations in imaging optical systems with near-circular aperture stops but otherwise without symmetry. What does occur is that the field dependence of an aberration often changes when symmetry is abandoned. Each aberration type develops a characteristic field behavior in a system without symmetry. Specifically, for example, astigmatism, develops a binodal field dependence; e.g., there are typically two points in the field with zero astigmatism, and typically neither point is on axis. This construct, nodal aberration theory, for understanding the aberrations in systems without symmetry becomes a direct extension of an optical designer's knowledge base. Through the use of real ray-based analysis methods, such as Zernike coefficients, it is possible to understand completely the aberrations of optical systems without symmetry in terms of rotationally symmetric aberration theory with the simple addition of the concept of field nodes.


Neurofeedback training aimed to improve focused attention and alertness in children with ADHD: a study of relative power of EEG rhythms using custom-made software application.
Neurofeedback is a nonpharmacological treatment for attention-deficit hyperactivity disorder (ADHD). We propose that operant conditioning of electroencephalogram (EEG) in neurofeedback training aimed to mitigate inattention and low arousal in ADHD, will be accompanied by changes in EEG bands' relative power. Patients were 18 children diagnosed with ADHD. The neurofeedback protocol ("Focus/Alertness" by Peak Achievement Trainer) has a focused attention and alertness training mode. The neurofeedback protocol provides one for Focus and one for Alertness. This does not allow for collecting information regarding changes in specific EEG bands (delta, theta, alpha, low and high beta, and gamma) power within the 2 to 45 Hz range. Quantitative EEG analysis was completed on each of twelve 25-minute-long sessions using a custom-made MatLab application to determine the relative power of each of the aforementioned EEG bands throughout each session, and from the first session to the last session. Additional statistical analysis determined significant changes in relative power within sessions (from minute 1 to minute 25) and between sessions (from session 1 to session 12). Analysis was of relative power of theta, alpha, low and high beta, theta/alpha, theta/beta, and theta/low beta and theta/high beta ratios. Additional secondary measures of patients' post-neurofeedback outcomes were assessed, using an audiovisual selective attention test (IVA + Plus) and behavioral evaluation scores from the Aberrant Behavior Checklist. Analysis of data computed in the MatLab application, determined that theta/low beta and theta/alpha ratios decreased significantly from session 1 to session 12, and from minute 1 to minute 25 within sessions. The findings regarding EEG changes resulting from brain wave self-regulation training, along with behavioral evaluations, will help elucidate neural mechanisms of neurofeedback aimed to improve focused attention and alertness in ADHD.


Evaluation of minor groove binders (MGBs) as novel anti-mycobacterial agents and the effect of using non-ionic surfactant vesicles as a delivery system to improve their efficacy.
The slow development of major advances in drug discovery for the treatment of Mycobacterium tuberculosis (Mtb) infection suggests a compelling need for evaluation of more effective drug therapies against TB. New classes of drugs are constantly being evaluated for anti-mycobacterial activity with currently a very limited number of new drugs approved for TB treatment. Minor groove binders (MGBs) have previously revealed promising antimicrobial activity against various infectious agents; however, they have not yet been screened against Mtb. The mycobactericidal activity of 96 MGB compounds against Mtb was determined using an H37Rv-GFP microplate assay. MGB hits were screened for their intracellular mycobactericidal efficacy against the clinical Beijing Mtb strain HN878 in bone-marrow-derived macrophages using standard cfu counting. Cell viability was assessed by CellTiter-Blue assays. Selected MGBs were encapsulated into non-ionic surfactant vesicles (NIVs) for drug delivery system evaluation. H37Rv-GFP screening yielded a hit-list of seven compounds at an MIC99 of between 0.39 and 1.56 μM. MGB-362 and MGB-364 displayed intracellular mycobactericidal activity against Mtb HN878 at an MIC50 of 4.09 and 4.19 μM, respectively, whilst being non-toxic. Subsequent encapsulation into NIVs demonstrated a 1.6- and 2.1-fold increased intracellular mycobacterial activity, similar to that of rifampicin when compared with MGB-alone formulation. MGB anti-mycobacterial activities together with non-toxic properties indicate that MGB compounds constitute an important new class of drug/chemical entity, which holds promise in future anti-TB therapy. Furthermore, the ability of NIVs to better deliver entrapped MGB compounds to an intracellular Mtb infection suggests further preclinical evaluation is warranted.


Germ cell differentiation and synaptonemal complex formation are disrupted in CPEB knockout mice.
CPEB is a sequence-specific RNA binding protein that regulates translation during vertebrate oocyte maturation. Adult female CPEB knockout mice contained vestigial ovaries that were devoid of oocytes; ovaries from mid-gestation embryos contained oocytes that were arrested at the pachytene stage. Male CPEB null mice also contained germ cells arrested at pachytene. The germ cells from the knockout mice harbored fragmented chromatin, suggesting a possible defect in homologous chromosome adhesion or synapsis. Two CPE-containing synaptonemal complex protein mRNAs, which interact with CPEB in vitro and in vivo, contained shortened poly(A) tails and mostly failed to sediment with polysomes in the null mice. Synaptonemal complexes were not detected in these animals. CPEB therefore controls germ cell differentiation by regulating the formation of the synaptonemal complex.


Implementing a Software Solution Across Multiple Ultrasound Vendors to Auto-fill Reports with Measurement Values.
Reliable transmission of ultrasound measurements into radiology reports is fraught with potential sources of error. In a conventional workflow, measurements are either written by hand on worksheets and/or dictated from worksheets or the images themselves into the radiology report. Valuable physician time is spent dictating, checking, and editing these values and this process is error-prone. Our approach was to use a transfer-software application to auto-populate measurements, with a goal of achieving >90% utilization rate by both technologists and radiologists. Implementation involved creating measurement fields for each measurement on each ultrasound unit of our multisite academic department. These fields were then mapped in both the transfer-software and the dictation software, to set up a 1:1:1 correspondence for each field. As a result, each measurement acquired by the technologist would automatically populate the radiology report within the dictation software. We created and mapped 128 fields for 39 exam templates. After implementation, technologist utilization rate was 86%-96% and overall radiologist utilization rate was 92%-93%. Radiology resident utilization rate was highest, at 95%-96%. We provide a guide for implementation and lessons learned.


Effect of hypoxia on abdominal motor unit activities in spontaneously breathing cats.
These experiments were designed to examine the behavior of external oblique motor units in spontaneously breathing cats during hypoxia and to estimate the contribution of recruitment and rate coding to changes in the integrated external oblique electromyogram (iEMG). Motor unit activities in the external oblique muscle were identified while the cats expired against a positive end-expiratory pressure (PEEP) of 1-2.5 cmH2O. After localization of unit activity, PEEP was removed, and recordings were made continuously for 3-4 min during hyperoxia, normoxia, and hypoxia. A total of 35 single motor unit activities were recorded from 10 cats. At each level of fractional concentration of end-tidal O2, the motor unit activity was characterized by an abrupt increase in mean discharge frequency, at approximately 30% of expiratory time, which then continued to increase gradually or remained constant before declining abruptly at the end of expiration. The transition from hyperoxia to normoxia and hypoxia was accompanied by an increase in the number of active motor units (16 of 35, 20 of 35, and 29 of 35, respectively) and by an increase in the mean discharge frequency of those units active during hyperoxia. The changes in motor unit activity recorded during hypoxia were accompanied by a significant increase in the average peak amplitude of the abdominal iEMG. Linear regression analysis revealed that motor unit rate coding was responsible for close to 60% of the increase in peak iEMG amplitude. The changes in abdominal motor unit activity and the external oblique iEMG that occurred during hypoxia were abolished if the arterial PCO2 was allowed to fall. We conclude that external oblique motor units are activated during the latter two-thirds of expiration and that rate coding and recruitment contribute almost equally to the increase in expiratory muscle activity that occurs with hypoxia. In addition, the excitation of abdominal motor units during hypoxia is critically dependent on changes in CO2 and/or tidal volume.


Accuracy of the Fitbit Zip for Measuring Steps for Adolescents With Visual Impairments.
Our purpose in this study was to document the criterion validity of the Fitbit Zip for measuring steps taken by youth with visual impairments (VI). A secondary purpose was to determine whether walking pace, mounting position, or relative position to the user's mobility device impacted the criterion validity of the device. Fourteen adolescent-aged individuals (Mage = 15.4; 13 male and 1 female) with VI participated in this study. Participants wore four Fitbit Zips at different mounting positions and completed two, 2-min walking trials while the lead investigator hand tallied steps. Measurement validity was analyzed using absolute percent error (APE), intraclass correlation coefficients estimated level of conformity, and paired samples t tests and Cohen's d effect sizes assessed APE relative to mounting positions. Results supported the use of the Fitbit Zip during regular-paced walking; however, caution must be used during activities exceeding regular walking speeds, as devices consistently underestimated steps.


Comparison of competitively primed and conventional allele-specific nucleic acid amplification.
A simulation of competitively primed allele-specific DNA amplification has been constructed and its behavior examined. This has shown that when the ratio of the amount of homoduplex misprime product to the total amount of amplimer is low, it increases by approximately one-fourth of the mispriming frequency with each doubling of the total amount of amplimer. When the ratio is high and reverse mispriming becomes significant, it asymptotes toward a value <0.5. An analogous simulation was carried out on conventional allele-specific DNA amplification. As expected, the ratio of the amount of amplimer in the positive and negative reactions closely approximates the mispriming frequency provided that amplification is exponential in both cases. This suggests that conventional allele-specific amplification has somewhat higher inherent specificity than competitively primed amplification. However, conventional allele-specific reactions are subject to a "catch-up" phase in which the positive reaction slows or stops, thus reducing the specificity. It was hypothesized that competitively primed reactions may be easier to optimize than conventional allele-specific reactions. This conjecture was supported experimentally. In addition, it was shown that the specificity of competitively primed reactions is a function of the degree of amplification.


Impact of thalassemia major on patients and their families.
To describe the burden of thalassemia major and its treatment, in terms of prevalence of iron-overload-related complications, direct and indirect costs, and the patient's physical and social well-being. From October 1999 to May 2000 a survey of patients with thalassemia major was conducted in ten countries: Cyprus, Egypt, Greece, Hong Kong, India, Iran, Italy, Jordan, Taiwan, and the United States. 1,888 questionnaires (65%) were returned. The responses suggest that nowadays patients begin blood transfusions, and most use desferrioxamine (84.8%), but iron-related complications, including life-threatening ones such as heart disease, are still common. There remains a need to improve the management of thalassemia, as many patients with iron-related complications experience physical and social limitations.


Electrochemical plasmonic metamaterials: towards fast electro-tuneable reflecting nanoshutters.
Self-assembling arrays of metallic nanoparticles at liquid|liquid or liquid|solid interfaces could deliver new platforms for tuneable optical systems. Such systems can switch between very-high and very-low reflectance states upon assembly and disassembly of nanoparticles at the interface, respectively. This encourages creation of electro-variably reversible mirror/window nanoplasmonic devices. However, the response time of these systems is usually limited by the rate-of-diffusion of the nanoparticles in the liquid, towards the interface and back. A large time-constant implies slow switching of the system, challenging the practical viability of such a system. Here we introduce a smart alternative to overcome this issue. We propose obtaining fast switching via electrically-induced rotation of a two-dimensional array of metal nanocuboids tethered to an ITO substrate. By applying potential to the ITO electrode the orientation of nanocuboids can be altered, which results in conversion of a highly-reflective nanoparticle layer into a transparent layer (or vice versa) within sub-second timescales. A theoretical method is developed based on the quasi-static effective-medium approach to analyse the optical response of such arrays, which is verified against full-wave simulations. Further theoretical analysis and estimates based on the potential energy of the nanoparticles in the two orientations corroborate the idea that voltage-controlled switching between the two states of a nanoparticle assembly is a viable option.


Isolated limb perfusion with tumor necrosis factor and melphalan for limb salvage in 186 patients with locally advanced soft tissue extremity sarcomas. The cumulative multicenter European experience.
The objective of the study was to achieve limb salvage in patients with locally advanced soft tissue sarcomas that can only be treated by amputation or functionally mutilating surgery by performing an isolated limb perfusion (ILP) with tumor necrosis factor (TNF) + melphalan (M) as induction biochemotherapy to obtain local control and make limb-sparing surgery possible. To increase the number of limb-sparing resections in the treatment of locally advanced extremity soft tissue sarcoma, preoperative radiation therapy or chemotherapy or a combination of the two often are applied. The ILP with cytostatic agents alone is another option but rarely is used because of rather poor results. The efficacy of the application of TNF in ILP markedly has changed this situation. In 8 cancer centers, 186 patients were treated over a period of almost 4.5 years. There were 107 (57%) primary and 79 (43%) recurrent sarcomas, mostly high grade (110 grade III; 51 grade II; and 25 very large, recurrent, or multiple grade I sarcomas). The composition of this series of patients is unusual: 42 patients (23%) had multifocal primary or multiple recurrent tumors; median tumor size was very large (16 cm); 25 patients (13%) had known systemic metastases at the time of the ILP. Patients underwent a 90-minute ILP at 39 to 40 C with TNF + melphalan. The first 55 patients also received interferon-tau. A delayed marginal resection of the tumor remnant was done 2 to 4 months after ILP. A major tumor response was seen in 82% of the patients rendering these large sarcomas resectable in most cases. Clinical response rates were: 33 complete response (CR) (18%), 106 partial response (PR) (57%), 42 no change (NC) (22%), and 5 progressive disease (PD) (3%). Final outcome was defined by clinical and pathologic response: 54 CR (29%), 99 PR (53%), 29 NC (16%), and 4 PD (2%). At a median follow-up of almost 2 years (22 months; range, 6-58 months), limb salvage was achieved in 82%. Regional toxicity was limited and systemic toxicity minimal to moderate, easily managed, with no toxic deaths. In the setting of isolated limb perfusion, TNF is an active anticancer drug in patients. The ILP with TNF + melphalan can be performed safely in many centers and is an effective induction treatment with a high response rate that can achieve limb salvage in patients with locally advanced extremity soft tissue sarcoma.


Resolution of an infection with Leishmania braziliensis confers complete protection to a subsequent challenge with Leishmania major in BALB/c mice.
Both Leishmania major and L. braziliensis induce cutaneous leishmaniasis in BALB/c mice. Whereas BALB/c mice die of infection with L. major, they cure an infection with L. braziliensis. We report here that after curing an infection with L. braziliensis, BALB/c mice are resistant to challenge with L. major. When challenged with L. major, L. braziliensis pre-treated BALB/c mice mounted a delayed-type hypersensitivity response to L. major and produced high amounts of interferon-gamma (IFN-gamma) but low amounts of interleukin-4. The IFN-gamma produced by the L. braziliensis pre-infected mice was involved in the protection seen against L. major challenge since treating the mice with a neutralizing anti-IFN-gamma abrogated the protection. This suggests that cross-reactive antigen epitopes exist between L. braziliensis and L. major and that pre-infection with L. braziliensis primes BALB/c mice to epitopes on L. major that can elicit a protective Th1 response to the parasite.


Loss of caveolin-1 accelerates neurodegeneration and aging.
The aged brain exhibits a loss in gray matter and a decrease in spines and synaptic densities that may represent a sequela for neurodegenerative diseases such as Alzheimer's. Membrane/lipid rafts (MLR), discrete regions of the plasmalemma enriched in cholesterol, glycosphingolipids, and sphingomyelin, are essential for the development and stabilization of synapses. Caveolin-1 (Cav-1), a cholesterol binding protein organizes synaptic signaling components within MLR. It is unknown whether loss of synapses is dependent on an age-related loss of Cav-1 expression and whether this has implications for neurodegenerative diseases such as Alzheimer's disease. We analyzed brains from young (Yg, 3-6 months), middle age (Md, 12 months), aged (Ag, >18 months), and young Cav-1 KO mice and show that localization of PSD-95, NR2A, NR2B, TrkBR, AMPAR, and Cav-1 to MLR is decreased in aged hippocampi. Young Cav-1 KO mice showed signs of premature neuronal aging and degeneration. Hippocampi synaptosomes from Cav-1 KO mice showed reduced PSD-95, NR2A, NR2B, and Cav-1, an inability to be protected against cerebral ischemia-reperfusion injury compared to young WT mice, increased Aβ, P-Tau, and astrogliosis, decreased cerebrovascular volume compared to young WT mice. As with aged hippocampi, Cav-1 KO brains showed significantly reduced synapses. Neuron-targeted re-expression of Cav-1 in Cav-1 KO neurons in vitro decreased Aβ expression. Therefore, Cav-1 represents a novel control point for healthy neuronal aging and loss of Cav-1 represents a non-mutational model for Alzheimer's disease.


Microscopic modeling of charge transport in sensing proteins.
: Sensing proteins (receptors) are nanostructures that exhibit very complex behaviors (ions pumping, conformational change, reaction catalysis, etc). They are constituted by a specific sequence of amino acids within a codified spatial organization. The functioning of these macromolecules is intrinsically connected with their spatial structure, which modifications are normally associated with their biological function. With the advance of nanotechnology, the investigation of the electrical properties of receptors has emerged as a demanding issue. Beside the fundamental interest, the possibility to exploit the electrical properties for the development of bioelectronic devices of new generations has attracted major interest. From the experimental side, we investigate three complementary kinds of measurements: (1) current-voltage (I-V) measurements in nanometric layers sandwiched between macroscopic contacts, (2) I-V measurements within an AFM environment in nanometric monolayers deposited on a conducting substrate, and (3) electrochemical impedance spectroscopy measurements on appropriate monolayers of self-assembled samples. From the theoretical side, a microscopic interpretation of these experiments is still a challenging issue. This paper reviews recent theoretical results carried out within the European project, Bioelectronic Olfactory Neuron Device, which provides a first quantitative interpretation of charge transport experiments exploiting static and dynamic electrical properties of several receptors. To this purpose, we have developed an impedance network protein analogue (INPA) which considers the interaction between neighboring amino acids within a given radius as responsible of charge transfer throughout the protein. The conformational change, due to the sensing action produced by the capture of the ligand (photon, odour), induces a modification of the spatial structure and, thus, of the electrical properties of the receptor. By a scaling procedure, the electrical change of the receptor when passing from the native to the active state is used to interpret the macroscopic measurement obtained within different methods. The developed INPA model is found to be very promising for a better understanding of the role of receptor topology in the mechanism responsible of charge transfer. Present results point favorably to the development of a new generation of nano-biosensors within the lab-on-chip strategy.