MRI Findings of Immune Checkpoint Inhibitor-Induced Hypophysitis: Possible Association with Fibrosis.
Hypophysitis is one of the well-known adverse effects of immune checkpoint inhibitors. Immune checkpoint inhibitor-induced hypophysitis frequently causes irreversible hypopituitarism, which requires long-term hormone replacement. Despite the high frequency and clinical significance, characteristic MR imaging findings of immune checkpoint inhibitor-induced hypophysitis have not been established. In the present study, we aimed to review and extract the MR imaging features of immune checkpoint inhibitor-induced hypophysitis. This retrospective international multicenter study comprised 20 patients with melanoma who were being treated with immune checkpoint inhibitors and clinically diagnosed with immune checkpoint inhibitor-induced hypophysitis. Three radiologists evaluated the following MR imaging findings: enlargement of the pituitary gland and stalk; homogeneity of enhancement of the pituitary gland; presence/absence of a well-defined poorly enhanced area and, if present, its location, shape, and signal intensity in T2WI; and enhancement pattern in contrast-enhanced dynamic MR imaging. Clinical symptoms and hormone levels were also recorded. Enlargement of the pituitary gland and stalk was observed in 12 and 20 patients, respectively. Nineteen patients showed poorly enhanced lesions (geographic hypoenhancing lesions) in the anterior lobe, and 11 of these lesions showed hypointensity on T2WI. Thyrotropin deficiency and corticotropin deficiency were observed in 19/20 and 12/17 patients, respectively, which persisted in 12/19 and 10/12 patients, respectively, throughout the study period. Pituitary geographic hypoenhancing lesions in the anterior lobe of the pituitary gland are characteristic and frequent MR imaging findings of immune checkpoint inhibitor-induced hypophysitis. They reflect fibrosis and are useful in distinguishing immune checkpoint inhibitor-induced hypophysitis from other types of hypophysitis/tumors.


Arm-specific dynamics of chromosome evolution in malaria mosquitoes.
The malaria mosquito species of subgenus Cellia have rich inversion polymorphisms that correlate with environmental variables. Polymorphic inversions tend to cluster on the chromosomal arms 2R and 2L but not on X, 3R and 3L in Anopheles gambiae and homologous arms in other species. However, it is unknown whether polymorphic inversions on homologous chromosomal arms of distantly related species from subgenus Cellia nonrandomly share similar sets of genes. It is also unclear if the evolutionary breakage of inversion-poor chromosomal arms is under constraints. To gain a better understanding of the arm-specific differences in the rates of genome rearrangements, we compared gene orders and established syntenic relationships among Anopheles gambiae, Anopheles funestus, and Anopheles stephensi. We provided evidence that polymorphic inversions on the 2R arms in these three species nonrandomly captured similar sets of genes. This nonrandom distribution of genes was not only a result of preservation of ancestral gene order but also an outcome of extensive reshuffling of gene orders that created new combinations of homologous genes within independently originated polymorphic inversions. The statistical analysis of distribution of conserved gene orders demonstrated that the autosomal arms differ in their tolerance to generating evolutionary breakpoints. The fastest evolving 2R autosomal arm was enriched with gene blocks conserved between only a pair of species. In contrast, all identified syntenic blocks were preserved on the slowly evolving 3R arm of An. gambiae and on the homologous arms of An. funestus and An. stephensi. Our results suggest that natural selection favors specific gene combinations within polymorphic inversions when distant species are exposed to similar environmental pressures. This knowledge could be useful for the discovery of genes responsible for an association of inversion polymorphisms with phenotypic variations in multiple species. Our data support the chromosomal arm specificity in rates of gene order disruption during mosquito evolution. We conclude that the distribution of breakpoint regions is evolutionary conserved on slowly evolving arms and tends to be lineage-specific on rapidly evolving arms.


Sudden survival improvement in critical neurotrauma: An exploratory analysis using a stratified statistical process control technique.
Outcome after trauma depends on patient characteristics, quality of care, and random events. The TRISS model predicts probability of survival (Ps) adjusted for Injury Severity Score (ISS), Revised Trauma Score (RTS), mechanism of injury, and age. Quality of care is often evaluated by calculating the number of "excess" survivors, year by year. In contrast, the Variable Life-Adjusted Display (VLAD) technique allows rapid detection of altered survival. VLAD adjusts each death or survival by the patient's risk status and graphically displays accumulated number of unexpected survivors over time. We evaluated outcome changes and their time relation to trauma service improvements. Observational, retrospective study of the total 2001-2011 trauma population from a Level I trauma centre. Outcome was 30-day survival. Ps was calculated with the TRISS model, 2005 coefficients. VLAD graphs were created for the entire population and for subpopulations stratified by ISS level, ISS body region (Head/Neck, Face, Chest, Abdomen/Pelvic contents, Extremities/Pelvic girdle, External), and maximum Abbreviated Injury Scale (maxAIS) score in each region. Piecewise linear regression identified VLAD graph breakpoints. 12,191 consecutive trauma patients (median age 35 years, 72% males, 91% blunt injury, 41% ISS≥16) formed the dataset. Their VLAD graph indicated performance equal to TRISS predicted survival until a sudden improvement in late 2004. From then survival remained improved but unchanged through 2011. Total number of excess survivors was 141. Inspection of subgroup VLAD graphs showed that the increased survival mainly occurred in patients having at least one Head/Neck AIS 5 injury. The effect was present in both isolated and multitraumatised maxAIS 5 Head/Neck trauma. The remaining trauma population showed unchanged survival, superior to TRISS predicted, throughout the study period. Important general and neurotrauma-targeted improvements in our trauma service could underlie our findings: A formalised trauma service, damage control resuscitation protocols, structured training, increased helicopter transfer capacity, consultant-based neurosurgical assessment, a doubling of emergency neurosurgical procedures, and improved neurointensive care. Stratified VLAD enables continuous, high-resolution system analysis. We encourage trauma centres to explore their data and to monitor future system changes.


Artichoke Polyphenols Sensitize Human Breast Cancer Cells to Chemotherapeutic Drugs via a ROS-Mediated Downregulation of Flap Endonuclease 1.
Combined treatment of several natural polyphenols and chemotherapeutic agents is more effective comparing to the drug alone in inhibiting cancer cell growth. Polyphenolic artichoke extracts (AEs) have been shown to have anticancer properties by triggering apoptosis or reactive oxygen species- (ROS-) mediated senescence when used at high or low doses, respectively. Our aim was to explore the chemosensitizing potential of AEs in order to enhance the efficacy of conventional chemotherapy in breast cancer cells. We employed breast cancer cell lines to assess the potential synergistic effect of a combined treatment of AEs/paclitaxel (PTX) or AEs/adriamycin (ADR) and to determine the underlying mechanisms correlated to this potential therapeutic approach. Our data shows that AEs/PTX reduced cell proliferation by increasing DNA damage response (DDR) mediated by Flap endonuclease 1 (FEN1) downregulation that results into enhanced breast cancer cell sensitivity to chemotherapeutic drugs. We demonstrated that ROS/Nrf2 and p-ERK pathways are two molecular mechanisms involved in the synergistic effect of AEs plus PTX treatment. To highlight the role of ROS herein, we report that the addition of antioxidant N-acetylcysteine (NAC) significantly decreased the antiproliferative effect of the combined treatment. A combined therapy could be able to reduce the dose of chemotherapeutic drugs, minimizing toxicity and side effects. Our results suggest the use of artichoke polyphenols as ROS-mediated sensitizers of chemotherapy paving the way for innovative and promising natural compound-based therapeutic strategies in oncology.


Profound block in thymocyte development in mice lacking p56lck.
The protein Lck (p56lck) has a relative molecular mass of 56,000 and belongs to the Src family of tyrosine kinases. It is expressed exclusively in lymphoid cells, predominantly in thymocytes and peripheral T cells. Lck associates specifically with the cytoplasmic domains of both CD4 and CD8 T-cell surface glycoproteins and interacts with the beta-chain of the interleukin-2 receptor, which implicates Lck activity in signal transduction during thymocyte ontogeny and activation of mature T cells. Here we generate an lck null mutation by homologous recombination in embryonic stem cells to evaluate the role of p56lck in T-cell development and activation. Lck-deficient mice show a pronounced thymic atrophy, with a dramatic reduction in the double-positive (CD4+CD8+) thymocyte population. Mature, single-positive thymocytes are not detectable in these mice and there are only very few peripheral T cells. These results illustrate the crucial role of this T-cell-specific tyrosine kinase in the thymocyte development.


Shifts in the Fecal Microbiota Associated with Adenomatous Polyps.
Adenomatous polyps are the most common precursor to colorectal cancer, the second leading cause of cancer-related death in the United States. We sought to learn more about early events of carcinogenesis by investigating shifts in the gut microbiota of patients with adenomas. We analyzed 16S rRNA gene sequences from the fecal microbiota of patients with adenomas (n = 233) and without (n = 547). Multiple taxa were significantly more abundant in patients with adenomas, including Bilophila, Desulfovibrio, proinflammatory bacteria in the genus Mogibacterium, and multiple Bacteroidetes species. Patients without adenomas had greater abundances of Veillonella, Firmicutes (Order Clostridia), and Actinobacteria (family Bifidobacteriales). Our findings were consistent with previously reported shifts in the gut microbiota of colorectal cancer patients. Importantly, the altered adenoma profile is predicted to increase primary and secondary bile acid production, as well as starch, sucrose, lipid, and phenylpropanoid metabolism. These data hint that increased sugar, protein, and lipid metabolism along with increased bile acid production could promote a colonic environment that supports the growth of bile-tolerant microbes such as Bilophilia and Desulfovibrio In turn, these microbes may produce genotoxic or inflammatory metabolites such as H2S and secondary bile acids, which could play a role in catalyzing adenoma development and eventually colorectal cancer. This study suggests a plausible biological mechanism to explain the links between shifts in the microbiota and colorectal cancer. This represents a first step toward resolving the complex interactions that shape the adenoma-carcinoma sequence of colorectal cancer and may facilitate personalized therapeutics focused on the microbiota. Cancer Epidemiol Biomarkers Prev; 26(1); 85-94. ©2016 AACR.


Micromolar levels of intracellular calcium reduce gap junctional permeability in lens cultures.
To investigate in bovine and embryonic chicken lens cultures the effects of elevated intracellular calcium on the permeability of gap junctions. To determine the changes in intracellular calcium using fura-2. To detect any changes in the phosphorylation of connexin43 after ionophore treatment. Lucifer yellow was micro-injected into individual cells, and dye spread to neighboring cells was evaluated. Intracellular calcium levels were measured using the calcium indicator, fura-2. Cultures were also labeled with 32P-orthophosphate followed by immunoprecipitation with antibodies specific for the gap junction protein, connexin43. Bovine lens cultures incubated in the presence of either A23187 or ionomycin showed a reduction in intercellular dye transfer. The intracellular calcium concentrations in bovine cells were increased from a mean value of 0.11 +/- .009 microM in the controls to a mean of 0.40 +/- .073 microM with ionomycin treatment. Subsequent addition of EGTA to the medium decreased the intracellular calcium concentrations to a mean of 0.26 +/- .113 microM and reversed the inhibition of dye spread found with ionomycin. With ionomycin in the medium, the phosphorylated form of connexin43 was not as prominent as in the controls. In contrast, these same treatments had no detectable effect on junctional permeability in the embryonic chicken lens cultures. Dye spread was equally extensive and rapid under control and ionophore conditions, even though fura studies showed an elevation in intracellular calcium levels. In the bovine cultures, physiologically relevant changes in the levels of cytoplasmic calcium markedly reduced dye transfer. The increase in cytoplasmic calcium was correlated with a change in the phosphorylation level of connexin43. The regulation of junctional communication in the chick lens cultures appears to differ significantly from that in the bovine system.


Aedes aegypti survival and dispersal estimated by mark-release-recapture in northern Australia.
The survival and dispersal of adult Aedes aegypti were estimated in northern Australia where sporadic outbreaks of Ae. aegypti-borne dengue viruses have occurred in recent years. Standard mark-release-recapture methods were used. In addition, a new sticky trap was used to capture the mosquitoes. Prior to the field study, the survival and effect of marking Ae. aegypti with fluorescent powder were determined in the laboratory. Mortality was age-dependent and the marked cohorts had higher survival rates than the untreated cohorts. Recapture rates of 13.0% and 3.6% over a seven-day period were achieved for two batches of marked Ae. aegypti released simultaneously at the field site. More males than females were recaptured although the proportion of females increased with time. The probability of daily survival was 0.91 and 0.86 for the blue- and pink-marked females, respectively, and 0.57 and 0.70 for the blue- and pink-marked and males, respectively. The mean distance traveled of recaptured Ae. aegypti was 56 m and 35 m for females and males, respectively. The maximum observed distance traveled of 160 m was the same for both sexes. The warm to hot and dry climatic conditions may have restricted the dispersal of released mosquitoes in this study. The frequency of recaptures at certain trap locations suggested that shade, wind, and the availability of hosts affected the distribution of Ae. aegypti within the study site.


On the calculation of equilibrium thermodynamic properties from molecular dynamics.
The purpose of statistical mechanics is to provide a route to the calculation of macroscopic properties of matter from their constituent microscopic components. It is well known that the macrostates emerge as ensemble averages of microstates. However, this is more often stated than implemented in computer simulation studies. Here we consider foundational aspects of statistical mechanics which are overlooked in most textbooks and research articles that purport to compute macroscopic behaviour from microscopic descriptions based on classical mechanics and show how due attention to these issues leads in directions which have not been widely appreciated in the field of molecular dynamics simulation.


Aromatase inhibition by 2-methyl indole hydrazone derivatives evaluated via molecular docking and in vitro activity studies.
A causal association is reported between prolonged exposures to elevated levels of estrogen and breast cancer. Therefore inhibiting aromatase (CYP19A), which catalyses the conversion of androgens to estrogens, is an important approach in prevention and treatment of estrogen receptor positive (ER+) breast cancer. Melatonin, a natural indolic hormone, is reported to prevent free radical induced carcinogenesis and block local estrogen synthesis in breast tissue via aromatase inhibition. However several features of melatonin limit its therapeutic use. In the present study aromatase inhibiting potential of 2-methyl indole hydrazones are investigated, and compared with melatonin, by two in vitro models; a cell-free assay using a fluorescence substrate and a cell-based assay where cell proliferation was determined in ER + human breast cancer cells (MCF-7 BUS) in the absence of estrogen and the presence of testosterone. Aromatase inhibitory effect is also explored by molecular modelling studies. In biological activity assays monochloro substituted indole hydrazones were found to have stronger aromatase inhibitory activity among all tested derivatives and were more active than melatonin. This finding is further confirmed by molecular modelling. These results may be useful in the design and synthesis of novel melatonin analogues with higher inhibitory potency against aromatase.


Concentrations of thromboxane metabolites in feline urine.
OBJECTIVE To determine the predominant thromboxane (TX) metabolite in urine of healthy cats, evaluate whether the method of sample collection would impact concentration of that metabolite, and propose a reference interval for that metabolite in urine of healthy cats. ANIMALS 17 cats (11 purpose-bred domestic shorthair cats, 5 client-owned domestic shorthair cats, and 1 client-owned Persian cat). PROCEDURES All cats were deemed healthy on the basis of results for physical examination, a CBC, serum biochemical analysis, urinalysis, and measurement of prothrombin time and activated partial thromboplastin time. Voided and cystocentesis urine samples (or both) were collected. Aliquots of urine were stored at -80°C until analysis. Concentrations of TXB2, 11-dehydroTXB2, and 2,3 dinorTXB2 were measured with commercially available ELISA kits. Urinary creatinine concentration was also measured. RESULTS 11-dehydroTXB2 was the most abundant compound, representing (mean ± SD) 59 ± 18% of the total amount of TX detected. In all samples, the concentration of 11-dehydroTXB2 was greater than that of 2,3 dinorTXB2 (mean, 4.2 ± 2.7-fold as high). Mean concentration of 11-dehydroTXB2 for the 17 cats was 0.57 ± 0.47 ng/mg of creatinine. A reference interval (based on the 5% to 95% confidence interval) of 0.10 to 2.1 ng of 11-dehydroTXB2/mg of creatinine was proposed for healthy cats. CONCLUSIONS AND CLINICAL RELEVANCE In this study, 11-dehydroTXB2 was the major TX metabolite in feline urine. Measurement of this metabolite may represent a noninvasive, convenient method for monitoring in vivo platelet activation in cats at risk for thromboembolism.


Effects of dietary soybean lecithin on growth performance, blood chemistry and immunity in juvenile stellate sturgeon (Acipenser stellatus).
An eleven weeks feeding trial was conducted to determine the effects of different levels of dietary soybean lecithin (SBL) on growth performance, blood chemistry and immunity in juvenile stellate sturgeon (Acipenser stellatus). Fish were fed seven isoproteic (44% crude protein) and isolipidic (17% crude fat) diets containing graded levels of SBL: 0 (control), 1, 2, 4, 6, 8 and 10%. Results showed that dietary SBL supplementation significantly improved the final body weight (BW) and weight gain (WG). Fish fed 6% SBL showed the highest BW and WG values in comparison to fish fed the control diet (P < 0.05), whereas increasing SBL levels above 6% had little practical benefit in terms of somatic growth performance. The inclusion of SBL in diets significantly improved the immune response as data from lysozyme, total Ig levels, alternative complement, phagocytic and bactericidal activities indicated (P < 0.05). The broken-line regression analysis of immunological variable revealed that depending on the parameter considered, the optimal SBL levels in diets for stellate sturgeon juveniles varied. In particular, dietary SBL levels requirements in stellate sturgeon when considering the phagocytic activity rate were determined at 3.3%, whereas 4.1-4.2% were recommended when considering data from lysozyme, alternative complement and bactericidal activities. In contrast, the highest minimum dietary SBL content was estimated at 6.9% when data from total Ig levels were considered. These results indicated that dietary PLs are required for boosting innate immunity in stellate sturgeon, although their minimal level changed depending on the immunological parameter considered. Therefore, we assume that SBL levels comprised between 3.3 and 6.9% may be used as a prophylactic measure to improve the health status in stellate sturgeon. Red blood cell count, hemoglobin and hematocrit levels increased with increasing dietary SBL levels, especially in those sturgeons fed the diet with 6% SBL (P < 0.05). In addition, white blood cell counts significantly increased as dietary SBL levels increased from 4 to 8% in comparison to the control group. Blood biochemistry was also affected by different dietary SBL levels. In particular, significantly higher levels of glucose, cholesterol, HDL and triglycerides were detected in fish fed >6%, >4%, >2% and 2% SBL, respectively (P < 0.05). Based on somatic growth parameters, blood chemistry and systemic immunity parameters, diets containing ca. 6% SBL are recommended for juvenile stellate sturgeon.


Depot antipsychotic medications in bipolar disorder: a review of the literature.
To review the literature on the efficacy and safety of depot formulations of first- and second-generation antipsychotic medications (FGAs and SGAs) in patients with bipolar disorder. We conducted a computer-aided MEDLINE search using the search terms 'depot antipsychotic', 'bipolar disorder' and 'compliance.' We identified eight published reports in bipolar patients regarding the use of depot FGAs, and six preliminary reports on the use of depot SGAs. These studies suggest that depots FGAs are efficacious in preventing manic episodes during the maintenance treatment of bipolar disorder. Several studies, however, indicate that depot FGAs may be associated with increased time with depressive symptoms, particularly in patients with a predominantly depressive course of illness. Preliminary data on the role of depot formulations of SGAs suggest that they reduce the frequency of both manic and depressive episodes during maintenance treatment, and are well tolerated by patients. After a careful risk-benefit analysis, depot antipsychotics may be considered for the long-term control of mood episodes in bipolar patients who have relapsed due to medication non-adherence or who have failed to respond to standard therapies. Depot FGAs should be avoided in patients with a high burden of illness from depressive symptoms and particularly in those judged to be at high risk of suicide. The available data on depot formulations of SGAs indicate that they are efficacious in the maintenance treatment of bipolar illness without increasing the burden of the depressive pole of the illness, but further systematic studies are required to definitively assess this.


Directional cell migration in vivo: Wnt at the crest.
Directional cell migration is essential for almost all organisms during embryonic development, in adult life and contributes to pathological conditions. This is particularly critical during embryogenesis where it is essential that cells end up in their correct, precise locations in order to build a normal embryo. Many cells have solved this problem by following a gradient of a chemoattractant usually secreted by their target tissues. Our recent research has found an alternative, complimentary, mechanism where intracellular signals are able to generate cell polarity and directional migration in absence of any external chemoattactant. We used neural crest cells to study cell migration in vivo, by performing live imagining of the neural crest cell migrating during embryo development. We show that the Planar Cell Polarity (PCP) or non-canonical Wnt signaling pathway interacts with the proteoglycan syndecan-4 to control the direction in which cell protrusions are generated, and in consequence, the direction of migration. By analyzing the activity of the small GTPases using in vivo FRET imaging we showed that PCP signaling activates RhoA, while syndecan-4 inhibits Rac, both at the back of the neural crest cell. Here we discuss a model where these signals are integrated to generate directional migration in vivo.


Effect of clonal reproduction on genetic structure in Pentaclethra macroloba (Fabaceae: Mimosoideae).
The existence of monodominant forests on well-drained soils in tropical regions has been widely reported. Such forests most likely result from a combination of both ecological and evolutionary factors. Under conditions of high seed and seedling mortality, vegetative reproduction could create a reproductive advantage leading to forest dominance, and profoundly affect the distribution of genetic variation in a clonal species. We investigated these effects in a low diversity forest site in Northeastern Costa Rica dominated by the species Pentaclethra macroloba, which sprouts from the root mass of fallen trees and from snapped trunks. We examined the population structure of juvenile P. macroloba growing in different soil types and across an elevational gradient. Using seven molecular markers, we genotyped 173 juvenile P. macroloba from 18 plots (six plots in seasonally inundated swamps, and 12 plots in upland non-swamp) spanning 50-300m in elevation at La Selva Biological Station and the adjacent Reserva Ecológica Bijagual in Northeastern Costa Rica. We answered two specific questions: (1) How extensive is clonal reproduction? and (2) what is the distribution of genetic diversity and structure? We found that clonal reproduction occurred exclusively within inundated swamp areas. However, there was no significant difference between genetic diversity measures in swamp and non-swamp plots, which were both generally low when compared with other tropical forest species. Genetic structure was significant across all plots (F(ST) = -0.109). However, genetic structure among swamp plots (F(ST) = 0.128) was higher than among non-swamp upland plots (F(ST) = 0.093). Additionally, spatial autocorrelation among individuals within non-swamp upland plots was significant from the 25 to 100m spatial scale, but not within swamp plots. The degree of overall genetic structure we found in P. macroloba is high for a tropical forest tree. The incidence of clonal reproduction is a contributing factor in genetic differentiation, but the high structure among plots without clonal reproduction indicates that other factors contribute as well.


Use of the North American guidelines for children's agricultural tasks with Hmong farm families.
This literature review synthesizes available studies on Hmong agricultural practices, patterns of childhood growth and development of Hmong children in the context of injury prevention, and potential application or adaptation of the North American Guidelines for Children's Agricultural Tasks (Lee and Marlenga, 1999) for Hmong children working in the U.S. Data from qualitative interviews, focus groups, case studies, and surveys were collected, categories were determined, and themes were identified. Field tools and practices, gender roles, and reasons for farming were examined, as well as physical and cognitive development of Hmong children and Hmong parenting techniques to describe factors related to farm task assignment of children. Current agricultural practices of Hmong in the U.S. can be described as generally small-scale operations that use mainly hand tools, manual labor, and local direct-marketing techniques. Specific practices include thinning, weeding, and hoeing; carrying tools, buckets, or baskets; setting plant supports; and watering. Hmong children appear to be given greater amounts of responsibility at earlier ages than North American children. Hmong parenting practices, as would be used in task assignment, are somewhat more authoritarian-based and lead to psychosocial skills that are more group-oriented than individual-oriented. Hmong children were found to be shorter than children in the U.S. of the same ages. This review suggests that the NAGCAT cannot be literally translated and disseminated to Hmong farming families as an injury prevention intervention. Further information is needed about what farm tasks Hmong children do and how Hmong parents assign those tasks to children.


Multicenter investigation of technical and clinical outcomes after thrombectomy for Proximal Medium Vessel Occlusion (pMeVO) by frontline technique.
Endovascular thrombectomy(EVT) is the standard of care for large vessel occlusion(LVO) stroke. Data on technical and clinical outcome in proximal medium vessel occlusions(pMeVOs) comparing frontline techniques remain limited. We report an international multicenter retrospective study of patients undergoing EVT for stroke at 32 centers between 2015-2021. Patients were divided into LVOs(ICA/M1/Vertebrobasilar) or pMeVOs(M2/A1/P1) and categorized by thrombectomy technique. Primary outcome was 90-day good functional outcome(mRS ≤ 2). Multivariate logistic regressions were used to evaluate the impact of technical variables on clinical outcomes. Propensity score matching was used to compare outcome in patients with pMeVO treated with aspiration versus stent-retriever. In the cohort of 5977 LVO and 1287 pMeVO patients, pMeVO did not independently predict good-outcome(p = 0.55). In pMeVO patients, successful recanalization irrespective of frontline technique(aOR = 3.2,p < 0.05), procedure time ≤ 1-h(aOR = 2.2,p < 0.05), and thrombectomy attempts ≤ 4(aOR = 2.8,p < 0.05) were independent predictors of good-outcomes.In a propensity-matched cohort of aspiration versus stent-retriever pMeVO patients, there was no difference in good-outcomes. The rates of hemorrhage were higher(9%vs.4%,p < 0.01) and procedure time longer(51-min vs. 33-min,p < 0.01) with stent-retriever, while the number of attempts was higher with aspiration(2.5vs.2,p < 0.01). Rates of hemorrhage and good-outcome showed an exponential relationship to procedural metrics, and were more dependent on time in the aspiration group compared to attempts in the stent-retriever group. Clinical outcomes following EVT for pMeVO are comparable to those in LVOs. The golden hour or 3-pass rules in LVO thrombectomy still apply to pMeVO thrombectomy. Different techniques may exhibit different futility metrics; SR thrombectomy was more influenced by attempts whereas aspiration was more dependent on procedure time.


Electroporation and RNA interference in the rodent retina in vivo and in vitro.
The large number of candidate genes made available by comprehensive genome analysis requires that relatively rapid techniques for the study of function be developed. Here, we report a rapid and convenient electroporation method for both gain- and loss-of-function studies in vivo and in vitro in the rodent retina. Plasmid DNA directly injected into the subretinal space of neonatal rodent pups was taken up by a significant fraction of exposed cells after several pulses of high voltage. With this technique, GFP expression vectors were efficiently transfected into retinal cells with little damage to the operated pups. Transfected GFP allowed clear visualization of cell morphologies, and the expression persisted for at least 50 days. DNA-based RNA interference vectors directed against two transcription factors important in photoreceptor development led to photoreceptor phenotypes similar to those of the corresponding knockout mice. Reporter constructs carrying retinal cell type-specific promoters were readily introduced into the retina in vivo, where they exhibited the appropriate expression patterns. Plasmid DNA was also efficiently transfected into retinal explants in vitro by high-voltage pulses.


Providers' advice concerning smoking cessation: Evidence from the Medical Expenditures Panel Survey.
We estimate how often adult smokers are advised to quit using a nationally representative sample of adults in the United States. Data are from the 2012-2013 household component of the United States (US) Medical Expenditures Panel Survey (MEPS). Current smoking and advice to quit offered by providers. Smoking was reported by 18.26% (CI 17.13%-19.38%) of 2012 MEPS respondents. Less than half of adult smokers (47.24%, CI 44.30%-50.19%) were advised to quit by their physicians although 17.57% (CI 15.37%-19.76%) had not seen a doctor in the last 12months. Advice to quit was given significantly less often to respondents classified as: aged 18-44 (40.29%), men (40.20%), less educated (42.26%), lower family income (43.51%), Hispanic (33.82%), never married (39.55%), and living outside the northeast. Smoking status at year 2 for patients who had received advice to quit was similar (85.13%: SE 1.62%) to those who had seen a physician but were not advised to quit (81.95%: SE 2.05%). Advice to quit smoking was less common than the use of common medical screening tests. Smoking cessation advice is given to less than half of current cigarette smokers and it is least likely to be given to the most vulnerable populations. Efforts to reduce smoking are deployed less often than other preventive practices. The rate of advice to quit has not changed over the last decade. Health care providers are missing an important opportunity to affect health behaviors and outcomes.


Proteomic and Post-Translational Modification Profiling of Exosome-Mimetic Nanovesicles Compared to Exosomes.
Issues associated with upscaling exosome production for therapeutic use may be overcome through utilizing artificial exosomes. Cell-derived mimetic nanovesicles (M-NVs) are a potentially promising alternative to exosomes for clinical applicability, demonstrating higher yield without incumbent production and isolation issues. Although several studies have shown that M-NVs have similar morphology, size and therapeutic potential compared to exosomes, comprehensive characterization and to what extent M-NVs components mimic exosomes remain elusive. M-NVs were generated through the extrusion of cells and proteomic profiling demonstrated an enrichment of proteins associated with membrane and cytosolic components. The proteomic data herein reveal a subset of proteins that are highly abundant in M-NVs in comparison to exosomes. M-NVs contain proteins that largely represent the parental cell proteome, whereas the profile of exosomal proteins highlight their endosomally derived origin. This advantage of M-NVs alleviates the necessity of endosomal sorting of endogenous therapeutic proteins or RNA into exosomes. This study also highlights differences in protein post-translational modifications among M-NVs, as distinct from exosomes. Overall this study provides key insights into defining the proteome composition of M-NVs as a distinct from exosomes, and the potential advantage of M-NVs as an alternative nanocarrier when spontaneous endosomal sorting of therapeutics are limited.


The assessment of intention-cue detection skills in children: implications for developmental psychopathology.
A reliable measure of children's skills in discriminating intention cues in others was developed for this investigation in order to test the hypothesis that intention-cue detection skill is related to social competence in children. Videotapes were prepared in which one child provoked another child. The intention of the first child varied across videotapes. The subject's task was to discriminate among types of intentions. Care was taken to ensure that scores on this measure were not confounded by a child's verbal capacity or general discrimination skill. This instrument was administered to 176 children in kindergarten, second grade, and fourth grade, who were identified by sociometric measures as having a peer status as popular, average, socially rejected, or socially neglected. Scores on this measure were found to increase as a function of increasing age, and normal children (popular and average) were found to score more highly than deviant children (neglected and rejected). The errors by deviant children tended to consist of erroneous labels of prosocial intentions as hostile. Also, children's statements about their probable behavioral responses to provocations by peers were found to vary as a function of subjects' perceptions of the intention of the peer causing the provocation, not as a function of the actual intention portrayed by the peer. Sociometric status differences in these responses were also found. These findings were consistent with a hypothesis of a developmental lag among socially deviant children in the acquisition of intention-cue detection skills.


Engineering shadows to fabricate optical metasurfaces.
Optical metasurfaces-patterned arrays of plasmonic nanoantennas that enable the precise manipulation of light-matter interactions-are emerging as critical components in many nanophotonic materials, including planar metamaterials, chemical and biological sensors, and photovoltaics. The development of these materials has been slowed by the difficulty of efficiently fabricating patterns with the required combinations of intricate nanoscale structure, high areal density, and/or heterogeneous composition. One convenient strategy that enables parallel fabrication of periodic nanopatterns uses self-assembled colloidal monolayers as shadow masks; this method has, however, not been extended beyond a small set of simple patterns and, thus, has remained incompatible with the broad design requirements of metasurfaces. This paper demonstrates a technique-shadow-sphere lithography (SSL)-that uses sequential deposition from multiple angles through plasma-etched microspheres to expand the variety and complexity of structures accessible by colloidal masks. SSL harnesses the entire, relatively unexplored, space of shadow-derived shapes and-with custom software to guide multiangled deposition-contains sufficient degrees of freedom to (i) design and fabricate a wide variety of metasurfaces that incorporate complex structures with small feature sizes and multiple materials and (ii) generate, in parallel, thousands of variations of structures for high-throughput screening of new patterns that may yield unexpected optical spectra. This generalized approach to engineering shadows of spheres provides a new strategy for efficient prototyping and discovery of periodic metasurfaces.


The immunological and psychological effects of bereavement: does grief counseling really make a difference? A pilot study.
This study evaluates psychological and immunological functioning after bereavement and the influence of group counseling. Eighteen widows (bereaved within 3 months of enrolment) and a reference group of 10 married control subjects were asked to fill in self-report scales and to donate a blood sample (T1). After T1, half of the widows (the experimental group) were randomly assigned to grief counseling (13 sessions over 4 months), while the other subjects (the control group) received no treatment. Seven months after bereavement (T2) or, in the case of the experimental group, immediately after the intervention, a follow-up was conducted in the widowed subsample using the same measures. Blood samples were analyzed to determine the total number of white blood cells, number of lymphocyte subsets, natural killer cell activity (NKCA) and lymphocyte proliferative response to phytohemagglutinin (PHA), anti-CD3 and pokeweed mitogen (PWM). At T1, we found significant differences between widows and non-widows regarding both psychological and immunological measures. Widows felt more anxious, depressed, hostile and agoraphobic. At T1, widows had a lower number of the CD19+CD5+ B cell subpopulation. The cell function tests for T and B cells showed higher responses in widows (lymphocyte proliferation response to PHA, anti-CD3 and PWM). No significant difference in NKCA was found between widows and non-widows. At T2, there appeared to be no significant difference between widows and non-widows on the psychological measures. With respect to the immunological measures, widows and non-widows showed no significant differences for the total number of white blood cells, number of lymphocyte subsets and NKCA. Consistent with our findings at T1, the lymphocyte proliferation response to PHA, anti-CD3 and PWM at T2 appeared to be higher in widows than in non-widows. Comparing the experimental group (widows) and the control group (widows) with respect to psychological measures at T1, widows in the experimental group felt more insufficient and had more sleep disturbances. With respect to the immunological measures, no differences were found between those two groups. When the same two groups were again compared at T2, no differences were found in any of the psychological or immunological measures (lymphocyte sub-populations, proliferation tests and the NKCA).


In situ mutation detection and visualization of intratumor heterogeneity for cancer research and diagnostics.
Current assays for somatic mutation analysis are based on extracts from tissue sections that often contain morphologically heterogeneous neoplastic regions with variable contents of normal stromal and inflammatory cells, obscuring the results of the assays. We have developed an RNA-based in situ mutation assay that targets oncogenic mutations in a multiplex fashion that resolves the heterogeneity of the tissue sample. Activating oncogenic mutations are targets for a new generation of cancer drugs. For anti-EGFR therapy prediction, we demonstrate reliable in situ detection of KRAS mutations in codon 12 and 13 in colon and lung cancers in three different types of routinely processed tissue materials. High-throughput screening of KRAS mutation status was successfully performed on a tissue microarray. Moreover, we show how the patterns of expressed mutated and wild-type alleles can be studied in situ in tumors with complex combinations of mutated EGFR, KRAS and TP53. This in situ method holds great promise as a tool to investigate the role of somatic mutations during tumor progression and for prediction of response to targeted therapy.


[Cryptococcal meningitis and neuropsychiatric consequences of HIV-infection].
A 49-year-old African-born male was admitted to hospital with an acute psychosis. He had been treated by an internist after being found to have hiv; as a result of non-compliance over a period of about four months his cd4-count had dropped to 40. Six months earlier he had developed a cryptococcal meningitis, which left him a number of neurological and psychiatric symptoms. During his stay in hospital there had to be good collaboration with the specialist in internal medicine whose dual task was to manage the patient's dramatically low cd4-account as well as his psychosis. Cryptococcal meningitis is a risk factor for psychiatric disorders and mortality in hiv-infected persons.


Changes in general and oral health-related quality of life in immediate or conventionally loaded dental implants: a nonrandomized clinical trial.
To evaluate changes in the general and oral health-related quality of life (using the European Quality of Life indicator and the Oral Health Impact Profile-49 [OHIP-49], respectively) of patients treated with conventionally or immediately loaded implants. This clinical trial consisted of a clinical oral examination and a questionnaire-based interview carried out before and after both surgery and definitive prosthetic rehabilitation in a consecutive sample of patients requiring dental implants. According to the clinical diagnosis and patient preference, patients were assigned to the immediate loading group (IL group; n = 29) or the conventional loading group (CL group; n = 75). The change summary scores and effect sizes were calculated in the intermediate stage and at the final follow-up, taking baseline scores as reference. The oral health-related quality of life and oral satisfaction after implant therapy were significantly better than at baseline, with an even greater benefit when the implants were loaded immediately than when prosthetic rehabilitation was delayed. However, there were no significant differences in between-group comparisons in the ratings of general health status. The effect size for the OHIP-49 exceeded the threshold value of 0.8 for the domains functional limitation, pain/discomfort, and psychological discomfort in both groups and also for physical disability and psychological disability in the IL group. A gradual improvement in oral well-being scores, but not in those of general well-being, were observed for both groups from the intermediate stage to the final evaluation. This benefit was markedly greater for the IL group.


Functional auditory disorders.
There are a number of auditory symptom syndromes that can develop without an organic basis. Some of these, such as nonorganic hearing loss, affect populations similar to those presenting with functional somatosensory and motor symptoms, while others, such as musical hallucination, affect populations with a significantly different demographic and require different treatment strategies. Many of these conditions owe their origin to measurably abnormal peripheral sensory pathology or brain network activity, but their pathological impact is often due, at least in part, to overamplification of the salience of these phenomena. For each syndrome, this chapter briefly outlines a definition, demographics, investigations, putative mechanisms, and treatment strategies. Consideration is given to what extent they can be considered to have a functional basis. Treatments are in many cases pragmatic and rudimentary, needing more work to be done in integrating insights from behavioral and cognitive psychology to auditory neuroscience. The audiology literature has historically equated the term functional with malingering, although this perception is, thankfully, slowly changing. These disorders transcend the disciplines of audiology, otorhinolaryngology, neurology and psychiatry, and a multidisciplinary approach is often rewarding.


Establishing clinical supervision in acute mental health inpatient units: acknowledging the challenges.
After decades of discussion about clinical supervision and mental health nursing, the reality is that many acute mental health inpatient settings continue to struggle with the notion of clinical supervision and the implementation process. In this article we delineate the key elements of clinical supervision, explore practical and dynamic difficulties associated with clinical supervision and question whether too much is being asked of this one process, especially in acute inpatient settings. For many mental health nurses, existing practices offer many of the purported benefits of clinical supervision. Ultimately, unless clinical supervision is better understood and implemented effectively, it is unlikely to meet expectations. Clinical supervision should ultimately be defined by the nurses participating in it. This article contributes to current discussions regarding the purpose of clinical supervision, the realities of its implementation, and in particular considers the role of clinical supervision relative to existing professional support opportunities.


Calculation of quantum well laser gain spectra.
This paper describes a method for calculating gain spectra of quantum well laser structures. The approach is based on the Semiconductor Bloch equations, with Coulomb correlation effects treated at the level of quantum kinetic theory in the Markovian limit. Results obtained from applying this method to an InGaN quantum well laser are presented.


GP frequent consulters: their prevalence, natural history, and contribution to rising workload.
A small proportion of patients use a disproportionate amount of general practitioners' (GPs') time. We demonstrate here that such frequent attending behaviour tends to persist through five-year follow-up, suggesting the need for the development of specific management strategies. We also show that, at any rate in one practice, total workload is increasing dramatically, and that frequent consulters make up a large part of the increase.


Simultaneous real-time imaging of surface and subsurface structures from a single space-frequency multiplexed photodisplacement interferogram.
A new parallel photodisplacement technique has been developed that achieves simultaneous real-time imaging of surface and subsurface structures from a single space-frequency multiplexed interferogram, which greatly simplifies the system and the optical alignment. A linear region of photodisplacement is excited on the sample for subsurface imaging by use of a line-focused intensity-modulated laser beam, and the displacement and surface information on reflectivity and topography are detected by a parallel heterodyne interferometer with a charge-coupled device linear image sensor used as a detector. The frequencies of three control signals for excitation and detection, that is, the heterodyne beat signal, modulation signal, and sensor gate pulse, are optimized such that surface and subsurface information components are space-frequency multiplexed into the sensor signal as orthogonal functions, allowing each to be discretely reproduced from Fourier coefficients. Preliminary experiments demonstrate that this technique is capable of simultaneous imaging of reflectivity, topography, and photodisplacement for the detection of subsurface lattice defects at a remarkable speed of only 0.26 s per 256 x 256 pixel area. This new technique is promising for use in nondestructive hybrid surface and subsurface inspection and other applications.


Measuring the neuromodulatory effects of drugs in man with positron emission tomography.
Cognitive activation in conjunction with pharmacological challenge was used to demonstrate neuromodulation in man. Using positron emission tomography (PET), measurements of regional cerebral blood flow were made during the performance of memory tasks, before and after the administration of apomorphine (dopamine agonist), buspirone (5-HT1A partial agonist) or placebo. Drug effects on memory-induced increases in regional cerebral blood flow were assessed, on a voxel-by-voxel basis, using statistical parametric mapping. Increases of regional cerebral blood flow in response to the memory challenge were attenuated by apomorphine in the dorsolateral prefrontal cortex and augmented in the retrosplenial region of the posterior cingulate. Conversely, buspirone attenuated blood flow increases in the retrosplenial region. These interactions between drugs and a cognitive challenge can best be interpreted as neuromodulatory effects.


Antifungal Activity of α-Sarcin against Penicillium digitatum: Proposal of a New Role for Fungal Ribotoxins.
Among the putative defense proteins that occur in fungi, one of the best studied is α-sarcin, produced by the mold Aspergillus giganteus. This protein is the most significant member of the ribotoxin family, which consists of extracellular rRNA ribonucleases that display cytotoxic activity toward animal cells. Ribotoxins are rRNA endonucleases that catalyze the hydrolysis of the phosphodiester bond between G4325 and A4326 from the rat 28S rRNA. The results of several experimental approaches have led to propose ribotoxins as insecticidal agents. In this work, we report that α-sarcin displays a strong antifungal activity against Penicillium digitatum, being able to enter into the cytosol where it inactivates the ribosomes, thus killing the cells and arresting the growth of the fungus. This is the first time that a ribotoxin has been found to display antifungal activity. Therefore, this protein could play, besides the already proposed insecticidal function, a role in nature as an antifungal agent.


Mouse Models of Muscle-invasive Bladder Cancer: Key Considerations for Clinical Translation Based on Molecular Subtypes.
In the past few years, research has suggested that molecular subtypes in muscle-invasive bladder cancer (MIBC) may be exploited to accelerate developments in clinical disease management and novel therapeutics. To review MIBC mouse models from a molecular subtype perspective, their advantages and limitations, and their applications in translational medicine, based on a PubMed search for publications from January 2000 to February 2018. Publications relevant to MIBC mouse models and their molecular subtypes were identified in a literature review. We classified the models according to the technique used for their establishment. For xenotransplant and allograft models, the inoculated cells and inoculated locations are the major determinants of molecular subtypes. Although the cell lines used in xenotransplant models can cover most of the basal-squamous and luminal subtypes, allograft models offer a more realistic environment in which to reconstruct aspects of the associated stromal and immune features. Autochthonous models, using genetic and/or chemical stimuli to induce disease progression, can also generate models with basal-squamous and luminal subtypes, but further molecular characterisation is needed since other mutational variants may be introduced in these models. We identified preclinical MIBC models with different subtype specifications and assessed their promise and current limitations. These models are versatile tools that can reproduce the molecular complexity of MIBC and support novel therapeutic development. Understanding which models of muscle-invasive bladder cancer most accurately represent the clinical situation is important for the development of novel drugs and disease management strategies. We review the different models currently available and their relevance to different clinical subtypes.


Spine Surgery and Blood Loss: Systematic Review of Clinical Evidence.
Spine surgery has been growing rapidly as a neurosurgical operation, with an increase of 220% over a 15-year period. Intraoperative blood transfusion is a major outcome determinant of spine procedures. Various approaches, including pharmacologic and nonpharmacologic therapies, have been tested to decrease both intraoperative and postoperative blood loss. The aim of this systematic review is to report clinical evidence on the relationship between intraoperative blood loss (primary outcome) and on transfusion requirements and postoperative complications (secondary outcomes) in patients undergoing spine surgery. A literature search of PubMed database was performed using 5 key words: spine surgery and transfusion; spine surgery and blood loss; spine surgery and blood complications; spine surgery and deep vein thrombosis; and spine surgery and pulmonary embolism. Clinical reports (randomized controlled trials, prospective and retrospective studies, and case reports) were selected. A total of 473 articles were examined; 450 were excluded, and 24 were selected for this systematic review. Selected articles were categorized into 3 subchapters: (1) drugs active on coagulation (12 studies): tranexamic acid, aminocaproic acid, aprotinin, and recombinant activated factor VII; (2) drugs not active on coagulation (5 studies): ketorolac, epoetin alfa, magnesium sulfate, propofol/sevoflurane, and omega-3 and fish oil; (3) nonpharmacologic approaches (7 studies): surgical tips, patient positioning, and general or spinal anesthesia. Several studies have shown a significant reduction in intraoperative bleeding during spine surgery and in the requirement for blood transfusion.


Early Complications and Mortality following Radical Cystectomy: Associations with Malnutrition and Obesity.
There are conflicting data regarding the impact of obesity on postoperative outcomes following radical cystectomy (RC) and how obesity and malnutrition interact in patients undergoing RC. To evaluate associations of body mass index (BMI), significant preoperative weight loss, and hypoalbuminemia with 30-day complications and mortality after RC. Review of the American College of Surgeons National Surgical Quality Improvement Program database identified 2,055 patients who underwent RC (2006-12). Univariate and multivariable logistic regression models were developed to assess associations between hypoalbuminemia (<3.5 g/dL), >10% preoperative weight loss, obesity as characterized by BMI (class I: 30-34.9, II: 35-39.9, III: ≥40 kg/m2), and 30-day complications and mortality. The median BMI of the study cohort was 27.82 kg/m2 with 22.4% classified as having class I, 7.5% class II, and 4.2% class III obesity, respectively. Hypoalbuminemia and >10% weight loss were present in 16.7% and 3.5%, respectively. Among obese patients, 13.4% had hypoalbuminemia. On multivariable analysis, class I (OR 1.43, p = 0.01), class II (OR 1.92, p < 0.001), and class III (OR 2.32, p < 0.001) obesity and hypoalbuminemia (OR 1.47, p = 0.02) were independently associated with 30-day complications, and class III obesity (OR 2.96, p = 0.02) and hypoalbuminemia (OR 2.33, p = 0.03) were independently associated with 30-day mortality. Increasing class of obesity and hypoalbuminemia were independently associated with increased complications following RC. Hypoalbuminemia and class III obesity were associated with early mortality. This study highlights the fact that malnutrition may coexist in obese patients and underscores the need to identify patients with malnutrition who may be candidates for preoperative nutritional optimization.


Identification and characterization of OGG1 mutations in patients with Alzheimer's disease.
Patients with Alzheimer's disease (AD) exhibit higher levels of 8-oxo-guanine (8-oxoG) DNA lesions in their brain, suggesting a reduced or defective 8-oxoG repair. To test this hypothesis, this study investigated 14 AD patients and 10 age-matched controls for mutations of the major 8-oxoG removal gene OGG1. Whereas no alterations were detected in any control samples, four AD patients exhibited mutations in OGG1, two carried a common single base (C796) deletion that alters the carboxyl terminal sequence of OGG1, and the other two had nucleotide alterations leading to single amino acid substitutions. In vitro biochemical assays revealed that the protein encoded by the C796-deleted OGG1 completely lost its 8-oxoG glycosylase activity, and that the two single residue-substituted OGG1 proteins showed a significant reduction in the glycosylase activity. These results were consistent with the fact that nuclear extracts derived from a limited number of AD patients with OGG1 mutations exhibited greatly reduced 8-oxoG glycosylase activity compared with age-matched controls and AD patients without OGG1 alterations. Our findings suggest that defects in OGG1 may be important in the pathogenesis of AD in a significant fraction of AD patients and provide new insight into the molecular basis for the disease.


Dose-ranging trial of enoxaparin for unstable angina: results of TIMI 11A. The Thrombolysis in Myocardial Infarction (TIMI) 11A Trial Investigators.
The Thrombolysis in Myocardial Infarction (TIMI) 11A trial compared the safety and tolerability of two weight-adjusted regimens of subcutaneous injections of enoxaparin, a low molecular weight heparin, in patients with unstable angina/non-Q wave myocardial infarction (NQMI). The optimal dose of enoxaparin in patients with arterial disorders has not been established. Patients with unstable angina/NQMI were treated over a 14-day period in an open label dose-ranging trial. During the in-hospital phase, patients received either 1.25 mg/kg body weight (dose tier 1) or 1.0 mg/kg (dose tier 2) of enoxaparin subcutaneously every 12 h. A fixed dose of either 60 mg (body weight > or = 65 kg) or 40 mg (body weight < 65 kg) was administered subcutaneously every 12 h after hospital discharge. In an initial cohort of 321 patients (dose tier 1), the rate of major bleeding through 14 days was 6.5% and occurred predominantly at instrumented sites. In a second cohort of 309 patients (dose tier 2), the rate of major hemorrhage was reduced to 1.9%. In both dose tiers, only 3% to 5% of patients withdrew consent for subcutaneous injections during the home treatment phase. Through 14 days, the incidence of death, recurrent myocardial infarction or recurrent ischemia requiring revascularization was 5.6% in dose tier 1 and 5.2% in dose tier 2. An acute phase regimen of enoxaparin (1.0 mg/kg every 12 h) is associated with an acceptable rate of major hemorrhage during the in-hospital phase. There is a high rate of patient compliance during the home treatment phase. A Phase III trial is now underway to test the benefits of uninterrupted treatment with enoxaparin during both the in-hospital and outpatient treatment phases.


Diversity, assembly and regulation of archaeal type IV pili-like and non-type-IV pili-like surface structures.
Archaea have evolved fascinating surface structures allowing rapid adaptation to changing environments. The archaeal surface appendages display such diverse biological roles as motility, adhesion, biofilm formation, exchange of genetic material and species-specific interactions and, in turn, increase fitness of the cells. Intriguingly, despite sharing the same functions with their bacterial counterparts, the assembly mechanism of many archaeal surface structures is rather related to assembly of bacterial type IV pili. This review summarizes our state-of-the-art knowledge about unique structural and biochemical properties of archaeal surface appendages with a particular focus on archaeal type IV pili-like structures. The latter comprise not only widely distributed archaella (formerly known as archaeal flagella), but also different highly specialized archaeal pili, which are often restricted to certain species. Recent findings regarding assembly mechanisms, structural aspects and physiological roles of these type IV pili-like structures will be discussed in detail. Recently, first regulatory proteins involved in transition from both planktonic to sessile lifestyle and in assembly of archaella were identified. To conclude, we provide novel insights into regulatory mechanisms underlying the assembly of archaeal surface structures.


A chromosome-level draft genome of the grain aphid Sitobion miscanthi.
Sitobion miscanthi is an ideal model for studying host plant specificity, parthenogenesis-based phenotypic plasticity, and interactions between insects and other species of various trophic levels, such as viruses, bacteria, plants, and natural enemies. However, the genome information for this species has not yet to be sequenced and published. Here, we analyzed the entire genome of a parthenogenetic female aphid colony using Pacific Biosciences long-read sequencing and Hi-C data to generate chromosome-length scaffolds and a highly contiguous genome assembly. The final draft genome assembly from 33.88 Gb of raw data was ∼397.90 Mb in size, with a 2.05 Mb contig N50. Nine chromosomes were further assembled based on Hi-C data to a 377.19 Mb final size with a 36.26 Mb scaffold N50. The identified repeat sequences accounted for 26.41% of the genome, and 16,006 protein-coding genes were annotated. According to the phylogenetic analysis, S. miscanthi is closely related to Acyrthosiphon pisum, with S. miscanthi diverging from their common ancestor ∼25.0-44.9 million years ago. We generated a high-quality draft of the S. miscanthi genome. This genome assembly should help promote research on the lifestyle and feeding specificity of aphids and their interactions with each other and species at other trophic levels. It can serve as a resource for accelerating genome-assisted improvements in insecticide-resistant management and environmentally safe aphid management.


Dynamic response to initial stage blindness in visual system development.
Sensitive periods and experience-dependent plasticity have become core issues in visual system development. Converging evidence indicates that visual experience is an indispensable factor in establishing mature visual system circuitry during sensitive periods and the visual system exhibits substantial plasticity while facing deprivation. The mechanisms that underlie the environmental regulation of visual system development and plasticity are of great interest but need further exploration. Here, we investigated a unique sample of human infants who experienced initial stage blindness (beginning at birth and lasting for 2-8 months) before the removal of bilateral cataracts. Retinal thickness (RT), axial length (AL), refractive status, visual grating acuity and genetic integrity were recorded during the preoperative period or at surgery and then during follow-up. The results showed that the development of the retina is malleable and associated with external environmental influences. Our work supported that the retina might play critical roles in the development of the experience-dependent visual system and its malleability might partly contribute to the sensitive period plasticity.


Simultaneous electrical-field-effect modulation of both top and bottom Dirac surface states of epitaxial thin films of three-dimensional topological insulators.
It is crucial for the studies of the transport properties and quantum effects related to Dirac surface states of three-dimensional topological insulators (3D TIs) to be able to simultaneously tune the chemical potentials of both top and bottom surfaces of a 3D TI thin film. We have realized this in molecular beam epitaxy-grown thin films of 3D TIs, as well as magnetic 3D TIs, by fabricating dual-gate structures on them. The films could be tuned between n-type and p-type by each gate alone. Combined application of two gates can reduce the carrier density of a TI film to a much lower level than with only one of them and enhance the film resistance by 10,000%, implying that Fermi level is tuned very close to the Dirac points of both top and bottom surface states without crossing any bulk band. The result promises applications of 3D TIs in field effect devices.


Chloroquine and nanoparticle drug delivery: A promising combination.
Clinically approved cancer therapies include small molecules, antibodies, and nanoparticles. There has been major progress in the treatment of several cancer types over recent decades. However, many challenges remain for optimal use of conventional and nanoparticle-based therapies in oncology including poor drug delivery, rapid clearance, and drug resistance. The antimalarial agent chloroquine has been found to mitigate some of these challenges by modulating cancer cells and the tissue microenvironment. Particularly, chloroquine was recently found to reduce immunological clearance of nanoparticles by resident macrophages in the liver, leading to increased tumor accumulation of nanodrugs. Additionally, chloroquine has been shown to improve drug delivery and efficacy through normalization of tumor vasculature and suppression of several oncogenic and stress-tolerance pathways, such as autophagy, that protect cancer cells from cytotoxic agents. This review will discuss the use of chloroquine as combination therapy to improve cancer treatment.


Interpretation of ambiguity: Differences between children and adolescents with and without an anxiety disorder.
Theory and treatment of anxiety disorders in young people are commonly based on the premise that interpretation biases found in anxious adults are also found in children and adolescents. Although there is some evidence that this may be the case, studies have not typically taken age into account, which is surprising given the normative changes in cognition that occur throughout childhood. The aim of the current study was to identify whether associations between anxiety disorder status and interpretation biases differed in children and adolescents. The responses of children (7-10 years) and adolescents (13-16 years) with and without anxiety disorders (n=120) were compared on an ambiguous scenarios task. Children and adolescents with an anxiety disorder showed significantly higher levels of threat interpretation and avoidant strategies than non-anxious children and adolescents. However, age significantly moderated the effect of anxiety disorder status on interpretation of ambiguity, in that adolescents with anxiety disorders showed significantly higher levels of threat interpretation and associated negative emotion than non-anxious adolescents, but a similar relationship was not observed among children. The findings suggest that theoretical accounts of interpretation biases in anxiety disorders in children and adolescents should distinguish between different developmental periods. For both ages, treatment that targets behavioral avoidance appears warranted. However, while adolescents are likely to benefit from treatment that addresses interpretation biases, there may be limited benefit for children under the age of ten.


The relationship between fibrosis and nodule structure and esophageal varices.
The aim of the present study was to evaluate the histopathological findings of cirrhosis together with clinical and laboratory parameters, and to investigate their relationship with esophageal varices that are portal hypertension findings. A total of 67 (42 male and 25 female) patients who were diagnosed with cirrhosis were included in the study. The mean age of the patients was 51.6±19.0 (1-81) years. The biopsy specimens of the patients were graded in terms of fibrosis, nodularity, loss of portal area, central venous loss, inflammation, and steatosis. The spleen sizes were graded ultrasonographically, and the esophageal varices were graded endoscopically. In the multivariate regression analysis, there was a correlation between the advanced disease stage (Child-Pugh score odds ratio (OR): 1.47, 95% confidence interval (CI): 1.018-2.121, p=0.040), presence of micronodularity (OR: 0.318, 95% CI: 0.120-0.842, p=0.021), grade of central venous loss (OR: 5.231, 95% CI: 1.132-24.176, p=0.034), and presence of esophageal varicose veins. Although thrombocytopenia and splenomegaly may predict the presence of large esophageal varices, cirrhosis histopathology is the main factor in the presence of varices.


Periodontal treatment is more effective in gastric Helicobacter pylori eradication in those patients who maintain good oral hygiene.
This study aimed to investigate the effect of periodontal treatment and oral hygiene on the eradication of gastric Helicobacter pylori. In this clinical trial, the 98 patients with gastric H. pylori infection that were enrolled received either triple-therapy regimen only or triple-therapy regimen plus periodontal treatment given during triple therapy. Eradication of H. pylori was checked at 3 months, and then after therapy using the urea breath test. The triple-therapy plus periodontal treatment regime resulted in a 64.7% eradication rate, and the triple-therapy regime alone resulted in a 51.1% eradication rate (P = 0.17). Additionally, subgroup analysis indicated that the beneficial effect of periodontal treatment on the gastric H. pylori eradication rate improved if adequate plaque control was maintained (P = 0.02). Multivariate logistic regression analysis showed that post-treatment oral hygiene status [as indicated by the Oral Hygiene Index (OHI)] was associated with H. pylori eradication (P = 0.02), but not with pretreatment oral hygiene status (P = 0.24). Oral hygiene measures without periodontal treatment appear to have a limited impact on H. pylori eradication. Post-treatment oral hygiene level (OHI ≤ 1.25) had a positive effect on H. pylori eradication, increased the gastric eradication rate, with an OR of 3.19, and the oral H. pylori eradication rate, with an OR of 4.57. Furthermore, if periodontal treatment was unsuccessful in eliminating oral H. pylori, as tested using the Campylobacter-like organism test, the OR for the unsuccessful gastric eradication increased 64-fold. Conclusion This result illustrates that the key factors for achieving successful gastric H. pylori eradication are professional periodontal treatment and the patients' later adherence to an oral hygiene regimen.


Fragmentation of the large subunit ribosomal RNA gene in oyster mitochondrial genomes.
Discontinuous genes have been observed in bacteria, archaea, and eukaryotic nuclei, mitochondria and chloroplasts. Gene discontinuity occurs in multiple forms: the two most frequent forms result from introns that are spliced out of the RNA and the resulting exons are spliced together to form a single transcript, and fragmented gene transcripts that are not covalently attached post-transcriptionally. Within the past few years, fragmented ribosomal RNA (rRNA) genes have been discovered in bilateral metazoan mitochondria, all within a group of related oysters. In this study, we have characterized this fragmentation with comparative analysis and experimentation. We present secondary structures, modeled using comparative sequence analysis of the discontinuous mitochondrial large subunit rRNA genes of the cupped oysters C. virginica, C. gigas, and C. hongkongensis. Comparative structure models for the large subunit rRNA in each of the three oyster species are generally similar to those for other bilateral metazoans. We also used RT-PCR and analyzed ESTs to determine if the two fragmented LSU rRNAs are spliced together. The two segments are transcribed separately, and not spliced together although they still form functional rRNAs and ribosomes. Although many examples of discontinuous ribosomal genes have been documented in bacteria and archaea, as well as the nuclei, chloroplasts, and mitochondria of eukaryotes, oysters are some of the first characterized examples of fragmented bilateral animal mitochondrial rRNA genes. The secondary structures of the oyster LSU rRNA fragments have been predicted on the basis of previous comparative metazoan mitochondrial LSU rRNA structure models.


Transcriptional adaptation in Caenorhabditis elegans.
Transcriptional adaptation is a recently described phenomenon by which a mutation in one gene leads to the transcriptional modulation of related genes, termed adapting genes. At the molecular level, it has been proposed that the mutant mRNA, rather than the loss of protein function, activates this response. While several examples of transcriptional adaptation have been reported in zebrafish embryos and in mouse cell lines, it is not known whether this phenomenon is observed across metazoans. Here we report transcriptional adaptation in C. elegans, and find that this process requires factors involved in mutant mRNA decay, as in zebrafish and mouse. We further uncover a requirement for Argonaute proteins and Dicer, factors involved in small RNA maturation and transport into the nucleus. Altogether, these results provide evidence for transcriptional adaptation in C. elegans, a powerful model to further investigate underlying molecular mechanisms.


Anti-CD22 and anti-CD79B antibody drug conjugates are active in different molecular diffuse large B-cell lymphoma subtypes.
Antibody drug conjugates (ADCs), in which cytotoxic drugs are linked to antibodies targeting antigens on tumor cells, represent promising novel agents for the treatment of malignant lymphomas. Pinatuzumab vedotin is an anti-CD22 ADC and polatuzumab vedotin an anti-CD79B ADC that are both linked to the microtubule-disrupting agent monomethyl auristatin E (MMAE). In the present study, we analyzed the activity of these agents in different molecular subtypes of diffuse large B-cell lymphoma (DLBCL) both in vitro and in early clinical trials. Both anti-CD22-MMAE and anti-CD79B-MMAE were highly active and induced cell death in the vast majority of activated B-cell-like (ABC) and germinal center B-cell-like (GCB) DLBCL cell lines. Similarly, both agents induced cytotoxicity in models with and without mutations in the signaling molecule CD79B. In line with these observations, relapsed and refractory DLBCL patients of both subtypes responded to these agents. Importantly, a strong correlation between CD22 and CD79B expression in vitro and in vivo was not detectable, indicating that patients should not be excluded from anti-CD22-MMAE or anti-CD79B-MMAE treatment because of low target expression. In summary, these studies suggest that pinatuzumab vedotin and polatuzumab vedotin are active agents for the treatment of patients with different subtypes of DLBCL.


Neptunism and Transformism: Robert Jameson and other Evolutionary Theorists in Early Nineteenth-Century Scotland.
This paper sheds new light on the prevalence of evolutionary ideas in Scotland in the early nineteenth century and establish what connections existed between the espousal of evolutionary theories and adherence to the directional history of the earth proposed by Abraham Gottlob Werner and his Scottish disciples. A possible connection between Wernerian geology and theories of the transmutation of species in Edinburgh in the period when Charles Darwin was a medical student in the city was suggested in an important 1991 paper by James Secord. This study aims to deepen our knowledge of this important episode in the history of evolutionary ideas and explore the relationship between these geological and evolutionary discourses. To do this it focuses on the circle of natural historians around Robert Jameson, Wernerian geologist and professor of natural history at the University of Edinburgh from 1804 to 1854. From the evidence gathered here there emerges a clear confirmation that the Wernerian model of geohistory facilitated the acceptance of evolutionary explanations of the history of life in early nineteenth-century Scotland. As Edinburgh was at this time the most important center of medical education in the English-speaking world, this almost certainly influenced the reception and development of evolutionary ideas in the decades that followed.


Parent calcium-rich-food practices/perceptions are associated with calcium intake among parents and their early adolescent children.
The study aimed to (i) segment parents of early adolescents into subgroups according to their Ca-rich-food (CRF) practices and perceptions regarding early adolescent CRF intake and (ii) determine whether Ca intake of parents and early adolescents differed by subgroup. A cross-sectional convenience sample of 509 parents and their early adolescent children completed a questionnaire in 2006-2007 to assess parent CRF practices and perceptions and to estimate parent and child Ca intakes. Self-administered questionnaires were completed in community settings or homes across nine US states. Parents self-reporting as Asian, Hispanic or non-Hispanic White with a child aged 10-13 years were recruited through youth or parent events. Three parent CRF practice/perception segments were identified, including 'Dedicated-Milk Providers/Drinkers' (49 %), 'Water Regulars' (30 %) and 'Sweet-Drink-Permissive Parents' (23 %). Dedicated-Milk Providers/Drinkers were somewhat older and more likely to be non-Hispanic White than other groups. Ca intakes from all food sources, milk/dairy foods and milk only, and milk intakes, were higher among early adolescent children of Dedicated-Milk Providers/Drinkers compared with early adolescents of parents in other segments. Soda pop intakes were highest for early adolescents with parents in the Water Regulars group than other groups. Dedicated-Milk Providers/Drinkers scored higher on culture/tradition, health benefits and ease of use/convenience subscales and lower on a dairy/milk intolerance subscale and were more likely to report eating family dinners daily than parents in the other groups. Parent education programmes should address CRF practices/perceptions tailored to parent group to improve Ca intake of early adolescent children.


Avalanches in dry and saturated disordered media at fracture.
This paper analyzes fracturing in inhomogeneous media under dry and fully saturated conditions. We adopt a central force model with continuous damage to study avalanche behavior in a two-dimensional truss lattice undergoing dilation. Multiple fractures can develop at once and a power-law distribution of the avalanche size is observed. The values for the power-law exponent are compared with the ones found in the literature and scale-free behavior is suggested. The fracture evolves intermittently in time because only some avalanches correspond to fracture advancement. A fully saturated model with continuous damage based on the extended Biot's theory is developed and avalanche behavior is studied in the presence of fluid, varying the fluid boundary conditions. We show that power-law behavior is destroyed when the fluid flux governs the problem. Fluid pressure behavior during intermittent crack tip advancement is studied for the continuous-damage fully saturated model. It is found that when mechanical loading prevails, the pressure rises when the crack advances, while when fluid loading prevails, the pressure drops when the crack advances.


Peracetic acid oxidation of saline waters in the absence and presence of H ₂O ₂: secondary oxidant and disinfection byproduct formation.
Peracetic acid (PAA) is a disinfectant considered for use in ballast water treatment, but its chemical behavior in such systems (i.e., saline waters) is largely unknown. In this study, the reactivity of PAA with halide ions (chloride and bromide) to form secondary oxidants (HOCl, HOBr) was investigated. For the PAA-chloride and PAA-bromide reactions, second-order rate constants of (1.47 ± 0.58) × 10(-5) and 0.24 ± 0.02 M(-1) s(-1) were determined for the formation of HOCl or HOBr, respectively. Hydrogen peroxide (H2O2), which is always present in PAA solutions, reduced HOCl or HOBr to chloride or bromide, respectively. As a consequence, in PAA-treated solutions with [H2O2] > [PAA], the HOBr (HOCl) steady-state concentrations were low with a limited formation of brominated (chlorinated) disinfection byproducts (DBPs). HOI (formed from the PAA-iodide reaction) affected this process because it can react with H2O2 back to iodide. H2O2 is thus consumed in a catalytic cycle and leads to less efficient HOBr scavenging at even low iodide concentrations (<1 μM). In PAA-treated solutions with [H2O2] < [PAA] and high bromide levels, mostly brominated DBPs are formed. In synthetic water, bromate was formed from the oxidation of bromide. In natural brackish waters, bromoform (CHBr3), bromoacetic acid (MBAA), dibromoacetic acid (DBAA), and tribromoacetic acid (TBAA) formed at up to 260, 106, 230, and 89 μg/L, respectively for doses of 2 mM (ca. 150 mg/L) PAA and [H2O2] < [PAA]. The same brackish waters, treated with PAA with [H2O2] ≫ [PAA], similar to conditions found in commercial PAA solutions, resulted in no trihalomethanes and only low haloacetic acid concentrations.


Emission tomography of flame radicals.
We describe a simple experimental arrangement for emission tomographic measurements of radicals in flames. Experimental determinations of two-dimensional spatially resolved distributions of excited-state CH in atmospheric-pressure flames are presented. Calibration of the distributions to absolute number densities is performed with a Rayleigh scattering technique. Methods for simultaneous recording of two to six emission projections and reconstruction from very few (two or three) projections are experimentally investigated. The potential of emission tomography with high temporal resolution for monitoring, e.g., explosions or turbulent flames, is discussed.


Addressing the diagnostic gaps in pyruvate kinase deficiency: Consensus recommendations on the diagnosis of pyruvate kinase deficiency.
Pyruvate kinase deficiency (PKD) is the most common enzyme defect of glycolysis and an important cause of hereditary, nonspherocytic hemolytic anemia. The disease has a worldwide geographical distribution but there are no verified data regarding its frequency. Difficulties in the diagnostic workflow and interpretation of PK enzyme assay likely play a role. By the creation of a global PKD International Working Group in 2016, involving 24 experts from 20 Centers of Expertise we studied the current gaps in the diagnosis of PKD in order to establish diagnostic guidelines. By means of a detailed survey and subsequent discussions, multiple aspects of the diagnosis of PKD were evaluated and discussed by members of Expert Centers from Europe, USA, and Asia directly involved in diagnosis. Broad consensus was reached among the Centers on many clinical and technical aspects of the diagnosis of PKD. The results of this study are here presented as recommendations for the diagnosis of PKD and used to prepare a diagnostic algorithm. This information might be helpful for other Centers to deliver timely and appropriate diagnosis and to increase awareness in PKD.


Epithelial-mesenchymal transition and tumor suppression are controlled by a reciprocal feedback loop between ZEB1 and Grainyhead-like-2.
Epithelial-mesenchymal transition (EMT) in carcinoma cells enhances malignant progression by promoting invasion and survival. EMT is induced by microenvironmental factors, including TGF-β and Wnt agonists, and by the E-box-binding transcription factors Twist, Snail, and ZEB. Grainyhead-like-2 (GRHL2), a member of the mammalian Grainyhead family of wound-healing regulatory transcription factors, suppresses EMT and restores sensitivity to anoikis by repressing ZEB1 expression and inhibiting TGF-β signaling. In this study, we elucidate the functional relationship between GRHL2 and ZEB1 in EMT/MET and tumor biology. At least three homeodomain proteins, Six1, LBX1, and HoxA5, transactivated the ZEB1 promoter, in the case of Six1, through direct protein-promoter interaction. GRHL2 altered the Six1-DNA complex, inhibiting this transactivation. Correspondingly, GRHL2 expression prevented tumor initiation in xenograft assays, sensitized breast cancer cells to paclitaxel, and suppressed the emergence of CD44(high)CD24(low) cells (defining the cancer stem cell phenotype in the cell type studied). GRHL2 was downregulated in recurrent mouse tumors that had evolved to an oncogene-independent, EMT-like state, supporting a role for GRHL2 downregulation in this phenotypic transition, modeling disease recurrence. The combination of TGF-β and Wnt activation repressed GRHL2 expression by direct interaction of ZEB1 with the GRHL2 promoter, inducing EMT. Together, our observations indicate that a reciprocal feedback loop between GRHL2 and ZEB1 controls epithelial versus mesenchymal phenotypes and EMT-driven tumor progression.


[Neuropsychological rehabilitation in the 20th century].
The first documents describing techniques and procedures to improve the cognitive functioning of people with brain injuries date back to the 17th century. Yet, governments show little interest in it and allocate scarce economic, personal and material resources, possibly because of the high mortality rate associated with brain injuries and the limited life expectancy of those who survive. It was not until the 20th century that neuropsychological rehabilitation, as it is conceived today, took its first steps. The evolution of neuropsychological rehabilitation over the last century can be structured in three periods: establishment, expansion and consolidation. The first two are closely related to the procedures developed in times of war (mainly the First and Second World Wars), and the period of consolidation is linked with the transfer of the advances made in the military field to the civilian population and the advent of digital technologies in cognitive rehabilitation. The history of neuropsychological rehabilitation in the 20th century shows two major conceptual changes, linked to profound modifications in the welfare policies deployed by various Western governments. The first took place during the First World War, when, in response to the growing number of veterans with brain injuries, governments decided to set up neurorehabilitation centres. And the second occurred in the 60s and 70s, when different governments transferred and generalised the advances achieved in the military sphere to the civilian population.


Landscape of somatic mutations in sporadic GH-secreting pituitary adenomas.
Alterations in the cAMP signaling pathway are common in hormonally active endocrine tumors. Somatic mutations at GNAS are causative in 30-40% of GH-secreting adenomas. Recently, mutations affecting the USP8 and PRKACA gene have been reported in ACTH-secreting pituitary adenomas and cortisol-secreting adrenocortical adenomas respectively. However, the pathogenesis of many GH-secreting adenomas remains unclear. Comprehensive genetic characterization of sporadic GH-secreting adenomas and identification of new driver mutations. Screening for somatic mutations was performed in 67 GH-secreting adenomas by targeted sequencing for GNAS, PRKACA, and USP8 mutations (n=31) and next-generation exome sequencing (n=36). By targeted sequencing, known activating mutations in GNAS were detected in five cases (16.1%), while no somatic mutations were observed in both PRKACA and USP8. Whole-exome sequencing identified 132 protein-altering somatic mutations in 31/36 tumors with a median of three mutations per sample (range: 1-13). The only recurrent mutations have been observed in GNAS (31.4% of cases). However, seven genes involved in cAMP signaling pathway were affected in 14 of 36 samples and eight samples harbored variants in genes involved in the calcium signaling or metabolism. At the enrichment analysis, several altered genes resulted to be associated with developmental processes. No significant correlation between genetic alterations and the clinical data was observed. This study provides a comprehensive analysis of somatic mutations in a large series of GH-secreting adenomas. No novel recurrent genetic alterations have been observed, but the data suggest that beside cAMP pathway, calcium signaling might be involved in the pathogenesis of these tumors.


Predicting spike timing of neocortical pyramidal neurons by simple threshold models.
Neurons generate spikes reliably with millisecond precision if driven by a fluctuating current--is it then possible to predict the spike timing knowing the input? We determined parameters of an adapting threshold model using data recorded in vitro from 24 layer 5 pyramidal neurons from rat somatosensory cortex, stimulated intracellularly by a fluctuating current simulating synaptic bombardment in vivo. The model generates output spikes whenever the membrane voltage (a filtered version of the input current) reaches a dynamic threshold. We find that for input currents with large fluctuation amplitude, up to 75% of the spike times can be predicted with a precision of +/-2 ms. Some of the intrinsic neuronal unreliability can be accounted for by a noisy threshold mechanism. Our results suggest that, under random current injection into the soma, (i) neuronal behavior in the subthreshold regime can be well approximated by a simple linear filter; and (ii) most of the nonlinearities are captured by a simple threshold process.


(Pro)insulin-specific regulatory T cells.
Regulatory anti-diabetogenic T cells (T(reg)) can be induced by the mucosal administration of insulin or proinsulin peptides, in the non-obese diabetic (NOD) mouse model of autoimmune type 1 diabetes. Naso-respirtory insulin (which avoids insulin degradation) induces CD8+ alpha(alpha) TCR gamma(delta) T(reg) whereas peptides that bind to the NOD MHC class II molecule, I-Ag7, insulin B9-23 and proinsulin B24-C36, induce CD4+ T(regs) Following naso-respiratory delivery of insulin to NOD mice increased numbers of CD8+ gamma(delta) T cells expressing interleukin (IL)10 are detected in the pancreatic lymph nodes. Neonatal (3 day) thymectomy (NTX) dramatically accelerates diabetes development in NOD mice, associated with lymphopaenia and a block in the maturation of mucosal intrepithelial lymphocytes (IEL), especially extrathymic-derived CD8+ alpha(alpha) TCR gamma(delta) IEL. Regulatory anti-diabetogenic T cells cannot be elicited by naso-respiratory insulin in NTX-NOD mice. Reconstitution of NTX-NOD mice with CD8+ alpha(alpha) TCR gamma(delta) T cells prevents diabetes. CD8+ gamma(delta) T(reg) are conceivably physiological and insulin-specific, induced by exposure to insulin in maternal milk. These findings infer an immunoregulatory role for extrathymic-derived IEL, developing under the influence of the thymus and conditioned by early exposure to the exogenous environment.


Effects of hyperglycemia on function of isolated mouse pancreatic islets transplanted under kidney capsule.
The insulin release from isolated pancreatic islets grafted under the kidney capsule was examined by means of a modified kidney-perfusion technique. The grafts, consisting of 150 C57BL/6 or 250 C57BL/Ks mouse islets, were implanted syngeneically under the left kidney capsule of normoglycemic or alloxan-induced diabetic recipients 4 wk before the perfusion. In both mouse strains, islets grafted to normoglycemic animals showed an immediate distinct peak of insulin release when challenged with high glucose, whereas no response was observed from islets grafted to hyperglycemic mice. In a similar way in C57BL/Ks mice, arginine stimulated insulin release from the islet grafts in normoglycemic but not in hyperglycemic recipients. Insulin treatment of the diabetic recipients, however, partially normalized the insulin response to glucose. Islet grafts were removed in toto and analyzed for contents of insulin, glucagon, somatostatin, and DNA or rates of glucose-stimulated (pro)insulin biosynthesis. In both mouse strains, islets implanted into hyperglycemic animals contained significantly less insulin, and their rates of (pro)insulin biosynthesis were markedly decreased. Insulin treatment only marginally affected these parameters. The glucagon content of the grafted islets was unaffected by the hyperglycemia in both strains of mice, whereas a significant decrease in the somatostatin content was observed in the C57BL/Ks mice. We concluded that grafted islets exposed to prolonged hyperglycemic stress become functionally impaired in mice of both strains. Our perfusion technique of islet-graft-bearing kidneys in combination with biochemical studies on the removed grafts provides a suitable model for studies of the effects of prolonged hyperglycemia on islet beta-cell function.


The UF/NCI family of hybrid computational phantoms representing the current US population of male and female children, adolescents, and adults--application to CT dosimetry.
Substantial increases in pediatric and adult obesity in the US have prompted a major revision to the current UF/NCI (University of Florida/National Cancer Institute) family of hybrid computational phantoms to more accurately reflect current trends in larger body morphometry. A decision was made to construct the new library in a gridded fashion by height/weight without further reference to age-dependent weight/height percentiles as these become quickly outdated. At each height/weight combination, circumferential parameters were defined and used for phantom construction. All morphometric data for the new library were taken from the CDC NHANES survey data over the time period 1999-2006, the most recent reported survey period. A subset of the phantom library was then used in a CT organ dose sensitivity study to examine the degree to which body morphometry influences the magnitude of organ doses for patients that are underweight to morbidly obese in body size. Using primary and secondary morphometric parameters, grids containing 100 adult male height/weight bins, 93 adult female height/weight bins, 85 pediatric male height/weight bins and 73 pediatric female height/weight bins were constructed. These grids served as the blueprints for construction of a comprehensive library of patient-dependent phantoms containing 351 computational phantoms. At a given phantom standing height, normalized CT organ doses were shown to linearly decrease with increasing phantom BMI for pediatric males, while curvilinear decreases in organ dose were shown with increasing phantom BMI for adult females. These results suggest that one very useful application of the phantom library would be the construction of a pre-computed dose library for CT imaging as needed for patient dose-tracking.


Prevalence and perceived health associated with insomnia based on DSM-IV-TR; International Statistical Classification of Diseases and Related Health Problems, Tenth Revision; and Research Diagnostic Criteria/International Classification of Sleep Disorders, Second Edition criteria: results from the America Insomnia Survey.
Although several diagnostic systems define insomnia, little is known about the implications of using one versus another of them. The America Insomnia Survey, an epidemiological survey of managed health care plan subscribers (n = 10,094), assessed insomnia with the Brief Insomnia Questionnaire, a clinically validated scale generating diagnoses according to DSM-IV-TR; International Statistical Classification of Diseases, Tenth Revision (ICD-10); and Research Diagnostic Criteria/International Classification of Sleep Disorders, Second Edition (RDC/ICSD-2) criteria. Regression analysis examines associations of insomnia according to the different systems with summary 12-item Short-Form Health Survey scales of perceived health and health utility. Insomnia prevalence estimates varied widely, from 22.1% for DSM-IV-TR to 3.9% for ICD-10 criteria. Although ICD insomnia was associated with significantly worse perceived health than DSM or RDC/ICSD insomnia, DSM-only cases also had significant decrements in perceived health. Because of its low prevalence, 66% of the population-level health disutility associated with overall insomnia and 84% of clinically relevant cases of overall insomnia were missed by ICD criteria. Insomnia is highly prevalent and associated with substantial decrements in perceived health. Although ICD criteria define a narrower and more severe subset of cases than DSM criteria, the fact that most health disutility associated with insomnia is missed by ICD criteria, while RDC/ICSD-only cases do not have significant decrements in perceived health, supports use of the broader DSM criteria.