Family experiences of inpatient mental health care for people with dementia.
This study investigates family carers experiences of inpatient mental health care for people with dementia. A mental health inpatient admission for a person with dementia is usually considered when a person is distressed and this distress leads to behaviours that are assessed to be risky for the person or others. Participants included seven family carers whose relative with dementia had been cared for within a mental health ward in the United Kingdom UK within the last 5 years. Interviews were used to explore the circumstances that led to the admission, expectations of mental health care, and perceptions of care during the admission and support received by family carers. Participants described their distress at the time of admission and how the process of admission sometimes added to their distress. Carers often felt excluded from their relatives care in hospital and many felt a loss of their rights. Participants felt that the mental health admission had a negative impact on their relative with dementia. Mental health law and legislation was difficult to navigate and carers were concerned about how much knowledge and understanding of dementia staff have. Findings suggest that family carers may benefit from targeted support during their relatives admission. Mental health wards could do more to recognise the expertise in care and knowledge of the person with dementia of family carers and involve them in planning care. More research is needed to explore the experiences and outcomes of people with dementia during such admissions.


Airway epithelial integrity is protected by a long-acting beta2-adrenergic receptor agonist.
Airway epithelial integrity may be impaired by bacterial exoproducts, which are able to degrade tight junction-associated proteins such as zonula occludens 1 (ZO-1). We have investigated the protective effect of salmeterol, a long-acting beta(2)-adrenergic agonist, on Pseudomonas aeruginosa-induced alteration of the epithelial junctional barrier. We demonstrate in human airway epithelial cells (HAEC) that salmeterol induces a time-dependent increase in ZO-1 protein, although no significant change in ZO-1 transcripts was observed. When HAEC cultures were exposed to P. aeruginosa (PAO1) supernatants, apical expression of ZO-1 protein was maintained in salmeterol-pretreated HAEC cultures, whereas it disappeared after PAO1 exposure in cultures not pretreated with salmeterol. Western blot experiments showed that the 220-kD ZO-1 protein was decreased after PAO1 incubation but was still present in salmeterol-pretreated HAEC extracts. The functional activity of ZO-1 protein was monitored by measuring transepithelial resistance and analyzing the diffusion of a low molecular weight tracer through the intercellular spaces. After PAO1 incubation, the epithelial integrity of HAEC was impaired, as shown by a decrease in transepithelial resistance and increased paracellular permeability, but was not significantly altered after salmeterol preincubation. These results demonstrate that salmeterol may contribute to the protection of the airway epithelium barrier against bacterial virulence factors.


Genetic origin and success of reintroduced white storks.
After their local extinction in 1954, White Storks (Ciconia ciconia) were reintroduced to Sweden in 1989. The founder population for the reintroduced birds originated in North Africa, rather than from the closest breeding population in northeastern Europe (defined here as native). A number of wild storks have immigrated spontaneously, and a few others of native origin have been acquired for captive breeding. Over the 17 years, 103 of the 241 breeding events by free storks have been by pairs in which at least one parent had some native ancestry. The pedigree for all birds is known, and from this I calculated the proportion of native ancestry for each individual, the inbreeding coefficient, and the kinship between parents. I analyzed how these genetic factors, together with rainfall during breeding, supplementary feeding, and management of the storks (whether parents were born or raised in captivity or free), affected brood size. I also analyzed whether storks with native ancestry had a higher likelihood of migrating. Together with weather and supplementary feeding during the breeding period, genetic origin strongly affected breeding performance. Pairs with entirely native ancestry had on average twice as many chicks as those of entirely African ancestry. Inbreeding and kinship between parents, or management of the parents, did not influence breeding performance significantly. Reproductive success of the African storks in Sweden is so low that they cannot form a sustainable population. In addition, birds with some native ancestry were more likely to migrate from Sweden than those with entirely African ancestry. The difference in performance between native and African storks may be due either to local adaptations or to the bottleneck that the African founding population went through during captive breeding. Overall, my results imply that use of a correct source population for reintroduction programs may be of greater consequence for the program's success than other genetic considerations or management of individuals.


Self-efficacy estimates for drug use practices predict risk reduction among injection drug users.
We used baseline outcome efficacy (OE) estimates for human immunodeficiency virus (HIV) risk reduction to predict subsequent risk reduction 6 months hence among 792 injection drug users in a prospective study. Declines in drug use, frequency of injection, and needle sharing were found among those with high OE scores after adjustment for baseline behavior and antecedent factors. No OE effect was found in multivariate analysis for shooting gallery attendance, a risk that substantially declined in this cohort. OE for needle disinfection was associated with reduced drug risk behaviors, but not for improved needle hygiene practices over time. The self-efficacy model is useful in understanding psychological factors in risk reduction among injection drug users.


Significance of incidentally detected thyroid tissue in lymph nodes of neck dissections in patients with head and neck carcinoma.
The incidental discovery of thyroid tissue in lymph nodes of neck dissections performed for a separate primary head and neck cancer is an unusual clinical entity. Careful screening of large number of lymph nodes in the neck dissection specimens by the pathologist is critical in picking up such cases. There is controversy regarding clinical significance of such incidentally detected thyroid tissue in cervical nodes as to whether these represent benign inclusions or whether they represent metastatic focus of an underlying thyroid cancer. The appropriate clinical approach in such cases is less clear because it occurs in the context of another malignancy, usually squamous cell carcinomas with a more aggressive potential. On reviewing the records of 1602 neck dissections done in patients with head and neck cancers over the years 2007-2011, this study identified 5 patients with incidentally detected thyroid tissue with features of malignancy in cervical lymph nodes. Subsequent thyroidectomies done in 4 cases showed primary thyroid cancer. The study's results emphasize the need for the clinician to do an accurate reevaluation and follow-up of patients with incidental occult metastasis for detection of primary thyroid tumor. A thorough sampling and screening of lymph nodes in neck dissection specimens by the pathologist is also essential. Incidentally discovered thyroid tissue in cervical lymph nodes need not always be benign inclusions. Aggressive therapy, however, may not be needed in all cases.


Exposure to atmospheric pollutants is associated with alterations of gut microbiota in spontaneously hypertensive rats.
Atmospheric particulate matter with a diameter <2.5 µm (PM2.5) and pollution are worldwide environmental problems and may have negative effects on cardiovascular disease through the lung and gut. The dynamics of intestinal microflora in response to particulate pollutants is unclear. The present study investigated changes in the gut microbiota related to pollutant exposure using spontaneously hypertensive rats (SHR). DNA was extracted from fecal samples. Amplicon Generation and the quality control of PCR products were performed. PCR products was sequenced on an Illumina HiSeq 2500 platform. Data analysis included: operational taxonomic unit (OTU) clustering and species annotation, alpha diversity, beta diversity, principal coordinates analysis (PCoA), and the use of PICRUSt bioinformatics software. The microbial diversity of the SHR rats was inversely associated with exposure to pollutants. In terms of relative abundance, 24 bacterial genera and 2 genera in particular (Actinobacillus and Fusobacterium) significantly declined, and one genus (Treponema) increased. Moreover, pollutant exposure was associated with the accumulation of genes from the gut microbiota that are implicated in cardiovascular diseases. From the long-term exposure experiment, rats appeared to respond to pollutant injury. In conclusion, these results suggest that the effects of atmospheric pollutants on organisms are not limited to the respiratory tract, but also include the gastrointestinal tract. Pollutants are likely to influence the intestinal microbiota and promote the progression of cardiovascular disease.


Acute volume loading exacerbates direct ventricular interaction in a model of COPD.
Volume loading increases left ventricular (LV) stroke volume (LVSV) through series interaction, but may paradoxically reduce LVSV in the presence of large increases in right ventricular (RV) afterload because of direct ventricular interaction (DVI). RV afterload is often increased in chronic obstructive pulmonary disease (COPD) as a result of pathological changes to respiratory mechanics, namely increased negative intrathoracic pressure (nITP), dynamic lung hyperinflation (DH), and increased pulmonary vascular resistance (PVR). These hallmarks of COPD negatively impact LV hemodynamics in normovolemia. However, it is unknown how these heart-lung interactions are impacted by acute volume loading. Twenty healthy subjects (23 ± 2 yr) completed the study protocol, involving acute volume loading via 20° head-down tilt (HDT) in isolation and with 1) inspiratory resistance of -20 cmH2O (HDT+nITP) and 2) nITP, expiratory resistance to induce DH and hypoxic-mediated increases in PVR (HDT+COPD model). LV volumes and geometry were assessed using triplane echocardiography. HDT significantly increased LVSV by 10 ± 10% through an 8 ± 6% increase in LV end-diastolic volume (LVEDV). HDT+nITP paradoxically decreased LVSV by 11 ± 12% and LVEDV by 6 ± 9% from supine baseline, or -14 ± 10% LVSV and -15 ± 13% LVEDV from HDT (P < 0.001). HDT+COPD model decreased LVSV (21 ± 10% and 28 ± 11%) and LVEDV (16 ± 10% and 22 ± 10%) from both supine and HDT, respectively (P < 0.001). Under all conditions, significant septal flattening (increased radius of septal curvature) occurred, indicating DVI. Thus, when RV afterload is increased and/or an external constraint to ventricular filling exists, acute volume loading appears to paradoxically reduce LVSV. These findings have important implications for understanding how volume status impacts cardiopulmonary interactions in COPD.NEW & NOTEWORTHY Volume loading may exacerbate adverse cardiopulmonary interaction in COPD; however, the mechanisms remain unclear. We found that when negative intrathoracic pressure is increased, acute volume loading paradoxically reduces stroke volume. This reduction in stroke volume is considerably greater in a model of COPD, owing to the effects of lung hyperinflation.


Prey exoskeletons influence the course of gastric evacuation in Atlantic cod Gadus morhua.
This study examined the effects of prey exoskeleton characteristics on gastric evacuation patterns in Atlantic cod Gadus morhua. Three distinct stages were highlighted in the gastric evacuation of crustacean prey characterized by a robust exoskeleton. The experiments confirmed that the three shrimp species, Pandalus borealis, Pandalus montagui and Eualus macilentus, and the crab Chionoecetes opilio, were evacuated from the stomach at different rates. The duration of all stages increased with increasing ash (and carbonate) content of the fresh prey. Thickness, chemical composition and morphology of the prey exoskeleton all affected gastric evacuation: duration of initial delay, overall evacuation rate and a decreased evacuation rate at the end of the process. The power exponential function (PEF), with its shape parameter, described the course of evacuation for these prey types well, especially the initial delay. The PEF does not, however, allow describing evacuation by the current stomach content mass independent of meal size, which limits its usefulness in estimating consumption rates of wild G. morhua. To predict and describe gastric evacuation of prey with a robust exoskeleton, it is therefore suggested that the square-root function be expanded with an initial lag phase, coupled to the mechanistically based cylinder model of gastric evacuation.


Priapism, ecstasy, and marijuana: is there a connection?
Priapism is a urological emergency with multiple aetiologies including drug induced. Currently, there have been no reports of priapism induced by the combination of ecstasy and marijuana. We speculated on the potential mechanisms for acute drug-induced priapism resulting from ingestion of these two common illicit drugs.


Protecting patient safety and privacy in the era of artificial intelligence.
The promise of artificial intelligence (AI) in health care has propelled a significant uptrend in the number of clinical trials in AI and global market spending in this novel technology. In vascular surgery, this technology has the ability to diagnose disease, predict disease outcomes, and assist with image-guided surgery. As we enter an era of rapid change, it is critical to evaluate the ethical concerns of AI, particularly as it may impact patient safety and privacy. This is particularly important to discuss in the early stages of AI, as technology frequently outpaces the policies and ethical guidelines regulating it. Issues at the forefront include patient privacy and confidentiality, protection of patient autonomy and informed consent, accuracy and applicability of this technology, and propagation of health care disparities. Vascular surgeons should be equipped to work with AI, as well as discuss its novel risks to patient safety and privacy.


Developmental changes in the structure of the rat fetal lung, with special reference to the airway smooth muscle and vasculature.
Structural changes in the developing rat lung were studied by a combined use of light microscopy including immunohistochemistry for a-smooth muscle actin (alpha-SMA) and scanning electron microscopy (SEM) using the KOH-collagenase digestion method. In the embryonic stage (E11-E13), the lung bud appeared as an outgrowth from the ventral wall of the foregut which grew caudally into the splanchnic mesoderm to form a pair of bronchial buds at the end. At E13, the airway smooth muscle cells first appeared around the bifurcation of the trachea. These smooth muscle cells were restricted to the dorsal surface of the tracheal epithelium, suggesting a difference in character between the dorsal and ventral sides of the mesenchymal cells in this region. During the pseudoglandular stage (E13-E18.5), the bronchial buds repeatedly gave off branches in the mesenchymal tissue. The smooth muscle cells in the bronchioles were spindle-shaped and arranged completely circularly around the epithelial tube, except that the terminal bud of bronchioles lacked the smooth muscles. The neck of the terminal bud was constantly surrounded by flat and irregularly-shaped immature smooth muscle cells, representing an early event in the smooth muscle cell differentiation from mesenchymal cells. In the canalicular to saccular stages (E18.5 to birth), the terminals of bronchioles became saccular, thus forming prospective alveolar acini. At birth, the alveolar wall became thinner than before birth, and the individual smooth muscle cells in bronchioles were elongated like a tape. As to the blood vessel differentiation, various sized sinusoidal spaces indicating the primitive blood vessels were already present in the mesenchymal tissue at E11.5. The endothelial cells of these sinusoidal spaces were irregularly shaped and sometimes extended their processes into the lumen. The network of tubular vessels appeared from E14.5. These vessels had tapering ends as well as transluminal trabeculae, suggesting that capillary growth proceeds by both the sprouting and partitioning (i.e., intussusception) of vessels in the pseudoglandular stage.


Coexpression patterns of vimentin and glial filament protein with cytokeratins in the normal, hyperplastic, and neoplastic breast.
The authors studied by immunohistochemistry the intermediate filament (IF) protein profile of 66 frozen samples of breast tissue, including normal parenchyma, all variants of fibrocystic disease (FCD), fibroadenomas, cystosarcoma phylloides, and ductal and lobular carcinomas. Monoclonal antibodies (MAbs) to cytokeratins included MAb KA 1, which binds to polypeptide 5 in a complex with polypeptide 14 and recognizes preferentially myoepithelial cells; MAb KA4, which binds to polypeptides 14, 15, 16 and 19; individual MAbs to polypeptides 7, 13, and 16, 17, 18, and 19, and the MAb mixture AE1/AE3. The authors also applied three MAbs to vimentin (Vim), and three MAbs to glial filament protein (GFP). Selected samples were studied by double-label immunofluorescence microscopy and by staining sequential sections with some of the said MAbs, an MAb to alpha-smooth muscle actin, and well-characterized polyclonal antibodies for the possible coexpression of diverse types of cytoskeletal proteins. Gel electrophoresis and immunoblot analysis also were performed. All samples reacted for cytokeratins with MAbs AE1/AE3, although the reaction did not involve all cells. Monoclonal antibody KA4 stained preferentially the luminal-secretory cells in the normal breast and in FCD, whereas it stained the vast majority of cells in all carcinomas. Monoclonal antibody KA1 stained preferentially the basal-myoepithelial cells of the normal breast and FCD while staining tumor cell subpopulations in 4 of 31 carcinomas. Vimentin-positive cells were found in 8 of 12 normal breasts and in 12 of 20 FCD; in most cases, Vim-reactive cells appeared to be myoepithelial, but occasional luminal cells were also stained. Variable subpopulations of Vim-positive cells were noted in 9 of 20 ductal and in 1 of 7 lobular carcinomas. Glial filament protein-reactive cells were found in normal breast lobules and ducts and in 15 of 20 cases of FCD; with rare exceptions, GFP-reactivity was restricted to basally located, myoepithelial-appearing cells. Occasional GFP-reactive cells were found in 3 of 31 carcinomas. Evaluation of sequential sections and double-label immunofluorescence microscopy showed the coexpression of certain cytokeratins (possibly including polypeptides 14 and 17) with vimentin and alpha-smooth muscle actin together with GFP in some myoepithelial cells. The presence of GFP in myoepithelial cells was confirmed by gel electrophoresis and immunoblotting. Our results indicate that coexpression of cytokeratin with vimentin and/or GFP is comparatively frequent in normal basal-myoepithelial cells of the breast.(ABSTRACT TRUNCATED AT 400 WORDS)


The control of melanoma in New Zealand.
This study estimated the impact of prevention, screening, early diagnosis, and treatment on the burden of melanoma in New Zealand. Cancer control plans and management guidelines were reviewed to identify activities that could reduce the burden of melanoma in New Zealand and an estimation was made of their effects on incidence and mortality. The base year for estimating changes in incidence and mortality was the published melanoma data for 2002. The registration of melanoma increased from 1037 new registrations in 1993 to 1487 in 1994 and peaked at 1759 in 1995. In 2002 a further increase occurred, to 1842 new registrations and 235 deaths from melanoma. It is likely that 328 of the 1842 new cases of melanoma in 2002 were directly attributable to severe sunburn. A reduction of 10% in the number of people getting severely sunburnt could prevent 28 melanoma cases per year. If 2% of melanoma deaths occur in high-risk individuals, approximately 4 deaths per year could be prevented by surveillance of high-risk groups. Thin melanoma has a very good prognosis: a 10% shift in the depth distribution into the thinnest depth category would result in about 29 deaths from melanoma prevented each year. The best avenues for reducing the burden of melanoma in New Zealand are prevention of excessive sun exposure and early diagnosis. Reducing severe sunburn and diagnosing a greater proportion of melanomas when they are thin would have the greatest impact on the incidence of and mortality from melanoma.


Prevalence of Suicidality in the European General Population: A Systematic Review and Meta-Analysis.
To conduct a systematic review and meta-analysis of the prevalence and variability in suicidality in the general adult population of Europe between 2008 and 2017. Studies containing original data on suicidality were identified in five electronic databases. Point, 12-month and lifetime prevalences were calculated for various types of suicidality. Pooled prevalence rates were calculated using a random effects model. Subgroup analysis and multivariate meta-regression were also performed. We identified 24 papers containing original data, which provided 97 prevalence rates for suicidality. The pooled point prevalence rate was 3.96% (2.37-5.56), pooled 12-month prevalence 2.9% (1.49-4.32), and pooled lifetime prevalence 5.55% (4.31-6.79). The subgroup analysis showed that lifetime prevalence figures for wishing to be dead and suicidal ideation were higher in areas with a population of less than 3,849 inhabitants and in Eastern Europe. Finally, the multivariate meta-regression showed differences with respect to the period and type of suicidality, lower and upper age thresholds, population size, and study area. Our data showed that approximately 21% of European individuals have wished to be dead at some point during their lifetime. Studies like this are necessary to highlight the need for efforts to prevent and intervene in suicidality.


Probing catalytic hinge bending motions in thermolysin-like proteases by glycine --> alanine mutations.
The active site of thermolysin-like proteases (TLPs) is located at the bottom of a cleft between the N- and C-terminal domains. Crystallographic studies have shown that the active-site cleft is more closed in ligand-binding TLPs than in ligand-free TLPs. Accordingly, it has been proposed that TLPs undergo a hinge-bending motion during catalysis resulting in "closure" and "opening" of the active-site cleft. Two hinge regions have been proposed. One is located around a conserved glycine 78; the second involves residues 135 and 136. The importance of conserved glycine residues in these hinge regions was studied experimentally by analyzing the effects of Gly --> Ala mutations on catalytic activity. Eight such mutations were made in the TLP of Bacillus stearothermophilus (TLP-ste) and their effects on activity toward casein and various peptide substrates were determined. Only the Gly78Ala, Gly136Ala, and Gly135Ala + Gly136Ala mutants decreased catalytic activity significantly. These mutants displayed a reduction in kcat/Km for 3-(2-furylacryloyl)-L-glycyl-L-leucine amide of 73%, 62%, and 96%, respectively. Comparisons of effects on kcat/Km for various substrates with effects on the Ki for phosphoramidon suggested that the mutation at position 78 primarily had an effect on substrate binding, whereas the mutations at positions 135 and 136 primarily influence kcat. The apparent importance of conserved glycine residues in proposed hinge-bending regions for TLP activity supports the idea that hinge-bending is an essential part of catalysis.


Dexfenfluramine: effects on food intake in various animal models.
The effects of dexfenfluramine on food intake of rats are compared and contrasted among several paradigms. Paradigms that involve overfeeding rather than deprivation, show a greater effect of the agent. Furthermore, both stress-induced eating as well as a food-motivated response (running) are particularly sensitive to inhibition by dexfenfluramine. The results of chronic administration of dexfenfluramine on both behavior and neurochemistry are reviewed, with particular reference to brain 5-HT. The effects of dexfenfluramine on diet selection and conditioned preferences are discussed. Finally, we suggest that species differences may exist in either the neurochemical and/or behavioral responses to dexfenfluramine.


A TEM study on melt-crystallized poly(butylene terephthalate).
A study was made to investigate an optimum condition for ruthenium tetraoxide staining of poly(butylene terephthalate) (PBT) with glass transition temperature as low as ca. 23 degrees C for TEM observation of melt-grown PBT crystals. The morphological study of ultrathin sections prepared based on optimum staining at 25 degrees C for 8 h revealed formation of fringed-micellar crystal nuclei in the early stage and folded-chain fringed-micellar crystals in the later stage of isothermal crystallization at 40 degrees C from melt. The fraction of chain-folded crystals increased with increasing crystallization temperature from the quantitative analysis of crystal thickness in comparison with the reported morphology using the replica method.


Role vs. entry-level competencies in competency-based education.
The real strength of the competency-based education effort lies in its emphasis on the total program. No longer can we, as educators, ask ourselves merely: "What do I want students to learn in my course?" The studies and learning opportunities of students must meet specific objectives developed on assessed needs in the profession. The resulting output can then be evaluated against standards or a set of criteria. Since implementation of a competency-based education program requires "adaptation rather than adoption," both the role-competency and entry-level approaches are valuable. Few professionals are willing to accept totally a program or syllabus developed by someone else. However, effective adaptation requires understanding of the total concept of competency-based education. In fact, the search for totality is the heart of the competency-based movement. By viewing the framework of competency-based education and thoroughly understanding all of the components of the program, professionals should be able to utilize the ideas of others, even though they are presented in varying formats with constantly changing semantics.


Brownian dynamics simulations of simplified cytochrome c molecules in the presence of a charged surface.
Simulations were performed for up to 150 simplified spherical horse heart cytochrome c molecules in the presence of a charged surface, which serves as an approximate model for a lipid membrane. Screened electrostatic and short-ranged attractive as well as repulsive van der Waals forces for interparticle and particle-membrane interactions are utilized in the simulations. At a distance from the membrane, where particle-membrane interactions are negligible, the simulation is coupled to a noninteraction continuum analogous to a heat bath [Geyer et al., J. Chem. Phys. 120, 4573 (2004)]. From the particles' density profiles perpendicular to the planar surface binding isotherms are derived and compared to experimental results [Heimburg et al. (1999)]. Using a negatively charged structureless membrane surface a saturation effect was found for relatively large particle concentrations. Since biological membranes often contain membrane proteins, we also studied the influence of additional charges on our model membrane mimicking bacterial reaction centers. We find that the onset of the saturation occurs for much lower concentrations and is sensitive to the detailed implementation. Therefore we suggest that local distortion of membrane planarity (undulation), or lipid demixing, or the presence of charged integral membrane proteins create preferential binding sites on the membrane. Only then do we observe saturation at physiological concentrations.


Inhibition of Wnt signalling dose-dependently impairs the acquisition and expression of amphetamine-induced conditioned place preference.
The mechanisms by which dopaminergic neurotransmission in the nucleus accumbens (NAc) is involved in incentive learning produced by rewarding stimuli remain unclear. Recently, Wnt signalling has been implicated in synaptic plasticity and learning and memory. Functional interactions between Wnt and dopamine (DA) signalling has been demonstrated using in vitro and tissue physiology approaches, however there remains a lack of in vivo research into the involvement of Wnt in DA-mediated learning in behaving animals. The present study assessed the role of Wnt signalling in DA-mediated incentive learning using the conditioned place preference (CPP) paradigm. We hypothesized that inhibition of Wnt with intra-NAc microinjections of Wnt palmitoylation inhibitor IWP-2 will dose-dependently block the acquisition and expression of amphetamine (AMPH)-induced CPP in rats. Intra-NAc IWP-2 (0.001, 0.05, 1.0 but not 0.0001μg/0.5μl/side) prior to conditioning with AMPH (20.0μg/0.5μl/side) blocked acquisition of CPP. Intra-NAc IWP-2 (0.05, 0.5, 1.0 but not 0.001μg/0.5μl/side) during test following conditioning with AMPH blocked expression but at a higher dose than was need to block acquisition. Sensitization of locomotor activity to AMPH was observed during conditioning and this effect was blocked in groups given IWP-2 prior to AMPH. However, intra-NAc IWP-2 during conditioning did not block the locomotor stimulant effects of AMPH. These results implicate Wnt in DA-mediated incentive learning and suggest that Wnt signalling may be more important for the acquisition of CPP then for its expression. However, mechanisms by which Wnt and DA signalling pathways interact to influence DA-mediated reward-related learning remain to be elucidated.


Histological heterogeneity in primary and metastatic classic combined hepatocellular-cholangiocarcinoma: a case series.
Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare and aggressive primary liver cancer with both hepatocellular and cholangiocellular differentiation. Due to its bi-phenotypic component, cHCC-CC is a heterogeneous tumour and histopathological analysis of metastatic deposits is poorly characterized. In this retrospective study, we describe four patients in whom the histology from resected specimens of both primary and recurrent and/or metastatic tumour was available for comparison and immunohistochemical characterization. Our study shows that recurrent or metastatic deposits replicate the heterogeneity of the primary cHCC-CC, that even originally small foci of divergent differentiation can become predominant later on and that hepatocellular and cholangiocellular components can show different tropism in distant organs. In our experience, the behaviour of recurrent/metastatic cHCC-CC is unpredictable and histological examination is necessary to guide treatment options at present.


White matter abnormalities in major depression: a tract-based spatial statistics and rumination study.
Increasing evidence indicates that major depressive disorder (MDD) is usually accompanied by altered white matter in the prefrontal cortex, the parietal lobe and the limbic system. As a behavioral abnormity of MDD, rumination has been believed to be a substantial indicator of the mental state of the depressive state. So far, however, no report that we are aware of has evaluated the relationship between white matter alterations and the ruminative state. In this study, we first explored the altered white matter using a tract-based spatial statistics (TBSS) method based on diffusion tensor imaging of 19 healthy and 16 depressive subjects. We then investigated correlations between the altered white matter microstructure in the identified altered regions and the severity of ruminations measured by the ruminative response scale. Our results demonstrated altered white matter microstructure in circuits connecting the prefrontal lobe, the parietal lobe and the limbic system (p<0.005, uncorrected), findings which support previous research. More importantly, the result also indicated that a greater alteration in the white matter is associated with a more ruminative state (p<0.05, Bonferroni corrected). The detected abnormalities in the white matter should be interpreted cautiously because of the small sample size in this study. This finding supports the psychometric significance of white matter deficits in MDD.


Cell choice for bioartificial livers.
It is unlikely that human hepatocytes can be isolated on a scale sufficient to treat more than a fraction of the patients who need bioartificial liver (BAL) treatment. The use of animal cells results in the concerns related to the transmission of infectious pathogens and immunologic and physiologic incompatibilities between the donor and humans. Human embryonic stem cells and bone marrow multipotent adult progenitor cells have received great attention as a possible source for BALs. The use of tightly regulated clonal hepatocyte cell lines would be attractive. Such cell lines grow economically in tissue culture and provide the advantage of uniformity, sterility, and freedom of pathogens. In this paper, the authors review the choice of cells for BALs and discuss our reversible immortalization system of human liver cells using a retroviral transfer of immortalizing genes and subsequent Cre/loxP-mediated site-specific recombination.


Histiocyte X positivity for nonspecific esterase.
The cell membrane and X bodies of histiocytes X from two cases of eosinophilic granuloma were stained by nonspecific esterase. The results show that histiocytes X possess a cell membrane exoenzyme similar to that of other histiocytes, such as alveolar macrophages, but the role of the X body as related to enzyme activity remains an unknown.


Development of learning facilitation roles for unregistered practitioners.
This article describes how unregistered practitioners, such as healthcare assistants and community-based mental health workers, can contribute to the learning, support and development of pre-registration nursing students in clinical practice. It presents the results of an unregistered practitioner co-mentoring scheme piloted in a mental health trust, and demonstrates its benefits for nursing students, unregistered practitioners and nurse mentors. The scheme delivers training and supervision for unregistered practitioners who are starting a formal role in clinical learning. It aims to recognise and develop the contribution of unregistered practitioners to student learning, and to enhance the learning environments in which nursing students train.


Taurine in development.
Taurine is a ubiquitous dietary constituent of most mammals and is present in especially high concentrations in the tissues of developing mammals. Research to date indicates that taurine plays an important role in the development of the nervous system and the process of migration in particular. It is speculated that taurine uptake and release, in conjunction with glutamate uptake and release, may represent one form of communication between neurons and glial cells. The need of taurine by the body is emphasized by the ability of the kidney to curtail taurine excretion to conserve taurine in the face of a low dietary taurine intake. The evidence for a special role of taurine in development is considered and discussed.


[Frequent use of psychiatric inpatient services analysed from three different perspectives].
Frequent utilization of psychiatric inpatient care was mainly analysed by quantitative methods. The present study combines quantitative with qualitative methods and discusses the results obtained from these different perspectives. The quantitative analysis is based on data from 184 schizophrenia patients, who were observed over a period of 2(1/2) years. Twenty of the identified frequent users and 6 employees of psychiatric facilities were interviewed by means of qualitative methods as to the causes of frequent use of inpatient care. Predictors of frequent use identified in the quantitative study were found again in the qualitative analysis. Opportunities for alternative care for frequent users suggested by the staff of psychiatric facilities include social treatment in the community, day structuring activities and sheltered work. Patients consider work, compliance securing and better contact with office based psychiatrists to be important factors. Patients and staff give different priorities to their suggestions for interventions, but are, in most cases, of the opinion, that part of hospital admissions of frequent users could be avoidable by means of alternative services.


Estimating tissue-specific discrimination factors and turnover rates of stable isotopes of nitrogen and carbon in the smallnose fanskate Sympterygia bonapartii (Rajidae).
This study aimed to estimate trophic discrimination factors (TDFs) and metabolic turnover rates of nitrogen and carbon stable isotopes in blood and muscle of the smallnose fanskate Sympterygia bonapartii by feeding six adult individuals, maintained in captivity, with a constant diet for 365 days. TDFs were estimated as the difference between δ(13) C or δ(15) N values of the food and the tissues of S. bonapartii after they had reached equilibrium with their diet. The duration of the experiment was enough to reach the equilibrium condition in blood for both elements (estimated time to reach 95% of turnover: C t95%blood = 150 days, N t95%blood = 290 days), whilst turnover rates could not be estimated for muscle because of variation among samples. Estimates of Δ(13) C and Δ(15) N values in blood and muscle using all individuals were Δ(13) Cblood = 1·7‰, Δ(13) Cmuscle = 1·3‰, Δ(15) Nblood = 2·5‰ and Δ(15) Nmuscle = 1·5‰, but there was evidence of differences of c.0·4‰ in the Δ(13) C values between sexes. The present values for TDFs and turnover rates constitute the first evidence for dietary switching in batoids based on long-term controlled feeding experiments. Overall, the results showed that S. bonapartii has relatively low turnover rates and isotopic measurements would not track seasonal movements adequately. The estimated Δ(13) C values in S. bonapartii blood and muscle were similar to previous estimations for elasmobranchs and to generally accepted values in bony fishes (Δ(13) C = 1·5‰). For Δ(15) N, the results were similar to published reports for blood but smaller than reports for muscle and notably smaller than the typical values used to estimate trophic position (Δ(15) N c. 3·4‰). Thus, trophic position estimations for elasmobranchs based on typical Δ(15) N values could lead to underestimates of actual trophic positions. Finally, the evidence of differences in TDFs between sexes reveals a need for more targeted research.


Quantitative analysis of the optic nerve of the horse (Thoroughbred).
Three optic nerves (L1, R2, R3) 12-18 mm behind the eyeball of the horse (Thoroughbred) were investigated quantitatively under light and electron microscopes. Thin sections at the thickness of 0.35 microm were cut, stained by toluidine blue and observed under the light microscope. The areas of the optic nerve and the axon bundles were 20.03 +/- 1.04 and 16.59 +/- 0.79 mm2 (mean +/- SD, n=3), respectively. The axon numbers for optic nerve L1, R2 and R3, estimated from light micrographs, were about 481 x 10(3), 543 x 10(3), and 494 x 10(3), respectively. Axons of optic nerve L1 were also counted from electron micrographs and the total number of 488 x 10(3) was received. Furthemore, axon diameters of optic nerve L1 were also measured from electron micrographs. The diameter of a circle with the same peripheral length as an axon, was regarded as its diameter. The medullary sheath of the axon was not included during measuring. Altogether 5,744 axons were measured and axon diameters were in a range of 0.23-12.69 microm, with a mean of 2.56 +/- 1.45 microm (mean +/- SD). A regional difference of axonal diameters was found across the optic nerve: the mean diameter of axons in the centrodorsal region (2.28 microm) was the smallest, and had significant difference with those in several peripheral regions (P<0.05).


Practical, modular, and general synthesis of 3-coumaranones through gold-catalyzed intermolecular alkyne oxidation strategy.
A gold-catalyzed intermolecular alkyne oxidation for the preparation of 3-coumaranones has been developed. Using 8-isopropylquinoline N-oxides as oxidants, the reactions of o-ethynylanisoles afford versatile 3-coumaranones in moderate to good isolated yields. The synthetic utility of this chemistry is also indicated by the synthesis of the natural product sulfuretin.


RepeatAnalyzer: a tool for analysing and managing short-sequence repeat data.
Short-sequence repeats (SSRs) occur in both prokaryotic and eukaryotic DNA, inter- and intragenically, and may be exact or inexact copies. When heterogeneous SSRs are present in a given locus, we can take advantage of the pattern of different repeats to genotype strains based on the SSRs. Cataloguing and tracking these repeats can be difficult as diverse groups of researchers are involved in the identification of the repeats. Additionally, the task is error-prone when done manually. We developed RepeatAnalyzer, a new software tool capable of tracking, managing, analysing and cataloguing SSRs and genotypes using Anaplasma marginale as a model species. RepeatAnalyzer's analysis capability includes novel metrics for measuring regional genetic diversity (corresponding to variety and regularity of SSR occurrence). As a part of its visualization capabilities, RepeatAnalyzer produces high quality maps of the geographic distribution of genotypes or SSRs over a region of interest. RepeatAnalyzer's repeat identification functionality was validated for all SSRs and genotypes reported in 21 publications, using 380 A. marginale isolates gathered from the five publications within that list that provided access to their isolates. The tool produced accurate genotyping results in every case. In addition, it uncovered a number of errors in the published literature: 11 cases where SSRs were misreported, 5 cases where two different SSRs had been given the same name, and 16 cases where two or more names had been given to a single SSR. The analysis and visualization functionalities of the tool are demonstrated using several examples. RepeatAnalyzer is a robust software tool that can be used for storing, managing, and analysing short-sequence repeats for the purpose of strain identification. The tool can be used for any set of SSRs regardless of species. When applied to A. marginale, our test case, we show that genotype lengths for a given region follow a normal distribution, while SSR frequencies follow a power-law-like distribution. Further, we find that over 90 % of repeats are 28 to 29 amino acids long, which is in agreement with conventional wisdom. Lastly, our analysis reveals that the most common edit distance is five or six, which is counter-intuitive since we expected that result to be closer to one, resulting from the simplest change from one repeat to another.


Transient increase in insulin-like growth factor I immunoreactivity in rat peripheral nerves exposed to vibrations.
Hind legs of adult rats were exposed to vibrations (81 Hz; amplitude 0.50 mm peak to peak) for 4 h during two consecutive days. The sciatic, tibial and plantar nerves were isolated and processed for immunohistochemical demonstration of IGF-I (insulin-like growth factor I; somatomedin C) immunoreactivity at different time intervals after the vibration exposure. In sham-exposed rats the axons in peripheral nerves showed no or faint IGF-I immunoreactivity while most Schwann cells were negative. Exposure of the hind legs to vibrations induced increased IGF-I immunoreactivity in the Schwann cells, demonstrable at the end of the exposure period and reaching maximal intensity 2-3 days after vibration exposure. Several distended axons similarly showed increased staining. The IGF-I immunoreactivity decreased after 7-10 days to almost the level in the control nerves. The most extensive changes were observed in the plantar nerves. The tibial nerves similarly expressed strongly increased IGF-I immunoreactivity in their Schwann cells. The sciatic nerve showed, however, only slightly to moderately increased staining. Cells in the epineurium of the plantar and, to a limited extent, of the tibial nerves expressed concomitantly increased IGF-I immunoreactivity. We conclude that the transiently increased IGF-I immunoreactivity in peripheral nerves reflects reactive changes caused by vibrations and most prominently expressed by the Schwann cells.


Estimating exposures from spray products using robotic simulations.
There is an increasing need for exposure data to enable more precise information for risk estimates and improved public health protection. While personal monitoring data are preferred, it is often difficult to collect due to the resources needed to complete a human research study. In this study, we successfully programmed a robotic arm to mimic human use (spraying) of a fabric crafts protector (FCP) and human cleaning (spraying and wiping) of a glass pane with glass cleaner (GC). The robot was then used in place of human subjects to assess inhalation exposures to volatile organic compounds (VOCs) during the use of the FCP and GC. Air sampling data were collected while the robot used the products to estimate personal exposures to VOCs. Average VOC concentrations were 1.57 ppm for FCP spraying and 0.17 ppm for GC spraying and wiping. During FCP spraying, average acetone concentrations were 0.88 ppm and average isopropyl alcohol concentrations were 0.26 ppm. During GC spraying and wiping, average 2-butoxyethanol concentrations were 0.15 ppm. Air sampling data were found to be within the range of data reported in the literature during human use of similar glass cleaning products. No data was found in the literature during use of fabric protector spray products. This study contributes exposure measurement data with detailed contextual information to help characterize inhalation exposures during the use of 2 spray products. In addition, the study offers a systematic, efficient method for generating exposure data which can be used to improve health and safety risk assessments used for public health protection.


Reducible or irreducible? Mathematical reasoning and the ontological method.
Science is often described as nothing but the practice of measurement. This perspective follows from longstanding respect for the roles mathematics and quantification have played as media through which alternative hypotheses are evaluated and experience becomes better managed. Many figures in the history of science and psychology have contributed to what has been called the "quantitative imperative," the demand that fields of study employ number and mathematics even when they do not constitute the language in which investigators think together. But what makes an area of study scientific is, of course, not the mere use of number, but communities of investigators who share common mathematical languages for exchanging quantitative and quantitative value. Such languages require rigorous theoretical underpinning, a basis in data sufficient to the task, and instruments traceable to reference standard quantitative metrics. The values shared and exchanged by such communities typically involve the application of mathematical models that specify the sufficient and invariant relationships necessary for rigorous theorizing and instrument equating. The mathematical metaphysics of science are explored with the aim of connecting principles of quantitative measurement with the structures of sufficient reason.


Chemotherapy and combined modality therapy for Hodgkin's disease: a progress report on Cancer and Leukemia Group B studies.
Between 1974 and 1977, the Cancer and Leukemia Group B (CALGB) initiated four studies which address current major questions in the therapy for Hodgkin's disease. The efficacy of chemotherapy alone as compared with combined modality therapy in patients with poor-prognostic stages I and II is evaluated in CALGB 7751. Currently, both therapies produce very high complete remission rates in asymptomatic patients; the remission rate is better with combined modality therapy in symptomatic patients. Single and combined modality therapies are compared for stage III patients in CALGB 7451. Complete remission rates have been similar, but relapse-free survival is superior for patients treated with local nodal radiotherapy followed by chemotherapy (P = 0.04). In particular, stage IIIA patients with nodular sclerosis seem to benefit from the inclusion of radiotherapy in their initial treatment. In CALGB 7551, the efficacy of chemotherapy alone versus chemotherapy plus radiotherapy to areas of bulky disease is under study in patients with stages IIIB and IV. Currently, a relapse rate of less than 10% has been seen among sites irradiated, and survival is best for patients treated with radiotherapy bracketed by chemotherapy. Finally, the role of two alternating non-cross-resistant combination chemotherapy programs is being studied in CALGB 7552. Relapse-free and overall survival is better with the doxorubicin-containing regimen than with either the alternating or alternate chemotherapy program. At present, the median followup for each of these studies is less than 5 years. Further observation is required to answer the critical questions relating to prolonged disease-free survival and cure.


Ocular adnexal lymphoma associated with IgG4+ chronic sclerosing dacryoadenitis: a previously undescribed complication of IgG4-related sclerosing disease.
IgG4-related sclerosing disease is a recently recognized inflammatory lesion frequently involving pancreas, submandibular gland, lacrimal gland, and lymph node. We report 3 cases of ocular adnexal lymphoma arising in IgG4-related chronic sclerosing dacryoadenitis, a phenomenon that has not been previously reported. The patients presented with bilateral or unilateral ocular adnexal mass usually present for many years. One patient also had asymptomatic diffuse lymphadenopathy. Two patients had biopsy-proven IgG4-related chronic sclerosing dacryoadenitis before the current presentation, and 1 had systemic involvement by IgG4-related sclerosing disease as evidenced by increased IgG4+ cells in a prior nasopharyngeal biopsy. Two cases showed features of extranodal marginal zone lymphoma of mucosa-associated lymphoid-tissue type (1 with large cell transformation) and 1 follicular lymphoma. Thus, the lymphoid hyperplasia of IgG4-related sclerosing disease can provide a substrate for the emergence of lymphoma. In addition, we report 3 cases of ocular adnexal extranodal marginal zone B-cell lymphoma that show sclerosing inflammation in the background and numerous IgG4+ monotypic plasma cells. In the absence of prior biopsies or information on serum IgG4 titer, it is unclear whether these cases represent lymphoma complicating IgG4-related sclerosing disease or de novo lymphoma. Nonetheless, these cases are distinctive in that the neoplastic cells express IgG4 (light chain restricted), whereas unselected cases of ocular adnexal lymphomas do not show IgG4 expression.


Coumarins and pyranocoumarins, potential novel pharmacophores for inhibition of measles virus replication.
A series of coumarin and pyranocoumarin analogues were evaluated in vitro for antiviral efficacy against measles virus (MV), strain Chicago. Of the 22 compounds tested for inhibition, six were found to have selectivity indices greater than 10. These were compounds 5-hydroxy-7-propionyloxy-4-propylcoumarin (2a), 5,7-bis(tosyloxy)-4-propylcoumarin (7); 5-hydroxy-4-propyl-7-tosyloxy-coumarin (8); 6,6-dimethyl-9-propionyloxy-4-propyl-2H,6H-benzo[1,2-b:3,4-b']dipyran-2-one (9); 6,6-dimethyl-9-pivaloyloxy-4-propyl-2H,6H-benzo[1,2-b:3,4-b']dipyran-2-one (10); and 7,8-cis-10,11,12-trans-4-propyl-6,6,10,11-tetramethyl-7,8,9-trihydroxy-2H,6H,12H-benzo[1 ,2-b:3,4-b':5,6-b'']tripyran-2-one (18). Three of the active drugs were propyl coumarin analogues (2a, 7 and 8), two were dipyranone or chromeno-coumarins (9 and 10), and one was a benzotripyranone with a coumarin nucleus (18). Some appeared to be rather specific and potent inhibitors of MV with EC50 values ranging from 0.2 to 50 microg/ml and the majority of the EC50 values being less than 5 pg/ml. The compounds inhibited an additional nine strains of MV, and in virucidal tests the drugs did not physically disrupt the virion to inhibit virus replication. The inhibitory activity for one of the compounds tested (7) was somewhat dependent on virus concentration and it was still active when added to cells up to 24 h after virus exposure. When used in combination with ribavirin, compound 7 appeared not to profoundly affect the antiviral efficacy of ribavirin or its cell-associated toxicity. However, a slightly antagonistic MV-inhibitory effect was observed at the highest concentration of ribavirin used in combination with most concentrations of compound 7 tested. This and related compounds may be valuable leads in the development of a potent and selective class of MV inhibitors that could be used in future in the clinic.


[Frequent episodic migraine and calcitonin gene-related peptide. Influence of treatment with topiramate and zonisamide on levels of the peptide].
The pathophysiology of pain in migraine is related to the activation of the trigeminovascular system by releasing vasoactive neuropeptides, the most important of which is calcitonin gene-related peptide (CGRP), which causes a neurogenic inflammation in the leptomeningeal vessels. To study whether CGRP is increased in frequent episodic migraine and whether preventive treatment with topiramate or zonisamide modifies its levels. We studied 28 patients with episodic migraine with or without aura, in accordance with the International Headache Society criteria, with a frequency of 4-14 days/month. Plasma levels of CGRP were determined in all the patients during an interictal period (> 72 hours without pain). Patients were divided at random into two treatment groups, one with 50 mg/day of topiramate and the other with 50 mg/day of zonisamide, for three months. At the end of the active period the CGRP level was analysed again. The control group consisted of nine healthy subjects. CGRP was significantly higher in the episodic migraine group than in the control group (50.61 ± 22.5 pg/mL versus 34.96 ± 17.03 pg/mL; p = 0.037). After treatment with neuromodulators no significant differences were found in the level of CGRP (46.11 ± 24.2 pg/mL basal versus 47.5 ± 24.88 pg/mL post-treatment). Neither were any differences found on analysing the topiramate and zonisamide groups individually. The plasma level of CGRP is increased in episodic migraine, and its levels are not modified by treatment with low doses of topiramate or zonisamide.


Dendritic cell immunotherapy for stage IV melanoma.
Active boosting of the antitumour immune response of patients with solid malignancies has been tested in a large number of trials. Isolated complete clinical responses have been reported, however, they have not been replicated in subsequent studies. We recently reported objective clinical responses to a dendritic cell/irradiated autologous tumour cell 'vaccine' in patients with distant metastatic (stage IV) melanoma. Here we describe our experience in a second cohort of patients with stage IV melanoma, using this dendritic cell-based immunotherapy in a cryopreserved format. Of 46 patients enrolled into the study, three had complete remission of all detectable disease, and a further three had partial clinical responses. These data confirm that dendritic cell-based immunotherapy has potential as a therapy in a limited number of patients with stage IV melanoma. To our knowledge, this is the first demonstration that cryopreserved dendritic cells can elicit complete clinical responses in patients with advanced cancer. Our observations support randomized controlled trials to validate the findings.


Nitration modifying function of proteins, hormones and neurotransmitters.
Several lines of evidence have been accumulated for occurrence of nitration in vivo. In this brief review, we summarized nitration studies on functional changes of proteins, hormones and neurotransmitters, before as well as after the discovery of peroxynitrite. Most of nitrated molecules exhibit less active properties than the parental compounds. It is still unknown whether nitration is merely a footprint of oxidative stress, an important pathway of nitric oxide metabolisms or a part of integral processes for maintaining cellular homeostasis.


Sensitivity enhancement and fringe reduction in tunable diode laser spectroscopy using hemispherical diffusers.
The use of diffuse, highly reflective optical components, in particular, a hemispherical BaSO4 diffuser, at the point of light injection into non-transparent or turbid media was evaluated as a means to increase the measurement sensitivity of spectroscopic absorption measurements. By performing the light injection from, e.g., an optical fiber through a component designed to make the light diffuse and to reflect (and thereby re-inject) light scattered from the sample, the total amount of light delivered into the sample is increased. Further, the occurrence of possible interference fringes is strongly reduced.


Statistics of current-activity fluctuations in asymmetric flow with exclusion.
We consider steady-state current activity statistics for the one-dimensional totally asymmetric simple exclusion process. With the help of the known operator algebra (for general open boundary conditions), as well as general probabilistic concepts (for the periodic case), we derive and evaluate closed-form expressions for the lowest three moments of the probability distribution function. These are confirmed, to excellent degree of accuracy, by numerical simulations. Further exact expressions and asymptotic approximations are provided for probability distributions and generating functions.


Scapular angular positioning at end range internal rotation in cases of glenohumeral internal rotation deficit.
Controlled laboratory study. Investigate the relationship between glenohumeral internal rotation range-of-motion deficit and 3-dimensional scapular angular positioning during active arm movements in participants with recent participation in overhead sports activity. Subacromial impingement is one of the most common shoulder pathologies and is multifactorial in etiology. Posterior glenohumeral joint capsule tightness has been theorized to contribute to one potential causal factor: abnormal scapular positioning. Twenty-three subjects, who had participated in competitive sports involving overhead activity within the last 5 years, were categorized into 2 groups based on the degree of glenohumeral internal rotation deficit (20% deficit threshold). Scapular angular positioning of subjects performing shoulder internal rotation from 90 degrees flexion and abduction shoulder positions was evaluated using 3-dimensional electromagnetic surface tracking. Additional sensors monitored trunk and humeral motion. Scapular position data at end range glenohumeral internal rotation, along with glenohumeral internal rotation range of motion measurements, were used to analyze the relationship between glenohumeral internal rotation deficit and scapular position using 2-way ANOVA and regression analyses. The internal rotation deficit group had significantly greater scapular anterior tilt (9.2 degrees difference, P = .04) across positions, as compared to the control group. Regression analysis demonstrated a significant association between glenohumeral internal rotation deficit and scapular position (tilting) during flexed internal rotation (r(2) = 0.37, P = .03) and for scapular position (anterior tilting and upward rotation) during abducted internal rotation (r = 0.35, P = .036). These findings demonstrate a significant relationship between glenohumeral internal rotation deficit and abnormal scapular positioning, particularly increased anterior tilt. This relationship identifies a possible mechanism for development of excessive scapular anterior tilt.


HPV16-E2 induces prophase arrest and activates the cellular DNA damage response in vitro and in precursor lesions of cervical carcinoma.
Cervical intraepithelial neoplasia (CIN) is caused by human papillomavirus (HPV) infection and is the precursor to cervical carcinoma. The completion of the HPV productive life cycle depends on the expression of viral proteins which further determines the severity of the cervical neoplasia. Initiation of the viral productive replication requires expression of the E2 viral protein that cooperates with the E1 viral DNA helicase. A decrease in the viral DNA replication ability and increase in the severity of cervical neoplasia is accompanied by simultaneous elevated expression of E6 and E7 oncoproteins. Here we reveal a novel and important role for the HPV16-E2 protein in controlling host cell cycle during malignant transformation. We showed that cells expressing HPV16-E2 in vitro are arrested in prophase alongside activation of a sustained DDR signal. We uncovered evidence that HPV16-E2 protein is present in vivo in cells that express both mitotic and DDR signals specifically in CIN3 lesions, immediate precursors of cancer, suggesting that E2 may be one of the drivers of genomic instability and carcinogenesis in vivo.


Analysis of the 206M polymorphic variant of the SLC26A6 gene encoding a Cl- oxalate transporter in patients with primary hyperparathyroidism.
Primary hyperparathyroidism (PHPT) is often complicated by kidney stones. Hypercalciuria and urine oxalate excretion are considered risk factors for urolithiasis in PHPT as well as in idiopathic stone-formers. Recently, the anion-exchanger SLC26A6 has been involved in the oxalate metabolism. We tested the hypothesis that the 206M polymorphic variant of SLC26A6 gene might contribute to the risk of kidney stones in PHPT. DNA samples from 145 PHPT patients and 129 age- and sex-matched healthy subjects were genotyped. The homozygous 206V genotype was the most frequent both in PHPT patients and controls (79.3 and 74.4%), while heterozygosity for the 206M allele was detected in 20.0 and 23.3% respectively. The homozygous 206M genotype was extremely rare, occurring in 0.7 and 2.3% of PHPT and healthy subjects respectively. In the PHPT cohort, the prevalence of urolithiasis did not differ between the V/V and V/M+M/M groups and urine oxalate excretions did not correlate with the genotype. Considering the subset of PHPT stone formers (n=74), calciuria was lower in V/M+M/M patients with respect to V/V stone-formers (4.40+/-1.88 vs 5.92+/-2.62 mg/kg per 24 h; mean+/-s.d., P=0.034). Finally, the SLC26A6 206M alleles were significantly related to the presence of hypertension (73.3 vs 47.8%), showing an OR of 4.8. Though the SLC26A6 206M polymorphism did not correlate with kidney stone development in PHPT patients, PHPT stone-formers harbouring the M allele had a lower hypercalciuria. This observation and the high prevalence of hypertension associated with the 206M polymorphism need further investigation.


Exploring Complexity of Deliberate Self-Poisoning through Network Analysis.
The purpose of this research was to examine the complexity of circumstances that result in deliberate self-poisoning cases. For the purposes of this paper, the cases were patients that presented for care and were admitted to the specialty hospital in Northwest of Iran. The research examined the problems preceding deliberate self-poisoning and the interrelations among them by applying network analysis methods. The network was scored for degrees of centrality and betweenness centrality. Structural analysis of network also was conducted using block modelling. The results showed that family conflicts had the highest score for degree of centrality among women, while the highest score for degree of centrality among men belonged to those dealing with drug addiction. Analysis for degree of betweenness centrality revealed that drug addiction had the highest score among men, whereas the highest score for women on betweenness centrality was related to physical illness. Structural analysis of the network showed differences in role that various problems played in intentional self-poisoning. The findings from this research can be used by public health authorities to create prevention programs that address the problems leading to deliberate self-poisoning.


Taxonomic additions of Embolemidae and Sclerogibbidae (Hymenoptera: Chrysidoidea) from Japan, with description of a new species of Trogloembolemus.
Ampulicomorpha thauma Rasnitsyn Matveev (Hymenoptera: Embolemidae) and Sclerogibba rossi Olmi (Hymenoptera: Sclerogibbidae) were newly recorded from Japan. Females of Embolemus walkeri Westwood were found in the soil together with nymphs of Cixiidae. Trogloembolemus okanoi sp. nov. is described and illustrated. The holotype ♀ was collected in the soil at a depth of one meter. A key to species of Japanese Embolemidae was updated.


Effect of symbiotic supplementation on glycemic control, lipid profiles and microalbuminuria in patients with non-obese type 2 diabetes: a randomized, double-blind, clinical trial.
The prevalent raise of type 2 diabetes (T2D) around the globe, are creating higher risk for cardiovascular diseases (CVDs) and increasing strain on each country's health care budget in the world. Microalbuminuria has appeared as a key parameter in diabetic patients. Microalbuminuria is also related to increased cardiovascular morbidity in people who are non-obese diabetic. Some studies have suggested that consumption of symbiotic foods might help improve the metabolic profile, inflammatory factors and biomarkers of oxidative stress. The aim of trial was to determine the effect of symbiotic supplementation on glycemic control, lipid profiles and microalbuminuria in non-obese T2D. In this randomized, double-blind, clinically controlled trial, 70 patients with T2D (28 females, 42 males) were randomly divided into two groups (n = 35 for each group). The symbiotic group (SG) consumed 500 mg/d of symbiotic supplementations containing probiotics (Lactobacillus family, Bifidobacterium family, Streptococus thermophilus), Prebiotics (Fructo oligosaccharide) and B group vitamins (1 mg), lactose (0.5 mg), malt-dextrin, magnesium saturate and the placebo group (PG) consumed capsules filled with row starch and also B group vitamins (1 mg), lactose (0.5 mg), malt-dextrin, magnesium saturate for 9 weeks. Fasting blood glucose (FBG), hemoglobin A1c (HbA1c), blood lipid profiles, 24-h dietary recalls, and anthropometric measurements were measured at the baseline and at the end of trial. SPSS software, version 16 was used to test the data and the results were expressed as mean ± standard deviation. Paired samples T-Test were used to compare continuous variables within groups. Comparison between different groups was performed through two independent samples T-Test. In the absence of normal distribution, the comparison between the groups was made using non-parametric Wilcoxon on signed ranks and Mann-Whitney tests. P values <0.05 was considered significant. Symbiotic supplementation decreased significantly, FBG (P = 0.05) and HbA1c (P < 0.01). There were no significant differences in lipid profiles within and between the groups at the end of study (P > 0.05). Microalbuminuria (P < 0.05) and HbA1c (P < 0.05) are increased significantly in PG at the end of the study. Furthermore, the mean changes of microalbuminuria and HbA1c experienced significant between the two groups. There was significant reduction in urea between two groups from baseline (P = 0.051). No significant changes in baseline were shown in creatinine among the two groups or within either groups (P > 0.05). The consumption of 500 mg/d symbiotic supplementation for 9 weeks could improve the HbA1c, BMI and Microalbuminuria in T2D. Although, No effect has been indicated on FBS, lipid profiles, urea and creatinine. The trial has been registered in the Iranian Registry of Clinical Trials IRCT2015072223284N1, identifier. Registered 21 May 2016 "retrospectively registered".


The use of an acellular dermal regenerative tissue matrix in the treatment of lower extremity wounds: a prospective 16-week pilot study.
A prospective, single-centre, randomized controlled study was performed to evaluate the effectiveness of Graftjacket, a human acellular regenerative tissue matrix as a treatment option for chronic non healing lower extremity wounds. Twenty-eight diabetic patients with full-thickness wounds that had been present for at least 6 weeks were treated with sharp debridement and randomized to a single application of Graftjacket tissue matrix plus mineral oil-soaked fluff compression dressing or to a control treatment of wound gel with gauze dressings. All patients were seen weekly. By week 16, 12 of 14 patients treated with Graftjacket tissue matrix demonstrated complete wound closure compared with 4 of 14 patients in the control group. Patients treated with Graftjacket tissue matrix showed a statistically significant higher percentage of wound healing with respect to wound area, and clinically significant differences in wound depth and wound volume. This comparison is not performed to demonstrate that the application of the Grafjacket is more effective than sharp debridement. This study is done to help assign a role to the use of Graftjacket matrix in lower extremity wound care.


Effect of cabergoline monotherapy in Cushing's disease: an individual participant data meta-analysis.
The primary treatment of choice for Cushing's disease (CD) is the removal of the pituitary adenoma by transsphenoidal surgery (TSS). The surgical failure is seen in up to 75% of cases depending on the experience of the surgeon in different studies. Medical therapy is one of the options for the treatment of recurrent or persistent CD. The primary outcome of this meta-analysis was to find the proportion of patients achieving normalisation of 24-h urinary free cortisol (remission of CD) following cabergoline monotherapy. Literature search was conducted in January 2018 in PubMed/MEDLINE database from its date of inception to 31st December 2017. The search strategy used was "[(cushing) OR Cushing's] AND cabergoline". Individual participant data were extracted from the included studies and risk of bias was analysed by review checklist proposed by MOOSE. The individual participant data of 124 patients from six observational studies were included in this meta-analysis. 92 patients (74.2%) had past pituitary surgery. The proportion of patients achieving remission of Cushing's disease (CD) with cabergoline monotherapy was 34% (95% confidence interval 0.26–0.43; P = 0.001) [corrected]. The previous surgery [odds ratio (OR) 28.4], duration of cabergoline monotherapy (OR 1.31) and maximum cabergoline dose (OR 0.19) were predictors for remission of CD. Mild and severe side effects were reported in 37.3% and 5.6% of patients, respectively, during cabergoline monotherapy. This meta-analysis shows that cabergoline monotherapy is a reasonable alternative for subjects with persistent or recurrent CD after TSS. It can also be used in CD patients either as a bridge therapy while waiting for surgery or in those unwilling for surgery or have contraindication to it.


Arginase inhibition by piceatannol-3'-O-β-D-glucopyranoside improves endothelial dysfunction via activation of endothelial nitric oxide synthase in ApoE-null mice fed a high-cholesterol diet.
Elevated plasma cholesterol is a hallmark of numerous cardiovascular diseases that are closely linked to endothelial dysfunction indicating decreased nitric oxide (NO) production in the endothelium. It has been previously demonstrated that piceatannol-3'-O-β-D-glucopyranoside (PG) inhibits arginase activity and reciprocally regulates NO production. Here, we aimed to ascertain whether PG ameliorates vascular function in wild-type (WT) and atherogenic model mice [apolipoprotein E-null mice (ApoE-/-)] and to investigate the possible underlying mechanism. Preincubation of aortic vessels from WT mice fed a normal diet (ND) with PG attenuated vasoconstriction response to U46619 and phenylephrine (PE), while the vasorelaxant response to acetylcholine (Ach) was markedly enhanced in an endothelium-dependent manner. However, the endothelium-independent NO donor, sodium nitroprusside (SNP), did not change vessel reactivity. In thoracic aorta from ApoE-/- mice, a high-cholesterol diet (HCD) induced an increase in arginase activity, a decrease in NO release and an increase in reactive oxygen species generation that was reversed by treatment with PG. The effect of PG was associated with enhanced stability of the eNOS dimer and was not dependent on the expression levels of arginase II and eNOS proteins, although eNOS expression was increased in ApoE-/- mice fed an HCD. Furthermore, PG treatment attenuated the PE-dependent contractile response, and significantly improved the Ach-dependent vasorelaxation response in aortic rings from ApoE-/- mice fed an HCD. On the other hand, PG incubation neither altered the contractile response to a high K+ solution nor the relaxation response to SNP. When analyzing the L-arginine content using high-performance liquid chromatography, PG incubation increased the intracellular L-arginine concentration. PG administration in the drinking water significantly reduced fatty streak formation in ApoE-/- mice fed an HCD. These data indicate that PG improves the pathophysiology of cholesterol-mediated endothelial dysfunction. Therefore, we conclude that the development of PG as a novel effective therapy for preventing atherosclerotic diseases is warranted.


Tissue maturation correlating to clinical manifestations in juvenile angiofibroma.
Juvenile nasopharyngeal angiofibroma is a rare benign tumor that affects young male patients and shows a characteristic development from its origin. It is not a true neoplasm, but shows features of vascular processes, developing into a more fibrous condition. The aim of this study was to correlate the clinical manifestations and the histologic findings of the tumor. Thirty-six patients without previous treatment were studied. We correlated the incidence and duration of the clinical manifestations (nasal obstruction, epistaxis, nasal and/or pharyngeal tumor, and facial deformity) and morphometric histologic analyses of the central region of the tumor (number, caliber, and presence of muscle cells in the vessel wall, and tissue maturity and cellularity). The duration of nasal obstruction, the presence of nasal and/or pharyngeal tumor, and facial deformity were significantly correlated with the number of vessels, the tissue maturation, and the cellularity of the tumor. Epistaxis showed a strong correlation with the presence of muscle fibers in the vessels. There are correlations between the duration of the clinical manifestations and histologic maturation in the central portion of the tumor.


Construction and co-expression of plasmid encoding xylitol dehydrogenase and a cofactor regeneration enzyme for the production of xylitol from D-arabitol.
The biotransformation of D-arabitol into xylitol was investigated with focus on the conversion of D-xylulose into xylitol. This critical conversion was accomplished using Escherichia coli to co-express a xylitol dehydrogenase gene from Gluconobacter oxydans and a cofactor regeneration enzyme gene which was a glucose dehydrogenase gene from Bacillus subtilis for system 1 and an alcohol dehydrogenase gene from G. oxydans for system 2. Both systems efficiently converted D-xylulose into xylitol without the addition of expensive NADH. Approximately 26.91 g/L xylitol was obtained from around 30 g/L D-xylulose within system 1 (E. coli Rosetta/Duet-xdh-gdh), with a 92% conversion yield, somewhat higher than that of system 2 (E. coli Rosetta/Duet-xdh-adh, 24.9 g/L, 85.2%). The xylitol yields for both systems were more than 3-fold higher compared to that of the G. oxydans NH-10 cells (7.32 g/L). The total turnover number (TTN), defined as the number of moles of xylitol formed per mole of NAD(+), was 32,100 for system 1 and 17,600 for system 2. Compared with that of G. oxydans NH-10, the TTN increased by 21-fold for system 1 and 11-fold for system 2, hence, the co-expression systems greatly enhanced the NADH supply for the conversion, benefiting the practical synthesis of xylitol.


Genetic and biological analyses of a herpes simplex virus intertypic recombinant reduced specifically for neurovirulence.
RS6 is a herpes simplex virus intertypic recombinant derived from type 1 strain 17 syn+ and type 2 strain HG52. With a 50% lethal dose of about 10(5) PFU after intracerebral inoculation of mice, RS6 was approximately 100,000 times less neurovirulent than either of its wild-type parental viruses were. When compared with strains 17 syn+ and HG52, RS6 replicated intermediately in primary mouse embryo fibroblasts in vitro at 38.5 degrees C (mouse temperature) and to wild-type peak titers in mouse feet in vivo. In contrast, following intracranial inoculation of mice, RS6 replicated significantly less well than did either of its parental viruses in brains. The genetic defect(s) responsible for the reduced neurovirulence of RS6 was stable after in vitro and in vivo serial passage, was not manifested as temperature-sensitive plaquing in vitro, and did not affect thymidine kinase expression. These data indicate that RS6 has a genetic defect(s) specifically affecting its ability to replicate in the mouse brain. Using marker rescue technologies, we increased the neurovirulence of RS6 and localized one genetic determinant(s) involved with the reduced neurovirulence of this agent to 0.72 to 0.87 map units (and, tentatively, to 0.79 to 0.83 map units) of the herpes simplex virus genome. When coupled with the work suggesting that thymidine kinase expression is essential for efficient replication in nerve tissues and earlier reports from this laboratory and others, the results presented in this study indicate that more than one herpes simplex virus gene is involved with neurovirulence.


[Anesthetic management with a laryngeal mask airway for gastrectomy in a patient with myotonic dystrophy].
We report a case of 50-year-old male with myotonic dystrophy who underwent distal gastrectomy. A laryngeal mask airway (LMA) was inserted easily without using a muscle relaxant after propofol injection. Anesthesia was maintained with continuous propofol infusion and epidural anesthesia. The airway management with LMA enabled us to evaluate patient's awareness and respiratory pattern appropriately at the end of anesthesia. No respiratory complications, such as respiratory depression or atelectasis, occurred after surgery. We consider that LMA is useful for anesthetic management in a patient with myotonic dystrophy.


Distinct functions of acj6 splice forms in odor receptor gene choice.
Individual olfactory receptor neurons (ORNs) selectively express one or a small number of odor receptors from among a large receptor repertoire. The expression of an odor receptor dictates the odor response spectrum of the ORN. The process of receptor gene choice relies in part on a combinatorial code of transcription factors. In Drosophila, the POU domain transcription factor Acj6 is one element of the transcription factor code. In acj6 null mutants, many ORNs do not express an appropriate odor receptor gene and thus are not correctly specified. We find that acj6 is alternatively spliced to yield many structurally distinct transcripts in the olfactory organs. We generate flies that express single splice forms of acj6 in an acj6(-) background. We find that different splice forms are functionally distinct; they differ in their abilities to specify ORN identities. Some individual splice forms can fully rescue the specification of some ORNs. Individual splice forms can function both positively and negatively in receptor gene regulation. ORNs differ in their requirements for splice forms; some are not fully rescued by any single splice form tested, suggesting that some ORNs may require the combinatorial action of multiple splice forms. Late expression of some acj6 splice forms is sufficient to rescue some ORN classes, consistent with a direct role for Acj6 isoforms in receptor gene expression. The results indicate that alternative splicing may add another level of richness to the regulatory code that underlies the process of odor receptor gene choice.


[Circadian rhythm of spontaneous ventricular arrhythmias in elderly patients with myocardial ischemia at low risk for sudden death].
In 26 patients (65-80 yr) with low risk of sudden death, the circadian rhythm of spontaneous ventricular arrhythmias was analyzed, throughout 72 h, by the Holter monitoring method. The prolonged ECG monitoring is indispensable to evaluate the real necessity of an antiarrhythmic therapy and to establish the therapeutic approach. Premature ventricular complexes (PVC): isolated, couplets and runs of ventricular tachycardia have been considered. The isolated PVC showed uniform distribution throughout 24h, with higher frequency/hour ratio (f/h) in females. Couplets and runs showed circadian diurnal distribution with higher f/h ratio in smokers and males. After analysis of the results, the patients were additionally subdivided into smokers and non-smokers. Since smokers showed a diurnal distribution of all kinds of arrhythmias, antiarrhythmic drugs whose pharmacological peak corresponds to the distribution peaks of arrhythmias were proposed. Non-smokers could be divided into two groups: a) patients with isolated extrasystoles which did not show a circadian rhythm of arrhythmias and who must be treated with retard-drugs, which give protection throughout 24h; b) patients with runs or couplets of PVC showing a circadian rhythm of arrhythmias and who must be treated with drugs whose pharmacological peak corresponds to the distribution peaks of arrhythmias.


Melatonin Represses Oil and Anthocyanin Accumulation in Seeds.
Previous studies have clearly demonstrated that the putative phytohormone melatonin functions directly in many aspects of plant growth and development. In Arabidopsis (Arabidopsis thaliana), the role of melatonin in seed oil and anthocyanin accumulation, and corresponding underlying mechanisms, remain unclear. Here, we found that serotonin N-acetyltransferase1 (SNAT1) and caffeic acid O-methyltransferase (COMT) genes were ubiquitously and highly expressed and essential for melatonin biosynthesis in Arabidopsis developing seeds. We demonstrated that blocking endogenous melatonin biosynthesis by knocking out SNAT1 and/or COMT significantly increased oil and anthocyanin content of mature seeds. In contrast, enhancement of melatonin signaling by exogenous application of melatonin led to a significant decrease in levels of seed oil and anthocyanins. Further gene expression analysis through RNA sequencing and reverse-transcription quantitative PCR demonstrated that the expression of a series of important genes involved in fatty acid and anthocyanin accumulation was significantly altered in snat1-1 comt-1 developing seeds during seed maturation. We also discovered that SNAT1 and COMT significantly regulated the accumulation of both mucilage and proanthocyanidins in mature seeds. These results not only help us understand the function of melatonin and provide valuable insights into the complicated regulatory network controlling oil and anthocyanin accumulation in seeds, but also divulge promising gene targets for improvement of both oil and flavonoids in seeds of oil-producing crops and plants.


[The WHO/ISUP grading system for renal carcinoma].
Histological tumor grading is an accepted prognostic parameter of renal cell carcinoma (RCC). In 2012, the International Society of Urologic Pathologists (ISUP) proposed a novel grading system for RCC, mainly based on the evaluation of nucleoli: grade 1 tumors have nucleoli that are inconspicuous and basophilic at ×400 magnification; grade 2 tumors have nucleoli that are clearly visible at ×400 magnification and eosinophilic; grade 3 tumors have clearly visible nucleoli at ×100 magnification; and grade 4 tumors have extreme pleomorphism or rhabdoid and/or sarcomatoid morphology. This grading system was validated for clear cell renal cell carcinoma and papillary renal cell carcinoma. At the same time, the ISUP proposed not grading chromophobe renal cell carcinomas according to this system. At a consensus conference in Zurich the World Health Organization (WHO) recommended the ISUP grading system; thus, the WHO/ISUP grading system is now going to be implemented internationally. The ISUP/WHO grading system has not been validated as a prognostic parameter for other tumor subtypes, but can be used for descriptive purposes.


Patient Acuity and Operative Technique Associated with Post-Colectomy Mortality Across New York State: an Analysis of 160,792 Patients over 20 years.
This study sought to characterize in-hospital post-colectomy mortality in New York State. One hundred sixty thousand seven hundred ninety-two patients who underwent colectomy from 1995 to 2014 were analyzed from the all-payer New York Statewide Planning and Research Cooperative System (SPARCS) database. Linear trends of in-hospital mortality rate over 20 years were calculated using log-linear regression models. Chi-square tests were used to compare categorical variables between patients. Multivariable regression models were further used to calculate risk of in-hospital mortality associated with specific demographics, co-morbidities, and perioperative complications. From 1995 to 2014, 7308 (4.5%) in-hospital mortalities occurred within 30 days of surgery. Over this time period, the rate of overall in-hospital post-colectomy mortality decreased by 3.3% (6.3 to 3%, p < 0.0001). The risk of in-hospital mortality for patients receiving emergent and elective surgery decreased by 1% (RR 0.99 [0.98-1.00], p = 0.0005) and 5% (RR 0.95 [0.94-0.96], p < 0.0001) each year, respectively. Patients who underwent open surgeries were more likely to experience in-hospital mortality (adjusted OR 3.65 [3.16-4.21], p < 0.0001), with an increased risk of in-hospital mortality each year (RR 1.01 [1.00-1.03], p = 0.0387). Numerous other risk factors were identified. In-hospital post-colectomy mortality decreased at a slower rate in emergent versus elective surgeries. The risk of in-hospital mortality has increased in open colectomies.


Electronic adherence monitoring identifies severe preschool wheezers who are steroid responsive.
Little is known about adherence to inhaled corticosteroids (ICS) in preschool children with troublesome wheeze. Children with aeroallergen senitization, or those reporting multiple trigger wheeze (MTW), are more likely to respond to ICS. We hypothesized that adherence to ICS and symptom control are only positively related in atopic children, or those reporting MTW. Patients aged 1 to 5 years with recurrent wheeze prescribed ICS were recruited from a tertiary respiratory clinic. Clinical phenotype and aeroallergen senitization were determined, and adherence assessed using an electronic monitoring device (Smartinhaler). Symptom control (test for respiratory and asthma control in kids [TRACK]), quality of life (PACQLQ), airway inflammation (offline exhaled nitric oxide) were assessed at baseline and follow-up. Forty-eight children (mean age 3.7 years; SD, 1.2) were monitored for a median of 112 (interquartile range [IQR], 91-126) days. At baseline n = 29 reported episodic viral wheeze and n = 19 reported MTW. Twenty-four out of 48 (50%) wheezers had suboptimal ICS adherence (<80%). Median adherence was 64% (IQR, 38-84). There was a significant increase in TRACK and PACQLQ in the group as a whole, unrelated to adherence. In subgroup analysis only atopic wheezers with moderate or good adherence ≥ 60% had a significant increase in TRACK. There was no relationship between clinical phenotype, and adherence or TRACK. In this pilot study, overall adherence to ICS was suboptimal and was positively related to symptom control in atopic wheezers only. Assessments of adherence are important in preschool troublesome wheezers before therapy escalation to help identify those with an ICS responsive phenotype.


Evaluation of memory in abacus learners.
Abacus is a method used by Chinese, Japanese and Koreans to improve mathematical skills. This system has now invaded our country. The improvement in mathematical skills is said to be due to a coordinated functioning of both right and left hemisphere. As learning and memory in any field is achieved by coordinating and analyzing the different sensory inputs, whether an abacus trainee would also improve the short-term memory as a whole was evaluated in our study. 50 children of average IQ between 5 and 12 years from 2 regular schools and 50 from an abacus institute were evaluated for short-term memory before and after a period of one and two years. The memory tests were taken from Wechsler memory scale, Mini mental state examination, Mann - Buitar visual memory screen for objects. The results showed that the abacus learners at the end of one and two years had a better visual and auditory memory when compared to non-abacus learners.


The role of MMP-9 and TIMP-1 in nasal polyp formation.
The complex structure of polyp formation is still unknown. Matrix metalloproteinases (MMPs), a family of zinc-dependant endopeptidases with proteolytic activities towards several components of extracellular matrix, play an important role in connective tissue remodeling. Tissue inhibitors of matrix metalloproteinases (TIMPs) are natural inhibitors of MMPs. The balance between MMP/TIMP is very critical in matrix remodeling and various physiological processes. Imbalances between these enzymes and inhibitors may cause pathological processes such as chronic inflammation, degenerative disease and tumour invasion. In our study we aimed at demonstrating MMP/TIMP imbalance in nasal polyposis, similar to other pathological processes. STZUDY DESIGN AND SETTING: Nasal polyp specimens were obtained from twenty patients with nasal polyposis during endoscopic sinus surgery. Bullous middle turbinates with normal appearing mucosa of fifteen non-smoker patients free of any allergic or infectious diseases of nose or sinuses were used as controls. We measured the MMP-9 and TIMP-1 levels in tissue specimens using an ELISA method. MMP-9 levels were significantly increased and TIMP-1 levels were significantly decreased in polyp tissues in comparison to controls with no correlation observed between MMP-9 levels and inflammatory cell populations. MMP-9 and TIMP-1 may play an active pathogenic role in nasal polyp formation. MMP-9 levels are regulated independently from inflammatory cell populations.


Apoer2-ICD-dependent regulation of hippocampal ribosome mRNA loading.
Background ApoE4, the most significant genetic risk factor for late-onset Alzheimer's disease (AD), sequesters a pro-synaptogenic Reelin receptor, Apoer2, in the endosomal compartment and prevents its normal recycling. In the adult brain, Reelin potentiates excitatory synapses and thereby protects against amyloid-β toxicity. Recently, a gain-of-function mutation in Reelin that is protective against early-onset AD has been described. Alternative splicing of the Apoer2 intracellular domain (Apoer2-ICD) regulates Apoer2 signaling. Splicing of juxtamembraneous exon 16 alters the g-secretase mediated release of the Apoer2-ICD as well as synapse number and LTP, and inclusion of exon 19 ameliorates behavioral deficits in an AD mouse model. The Apoer2-ICD has also been shown to alter transcription of synaptic genes. However, the role of Apoer2 splicing for transcriptional regulation and its role in AD pathogenesis is unknown. Methods To assess in vivo mRNA-primed ribosomes specifically in hippocampi transduced with Apoer2-ICD splice variants, we crossed wild-type, cKO, and Apoer2 cleavage-resistant mice to a Cre-inducible translating ribosome affinity purification (TRAP) model. This allowed us to perform RNA-Seq on ribosome-loaded mRNA harvested specifically from hippocampal cells transduced with Apoer2-ICDs. Results Across all conditions, we observed ~ 4,700 altered ribosome-associated transcripts, several of which comprise key synaptic components such as extracellular matrix and focal adhesions with concomitant perturbation of critical signaling cascades, energy metabolism, translation, and apoptosis. We further demonstrated the ability of the Apoer2-ICD to rescue many of these altered transcripts, underscoring the importance of Apoer2 splicing in synaptic homeostasis. A variety of these altered genes have been implicated in AD, demonstrating how dysregulated Apoer2 splicing may contribute to neurodegeneration. Conclusions Our findings demonstrate how alternative splicing of the APOE and Reelin receptor Apoer2 and release of the Apoer2-ICD regulates numerous ribosome-associated transcripts in mouse hippocampi in vivo . These transcripts comprise a wide range of functions, and alterations in these transcripts suggest a mechanistic basis for the synaptic deficits seen in Apoer2 mutant mice and AD patients. Our findings, together with the recently reported AD-protective effects of a Reelin gain-of-function mutation in the presence of an early-onset AD mutation in Presenilin-1, implicate the Reelin/Apoer2 pathway as a target for AD therapeutics.


Learning to swim efficiently in a nonuniform flow field.
Microswimmers can acquire information on the surrounding fluid by sensing mechanical queues. They can then navigate in response to these signals. We analyze this navigation by combining deep reinforcement learning with direct numerical simulations to resolve the hydrodynamics. We study how local and nonlocal information can be used to train a swimmer to achieve particular swimming tasks in a nonuniform flow field, in particular, a zigzag shear flow. The swimming tasks are (1) learning how to swim in the vorticity direction, (2) learning how to swim in the shear-gradient direction, and (3) learning how to swim in the shear-flow direction. We find that access to laboratory frame information on the swimmer's instantaneous orientation is all that is required in order to reach the optimal policy for tasks (1) and (2). However, information on both the translational and rotational velocities seems to be required to accomplish task (3). Inspired by biological microorganisms, we also consider the case where the swimmers sense local information, i.e., surface hydrodynamic forces, together with a signal direction. This might correspond to gravity or, for microorganisms with light sensors, a light source. In this case, we show that the swimmer can reach a comparable level of performance to that of a swimmer with access to laboratory frame variables. We also analyze the role of different swimming modes, i.e., pusher, puller, and neutral.


Early-onset schizophrenia: a 15-year follow-up.
The study describes the psychopathological and social outcome of patients treated for schizophrenia in adolescence (mean age at onset 16.0 years/SD 1.52) after a mean follow-up period of 15.4 years (10.2-21.2 years). Out of 55 patients consecutively admitted to hospital, 47 (85 %) could be traced and 39 (71 %) could be re-examined. At follow-up, 33/39 patients (85 %) had had at least one readmission. Full remission of global psychopathological symptoms [Clinical Global Impression (CGI) <or= 2] was found in 3/39 (8 %),a moderate outcome (CGI=3-5) in 22/39 (56 %), and a poor outcome (CGI=6-8) was seen in 14/39 (36 %). Severe or very severe impairments of global social functioning [Global Assessment of Social Function (GAS)< 51] were observed in 20/39 (51 %). The best predictor of global psychopathological and psychosocial outcome was type of onset (CGI: Beta=0.36, GAS: Beta=-0.37). A poor outcome was seen in 22 out of 25 cases with insidious onset. All predictors together explained 58% of the variance in the Positive and Negative Syndrome (PANSS) negative symptom ratings at follow-up. Gender, duration of first inpatient treatment and duration of untreated psychosis were of no predictive value for outcome. The nature of the diagnosis in the first episode strongly predicted the diagnosis given for the whole course after 15 years. In 26/37 cases (70 %), diagnosis at onset and overall diagnoses were the same. Our finding of an incidence of 61% insidious onset is similar to that in adult onset schizophrenia (AOS), but different to very early onset schizophrenia (VEOS), which shows a higher rate of insidious onset, cognitive impairment and poor outcome. Therefore, it seems that VEOS is a special group compared with early onset schizophrenia (EOS) and AOS.


SPME-Based Ca-History Method for Measuring SVOC Diffusion Coefficients in Clothing Material.
Clothes play an important role in dermal exposure to indoor semivolatile organic compounds (SVOCs). The diffusion coefficient of SVOCs in clothing material (Dm) is essential for estimating SVOC sorption by clothing material and subsequent dermal exposure to SVOCs. However, few studies have reported the measured Dm for clothing materials. In this paper, we present the solid-phase microextraction (SPME) based Ca-history method. To the best of our knowledge, this is the first try to measure Dm with known relative standard deviation (RSD). A thin sealed chamber is formed by a circular ring and two pieces of flat SVOC source materials that are tightly covered by the targeted clothing materials. Dm is obtained by applying an SVOC mass transfer model in the chamber to the history of gas-phase SVOC concentrations (Ca) in the chamber measured by SPME. Dm's of three SVOCs, di-iso-butyl phthalate (DiBP), di-n-butyl phthalate (DnBP), and tris(1-chloro-2-propyl) phosphate (TCPP), in a cotton T-shirt can be obtained within 16 days, with RSD less than 3%. This study should prove useful for measuring SVOC Dm in various sink materials. Further studies are expected to facilitate application of this method and investigate the effects of temperature, relative humidity, and clothing material on Dm.