Nitric oxide inhibits enterocyte migration through activation of RhoA-GTPase in a SHP-2-dependent manner.
Diseases of intestinal inflammation like necrotizing enterocolitis (NEC) are associated with impaired epithelial barrier integrity and the sustained release of intestinal nitric oxide (NO). NO modifies the cytoskeletal regulator RhoA-GTPase, suggesting that NO could affect barrier healing by inhibiting intestinal restitution. We now hypothesize that NO inhibits enterocyte migration through RhoA-GTPase and sought to determine the pathways involved. The induction of NEC was associated with increased enterocyte NO release and impaired migration of bromodeoxyuridine-labeled enterocytes from terminal ileal crypts to villus tips. In IEC-6 enterocytes, NO significantly inhibited enterocyte migration and activated RhoA-GTPase while increasing the formation of stress fibers. In parallel, exposure of IEC-6 cells to NO increased the phosphorylation of focal adhesion kinase (pFAK) and caused a striking increase in cell-matrix adhesiveness, suggesting a mechanism by which NO could impair enterocyte migration. NEC was associated with increased expression of pFAK in the terminal ileal mucosa of wild-type mice and a corresponding increase in disease severity compared with inducible NO synthase knockout mice, confirming the dependence of NO for FAK phosphorylation in vivo and its role in the pathogenesis of NEC. Strikingly, inhibition of the protein tyrosine phosphatase SHP-2 in IEC-6 cells prevented the activation of RhoA by NO, restored focal adhesions, and reversed the inhibitory effects of NO on enterocyte migration. These data indicate that NO impairs mucosal healing by inhibiting enterocyte migration through activation of RhoA in a SHP-2-dependent manner and support a possible role for SHP-2 as a therapeutic target in diseases of intestinal inflammation like NEC.


Brain aquaporin-4 in experimental acute liver failure.
Intracranial hypertension caused by brain edema and associated astrocyte swelling is a potentially lethal complication of acute liver failure (ALF). Mechanisms of edema formation are not well understood, but elevated levels of blood and brain ammonia and its by-product glutamine have been implicated in this process. Since aquaporin-4 (AQP4) has been implicated in brain edema in other conditions, we examined its role in a rat model of ALF induced by the hepatotoxin thioacetamide. Rats with ALF showed increased AQP4 protein in the plasma membrane (PM). Total tissue levels of AQP4 protein and mRNA levels were not altered, indicating that increased AQP4 is not transcriptionally mediated but likely reflects a more stable anchoring of AQP4 to the PM and/or interference with its degradation. An increase inAQP4 immunoreactivity in thePM was observed in perivascular astrocytes in ALF. Rats with ALF also showed increased levels of α-syntrophin, a protein involved in anchoringAQP4 to perivascular astrocytic end-feet. Increased AQP4 andα-syntrophin levels were inhibited by L-histidine, an inhibitor of glutamine transport into mitochondria, suggesting a role for glutamine in the increase of PM levels of AQP4. These results indicate that increased AQP4 PM levels in perivascular astrocytic end-feet are likely critical to the development of brain edema in ALF.


Hypothalamic and pituitary expression of ghrelin receptor message is increased during lactation.
In the lactating rat there is a dramatic increase in food intake that peaks at around day 15 postpartum, a time when pups are near weaning age, yet still fully dependant on maternal nourishment. We examined whether the orexigenic hormone ghrelin plays a role in increasing food intake during lactation. To do this, we compared plasma levels ghrelin, as well as brain and pituitary expression of the growth hormone secretagogue receptor (GHS-R 1a) rats in one of three groups: (1) dams whose litters were removed the day after giving birth (non-lactating); (2) dams whose litters were removed on day 13 postpartum (litter removed), and dams allowed keeping their litters (lactating). On day 15 postpartum, all dams were decapitated and trunk blood collected for plasma analysis of active ghrelin levels. Also, brain and pituitaries were collected and snap frozen using liquid nitrogen and stored at -80 degrees C before mRNA extraction and RT-PCR analysis. Results show no differences in ghrelin concentrations between lactating and non-lactating rats. Hypothalamic and pituitary expression of GHS-R 1a, however, was significantly increased in lactating animals compared to non-lactating animals. Interestingly, litter removed dams had higher levels of plasma ghrelin concentrations than either lactating or non-lactating females. Furthermore, GHS-R mRNA expression in these animals remained elevated in the pituitary but not the hypothalamus. These data suggest that the hypothalamus and pituitary of lactating rats are more sensitive to the effects of ghrelin, and that hypothalamic sensitivity to ghrelin depends on the presence of a suckling litter.


[The influence of positive or negative information from facial expressions on preference judgment: Examination of quantity and ratio].
Our preferences are influenced by the presence of others. However, it is unclear how the simultaneous presence of multiple others influences preference judgment. In this study, we presented multiple happy or disgust face images around a target and examined their influence on target preference. In Experiment 1, we presented only happy or disgust faces in order to examine the influence of quantity. In Experiment 2 and 3, we manipulated the ratio of happy or disgust and neutral faces. Findings revealed that the happy face increased the target preference and its effect varied by the ratio of happy faces. On the other hand, the disgust face decreased the target preference only if there was one such face. These results indicate that although the numeric information of others' facial expressions influences preference judgment, this influence differs with the nature of others' expressions.


Review of global neurosurgery education: Horizon of Neurosurgery in the Developing Countries.
Globally, the discipline of neurosurgery has evolved remarkably fast. Despite being one of the latest medical specialties, which appeared only around hundred years ago, it has witnessed innovations in the aspects of diagnostics methods, macro and micro surgical techniques, and treatment modalities. Unfortunately, this development is not evenly distributed between developed and developing countries. The same is the case with neurosurgical education and training, which developed from only traditional apprentice programs in the past to more structured, competence-based programs with various teaching methods being utilized, in recent times. A similar gap can be observed between developed and developing counties when it comes to neurosurgical education. Fortunately, most of the scholars working in this field do understand the coherent relationship between neurosurgical education and neurosurgical practice. In context to this understanding, a symposium was organized during the World Federation of Neurological Surgeons (WFNS) Special World Congress Beijing 2019. This symposium was the brain child of Prof. Yoko Kato-one of the eminent leaders in neurosurgery and an inspiration for female neurosurgeons. Invited speakers from different continents presented the stages of development of neurosurgical education in their respective countries. This paper summarizes the outcome of these presentations, with particular emphasis on and the challenges faced by developing countries in terms of neurosurgical education and strategies to cope with these challenges.


Statistical Methods for Tissue Array Images - Algorithmic Scoring and Co-training.
Recent advances in tissue microarray technology have allowed immunohistochemistry to become a powerful medium-to-high throughput analysis tool, particularly for the validation of diagnostic and prognostic biomarkers. However, as study size grows, the manual evaluation of these assays becomes a prohibitive limitation; it vastly reduces throughput and greatly increases variability and expense. We propose an algorithm-Tissue Array Co-Occurrence Matrix Analysis (TACOMA)-for quantifying cellular phenotypes based on textural regularity summarized by local inter-pixel relationships. The algorithm can be easily trained for any staining pattern, is absent of sensitive tuning parameters and has the ability to report salient pixels in an image that contribute to its score. Pathologists' input via informative training patches is an important aspect of the algorithm that allows the training for any specific marker or cell type. With co-training, the error rate of TACOMA can be reduced substantially for a very small training sample (e.g., with size 30). We give theoretical insights into the success of co-training via thinning of the feature set in a high dimensional setting when there is "sufficient" redundancy among the features. TACOMA is flexible, transparent and provides a scoring process that can be evaluated with clarity and confidence. In a study based on an estrogen receptor (ER) marker, we show that TACOMA is comparable to, or outperforms, pathologists' performance in terms of accuracy and repeatability.


'I don't think I ever had food poisoning'. A practice-based approach to understanding foodborne disease that originates in the home.
Food stored, prepared, cooked and eaten at home contributes to foodborne disease which, globally, presents a significant public health burden. The aim of the study reported here was to investigate, analyse and interpret domestic kitchen practices in order to provide fresh insight about how the domestic setting might influence food safety. Using current theories of practice meant the research, which drew on qualitative and ethnographic methods, could investigate people and material things in the domestic kitchen setting whilst taking account of people's actions, values, experiences and beliefs. Data from 20 UK households revealed the extent to which kitchens are used for a range of non-food related activities and the ways that foodwork extends beyond the boundaries of the kitchen. The youngest children, the oldest adults and the family pets all had agency in the kitchen, which has implications for preventing foodborne disease. What was observed, filmed and photographed was not a single practice but a series of entangled encounters and actions embedded and repeated, often inconsistently, by the individuals involved. Households derived logics and principles about foodwork that represented rules of thumb about 'how things are done' that included using the senses and experiential knowledge when judging whether food is safe to eat. Overall, food safety was subsumed within the practice of 'being' a household and living everyday life in the kitchen. Current theories of practice are an effective way of understanding foodborne disease and offer a novel approach to exploring food safety in the home.


Population-based geographic variations in DXA bone density in Europe: the EVOS Study. European Vertebral Osteoporosis.
The purpose of this study was to investigate variations in bone density between 16 European populations, 13 of which were participants in the European Vertebral Osteoporosis Study (EVOS). Men and women aged 50-80 years were recruited randomly from local population registers, stratified in 5-year age bands. The other three centres recruited similarly. Random samples of 20-100% of EVOS subjects were invited for dual-energy X-ray absorptiometry (DXA) densitometry of the lumbar spine and/or proximal femur using Hologic, Lunar or Norland pencil beam machines or, in one centre, a Sopha fan-beam machine. Cross-calibration of the different machines was undertaken using the European Spine Phantom prototype (ESPp). Highly significant differences in mean bone density were demonstrated between centres, giving rise to between centre SDs in bone density that were about a quarter of a population SD. These differences persisted when centres using Hologic machines and centres using Lunar machines were considered separately. The centres were ranked differently according to whether male or female subjects were being considered and according to site of measurement (L2-4, femoral neck or femoral trochanter). As expected, bone mineral density (BMD) had a curvilinear relationship with age, and apparent rates of decrease slowed as age advanced past 50 years in both sexes. In the spine, not only did male BMD usually appear to increase with age, but there was a highly significant difference between centres in the age effect in both sexes, suggesting a variability in the impact of osteoarthritis between centres. Weight was consistently positively associated with BMD, but the effects of height and armspan were less consistent. Logarithmic transformation was needed to normalize the regressions of BMD on the independent variates, and after transformation, all sites except the femoral neck in females showed significant increases in SD with age. Interestingly, the effect of increasing weight was to decrease dispersion in proximal femur measurements in both sexes, further accentuating the tendency in women for low body mass index to be associated with osteoporosis as defined by densitometry. It is concluded that there are major differences between BMD values in European population samples which, with variations in anthropometric variables, have the potential to contribute substantially to variations in rates of osteoporotic fracture risk in Europe.


Occupational therapy home programs for cerebral palsy: double-blind, randomized, controlled trial.
The goal was to assess the effectiveness of an occupational therapy home program (OTHP), compared with no OTHP, with respect to function and parent satisfaction with child function, participation, goal attainment, and quality of upper limb skill in school-aged children with cerebral palsy. Thirty-six children with cerebral palsy (mean age: 7.7 years; male: 69%; Gross Motor Function Classification System: level I, 47%; level II, 14%; level III, 16%; level IV, 7%; level V, 16%; spasticity, 85%; dyskinesia, 14%; ataxia, 3%) were randomly and equally assigned to OTHPs for 8 or 4 weeks or to no OTHP. The primary end point was Canadian Occupational Performance Measure scores 8 weeks after baseline. Secondary measures were recorded at 4 and 8 weeks. Eight weeks of OTHP produced statistically significant differences in function and parent satisfaction with function, compared with no OTHP. Parents in the 4-week OTHP group did not discontinue use at 4 weeks, as instructed, and continued for 8 weeks; results demonstrated statistically significant differences, compared with no OTHP. There was no difference in primary or secondary end point measures between intervention groups. Pediatricians can advise families that OTHPs developed with a collaborative, evidence-based approach and implemented by parents at home were clinically effective if implemented 17.5 times per month for an average of 16.5 minutes per session.


Association Between Antifibrinolytic Therapy and Perioperative Outcomes in Patients With Coronary Artery Stents Undergoing Noncardiac Surgery.
Patients with existing coronary artery stents are at an increased risk for major adverse cardiac events (MACEs) when undergoing noncardiac surgery (NCS). Although the use of antifibrinolytic (AF) therapy in NCS has significantly increased in the past decade, the relationship between perioperative AF use and its association with MACEs among patients with existing coronary artery stents has yet to be assessed. In this study, we aim to evaluate the association of MACEs in patients with existing coronary artery stents who receive perioperative AF therapy during orthopedic surgery. A single-center retrospective cohort study was conducted in adult patients with existing coronary artery stents who underwent orthopedic surgery from 2008 to 2018. Two cohorts were established: patients with existing coronary artery stents who did not receive perioperative AF and patients with coronary artery stents who received perioperative AF. Associations between AF use and the primary outcome of MACEs within 30 days postoperatively and the secondary outcomes of thrombotic complications, excessive surgical bleeding, and intensive care unit (ICU) admissions were analyzed using logistic regression models. Inverse probability of treatment weighting was used to control for confounding. Secondary analyses examining the association between coronary stent type/timing and the outcomes of interest were performed using unadjusted logistic regression models. A total of 473 patients met study criteria, including 294 who did not receive AF and 179 patients who received AF. MACEs occurred in 15 (5.1%) patients who did not receive AF and 1 (0.6%) who received AF (P = .007). In weighted analyses, no significant difference was found in patients who received AF with regard to MACEs (odds ratio [OR] = 0.13, 95% confidence interval [CI], 0.01-1.74, P = .12), thrombotic complications (OR = 1.19, 95% CI, 0.53-2.68, P = .68), or excessive surgical bleeding (OR = 0.13, 95% CI, 0.01-2.23, P = .16) compared to patients who did not receive AF. The results of this study are inconclusive whether an association exists between perioperative AF use in patients with coronary artery stents and the outcome of MACEs compared to patients who did not receive perioperative AF therapy. The authors acknowledge that the imprecise CI hinders the ability to definitively determine whether an association exists in the study population. Further large prospective studies, powered to detect differences in MACEs, are needed to assess the safety of perioperative AF in patients with existing coronary artery stents and to clarify the mechanism of perioperative MACEs in this high-risk population.


Functional profiling of the Saccharomyces cerevisiae genome.
Determining the effect of gene deletion is a fundamental approach to understanding gene function. Conventional genetic screens exhibit biases, and genes contributing to a phenotype are often missed. We systematically constructed a nearly complete collection of gene-deletion mutants (96% of annotated open reading frames, or ORFs) of the yeast Saccharomyces cerevisiae. DNA sequences dubbed 'molecular bar codes' uniquely identify each strain, enabling their growth to be analysed in parallel and the fitness contribution of each gene to be quantitatively assessed by hybridization to high-density oligonucleotide arrays. We show that previously known and new genes are necessary for optimal growth under six well-studied conditions: high salt, sorbitol, galactose, pH 8, minimal medium and nystatin treatment. Less than 7% of genes that exhibit a significant increase in messenger RNA expression are also required for optimal growth in four of the tested conditions. Our results validate the yeast gene-deletion collection as a valuable resource for functional genomics.


Trends in disability and related chronic conditions among the forty-and-over population: 1997-2010.
Downward trends in activity limitations among the older U.S. population have recently plateaued, while activity limitation among the pre-retirement population has increased. Update temporal trends in limitations in sensory and physical functions, instrumental activities of daily living (IADLs), and activities of daily living (ADLs) for the 40-64 and 65-and-over U.S. populations; assess the extent to which trends in education, smoking, and obesity could account for the trends in limitations; and examine trends in conditions cited as causes of limitations, their durations, and proportion of life spent with them. Multivariate analysis of the 1997-2010 National Health Interview Survey. For the younger group, there have been increases in all limitations, except trouble hearing, which has declined. Increased obesity could account for the increases in vision, physical function, and IADL limitations. Musculoskeletal conditions, such as arthritis and back/neck problems, are frequently cited as causes of limitation, and there are growing roles for depression and nervous system conditions. For the 65-and-over group, there have been decreases in all limitations, except difficulty with physical functions, which is up. Increased education could account for the decline in ADL limitation, and increased obesity could account for increased difficulty with physical functions. Musculoskeletal conditions are also frequently cited as causes of limitation, but declines in heart- and vision-related limitations have been important. Trends should continue to be monitored closely for both groups, since younger people have not experienced the improvements of the older group, but are its future members.


Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis.
Pathological fibrosis is driven by a feedback loop in which the fibrotic extracellular matrix is both a cause and consequence of fibroblast activation. However, the molecular mechanisms underlying this process remain poorly understood. Here we identify yes-associated protein (YAP) (homolog of drosophila Yki) and transcriptional coactivator with PDZ-binding motif (TAZ) (also known as Wwtr1), transcriptional effectors of the Hippo pathway, as key matrix stiffness-regulated coordinators of fibroblast activation and matrix synthesis. YAP and TAZ are prominently expressed in fibrotic but not healthy lung tissue, with particularly pronounced nuclear expression of TAZ in spindle-shaped fibroblastic cells. In culture, both YAP and TAZ accumulate in the nuclei of fibroblasts grown on pathologically stiff matrices but not physiologically compliant matrices. Knockdown of YAP and TAZ together in vitro attenuates key fibroblast functions, including matrix synthesis, contraction, and proliferation, and does so exclusively on pathologically stiff matrices. Profibrotic effects of YAP and TAZ operate, in part, through their transcriptional target plasminogen activator inhibitor-1, which is regulated by matrix stiffness independent of transforming growth factor-β signaling. Immortalized fibroblasts conditionally expressing active YAP or TAZ mutant proteins overcome soft matrix limitations on growth and promote fibrosis when adoptively transferred to the murine lung, demonstrating the ability of fibroblast YAP/TAZ activation to drive a profibrotic response in vivo. Together, these results identify YAP and TAZ as mechanoactivated coordinators of the matrix-driven feedback loop that amplifies and sustains fibrosis.


The Zollinger-Ellison syndrome. A case report.
A vagotomy and antrectomy was performed on a 15-year-old boy with a malignant gastrinoma for emergency control of massive upper gastro-intestinal haemorrhage from a large posterior penetrating duodenal ulcer in the presence of jejunal ulceration and liver metastases. Hypergastrinaemia was confirmed by elevated serum gastrin levels. In the short term postoperatively the patient's disease has been controlled with oral cimetidine. Although controversy continues over the efficacy of cimetidine in the management of gastrinomas, medical treatment should be considered as an alternative to total gastrectomy in children with malignant gastrinomas because they are often slow-growing, indolent and compatible with long survival.


Assessment of Utilization of Rehabilitation Services among Stroke Survivors.
Rehabilitation is probably one of the most important phases of recovery for many stroke survivors. The current study was conducted with the objective to assess the utilization of rehabilitation services and factors affecting nonutilization of rehabilitation services among the stroke survivors. The current study was carried out in the Neuro Outpatient Department of a tertiary care hospital in India. It was a descriptive study. Consecutive 55 stroke survivors who had met the inclusion and exclusion criteria were recruited in this study. Self-structured rehabilitation tool was used to collect the data. Data were analyzed using the descriptive and inferential statistics. Majority of the patients comprised 70.9% of males and 29.1% of females. Among participants, 70.90% were aware about rehabilitation, 67% were utilizing rehabilitation services, whereas 33% were not utilizing rehabilitation services. In the current study, certain reasons were found behind not utilizing rehabilitation services. There were 83.3% of participants who had lack of awareness about rehabilitation services and 61.1% of participants who had no availability of rehabilitation services. Only 45.5% of rural inhabitants were utilizing rehabilitation services as compared to 81.2% of urban inhabitants and 83.23% of suburban inhabitants. Rehabilitation is of utmost importance. Hemiparesis, difficulty in performing activity of daily living, difficulty in performing social activities, and difficulty in reasoning were the most common problems faced by people suffering stroke after discharge from the hospital. There was lack of awareness and utilization of rehabilitation services by patients among Indian stroke population. Hence, health workers have an immense role in educating, motivating, and ensuring that rehabilitation services in rural inhabitants.


Trans-10, cis-12 conjugated linoleic acid decreases de novo lipid synthesis in human adipocytes.
Conjugated linoleic acid (CLA) reduces adiposity in vivo. However, mechanisms mediating these changes are unclear. Therefore, we treated cultures of human adipocytes with trans-10, cis-12 (10,12) CLA, cis-9, trans-11 (9,11) CLA or other trans fatty acids (FA), and measured indices of lipid metabolism. The lipid-lowering effects of 10,12 CLA were unique, as other trans FA did not reduce TG content to the same extent. Using low levels of [(14)C]-CLA isomers, it was shown that both isomers were readily incorporated into acylglycerols and phospholipids, albeit at lower levels than [(14)C]-oleic or [(14)C]-linoleic acids. When using [(14)C]-acetic acid and [(14)C]-pyruvic acid as substrates, 30 μM 10,12 CLA, but not 9,11 CLA, decreased de novo synthesis of triglyceride, free FA, diacylglycerol, cholesterol esters, cardiolipin, phospholipids and ceramides within 3-24 h. Treatment with 30 μM 10,12 CLA, but not 9,11 CLA, decreased total cellular lipids within 3 days and the ratio of monounsaturated FA (MUFA) to saturated FA, and increased C18:0 acyl-CoA levels within 24 h. Consistent with these data, stearoyl-CoA desaturase (SCD)-1 mRNA and protein levels were down-regulated by 10,12 CLA within 7-12 h, respectively. The mRNA levels of liver X receptor (LXR)α and sterol regulatory element binding protein (SREBP)-1c, transcription factors that regulate SCD-1, were decreased by 10,12 CLA within 5 h. These data suggest that the isomer-specific decrease in de novo lipid synthesis by 10,12 CLA is due, in part, to the rapid repression of lipogenic transcription factors that regulate MUFA synthesis, suggesting an anti-obesity mechanism unique to this trans FA.


Bayesian methods for the conformational classification of eight-membered rings.
Two methods for the classification of eight-membered rings based on a Bayesian analysis are presented. The two methods share the same probabilistic model for the measurement of torsion angles, but while the first method uses the canonical forms of cyclooctane and, given an empirical sequence of eight torsion angles, yields the probability that the associated structure corresponds to each of the ten canonical conformations, the second method does not assume previous knowledge of existing conformations and yields a clustering classification of a data set, allowing new conformations to be detected. Both methods have been tested using the conformational classification of Csp3 eight-membered rings described in the literature. The methods have also been employed to classify the solid-state conformation in Csp3 eight-membered rings using data retrieved from an updated version of the Cambridge Structural Database (CSD).


Elevated activation of CaMKIIα in the CPEB3-knockout hippocampus impairs a specific form of NMDAR-dependent synaptic depotentiation.
Cytoplasmic polyadenylation element binding protein 3 (CPEB3) is a sequence-specific RNA-binding protein that confines the strength of glutamatergic synapses by translationally downregulating the expression of multiple plasticity-related proteins (PRPs), including the N-methyl-D-aspartate receptor (NMDAR) and the postsynaptic density protein 95 (PSD95). CPEB3 knockout (KO) mice exhibit hippocampus-dependent abnormalities related not only to long-term spatial memory but also to the short-term acquisition and extinction of contextual fear memory. In this study, we identified a specific form of NMDAR-dependent synaptic depotentiation (DPT) that is impaired in the adult CPEB3 KO hippocampus. In parallel, cultured KO neurons also exhibited delayed morphological and biochemical responses under NMDA-induced chemical long-term depression (c-LTD). The c-LTD defects in the KO neurons include elevated activation of calcium/calmodulin-dependent protein kinase II alpha subunit (CaMKIIα), increased Ser831 phosphorylation of GluA1 and slow degradation of PSD95 and GluA1. Because transient pharmacological suppression of CaMKIIα activity during the DPT-initiating phase successfully reversed the LTP in the KO hippocampus, DPT and c-LTD in the two different systems shared common molecular defects due to the absence of CPEB3. Together, our results suggest that CPEB3 deficiency imbalances NMDAR-activated CaMKIIα signaling, which consequently fails to depress synaptic strength under certain stimulation conditions.


Forgiving Adolescents: Far From Depression, Close to Well-Being.
Forgiveness has been proven to be an effective way of regulating negative affect and decreasing depression. This study aimed at examining the relationship among constructs particularly relevant to adolescents' well-being, including forgivingness (dispositional forgiveness) anger, depression and Hedonic Balance (HB). Specifically, using a structural equation modelling approach, the fully mediational role of the different facets of anger in the relationship between forgiveness and depression was tested in 773 adolescents, of which 69% girls. Results showed that forgivingness was positively and negatively related to, respectively, HB and depression, through a general effect of anger, suggesting that more forgiving adolescents had higher HB and lower depression as they reported a lower general tendency to experience anger. Forgivingness was also positively related both to HB and to depression through the mediation of all the facets of Anger. Moreover, only for HB, a specific effect of Anger-control was found, suggesting that more forgiving adolescents had higher HB as they reported higher strategies to control anger in a functional manner. The model invariance was supported across gender. Our results suggest that forgiveness is a significant protective factor against depression for adolescents, helping them to effectively control and manage anger, thus fostering emotional health. An important clinical implication of our study regards the potential of forgiveness as a resource for well-being in therapy: among the various possible protective factors in adolescence, forgiveness has the added advantage that it can be fostered in clinical settings, and working on forgiveness in psychotherapy or in counselling could decrease adolescent depression and improve well-being.


High affinity forskolin inhibition of L-type Ca2+ current in cardiac cells.
The diterpene forskolin is widely known for its ability to directly activate adenylyl cyclase and consequently increase intracellular cAMP. In cardiac cells, one result is a cAMP-mediated increase in the L-type Ca2(+)-channel current (ICa). However, forskolin was also shown recently to affect a number of ionic channels in noncardiac cells by mechanisms that do not involve activation of adenylyl cyclase. The present study reveals such an effect of forskolin on cardiac Ca2+ channels. Indeed, under appropriate conditions, forskolin was found to cause an inhibition of ICa. Although the stimulation of adenylyl cyclase and ICa requires micromolar concentrations of forskolin, the inhibitory effect of forskolin was observed in the nanomolar range of concentrations, i.e., 2-3 orders of magnitude lower. This high affinity forskolin inhibition of ICa was observed when ICa was previously enhanced via a cAMP-dependent pathway, but not when ICa was at its basal level or when the current was elevated by the dihydropyridine Bay K 8644. The inhibitory effect occurred at a site of action remote from adenylyl cyclase, because forskolin similarly inhibited ICa that had been previously elevated by isoprenaline (a beta-adrenergic agonist) or directly by intracellular perfusion with cAMP. Under these conditions, forskolin was inhibitory when applied to either side of the cell membrane, but only in its lipid-soluble form. The inhibitory effect of forskolin appeared to be independent of membrane potential and was not accompanied by a change in the time constants of ICa activation and inactivation. This may indicate that forskolin mainly reduces the number of functional Ca2+ channels without changing the gating of individual channels. However, the reduction in ICa amplitude was not equally distributed among the different exponential components that constitute ICa, which suggests that forskolin also modifies the resting state of the channels. This novel high affinity forskolin inhibition of ICa may take place at some step in the pathway between cAMP and Ca2+ channel phosphorylation and/or at Ca2+ channels only after they have been phosphorylated.


The relationship between trough drug concentrations and ductal closure in preterm infants treated with three-dose-oral ibuprofen.
The aim of the present study was to characterize the pharmacokinetic profile of oral ibuprofen on consecutive 3 d by trough serum levels, and if possible to define a cut-off level for ductal closure in preterm infants. The study enrolled 20 preterm infants with gestational age ≤30 weeks, birth weight <1250 g and hemodynamically significant patent ductus arteriosus (hsPDA). Patients received oral ibuprofen at an initial dose of 10 mg/kg, followed by 5 mg/kg at 24 and 48 h. Patients were compared for serum ibuprofen levels in addition to their demographic and clinical data in case of their response to the treatment. hsPDA closed in 16 (80%) of the patients. Although mean ibuprofen levels on consecutive 3 d showed a plateau in general, ibuprofen serum levels on the first treatment day were statistically low in patients with unclosed hsPDA (p = 0.003). The optimal cut-off value for serum ibuprofen level on the first treatment day was measured as 5.5 mg/l with 100% sensitivity and 93% specificity. Serum ibuprofen level on the first treatment day seems to be an important factor for a successful ductal closure. Target concentration approach by the evaluation of trough level may be applicable to real-time dosing strategy.


Emergency excretory urography in blunt abdominal trauma.
In a prospective study the authors correlated the degree of hematuria and of blunt abdominal trauma with the results of emergency excretory urography. Urograms were obtained for 37 patients who presented with blunt abdominal trauma, no gross hematuria and at least five erythrocytes per high-power field (hpf) on microscopic urinalysis. Microscopic hematuria was defined as an erythrocyte count of more than 5 and fewer than 50 per hpf. Major trauma was defined as shock (systolic blood pressure of less than 90 mm Hg), fracture of the lumbar spine, the pelvis or the lower ribs, ecchymosis in the flank or acute abdominal injury. Contusions and small subcapsular hematomas were defined as nonsignificant renal injuries; all other renal injuries were defined as significant. Of 17 patients with minor blunt abdominal trauma 14 had fewer than 50 erythrocytes per hpf; none of these had a significant renal injury, whereas 1 of the 3 with more than 50 erythrocytes per hpf did have a significant injury. Of 20 patients with major trauma 5 had a significant renal injury. The authors conclude that microscopic hematuria associated with blunt abdominal trauma but without shock or major nongenitourinary injury does not warrant routine excretory urography.


Innate immunity activation on biomaterial surfaces: a mechanistic model and coping strategies.
When an artificial biomaterial (e.g., a stent or implantable pump) is exposed to blood, plasma proteins immediately adhere to the surface, creating a new interface between the biomaterial and the blood. The recognition proteins within the complement and contact activation/coagulation cascade systems of the blood will be bound to, or inserted into, this protein film and generate different mediators that will activate polymorphonuclear leukocytes and monocytes, as well as platelets. Under clinical conditions, the ultimate outcome of these processes may be thrombotic and inflammatory reactions, and consequently the composition and conformation of the proteins in the initial layer formed on the surface will to a large extent determine the outcome of a treatment involving the biomaterial, affecting both the functionality of the material and the patient's life quality. This review presents models of biomaterial-induced activation processes and describes various strategies to attenuate potential adverse reactions by conjugating bioactive molecules to surfaces or by introducing nanostructures.


Neuromuscular ventilatory insufficiency: effect of home mechanical ventilator use v oxygen therapy on pneumonia and hospitalization rates.
The purpose of this study was to determine rates of pneumonia and hospitalization for patients receiving oxygen therapy, patients having indwelling tracheostomy tubes, and those using tracheostomy or noninvasive methods of home mechanical ventilation. Six hundred eighty-four users of assisted ventilation for 13,751 patient-years or 19.8 years per patient were surveyed by mail and twice by telephone over a span of four years. Pneumonia and hospitalization rates were significantly higher for ventilator users with chronic obstructive pulmonary disease or with neuromuscular ventilatory insufficiency and gastrostomy tubes than for ventilator users with neuromuscular ventilatory insufficiency without gastrostomy tubes. Of the latter group, more than 90% of the pneumonias and hospitalizations were triggered by otherwise benign intercurrent upper respiratory tract infections. Oxygen therapy was associated with a significantly (P < 0.001) higher rate of pneumonias and hospitalizations than that seen for untreated patients after initial episodes of respiratory distress or during the use of either tracheostomy intermittent positive pressure ventilation or noninvasive ventilatory assistance methods. The lowest pneumonia and hospitalization rates (P < 0.001) were by full-time, noninvasive intermittent positive pressure ventilation users. We conclude that oxygen therapy is not an effective substitute for assisted ventilation for patients with primarily ventilatory insufficiency. Noninvasive ventilatory aids can be used effectively for up to full-time ventilatory support for patients with neuromuscular conditions whose bulbar muscle function is adequate to avert the need for gastrostomy tube placement.


Tuning transition metal carbide activity by surface metal alloying: a case study on CO2 capture and activation.
CO2 is one of the main actors in the greenhouse effect and its removal from the atmosphere is becoming an urgent need. Thus, CO2 capture and storage (CCS) and CO2 capture and usage (CCU) are intensively investigated technologies to decrease the concentration of atmospheric CO2. Both CCS and CCU require appropriate materials to adsorb/release and adsorb/activate CO2, respectively. Recently, it has been theoretically and experimentally shown that transition metal carbides (TMC) are able to capture, store, and activate CO2. To further improve the adsorption capacity of these materials, a deep understanding of the atomic level processes involved is essential. In the present work, we theoretically investigate the possible effects of surface metal doping of these TMCs by taking TiC as a textbook case and Cr, Hf, Mo, Nb, Ta, V, W, and Zr as dopants. Using periodic slab models with large supercells and state-of-the-art density functional theory based calculations we show that CO2 adsorption is enhanced by doping with metals down a group but worsened along the d series. Adsorption sites, dispersion and coverage appear to play a minor, secondary constant effect. The dopant-induced adsorption enhancement is highly biased by the charge rearrangement at the surface. In all cases, CO2 activation is found but doping can shift the desorption temperature by up to 135 K.


Spectral Hole Burning in Cyanobacterial Photosystem I with P700 in Oxidized and Neutral States.
We explored the rich satellite hole structures emerging as a result of spectral hole burning in cyanobacterial photosystem I (PSI) and demonstrated that hole burning properties of PSI, particularly at high resolution, are strongly affected by the oxidation state of the primary donor P700, as P700+ effectively quenches the excitations of the lowest-energy antenna states responsible for fluorescence. Obtaining better control of this variable will be crucial for high-resolution ensemble experiments on protein energy landscapes in PSI. The separate nonphotochemical spectral hole burning (NPHB) signatures of various red antenna states were obtained, allowing for additional constraints on excitonic structure-based calculations. Preliminary evidence is presented for an additional red state of PSI of T. elongatus peaked at 712.6 nm, distinct from previously reported C708 and C715 states and possibly involving chlorophyll B15. Excitation at wavelengths as long as 800 nm results in charge separation at cryogenic temperatures in PSI also in Synechocystis sp. PCC 6803. Both the "P700+ minus P700" holes and nonphotochemical spectral holes were subjected to thermocycling. The distribution of barriers manifesting in recovery of the "P700+ minus P700" signature contains two components in sample-dependent proportions, likely reflecting the percentages of FA and FB clusters being successfully prereduced before the optical experiment. The barrier distribution for the recovery of the lower-energy nonphotochemical spectral holes resembles those observed for other pigment-protein complexes, suggesting similar structural elements are responsible for NPHB. Higher-energy components exhibit evidence of "domino effects" such as shifts of certain bands persisting past the lower-energy hole recovery. Thus, conformational changes triggered by excitation of one pigment likely can affect multiple pigments in this tightly packed system.


Molecular mechanism of the bifunctional role of lipopolysaccharide in osteoclastogenesis.
Lipopolysaccharide (LPS), a common bacteria-derived product, has long been recognized as a key factor implicated in periodontal bone loss. However, the precise cellular and molecular mechanisms by which LPS induces bone loss still remains controversial. Here, we show that LPS inhibited osteoclastogenesis from freshly isolated osteoclast precursors but stimulated osteoclast formation from those pretreated with RANKL in vitro in tissue culture dishes, bone slices, and a co-culture system containing osteoblasts, indicating that RANKL-mediated lineage commitment is a prerequisite for LPS-induced osteoclastogenesis. Moreover, the RANKL-mediated lineage commitment is long term, irreversible, and TLR4-dependent. LPS exerts the dual function primarily by modulating the expression of NFATc1, a master regulator of osteoclastogenesis, in that it abolished RANKL-induced NFATc1 expression in freshly isolated osteoclast precursors but stimulated its expression in RANKL-pretreated cells. In addition, LPS prolonged osteoclast survival by activating the Akt, NF-kappaB, and ERK pathways. Our current work has not only unambiguously defined the role of LPS in osteoclastogenesis but also has elucidated the molecular mechanism underlying its complex functions in osteoclast formation and survival, thus laying a foundation for future delineation of the precise mechanism of periodontal bone loss.


Effects of octreotide and insulin on colon cancer cellular proliferation and correlation with hTERT activity.
Peptide hormone somatostatin and its receptors have a wide range of physiological functions and play a role in the treatment of numerous human diseases, including colorectal cancer. Octreotide, a synthetic somatostatin-analog peptide, inhibits growth of colonic cancer cells primarily by binding to G-protein coupled receptors and elicits cellular responses through second-messenger systems. Insulin also initiates mitogenic signals in certain cell types. The objective of the present study was to explore the effects of octreotide with or without insulin treatment, on Caco-2 and HT-29 human colon-cancer cell proliferation and to correlate their effects with the activation of telomerase reverse transcriptase (hTERT). The involvement of protein tyrosine phosphatases in the regulation of the anti-proliferative effect of octreotide was also evaluated. Sodium orthovanadate was used to reverse the anti- proliferative effect of octreotide. Telomerase activity was determined for each time point under octreotide and/or insulin treatment. Elevated expression of sst1, sst2 and sst5 was confirmed in both cell lines by RT-PCR. Immunocytochemistry detected sst1, sst2A, sst2B, sst3, sst4 and sst5 protein expression in the membranes of both cell lines. Octreotide inhibited the proliferation of Caco-2 and HT-29 cells in a time and dose-dependent manner. Insulin exerted proliferative effects in Caco-2 cells and octreotide reversed its effect in both cell lines. Sodium orthovanadate suppressed the anti-proliferative effect of octreotide both in Caco-2 and HT-29 cells. Telomerase activity was significantly reduced when Caco-2 cells were exposed to octreotide, under serum-free cultured medium. On the other hand, telomerase attenuation after octreotide treatment could not counteract the actions of insulin on both cells. Our data indicate that the use of octreotide could provide a possible therapeutic approach to the management of certain patients who suffer from colon cancer.


American Academy of Pediatrics. Committee on Infectious Diseases. Age for routine administration of the second dose of measles-mumps-rubella vaccine.
The purpose of this statement is to inform physicians of a modification in the recommendation of the appropriate age for routine administration of the second dose of measles-mumps-rubella (MMR) vaccine. The implementation of the two-dose measles vaccine schedule has improved the control of measles, but some outbreaks continue to occur in school children, although >/= to 95% of children in school have received one dose of vaccine. Because most measles vaccine failures are attributable to failure to respond to the first dose, that all children receive two doses of measles-containing vaccine is essential for the control of measles. Routine administration of the second dose of MMR vaccine at school entry (4 to 6 years of age) will help prevent school-based outbreaks. Physicians should continue to review the records of all children 11 to 12 years of age to be certain that they have received two doses of MMR vaccine after their first birthday. Documenting that all school children have received two doses of measles-containing vaccine by the year 2001 will help ensure the elimination of measles in the United States and contribute to the global effort to control and possible eradicate measles.


Hereditary nonpolyposis colorectal cancer (Lynch syndromes I & II). Genetics, pathology, natural history, and cancer control, Part I.
Hereditary nonpolyposis colorectal cancer (HNPCC) is common, accounting for about 4-6% of the total colorectal cancer burden. It is heterogeneous and appears to be delineated into two clinical subsets, Lynch syndromes I and II. Lynch syndrome I is characterized by an autosomal dominantly inherited proclivity to early onset colonic cancer with proximal predominance and an excess of multiple primary colonic cancer. Lynch syndrome II has all of these features plus extracolonic cancer sites, the most common of which is endometrial carcinoma. The lack of premonitory physical signs or biomarkers of HNPCC makes diagnosis difficult. A careful family history, tempered by an understanding of the clinical and pathologic features of HNPCC, is the key to its assessment. This paper reviews HNPCC's natural history, its integral extracolonic cancer associations, its differential diagnosis, surveillance, and management strategies. Attention is focused upon the need for biomarker research in the interest of improving control of HNPCC.


Linking Neurons to Network Function and Behavior by Two-Photon Holographic Optogenetics and Volumetric Imaging.
We introduce a flexible method for high-resolution interrogation of circuit function, which combines simultaneous 3D two-photon stimulation of multiple targeted neurons, volumetric functional imaging, and quantitative behavioral tracking. This integrated approach was applied to dissect how an ensemble of premotor neurons in the larval zebrafish brain drives a basic motor program, the bending of the tail. We developed an iterative photostimulation strategy to identify minimal subsets of channelrhodopsin (ChR2)-expressing neurons that are sufficient to initiate tail movements. At the same time, the induced network activity was recorded by multiplane GCaMP6 imaging across the brain. From this dataset, we computationally identified activity patterns associated with distinct components of the elicited behavior and characterized the contributions of individual neurons. Using photoactivatable GFP (paGFP), we extended our protocol to visualize single functionally identified neurons and reconstruct their morphologies. Together, this toolkit enables linking behavior to circuit activity with unprecedented resolution.


Unravelling the origin of the high-catalytic activity of supported Au: a density-functional theory-based interpretation.
Using first principles DF calculations we have studied the structural and catalytic properties of Au supported on TiOx-Mo(112) films. Our theoretical models are consistent with an initial (8 x 2) Mo(112)-Ti2O3 pattern which after Au deposition gives rise to ordered Au films that completely wet the surface. The oxidation of CO on model surfaces at coverage 1, 4/3, and 5/2 ML has been analyzed. The oxidation proceeds through a peroxo-like complex in which molecular oxygen is simultaneously bound to the CO and the surface. The energy barrier computed for a Au coverage of 4/3 ML is found significantly lower in agreement with the unusual high activity observed for this catalyst. The detailed analysis of the geometry and electronic structure provides a fundamental understanding of the reaction.


Therapeutic vaccination against murine lymphoma by intratumoral injection of naive dendritic cells.
Dendritic cells are potent antigen-presenting cells that can induce both immune responses and tolerance depending on their state of activation. Immunologic tolerance to established tumors is a major impediment for the development of effective cancer immunotherapy. Dendritic cells may be deficient in number or in function at the tumor site. To address this problem, we evaluated the ability of immature naïve dendritic cells to induce an antitumor immune response when injected directly into a murine B-cell lymphoma. Mice with advanced transplanted syngeneic tumor were given intratumoral injections of bone marrow-derived dendritic cells. Intratumoral dendritic cell injection alone had no antitumor effect. Systemic chemotherapy alone resulted in only transient tumor regression. However, the intratumoral injection of dendritic cells after chemotherapy led to complete, long-term tumor regression in the majority of treated mice. This dendritic cell-mediated antitumor effect was systemic, resulting in simultaneous elimination of the tumor at second uninjected sites. In addition, it resulted in long-term memory with resistance to tumor rechallenge. Both CD4+ and CD8+ T cells are necessary for the antitumor effect. Furthermore, tumors that occasionally recurred in mice with initial complete tumor regression could be retreated by the same combined chemoimmunotherapy approach. These results show that immunotherapy can succeed in the setting of advanced lymphoma if dendritic cells are restored and loaded with tumor antigens in situ at a single tumor site.


Detection of Merkel cell polyomavirus in epidermodysplasia-verruciformis-associated skin neoplasms.
Epidermodysplasia verruciformis (EV) is a rare genodermatosis that is characterized by susceptibility to infection with specific human papillomavirus (HPV) genotypes. Among polyomaviruses, the novel Merkel cell polyomavirus (MCPyV) has been found in different epithelial skin neoplasias. To examine whether EV is associated with cutaneous MCPyV infection. We used MCPyV-specific PCR to study skin neoplasms of 6 congenital EV patients and of 1 patient with acquired EV. In all congenital EV patients, MCPyV DNA was found in carcinomas in situ, in invasive squamous cell carcinomas and in common warts. In 4 of these patients, the MCPyV-positive skin lesions were from different anatomic locations. In addition, 1 immunosuppressed patient suffering from acquired EV harbored MCPyV DNA in 2 common warts. In contrast, 7 normal skin samples tested negative for MCPyV DNA. Only 2 out of 24 carcinomas in situ (8.3%) and 2 out of 30 common warts (6.7%) from immunocompetent individuals were positive for MCPyV DNA. The strong association of EV-associated skin neoplasms with MCPyV suggests a unique susceptibility of EV patients to infections with MCPyV. Both MCPyV and EV-HPV may act as synergistic oncogenic cofactors in the development of EV-associated skin neoplasms.


A hybrid electrospun-extruded polydioxanone suture for tendon tissue regeneration.
Many surgical tendon repairs fail despite advances in surgical materials and techniques. Tendon repair failure can be partially attributed to the tendon's poor intrinsic healing capacity and the repurposing of sutures from other clinical applications. Electrospun materials show promise as a biological scaffold to support endogenous tendon repair, but their relatively low tensile strength has limited their clinical translation. It is hypothesized that combining electrospun fibres with a stronger material may improve the suture's mechanical properties while retaining biophysical cues necessary to encourage cell-mediated repair. This paper describes the production of a hybrid electrospun-extruded suture with a sheath of submicron electrospun fibres and a core of melt-extruded fibres. The porosity and tensile strength of this hybrid suture is compared to an electrospun-only braided suture and clinically used sutures Vicryl and PDS. Bioactivity is assessed by measuring the adsorbed serum proteins on electrospun and melt-extruded filaments using mass spectrometry. Human hamstring tendon fibroblast attachment and proliferation was quantified and compared between the hybrid and control sutures. Combining an electrospun sheath with melt-extruded cores created a hybrid braid with increased tensile strength (70.1±0.3N) compared to an electrospun only suture (12.9±1N, p<0.0001). The hybrid suture had a similar force at break to clinical sutures, but lower stiffness and stress. The Young's modulus was 772.6±32Mpa for the hybrid suture, 1693.0±69Mpa for PDS, and 3838.0±132MPa for Vicryl, p<0.0001. Hybrid sutures had lower overall porosity than electrospun-only sutures (40±4% and 60±7%, respectively, p=0.0018) but had a significantly larger overall porosity and average pore diameter compared to surgical sutures. There were similar clusters of adsorbed proteins on electrospun and melt-extruded filaments, which were distinct from PDS. Tendon fibroblast attachment and cell proliferation on hybrid and electrospun sutures were significantly higher than on clinical sutures. This study demonstrated that a bioactive suture with increased tensile strength and lower stiffness could be produced by adding a core of 10um melt-extruded fibres to a sheath of electrospun fibres. In contrast to currently used sutures, the hybrid sutures promoted a bioactive response: serum proteins adsorbed, and fibroblasts attached, survived, grew along the sutures, and adopted appropriate morphologies.


The fragile X mental retardation protein is a molecular adaptor between the neurospecific KIF3C kinesin and dendritic RNA granules.
Fragile X mental retardation 1 protein (FMRP) is an RNA-binding protein whose absence results in the fragile X syndrome, the most common inherited form of mental retardation. FMRP contains multiple domains with apparently differential affinity to mRNA and interacts also with protein partners present in ribonucleoprotein complexes called RNA granules. In neurons, these particles travel along dendrites and axons to translocate mRNAs to specific destinations in spines and growth cones, where local synthesis of neuro-specific proteins is taking place. However, the molecular mechanisms of how RNA granules are translocated to dendrites remained unknown. We report here the identification and characterization of the motor protein KIF3C as a novel FMRP-interacting protein. In addition, using time-lapse videomicroscopy, we studied the dynamics and kinetics of FMRP-containing RNA granules in dendrites and show that a KIF3C dominant-negative impedes their distal transport. We therefore propose that, in addition to modulate the translation of its mRNA targets, FMRP acts also as a molecular adaptor between RNA granules and the neurospecific kinesin KIF3C that powers their transport along neuronal microtubules.


Treatment of recurrent respiratory papillomatosis with human leukocyte interferon. Results of a multicenter randomized clinical trial.
Recurrent respiratory papillomatosis is a relentless disease of viral origin in which squamous papillomas frequently obstruct the respiratory tract of children and young adults. No therapy has been proved to be curative for this process. Recent reports have suggested that interferon may cure or dramatically control airway papillomatosis. We evaluated the efficacy of human leukocyte interferon in the treatment of respiratory papillomatosis. One hundred twenty-three patients were randomly assigned to receive treatment with either surgery plus interferon or surgery alone. Interferon (2 X 10(6) IU per square meter of body-surface area) was given daily for one week, then three times per week for one year; treatment was followed by a year of observation, without the drug. Both study groups underwent serial endoscopy to remove papillomas and to document the efficacy of treatment during the two years of study. During the first six months, the growth rate of papillomas in the interferon group was significantly lower than in the control group (P = 0.0007). This difference diminished during the second six months and was no longer statistically significant (P = 0.68). Our data do not show that interferon is either curative or of substantial value as an adjunctive agent in the long-term management of recurrent respiratory papillomatosis. The initial benefit of interferon is not sustained.


Long term puzzles of the CH and CD energetics and related phenomena revisited; solutions sought through REMPI-photofragmentations of bromomethanes.
Ever since the pioneering work by Herzberg and Johns in 1969 (The Astrophysical Journal, 1969, 158, 399) the spectral assignment and the energetics of the fundamental molecular fragment CH, in the region of 63 000-65 000 cm(-1) (7.81-8.06 eV), have remained a puzzle to a large extent. The dissociation of bromoform and deuterated bromoform following two-photon resonance excitations to molecular Rydberg states forms the fragment species CH* and CD* in the excited state A(2)Δ(v' =0) as well as carbon and bromine atoms in the ground and first excited states, C/C* and Br/Br*. Further (1r + 1i)REMPI of CH* and CD* resonance excites the fragments to the energy region of concern, whereas the atom fragments were identified by further (2r + 1i)REMPI. Analysis based on spectral simulations, isotope shifts and comparison with other data allowed spectral identifications, assignments and partial characterization of four highly excited bound states for each of the molecular fragments (CH**/CD**); including the (3)(2)Π valence state and the (4)(2)Π Rydberg state, for the first time. Perturbations, shown as line-shifts, line-intensity and/or line-width alterations, due to the level-to-level state interactions between the bound states and predissociations by a repulsive state are recognized. Recording of C(+) signals in REMPI of several bromomethanes for a one-photon energy of about 40 333 cm(-1) allows the clarification of a mystery concerning a broad C(+) band frequently observed. This work, presented, demonstrates the usefulness of molecular REMPI for fragment analysis.


Collaboration and competition: ethics in toxicology.
From animal research through adverse events in clinical trials to health scares around food contamination, toxicology has frequently been a focus of scientific and societal concern. As these concerns shift with each new drug, new technology or public health scare, how can toxicology stay current, relevant and ethical? Two of the biggest ethical challenges in pharmaceutical toxicology are the use of animals in testing and the high safety-related attrition rates in new drug development. Both of these require progress in the discipline that will only be driven by research funding. Yet, very little is invested in these two fields compared with investment in new efficacy models, new disease targets and new technologies. How can this be addressed? Here, we explore current paradigms in toxicology that may have the potential for perceived or actual unethical ramifications. We discuss the underpinnings of such practices and make recommendations for change around peer review, resourcing, transparency and data sharing. These ideas build on the analysis presented in the 2004 Paton Prize lecture (Purchase, 2004) where issues around conflict of interest (COI), collaboration and competition in the context of ethical behaviours were highlighted. These areas are clearly relevant to many aspects of scientific research but here we focus on toxicology and specifically toxicology in the pharmaceutical industry.


The winged-helix transcription factor HNF-3 beta is required for notochord development in the mouse embryo.
HNF-3 beta, a transcription factor of the winged-helix family, is expressed in embryonic and adult endoderm and also in midline cells of the node, notochord, and floor plate in mouse embryos. To define the function of HNF-3 beta, a targeted mutation in the HNF-3 beta locus was generated by homologous recombination in embryonic stem cells. Mice lacking HNF-3 beta die by embryonic day (E) 10-11. Mutant embryos examined from E6.5 to E9.5 do not form a distinct node and lack a notochord. In addition, mutant embryos show marked defects in the organization of somites and neural tube that may result from the absence of the notochord. The neural tube of mutant embryos exhibits overt anteroposterior polarity but lacks a floor plate and motor neurons. Endodermal cells are present but fail to form a gut tube in mutant embryos. These studies indicate that HNF-3 beta has an essential role in the development of axial mesoderm in mouse embryos.


A dimer of bis-(N-heterocyclic carbene)rhodium(I) centres spanned by a dibenzo-18-crown-6 bridge from synchrotron radiation.
The compound (μ-3,3',3'',3'''-{[2,5,8,15,18,21-hexa-oxatricyclo-[126.96.36.199(9,14)]hexa-cosa-1(22),9,11,13,23,25-hexa-ene-11,12,24,25-tetra-yl]tetra-kis-(methyl-ene)}tetra-kis-(1-methyl-1H-imidazol-2-yl))bis-[(η(4)-cyclo-octa-1,4-diene)rhodium(I)] bis-(hexa-fluoridophosphate) acetonitrile sesquisolvate dihydrate, [Rh2(C8H12)2(C40H42N8O6)](PF6)2·1.5CH3CN·2H2O, crystallized from acetonitrile under an atmosphere of diethyl ether. In the crystal structure, the complex cation exhibits two square-planar Rh(I) centres, each bound by a cyclo-octa-diene (COD) ligand and by two adjacent imidazolyl-idene N-heterocyclic carbene (NHC) donors from the same phen-oxy ring of the {[dibenzo-18-crown-6-11,12,24,25-tetra-yl]tetra-kis-(methyl-ene)}tetra-kis-(1-methyl-1H-imidazol-2-yl) (L) ligand. The dibenzo-crown ether bridge of L spans the Rh centres and forms hydrogen bonds with water mol-ecules. One water mol-ecule with half occupancy bridges adjacent macrocycles in the lattice. Another water with full occupancy forms weak hydrogen bonds to the crown ether O atoms and is, in turn, part hydrogen bonded by a lattice water with half occupancy. The latter water is within hydrogen-bonding distance of a fourth water also with partial occupancy. The result of these inter-actions is the formation of a layer in the ab plane. Two PF6(-) ions, one of which is twofold disordered, and one ordered and one twofold disordered (with 0.5 occupancy) lattice acetonitrile mol-ecules complete the crystal structure.


Therapeutic hypothermia during neonatal transport: data from the California Perinatal Quality Care Collaborative (CPQCC) and California Perinatal Transport System (CPeTS) for 2010.
To evaluate cooling practices and neonatal outcomes in the state of California during 2010 using the California Perinatal Quality Care Collaborative and California Perinatal Transport System databases. Database analysis to determine the perinatal and neonatal demographics and outcomes of neonates cooled in transport or after admission to a cooling center. Of the 223 infants receiving therapeutic hypothermia for hypoxic ischemic encephalopathy (HIE) in California during 2010, 69% were cooled during transport. Despite the frequent use of cooling in transport, cooling center admission temperature was in the target range (33-34 °C) in only 62 (44%). Among cooled infants, gestational age was <35 weeks in 10 (4.5%). For outborn and transported infants, chronologic age at the time of cooling initiation was >6 h in 20 (11%). When initiated at the birth hospital, cooling was initiated at <6 h of age in 131 (92.9%). More than half of the infants cooled in transport do not achieve target temperature by the time of arrival at the cooling center. The use of cooling devices may improve temperature regulation on transport.


Does a Preschool Social and Emotional Learning Intervention Pay Off for Classroom Instruction and Children's Behavior and Academic Skills? Evidence From the Foundations of Learning Project.
This article tests the hypothesis that children's learning environment will improve through a social and emotional learning (SEL) intervention that provides preschool teachers with new skills to manage children's disruptive behavior by reporting results from the Foundations of Learning (FOL) Demonstration, a place-randomized, experimental evaluation conducted by MDRC. Research Findings: Findings demonstrate that the FOL intervention improved teachers' ability to address children's behavior problems and to provide a positive emotional climate in their classrooms. Importantly, the FOL intervention also improved the number of minutes of instructional time, although the quality of teachers' instruction was not improved. Finally, FOL benefited children's observed behavior in classrooms, with lower levels of conflictual interactions and, at the trend level, higher levels of engagement in classrooms activities, relative to similar students randomly assigned to control classrooms. Practice or Policy: This study is one of an emerging body of research on the efficacy of SEL programs for preschool children living in poverty. Understanding the value-added of these programs (e.g., in increased instructional time and increased classroom engagement) as well as their limitations (e.g., in teachers' instructional quality and children's academic skills) will help us design the next set of more effective interventions for low-income children.


Yoga as the "next wave" of therapeutic modalities for treatment of insomnia.
Insomnia rates continue to rise, especially among specific populations. Current nonpharmacological treatments rely primarily upon cognitive behavioral therapy for insomnia (CBT-I), which was introduced in the 1970s. Newer treatments have incorporated CBT "third wave" techniques, including mindfulness and acceptance techniques. Yoga practice is well suited to complement existing therapies and to address sleep problems in a more holistic way. Current theoretical and empirical approaches to treating insomnia are discussed, with an emphasis on the role of yoga in addressing precipitating and perpetuating factors in insomnia that have previously been largely overlooked.An estimated one-third of U.S. adults suffer from insomnia (Chen, Gelaye, & Williams, 2013; Mellinger, Balter, & Uhlenhuth, 1985; Ohayon, 2002), and the problem appears to be growing. While treatment for insomnia has helped to alleviate the problem for some (Irwin, Cole, & Nicassio, 2006; Morin et al., 2009), prevalence of insomnia is on the rise, especially among certain groups, including elderly and military populations (Morin, 2009; Mysliwiec et al., 2013). Rising rates of insomnia have been attributed to changes in lifestyle and environmental factors, including increased reliance on technology and decreased synchrony with natural wake-sleep rhythms (Brahinsky, 2013; Wallace-Guy et al., 2002; Yun, Bazar, Gerber, Lee, & Daniel, 2005).


Levels of naturally occurring DNA polymorphism correlate with recombination rates in D. melanogaster.
Two genomic regions with unusually low recombination rates in Drosophila melanogaster have normal levels of divergence but greatly reduced nucleotide diversity, apparently resulting from the fixation of advantageous mutations and the associated hitch-hiking effect. Here we show that for 20 gene regions from across the genome, the amount of nucleotide diversity in natural populations of D. melanogaster is positively correlated with the regional rate of recombination. This cannot be explained by variation in mutation rates and/or functional constraint, because we observe no correlation between recombination rates and DNA sequence divergence between D. melanogaster and its sibling species, D. simulans. We suggest that the correlation may result from genetic hitch-hiking associated with the fixation of advantageous mutants. Hitch-hiking thus seems to occur over a large fraction of the Drosophila genome and may constitute a major constraint on levels of genetic variation in nature.


Pierre robin sequence in a neonate with suckling difficulty and weight loss.
Pierre Robin sequence (PRS) is a combination of micrognathia and glossoptosis that leads to airway obstruction, feeding problems, and potentially other sequelae that can complicate early life. Currently, therapy for these newborns and infants is focused on preventing fatality or complications until the jaw can grow sufficiently to correct airway obstruction and associated problems. For patients with mild PRS, treatments include conservative measures such as airway maintenance and a feeding tube. For more severe cases, a surgical procedure is necessary. To the authors' knowledge, the effectiveness of osteopathic manipulative treatment of patients with PRS has not been reported in the literature. The current case describes the use of osteopathic manipulative treatment to help alleviate difficulties with breathing and latch and suckling in a 15-day-old newborn with PRS.


Variation in compound eye structure: effects of diet and family.
Studies of compound eyes have revealed that variation in eye structure can substantially affect visual performance. Here, we investigate the degree to which a stressful rearing environment, which decreases body size, affects the eye phenotype. Full siblings of the Orange Sulphur butterfly, Colias eurytheme, were collected from known parents and split within families among two diet treatments that varied in quality. In both sexes, individuals reared on the high-quality diet had larger eye height and anterior facet diameter, and therefore, by inference, superior vision. However, relative to their reduced body size, individuals reared on low-quality diet had proportionally larger eyes and facets than individuals reared on high-quality diet. We interpret this finding as evidence that butterflies encountering nutritional stress increased proportional investment in eye development to reduce loss of visual performance. We also found significant broad-sense genetic variation underlying eye structure in both males and females, and report novel heritability estimates for eye height and facet diameter. Surprisingly, there was greater genetic variation in eye height among males than among females, despite apparently stronger directional selection on male vision. We discuss the implications of these data for our understanding of eye development and evolution.


Physicochemical characteristics and biological effects of nickel oxides.
Ten nickel oxides and nickel-copper oxides, which all contained NiO (bunsenite) as the predominant crystalline phase, were assayed as follows: in vitro dissolution tests in water and body fluids; in vitro phagocytosis tests in Chinese hamster ovary and C3H-10T1/2 cells; morphological transformation and cytotoxicity tests in cultured Syrian hamster embryo (SHE) cells; erythropoiesis stimulation assay by intrarenal administration to Fischer-344 rats; and scoring the renal histopathologic responses in rats killed 3 months post-injection. The test compounds differed substantially in their biological effects when tested in the various experimental systems. Based upon highly significant concordance of ranked results in the assays (P less than 0.001), six colligative biological attributes of the compounds were identified: (i) dissolution half-times in rat serum and renal cytosol; (ii) phagocytosis by C3H-10T1/2 cells; (iii) morphological transformation of SHE cells; (iv) erythropoiesis stimulation in rats; (v) induction of tubular hyperplasia in rat kidneys; and (vi) induction of arteriosclerosis in rat kidneys. Strong rank correlation (P less than 0.01) between results of the cell transformation and erythropoiesis stimulation assays is especially notable, since the compounds were tested by blind protocols in independent laboratories. The presence of high surface area and demonstrable Ni(III) were two physicochemical characteristics that were associated with the greatest biological effects of nickel oxides.


Inequalities in availability of National Health Service general dental practitioners in England and Wales.
To model the inequalities in availability of National Health Service general dental practitioners in England and Wales in relation to key socio-demographic factors. Current estimates of the numbers of NHS general dental practitioners for each health authority were related to data from the 1991 census using Poisson regression models, and generalised estimating equations to allow for correlation between results for neighbouring health authorities. An 'average' health authority, without a dental school, would be expected to have 2,138 residents for every NHS dentist. Controlling for relevant factors, health authorities with higher proportions of the following are associated with lower (better) population to dentist ratios by the amounts shown: each 1% higher female population (-11.8%; 95%CI -19.1%, -3.9% P = 0.004); each 1% greater South Asian population (-1.4%; 95%CI -2.1%, -0.7% P <0.001). A health authority with a dental school is associated with a more favourable ratio compared with one without such a facility (-9.2%; 95%CI -16.2%, -1.6% P = 0.019). Each additional 1% of the following are associated with a worse ratio by the amounts shown: children aged 0 to 14 years old (+5.2%; 95% CI +2.4%, +8.1% P < 0.001); adults aged over 65 years old (+2.8%, 95%CI +1.0%, +4.7% P =0.002); households without a car (+0.8%; 95%CI 0.0%, +1.6% P =0.042). Ensuring access to dental care may be a more complex issue than simply providing adequate numbers of dentists at a national level. Any manpower planning exercise should additionally consider local factors that may act as incentives or disincentives to those professionals who provide care.


'Mental health day' sickness absence amongst nurses and midwives: workplace, workforce, psychosocial and health characteristics.
To examine the workforce, workplace, psychosocial and health characteristics of nurses and midwives in relation to their reported use of sickness absence described as 'mental health days'. The occupational stress associated with the nursing profession is increasingly recognized and nurse/midwifery absenteeism is a significant global problem. Taking a 'mental health day' as sickness absence is a common phenomenon in Australian health care. No previous studies have empirically explored the characteristics of nurses and midwives using such sickness absence. Online cross-sectional survey. Survey comprising validated tools and questions on workplace and health characteristics was distributed to nurses and midwives in New South Wales, Australia, between May 2014 - February 2015. Sample characteristics were reported using descriptive statistics. Factors independently predictive of 'mental health day' reportage were determined using logistic regression. Fifty-four percentage of the n = 5041 nurse and midwife respondents took 'mental health days'. Those affected were significantly more likely to be at younger ages, working shifts with less time sitting at work; to report workplace abuse and plans to leave; having been admitted to hospital in previous 12 months; to be current smokers; to report mental health problems, accomplishing less due to emotional problems and current psychotropic medication use. Specific characteristics of nurses and midwives who report taking 'mental health day' sickness absence offer healthcare administrators and managers opportunities for early identification and intervention with workplace measures and support frameworks to promote well-being, health promotion and safety.


Molecular characterization of highly pathogenic H5N1 avian influenza viruses isolated in Sweden in 2006.
The analysis of the nonstructural (NS) gene of the highly pathogenic (HP) H5N1 avian influenza viruses (AIV) isolated in Sweden early 2006 indicated the co-circulation of two sub-lineages of these viruses at that time. In order to complete the information on their genetic features and relation to other HP H5N1 AIVs the seven additional genes of twelve Swedish isolates were amplified in full length, sequenced, and characterized. The presence of two sub-lineages of HP H5N1 AIVs in Sweden in 2006 was further confirmed by the phylogenetic analysis of approximately the 95% of the genome of twelve isolates that were selected on the base of differences in geographic location, timing and animal species of origin. Ten of the analyzed viruses belonged to sub-clade 2.2.2. and grouped together with German and Danish isolates, while two 2.2.1. sub-clade viruses formed a cluster with isolates of Egyptian, Italian, Slovenian, and Nigerian origin. The revealed amino acid differences between the two sub-groups of Swedish viruses affected the predicted antigenicity of the surface glycoproteins, haemagglutinin and neuraminidase, rather than the nucleoprotein, polymerase basic protein 2, and polymerase acidic protein, the main targets of the cellular immune responses. The distinctive characteristics between members of the two subgroups were identified and described. The comprehensive genetic characterization of HP H5N1 AIVs isolated in Sweden during the spring of 2006 is reported. Our data support previous findings on the coincidental spread of multiple sub-lineage H5N1 HPAIVs via migrating aquatic birds to large distance from their origin. The detection of 2.2.1. sub-clade viruses in Sweden adds further data regarding their spread in the North of Europe in 2006. The close genetic relationship of Swedish isolates sub-clade 2.2.2. to the contemporary German and Danish isolates supports the proposition of the introduction and spread of a single variant of 2.2.2. sub-clade H5N1 avian influenza viruses in the Baltic region. The presented findings underline the importance of whole genome analysis.


Degradation of eukaryotic polypeptide chain initiation factor (eIF) 4G in response to induction of apoptosis in human lymphoma cell lines.
We have investigated the effect of inducing apoptosis in BJAB and Jurkat cells on the cellular content of several polypeptide chain initiation factors. Serum deprivation results in inhibition of protein synthesis and induction of apoptosis in BJAB cells; at early times, there is selective degradation of polypeptide initiation factor eIF4G but no major losses of other key initiation factors. The disappearance of full length eIF4G is accompanied by the appearance of smaller forms of the protein, including a major product of approximately 76 kDa. Apoptosis induced by cycloheximide results in similar effects. Both total cytoplasmic eIF4G and eIF4G associated with eIF4E are degraded with a half-life of 2-4 h under these conditions. Treatment of serum-starved or cycloheximide-treated cells with Z-VAD.FMK or Z-DEVD.FMK, which inhibit caspases required for apoptosis, protects eIF4G from degradation and blocks the appearance of the ca. 76 kDa product. Exposure of BJAB cells to rapamycin rapidly inhibits protein synthesis but does not lead to acute degradation of eIF4G. In both BJAB and Jurkat cells induction of apoptosis with anti-Fas antibody or etoposide also results in the selective loss of eIF4G, which is inhibitable by Z-VAD.FMK. These data suggest that eIF4G is selectively targeted for cleavage as cells undergo apoptosis and is a substrate for proteases activated during this process.


Betulinic acid, derived from the desert lavender Hyptis emoryi, attenuates paclitaxel-, HIV-, and nerve injury-associated peripheral sensory neuropathy via block of N- and T-type calcium channels.
The Federal Pain Research Strategy recommended development of nonopioid analgesics as a top priority in its strategic plan to address the significant public health crisis and individual burden of chronic pain faced by >100 million Americans. Motivated by this challenge, a natural product extracts library was screened and identified a plant extract that targets activity of voltage-gated calcium channels. This profile is of interest as a potential treatment for neuropathic pain. The active extract derived from the desert lavender plant native to southwestern United States, when subjected to bioassay-guided fractionation, afforded 3 compounds identified as pentacyclic triterpenoids, betulinic acid (BA), oleanolic acid, and ursolic acid. Betulinic acid inhibited depolarization-evoked calcium influx in dorsal root ganglion (DRG) neurons predominantly through targeting low-voltage-gated (Cav3 or T-type) and CaV2.2 (N-type) calcium channels. Voltage-clamp electrophysiology experiments revealed a reduction of Ca, but not Na, currents in sensory neurons after BA exposure. Betulinic acid inhibited spontaneous excitatory postsynaptic currents and depolarization-evoked release of calcitonin gene-related peptide from lumbar spinal cord slices. Notably, BA did not engage human mu, delta, or kappa opioid receptors. Intrathecal administration of BA reversed mechanical allodynia in rat models of chemotherapy-induced peripheral neuropathy and HIV-associated peripheral sensory neuropathy as well as a mouse model of partial sciatic nerve ligation without effects on locomotion. The broad-spectrum biological and medicinal properties reported, including anti-HIV and anticancer activities of BA and its derivatives, position this plant-derived small molecule natural product as a potential nonopioid therapy for management of chronic pain.


Renal function in long-duration type I diabetes.
The development of persistent proteinuria is reported to be uncommon after 30 years of type I diabetes, and the significance of microalbuminuria in patients with long-duration diabetes is unclear. We therefore undertook to study, in detail, renal function in patients with long-duration type I diabetes. We measured albumin excretion rate (AER), glomerular filtration rate (GFR), and serum creatinine in 140 patients with > or = 30 years of type I diabetes. We also assessed patients for other micro- macrovascular complications of diabetes together with factors implicated in the development of diabetic renal disease. Of the patients, 23% had microalbuminuria (AER 20-200 micrograms/min and/or urinary albumin-to-creatinine ratio [ACR] > 2.5 mg/mmol [men] or > 3.5 mg/mmol [women] and dipstick negative for proteinuria), 4% had overt nephropathy (AER > 200 micrograms/min or persistent dipstick positive proteinuria), and 73% were normoalbuminuric (AER < 20 micrograms/min or ACR < 2.5 mg/mmol [men], < 3.5 mg/mmol [women]). Patients with microalbuminuria had lower GFR (81.5 +/- 30.2 vs. 96.0 +/- 20.3 ml.min-1.1.73 m-2; P = 0.06) and higher serum creatinine (104 +/- 32 vs. 92 +/- 16 mumol/l; P = 0.06) than those patients with normoalbuminuria. Both serum creatinine (P < 0.05) and tobacco consumption (P = 0.01) were significantly and independently related to elevated albumin excretion. A substantial proportion of these patients have microalbuminuria and evidence of impaired renal function, suggesting that progression to end-stage renal failure may still be inevitable. Clinicians should continue to monitor renal function in these patients. The relationship between tobacco consumption and nephropathy also makes clear the need to reduce cigarette smoking in the diabetic population.


Diagnostic tests for feline hyperthyroidism.
Until recently, the diagnosis of hyperthyroidism in cats was thought to be simple; however, not all cases of the disease are straightforward. Although single resting serum thyroid-hormone determinations may well be adequate to confirm the diagnosis, in many cases, the diagnosis of feline hyperthyroidism requires more extensive investigation.


Narrowband Bragg reflectors in Ti:LiNbO3 optical waveguides.
Bragg grating reflectors etched in amorphous silicon overlay films have been integrated with Ti:LiNbO3 optical waveguides to obtain a narrow (0.05 nm) reflectance spectrum with a > 20 dB dip in the transmittance spectrum. These results were realized at a wavelength of 1542.7 nm for TE polarization on an x-cut, y-propagating substrate with gratings etched to a depth of approximately 93 nm in a 105 nm thick silicon film over a length of 12.5 mm. The reflectance in the channel waveguides is found to be strongly dependent on the depth of the etched grating. The effect of the Bragg waveguide loss factor on the transmittance and reflectance spectra is investigated by using a model for contradirectional coupling that includes an attenuation coefficient. The values for coupling constants kappa and amplitude attenuation constants alpha of samples etched for different time durations to control the grating depths are obtained from the model through the use of the depth of the dips in the transmittance spectra and the spectral widths of the reflectance peaks. It is concluded that the corrugated Si overlay film increases the insertion loss by approximately 2.7 dB, and the loss is not significantly affected by the grating depth.


Spectroscopy and dynamics of the HOCO radical: insights into the OH + CO → H + CO2 reaction.
After more than forty years of scrutiny, crucial new details regarding the elementary reaction OH + CO → H + CO2 are still emerging from experimental and theoretical studies of the HOCO radical intermediate. In this perspective, previous studies of this elementary reaction and the structure and energetics of the HOCO radical will be briefly reviewed. Particular attention will be paid to the experimental techniques used in our laboratory to prepare excited HOCO radicals by both photodetachment and dissociative photodetachment of HOCO(-). These experiments directly probe the dynamics occurring on the ground and excited states of the HOCO radical, and are sensitive to both direct and tunneling-induced dissociation. Photoelectron-photofragment coincidence experiments on HOCO(-) in particular have been used to study tunneling from the HOCO well to form H + CO2 products. In addition, new experimental insights into the OH + CO entrance channel for the reaction will be presented. These studies have provided a number of constraints on the potential energy surface for this system from an energetic and dynamical perspective, and have helped spur a renewed effort to characterize the global potential energy surface and reaction dynamics of this fundamental chemical reaction. Outstanding questions and new directions for future work on the HOCO radical will be discussed.


Quantitation of a spin polarization-induced nuclear Overhauser effect (SPINOE) between a hyperpolarized (13) C-labeled cell metabolite and water protons.
The spin polarization-induced nuclear Overhauser effect (SPINOE) describes the enhancement of spin polarization of solvent nuclei by the hyperpolarized spins of a solute. In this communication we demonstrate that SPINOEs can be observed between [1,4-(13) C2 ]fumarate, hyperpolarized using the dissolution dynamic nuclear polarization technique, and solvent water protons. We derive a theoretical expression for the expected enhancement and demonstrate that this fits well with experimental measurements. Although the magnitude of the effect is relatively small (around 2% measured here), the SPINOE increases at lower field strengths, so that at clinically relevant magnetic fields (1.5-3 T) it may be possible to track the passage through the circulation of a bolus containing a hyperpolarized (13) C-labeled substrate through the increase in solvent water (1) H signal.


Changes in extracellular action potential detect kainic acid and trimethyltin toxicity in hippocampal slice preparations earlier than do MAP2 density measurements.
In vitro electrophysiological techniques for the assessment of neurotoxicity could have several advantages over other methods in current use, including the ability to detect damage at a very early stage, and could further assist in replacing animal experimentation in vivo. We investigated how an electrophysiological parameter, the extracellularly-recorded compound action potential ("population spike", PS) could be used as a marker of in vitro neurotoxicity in the case of two well-known toxic compounds, kainic acid (KA) and trimethyltin (TMT). We compared the use of this electrophysiological endpoint with changes in immunoreactivity for microtubule-associated protein 2 (MAP2), a standard histological test for neurotoxicity. We found that both toxic compounds reliably caused disappearance of the PS, and that such disappearance occurred after only 1 hour of exposure to the drug. By contrast, densitometric measurements of MAP2 immunoreactivity were unaffected by both KA and TMT after such a short exposure time. We conclude that, in the case of KA and TMT, the extracellular PS was abolished at a very early time-point, when MAP2 immunoreactivity levels were still comparable to those of the untreated controls. Electrophysiology could be a reliable and early indicator of neurotoxicity, which could improve our ability to test for neurotoxicity in vitro, thus further replacing the need for in vivo experimentation.


Dual-plane in-line digital holography based on liquid crystal on silicon spatial light modulator.
A dual-plane in-line digital holographic method is proposed with a liquid crystal on silicon (LCOS) spatial light modulator (SLM) for recording holograms at two slightly displaced planes. The computer-generated chirp-like complex reflectance is displayed on the LCOS SLM to adapt the object beam at two planes for recording two holograms processed to eliminate the DC term and twin image accurately; no mechanical components or manual operation during data acquisition is required. The proposed approach improves the speed, accuracy, and stability of the experiment. Computer simulation and experiments for both amplitude and phase objects are carried out to validate the proposed method.


Reassessing the Role of Entamoeba gingivalis in Periodontitis.
The protozoan Entamoeba gingivalis resides in the oral cavity and is frequently observed in the periodontal pockets of humans and pets. This species of Entamoeba is closely related to the human pathogen Entamoeba histolytica, the agent of amoebiasis. Although E. gingivalis is highly enriched in people with periodontitis (a disease in which inflammation and bone loss correlate with changes in the microbial flora), the potential role of this protozoan in oral infectious diseases is not known. Periodontitis affects half the adult population in the world, eventually leads to edentulism, and has been linked to other pathologies, like diabetes and cardiovascular diseases. As aging is a risk factor for the disorder, it is considered an inevitable physiological process, even though it can be prevented and cured. However, the impact of periodontitis on the patient's health and quality of life, as well as its economic burden, are underestimated. Commonly accepted models explain the progression from health to gingivitis and then periodontitis by a gradual change in the identity and proportion of bacterial microorganisms in the gingival crevices. Though not pathognomonic, inflammation is always present in periodontitis. The recruitment of leukocytes to inflamed gums and their passage to the periodontal pocket lumen are speculated to fuel both tissue destruction and the development of the flora. The individual contribution to the disease of each bacterial species is difficult to establish and the eventual role of protozoa in the fate of this disease has been ignored. Following recent scientific findings, we discuss the relevance of these data and propose that the status of E. gingivalis be reconsidered as a potential pathogen contributing to periodontitis.


Occupational dust or gas exposure and prevalences of respiratory symptoms and asthma in a general population.
The relationship of occupational airborne, exposure to respiratory symptoms and asthma was examined using a self-administered questionnaire in a cross-sectional survey of a random sample (n = 4,992 subjects) of the general population aged 15-70 yrs of Hordaland county, Norway. The response rate was 90%. Twenty nine percent of the population had a history of occupational dust or gas exposure, 5% reported having been exposed to asbestos at work, and 4% reported quartz exposure. A history of occupational dust or gas exposure was associated with morning cough, chronic cough, phlegm when coughing, breathlessness on exercise, occasional wheezing and a physician's diagnosis of asthma after adjusting for sex, age, smoking habits and urban-rural area of residence. The adjusted relative odds ratios for the respiratory disorders in subjects exposed to dust or gas ranged from 1.6-1.9. The population attributable risk of occupational dust or gas exposure for the respiratory disorders ranged from 11-19%. The study indicates that respiratory disorders are independently associated with occupational airborne exposure in a Norwegian general population sample.