Alterations of blood pressure in type 1 diabetic children and adolescents.
The aim of this study was to assess the association between metabolic control, microalbuminuria, and diabetic nephropathy with ambulatory blood pressure monitoring (ABPM) in normotensive individuals with type 1 diabetes mellitus (DM). ABPM was undertaken in 68 normotensive type 1 diabetic patients with a mean age of 14.4+/-4.2 years. Microalbuminuria was diagnosed on the basis of a urinary albumin excretion rate grater than 20 microg/min in two of the three 24-h urine collections. Hypertension (HT) frequency was greater in the microalbuminuric patients than normoalbuminuric patients (54 vs 17.54%, p=0.05) with ABPM. Microalbuminuric patients had a higher diastolic pressure burden than normoalbuminuric patients. There were no differences in systolic and diastolic dips between the two groups. Diastolic pressure loads in all periods showed a significant correlation with duration of diabetes, mean HbA1c from the onset of diabetes, and level of microalbuminuria. Nocturnal dipping was reduced in 41.2% of the patients. In the normoalbuminuric group 41.1% and in the microalbuminuric group 63.6% were nondippers. Our data demonstrate higher 24-h and daytime diastolic blood pressure load and loss of nocturnal dip in type 1 diabetic adolescents and children. High diastolic blood pressure burden in diabetic patients could represent a risk for nephropathy.


Biogeographical patterns of soil bacterial communities.
This study provides the first maps of variations in bacterial community structure on a broad scale based on genotyping of DNA extracts from 593 soils from four different regions of France (North, Brittany, South-East and Landes). Soils were obtained from the soil library of RMQS ('Réseau de Mesures de la Qualité des Sols' = French soil quality monitoring network). The relevance of a biogeographic approach for studying bacterial communities was demonstrated by the great variability in community structure and specific geographical patterns within and between the four regions. The data indicated that the distribution of bacterial community composition might be more related to local factors such as soil type and land cover than to more global factors such as climatic and geomorphologic characteristics. Furthermore, the regional pools of biodiversity could be ordered: South-East ≥ North > Brittany > Landes, according to the observed regional variability of the bacterial communities, which could be helpful for improving land use in accordance with soil biodiversity management.


Prevalence of Cryptosporidium Carriage and Disease in Children With Primary Immune Deficiencies Undergoing Hematopoietic Stem Cell Transplant in Northern Europe.
A prospective cohort study of children with primary immunodeficiencies undergoing hematopoietic stem cell transplant in the United Kingdom investigated the extent and significance of Cryptosporidium carriage in this high risk group. Three of 42 children recruited were infected with Cryptosporidium, a lower proportion than previously described. One had serious disease. The underlying immunodeficiency likely had a bearing on the clinical presentation and possible outcome of infection.


Prep School for Poor Kids: The Long-Run Impacts of Head Start on Human Capital and Economic Self-Sufficiency.
This paper evaluates the long-run effects of Head Start using large-scale, restricted administrative data. Using the county rollout of Head Start between 1965 and 1980 and age-eligibility cutoffs for school entry, we find that Head Start generated large increases in adult human capital and economic self-sufficiency, including a 0.65-year increase in schooling, a 2.7 percent increase in high school completion, an 8.5 percent increase in college enrollment, and a 39 percent increase in college completion. These estimates imply sizable, long-term returns to investments in means-tested, public preschool programs.


Halorientalis persicus sp. nov., an extremely halophilic archaeon isolated from a salt lake and emended description of the genus Halorientalis.
An extremely halophilic archaeon, strain D108(T), was isolated from a brine sample of Aran-Bidgol salt lake in Iran. The novel strain was cream-pigmented, motile, pleomorphic rod-shaped and required at least 2.5 M NaCl but not MgCl2 for growth. Optimal growth was achieved with 4.3 M NaCl and 0.1 M MgCl2. The optimum pH and temperature for growth were pH 7.5 and 40 °C, respectively, and the strain was able to grow over a pH range of 6.5 to 9.0, and a temperature range of 30 to 50 °C. Phylogenetic analysis based on 16S rRNA gene sequence comparisons revealed that strain D108(T) clustered with the type strain of the sole species of the genus Halorientalis, Halorientalis regularis TNN28(T), with a sequence similarity of 98.8 %. The polar lipid pattern of strain D108(T) consisted of phosphatidylglycerol, phosphatidylglycerol phosphate methyl ester, one phosphoglycolipid and two glycolipids. The only quinone present was MK-8(II-H2). The DNA G+C content of strain D108(T) was 62.8 mol%. DNA-DNA hybridization studies (45 % with Halorientalis regularis IBRC-M 10760(T)), as well as biochemical and physiological characterization, allowed strain D108(T) to be differentiated from Halorientalis regularis. A novel species of the genus Halorientalis, Halorientalis persicus sp. nov., is therefore proposed to accommodate this strain. The type strain is D108(T) ( = IBRC-M 10043(T) = CECT 8375(T)). An emended description of the genus Halorientalis is also proposed.


Effects of soy isoflavones on atherosclerosis: potential mechanisms.
It has long been recognized that coronary heart disease rates are lower in Japan, where soy consumption is common, than in Western countries. In experimental studies, atherosclerosis was reduced in animals fed diets containing soy protein compared with those fed diets with animal protein. Recently, several lines of evidence have suggested that the components of soy protein that lower lipid concentrations are extractable by alcohol (eg, the isoflavones genistein and daidzein). We recently evaluated the relative effect of the soy protein versus the alcohol-extractable components of soy on cardiovascular disease and its risk factors. Young male and female cynomolgus monkeys were fed diets that contained either 1) casein-lactalbumin as the source of protein (casein), 2) soy protein isolate from which the isoflavones were alcohol extracted (SPI-), or 3) isoflavone-intact soy protein (SPI+). The SPI+ group had significant improvements in LDL cholesterol and HDL cholesterol. Only HDL cholesterol was significantly improved in the SPI- group males compared with the casein group. The casein group had the most atherosclerosis, the SPI+ group had the least, and the SPI- group was intermediate but did not differ significantly from the casein group. Potential mechanisms by which soy isoflavones might prevent atherosclerosis include a beneficial effect on plasma lipid concentrations, antioxidant effects, antiproliferative and antimigratory effects on smooth muscle cells, effects on thrombus formation, and maintenance of normal vascular reactivity.


The Met-196 -> Arg variation of human tumor necrosis factor receptor 2 (TNFR2) affects TNF-alpha-induced apoptosis by impaired NF-kappaB signaling and target gene expression.
Tumor necrosis factor-alpha (TNF-alpha)-induced signaling is pivotally involved in the pathogenesis of chronic inflammatory diseases. A polymorphism in the TNF receptor 2 (TNFR2) gene resulting in a juxtamembrane inversion from methionine (TNFR2(196MET)) to arginine (TNFR2(196ARG)) has been genetically associated with an increased risk for systemic lupus erythematosus and familial rheumatoid arthritis. Albeit the mutation does not affect the TNF binding kinetics of TNFR2, the present study provides evidence that the mutation results in a significantly lower capability to induce TNFR2-mediated NF-kappaB activation. Pretriggering of TNFR2 with a receptor-specific mutein leads to an enhancement of TNFR1-induced apoptosis, which is further increased in cells carrying the TNFR2(196ARG) variant. A diminished induction of NF-kappaB-dependent target genes conveying either anti-apoptotic or pro-inflammatory functions, such as cIAP1, TRAF1, IL-6, or IL-8 is observed. The mutated form TNFR2(196ARG) shows a reduction of inducible TRAF2 recruitment upon TNF-alpha stimulation. The findings suggest a common molecular mechanism for the involvement of the TNFR2(196ARG) variant in the etiopathogenesis of different chronic inflammatory disorders.


Oral clefts and vitamin supplementation.
The evidence linking low levels of folic acid and orofacial clefting (OFC) is presently equivocal. There is stronger evidence for the role of folic acid supplementation in protection against the occurrence and recurrence of neural tube defects. The present investigation tested the hypotheses that cleft lip, cleft palate, or both are inversely associated with maternal intake of dietary and supplemental vitamins during the periconceptional period and first 4 months of pregnancy in a Brazilian population. A population-based, case-control study of cleft lip with or without cleft palate (CL(P)) and isolated cleft palate (CP) in a Brazilian population. In structured interviews, case histories were taken from the mothers of a consecutive sample of 450 infants born with nonsyndromic OFC. Mothers who had children with CL(P) were less likely to have been supplemented during the periconceptional period. The statistical significance of the difference in prevalence of the use of supplements between mothers of patients and of controls was greater for the CL(P) group: p < .05 for CP and p < .001 for CL(P). Multivariate analysis confirmed this finding of a protective effect for both types of orofacial cleft. The use of vitamin supplements in the first 4 months of pregnancy was suggestive of a protective effect against the occurrence of CP and CL(P) in this population. The significance of an association between multivitamin supplementation and OFC and the possible role of gene/environment interaction are discussed.


Genomic and genetic sequence information of strains assigned to the genus Rhodopseudomonas reveal the great heterogeneity of the group and identify strain Rhodopseudomonas palustris DSM 123T as the authentic type strain of this species.
The genus Rhodopseudomonas, containing purple nonsulfur photosynthetic Proteobacteria, has a number of strains that belong to different species, although many of them are collectively called Rhodopseudomonas palustris. The type species R. palustris and closely related species are the focus of this paper. The comparison of available genome sequences indicate that the following Rhodopseudomonas species are well recognized: R. palustris (strains ATH 2.1.6T=DSM 123T=NBRC 100419T and BisB5), Rhodopseudomonas rutila (strains R1T, DSM 126, CGA009, ATH 2.1.37, Eli 1980, ATCC 17001 and TIE1), Rhodopseudomonas pentothenatexigens JA575T and Rhodopseudomonas faecalis JCM 11668T. Other strains for which genome sequences are available are distinct from these four species. Evidence is presented that R. palustris strain ATH 2.1.6T-KCM as obtained directly from the van Niel collection by one of us (T.E.M.) is identical to the DSMZ deposit DSM 123T of ATH 2.1.6T, but not to the deposit at ATCC 17001. The amino acid sequences of the cytochromes C2 and C556 from R. palustris strain ATH 2.1.6T-KCM are in complete agreement with the translated genome sequences of R. palustris DSM 123T. In addition, the 16S rRNA gene sequence of R. palustris NBRC 100419T completely matches that of strain DSM 123T. In conclusion, the type strain of R. palustris ATH 2.1.6T is correctly represented by DSM 123T and NBRC 100419T. However, the deposit at ATCC 17001 has properties that do not conform with properties of authentic R. palustris, but rather indicate that this is a strain of R. rutila. The previously suggested assignment of the type strain of R. palustris DSM 123T to the new species R. pseudopalustris was incorrect because strain DSM 123T is the authentic type strain of R. palustris.


Palladium-Catalyzed ( Z)-Selective Allylation of Nitroalkanes: Access to Highly Functionalized Homoallylic Scaffolds.
Nitroalkanes undergo decarboxylative allylation in the presence of vinyl-substituted cyclic carbonates, providing a wide variety of functionalized homoallylated compounds with exquisite stereocontrol. This Pd-mediated procedure features operational simplicity, versatile substrate combinations, and also allows for the sequential introduction of different allyl groups in the nitroalkane scaffolds with high levels of stereocontrol through the intermediacy of a ( Z)-configured palladacyclic intermediate. As far as we know, the developed protocol is the first general Pd-mediated methodology toward ( Z)-configured homoallylic nitroalkanes with attractive functional group diversity.


The epidemiology of Staphylococcus aureus carriage in patients attending inner city sexually transmitted infections and community clinics in Calgary, Canada.
Although the nares represent the most common carriage site for traditional hospital-associated strains of Staphylococcus aureus (SA), the predominant site of carriage of SA in the community is less certain. We conducted a cross-sectional study in 285 patients attending sexually transmitted diseases and inner-city clinics to evaluate the prevalence, body site colonisation and risk factors associated with carriage of methicillin susceptible SA (MSSA). All isolates were characterized by pulsed field gel electrophoresis, staphylococcal cassette chromosome mec, staphylococcal protein A and multilocus sequence typing. The prevalence of colonisation with SA was 57.5% (164/285); 162 (56.8%) participants were colonized with MSSA, and 4 (1.4%) with methicillin-resistant SA (MRSA), 2 of them were co-colonised with both MRSA and MSSA. The most common sites of colonisation were the throat (73.1%), nares (65.2%) and interdigital web spaces of the hand (21.3%). Three out of 4 MRSA isolates were USA300-MRSA strains. Twelve MSSA isolates were closely related to the USA300 CA-MRSA. We identified sexual behaviours such as having more than 6 heterosexual sexual partners in the last 6 months and trimming pubic hair to be independently associated with MSSA colonisation, and more specifically practicing oral sex as a risk factor for throat colonisation. There is a high prevalence of MSSA carriage in this population, with a low prevalence of MRSA. The throat was the most common site of carriage and sexual behaviours were found to be risk factors for MSSA colonisation. Close strain relatedness of MSSA and USA300-MRSA isolates suggests either gain or loss of the SCCmec element, respectively.


Identification of Gnr1p, a negative regulator of G alpha signalling in Schizosaccharomyces pombe, and its complementation by human G beta subunits.
G protein-coupled receptors (GPCRs) are involved in the response of eukaryotic cells to a wide variety of stimuli, traditionally mediating their effects through heterotrimeric G proteins comprised of G alpha, G beta and G gamma subunits. The fission yeast Schizosaccharomyces pombe is an established tool for GPCR research, possessing two G alpha-dependent signalling cascades. A complete G alpha beta gamma complex has been characterised for the glucose-sensing pathway, but only the G alpha subunit, Gpa1p, has been identified in the pheromone-response pathway. Here, we report the use of the yeast two-hybrid system to identify a novel protein, Gnr1p, which interacts with Gpa1p. Gnr1p is predicted to contain seven WD repeats and to adopt a structure similar to typical G beta subunits. Disruption and overexpression studies reveal that Gnr1p negatively regulates the pheromone-response pathway but is not required for signalling. Human G beta subunits complement the loss of Gnr1p, functioning as negative regulators of G alpha signalling in fission yeast.


Oxycodone versus codeine for triage pain in children with suspected forearm fracture: a randomized controlled trial.
To compare the efficacy of pain reduction of triage oxycodone (O) versus codeine (C) to children with suspected forearm fractures. Children, aged 4 to 17 years, were randomized to receive O (0.2 mg/kg; maximum, 15 mg) or C (2 mg/kg; maximum, 120 mg) if isolated forearm fracture was suspected by the emergency department (ED) triage nurse. All other ED staff were blinded to the assignment. The primary outcome measure was a 5-point facial scale (0 = no pain, 4 = severe) completed by subjects to assess pain at baseline then at 30-minute intervals until ED discharge or procedural sedation for fractures requiring reduction. Ten adverse effects were assessed at baseline and the succeeding intervals. Identification of the most painful part of the visit was assessed at discharge. Efficacy and adverse effects of O versus C were compared using generalized estimate equation modeling. One hundred seven subjects (mean age, 10.4 years; African American, 55%; males, 56%) were randomized to O (n = 51) or C (n= 56). Subjects taking O reported a pain score significantly lower than subjects taking C (0.4 faces, P = 0.01). Minor adverse effects occurred in both groups, but itching occurred less in O subjects (odds ratio, 0.37; 95% confidence interval, 0.14-0.99). The most painful part of the visit was radiography (O = 41%, C = 38%) followed by extremity examination (O = 16%, C = 13%) then casting (O = 8%, C = 13%). Triage-administered O tended toward greater pain reduction compared with C in children with suspected forearm fractures. Although minor adverse effects occurred in both groups, itching occurred more in C. Identification of radiography as the most painful part of fracture evaluation underscores the need for early triage administration of analgesia for suspected fractures.


[Lower limb varicose veins as a manifestation of undifferentiated connective tissue dysplasia].
Analysed herein are the data of 737 patients (a total of 745 lower limbs) suffering from lower-limb varicose veins (LLVV) and subjected to treatment at the Surgical Department consisting of crossectomy, truncal and tributary phlebectomy, dissection of perforant veins exclusively in the basin of the great saphenous vein. Relapses during five-year follow up occurred in 13.8% (102/745) of cases. Based on clinical signs and laboratory findings we studied the effect of the factor of undifferentiated connective tissue dysplasia (UDCTD) on the development of lower-limb varicosity. We carried out comparative analysis in the groups with relapsing LLVV (n=43), without relapses (n=39) and control group comprising volunteers not suffering from LLVV (n=37). The median of blood serum total oxiprolin concentration in LLVV patients both with and without relapses was elevated and amounted to 18.4 (IR 14.9-19.65) and 14.3 (IR 13.1-16.5) versus 8.35 (5.75-9.75) μmol/l, respectively. The mode of the clinical parameter of UDCTD degree in accordance with the rating scale of Smolnova T.Yu. (2003) in the group of patients with LLVV relapses turned out to be higher (Mo=19) than in the group of patients without relapses (Mo=10, p=0.003). The lowest score was in the control group. In patients having immediate relatives with LLVV the level of blood serum total oxiprolin and clinical scores of LLVV turned out to be statistically significantly higher. Hence, based on the obtained during the study clinical and laboratory findings it may be supposed that undifferentiated connective tissue dysplasia plays an important part in the development of both lower limb varicosity and relapses thereof.


Third harmonics nonlinear susceptibility in supercooled liquids: a comparison to the box model.
The box model, originally introduced to account for the nonresonant hole burning (NHB) dielectric experiments in supercooled liquids, is compared to the measurements of the third harmonics P(3) of the polarisation, reported recently in glycerol, close to the glass transition temperature T(g) [C. Crauste-Thibierge, C. Brun, F. Ladieu, D. L'Hôte, G. Biroli, and J.-P. Bouchaud, Phys. Rev. Lett. 104, 165703 (2010)]. In this model, each box is a distinct dynamical relaxing entity (hereafter called dynamical heterogeneity (DH)) which follows a Debye dynamics with its own relaxation time τ(dh). When it is submitted to a strong electric field, the model posits that a temperature increase δT(dh), depending on τ(dh), arises due to the dissipation of the electrical power. Each DH has thus its own temperature increase, on top of the temperature increase of the phonon bath δT(ph). Contrary to the "fast" hole burning experiments where δT(ph) is usually neglected, the P(3) measurements are, from a thermal point of view, fully in a stationary regime, which means that δT(ph) can no longer be neglected a priori. This is why the version of the box model that we study here takes δT(ph) into account, which implies that the δT(dh) of the DHs are all coupled together. The value of P(3), including both the "intrinsic" contribution of each DH as well as the "spurious" one coming from δT(ph), is computed within this box model and compared to the P(3) measurements for glycerol, in the same range of frequencies and temperatures T. Qualitatively, we find that this version of the box model shares with experiments some nontrivial features, e.g., the existence of a peak at finite frequency in the modulus of P(3) as well as its order of magnitude. Quantitatively, however, some experimental features are not accounted for by this model. We show that these differences between the model and the experiments do not come from δT(ph) but from the "intrinsic" contribution of the DHs. Finally, we show that the interferences between the 3ω response of the various DHs are the most important issue leading to the discrepancies between the box model prediction and the experiments. We argue that this could explain why the box model is quite successful to account for some kinds of nonlinear experiments (such as NHB) performed close to T(g), even if it does not completely account for all of them (such as the P(3) measurements). This conclusion is supported by an analytical argument which helps understanding how a "space-free" model as the box model is able to account for some of the experimental nonlinear features.


Diagnosing callous-unemotional personality traits by heart rate orienting responses to images inducing threat and distress.
The present study aimed at developing a rather easily applicable method of testing physiological reactions to images of threats and misery. To this end, rapid-changing, transient heart rate orienting responses were used for gaining physiologically based, objective responses to the images. Additionally, subjective ratings were obtained. A significant insensitivity to other's welfare and well-being was already demonstrated as a core feature of callous-unemotional personalities. Thus, physiologically based methods may supplement and possibly improve existing assessments and, in particular, may contribute to a multimodal assessment of psychopathic traits. Out of a non-forensic community sample of 122 men, we selected two extreme groups of 30 participants with the lowest and highest callous-unemotional traits respectively, ascertained by questionnaires. As expected, participants with higher scores of callous-unemotional traits showed smaller responses to distress cues in both heart rate responses and subjective ratings. Moreover, within the group with high callous-unemotional traits heart rate responses to threatening as well as distress cues did not significantly differ from responses to neutral pictures. The study provides further evidence for the idea that a lack of responsiveness to distress cues may be seen as a central feature of callous-unemotional personalities.


The evolutionary diversification of LSF and Grainyhead transcription factors preceded the radiation of basal animal lineages.
The transcription factors of the LSF/Grainyhead (GRH) family are characterized by the possession of a distinctive DNA-binding domain that bears no clear relationship to other known DNA-binding domains, with the possible exception of the p53 core domain. In triploblastic animals, the LSF and GRH subfamilies have diverged extensively with respect to their biological roles, general expression patterns, and mechanism of DNA binding. For example, Grainyhead (GRH) homologs are expressed primarily in the epidermis, and they appear to play an ancient role in maintaining the epidermal barrier. By contrast, LSF homologs are more widely expressed, and they regulate general cellular functions such as cell cycle progression and survival in addition to cell-lineage specific gene expression. To illuminate the early evolution of this family and reconstruct the functional divergence of LSF and GRH, we compared homologs from 18 phylogenetically diverse taxa, including four basal animals (Nematostella vectensis, Vallicula multiformis, Trichoplax adhaerens, and Amphimedon queenslandica), a choanoflagellate (Monosiga brevicollis) and several fungi. Phylogenetic and bioinformatic analyses of these sequences indicate that (1) the LSF/GRH gene family originated prior to the animal-fungal divergence, and (2) the functional diversification of the LSF and GRH subfamilies occurred prior to the divergence between sponges and eumetazoans. Aspects of the domain architecture of LSF/GRH proteins are well conserved between fungi, choanoflagellates, and metazoans, though within the Metazoa, the LSF and GRH families are clearly distinct. We failed to identify a convincing LSF/GRH homolog in the sequenced genomes of the algae Volvox carteri and Chlamydomonas reinhardtii or the amoebozoan Dictyostelium purpureum. Interestingly, the ancestral GRH locus has become split into two separate loci in the sea anemone Nematostella, with one locus encoding a DNA binding domain and the other locus encoding the dimerization domain. In metazoans, LSF and GRH proteins play a number of roles that are essential to achieving and maintaining multicellularity. It is now clear that this protein family already existed in the unicellular ancestor of animals, choanoflagellates, and fungi. However, the diversification of distinct LSF and GRH subfamilies appears to be a metazoan invention. Given the conserved role of GRH in maintaining epithelial integrity in vertebrates, insects, and nematodes, it is noteworthy that the evolutionary origin of Grh appears roughly coincident with the evolutionary origin of the epithelium.


Mean response times, variability, and skew in the responding of ADHD children: a response time distributional approach.
Response time (RT) distributions from three fixed foreperiod conditions (2, 4, and 8 s) in a warned four-choice RT task were obtained for a group of boys with attention-deficit/hyperactivity disorder, combined type (ADHD; n = 17) and for two groups of normal control boys (age-matched, n = 18, and younger-aged, n = 10). Quantitative measures of distributional shape were derived by fitting the ex-Gaussian distributional model to the individual RT data. Statistical results indicate that the ADHD distributions differ from the age-matched control distributions with respect to the size of the tail (larger for the ADHD boys), but differ from the younger control distributions with respect to the location of the leading edge (slower for the younger control boys). Receiver operating characteristic (ROC) results reveal that the ex-Gaussian exponential component is highly diagnostic of the ADHD boys.


Enhancement of beta-glucosidase and beta-galactosidase of Trigonella foenum-graecum by exposure to the allelochemical mimosine.
Glycohydrolases assume significance in the metabolism of biological systems and have important industrial applications in the areas of pharmaceuticals, food, and medicine. Glycosidases were screened in germinating seeds, and attempts were made to enhance their levels. Screening of glycosidases in the seedlings during a 72 h germination period revealed higher levels of beta-glucosidase and beta-galactosidase in Trigonella foenum-graecum compared to Cicer arietinum and Vigna radiata. Activity of beta-galactosidase was in general higher than that of beta-glucosidase in all the seedlings tested. During growth, exposure of the seedlings to an allelochemical, mimosine, at 0.1 mM resulted in the enhancement of enzyme levels by 50% in the seedlings of T. foenum-graecum, whereas the addition of mimosine to the assay medium in vitro did not affect the enzyme activities. Hydrolytic activity was enhanced by addition of glycerol in the medium up to 0.1 M in the case of beta-glucosidase and with 0.05 M in the case of beta-galactosidase. In general, the hydrolytic rate was higher by about 30% in the seedlings exposed to mimosine compared to that of the control. Concomitant enhancement in the rates of transgalactosidation by 51% and transglucosidation by 23% was also noted, underscoring the relevance of plant glycohydrolases for appropriate applications.


Basolateral Amygdala Corticotrophin Releasing Factor Receptor 2 Interacts with Nonmuscle Myosin II to Destabilize Memory.
Inhibiting the actin motor ATPase nonmuscle myosin II (NMII) with blebbistatin (Blebb) in the basolateral amgydala (BLA) depolymerizes actin, resulting in an immediate, retrieval-independent disruption of methamphetamine (METH)-associated memory. The effect is highly selective, as NMII inhibition has no effect in other relevant brain regions (e.g. dorsal hippocampus [dPHC], nucleus accumbens [NAc]), nor does it interfere with associations for other aversive or appetitive stimuli, including cocaine (COC). To investigate a potential source of this specificity, pharmacokinetic differences in METH and COC brain exposure were examined. Replicating METH's longer half-life with COC did not render the COC association susceptible to disruption by NMII inhibition. Therefore, transcriptional differences were next assessed. Comparative RNA-seq profiling in the BLA, dHPC and NAc following METH or COC conditioning identified crhr2, which encodes the corticotrophin releasing factor receptor 2 (CRF2), as uniquely upregulated by METH in the BLA. CRF2 antagonism with Astressin-2B (AS2B) had no effect on METH-associated memory after consolidation, allowing for determination of CRF2 influences on NMII-based susceptibility after METH conditioning. Pretreatment with AS2B occluded the ability of Blebb to disrupt an established METH-associated memory. Alternatively, the Blebb-induced, retrieval-independent memory disruption seen with METH was mimicked for COC when combined with CRF2 overexpression in the BLA and its ligand, UCN3 during conditioning. These results indicate that BLA CRF2 receptor activation during learning can prevent stabilization of the actin-myosin cytoskeleton supporting the memory, rendering it vulnerable to disruption via NMII inhibition. CRF2 represents an interesting target for BLA-dependent memory destabilization via downstream effects on NMII.


Expression of CD66a (human C-CAM) and other members of the carcinoembryonic antigen gene family of adhesion molecules in human colorectal adenomas.
Among the members of the carcinoembryonic antigen (CEA) family, CD66a (human C-CAM) and CGM2 (CEA gene family member 2) mRNAs are frequently down-regulated in colorectal cancer. In contrast, nonspecific cross-reactive antigen (NCA) mRNA is overexpressed in the majority of these carcinomas. In animal models, the rodent homologues of CD66a have been shown to act as tumor suppressors, suggesting an important role in carcinogenesis. Here we investigate the mRNAs of CD66a, CGM2, and NCA in 22 human colorectal adenomas and the respective normal mucosa specimens by Northern blots. The expression of both CD66a and CGM2 changed in a concomitant fashion. Using oligonucleotides specific for the N-terminal domains, two CD66a transcripts 3.9 and 1.5 kb in size were identified. These showed a greater than 50% down-regulation in 20 of 22 and 18 of 22 adenomas, respectively. Reduction of the CGM2 message was observed in 21 of 22 cases. Complete or near-complete losses of the CD66a 3.9-kb mRNA and the CGM2 message were found in 13 of 22 and 15 of 22 of the tumors, respectively. The medians of CD66a and CGM2 expressions were between 0.3 and 0.0, respectively. The tumor:normal ratio of NCA mRNA expression was increased up to 2.4-fold in 11 of 22 adenomas. Altogether, these results compare well to the changes reported previously for colorectal carcinomas. The high frequency and early appearance of dysregulation of members of the carcinoembryonic antigen family during colorectal tumorigenesis suggests that these changes may be important for the development of the malignant phenotype.


[Evidence of effectiveness and prevention of occupational cancer].
The persistence of exposure to carcinogens at work in member States of the European union and in other industrialised countries has been repeatedly reported, and prompts for the epidemiologic assessment of trends in cancer risk according to changes in exposure distribution. Epidemiological evidence of risk reduction could be produced for all agents classified by the International agency for cancer research as Group 1 agents (human carcinogens). However, such evidence is available only for a much more limited number of agents. Benzene and asbestos are used as case-studies, given the very large number of epidemiological studies conducted on populations exposed to them. Only five studies assessed cancer risk after exposure cessation, and in four of them cessation was due to dismission of the industrial activities rather than to the introduction of industrial hygiene measures. The bases for assessment of effectiveness in the field of occupational (and environmental) prevention differ from those of evidence-based medicine. The burden of proof should be on the employer to demonstrate that a given industry can be operated safely; once evidences of adverse effects have been found, that should be per se sufficient to enforce strict control of exposures. From a methodological point of view, it would be either impossible or unethical to conduct controlled trials to assess effectiveness, and in general the highest level of evidence that can be reasonably achieved is that provided by observational studies.


Ownership in Name, But not Necessarily in Action Comment on "It's About the Idea Hitting the Bull's Eye": How Aid Effectiveness Can Catalyse the Scale-up of Health Innovations".
A recently-published paper by Wickremasinghe et al assesses the scalability of pilot projects in three countries using the aid effectiveness agenda as an analytical framework. The authors report uneven progress and recommend applying aid effectiveness principles to improve the scalability of projects. This commentary focuses on one key principle of aid effectiveness - country ownership; it describes difficulties in defining and achieving it, and provides practical steps donors and recipient governments can take to move forward towards country ownership.


Sexual orientation perception involves gendered facial cues.
Perceivers can accurately judge a face's sexual orientation, but the perceptual mechanisms mediating this remain obscure. The authors hypothesized that stereotypes casting gays and lesbians as gender "inverts," in cultural circulation for a century and a half, lead perceivers to use gendered facial cues to infer sexual orientation. Using computer-generated faces, Study 1 showed that as two facial dimensions (shape and texture) became more gender inverted, targets were more likely to be judged as gay or lesbian. Study 2 showed that real faces appearing more gender inverted were more likely to be judged as gay or lesbian. Furthermore, the stereotypic use of gendered cues influenced the accurate judgment of sexual orientation. Although using gendered cues increased the accuracy of sexual orientation judgments overall, Study 3 showed that judgments were reliably mistaken for targets that countered stereotypes. Together, the findings demonstrate that perceivers utilize gendered facial cues to glean another's sexual orientation, and this influences the accuracy or error of judgments.


A Flexible Conductive Electrode Using Boronic-Acid Modified Carbon Dots.
Flexible electrodes are becoming a topic of interest for a range of applications including implantation. They can be used for neural signal recording and for electrical stimulation of atrophying muscles. Unlike the traditionally used metal electrodes that are harsh to the body's tissues, flexible electrodes conduct electricity while preserving the delicate tissues. Polydimethylsiloxane (PDMS), a non-conductive synthetic polymer characterized by its flexibility, low cost, biocompatibility, and durability during implantation, has been explored as a matrix for flexible electrodes. This study reports the synthesis of composite boronic acid-modified carbon dots (BA-CDs)/PDMS electrode materials. The performance of the composite electrode is evaluated electrochemically (for its conductivity and charge storage capacity) and mechanically (Young's modulus). Furthermore, the effect of increasing the PDMS crosslinking density on the electrode's performance is studied based on the hypothesis that a higher crosslinking will bring the BA-CDs closer together, thereby facilitating the movement of electrons. Results of this study showed that incorporating 10% BA-CDs dispersed with 16% glycerol in 74% PDMS with a higher crosslinking density resulted in a bulk impedance of 47.7 Ω and a conductivity of 2.68×10-3 S/cm, both of which surpassed that of the same composition with lower crosslinking. The synthesized flexible electrode material was capable of charge storage although the charge storage capacity (0.00365 mC/cm2) was lower than the safe limit for some tissue activation. Furthermore, the electrode maintained a modulus of elasticity (0.2322 MPa) that is compatible with biological soft tissues.Clinical Relevance- This study reports a conductive electrode that has a flexibility compatible with that of biological tissues for future purposes such as neural signal recording and tissue electrical stimulation (e.g. atrophying muscles). The reported BA-CD/PDMS electrode overcomes the limitations of the harsh metals previously used as implantable electrodes that harm the biological tissues due to their high rigidity.


Establishing the South Australian Macrobenthic Traits (SAMT) database: A trait classification for functional assessments.
Trait-based approaches are increasingly used as a proxy for understanding the relationship between biodiversity and ecosystem functioning. Macrobenthic fauna are considered one of the major providers of ecosystem functions in marine soft sediments; however, several gaps persist in the knowledge of their trait classification, limiting the potential use of functional assessments. While trait databases are available for the well-studied North Atlantic benthic fauna, no such trait classification system exists for Australia. Here, we present the South Australian Macrobenthic Traits (SAMT) database, the first comprehensive assessment of macrobenthic fauna traits in temperate Australian waters. The SAMT database includes 13 traits and 54 trait-modalities (e.g., life history, morphology, physiology, and behavior), and is based on records of macrobenthic fauna from South Australia. We provide trait information for more than 250 macrobenthic taxa, including outcomes from a fuzzy coding procedure, as well as an R package for using and analyzing the SAMT database. The establishment of the SAMT constitutes the foundation for a comprehensive macrobenthic trait database for the wider southern Australian region that could facilitate future research on functional perspectives, such as assessments of functional diversity and changes to ecosystem functioning.


The effect of endometrial thickness on in vitro fertilization (IVF)-embryo transfer/intracytoplasmic sperm injection (ICSI) outcome.
The value of measuring the endometrial thickness and studying the endometrial receptivity in the context of assisted conception remains a contentious issue. A prospective analysis was carried out to determine the effect of endometrial thickness on IVF - embryo transfer/ICSI outcome in dedicated Assisted Reproductive Technology (ART) units in Abuja and Rivers State, Nigeria. Two hundred and fifty one patients who met the inclusion criteria were analysed. They were grouped on the basis of endometrial thickness into 3 groups; <7 mm, 7 - 14 mm and >14 mm. The main outcome measure was clinical pregnancy. There were significantly more pregnancies in the 7 - 14 mm endometrial thickness group compared to the <7 mm and >14 mm groups, p=0.004 and p<0.0001 respectively. The findings suggest that following IVF/ICSI, significantly more pregnancies occurred when the endometrial thickness was between 7 and 14 mm.


Blood biochemical status of deep-sea sharks following longline capture in the Gulf of Mexico.
Prior to the Deepwater Horizon (DWH) oil spill, little research effort was focused on studying deep-sea sharks in the Gulf of Mexico (GoM). While the biology of these fishes remains virtually unknown, they are routinely captured in commercial fisheries as bycatch. In the absence of basic biological data, and with the probability of post-release survival unknown for most species, effective management plans cannot be formulated, making populations highly susceptible to overfishing. Any potential detrimental effects of the DWH oil spill, which occurred at 1500 m deep, are also unknown. Following longline capture, we characterized the physiological blood biochemical parameters related to secondary stress and compared them among seven shark species occurring on the continental shelf edge and slope in the GoM at depths ranging from 200 to 2000 m. We also investigated the relationship between blood parameters and depth as well as proximity to the oil spill site. The deep-sea sharks examined here exhibited variability in blood chemistry associated with the secondary stress response, with values falling within published records for previously studied elasmobranchs. Results suggested that there is greater relative physiological stress in shallower-dwelling sharks as well as smaller-bodied sharks. Further, the rate of core temperature warming was fastest in smaller bodied sharks, which likely contributes to greater physiological stress. The core temperatures of the larger-bodied, deeper-dwelling species were not altered as drastically as the smaller-bodied sharks after being hauled to the surface. Any chronic physiological effects of the oil spill were not detectable as there were no relevant correlations between blood chemistry metrics and proximity to the DWH oil spill site.


Human plasma alpha 2-macroglobulin. An inhibitor of plasma kallikrein.
Activation of plasma kallikrein arginine esterase activity by kaolin resulted in peak activity at 1 min of incubation and a 50% reduction in activity at 5 min in normal plasma, and 30% reduction in the plasma of patients with hereditary angioneurotic edema who lacked the C1 inactivator. The peak esterolytic activity was inhibited by soybean trypsin inhibitor whereas the 5 min activity was resistant to this inhibitor. Acid treatment of normal and hereditary angioneurotic edema plasma destroyed the factor responsible for the fall in esterase activity at 5 min and the factor which rendered the esterase resistant to soybean trypsin inhibitor. Purified alpha(2)-macroglobulin inhibited approximately 50% of the TAMe esterase activity of purified plasma kallikrein without changing its activity toward basic amino acid esters. The interaction between the alpha(2)-macroglobulin and kallikrein resulted in alterations in the gel filtration chromatographic pattern of the TAMe esterase and biologic activity of kallikrein, indicating that kallikrein was bound to the alpha(2)-macroglobulin. The TAMe esterase activity of this complex, isolated by column chromatography, was resistant to C1 inactivator and SBTI. Studies of incubation mixtures of kallikrein, alpha(2)-macroglobulin and C1 inactivator suggested that these inhibitors compete for the enzyme, and that the alpha(2)-macroglobulin partially protects the esterase activity of kallikrein from C1 inactivator. The alpha(2)-macroglobulin isolated from kaolin-activated plasma possessed 240 times the esterolytic activity of the alpha(2)-macroglobulin purified from plasma treated with inhibitors of kallikrein and of its activation. The alpha(2)-macroglobulin blocked the uterine-containing activity and vascular permeability-inducing effects of plasma kallikrein. These studies suggest that the alpha(2)-macroglobulin is a major plasma inhibitor of kallikrein and provide a new example of an interrelationship between the coagulation, fibrinolytic, and kallikrein enzyme systems.


A comparison between ultrasonic array beamforming and super resolution imaging algorithms for non-destructive evaluation.
In this paper the total focusing method, the so called gold standard in classical beamforming, is compared with the widely used time-reversal MUSIC super resolution technique in terms of its ability to resolve closely spaced scatterers in a solid. The algorithms are tested with simulated and experimental array data, each containing different noise levels. The performance of the algorithms is evaluated in terms of lateral resolution and sensitivity to noise. It is shown that for the weak noise situation (SNR>20 dB), time-reversal MUSIC provides significantly enhanced lateral resolution when compared to the total focusing method, breaking the diffraction limit. However, for higher noise levels, the total focusing method is shown to be robust, whilst the performance of time-reversal MUSIC is degraded. The influence of multiple scattering on the imaging algorithms is also investigated and shown to be small.


Ludwig's angina.
Ludwig's angina is a cellulitis frequently occurring as a result of infections of the second and third lower molar. Despite a decrease in mortality from 50% to less than 10% since the introduction of antibiotics, it remains a rare but life-threatening illness. The potential for rapid respiratory obstruction is the greatest concern. Familiarity with the anatomy of the neck and recognition of symptoms are essential for effective treatment. Treatment focuses on maintenance of an airway, antibiotic therapy, and surgery. Asphyxia, aspiration, mediastinitis, pneumonia, empyema, and septicemia are possible complications.


The need for comprehensive diet studies to assess the relation of lipids to cancer.
Dietary lipids have been linked by both basic research and epidemiological evidence to the etiology of some cancers. It is yet unclear which lipid(s) may be active in the carcinogenic process, but one promising hypothesis concerns the interaction of cholesterol metabolites, considered a risk factor for colon cancer, and dietary fiber which may have a protective role. A multidisciplinary case control study currently underway is investigating the relationship and possible mode of action of fiber and bile acids on colon cancer. The study has epidemiological, biochemical, and pharmacological components that have been designed to integrate data on the intake and fate of lipids, dietary fiber, and other nutritional parameters in colon cancer cases and matched controls and in animal models. Subcomponents of the study deal specifically with the characterization of dietary fiber constituents and their in vivo effect on lipid metabolism.


Digital approach to informed consent in bariatric surgery: a randomized controlled trial.
Informed consent is of paramount importance in surgery. Digital media can be used to enhance patient's comprehension of the proposed operation. The objective of this study was to examine the effects of adding a digital educational platform (DEP) to a standard verbal consent (SVC) for a laparoscopic Roux-en-Y gastric bypass (LRYGB) on patient's knowledge of the procedure, satisfaction with the clinical encounter and duration of the consent appointment. This prospective non-blinded randomized controlled trial allocated 51 patients, who were candidates for a LRYGB, into DEP+SVC (intervention, n = 26) or SVC (control, n = 25) groups. Data were collected at one Bariatric Centre of Excellence (Ontario, Canada) between December 2018 and December 2019. DEP consisted of a 29-slide video-supplemented module detailing the risks, benefits, expectations and outcomes for the LRYGB. Primary outcome was knowledge about the LRYGB operation following the consent discussion. Secondary outcomes were knowledge retention, patient satisfaction, and duration of time required to obtain an informed consent. Baseline demographic data were equivalent between groups except for a greater proportion of male patients in the DEP+SVC group (7/19 vs 0/25; p < 0.01). Baseline procedure-specific knowledge was equivalent between the groups (72.3 ± 11.3% vs 74.7 ± 9.6%; p = 0.41). Post-consent knowledge was significantly higher in the DEP + SVC vs SVC group (85.0 ± 8.8% vs 78.7 ± 8.7%; p = 0.01; ES = 0.72). The duration of time to obtain informed consent was significantly shorter for the DEP + SVC vs SVC group (358 ± 198 sec vs 751 ± 212 sec; p < 0.01; ES = 1.92). There was no difference in knowledge retention at 4-6 weeks (84.4 ± 10.2% vs 82.9 ± 6.8%; p = 0.55) and in patient satisfaction (31.5 ± 1.1 vs 31 ± 2.7; p = 0.10). The addition of a DEP online module to a standard verbal consent for LRYGB resulted in improved patient's understanding of the procedure-specific risks and benefits, high patient satisfaction, and over 50% time savings for the bariatric surgeon conducting the consent discussion.


3D high-density microelectrode array with optical stimulation and drug delivery for investigating neural circuit dynamics.
Investigation of neural circuit dynamics is crucial for deciphering the functional connections among regions of the brain and understanding the mechanism of brain dysfunction. Despite the advancements of neural circuit models in vitro, technologies for both precisely monitoring and modulating neural activities within three-dimensional (3D) neural circuit models have yet to be developed. Specifically, no existing 3D microelectrode arrays (MEAs) have integrated capabilities to stimulate surrounding neurons and to monitor the temporal evolution of the formation of a neural network in real time. Herein, we present a 3D high-density multifunctional MEA with optical stimulation and drug delivery for investigating neural circuit dynamics within engineered 3D neural tissues. We demonstrate precise measurements of synaptic latencies in 3D neural networks. We expect our 3D multifunctional MEA to open up opportunities for studies of neural circuits through precise, in vitro investigations of neural circuit dynamics with 3D brain models.


Toll-Like Receptor 3 Is Involved in Detection of Enterovirus A71 Infection and Targeted by Viral 2A Protease.
Enterovirus A71 (EV-A71) has emerged as a major pathogen causing hand, foot, and mouth disease, as well as neurological disorders. The host immune response affects the outcomes of EV-A71 infection, leading to either resolution or disease progression. However, the mechanisms of how the mammalian innate immune system detects EV-A71 infection to elicit antiviral immunity remain elusive. Here, we report that the Toll-like receptor 3 (TLR3) is a key viral RNA sensor for sensing EV-A71 infection to trigger antiviral immunity. Expression of TLR3 in HEK293 cells enabled the cells to sense EV-A71 infection, leading to type I, IFN-mediated antiviral immunity. Viral double-stranded RNA derived from EV-A71 infection was a key ligand for TLR3 detection. Silencing of TLR3 in mouse and human primary immune cells impaired the activation of IFN-β upon EV-A71 infection, thus reinforcing the importance of the TLR3 pathway in defending against EV-A71 infection. Our results further demonstrated that TLR3 was a target of EV-A71 infection. EV-A71 protease 2A was implicated in the downregulation of TLR3. Together, our results not only demonstrate the importance of the TLR3 pathway in response to EV-A71 infection, but also reveal the involvement of EV-A71 protease 2A in subverting TLR3-mediated antiviral defenses.


Mutagenicity studies in Salmonella typhimurium on some carcinogenic N-nitramines in vitro and in the host-mediated assay in rats.
N-Nitrodimethylamine, N-nitrodiethylamine, N-nitromorpholine and their N-nitroso analogs, N-nitrosodimethylamine, N-nitrosodiethylamine, and N-nitrosomorpholine, were tested in Salmonella typhimurium strains TA100 and TA1530. The mutagenicity of all compounds, except N-nitrodiethylamine, was demonstrated in liquid incubation assays in at least one of the tester strains; it required the presence of a postmitochondrial supernatant from the liver of Aroclor-treated rats, reduced nicotinamide adenine dinucleotide phosphate-generating system, and oxygen. When compared on a molar basis with their N-nitroso analogs, N-nitromorpholine was about 10 times less mutagenic and N-nitrodimethylamine about 70 times less mutagenic. Addition of disulfiram to the assays at a final concentration of 0.1 mM efficiently inhibited mutagenesis by all nitro and nitroso compounds; ascorbic acid at a 7.4 mM concentration produced less inhibition. Mutagenic activity of the three nitramines was also determined in the host-mediated assay in rats. After p.o. administration of each of the N-nitramines, cells of S. typhimurium strains TA1530 and TA100 that had been injected i.p. were isolated from the peritoneal liquid after 1, 3, and 6 hr. All three nitramines were found to be mutagenic for strain TA1530 but not for TA100. Mutation frequencies (number of histidine revertants per 10(6) surviving cells) were in the descending order N-nitromorpholine greater than N-nitrodiemethylamine greater than N-nitrodiethylamine. After a p.o. dose of N-nitrodiethylamine to rats, bacteria were also isolated from liver, lungs, and kidneys. Mutation frequency was highest in bacteria recovered from the liver but was not increased in those obtained from lungs and kidneys. The data suggest that carcinogenic nitramines exert their mutagenic effects through the formation of alkylating intermediates.


Consensus on Outcome Measures for Glaucoma Effectiveness Trials: Results From a Delphi and Nominal Group Technique Approaches.
Comparing the relative effectiveness of interventions across glaucoma trials can be problematic due to differences in definitions of outcomes. We sought to identify a key set of clinical outcomes and reach consensus on how best to measure them from the perspective of glaucoma experts. A 2-round electronic Delphi survey was conducted. Round 1 involved 25 items identified from a systematic review. Round 2 was developed based on information gathered in round 1. A 10-point Likert scale was used to quantify importance and consensus of outcomes (7 outcomes) and ways of measuring them (44 measures). Experts were identified through 2 glaucoma societies membership-the UK and Eire Glaucoma Society and the European Glaucoma Society. A Nominal Group Technique (NGT) followed the Delphi process. Results were analyzed using descriptive statistics. A total of 65 participants completed round 1 out of 320; of whom 56 completed round 2 (86%). Agreement on the importance of outcomes was reached on 48/51 items (94%). Intraocular pressure (IOP), visual field (VF), safety, and anatomic outcomes were classified as highly important. Regarding methods of measurement of IOP, "mean follow-up IOP" using Goldmann applanation tonometry achieved the highest importance, whereas for evaluating VFs "global index mean deviation/defect (MD)" and "rate of VF progression" were the most important. Retinal nerve fiber layer (RNFL) thickness measured by optical coherence tomography (OCT) was identified as highly important. The NGT results reached consensus on "change of IOP (mean of 3 consecutive measurements taken at fixed time of day) from baseline," change of VF-MD values (3 reliable VFs at baseline and follow-up visit) from baseline, and change of RNFL thickness (2 good quality OCT images) from baseline. Consensus was reached among glaucoma experts on how best to measure IOP, VF, and anatomic outcomes in glaucoma randomized controlled trials.


Insulin degradation by hepatocytes in primary culture.
The mechanism by which the liver degrades insulin has not yet been completely clarified. In intact, non-"leaky" cells the primary process seems to be mediated by initial receptor binding. We now demonstrate that isolated rat hepatocytes in primary culture are suitable for examining insulin degradation. Hepatocytes did not leak degrading activity into the medium, and thus, the degradation seen was essentially exclusively cell mediated. [125I]Iodoinsulin degradation by these cells was dependent on time and cell concentration. There was a short lag time before degradation products could be detected in the medium. After incubation with the hepatocytes, three peaks of 125I-labeled material could be separated by chromatography on Sephadex G-50. The same three peaks were seen with 125I-labeled material extracted from the cells. When [3H]insulin, labeled exclusively at the B-1 phenylalanine residue, was incubated with the cells, additional peaks of labeled material were recovered from the column. These additional peaks were intermediate in size between insulin and iodotyrosine, suggesting the production of products smaller than insulin but larger than individual amino acids. In order to begin to characterize the subcellular mechanisms for insulin metabolism, the effect of various potential inhibitors on insulin degradation were examined. The most effective inhibitors were N-ethylmaleimide, bacitracin, and Kunitz pancreatic trypsin inhibitor. Chloroquine decreased degradation only 10%, and NH4Cl had no detectable effect. The effect of the inhibitors on the purified insulin-degrading enzyme, insulin protease, was also examined. The purified enzyme responded essentially identically as the intact cells to the various inhibitors. From all these data it would seem that lysosomal degradation of insulin in the hepatocyte may be a relatively minor pathway and the neutral protease may play a major role.


Potent Acid Suppression With Vonoprazan vs Proton Pump Inhibitors Does Not Have Higher Association With Clostridioides difficile Infection.
Proton pump inhibitors (PPIs) are associated with the onset of Clostridioides difficile infection (CDI). Although a new potassium-competitive acid blocker, vonoprazan, consistently shows a more potent acid inhibitory effect in comparison to PPIs, the risk of CDI in vonoprazan-treated patients relative to those treated with PPIs is unknown. In this retrospective case-control study, using a nationwide hospital-based administrative database in Japan, we investigated the association of the onset of CDI in patients treated with vonoprazan. A CDI case was defined as a case in which a patient was diagnosed and treated for CDI. For each CDI case, 3 non-CDI patients were extracted as controls. Information on the usage of acid suppressants in the 2 months before the onset of CDI and other confounding factors was collected. Relative associations of gastric acid suppressants with the onset of CDI were estimated. A total of 4,466 CDI cases and 13,220 of non-CDI controls were extracted. A multivariate conditional regression analysis revealed that PPI or vonoprazan use was modestly, but significantly associated with CDI (odds ratio [95% confidence interval]: PPI, 1.3 [1.2-1.4]; vonoprazan, 1.4 [1.2-1.7]). With PPI users as a reference, vonoprazan did not show a stronger association with CDI (odds ratio [95% confidence interval]: 1.07 [0.91-1.26]). We found a significant positive association between vonoprazan use and CDI; however, the magnitude of the association was not beyond that in PPI users. This is the first report on any potential adverse effects of vonoprazan.


Lamotrigine adjunctive therapy for refractory generalized tonic-clonic seizures.
Primary generalized tonic-clonic seizures are one of a number of generalized seizure types which also includes absence, myoclonic and atonic seizures. Effective control of tonic-clonic seizures is required to reduce the risk of injury and death and to improve quality of life. While most people achieve seizure control with one antiepileptic drug, around 30% do not and usually take a combination of antiepileptic drugs. To assess the effectiveness of adjunctive lamotrigine for refractory primary generalized tonic-clonic seizures. We searched the Cochrane Epilepsy Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) and MEDLINE (Ovid) 1950 to June 2010. No language restrictions were imposed. We also contacted GlaxoSmithKline, manufacturers of lamotrigine. Randomised parallel or cross-over add-on trials of add-on lamotrigine for refractory primary generalized tonic-clonic seizures. Outcome measures were: proportion of people (1) with 50% or greater reduction in frequency; (2) with cessation of seizures; (3) who had treatment withdrawn; (4) with adverse effects; and (5) cognitive effects; (6) quality of life outcome measures. Data were independently extracted by review authors. Two small trials were found that met the inclusion criteria. Due to differences in study design we decided not to undertake a meta-analysis. One placebo controlled cross-over trial (26 participants) showed a significant 50% reduction in tonic-clonic seizure frequency with lamotrigine. Rash was the only adverse effect causing discontinuation (N = 7). A placebo controlled parallel trial comparing 117 participants found a significant median percent reduction in tonic-clonic seizure frequency of 66.5% with lamotrigine compared with 34.2% with placebo (P = 0.006). The most common adverse events were dizziness, somnolence and nausea. Two short term trials indicate that lamotrigine has efficacy against primary generalized tonic-clonic seizures; however, this evidence is insufficient to inform clinical practice and longer term active controlled trials are required.


Complex organic molecules along the accretion flow in isolated and externally irradiated protoplanetary disks.
The birth environment of the Sun will have influenced the physical and chemical structure of the pre-solar nebula, including the attainable chemical complexity reached in the disk, important for prebiotic chemistry. The formation and distribution of complex organic molecules (COMs) in a disk around a T Tauri star is investigated for two scenarios: (i) an isolated disk, and (ii) a disk irradiated externally by a nearby massive star. The chemistry is calculated along the accretion flow from the outer disk inwards using a comprehensive network which includes gas-phase reactions, gas-grain interactions, and thermal grain-surface chemistry. Two simulations are performed, one beginning with complex ices and one with simple ices only. For the isolated disk, COMs are transported without major chemical alteration into the inner disk where they thermally desorb into the gas reaching an abundance representative of the initial assumed ice abundance. For simple ices, COMs can efficiently form on grain surfaces under the conditions in the outer disk. Gas-phase COMs are released into the molecular layer via photodesorption. For the irradiated disk, complex ices are also transported inwards; however, they undergo thermal processing caused by the warmer conditions in the irradiated disk which tends to reduce their abundance along the accretion flow. For simple ices, grain-surface chemistry cannot efficiently synthesise COMs in the outer disk because the necessary grain-surface radicals, which tend to be particularly volatile, are not sufficiently abundant on the grain surfaces. Gas-phase COMs are formed in the inner region of the irradiated disk via gas-phase chemistry induced by the desorption of strongly bound molecules such as methanol; hence, the abundances are not representative of the initial molecular abundances injected into the outer disk. These results suggest that the composition of comets formed in isolated disks may differ from those formed in externally irradiated disks with the latter composed of more simple ices.


Anxiety and depressive symptoms and missing breast cancer and cervical screening: results from Brazos valley community health survey.
Breast and cervical cancer screening are associated with dramatically reduced cancer mortality. Mental illnesses have been demonstrated to influence preventative behaviours. This study aims to explore whether anxiety or depressive symptoms is associated with breast and cervical cancer screening. We analyzed data (n = 3104) from the 2013 Brazos Valley Community Health Assessment. The GAD-7 Scale was used to assess the anxiety level, and PHQ-2 was used to assess the depressive symptoms. Stata 15.0 statistical software was used to perform descriptive and logistic regression analysis. Overall, 80.61% of women in each sample met breast cancer or cervical cancer screening guidelines, respectfully. Anxiety was associated with missing breast and cervical cancer screening, but the association was only significant for cervical cancer (OR = 1.430, CI = 1.009, 2.026), not for breast cancer (OR = 1.406, CI = .952, 2.078). Depressive symptom was significantly associated with missing breast (OR = 1.502, CI = 1.051, 2.149) and cervical (OR = 1.689, CI = 1.208, 2.362) cancer screening after controlling for demographics. Women with depressive symptoms and anxiety had higher odds of missing breast and cervical cancer screening. Health promotion programs should consider targeting individuals with anxiety and depression to improve cancer-screening rates..


Acidic oligosaccharide sugar chain, a marine-derived acidic oligosaccharide, inhibits the cytotoxicity and aggregation of amyloid beta protein.
In this paper, we investigated interactions of the acidic oligosaccharide sugar chain (AOSC), derived from brown algae Echlonia kurome OKAM, with amyloid beta protein (Abeta). We observed that AOSC inhibited the toxicity induced by Abeta in both primarily cortical cells and the SH-SY5Y cell line. We also observed that AOSC inhibited the apoptosis induced by Abeta in SH-SY5Y by reducing the elevated level of intracellular calcium concentration ([Ca(2+)](i)) and suppressing the generation of reactive oxygen species. Surface plasmon resonance analysis demonstrated that AOSC had affinity for both freshly-dissolved Abeta and 48-h incubated Abeta. Furthermore, AOSC blocked the fibril formation of Abeta, which may be responsible for its anti-cytotoxic effects. Thus, our results indicate that AOSC might be a potentially therapeutic compound for Alzheimer's disease.


Age differences in alcohol prototype perceptions and willingness to drink in U.K. adolescents.
Using the prototype willingness model (PWM) as a framework, this study sought to explore the relationship between prototype perceptions, willingness and alcohol consumption in a sample of adolescents in the United Kingdom (UK). Adolescents aged 11-17 were asked about their alcohol prototype perceptions, willingness to drink, intentions, alcohol consumption, drunkenness and harms using a cross-sectional online survey. Participants were recruited through opportunity sampling via schools and parents. The survey was completed by 178 respondents (51% female; 91 aged 11-15, 87 aged 16-17). Multivariate analysis revealed significant differences between participants aged 11-15 and 16-17 on PWM measures, even when experience with drinking was accounted for (p < .001). There were significant interactions (p < .001) between age and prototype perceptions; younger participants rated non-drinker prototypes as more favourable and more similar to the self than 16- and 17-year-old participants. Willingness and intentions interacted with age; both measures were similar in 16- and 17-year-olds, whereas younger participants scored significantly higher on willingness than intentions (p < .001). Three distinct scales of prototype descriptions were identified in principal components analysis. Characteristics related to sociability significantly predicted willingness to drink alcohol in the sample (p < .001). This study extends previous research by demonstrating that the PWM can provide a theoretical explanation of adolescent drinking in the UK. The results suggest that 11- to 15-year-olds may be the most suitable age for an intervention that targets alcohol prototypes, with a focus on sociability characteristics.


Tensile strain induced half-metallicity in graphene-like carbon nitride.
Polymeric graphitic carbon nitride materials exhibit exotic properties superior to graphene which are promising for applications in energy conversion, environment protection, and spintronics devices. We propose a two-dimensional (2D) framework of graphene-like carbon nitride composing of C9N7 units connected by nitrogen atoms. From first-principles, we demonstrate that this 2D carbon nitride has a spin-polarized ground state and exhibits metallic electronic properties, in contrast to commonly studied graphitic carbon nitrides which are nonmagnetic semiconductors. Additionally, half-metallicity can be achieved in this framework by applying tensile strain. The realization will be beneficial for spintronics as a candidate material for a spin-current generator. More importantly, this provides a feasible way to realize half-metallicity in experiments.


1-Year Outcomes Following Transfemoral Transseptal Transcatheter Mitral Valve Replacement: The HighLife TSMVR Feasibility Study.
A significant number of patients with severe mitral regurgitation (MR) are not suitable for either surgical or transcatheter edge-to-edge repair because of high surgical risk or inappropriate mitral valve anatomy. The aim of this study was to evaluate the HighLife Trans-Septal Mitral Valve Replacement (TSMVR) system in patients with symptomatic MR and high surgical risk. This prospective, multicenter, nonrandomized feasibility study evaluated the safety and performance of the HighLife TSMVR system in patients with moderate to severe or severe symptomatic MR during 1-year follow-up. Echocardiographic data were assessed at an independent core laboratory. A total of 30 patients (mean age 75.6 years, 27% women, median Society of Thoracic Surgeons score 5.5%) with severe MR (90% with secondary MR, median left ventricular ejection fraction 43%) were treated at 13 sites. In 27 of the 30 patients, the HighLife TSMVR system was implanted successfully (technical success rate 90%). Device success at 30 days was 83%. After 1 year, 5 patients (17%) had died. None of the patients who underwent implantation required mitral valve reintervention. All patients who underwent implantation had no or trace (78%) or mild (22%) MR, the mean gradient of the HighLife valve was 5.1 mm Hg, and there were no signs of left ventricular outflow tract obstruction (mean gradient 2.0 mm Hg). The 1-year results from the HighLife TSMVR feasibility study demonstrate a high technical success rate, excellent valve function, no left ventricular outflow tract obstruction, and no need for mitral valve reintervention. Additional patient outcomes and longer follow-up are needed to confirm these findings. (Expanded Study of the HighLife 28mm Trans-Septal Trans-Catheter Mitral Valve in Patients With Moderate-Severe or Severe Mitral Regurgitation and at High Surgical Risk; NCT04029363).


VARIETAL RESISTANCE TO CONTROL FUSARIUM WILTS OF LEAFY VEGETABLES UNDER GREENHOUSE.
Fusarium wilts of leafy vegetables are difficult to manage under intensive cropping systems. The objective of this study was to evaluate, in three experimental trials, the susceptibility of commercial cultivars of lettuce, wild and cultivated rocket and lamb's lettuce to Fusarium wilts in orderto provide information to breeders, as well as to growers. Some of the cultivars of lettuce tested were completely resistant to the three races of Fusarium wilt. It is interesting to observe that most of the resistant cultivars were 'Batavia red'. Only few rocket cultivars commercially available show a partial resistant reaction to F. oxysporum f.sp. raphani, while, varietal resistance is not applicable at the moment to control Fusarium wilt of lamb's lettuce. The integration of cultural practices, use of resistant cultivars, when available, chemicals and biological control agents, permit to prevent and manage these important diseases on leafy vegetables for fresh-cut production.


The central role of broken bond-bending constraints in promoting glass formation in the oxides.
A glass network of N atoms with n(1) of the atoms with a coordination number of 1, and m(2) of the atoms with a coordination number of 2 about which the bond-angle constraint is broken, will in general display a stiffness threshold (rigidity percolation threshold) when the average coordination increases to a critical value (r)(c) = 2.4 - 0.4 (n(1) - m(2))/N. Silica and sodium tellurate glasses provide model examples for which this general relation predicts the observed rigidity percolation threshold; this relation predicts the percolation threshold only if one includes broken bond-bending constraints due to bridging oxygen in the former network and nonbridging oxygen in the latter network. The rigidity percolation threshold in (Na(2)O)x,(TeO(2))1-x glasses observed to occur near x approximately 0.18 in tellurium-125 Lamb-Mössbauer factor measurments.


TRPV6, TRPM6 and TRPM7 Do Not Contribute to Hair-Cell Mechanotransduction.
Hair cells of the inner ear transduce mechanical stimuli like sound or head movements into electrical signals, which are propagated to the central nervous system. The hair-cell mechanotransduction channel remains unidentified. We tested whether three transient receptor channel (TRP) family members, TRPV6, TRPM6 and TRPM7, were necessary for transduction. TRPV6 interacted with USH1C (harmonin), a scaffolding protein that participates in transduction. Using a cysteine-substitution knock-in mouse line and methanethiosulfonate (MTS) reagents selective for this allele, we found that inhibition of TRPV6 had no effect on transduction in mouse cochlear hair cells. TRPM6 and TRPM7 each interacted with the tip-link component PCDH15 in cultured eukaryotic cells, which suggested they might be part of the transduction complex. Cochlear hair cell transduction was not affected by manipulations of Mg2+, however, which normally perturbs TRPM6 and TRPM7. To definitively examine the role of these two channels in transduction, we showed that deletion of either or both of their genes selectively in hair cells had no effect on auditory function. We suggest that TRPV6, TRPM6 and TRPM7 are unlikely to be the pore-forming subunit of the hair-cell transduction channel.


Correlation of time to platelet engraftment with amount of transplanted CD34+CD41+ cells after allogeneic bone marrow transplantation.
A major problem after autologous or allogeneic stem cell transplantation is prolonged thrombocytopenia. There are several studies published about correlations of the composition of the graft and time to platelet engraftment for autologous transplantation but only a few studies for allogeneic transplantation. In our study, we wanted to find out whether the correlation between the time to platelet engraftment and amount of transplanted CD34(+)CD41(+) cells described previously after autologous peripheral blood stem cell transplantation could be reproduced in the allogeneic bone marrow transplantation setting. We found correlations not only for the number of transplanted CD34(+) cells with the time to leukocyte engraftment (r = -0.32, p = 0.045) but also for the number of transplanted CD34(+)CD41(+) cells and time to platelet engraftment (r = -0.34, p = 0.038), which were both statistically significant. A significant correlation between transplanted CD34(+) cells versus platelet engraftment and transplanted CD34(+)CD41(+) cells versus leukocyte engraftment was not found. The finding that the amount of committed megakaryocyte progenitor cells in the graft is an important predictive factor for platelet engraftment after allogeneic bone marrow transplantation might be the base for future studies of ex vivo expansion of clonable megakaryocyte precursors.


ClC-2 regulates mucosal barrier function associated with structural changes to the villus and epithelial tight junction.
We have previously shown an important role of the chloride channel ClC-2 in orchestrating repair of tight junctions in ischemia-injured mucosa. In this study, we examined the role of ClC-2 in regulating barrier function of normal murine intestinal mucosa. Ex vivo, ClC-2-/- ileal mucosa mounted in Ussing chambers had significantly higher transepithelial electrical resistance (TER) and reduced [(3)H]mannitol mucosal-to-serosal flux compared with wild-type (WT) mouse mucosa. We also noted that ileum from ClC-2-/- mice had a significantly reduced in vivo [(3)H]mannitol blood-to-lumen clearance compared with WT animals. By scanning electron microscopy, flat leaflike villi were found to have tapering, rounded apical tips in ClC-2-/- mucosa. By transmission electron microscopy, the apical intercellular tight junctions in ClC-2-/- intestine revealed lateral membranes that were less well defined but closely aligned compared with electron-dense and closely apposed tight junctions in WT mucosa. The width of apical tight junctions was significantly reduced in ClC-2-/- intestine. Such an alteration in tight junction ultrastructure was also noted in the testicular tissue from ClC-2-/- mice. The ClC-2-/- intestinal mucosa had reduced expression of phospho-myosin light chain (MLC), and inhibition of myosin light chain kinase (MLCK) in WT mucosa partially increased TER toward the TER in ClC-2-/- intestine. Contrary to our prior work on the reparative role of ClC-2 in injured mucosa, this study indicates that ClC-2 reduces barrier function in normal mucosa. The mechanisms underlying these differing roles are not entirely clear, although ultrastructural morphology of tight junctions and MLCK appear to be important to the function of ClC-2 in normal mucosa.


Pedunculopontine nucleus deep brain stimulation in Parkinson's disease: A clinical review.
Pedunculopontine nucleus region deep brain stimulation (DBS) is a promising but experimental therapy for axial motor deficits in Parkinson's disease (PD), particularly gait freezing and falls. Here, we summarise the clinical application and outcomes reported during the past 10 years. The published dataset is limited, comprising fewer than 100 cases. Furthermore, there is great variability in clinical methodology between and within surgical centers. The most common indication has been severe medication refractory gait freezing (often associated with postural instability). Some patients received lone pedunculopontine nucleus DBS (unilateral or bilateral) and some received costimulation of the subthalamic nucleus or internal pallidum. Both rostral and caudal pedunculopontine nucleus subregions have been targeted. However, the spread of stimulation and variance in targeting means that neighboring brain stem regions may be implicated in any response. Low stimulation frequencies are typically employed (20-80 Hertz). The fluctuating nature of gait freezing can confound programming and outcome assessments. Although firm conclusions cannot be drawn on therapeutic efficacy, the literature suggests that medication refractory gait freezing and falls can improve. The impact on postural instability is unclear. Most groups report a lack of benefit on gait or limb akinesia or dopaminergic medication requirements. The key question is whether pedunculopontine nucleus DBS can improve quality of life in PD. So far, the evidence supporting such an effect is minimal. Development of pedunculopontine nucleus DBS to become a reliable, established therapy would likely require a collaborative effort between experienced centres to clarify biomarkers predictive of response and the optimal clinical methodology. © 2017 International Parkinson and Movement Disorder Society.


[Lymphoid tissue in the wall of adult human gallbladder].
Lymphoid structures of mucosa and muscular coat from the gall bladder cervix, body and fornix were examined in histological preparations using morphometry and methods of variation statistics. Lymphocyte concentration in the organ walls grows proportionally to age. In the first period of maturity lymphoid nodules are absent in mucosal lamina propria while lymphoid nodules are rarely encountered among the cells of the fibroblastic series. Connective tissue layers of muscular coat are predominant sites of lymphoid aggregations. Senescence is characterised by the appearance of lymphoid nodules in the gall bladder mucosa. Cell concentration, structure and composition per unit area depend on nodule localization and the age of the individual.


Compliance with published recommendations for postoperative antibiotic management of children with appendicitis: A chart audit.
Recommendations for postoperative antibiotics for appendicitis were published by the American Pediatric Surgical Association (APSA) in 2010. However, implementation of practice recommendations often takes years. We measured compliance of pediatric surgeons (who receive reminders every 6months from the Division Chief) with the APSA recommendations. With Research Ethics Board approval, we completed a retrospective review of children who underwent appendectomy since 2010. Compliance with APSA recommendations was analyzed descriptively. Agreement between pediatric surgeons and pathologists was analyzed by kappa. We reviewed 242 charts. Patients were excluded for missing data (n=5) and diagnosis other than appendicitis (n=27), resulting in 210 patients with appendicitis (119 acute, 91 perforated). Agreement of perforation status between surgeons and pathologists was good (κ=0.75; 95% CI: 0.66-0.83). Many patients with nonperforated appendicitis received antibiotics in excess of the APSA recommendations (62/119 (52%)), as did those with uncomplicated perforated appendicitis (52/84 (62%)). Despite the availability of published recommendations, surgeons continue to prescribe postoperative antibiotics for appendicitis in excess of the recommendations. Overtreatment leads to potential medication errors and increased length-of-stay/medication costs. An intensive implementation program with ongoing education/monitoring may improve compliance with established recommendations to decrease the use of excess postoperative antibiotics and their associated costs/risks.


Myoglobin--a marker of reperfusion and a prognostic indicator in patients with acute myocardial infarction.
Early noninvasive identification of patients with occluded infarct-related arteries after thrombolysis has important prognostic and therapeutic implications. Recent reports indicate that plasma kinetics of cardiac marker proteins could be very useful in diagnosis of myocardial reperfusion. Although angiographic assessment remains the ideal procedure for determining patency, it is expensive, invasive, not within the reach of most patients in developing countries, and the long-term follow-up data are still sparse. The present study was undertaken to investigate whether plasma kinetics of myoglobin in conjunction with clinical markers and another biochemical marker, creatine kinase, could be used to predict myocardial reperfusion more accurately and to investigate the correlation between myoglobin release after thrombolysis and mortality in patients with acute myocardial infarction (AMI) over a follow-up period of 18 months. Eighty-three consecutive patients with AMI receiving streptokinase treatment were studied for plasma kinetics of myoglobin in conjunction with clinical markers and creatine kinase to predict reperfusion and were followed for a period of 18 months. Increased baseline mean +/- standard deviation levels of myoglobin were observed among "nonresponders" to streptokinase treatment compared with "responders" (469 +/- 386 microg/l vs. 270 +/- 211 microg/l). There was significantly more release of myoglobin following thrombolytic treatment among the responders than among the nonresponders (mean ratio of myoglobin levels at 90 min to 0 min 6.01 +/- 9.2 vs. 1.03 +/- 0.64). In a follow-up of 61 patients over a period of 18 months, 31% mortality was observed in the nonresponder group compared with 11.7% in the responder group. In responders, the mean ratio of myoglobin levels at 90 and 0 min was significantly less among those who died (p = 0.019) than among those who survived. A myoglobin release profile in combination with other clinical markers offers inexpensive, noninvasive, and a reasonably reliable way of assessing coronary artery patency after thrombolytic treatment.


Severity of Omicron (B.1.1.529) and Delta (B.1.617.2) SARS-CoV-2 infection among hospitalised adults: A prospective cohort study in Bristol, United Kingdom.
There is an urgent public health need to evaluate disease severity in adults hospitalised with Delta and Omicron SARS-CoV-2 variant infections. However, limited data exist assessing severity of disease in adults hospitalised with Omicron SARS-CoV-2 infections, and to what extent patient-factors, including vaccination, age, frailty and pre-existing disease, affect variant-dependent disease severity. A prospective cohort study of adults (≥18 years of age) hospitalised with acute lower respiratory tract disease at acute care hospitals in Bristol, UK conducted over 10-months. Delta or Omicron SARS-CoV-2 infection was defined by positive SARS-CoV-2 PCR and variant identification or inferred by dominant circulating variant. We constructed adjusted regression analyses to assess disease severity using three different measures: FiO2 >28% (fraction inspired oxygen), World Health Organization (WHO) outcome score >5 (assessing need for ventilatory support), and hospital length of stay (LOS) >3 days following admission for Omicron or Delta infection. Independent of other variables, including vaccination, Omicron variant infection in hospitalised adults was associated with lower severity than Delta. Risk reductions were 58%, 67%, and 16% for supplementary oxygen with >28% FiO2 [Relative Risk (RR) = 0.42 (95%CI: 0.34-0.52), P < 0.001], WHO outcome score >5 [RR = 0.33 (95%CI: 0.21-0.50), P < 0.001], and to have had a LOS > 3 days [RR = 0.84 (95%CI: 0.76-0.92), P < 0.001]. Younger age and vaccination with two or three doses were also independently associated with lower COVID-19 severity. We provide reassuring evidence that Omicron infection results in less serious adverse outcomes than Delta in hospitalised patients. Despite lower severity relative to Delta, Omicron infection still resulted in substantial patient and public health burden and an increased admission rate of older patients with Omicron which counteracts some of the benefit arising from less severe disease. AvonCAP is an investigator-led project funded under a collaborative agreement by Pfizer.


Mutant huntingtin does not cross the mitochondrial outer membrane.
Mutant huntingtin (mHTT) is associated with mitochondria, but the exact mitochondrial location of mHTT has not been definitively established. Recently, it was reported that mHTT is present in the intermembrane space and inhibits mitochondrial protein import by interacting with TIM23, a major component of mitochondrial protein import machinery, but evidence for functional ramifications were not provided. We assessed mHTT location using synaptic and nonsynaptic mitochondria isolated from brains of YAC128 mice and subjected to alkali treatment or limited trypsin digestion. Mitochondria were purified either with discontinuous Percoll gradient or with anti-TOM22-conjugated iron microbeads. We also used mitochondria isolated from postmortem brain tissues of unaffected individuals and HD patients. Our results demonstrate that mHTT is located on the cytosolic side of the mitochondrial outer membrane (MOM) but does not cross it. This refutes the hypothesis that mHTT may interact with TIM23 and inhibit mitochondrial protein import. The levels of expression of nuclear-encoded, TIM23-transported mitochondrial proteins ACO2, TUFM, IDH3A, CLPP and mitochondrially encoded and synthesized protein mtCO1 were similar in mitochondria from YAC128 mice and their wild-type littermates as well as in mitochondria from postmortem brain tissues of unaffected individuals and HD patients, supporting the lack of deficit in mitochondrial protein import. Regardless of purification technique, mitochondria from YAC128 and WT mice had similar respiratory activities and mitochondrial membrane potentials. Thus, our data argue against mHTT crossing the MOM and entering into the mitochondrial intermembrane space, making it highly unlikely that mHTT interacts with TIM23 and inhibits protein import in intact mitochondria.


Rostral elements of sympatho-motor circuitry: a virally mediated transsynaptic tracing study.
Numerous physiological and emotionally motivated behaviors, including locomotion, exercise, escape, and attack behaviors as well as passive coping responses, require concomitant activation of motor and sympathetic efferents. Such functional heterogeneity suggests the existence of dual function neurons that can simultaneously coordinate motor and sympathetic output. Because previous physiological investigations have implicated a number of mesencephalic and telencephalic regions in mediating these behaviors, we hypothesized the presence of dual function sympatho-motor neurons in these neural structures. To test this hypothesis, we used recombinant strains of the pseudorabies virus (PRV) for transsynaptic tract-tracing. PRV-152, a strain that expresses enhanced green fluorescent protein, was injected into sympathectomized gastrocnemius muscle, whereas PRV-BaBlu, which expresses beta-galactosidase, was injected into the adrenal gland in the same animals. Although coinfected neurons were detected in a number of mesencephalic and telencephalic regions, >50% of such neurons were located within specific subdivisions of two general areas: the hypothalamus and periaqueductal gray. These subdivisions included the ventrolateral periaqueductal gray, dorsomedial hypothalamus, dorsolateral lateral hypothalamus, and ventral portion of the medial parvocellular subdivision of the paraventricular nucleus of the hypothalamus (PVN). A subset of the sympatho-motor neurons within the PVN also contained either arginine vasopressin or oxytocin. This sympatho-motor circuitry likely plays an important role in mediating different aspects of stress responses and emotionally motivated behaviors.


Video-assisted thoracic surgery for pulmonary sequestration compared with posterolateral thoracotomy.
Pulmonary sequestration is a rare congenital malformation of the lungs. This study aims to evaluate the effectiveness of video-assisted thoracic surgery for the treatment of pulmonary sequestration in a larger series compared with posterolateral thoracotomy. The files of 42 patients with pulmonary sequestration treated via video-assisted thoracic surgery (18 cases) and posterolateral thoracotomy (24 cases) between September 2005 and May 2012 from a single institute were retrospectively reviewed. Data were collected regarding the patient demographics, medical history, preoperative investigations, intraoperative findings, and postoperative course. All sequestration lung lesions were found in the lower lobes (31 on the left, 11 on the right), with feeding arteries arising from the thoracic aorta (34 cases) and the abdominal aorta (8 cases). Thirty-nine cases of sequestration were intralobar, and only 3 cases were extralobar. All patients achieved successful resection (including 37 lobectomies, 2 pneumonectomies, and 3 resections of the extralobar lesion). In the video-assisted thoracic surgery group, 1 case was converted to thoracotomy because of an injury to the aberrant artery; 1 case had injury to the left lower pulmonary vein and 1 case had injury to the aberrant artery, which were successfully treated without conversion. No significant differences were found between the 2 groups (video-assisted thoracic surgery vs posterolateral thoracotomy) in terms of the duration of operation, blood loss, amount of chest drainage, duration of chest drainage, length of postoperative hospital stay, and complications. Video-assisted thoracic surgery resection for pulmonary sequestration is feasible, although it should be performed by an experienced surgeon with awareness of the potential risk of severe vascular injury.


[Specificities of supportive care in geriatric oncology].
Supportive care in geriatric oncology is crucial care that should be proposed from the beginning of cancer treatment. More than the quantity of life, the quality of life is a primary goal when treating cancer in the older patients. An initial assessment of the frailty of the older patients should be carried out. The eight domains requiring in-depth assessment are social environment, functional status, walking and balance, cognition, psychological status, co-morbidity and polypharmacy, nutrition and sensory deficiencies. The alteration of these domains has an impact on the patient's outcome, his quality of life and the tolerance of the treatment. One of the major challenges is to maintain the autonomy of the older patient, which involves preserving his functional status, his neuropsychological state and his nutritional state. Corrective actions for each of the domains must be implemented and must be adjusted throughout the course. It is also important to anticipate risks that may compromise or delay the continuation of anti-tumor treatment such as falls, delirium, organ decompensation, iatrogenic risk and social isolation.


Spatial and temporal variations in mango colour, acidity, and sweetness in relation to temperature and ethylene gradients within the fruit.
Managing fruit quality is complex because many different attributes have to be taken into account, which are themselves subjected to spatial and temporal variations. Heterogeneous fruit quality has been assumed to be partly related to temperature and maturity gradients within the fruit. To test this assumption, we measured the spatial variability of certain mango fruit quality traits: colour of the peel and of the flesh, and sourness and sweetness, at different stages of fruit maturity using destructive methods as well as vis-NIR reflectance. The spatial variability of mango quality traits was compared to internal variations in thermal time, simulated by a physical model, and to internal variations in maturity, using ethylene content as an indicator. All the fruit quality indicators analysed showed significant spatial and temporal variations, regardless of the measurement method used. The heterogeneity of internal fruit quality traits was not correlated with the marked internal temperature gradient we modelled. However, variations in ethylene content revealed a strong internal maturity gradient which was correlated with the spatial variations in measured mango quality traits. Nonetheless, alone, the internal maturity gradient did not explain the variability of fruit quality traits, suggesting that other factors, such as gas, abscisic acid and water gradients, are also involved.


Controlling the electronic properties of 2D/3D pillared graphene and glass-like carbon via metal atom doping.
We present the results of investigation of the nanopore filling of planar layered and bulk pillared graphene (PGR) as well as films and 3D samples of glass-like porous carbon (GLC) with potassium atoms. The patterns of charge transfer, electronic structure, and shift of the Fermi level during the filling of nanopores with potassium atoms are established. It is found that the greatest charge transfer from potassium atoms to the carbon framework is observed in PGR with a density of 1.1-1.4 g cm-3 (that is, with a nanopore volume of 1300-1800 nm3) regardless of the framework topology. The maximum charge transfer occurs already when the mass fraction of potassium is 12 wt%. At the same potassium concentration, a maximum shift of the Fermi level to zero by ∼3 eV occurs in a bilayer PGR film with a density of 1.4 g cm-3. Thus, our work shows for the first time that the electronic properties of nanoporous materials doped with alkaline earth metals (in particular, potassium) can be controlled by varying the volume of doped nanopores, i.e. by controlling the density of the nanoporous material. We first demonstrated that the potassium doping of PGR would be more effective than potassium doping of GLC. It is established that 2D samples of PGR and GLC completely reproduce the electronic properties of the bulk samples and even surpass them in some parameters. To carry out research, we developed a new method for nanopore filling with dopant atoms based on both the randomness of the nanopore filling and the energy advantage of this process. This method allows us to reliably determine the maximum possible mass fraction (wt%) of dopant atoms of any porous material.


Chromatin context and ncRNA highlight targets of MeCP2 in brain.
The discovery that Rett syndrome (RTT) is caused by mutation of the methyl-CpG-binding-protein MeCP2 provided a major breakthrough in understanding the neurodevelopmental disorder and accelerated MeCP2 research. However, gene regulation by MeCP2 is complicated. The current consensus for MeCP2 remains as a classical repressor complex, with major emphasis on its role in methylation-dependent binding and repression. However, recent evidence indicates additional regulatory roles, suggesting non-classical mechanisms in gene activation. This has opened the field of MeCP2 research and suggests that the gene targets may not be the usual suspects, that is, dependent only on DNA methylation. Here we examine how chromatin binding and sequence preference may confer MeCP2 functionality, and connect relevant pathways in an active genome. Finding both genomic and proteomic evidence to indicate MeCP2 spliceosome interaction, we consequently discovered broad MeCP2 enrichment of the transcriptome while our focus toward long non-coding RNA (lncRNA) revealed MeCP2 association with RNCR3. Our data may indicate an as-yet-unappreciated role between lncRNA and MeCP2. We hypothesize that ncRNA may mediate chromatin-remodeling events by interacting with MeCP2, thereby conferring changes in gene expression. We consider that these results may suggest new mechanisms of gene regulation conferred by MeCP2 and its interactions upon chromatin structure and gene function.