Multipath variational transition state theory: rate constant of the 1,4-hydrogen shift isomerization of the 2-cyclohexylethyl radical.
We propose a new formulation of variational transition state theory called multipath variational transition state theory (MP-VTST). We employ this new formulation to calculate the forward and reverse thermal rate constant of the 1,4-hydrogen shift isomerization of the 2-cyclohexylethyl radical in the gas phase. First, we find and optimize all the local-minimum-energy structures of the reaction, product, and transition state. Then, for the lowest-energy transition state structures, we calculate the reaction path by using multiconfiguration Shepard interpolation (MSCI) method to represent the potential energy surface, and, from this representation, we also calculate the ground-state vibrationally adiabatic potential energy curve, the reaction-path curvature vector, and the generalized free energy of activation profile. With this information, the path-averaged generalized transmission coefficients <γ> are evaluated. Then, thermal rate constant containing the multiple-structure anharmonicity and torsional anharmonicity effects is calculated using multistructural transition state theory (MS-TST). The final MP-VTST thermal rate constant is obtained by multiplying k(MS-T)(MS-TST) by <γ>. In these calculations, the M06 density functional is utilized to compute the energy, gradient, and Hessian at the Shepard points, and the M06-2X density functional is used to obtain the structures (conformers) of the reactant, product, and the saddle point for computing the multistructural anharmonicity factors.


Warming and Nitrogen Addition Alter Photosynthetic Pigments, Sugars and Nutrients in a Temperate Meadow Ecosystem.
Global warming and nitrogen (N) deposition have an important influence on terrestrial ecosystems; however, the influence of warming and N deposition on plant photosynthetic products and nutrient cycling in plants is not well understood. We examined the effects of 3 years of warming and N addition on the plant photosynthetic products, foliar chemistry and stoichiometric ratios of two dominant species, i.e., Leymus chinensis and Phragmites communis, in a temperate meadow in northeastern China. Warming significantly increased the chlorophyll content and soluble sugars in L. chinensis but had no impact on the carotenoid and fructose contents. N addition caused a significant increase in the carotenoid and fructose contents. Warming and N addition had little impact on the photosynthetic products of P. communis. Warming caused significant decreases in the N and phosphorus (P) concentrations and significantly increased the carbon (C):P and N:P ratios of L. chinensis, but not the C concentration or the C:N ratio. N addition significantly increased the N concentration, C:P and N:P ratios, but significantly reduced the C:N ratio of L. chinensis. Warming significantly increased P. communis C and P concentrations, and the C:N and C:P ratios, whereas N addition increased the C, N and P concentrations but had no impact on the stoichiometric variables. This study suggests that both warming and N addition have direct impacts on plant photosynthates and elemental stoichiometry, which may play a vital role in plant-mediated biogeochemical cycling in temperate meadow ecosystems.


Energy-dispersive absorption spectroscopy for hard-X-ray micro-XAS applications.
Originally developed for time-resolved X-ray absorption spectroscopy (XAS), energy-dispersive absorption spectroscopy offers new opportunities for applications such as fluorescence detection and microbeams for scanning probe spectroscopy, thanks to recent developments in both instrumentation and optics. In this context, this paper presents a first example of chemical mapping recorded at ID24, the energy-dispersive XAS beamline at the ESRF. Attributes of this geometry for microanalysis are addressed. Finally, present and future plans are discussed and developed in the light of the evolution of the focal spot on this instrument in the past ten years.


Fructose: metabolic, hedonic, and societal parallels with ethanol.
Rates of fructose consumption continue to rise nationwide and have been linked to rising rates of obesity, type 2 diabetes, and metabolic syndrome. Because obesity has been equated with addiction, and because of their evolutionary commonalities, we chose to examine the metabolic, hedonic, and societal similarities between fructose and its fermentation byproduct ethanol. Elucidation of fructose metabolism in liver and fructose action in brain demonstrate three parallelisms with ethanol. First, hepatic fructose metabolism is similar to ethanol, as they both serve as substrates for de novo lipogenesis, and in the process both promote hepatic insulin resistance, dyslipidemia, and hepatic steatosis. Second, fructosylation of proteins with resultant superoxide formation can result in hepatic inflammation similar to acetaldehyde, an intermediary metabolite of ethanol. Lastly, by stimulating the "hedonic pathway" of the brain both directly and indirectly, fructose creates habituation, and possibly dependence; also paralleling ethanol. Thus, fructose induces alterations in both hepatic metabolism and central nervous system energy signaling, leading to a "vicious cycle" of excessive consumption and disease consistent with metabolic syndrome. On a societal level, the treatment of fructose as a commodity exhibits market similarities to ethanol. Analogous to ethanol, societal efforts to reduce fructose consumption will likely be necessary to combat the obesity epidemic.


Targeted mutations in the ATR pathway define agent-specific requirements for cancer cell growth and survival.
Many anticancer agents induce DNA strand breaks or cause the accumulation of DNA replication intermediates. The protein encoded by ataxia-telangiectasia mutated and Rad 3-related (ATR) generates signals in response to these altered DNA structures and activates cellular survival responses. Accordingly, ATR has drawn increased attention as a potential target for novel therapeutic strategies designed to potentiate the effects of existing drugs. In this study, we use a unique panel of genetically modified human cancer cells to unambiguously test the roles of upstream and downstream components of the ATR pathway in the responses to common therapeutic agents. Upstream, the S-phase-specific cyclin-dependent kinase (Cdk) 2 was required for robust activation of ATR in response to diverse chemotherapeutic agents. While Cdk2-mediated ATR activation promoted cell survival after treatment with many drugs, signaling from ATR directly to the checkpoint kinase Chk1 was required for survival responses to only a subset of the drugs tested. These results show that specifically inhibiting the Cdk2/ATR/Chk1 pathway via distinct regulators can differentially sensitize cancer cells to a wide range of therapeutic agents.


Protection against aerosol Mycobacterium tuberculosis infection using Mycobacterium bovis Bacillus Calmette Guérin-infected dendritic cells.
In the lung, dendritic cells (DC) are key antigen-presenting cells capable of triggering specific cellular responses to inhaled pathogens, and thus, they may be important in the initiation of an early response to mycobacterial infections. The ability of DC to enhance antigen presentation to naive T cells within the lungs was characterized with respect to Mycobacterium bovis Bacillus Calmette Guérin (BCG) vaccination against M. tuberculosis infection. In vitro derived DC were infected with BCG, which induced their maturation, as shown by the increased expression of MHC class II antigens, CD80 and CD86 co-stimulatory molecules. The synthesis of mRNA for IL-1, IL-6, IL-12, IL-10 and IL-1 receptor antagonist was also enhanced. When administered intratracheally in mice, infected DC induced a potent T cell response and the production of IFN-gamma to mycobacterial antigens in the mediastinal lymph nodes, leading to a significant protection against aerosol M. tuberculosis infection. Intriguingly, although the vaccination schedule for BCG-infected DC was much shorter than subcutaneous BCG vaccination (7 days as compared to 100 days), both types of vaccination showed similar levels of protection. These data confirm that DC can be potent inducers of a cellular immune response against mycobacteria and support the concept of combining DC strategies with mycobacterial vaccines for protective immunity against tuberculosis.


Production of tumor necrosis factor by human osteoblasts is modulated by other cytokines, but not by osteotropic hormones.
Human osteoblast cultures derived as out-growths from trabecular bone released tumor necrosis factor (TNF alpha) upon stimulation of the cells with human recombinant interleukin 1 (IL1; 10(-13)-10(-11) M), human recombinant granulocyte-macrophage colony-stimulating factor (100-1000 U/ml), and bacterial lipopolysaccharide (5-500 ng/ml). The osteotropic hormones 1,25-dihydroxyvitamin D3, PTH, and calcitonin had no effect on TNF production. The TNF released by the osteoblasts was identified as TNF alpha, using a specific anti-TNF alpha monoclonal antibody to neutralize its activity. Immunohistochemical staining of the cells using the same antibody revealed that all of the cells in the cultures were capable of producing TNF alpha, including those that also expressed alkaline phosphatase activity. Immunoreactive protein could be detected in the perinuclear region when cells were cultured in the presence of monensin, suggesting accumulation of newly synthesised protein in the Golgi apparatus. These results suggest that human osteoblasts, which have been shown previously to respond to TNF alpha, can synthesize and release TNF in response to IL1 and granulocyte-macrophage colony-stimulating factor. TNF may, therefore, not only have a pathological role in conditions of chronic inflammation, but also may act as a local paracrine or autocrine regulator of osteoblast function.


Effect of Early Grade Retention on School Completion: A Prospective Study.
This 14 year prospective study investigated the effect of retention in grades 1-5 on high school completion (diploma, GED, or drop out). Participants were 734 (52.7% males) ethnically diverse, academically at-risk students recruited from Texas schools into the study when they were in first grade (mean age = 6.57). Propensity score weighting successfully equated the 256 retained students and the 478 students continuously promoted students on 65 covariates assessed in grade 1. At the end of 14 years, 477 had earned a diploma, 21 had obtained a GED, 110 had dropped out, and 126 were missing school completion status. Using multinomial logistic regression with high school graduation as the reference outcome, retention led to a significant increase in the likelihood of dropping out of high school (odds ratio = 2.61), above students' propensity to be retained and additional covariates. The contrast between graduation and GED outcomes was not significant. A significant Retention X Ethnicity X Gender interaction was obtained: The negative effect of retention was strongest for African American and Hispanic girls. Even though grade retention in the elementary grades does not harm students in terms of their academic achievement or educational motivation at the transition to high school, retention increases the odds that a student will drop out of school before obtaining a high school diploma.


Molecularly imprinted polymers based on SBA-15 for selective solid-phase extraction of baicalein from plasma samples.
Highly selective molecularly imprinted mesoporous silica polymer (SBA-15@MIP) for baicalein (BAI) extraction was synthesized using a surface molecular imprinting technique on the SBA-15 supporter. Computational simulation was used to predict the optimal functional monomer for the rational design of SBA-15@MIP. Meanwhile, high adsorption capacity was obtained when a suitable yield of molecularly imprinted polymers (MIPs) layer was grafted onto the surface of SBA-15. Characterization and performance tests of the obtained polymer revealed that SBA-15@MIP possessed a highly ordered mesoporous structure, reached saturated adsorption within 60 min, and exhibited higher sorption capacity to the target molecule BAI compared with non-imprinted mesoporous silica polymer (SBA-15@NIP) and SBA-15. Finally, SBA-15@MIP was successfully applied to solid-phase extraction (SPE) coupled with high-performance liquid chromatography and ultraviolet detection (HPLC-UV) for the determination of trace BAI in plasma samples. Mean recoveries of BAI through the molecularly imprinted solid-phase extraction (MISPE) sorbent, non-imprinted solid-phase extraction (NISPE) sorbent, and SBA-15 solid-phase extraction (SBA-15-SPE) sorbent were 94.4, 22.7, and 10.7 %, respectively, and the relative standard deviations were 2.9, 2.6, and 3.6 %, respectively. These results reveal that SBA-15@MIP as a SPE sorbent has good applicability to selectively separate and enrich trace BAI from complex samples.


Physician practices regarding contraindications to oral anticoagulation in atrial fibrillation: findings from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry.
Oral anticoagulation (OAC) therapy reduces the risk of thromboembolic events associated with atrial fibrillation (AF), yet a substantial proportion of patients with AF are not prescribed OAC. The aim of this study is to describe the frequencies of and factors associated with OAC contraindications in contemporary clinical practice. We analyzed data from the ORBIT-AF study, a national, prospective, outpatient registry of incident and prevalent AF. Oral anticoagulation contraindications were uniformly collected at enrollment by site personnel using a predefined list. Baseline patient and provider characteristics were compared between participants with and without documented OAC contraindications. From June 2010 to August 2011, 10,130 patients 18 years or older with electrocardiographically documented AF were enrolled at 176 practices. Of these, 1,330 (13.1%) had contraindications documented at the baseline visit: prior bleed (27.7%), patient refusal/preference (27.5%), high bleeding risk (18.0%), frequent falls/frailty (17.6%), need for dual antiplatelet therapy (10.4%), unable to adhere/monitor warfarin (6.0%), comorbid illness (5.3%), prior intracranial hemorrhage (5.0%), allergy (2.4%), occupational risk (0.8%), pregnancy (0.2%), and other (12.6%). Among patients with reported contraindications, 30.3% were taking warfarin or dabigatran, as compared with 83.0% of those without reported contraindications. Besides "patient refusal/preference," being labeled as having frequent falls or being frail was associated with the lowest OAC use among patients with high stroke risk. Contraindications to OAC therapy among patients with AF are common but subjective. Many patients with reported contraindications were receiving OAC, suggesting that the perceived benefit outweighed the potential harm posed by the relative contraindication.


Childhood generalized specific phobia as an early marker of internalizing psychopathology across the lifespan: results from the World Mental Health Surveys.
Specific phobia (SP) is a relatively common disorder associated with high levels of psychiatric comorbidity. Because of its early onset, SP may be a useful early marker of internalizing psychopathology, especially if generalized to multiple situations. This study aimed to evaluate the association of childhood generalized SP with comorbid internalizing disorders. We conducted retrospective analyses of the cross-sectional population-based World Mental Health Surveys using the Composite International Diagnostic Interview. Outcomes were lifetime prevalence, age of onset, and persistence of internalizing disorders; past-month disability; lifetime suicidality; and 12-month serious mental illness. Logistic and linear regressions were used to assess the association of these outcomes with the number of subtypes of childhood-onset (< 13 years) SP. Among 123,628 respondents from 25 countries, retrospectively reported prevalence of childhood SP was 5.9%, 56% of whom reported one, 25% two, 10% three, and 8% four or more subtypes. Lifetime prevalence of internalizing disorders increased from 18.2% among those without childhood SP to 46.3% among those with one and 75.6% those with 4+ subtypes (OR = 2.4, 95% CI 2.3-2.5, p < 0.001). Twelve-month persistence of lifetime internalizing comorbidity at interview increased from 47.9% among those without childhood SP to 59.0% and 79.1% among those with 1 and 4+ subtypes (OR = 1.4, 95% CI 1.4-1.5, p < 0.001). Respondents with 4+ subtypes also reported significantly more disability (3.5 days out of role in the past month) than those without childhood SP (1.1 days) or with only 1 subtype (1.8 days) (B = 0.56, SE 0.06, p < 0.001) and a much higher rate of lifetime suicide attempts (16.8%) than those without childhood SP (2.0%) or with only 1 subtype (6.5%) (OR = 1.7, 95% CI 1.7-1.8, p < 0.001). This large international study shows that childhood-onset generalized SP is related to adverse outcomes in the internalizing domain throughout the life course. Comorbidity, persistence, and severity of internalizing disorders all increased with the number of childhood SP subtypes. Although our study cannot establish whether SP is causally associated with these poor outcomes or whether other factors, such as a shared underlying vulnerability, explain the association, our findings clearly show that childhood generalized SP identifies an important target group for early intervention.


Dissecting the illegal ivory trade: an analysis of ivory seizures data.
Reliable evidence of trends in the illegal ivory trade is important for informing decision making for elephants but it is difficult to obtain due to the covert nature of the trade. The Elephant Trade Information System, a global database of reported seizures of illegal ivory, holds the only extensive information on illicit trade available. However inherent biases in seizure data make it difficult to infer trends; countries differ in their ability to make and report seizures and these differences cannot be directly measured. We developed a new modelling framework to provide quantitative evidence on trends in the illegal ivory trade from seizures data. The framework used Bayesian hierarchical latent variable models to reduce bias in seizures data by identifying proxy variables that describe the variability in seizure and reporting rates between countries and over time. Models produced bias-adjusted smoothed estimates of relative trends in illegal ivory activity for raw and worked ivory in three weight classes. Activity is represented by two indicators describing the number of illegal ivory transactions--Transactions Index--and the total weight of illegal ivory transactions--Weights Index--at global, regional or national levels. Globally, activity was found to be rapidly increasing and at its highest level for 16 years, more than doubling from 2007 to 2011 and tripling from 1998 to 2011. Over 70% of the Transactions Index is from shipments of worked ivory weighing less than 10 kg and the rapid increase since 2007 is mainly due to increased consumption in China. Over 70% of the Weights Index is from shipments of raw ivory weighing at least 100 kg mainly moving from Central and East Africa to Southeast and East Asia. The results tie together recent findings on trends in poaching rates, declining populations and consumption and provide detailed evidence to inform international decision making on elephants.


Exceptionally high-affinity Ras binders that remodel its effector domain.
The Ras proteins are aberrantly activated in a wide range of human cancers, often endowing tumors with aggressive properties and resistance to therapy. Decades of effort to develop direct Ras inhibitors for clinical use have thus far failed, largely because of a lack of adequate small-molecule-binding pockets on the Ras surface. Here, we report the discovery of Ras-binding miniproteins from a naïve library and their evolution to afford versions with midpicomolar affinity to Ras. A series of biochemical experiments indicated that these miniproteins bind to the Ras effector domain as dimers, and high-resolution crystal structures revealed that these miniprotein dimers bind Ras in an unprecedented mode in which the Ras effector domain is remodeled to expose an extended pocket that connects two isolated pockets previously found to engage small-molecule ligands. We also report a Ras point mutant that stabilizes the protein in the open conformation trapped by these miniproteins. These findings provide new tools for studying Ras structure and function and present opportunities for the development of both miniprotein and small-molecule inhibitors that directly target the Ras proteins.


Incidence of extrapleural malignant mesothelioma and asbestos exposure, from the Italian national register.
The epidemiology of extrapleural malignant mesothelioma is rarely discussed and the risk of misdiagnosis and the very low incidence complicate the picture. This study presents data on extrapleural malignant mesothelioma from the Italian National Mesothelioma Register (ReNaM). ReNaM works on a regional basis, searching for cases and interviewing subjects to investigate asbestos exposure. Classification and code criteria for certainty of diagnosis and exposure modalities are set by national guidelines. Between 1993 and 2004, 681 cases were collected. Incidence measures and exposure data refer to the ReNaM database. Age-standardised rates were estimated by the direct method using the Italian resident population in 2001. Correlations between the incidence of pleural and non-pleural malignant mesothelioma for the 103 Italian provinces were analysed. Standardised incidence rates (Italy, 2004, per million inhabitants) were 2.1 and 1.2 cases for the peritoneal site (in men and women, respectively), 0.2 cases for the tunica vaginalis testis, and 0.1 in the pericardial site, varying widely in different parts of the country. Mean age at diagnosis for all extrapleural malignant mesothelioma cases was 64.4 years and the men/women ratio was 1.57:1. Median latency was over 40 years for all extrapleural sites combined. The correlation between pleural and peritoneal mesothelioma was 0.71 (Pearson's r coefficient, p<0.001). Modalities of exposure to asbestos fibres were investigated for 392 cases. The rarity of the disease, the low specificity of diagnosis and difficulties in identifying the modalities of asbestos exposure call for caution in discussing aetiological factors other than asbestos.


Keio multicenter trial in high-dose interferon-alpha 2b treatment for chronic hepatitis C. Keio Interferon-alpha 2b Study Group.
The efficacy of two different high-dose treatment of IFN-alpha 2b was evaluated in this study. Serum hepatitis C virus (HCV) RNA levels were semi-quantified by simplified reverse transcription-polymerase chain reaction. Seventy-one patients with chronic hepatitis C received 10 million units of IFN-alpha 2b daily for 2 weeks or twice a week for 24 weeks. Alanine aminotransferase (ALT) levels overall normalized in 78.1% and 51.6% of the cases at the end of the therapy and 6 months after that, respectively. HCV RNA disappeared in 71.9% and 35.7% of the patients at the end of the therapy and 6 months after that, respectively. There was no significant difference between the 2 different regimes. The efficacy of the treatment was fair in cases in which the pretreatment level of the viral amount was low. The results of this study indicate that daily administration of IFN in the first 2 weeks during 6-month course does not increase the efficacy of the therapy in such a high-dose treatment regime.


Assessment of the impedance cardiogram recorded by an automated external defibrillator during clinical cardiac arrest.
To assess the impedance cardiogram recorded by an automated external defibrillator during cardiac arrest to facilitate emergency care by lay persons. Lay persons are poor at emergency pulse checks (sensitivity 84%, specificity 36%); guidelines recommend they should not be performed. The impedance cardiogram (dZ/dt) is used to indicate stroke volume. Can an impedance cardiogram algorithm in a defibrillator determine rapidly circulatory arrest and facilitate prompt initiation of external cardiac massage? Clinical study. University hospital. Phase 1 patients attended for myocardial perfusion imaging. Phase 2 patients were recruited during cardiac arrest. This group included nonarrest controls. The impedance cardiogram was recorded through defibrillator/electrocardiographic pads oriented in the standard cardiac arrest position. Phase 1: Stroke volumes from gated myocardial perfusion imaging scans were correlated with parameters from the impedance cardiogram system (dZ/dt(max) and the peak amplitude of the Fast Fourier Transform of dZ/dt between 1.5 Hz and 4.5 Hz). Multivariate analysis was performed to fit stroke volumes from gated myocardial perfusion imaging scans with linear and quadratic terms for dZ/dt(max) and the Fast Fourier Transform to identify significant parameters for incorporation into a cardiac arrest diagnostic algorithm. The square of the peak amplitude of the Fast Fourier Transform of dZ/dt was the best predictor of reduction in stroke volumes from gated myocardial perfusion imaging scans (range = 33-85 mL; p = .016). Having established that the two pad impedance cardiogram system could detect differences in stroke volumes from gated myocardial perfusion imaging scans, we assessed its performance in diagnosing cardiac arrest. Phase 2: The impedance cardiogram was recorded in 132 "cardiac arrest" patients (53 training, 79 validation) and 97 controls (47 training, 50 validation): the diagnostic algorithm indicated cardiac arrest with sensitivities and specificities (+/- exact 95% confidence intervals) of 89.1% (85.4-92.1) and 99.6% (99.4-99.7; training) and 81.1% (77.6-84.3) and 97% (96.7-97.4; validation). The impedance cardiogram algorithm is a significant marker of circulatory collapse. Automated defibrillators with an integrated impedance cardiogram could improve emergency care by lay persons, enabling rapid and appropriate initiation of external cardiac massage.


[Clinical spectrum and treatment strategy in anti-NMDA receptor encephalitis: current status and issues].
Anti-NMDA receptor encephalitis is a disorder caused by IgG antibodies to the extracellular conformal epitope of the NR1 subunits. This disorder predominantly affects young female with ovarian teratoma;however, any person of any age, unrelated to gender or the presence of tumor, can be affected. This disorder usually follows multistage beginning with prodromal symptoms, followed by psychiatric symptoms, unresponsive state accompanied by intractable dyskinesias, seizure and central hypoventilation. Diversity of clinical spectrum has recently been emphasized based on antibody detection in various disorders, including schizophrenia, epilepsy, CJD, neuromyelitis optica, and HSV encephalitis, but these data must be cautiously interpreted; low serum titers may be false positive or clinically not relevant. This disorder has been regarded as treatment-responsive; however, only a half of the patients respond to the first-line immunotherapy (corticosteroids, immunoglobulins or plasma exchange) or tumor removal, and 19 percent remain highly disabled at 24 months with an estimated morality rate of 7%. In refractory cases early initiation of the second-line immunotherapy (rituximab and/or cyclophosphamide) recommended; however, it is difficult to follow the recommendation due to many issues, among those, off-label use is the major reason that prevents initiation of the second-line immunotherapy in Japan.


Lymphoplasmacytic Lymphoma With a Non-IgM Paraprotein Shows Clinical and Pathologic Heterogeneity and May Harbor MYD88 L265P Mutations.
Lymphoplasmacytic lymphoma (LPL) with non-immunoglobulin M (IgM) paraproteinemia remains poorly understood. The goal of this study was to investigate the clinicopathologic features of LPL in the bone marrow in patients with immunoglobulin G (IgG) or immunoglobulin A (IgA) paraproteins and evaluate MYD88 L265P mutation status to determine the relationship of these cases to Waldenström macroglobulinemia (WM). Bone marrows from LPL cases with IgG or IgA paraproteins diagnosed between January 1, 2007, and June 30, 2014, were retrieved from the clinical archive. Clinicopathologic features were retrospectively reviewed. MYD88 L265P mutation status was assessed by allele-specific polymerase chain reaction prospectively on all cases. Of 27 cases, four were reclassified as multiple myeloma, all MYD88 mutation negative. MYD88 L265P mutations were present in 10 (43%) of 23 remaining cases. No association between MYD88 status and bone marrow morphologic or phenotypic features, including the presence of Dutcher bodies, mast cells, expression of CD19 by plasma cells, or hemosiderin, was identified, although these features were present in a subset of cases, similar to WM. Clinical features of WM such as hyperviscosity were uncommon in this group and did not correlate with MYD88 status. Non-IgM LPLs are a clinically and pathologically heterogeneous group and often harbor MYD88 L265P mutation, albeit at a lower rate than classic WM. MYD88 status does not correlate with any specific pathologic or clinical manifestations.


In vivo validation of the multicomponent powder (Vitachelox®) against the deposition of polluting ions.
The purpose of this in vivo study is to evaluate the acute clinical application of a multicomponent powder (Vitachelox®), including three naturally occurring standardized extracts rich in polyphenols (grape seed extract, green tea extract, oak wood/bark extract), on healthy volunteers by measuring prevention of any metal deposition within the stratum corneum (SC) following a 6-h exposure period in a polluted environment. In this in vivo study, we evaluated the skin protective activity of the multicomponent powder formulated in a base emulsion compared to a relevant placebo cream. Using the tape stripping method, SC samples of face skin obtained from 30 healthy volunteers were compared following a 6-h exposure in a polluted area. No statistically significant variations on the amount of heavy metals were found in the samples of SC cells obtained from the hemi-faces treated with the multicomponent powder, with respect to baseline. On the contrary, a significantly higher concentration of heavy metals was found in the cells samples obtained from the hemi-faces treated with the placebo cream. In particular, an increased concentration of heavy metals superior to 100% were found for iron and zinc (+130.2% and +142.6%, respectively; p<0.001). This in vivo study validates and extends previous in vitro findings, indicating that the multicomponent powder allows the prevention of any metal deposition within the SC following exposure in a polluted environment. Our results suggest that the test product could play an effective role in counteracting skin damages induced by air pollution.


Pharmacological basis for the medicinal use of ginger in gastrointestinal disorders.
Ginger (rhizome of Zingiber officinale) has been widely used for centuries in gastrointestinal disorders, particularly dyspepsia, but its precise mode of action has yet to be elucidated. This study was undertaken to study the prokinetic action of ginger and its possible mechanism of action. Prokinetic activity of ginger extract (Zo.Cr) was confirmed in an in vivo test when it enhanced the intestinal travel of charcoal meal in mice. This propulsive effect of the extract, similar to that of carbachol, was blocked in atropine-pretreated mice, a standard cholinergic antagonist. Likewise, Zo.Cr showed an atropine-sensitive dose-dependent spasmogenic effect in vitro as well as in isolated rat and mouse stomach fundus tissues. In atropinized tissue, it showed spasmolytic activity as shown by the inhibition of 5-HT- and K+-induced contractions. A spasmolytic effect was also observed in other gut preparations either as noncompetitive inhibition of agonist dose-response curves, inhibition of high K+(80 mM)-induced contractions, or displacement of Ca2+ dose-response curves to the right, indicating a calcium antagonist effect. Phytochemical analysis revealed the presence of saponins, flavonoids, and alkaloids in the crude extract. These data indicate that Zo.Cr contains a cholinergic, spasmogenic component evident in stomach fundus preparations which provides a sound mechanistic insight for the prokinetic action of ginger. In addition, the presence of a spasmolytic constituent(s) of the calcium antagonist type may explain its use in hyperactive states of gut like colic and diarrhea.


Incidental subcortical lesions identified on magnetic resonance imaging in the elderly. II. Postmortem pathological correlations.
The pathological correlates of subcortical lesions noted on magnetic resonance imaging (MRI) in the elderly are not known. Postmortem in vitro proton MRI was performed on the brains of seven consecutive elderly patients dying of nonneurologic causes. Scans were done in the fresh and fixed states with the specimen immersed in saline and formaldehyde respectively. A 1.5 Tesla superconductive system was used with a multiple spin-echo protocol generating T2 weighted images. Subcortical MRI lesions were localized in three dimensions and identified at brain cutting. In addition, pathological correlations were obtained from an eighth patient who underwent MRI eleven days before death. Histological examinations were performed in a blinded fashion, including control areas from the same brains. Subcortical MRI lesions were found to be associated with arteriosclerosis, dilated perivascular spaces, and vascular ectasia (p less than 0.05). These histological changes were characteristic of "état criblé" which, like subcortical MRI lesions, is associated with age and hypertension. Shrinkage (or atrophy) of the brain parenchyma around ectatic blood vessels would result in an extensive network of tunnels filled with extracellular water. The proton MRI signal from such areas of the brain would be increased. Gliosis and small areas of infarction occasionally coexisted with "état criblé," but these were not present in all areas with MRI lesions and could not be distinguished by MRI signal alone. In conclusion, clinical and pathological correlations lend support to the uniform hypothesis that MRI provides a nonspecific index of brain parenchymal alterations caused by aging and chronic cerebrovascular disease.


Determinants of Slow-Wave Activity in Overweight and Obese Adults: Roles of Sex, Obstructive Sleep Apnea and Testosterone Levels.
Background: Slow-wave activity (SWA) in non-rapid eye movement (NREM) sleep, obtained by spectral analysis of the electroencephalogram, is a marker of the depth or intensity of NREM sleep. Higher levels of SWA are associated with lower arousability during NREM sleep and protect against sleep fragmentation. Multiple studies have documented that SWA levels are higher in lean women, compared to age-matched lean men, but whether these differences persist in obese subjects is unclear. Obstructive sleep apnea (OSA), a condition associated with obesity, is more prevalent in men than in women. Sex differences in SWA could therefore be one of the factors predisposing men to OSA. Furthermore, we hypothesized that higher levels of testosterone may be associated with lower levels of SWA. Objective: The aim of the current study was to identify sex differences in the determinants of SWA in young and middle-aged overweight and obese adults. Methods: We enrolled 101 overweight and obese but otherwise healthy participants from the community (44 men, 57 women) in this cross-sectional study. Participants underwent an overnight in-laboratory polysomnogram. The recordings were submitted to sleep staging and spectral analysis. Sex differences and the potential contribution of testosterone levels were evaluated after adjusting for age, body mass index and race/ethnicity. Results: OSA was present in 66% of men and in 44% of women. After adjustment for differences in age, race/ethnicity and BMI, the odds ratio for OSA in men vs. women was 3.17 (95% CI 1.14-9.43, p = 0.027). There was a graded inverse relationship between the apnea-hypopnea index (AHI) and SWA in men (β = -0.21, p = 0.018) but not in women (β = 0.10, p = 0.207). In a multivariate regression model, higher testosterone levels were independently associated with lower SWA in men after controlling for age, race/ethnicity and apnea-hypopnea index (β = -0.56, p = 0.025). Conclusion: Increasing severity of OSA was associated with significant decrease in sleep intensity in men but not in women. Higher testosterone levels were associated with lower sleep intensity in men. Men with higher testosterone levels may therefore have lower arousal thresholds and higher ventilatory instability in NREM sleep, and be at greater risk of OSA.


Testicular degeneration in Bclw-deficient mice.
To identify genes required for mammalian spermatogenesis, we screened lines of mutant mice created using a retroviral gene-trap system for male infertility. Homozygous ROSA41 male mice exhibit sterility associated with progressive testicular degeneration. Germ-cell defects are first observed at 19 days post-natal (p19). Spermatogenesis is blocked during late spermiogenesis in young adults. Gradual depletion of all stages of germ cells results in a Sertoli-cell-only phenotype by approximately six months of age. Subsequently, almost all Sertoli cells are lost from the seminiferous tubules and the Leydig cell population is reduced. Molecular analysis indicates that the gene mutated is Bclw, a death-protecting member of the Bcl2 family. The mutant allele of Bclw in ROSA41 does not produce a Bclw polypeptide. Expression of Bclw in the testis appears to be restricted to elongating spermatids and Sertoli cells. Potential roles for Bclw in testicular function are discussed.


Alloreactive regulatory T cells generated with retinoic acid prevent skin allograft rejection.
CD4(+) CD25(+) Foxp3(+) regulatory T (Treg) cells mediate immunological self-tolerance and suppress immune responses. Retinoic acid (RA), a natural metabolite of vitamin A, has been reported to enhance the differentiation of Treg cells in the presence of TGF-β. In this study, we show that the co-culture of naive T cells from C57BL/6 mice with allogeneic antigen-presenting cells (APCs) from BALB/c mice in the presence of TGF-β, RA, and IL-2 resulted in a striking enrichment of Foxp3(+) T cells. These RA in vitro-induced regulatory T (RA-iTreg) cells did not secrete Th1-, Th2-, or Th17-related cytokines, showed a nonbiased homing potential, and expressed several cell surface molecules related to Treg-cell suppressive potential. Accordingly, these RA-iTreg cells suppressed T-cell proliferation and inhibited cytokine production by T cells in in vitro assays. Moreover, following adoptive transfer, RA-iTreg cells maintained Foxp3 expression and their suppressive capacity. Finally, RA-iTreg cells showed alloantigen-specific immunosuppressive capacity in a skin allograft model in immunodeficient mice. Altogether, these data indicate that functional and stable allogeneic-specific Treg cells may be generated using TGF-β, RA, and IL-2. Thus, RA-iTreg cells may have a potential use in the development of more effective cellular therapies in clinical transplantation.


In vivo dynamics of clathrin and its adaptor-dependent recruitment to the actin-based endocytic machinery in yeast.
Clathrin-mediated transport is a major pathway for endocytosis. However, in yeast, where cortical actin patches are essential for endocytosis, plasma membrane-associated clathrin has never been observed. Using live cell imaging, we demonstrate cortical clathrin in association with the actin-based endocytic machinery in yeast. Fluorescently tagged clathrin is found in highly mobile internal trans-Golgi/endosomal structures and in smaller cortical patches. Total internal reflection fluorescence microscopy showed that cortical patches are likely endocytic sites, as clathrin is recruited prior to a burst of intensity of the actin patch/endocytic marker, Abp1. Clathrin also accumulates at the cortex with internalizing alpha factor receptor, Ste2p. Cortical clathrin localizes with epsins Ent1/2p and AP180s, and its recruitment to the surface is dependent upon these adaptors. In contrast, Sla2p, End3p, Pan1p, and a dynamic actin cytoskeleton are not required for clathrin assembly or exchange but are required for the mobility, maturation, and/or turnover of clathrin-containing endocytic structures.


3D matters! 3D-RISM and 3D convolutional neural network for accurate bioaccumulation prediction.
In this work, we present a new method for predicting complex physical-chemical properties of organic molecules. The approach utilizes 3D convolutional neural network (ActivNet4) that uses solvent spatial distributions around solutes as input. These spatial distributions are obtained by a molecular theory called three-dimensional reference interaction site model. We have shown that the method allows one to achieve a good accuracy of prediction of bioconcentration factor which is difficult to predict by direct application of methods of molecular theory or simulations. Our research demonstrates that combination of molecular theories with modern machine learning approaches can be effectively used for predicting properties that are otherwise inaccessible to purely theory-based models.


Removing the boundaries: palliative care for patients with heart failure.
This study aimed to explore the experiences of patients with severe heart failure and identify their needs for palliative care. A qualitative design was chosen. Semi-structured interviews were used for data collection and patients were interviewed in their homes. The sample consisted of 20 patients with a confirmed diagnosis of heart failure. Patients were between 60 and 83 years. Patients reported difficulties in walking, extreme fatigue and problems managing daily activities. Having to rely on family, friends and neighbours was common, causing feelings of being a burden, loneliness and isolation. Patients talked about dying as well as their fears and frustrations in living with heart failure. Barriers to accessing information and social services were identified. None of these patients had been referred to specialist palliative care services. Patients' experiences were similar to those of patients living with advanced cancer and yet they received little support. Comprehensive routine assessment of the palliative care needs of patients living with severe heart failure is recommended.


Molecular cloning and characterization of profilin-3: a novel cytoskeleton-associated gene expressed in rat kidney and testes.
Profilin is a small actin-binding protein that is involved in diverse functions such as maintaining cell structure integrity, cell mobility, tumor cell metastasis, as well as growth factor signal transduction. In this paper, we describe the molecular cloning and characterization of a novel form of profilin, termed profilin-3, from rat kidney using a PCR-based procedure for isolating tissue-specific genes. The profilin-3 cDNA encoded 137 amino acids, and it shared extensive homology to profilin-1 and profilin-2 from mice and humans. More strikingly, the expression of profilin-3 was highly selective, and its mRNA was only found in the kidney and to a much lesser extent in the testis. The size of the mRNA for profilin-3 in the testis was 1.2 kb, while in kidney it was approximately 4.4-5 kb, suggesting the presence of tissue-specific transcription from different promoters. In addition, we also found that the expression of profilin-3 mRNA was significantly elevated in two types of renal diseases: diabetic nephropathy (db/db mice) and polycystic kidney diseases (cpk mice). Similar to profilin-1 and profilin-2, profilin-3 was localized in the cytoplasmic domain. Furthermore, it was capable of interacting with actin and poly-L-proline in an in vitro assay as well as in transfected cells. These results strongly suggest that, contrary to the ubiquitous presence of profilin-1 and profilin-2, there is a tissue-specific form of these cytoskeleton-regulatory proteins and that the kidney/testes-specific profilin-3 may play a unique role in renal and/or reproductive functions.


Path Following, Obstacle Detection and Obstacle Avoidance for Thrusted Underwater Snake Robots.
The use of unmanned underwater vehicles is steadily increasing for a variety of applications such as mapping, monitoring, inspection and intervention within several research fields and industries, e.g., oceanography, marine biology, military, and oil and gas. Particularly interesting types of unmanned underwater vehicles are bio-inspired robots such as underwater snake robots (USRs). Due to their flexible and slender body, these versatile robots are highly maneuverable and have better access capabilities than more conventional remotely operated vehicles (ROVs). Moreover, the long and slender body allows for energy-efficient transit over long distances similar to torpedo-shaped autonomous underwater vehicles (AUVs). In addition, USRs are capable of performing light intervention tasks, thereby providing intervention capabilities which exceed those of AUVs and inspection class ROVs. USRs may also propel themselves using energy-efficient motion patterns inspired by their biological counterparts. They can thereby increase the propulsion efficiency during transit and maneuvering, which is among the great challenges for autonomous underwater vehicles. In this paper, a control system for path following, and algorithms for obstacle detection and avoidance, are presented for a USR with thrusters attached at the tail module. The position of the obstacles is detected using a single camera in the head module of the USR and a developed computer vision algorithm. For the proposed control concept the robot joints are used for directional control while the thrusters are used for forward propulsion. The USR circumvents obstacles by following a circular path around them before converging back to the main straight line path when this is safe. Experimental results that validate the proposed methods are also presented.


Subsurface valleys and geoarcheology of the eastern sahara revealed by shuttle radar.
The shuttle imaging radar (SIR-A) carried on the space shuttle Columbia in November 1981 penetrated the extremely dry Selima Sand Sheet, dunes, and drift sand of the eastern Sahara, revealing previously unknown buried valleys, geologic structures, and possible Stone Age occupation sites. Radar responses from bedrock and gravel surfaces beneath windblown sand several centimeters to possibly meters thick delineate sand- and alluvium-filled valleys, some nearly as wide as the Nile Valley and perhaps as old as middle Tertiary. The now-vanished major river systems that carved these large valleys probably accomplished most of the erosional stripping of this extraordinarily flat, hyperarid region. Underfit and incised dry wadis, many superimposed on the large valleys, represent erosion by intermittent running water, probably during Quaternary pluvials. Stone Age artifacts associated with soils in the alluvium suggest that areas near the wadis may have been sites of early human occupation. The presence of old drainage networks beneath the sand sheet provides a geologic explanation for the locations of many playas and present-day oases which have been centers of episodic human habitation. Radar penetration of dry sand and soils varies with the wavelength of the incident signals (24 centimeters for the SIR-A system), incidence angle, and the electrical properties of the materials, which are largely determined by moisture content. The calculated depth of radar penetration of dry sand and granules, based on laboratory measurements of the electrical properties of samples from the Selima Sand Sheet, is at least 5 meters. Recent (September 1982) field studies in Egypt verified SIR-A signal penetration depths of at least 1 meter in the Selima Sand Sheet and in drift sand and 2 or more meters in sand dunes.


Clinical and radiographic outcomes following traumatic Grade 1 and 2 carotid artery injuries: a 10-year retrospective analysis from a Level I trauma center. The Parkland Carotid and Vertebral Artery Injury Survey.
Proper screening, management, and follow-up of Grade 1 and 2 blunt carotid artery injuries (BCIs) remains controversial. These low-grade BCIs were analyzed to define their natural history and establish a rational management plan based on lesion progression and cerebral infarction. A retrospective review of a prospectively maintained database of all blunt traumatic carotid and vertebral artery injuries treated between August 2003 and April 2013 was performed and Grade 1 and 2 BCIs were identified. Grade 1 injuries are defined as a vessel lumen stenosis of less than 25%, and Grade 2 injuries are defined as a stenosis of the vessel lumen between 25% and 50%. Demographic information, radiographic imaging, number of imaging sessions performed per individual, length of radiographic follow-up, radiographic outcome at end of follow-up, treatment(s) provided, and documentation of ischemic stroke or transient ischemic attack were recorded. One hundred seventeen Grade 1 and 2 BCIs in 100 patients were identified and available for follow-up. The mean follow-up duration was 60 days. Final imaging of Grade 1 and 2 BCIs demonstrated that 64% of cases had resolved, 13% of cases were radiographically stable, and 9% were improved, whereas 14% radiographically worsened. Of the treatments received, 54% of cases were treated with acetylsalicylic acid (ASA), 31% received no treatment, and 15% received various medications and treatments, including endovascular stenting. There was 1 cerebral infarction that was thought to be related to bilateral Grade 2 BCI, which developed soon after hospital admission. The majority of Grade 1 and 2 BCIs remained stable or improved at final follow-up. Despite a 14% rate of radiographic worsening in the Grade 1 and 2 BCIs cohort, there were no adverse clinical outcomes associated with these radiographic changes. The stroke rate was 1% in this low-grade BCIs cohort, which may be an overestimate. The use of ASA or other antiplatelet or anticoagulant medications in these low-grade BCIs did not appear to correlate with radiographic injury stability, nor with a decreased rate of cerebral infarction. Although these data suggest that these Grade 1 and 2 BCIs may require less intensive radiographic follow-up, future prospective studies are needed to make conclusive changes related to treatment and management.


Vocal conditioning in kea parrots (Nestor notabilis).
In laboratory studies of vocal behavior in animals, subjects are normally isolated in a sound-insulated chamber for recording, but such socially isolated conditions may reduce the chances that they will vocalize. Indeed, past studies using such methods have faced the challenge that subjects remained silent. Knowledge of conditions under which subjects are more likely to vocalize could thus improve experimental design. This study investigated (a) whether kea (Nestor notabilis) could be trained to increase vocal production using operant conditioning and (b) the conditions under which such training was feasible. We found that visual contact with other kea increased the chances that a subject would vocalize spontaneously, therefore making training through positive reinforcement possible. In the conditions where kea could only hear but not see the rest of the group, they were much less likely to vocalize. Subjects were quickly trained to increase vocal production while in visual contact with other kea, and the training remained effective even when visual access later was removed. The procedure described here could be used as a first step in future laboratory studies of vocal behavior, carried out before subjects are isolated, to overcome the challenge of inducing isolated subjects to vocalize. (PsycINFO Database Record


Transcriptome-based identification of candidate membrane proteins.
A full understanding of leukocyte responses to external stimuli requires knowledge of the full complement of proteins found on their surfaces. Systematic examination of the mammalian cell surfaces at the protein level is hampered by technical difficulties associated with proteomic analysis of so many membrane proteins and the large amounts of starting material required. The use of transcriptomic analyses avoids challenges associated with protein stability and separation and enables the inclusion of an amplification step; thus allowing the use of cell numbers applicable to the study of sub populations of, for example, primary lymphocytes. Here we present a transcriptomic methodology based on Serial Analysis of Gene Expression (SAGE) to recover an essentially complete and quantitative profile of mRNA species in a particular cell. We discuss how, using bioinformatic tools accessible to standard desktop computers, plasma membrane proteins can be identified in silico, from this list. While we describe the use of this approach to characterise the cell surface protein complement of a resting CD8(+) T-cell clone, it is theoretically applicable to any cell surface, where a suitable pure population of cells is available.


Lrp4 is a receptor for Agrin and forms a complex with MuSK.
Neuromuscular synapse formation requires a complex exchange of signals between motor neurons and skeletal muscle fibers, leading to the accumulation of postsynaptic proteins, including acetylcholine receptors in the muscle membrane and specialized release sites, or active zones in the presynaptic nerve terminal. MuSK, a receptor tyrosine kinase that is expressed in skeletal muscle, and Agrin, a motor neuron-derived ligand that stimulates MuSK phosphorylation, play critical roles in synaptic differentiation, as synapses do not form in their absence, and mutations in MuSK or downstream effectors are a major cause of a group of neuromuscular disorders, termed congenital myasthenic syndromes (CMS). How Agrin activates MuSK and stimulates synaptic differentiation is not known and remains a fundamental gap in our understanding of signaling at neuromuscular synapses. Here, we report that Lrp4, a member of the LDLR family, is a receptor for Agrin, forms a complex with MuSK, and mediates MuSK activation by Agrin.


Computed tomography in nonalcoholic fatty liver disease: a useful tool for hepatosteatosis assessment?
The value and/or limitations of computed tomography (CT) in assessment of hepatosteatosis are not well studied in nonalcoholic fatty liver disease (NAFLD). We prospectively evaluated the accuracy of CT in assessing the amount of hepatosteatosis in NAFLD patients and the impact of demographic and histopathologic variables on CT images. Forty patients with biopsy-proven NAFLD were eligible. Of these, 10 exhibited hepatic iron overload. Liver and spleen attenuation measurements were obtained and spleen-minus-liver attenuation difference (DeltaS-LA) was calculated. A good correlation between DeltaS-LA and pathological hepatosteatosis was observed (r = 0.837, P < 0.0001). Liver iron overload did not affect this correlation, although the mean DeltaS-LA was significantly lower in patients with iron overload. No correlation was detected between DeltaS-LA and hepatic inflammation, fibrosis, or body mass index. We conclude that DeltaS-LA derived from CT may be a useful tool for predicting the amount of hepatosteatosis in NAFLD patients as it is not affected by various individual factors.


Residential Location and Kidney Transplant Outcomes in Indigenous Compared With Nonindigenous Australians.
Indigenous Australians experience significantly worse graft and patient outcomes after kidney transplantation compared with nonindigenous Australians. It is unclear whether rural versus urban residential location might contribute to this. All adult patients from the Australia and New Zealand Dialysis and Transplant Registry who received a kidney transplant in Australia between January 1, 2000, and December 31, 2012, were investigated. Patients' residential location was classified as urban (major city + inner regional) or rural (outer regional - very remote) using the Australian Bureau of Statistics Remoteness Area Classification. Of 7826 kidney transplant recipients, 271 (3%) were indigenous. Sixty-three percent of indigenous Australians lived in rural locations compared with 10% of nonindigenous Australians (P < 0.001). In adjusted analyses, the hazards ratio for graft loss for Indigenous compared with non-Indigenous race was 1.59 (95% confidence interval [95% CI], 1.01-2.50; P = 0.046). Residential location was not associated with graft survival. Both indigenous race and residential location influenced patient survival, with an adjusted hazards ratio for death of 1.94 (95% CI, 1.23-3.05; P = 0.004) comparing indigenous with nonindigenous and 1.26 (95% CI, 1.01-1.58; P = 0.043) comparing rural with urban recipients. Five-year graft and patient survivals were 70% (95% CI, 60%-78%) and 69% (95% CI, 61%-76%) in rural indigenous recipients compared with 91% (95% CI, 90%-92%) and 92% (95% CI, 91%-93%) in urban nonindigenous recipients. Indigenous kidney transplant recipients experience worse patient and graft survival compared with nonindigenous recipients, whereas rural residential location is associated with patient but not graft survival. Of all groups, indigenous recipients residing in rural locations experienced the lowest 5-year graft and patient survivals.


Obesity paradox in Korean patients undergoing primary percutaneous coronary intervention in ST-segment elevation myocardial infarction.
The effect of body mass index (BMI) on outcomes after primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) is not well known. In patients registered in the Korean Acute Myocardial Infarction Registry (KAMIR) between November 2005 and November 2007, 3824 STEMI patients who arrived at hospital within 12h after onset of chest pain and underwent primary PCI were analyzed, and divided into four groups according to their BMI: underweight (BMI<18.5 kg/m(2), n=129); normal weight (18.5 < or =BMI <23.0 kg/m(2), n=1253); overweight (23.0 < or =BMI <27.5 kg/m(2), n=1959); and obese (BMI > or =27.5 kg/m(2), n=483). In-hospital mortality, revascularization in 1 year, mortality in 1 year, and overall mortality were compared between groups. Overweight and obese group were significantly younger, had normal left ventricular ejection fraction, and were more likely to be men with a higher incidence of hypertension, diabetes, and hyperlipidemia. There were no significant differences in symptom-to-door time and door-to-balloon time between groups. Obese patients had significantly lower in-hospital and overall mortalities. Major adverse cardiac events showed a bimodal pattern. Obese STEMI patients treated with primary PCI were associated with lower mortality, which may be explained by better use of medical treatment, hemodynamic stability, and younger age.


Differential citation rates of major cardiovascular clinical trials according to source of funding: a survey from 2000 to 2005.
Prior work indicates that therapeutic trials funded by for-profit organizations are more likely to report positive findings than trials funded by not-for-profit organizations. What impact, if any, funding source has on subsequent dissemination of trial data is uncertain. To address this issue, we used the number of citations per publication per year to assess differences in trial dissemination according to funding source. We assessed 303 consecutive superiority trials of cardiovascular medicine published between January 1, 2000, and July 30, 2005, in the Journal of the American Medical Association, The Lancet, and the New England Journal of Medicine. The primary outcome measure was the number of citations per publication per year up to December 31, 2006. Overall, the median number of citations per publication per year was 46 for trials funded exclusively by for-profit organizations, 37 for trials jointly funded, and 29 for trials funded by not-for-profit organizations (P=0.0007). Higher citation rates for trials funded by for-profit organizations were consistently observed in analyses stratified by journal and various trial design features and were most striking when the new intervention was favored over the standard of care; in this subgroup, the median number of citations per publication per year was 52 for trials funded by for-profit organizations compared with 25 for trials funded by not-for-profit organizations (P=0.0006). In marked contrast, in analyses limited to trials in which the new intervention was significantly worse than the standard of care, an inverse pattern was observed with fewer citations per publication per year for trials funded by for-profit organizations compared with not-for-profit organizations (33 versus 41; P=0.048). Higher citation rates were observed for industry-funded trials than for federally funded trials even when the trials dealt with similar issues and were published back-to-back in the same journal. Dissemination of clinical trial results is important for clinical practice but appears to be biased in favor of for-profit entities. Consideration should be given to more extensive promotion of clinical trial results that are funded by not-for-profit organizations.


Single-molecule analysis reveals changes in the DNA replication program for the POU5F1 locus upon human embryonic stem cell differentiation.
Human embryonic stem cells (hESCs), due to their pluripotent nature, represent a particularly relevant model system to study the relationship between the replication program and differentiation state. Here, we define the basic properties of the replication program in hESCs and compare them to the programs of hESC-derived multipotent cells (neural rosette cells) and primary differentiated cells (microvascular endothelial cells [MECs]). We characterized three genomic loci: two pluripotency regulatory genes, POU5F1 (OCT4) and NANOG, and the IGH locus, a locus that is transcriptionally active specifically in B-lineage cells. We applied a high-resolution approach to capture images of individual replicated DNA molecules. We demonstrate that for the loci studied, several basic properties of replication, including the average speed of replication forks and the average density of initiation sites, were conserved among the cells analyzed. We also demonstrate, for the first time, the presence of initiation zones in hESCs. However, significant differences were evident in other aspects of replication for the DNA segment containing the POU5F1 gene. Specifically, the locations of centers of initiation zones and the direction of replication fork progression through the POU5F1 gene were conserved in two independent hESC lines but were different in hESC-derived multipotent cells and MECs. Thus, our data identify features of the replication program characteristic of hESCs and define specific changes in replication during hESC differentiation.


Lipopolysaccharide and cytokine augmentation of human monocyte IgA receptor expression and function.
Receptors for IgA (Fc alpha R) are found on phagocytic cells in the peripheral blood and tissues associated with mucosal areas where IgA Abs constitute a major line of defense. Because Fc alpha R are capable of triggering protective functions of monocytes and neutrophils, such as phagocytosis and the oxidative burst, they may be important in amplifying the antimicrobial effects of IgA. Various cytokines play a role in regulating function and FcR expression of monocytes, macrophages, and neutrophils. The present studies examine the modulation of monocyte Fc alpha R by LPS and cytokines. LPS strongly up-regulated monocyte Fc alpha R expression. TNF and IL-1, produced in response to LPS, promoted Fc alpha R increase, as did GM-CSF; whereas IFN-gamma down-regulated Fc alpha R. Increased receptor expression was accompanied by augmented IgA-mediated phagocytosis. An increase in Fc alpha R-specific mRNA was detected in monocytes treated with TNF, IL-1, GM-CSF, and LPS; whereas message was reduced in cells treated with IFN-gamma. Monocyte-derived macrophages and cells of the Monomac 6 monocyte-like line expressed greater numbers of Fc alpha R than monocytes but were less responsive to LPS and TNF. Cell lines THP-1 and U937, which expressed similar or lower levels of Fc alpha R than monocytes, displayed an increase in Fc alpha R in response to LPS and, to various degrees, to TNF, IL-1, and GM-CSF. These results indicate that Fc alpha R on monocytes are modulated by endotoxin and an array of cytokines distinct from those that regulate expression of FcR for IgG.


Translating evidence into policy in low-income countries: lessons from co-trimoxazole preventive therapy.
In the April 2010 issue of this journal, Date et al. expressed concern over the slow scale-up in low-income settings of two therapies for the prevention of opportunistic infections in people living with the human immunodeficiency virus: co-trimoxazole prophylaxis and isoniazid preventive therapy. This short paper discusses the important ways in which policy analysis can be of use in understanding and explaining how and why certain evidence makes its way into policy and practice and what local factors influence this process. Key lessons about policy development are drawn from the research evidence on co-trimoxazole prophylaxis, as such lessons may prove helpful to those who seek to influence the development of national policy on isoniazid preventive therapy and other treatments. Researchers are encouraged to disseminate their findings in a manner that is clear, but they must also pay attention to how structural, institutional and political factors shape policy development and implementation. Doing so will help them to understand and address the concerns raised by Date et al. and other experts. Mainstreaming policy analysis approaches that explain how local factors shape the uptake of research evidence can provide an additional tool for researchers who feel frustrated because their research findings have not made their way into policy and practice.


Analysis of the stability and optimizing operation of the single-side-band modulator based on re-circulating frequency shifter used for the T-bit/s optical communication transmission.
The stability of single-sideband (SSB) modulator based recirculating frequency shifter (RFS) is analyzed theoretically. The optimum radio frequency (RF) drive peak-to-peak voltage used to drive the modulator is studied with considering the amplified spontaneous emission (ASE) noise of optical amplifier and crosstalk so as to obtain a maximum overall effective optical signal to noise ratio (OSNR) which is defined to quantify the quality of generated tones. Small desired tones number and lower RF peak-to-peak voltage can reduce the crosstalk effectively. While the trade-off should be considered since the larger desired tones number it is, the higher optimum drive voltage should be used when the SSB-based RFS reached the maximum OSNR. The theoretical results show that the optimum operation condition is helpful to improve the performance of RFS which can be a good application for the T-bit/s optical transmission in practice.


XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy.
Mutations in superoxide dismutase-1 (SOD1) cause familial amyotrophic lateral sclerosis (fALS). Recent evidence implicates adaptive responses to endoplasmic reticulum (ER) stress in the disease process via a pathway known as the unfolded protein response (UPR). Here, we investigated the contribution to fALS of X-box-binding protein-1 (XBP-1), a key UPR transcription factor that regulates genes involved in protein folding and quality control. Despite expectations that XBP-1 deficiency would enhance the pathogenesis of mutant SOD1, we observed a dramatic decrease in its toxicity due to an enhanced clearance of mutant SOD1 aggregates by macroautophagy, a cellular pathway involved in lysosome-mediated protein degradation. To validate these observations in vivo, we generated mutant SOD1 transgenic mice with specific deletion of XBP-1 in the nervous system. XBP-1-deficient mice were more resistant to developing disease, correlating with increased levels of autophagy in motoneurons and reduced accumulation of mutant SOD1 aggregates in the spinal cord. Post-mortem spinal cord samples from patients with sporadic ALS and fALS displayed a marked activation of both the UPR and autophagy. Our results reveal a new function of XBP-1 in the control of autophagy and indicate critical cross-talk between these two signaling pathways that can provide protection against neurodegeneration.


Emerging roles for dynamic aquaporin-4 subcellular relocalization in CNS water homeostasis.
Aquaporin channels facilitate bidirectional water flow in all cells and tissues. AQP4 is highly expressed in astrocytes. In the CNS, it is enriched in astrocyte endfeet, at synapses, and at the glia limitans, where it mediates water exchange across the blood-spinal cord and blood-brain barriers (BSCB/BBB), and controls cell volume, extracellular space volume, and astrocyte migration. Perivascular enrichment of AQP4 at the BSCB/BBB suggests a role in glymphatic function. Recently, we have demonstrated that AQP4 localization is also dynamically regulated at the subcellular level, affecting membrane water permeability. Ageing, cerebrovascular disease, traumatic CNS injury, and sleep disruption are established and emerging risk factors in developing neurodegeneration, and in animal models of each, impairment of glymphatic function is associated with changes in perivascular AQP4 localization. CNS oedema is caused by passive water influx through AQP4 in response to osmotic imbalances. We have demonstrated that reducing dynamic relocalization of AQP4 to the BSCB/BBB reduces CNS oedema and accelerates functional recovery in rodent models. Given the difficulties in developing pore-blocking AQP4 inhibitors, targeting AQP4 subcellular localization opens up new treatment avenues for CNS oedema, neurovascular and neurodegenerative diseases, and provides a framework to address fundamental questions about water homeostasis in health and disease.


Lipids and carotid plaque in the Northern Manhattan Study (NOMAS).
Lipids, particularly low-density (LDL) and high-density (HDL) lipoproteins, are associated with increased risk of stroke and cardiovascular disease, probably due to atherosclerosis. The objective of this cross-sectional analysis was to investigate the relation between blood lipids and carotid plaque. As part of a prospective population-based study to determine the incidence and risk factors of stroke in a multiethnic population, we evaluated 1804 participants with lipid measurements and B-mode ultrasound of carotid arteries (mean age 69 +/- 10 years; 40% men; 51% Hispanic, 26% black, 23% white). The association between lipid parameters and carotid plaque was analyzed by multiple logistic regression. Plaque was present in 61% of participants. Mean total cholesterol was 202 +/- 41 mg/dl. After controlling for other lipid parameters, demographics, and risk factors, the only cholesterol subfraction associated with carotid plaque was LDL (OR per standard deviation (SD) = 1.14, 95% CI 1.02-1.27). Neither HDL nor triglycerides independently predicted carotid plaque. Apolipoprotein B (ApoB) was also associated with risk of plaque (OR per SD = 1.29, 95% CI 1.03-1.60). Apolipoprotein A-I (apoA-1) was associated with a decrease in multiple plaques (OR per SD = 0.76, 95% CI 0.60-0.97), while lipoprotein a was associated with an increased risk of multiple plaques (OR per SD = 1.31, 95% CI 1.03-1.66). ApoB:ApoA-I had the strongest relation with carotid plaque (OR per SD = 1.35, 95% CI 1.08-1.69). Among the common lipid parameters, LDL has the strongest relation with carotid plaque. Other lipid precursor proteins such as ApoB and ApoA-I may be stronger predictors of subclinical atherosclerosis, however, and better targets for treatment to reduce plaque formation and risk of cerebrovascular disease.


Experimental infection of chickens by a flagellated motile strain of Salmonella enterica serovar Gallinarum biovar Gallinarum.
Salmonella enterica subsp. enterica serovar Gallinarum biovar Gallinarum (SG) causes fowl typhoid (FT), a septicaemic disease which can result in high mortality in poultry flocks. The absence of flagella in SG is thought to favour systemic invasion, since bacterial recognition via Toll-like receptor (TLR)-5 does not take place during the early stages of FT. In the present study, chicks susceptible to FT were inoculated with a wild type SG (SG) or its flagellated motile derivative (SG Fla(+)). In experiment 1, mortality and clinical signs were assessed, whereas in experiment 2, gross pathology, histopathology, systemic invasion and immune responses were evaluated. SG Fla(+) infection resulted in later development of clinical signs, lower mortality, lower bacterial numbers in the liver and spleen, and less severe pathological changes compared to SG. The CD8(+) T lymphocyte population was higher in the livers of chicks infected with SG at 4 days post-inoculation (dpi). Chicks infected with SG had increased expression of interleukin (IL)-6 mRNA in the caecal tonsil at 1 dpi and increased expression of IL-18 mRNA in the spleen at 4 dpi. In contrast, the CD4(+) T lymphocyte population was higher at 6 dpi in the livers of birds infected with SG Fla(+). Therefore, flagella appeared to modulate the chicken immune response towards a CD4(+) T profile, resulting in more efficient bacterial clearance from systemic sites and milder infection.


Genome-wide scan for signatures of human population differentiation and their relationship with natural selection, functional pathways and diseases.
Genetic differences both between individuals and populations are studied for their evolutionary relevance and for their potential medical applications. Most of the genetic differentiation among populations are caused by random drift that should affect all loci across the genome in a similar manner. When a locus shows extraordinary high or low levels of population differentiation, this may be interpreted as evidence for natural selection. The most used measure of population differentiation was devised by Wright and is known as fixation index, or F(ST). We performed a genome-wide estimation of F(ST) on about 4 millions of SNPs from HapMap project data. We demonstrated a heterogeneous distribution of F(ST) values between autosomes and heterochromosomes. When we compared the F(ST) values obtained in this study with another evolutionary measure obtained by comparative interspecific approach, we found that genes under positive selection appeared to show low levels of population differentiation. We applied a gene set approach, widely used for microarray data analysis, to detect functional pathways under selection. We found that one pathway related to antigen processing and presentation showed low levels of F(ST), while several pathways related to cell signalling, growth and morphogenesis showed high F(ST) values. Finally, we detected a signature of selection within genes associated with human complex diseases. These results can help to identify which process occurred during human evolution and adaptation to different environments. They also support the hypothesis that common diseases could have a genetic background shaped by human evolution.


Mitogen-activated protein kinase p38 controls the expression and posttranslational modification of tristetraprolin, a regulator of tumor necrosis factor alpha mRNA stability.
Signal transduction pathways regulate gene expression in part by modulating the stability of specific mRNAs. For example, the mitogen-activated protein kinase (MAPK) p38 pathway mediates stabilization of tumor necrosis factor alpha (TNF-alpha) mRNA in myeloid cells stimulated with bacterial lipopolysaccharide (LPS). The zinc finger protein tristetraprolin (TTP) is expressed in response to LPS and regulates the stability of TNF-alpha mRNA. We show that stimulation of RAW264.7 mouse macrophages with LPS induces the binding of TTP to the TNF-alpha 3' untranslated region. The p38 pathway is required for the induction of TNF-alpha RNA-binding activity and for the expression of TTP protein and mRNA. Following stimulation with LPS, TTP is expressed in multiple, differentially phosphorylated forms. We present evidence that phosphorylation of TTP is mediated by the p38-regulated kinase MAPKAPK2 (MAPK-activated protein kinase 2). Our findings demonstrate a direct link between a specific signal transduction pathway and a specific RNA-binding protein, both of which are known to regulate TNF-alpha gene expression at a posttranscriptional level.


Driver sleepiness on YouTube: A content analysis.
Driver sleepiness is a major contributor to severe crashes and fatalities on our roads. Many people continue to drive despite being aware of feeling tired. Prevention relies heavily on education campaigns as it is difficult to police driver sleepiness. The video sharing social media site YouTube is extremely popular, particularly with at risk driver demographics. Content and popularity of uploaded videos can provide insight into the quality of publicly accessible driver sleepiness information. The purpose of this research was to answer two questions; firstly, how prevalent are driver sleepiness videos on YouTube? And secondly, what are the general characteristics of driver sleepiness videos in terms of (a) outlook on driver sleepiness, (b) tone, (c) countermeasures to driver sleepiness, and, (d) driver demographics. Using a keywords search, 442 relevant videos were found from a five year period (2nd December 2009-2nd December 2014). Tone, outlook, and countermeasure use were thematically coded. Driver demographic and video popularity data also were recorded. The majority of videos portrayed driver sleepiness as dangerous. However, videos that had an outlook towards driver sleepiness being amusing were viewed more often and had more mean per video comments and likes. Humorous videos regardless of outlook, were most popular. Most information regarding countermeasures to deal with driver sleepiness was accurate. Worryingly, 39.8% of videos with countermeasure information contained some kind of ineffective countermeasure. The use of humour to convey messages about the dangers of driver sleepiness may be a useful approach in educational interventions.


The apolipoprotein B/apolipoprotein A-I ratio as a potential marker of plasma atherogenicity.
The apolipoprotein (apo) B/apoA-I ratio represents the balance between apoB-rich atherogenic particles and apoA-I-rich antiatherogenic particles, and this ratio is considered to be a marker of cardiovascular risk. Although many studies have demonstrated the importance of the apoB/apoA-I ratio in predicting the presence or absence of cardiovascular disease, less is known about apoB/apoA-I ratio as a marker of plasma atherogenicity. A total of 157 normolipidemic men aged 20-59 years were included in the study. The plasma levels of total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), apoA-I, apoB, and apoE were determined after a 12 h fasting period. The median of the apoB/apoA-I ratio in the studied normolipidemic subjects was 0.52, with values ranging from 0.19 to 2.60. The percentage of subjects with the apoB/apoA-I ratio exceeding 0.9 (the accepted risk value of cardiovascular disease) was 19.1%. The subjects with apoB/apoA-I>0.9 were characterized by higher TG levels and atherogenic index of plasma (AIP) and lower values of ratio of low-density lipoprotein cholesterol (LDL-C) to apoB (LDL-C/apoB) and apoE levels compared with men with apoB/apoA-I<0.9. Despite normolipidemia, the subjects with the unfavorable apoB/apoA-I ratio had more atherogenic lipid profile.


Ubiquitination and degradation of homeodomain-interacting protein kinase 2 by WD40 repeat/SOCS box protein WSB-1.
Homeodomain-interacting protein kinase 2 (HIPK2) is a member of the nuclear protein kinase family, which induces both p53- and CtBP-mediated apoptosis. Levels of HIPK2 were increased by UV irradiation and cisplatin treatment, thereby implying the degradation of HIPK2 in cells under normal conditions. Here, we indicate that HIPK2 is ubiquitinated and degraded by the WD40-repeat/SOCS box protein WSB-1, a process that is blocked under DNA damage conditions. Yeast two-hybrid screening was conducted to identify the proteins that interact with HIPK2. WSB-1, an E3 ubiquitin ligase, was characterized as an HIPK2-interacting protein. The coexpression of WSB-1 resulted in the degradation of HIPK2 via its C-terminal region. Domain analysis of WSB-1 showed that WD40-repeats and the SOCS box were required for its interaction with and degradation of HIPK2, respectively. In support of the degradation of HIPK2 by WSB-1, HIPK2 was polyubiquitinated by WSB-1 in vitro and in vivo. The knockdown of endogenous WSB-1 with the expression of short hairpin RNA against WSB-1 increases the stability of endogenous HIPK2 and resulted in the accumulation of HIPK2. The ubiquitination and degradation of HIPK2 by WSB-1 was inhibited completely via the administration of DNA damage reagents, including Adriamycin and cisplatin. These findings effectively illustrate the regulatory mechanisms by which HIPK2 is maintained at a low level, by WSB-1 in cells under normal conditions, and stabilized by genotoxic stresses.


Barriers and Facilitators to Deaf Trauma Survivors' Help-Seeking Behavior: Lessons for Behavioral Clinical Trials Research.
Deaf individuals experience significant obstacles to participating in behavioral health research when careful consideration is not given to accessibility during the design of study methodology. To inform such considerations, we conducted an exploratory secondary analysis of a mixed-methods study that originally explored 16 Deaf trauma survivors' help-seeking experiences. Our objective was to identify key findings and qualitative themes from consumers' own words that could be applied to the design of behavioral clinical trials methodology. In many ways, the themes that emerged were not wholly dissimilar from the general preferences of members of other sociolinguistic minority groups-a need for communication access, empathy, respect, strict confidentiality procedures, trust, and transparency of the research process. Yet, how these themes are applied to the inclusion of Deaf research participants is distinct from any other sociolinguistic minority population, given Deaf people's unique sensory and linguistic characteristics. We summarize our findings in a preliminary "Checklist for Designing Deaf Behavioral Clinical Trials" to operationalize the steps researchers can take to apply Deaf-friendly approaches in their empirical work.


Delayed spinal cord infarction following anterior cervical surgical decompression.
Anterior cervical discectomy and fusion (ACDF) for cord compression is a safe and effective procedure with good outcomes. However, worsening of myelopathy is the most feared adverse event of the surgery. We report the case of a 36-year-old male patient who presented with an acute non-traumatic C5-6 cervical disc herniation causing incomplete quadriparesis. He underwent an uncomplicated ACDF at C5-6, and after an initial period of improvement, he developed a delayed onset of an anterior cord syndrome on day 3, without any discerning cause. We have reviewed similar cases reported in the literature and believe that our patient's postsurgical course is consistent with a delayed ischaemic/reperfusion injury to the cord following surgical decompression and restoration of blood flow through the anterior spinal artery and we make suggestions for management of such clinical events.


Radiographic measurement of the distal tibiofibular syndesmosis has limited use.
Radiographs of 20 plastinated human cadaveric lower legs were obtained in 12 positions of rotation to determine the optimal parameter for reliable assessment of syndesmotic and ankle integrity, and to assess the effect of positioning of the ankle on this parameter. Three observers measured eight parameters twice after four repetitions of ankle positioning. Intraclass correlation coefficients and reproducibility were assessed. Some tibiofibular overlap was present in all radiographs in any position of rotation. The medial clear space was smaller than or equal to the superior clear space in all radiographs. Intraclass correlation coefficients of the other parameters were too weak for reliable quantitative measurements, as was shown with a mixed model analysis of variance. This resulted from the inability to reproduce ankle positioning, even under optimal laboratory circumstances. This study shows that no optimal radiographic parameter exists to assess syndesmotic integrity. Tibiofibular overlap and medial and superior clear space are the most useful, because one-sided traumatic absence of tibiofibular overlap may be an indication of syndesmotic injury, and a medial clear space larger than a superior clear space is indicative of deltoid injury. Additional quantitative measurement of all syndesmotic parameters with repeated radiographs of the ankle cannot be done reliably and therefore are of little value.


Latest advances in aging research and drug discovery.
An increasing aging population poses a significant challenge to societies worldwide. A better understanding of the molecular, cellular, organ, tissue, physiological, psychological, and even sociological changes that occur with aging is needed in order to treat age-associated diseases. The field of aging research is rapidly expanding with multiple advances transpiring in many previously disconnected areas. Several major pharmaceutical, biotechnology, and consumer companies made aging research a priority and are building internal expertise, integrating aging research into traditional business models and exploring new go-to-market strategies. Many of these efforts are spearheaded by the latest advances in artificial intelligence, namely deep learning, including generative and reinforcement learning. To facilitate these trends, the Center for Healthy Aging at the University of Copenhagen and Insilico Medicine are building a community of Key Opinion Leaders (KOLs) in these areas and launched the annual conference series titled "Aging Research and Drug Discovery (ARDD)" held in the capital of the pharmaceutical industry, Basel, Switzerland (www.agingpharma.org). This ARDD collection contains summaries from the 6th annual meeting that explored aging mechanisms and new interventions in age-associated diseases. The 7th annual ARDD exhibition will transpire 2nd-4th of September, 2020, in Basel.


Borrelia parkeri in Ornithodoros parkeri (Ixodida: Argasidae) Collected Using Compact Dry Ice Traps in Madera County, California.
Tick-borne relapsing fever (TBRF) is a potentially serious vector-borne disease endemic to the western United States. Vector surveillance is compromised by the nidicolous life history of the three Ornithodoros species that transmit TBRF to people in this region. Large-scale stationary trapping methods were developed to survey a wide geographical range of Ornithodoros spp. which are known to vector relapsing fever Borrelia spp. in California. Ninety-six Ornithodoros parkeri were collected from four locations in the foothills of Fresno and Madera Counties. Two of these O. parkeri nymphs were PCR positive for Borrelia parkeri, and their collection at a popular recreation site increases the public health concern.


Power budget improvement of symmetric 40-Gb/s DML-based TWDM-PON system.
We propose a symmetric 40-Gb/s time and wavelength division multiplexed passive optical network (TWDM-PON) system with directly modulated laser (DML) as both downstream and upstream transmitters. A single bi-pass delay interferometer (DI), deployed in the optical line terminal (OLT), is used to mitigate multiple channels' signal distortions induced by laser chirp and fiber chromatic dispersion. With the help of the DI, we successfully demonstrate error-free transmission with the aggregate capacity of 40 Gb/s over different transmission distance. And in back-to-back case, by using a 0.2-nm free spectrum range (FSR) DI, ~11 dB optical power budget improvement is achieved at a bit error ratio of 1e-3. Owing to this high power budget, the maximum reach can be extended to 50 km for 1024 splits, 75 km for 256 splits, and 100 km for 64 splits. Meanwhile, the impacts of FSR of DI and laser wavelength shift on system performance are investigated in terms of receiver sensitivity. It is shown that, our system can achieve more than 43-dB power budget and support ± 2.5-GHz wavelength shift when the FSR is less than 0.2 nm.


Accounting for future costs in medical cost-effectiveness analysis.
Most medical cost-effectiveness analyses include future costs only for related illnesses, but this approach is controversial. This paper demonstrates that cost-effectiveness analysis is consistent with lifetime utility maximization only if it includes all future medical and non-medical expenditures. Estimates of the magnitude of these future costs suggest that they may substantially alter both the absolute and relative cost-effectiveness of medical interventions, particularly when an intervention increases length of life more than quality of life. In older populations, current methods overstate the cost-effectiveness of interventions which extend life compared to interventions which improve the quality of life.


Nurse-led care in dermatology: a review of the literature.
Nurses play lead roles in the delivery of care in dermatology. While a number of primary studies have been conducted evaluating nurse-led care in dermatology, review and synthesis of the findings from these studies has not been undertaken. To systematically identify, summarize and critically appraise the current evidence regarding the impact and effectiveness of nurse-led care in dermatology. Systematic searches were done of CINAHL, MEDLINE, British Nursing Index and the Royal College of Nursing Library Catalogue from 1990 until March 2005. The searches were not restricted to the U.K., and were supplemented by an extensive hand search of the literature through references identified from retrieved articles and by contact with experts in the field. A total of 14 relevant publications were identified (and included findings from both primary and secondary care), of which five were descriptions of nursing activities, five were evaluations of nurse interventions and four were patient evaluations of nurse-led care. The evidence emerging from the literature indicates that nurses are treating a number of dermatological conditions, primarily using treatment protocols, across a broad range of clinical settings. However, there is a lack of confidence among nurses working in primary care (predominantly practice nurses) to treat some of these conditions (including scalp scaling in psoriasis and infected eczema). Although the importance of education is recognized, the educational needs of these nurses are frequently unmet. The benefits of nurse interventions on service delivery include a reduction in the severity of condition and more effective use of topical therapies. Patients report faster access to treatment, a reduction in referrals to the GP or dermatologist, and an increase in knowledge of their condition. Nurses frequently play lead roles in the diverse range of models of care that exist in dermatology. Although findings of the review are generally positive, there are methodological weaknesses and under-researched issues, e.g. cost effectiveness of nurse-led care, and extended independent and supplementary nurse prescribing in dermatology, that point to the need for further rigorous evaluation.


Expression of a 130-kDa mesothelial and ciliated cell Ag (MCp130) in normal and developing human and rat lung and its role as a diagnostic marker for mesotheliomas and tumors of the female reproductive system.
Proteins in human lung lavage were analyzed to identify cell-specific markers for potential use in the study of the biology and pathology of pulmonary cells. Proteins associated with pulmonary surfactant were used to raise mAb. An Ab to a 130-kDa protein (MCp130) was reactive with ciliated and mesothelial cells. Expression of this Ag in normal organs, developing lung, and tumors was investigated. By Western blotting, the Ab stained a protein of about 130 kDa. In formalin-fixed, paraffin-embedded tissues from adult human and rat organs, the Ab specifically stained the luminal/apical surfaces of pulmonary and nonpulmonary ciliated and mesothelial cells. Staining of fetal airway cells was independent of ciliation. Airway cell staining was detectable in human fetal lungs at 12 weeks of gestation and at Day 18 of gestation in fetal rat. The Ab reacted with human and rat fetal mesothelial cells at the gestational ages of 15 weeks and 17 days, respectively. It also stained ciliated cells in endosalpinx and endometrium. Human epithelial mesotheliomas and ovarian and endometrial carcinomas stained selectively, whereas other pulmonary tumors and tumors of other organs did not react with the Ab. This 130-kDa mesothelial and ciliated cell plasma membrane protein appears in developing lung at an earlier age than secretory proteins. The marker is of potential use in the study of development of the different cell lineages in the lung and female reproductive tract. The Ab is expected to be useful in the diagnosis of epithelial mesotheliomas and ovarian/endometrial carcinomas, because it selectively stains these tumors and is reactive with formalin-fixed, paraffin-embedded tissues.


Using hierarchical models to estimate effects of ocean anomalies on north-west Pacific Chinook salmon Oncorhynchus tshawytscha recruitment.
The high variability in survival over the past three decades of north-west Pacific Chinook salmon Oncorhynchus tshawytscha is summarized for 24 stocks and analysed using hierarchical Bayesian models. Results from a simple model indicate that recruitment anomalies appear to be correlated in time and space. A simple model with a covariate based on basin-scale effects (Pacific Decadal Oscillation and El Niño Southern Oscillation) and local-scale effects (sea surface temperature, SST anomaly) was introduced to explain this variability. The model still exhibited residual patterns that were removed when a random-walk component was added to the model. The analysis indicates that recruitment is negatively related to SST anomaly for all stocks and the effect of basin-scale variables is negligible. The effect of climate over the next century is expected to result in estimated recruitment declining by an average of 13% for O. tshawytscha stocks coastwide.


Ketamine-induced oscillations in the motor circuit of the rat basal ganglia.
Oscillatory activity can be widely recorded in the cortex and basal ganglia. This activity may play a role not only in the physiology of movement, perception and cognition, but also in the pathophysiology of psychiatric and neurological diseases like schizophrenia or Parkinson's disease. Ketamine administration has been shown to cause an increase in gamma activity in cortical and subcortical structures, and an increase in 150 Hz oscillations in the nucleus accumbens in healthy rats, together with hyperlocomotion.We recorded local field potentials from motor cortex, caudate-putamen (CPU), substantia nigra pars reticulata (SNr) and subthalamic nucleus (STN) in 20 awake rats before and after the administration of ketamine at three different subanesthetic doses (10, 25 and 50 mg/Kg), and saline as control condition. Motor behavior was semiautomatically quantified by custom-made software specifically developed for this setting.Ketamine induced coherent oscillations in low gamma (~ 50 Hz), high gamma (~ 80 Hz) and high frequency (HFO, ~ 150 Hz) bands, with different behavior in the four structures studied. While oscillatory activity at these three peaks was widespread across all structures, interactions showed a different pattern for each frequency band. Imaginary coherence at 150 Hz was maximum between motor cortex and the different basal ganglia nuclei, while low gamma coherence connected motor cortex with CPU and high gamma coherence was more constrained to the basal ganglia nuclei. Power at three bands correlated with the motor activity of the animal, but only coherence values in the HFO and high gamma range correlated with movement. Interactions in the low gamma band did not show a direct relationship to movement.These results suggest that the motor effects of ketamine administration may be primarily mediated by the induction of coherent widespread high-frequency activity in the motor circuit of the basal ganglia, together with a frequency-specific pattern of connectivity among the structures analyzed.


Detection of Theileria and Babesia infections amongst asymptomatic cattle in Portugal.
Piroplasmosis caused by tick-borne hemoprotozoans of several Theileria and Babesia species has a major impact on livestock production worldwide. A reverse line blotting assay that includes genus- and species-specific probes for Theileria and Babesia species was used to assess the occurrence of these parasites in blood samples collected from 1407 healthy bovines throughout mainland Portugal. The global prevalence of piroplasm-infected animals was 36.8%, although significant differences were found between various regions. Higher prevalence was found in the southern regions (42.4% in Lisbon and Tagus Valley, 51.6% in Alentejo, and 40.0% in Algarve) compared to central (23.1%) and northern (12.8%) Portugal. Theileria annulata was the most frequently found species with a prevalence of 21.3%. The prevalence values of this pathogenic species were higher in the southern regions. The second most prevalent species was T. buffeli that infected 10.1% of the bovines. A low prevalence was found for Babesia infections (7.9%) with B. bigemina as the most frequent species. Some animals were infected with T. ovis and B. occultans. Veterinary practitioners and stakeholders should be made aware of the existence of a relatively high prevalence of carrier animals infected with T. annulata in Portugal, given the potential threat this pathogenic parasite represents to the cattle industry.