Two-dimensional ternary chalcogenide nanodots with spatially controlled catalytic activity for bacteria infected wound treatment.
Nanozymes hold great prospects for bacteria-infected wound management, yet the spatial control of their catalytic activity in infected area and normal tissues remains mired by the heterogeneity of tissue microenvironment. Here, we develop a novel two-dimensional ternary chalcogenide nanodots (Cu2MoS4, CMS NDs) with renal clearable ability and controlled catalytic activity for bacteria-infected wound treatment. The two-dimensional CMS NDs (∼4 nm) are prepared by a simple microwave-assisted chemical synthetic route. Our results show that CMS NDs not only have peroxidase-like activity in a pH-dependent manner (pH < 5.5). Based on the generation of hydroxyl radical (OH) by adding H2O2, CMS NDs show > 2 log bacterial inactivation for both Gram-positive methicillin-resistant Staphylococcus aureus (MRSA) and Gram-negative Escherichia coli (E. coli) under the acidic condition. Moreover, CMS NDs show good biocompatibility and can be excreted by the kidney in mice. In vivo results display that CMS NDs show good therapeutic effect against bacteria infected wound in the presence of H2O2, but no damage for normal tissues. Taken together, this work provides a renal clearable two-dimensional nanozyme with spatially controlled catalytic activity for the treatment of wounds and bacterial infections on the skin surface.


Maintenance of Adaptive Dynamics and No Detectable Load in a Range-Edge Outcrossing Plant Population.
During range expansion, edge populations are expected to face increased genetic drift, which in turn can alter and potentially compromise adaptive dynamics, preventing the removal of deleterious mutations and slowing down adaptation. Here, we contrast populations of the European subspecies Arabidopsis lyrata ssp. petraea, which expanded its Northern range after the last glaciation. We document a sharp decline in effective population size in the range-edge population and observe that nonsynonymous variants segregate at higher frequencies. We detect a 4.9% excess of derived nonsynonymous variants per individual in the range-edge population, suggesting an increase of the genomic burden of deleterious mutations. Inference of the fitness effects of mutations and modeling of allele frequencies under the explicit demographic history of each population predicts a depletion of rare deleterious variants in the range-edge population, but an enrichment for fixed ones, consistent with the bottleneck effect. However, the demographic history of the range-edge population predicts a small net decrease in per-individual fitness. Consistent with this prediction, the range-edge population is not impaired in its growth and survival measured in a common garden experiment. We further observe that the allelic diversity at the self-incompatibility locus, which ensures strict outcrossing and evolves under negative frequency-dependent selection, has remained unchanged. Genomic footprints indicative of selective sweeps are broader in the Northern population but not less frequent. We conclude that the outcrossing species A. lyrata ssp. petraea shows a strong resilience to the effect of range expansion.


A new generation of mesenchymal stromal/stem cells differentially trained by immunoregulatory probiotics in a lupus microenvironment.
Increasing evidence suggests that multipotent mesenchymal stem/stromal cells (MSCs) are a promising intervention strategy in treating autoimmune inflammatory diseases. It should be stated that systemic immunoregulation is increasingly recognized among the beneficial effects of MSCs and probiotics in treating morbid autoimmune disorders such as lupus. This study aimed to determine if immunoregulatory probiotics L. rhamnosus or L. delbrueckii can change the immunomodulatory effects of MSCs in lupus-like disease. Pristane-induced lupus (PIL) mice model was created via intraperitoneal injection of Pristane and then confirmed. Naïve MSCs (N-MSCs) were coincubated with two Lactobacillus strains, rhamnosus (R-MSCs) or delbrueckii (D-MSCs), and/or a combination of both (DR-MSCs) for 48 h, then administrated intravenously in separate groups. Negative (PBS-treated normal mice) and positive control groups (PBS-treated lupus mice) were also investigated. At the end of the study, flow cytometry and enzyme-linked immunosorbent assay (ELISA) analysis were used to determine the percentage of Th cell subpopulations in splenocytes and the level of their master cytokines in sera, respectively. Moreover, lupus nephritis was investigated and compared. Analysis of variance (ANOVA) was used for multiple comparisons. Abnormalities in serum levels of anti-dsDNA antibodies, creatinine, and urine proteinuria were significantly suppressed by MSCs transplantation, whereas engrafted MSCs coincubation with both L. strains did a lesser effect on anti-dsDNA antibodies. L. rhamnosus significantly escalated the ability of MSCs to scale down the inflammatory cytokines (IFN-ɣ, IL-17), while L. delbrueckii significantly elevated the capacity of MSCs to scale down the percentage of Th cell subpopulations. However, incubation with both strains induced MSCs with augmented capacity in introducing inflammatory cytokines (IFN-ɣ, IL-17). Strikingly, R-MSCs directly restored the serum level of TGF-β more effectively and showed more significant improvement in disease parameters than N-MSCs. These results suggest that R-MSCs significantly attenuate lupus disease by further skew the immune phenotype of MSCs toward increased immunoregulation. Results demonstrated that Lactobacillus strains showed different capabilities in training/inducing new abilities in MSCs, in such a way that pretreated MSCs with L. rhamnosus might benefit the treatment of lupus-like symptoms, given their desirable properties.


Weight-bearing shifts of hemiparetic and healthy adults upon stepping on stairs of various heights.
To examine and compare the effect of stepping on stairs of various heights on lower extremity weight bearing in hemiparetic patients. Flieman Geriatric Rehabilitation Hospital, Haifa, Israel. Fifteen ambulatory hemiparetic patients following an acute cerebrovascular accident, and 16 age-matched healthy controls. Each subject was tested twice on two consecutive days in five weight-bearing positions which included level stance and stepping with either leg on 10-cm- and 17-cm-high steps. Data concerning weight distribution on the lower extremities were collected by two computerized forceplates. Weight borne by each foot expressed as percentage of overall body weight. In the attempted symmetrical level stance, the percentage of body weight borne by the paretic limb of the stroke patients was significantly lower than that of the nonparetic limb. Placing one foot on a step induced a weight shift to the foot placed on the floor regardless of step height. Weight shifting to the paretic limb was, however, significantly lower than to the nonparetic limb. Weight shifting to the nonparetic limb was significantly lower than to the corresponding limb of healthy individuals. Step height had no significant effect on weight distributions on the feet. Raising a foot on a step appears to be an appropriate strategy for weight shift training of stroke patients. Since weight shifting to both the paretic and nonparetic limb of stroke patients is impaired, treatment strategies should include training in weight shifting to both lower extremities.


Cytochrome P450c17alpha gene (CYP17) polymorphism predicts use of hormone replacement therapy.
We investigated whether a polymorphism in the cytochrome P450c17alpha gene (CYP17), which is associated with higher endogenous hormone levels, influences the use of hormone replacement therapy (HRT). The study included 749 postmenopausal women ages 44-75 years at baseline randomly selected from a larger multiethnic cohort. African-American, Japanese, Latina, and white women were included in the study. Women who carry the CYP17 A2/A2 genotype were about half as likely as women with the A1/A1 genotype to be current HRT users (odds ratio = 0.52; 95% confidence interval, 0.31-0.86). This association was present in all four racial/ethnic groups and for women above and below the median weight of 150 pounds. These findings suggest that the actual risk of breast cancer associated with HRT use may be higher than previously reported.


New practical algorithm for modelling analyte recovery in bioanalytical reversed phase and mixed-mode solid phase extraction.
Solid phase extraction (SPE) is a widely used method for sample cleanup and sample concentration in bioanalytical sample preparation. A few methods to model the retention behaviour on SPE cartridges have been described previously but they are either not applicable to ionised species or are not suitable when using multiple wash and elution steps with solvents differing in volume, modifier concentration and acidity. Furthermore, these models were not applied to mixed mode SPE sorbents. In order to overcome these limitations a new SPE modelling algorithm was proposed. The retention behaviour was determined directly on the SPE cartridge by connecting the cartridge online with an HPLC system using a simple but suitable device that was developed and described. The results from these online experiments were used to model the elution behaviour using a quadratic retention function combined with an exponentially modified Gaussian peak shape model to predict analyte recovery under different wash and elution conditions. The validity of the proposed algorithm was tested using practical SPE experiments with an aqueous test mixture as well as with spiked human plasma. Different sequential wash and elution steps were performed using solvents differing in volume and composition. The predicted band shape and recoveries in each collected step were in good agreement with the results obtained from practical experiments. The proposed algorithm is very useful for the description of the SPE behaviour of the analytes on the actual used SPE cartridge and can be used in structural and automated SPE method development.


Photochemically driven redox chemistry induces protocell membrane pearling and division.
Prior to the evolution of complex biochemical machinery, the growth and division of simple primitive cells (protocells) must have been driven by environmental factors. We have previously demonstrated two pathways for fatty acid vesicle growth in which initially spherical vesicles grow into long filamentous vesicles; division is then mediated by fluid shear forces. Here we describe a different pathway for division that is independent of external mechanical forces. We show that the illumination of filamentous fatty acid vesicles containing either a fluorescent dye in the encapsulated aqueous phase, or hydroxypyrene in the membrane, rapidly induces pearling and subsequent division in the presence of thiols. The mechanism of this photochemically driven pathway most likely involves the generation of reactive oxygen species, which oxidize thiols to disulfide-containing compounds that associate with fatty acid membranes, inducing a change in surface tension and causing pearling and subsequent division. This vesicle division pathway provides an alternative route for the emergence of early self-replicating cell-like structures, particularly in thiol-rich surface environments where UV-absorbing polycyclic aromatic hydrocarbons (PAHs) could have facilitated protocell division. The subsequent evolution of cellular metabolic processes controlling the thiol:disulfide redox state would have enabled autonomous cellular control of the timing of cell division, a major step in the origin of cellular life.


Expression of type I collagen pro-alpha 2 chain mRNA in adult human permanent teeth as revealed by in situ hybridization.
The expression of the gene COL1A2, coding for the pro-alpha 2 chain of type I pro-collagen, was analyzed in fully developed human permanent teeth. The teeth were fixed with formalin, demineralized with EDTA for about ten weeks, and embedded in paraffin. Pro-alpha 2(I) mRNA was localized in the sections by in situ hybridization, with use of [35S)]-labeled single-stranded RNA probes. The amount of mRNA for pro-alpha 2(I) collagen chain, as indicated by the relative densities of silver grains and the grain counts per cell in autoradiography, was high in odontoblasts, whereas in pulpal fibroblasts it was low. High levels of pro-alpha 2(I)mRNA expression were also present in those odontoblasts which had elaborated new dentin matrix in response to dental caries. Expression in the periodontal ligament, including the cementoblast layer, was slightly stronger than that in odontoblasts. The intense expression of pro-alpha 2(I) mRNA in odontoblasts of adult teeth suggests that even after the completion of primary dentin formation, they continue to synthesize heterotrimeric type I collagen molecules. Cell type-specific differences in the expression of pro-alpha 2(I) mRNA imply that type I collagen probably plays a major role in the regulation of the structure and function of dental tissues. Finally, in situ hybridization enabled pro-alpha 2(I) collagen mRNA to be detected in tissue sections even after prolonged demineralization, and thus it proved to be a valuable technique for analysis of gene expression in adult dental tissues, as shown here for COL1A2.


Complete primary structure of the alpha 1-chain of human basement membrane (type IV) collagen.
We have determined the primary structure of the alpha 1(IV)-chain of human type IV collagen by nucleotide sequencing of overlapping cDNA clones that were isolated from a human placental cDNA library. The present data provide the sequence of 295 amino acids not previously determined. Altogether, the alpha 1(IV)-chain contains 1642 amino acids and has a molecular mass of 157625 Da. There are 1413 residues in the collagenous domain and 229 amino acids in the carboxy-terminal globular domain. The human alpha 1(IV)-chain contains a total of 21 interruptions in the collagenous Gly-X-Y repeat sequence. These interruptions vary in length between two and eleven residues. The alpha 1(IV)-chain contains four cysteine residues in the triple-helical domain, four cysteines in the 15-residue long noncollagenous sequence at the amino-terminus and 12 cysteines in the carboxy-terminal NC-domain.


Plant sterol ester-enriched milk and yoghurt effectively reduce serum cholesterol in modestly hypercholesterolemic subjects.
The cholesterol-lowering efficacy of plant sterol esters (PSteE) or stanol esters (PStaE) in regular- and low-fat spreads has been consistently demonstrated, while their effectiveness in a low-fat, aqueous food carrier such as milk and yoghurt is less well established. Two studies were carried out to assess the cholesterol-lowering effect of PSteE-enriched low-fat milk and PSteE- and PStaE-enriched low-fat yoghurt in modestly hypercholesterolemic subjects (total cholesterol between 5-7.5 mmol/l). Study one was a single blind crossover design with 4 phases of 3-week interventions. Subjects consumed 300 ml/d of placebo or PSteE-milk (2.0 g plant sterols/d) alone or combined with 25 g/d of placebo or PSteE-spread. Study two was a fully randomised, double blind crossover design with 3 phases of 3-week interventions. Subjects consumed 2 portions (150 g tubs each) of placebo, PSteE-yoghurt (1.8 g plant sterols/d) or PStaE-yoghurt (1.7 g plant stanols/d). In study one 39 subjects (21 men and 18 women) and in study two 40 subjects (17 men and 23 women) completed the dietary intervention. In study one, PSteE-milk and PSteE-spread were equally efficacious in lowering total and LDL-cholesterol as compared to placebo by 6-8% and 8-10%, respectively. No significant additional cholesterol-lowering was observed with the combination of PSteE-milk and PSteE-spread (4 g plant sterols/d). PSteE-enriched milk and the combination of PSteE-enriched milk plus spread both lowered lipid-adjusted serum beta-carotene concentrations by 10-14% (P < 0.02),while the PSteE-rich spread alone did not significantly alter serum beta-carotene levels. In study two, the PSteE- and PStaE-enriched yoghurts reduced LDL-cholesterol significantly compared to placebo by 0.27 +/- 0.05 mmol/l (6%) and 0.23 +/- 0.05 mmol/l (5%), respectively. In both studies, there was no effect on HDL-cholesterol and triacylglycerol concentrations. Plant sterols in the form of their esters when provided in lowfat milk and yoghurt are effective in lowering total and LDL-cholesterol.


Association of working hours with biological indices related to the cardiovascular system among engineers in a machinery manufacturing company.
A field survey of 278 engineers (20-59 years) in a machinery manufacturing company was conducted to investigate the association of working hours with biological indices related to the cardiovascular system (heart rate variability, blood pressure and serum levels of magnesium, dehydroepiandrosterone sulfate <DHEA-S> and cholesterol). Average working hours (defined as <"hours at workplace" + "half a commuting time">) and sleeping hours in this study were 60.2 +/- 6.3 hr/week and 6.6 +/- 0.8 hr/day respectively. There were no significant relationships between working hours and biological indices related to the cardiovascular system, but sleeping hours was closely related to working hours negatively. Furthermore, the serum DHEA-S level was significantly related to sleeping hours positively. Combining these two results, it appeared that long working hours might lower the serum DHEA-S level due to the reduction of sleeping hours.


A risk-adapted approach using US features and FNA results in the management of thyroid incidentalomas identified by 18F-FDG PET.
To assess the risk of malignancy of thyroid incidentalomas found on 18F-FDG PET/CT by US features and cytologic results, and to evaluate the clinical usage of a combination of US features and cytology for post-FNA management of thyroid incidentalomas on 18F-FDG PET/CT. From September 2006 to December 2008, 132 patients with 134 thyroid incidentalomas detected on 18F-FDG PET/CT who had undergone US and US-FNA were included in this study. We evaluated the malignancy rate of thyroid incidentalomas in different subgroups subdivided by US features and US-FNA cytology results. Several variables were compared between the benign and malignant group. The risk of malignancy was 58.2 % (78/132) in thyroid incidentalomas on 18F-FDG PET/CT. Age, gender, and tumor size were not significantly different between the malignant and benign group. Malignancy rate of thyroid incidentalomas was significantly higher in the suspicious malignant (88.9 %) than in the probably benign group (11.3 %) on US (p < 0.001). Malignancy rates were high in thyroid nodules with "malignancy", "suspicious for malignancy", or "follicular neoplasm" on cytologic results, regardless of US features. However, malignancy rates of thyroid incidentalomas with "unsatisfactory" or "benign" results on cytology were higher in the suspicious malignant (75 %, 12.5 %, respectively) than in the probably benign (0 %) group on US. This study demonstrated that the risk of malignancy was high in thyroid incidentalomas on 18F-FDG PET/CT even without suspicious US features. However, there was no malignancy in nodules with no suspicious US features and benign cytology. Based on these results, we concluded that US may not replace FNA in the diagnosis of PET incidentalomas, and that a follow-up may be considered of thyroid incidentalomas with benign cytology and no suspicious US features.


Robust isothermal electric control of exchange bias at room temperature.
Voltage-controlled spin electronics is crucial for continued progress in information technology. It aims at reduced power consumption, increased integration density and enhanced functionality where non-volatile memory is combined with high-speed logical processing. Promising spintronic device concepts use the electric control of interface and surface magnetization. From the combination of magnetometry, spin-polarized photoemission spectroscopy, symmetry arguments and first-principles calculations, we show that the (0001) surface of magnetoelectric Cr(2)O(3) has a roughness-insensitive, electrically switchable magnetization. Using a ferromagnetic Pd/Co multilayer deposited on the (0001) surface of a Cr(2)O(3) single crystal, we achieve reversible, room-temperature isothermal switching of the exchange-bias field between positive and negative values by reversing the electric field while maintaining a permanent magnetic field. This effect reflects the switching of the bulk antiferromagnetic domain state and the interface magnetization coupled to it. The switchable exchange bias sets in exactly at the bulk Néel temperature.


Antigen-Triggered Logic-Gating of DNA Nanodevices.
Synthetic nanoscale devices that reconfigure dynamically in response to physiological stimuli could offer new avenues for diagnostics and therapy. Here, we report a strategy for controlling the state of DNA nanodevices based on sensing antigens with IgG antibodies. To this end, we use IgG antibodies as structural elements to kinetically trap reconfigurable DNA origami structures in metastable states. Addition of soluble antigens displace the IgGs from the objects and triggers reconfiguration. We demonstrate this mechanism by antigen-triggered disassembly of DNA origami shells for two different IgGs and their cognate antigens, and we determined the corresponding dose response curves. We also describe the logic-gated actuation of DNA objects with combinations of antigens, as demonstrated with AND-type shells that disassemble only when two different antigens are detected simultaneously. We apply our system for the antigen-triggered release of molecular payload as exemplified by the release of virus particles that we loaded into the DNA origami shells. We expect our approach to be applicable in many types of DNA nanostructures and with many other IgG-antigen combinations.


KRAS mutations and M2PK upregulation in stool samples from individuals with positive fecal occult blood tests screened for colorectal cancer.
Screening for colorectal cancer (CRC) requires non-invasive methods of high diagnostic sensitivity and specificity. We evaluated the measurement of genetic and protein biomarkers of CRC in stool samples with the aim of testing their clinical utility in a CRC screening program. Individuals aged 53-75 years who were at risk of CRC and immunochemical fecal occult blood test (iFOBT) positive were invited to submit stool samples for molecular testing prior to colonoscopy. KRAS codon 12 Gly→Asp, Gly, Val, and codon 13 Gly→Cys gene mutations were tested using an in-house real-time ARMS PCR method. M2PK levels in stool samples were measured utilizing a commercial ELISA kit. At colonoscopy, 7.6% of patients were found to have CRC, 50% had adenomas, 10.6% had hyperplastic polyps, 20.2% had diverticulosis and hemorrhoids, and 11.6% had normal mucosa. The best sensitivity for CRC (50%) was found in those cases where M2PK and KRAS abnormalities coexisted. M2PK showed a detection rate of 40.3% for adenomas but the combination of M2PK and KRAS abnormalities was found in only 5.7% of adenomas (P <0.01). iFOBT was false positive in 31.8% of cases in which colonoscopy excluded neoplastic lesions, while the coexistence of molecular and enzymatic abnormalities was more specific with false positive rates between 8.3% and 9.0% (P <0.05). Our molecular screening approach demonstrates that detection of cancer-associated biomarkers measured in iFOBT-positive stool samples could help separate true from false positives in a FOBT-based screening process. M2PK showed particular promise for the detection of CRC and adenomas.


Do ravens show consolation? Responses to distressed others.
Bystander affiliation (post-conflict affiliation from an uninvolved bystander to the conflict victim) may represent an expression of empathy in which the bystander consoles the victim to alleviate the victim's distress ("consolation"). However, alternative hypotheses for the function of bystander affiliation also exist. Determining whether ravens spontaneously offer consolation to distressed partners may not only help us to understand how animals deal with the costs of aggressive conflict, but may also play an important role in the empathy debate. This study investigates the post-conflict behavior of ravens, applying the predictive framework for the function of bystander affiliation for the first time in a non-ape species. We found weak evidence for reconciliation (post-conflict affiliation between former opponents), but strong evidence for both bystander affiliation and solicited bystander affiliation (post-conflict affiliation from the victim to a bystander). Bystanders involved in both interactions were likely to share a valuable relationship with the victim. Bystander affiliation offered to the victim was more likely to occur after intense conflicts. Renewed aggression was less likely to occur after the victim solicited affiliation from a bystander. Our findings suggest that in ravens, bystanders may console victims with whom they share a valuable relationship, thus alleviating the victims' post-conflict distress. Conversely victims may affiliate with bystanders after a conflict in order to reduce the likelihood of renewed aggression. These results stress the importance of relationship quality in determining the occurrence and function of post-conflict interactions, and show that ravens may be sensitive to the emotions of others.


A palladium iodide-catalyzed carbonylative approach to functionalized pyrrole derivatives.
A novel and convenient approach to functionalized pyrroles is presented, based on Pd-catalyzed oxidative heterocyclization-alkoxycarbonylation of readily available N-Boc-1-amino-3-yn-2-ols. Reactions were carried out in alcoholic solvents at 80-100 °C and under 20 atm (at 25 °C) of a 4:1 mixture of CO-air, in the presence of the PdI(2)-KI catalytic system (2-5 mol % of PdI(2), KI/PdI(2) molar ratio = 10). In the case of N-Boc-1-amino-3-yn-2-ols 3, bearing alkyl or aryl substituents, the carbonylation reaction led to a mixture of Boc-protected and N-unsubstituted pyrrole-3-carboxylic esters 4 and 5, respectively. This mixture could be conveniently and quantitatively converted into deprotected pyrrole-3-carboxylic esters 5 by a simple basic treatment. In the case of diastereomeric (3RS,4RS)- and (3RS,4SR)-N-Boc-3-amino-2-methyldec-5-yn-4-ol (syn-3f and anti-3f, respectively, whose relative configuration was determined by X-ray crystallographic analysis), no particular difference was observed in the reactivity of the two diastereomers between them and with respect to the diastereomeric mixture (3S,4S) + (3S,4R). Interestingly, N-Boc-2-alkynyl-1-amino-3-yn-2-ols 6, bearing an additional alkynyl substituent α to the hydroxyl group, spontaneously underwent N-deprotection under the reaction conditions and regioselective water addition to the alkynyl group at C-3 of the corresponding pyrrole-3-carboxylic ester derivative, thus directly affording highly functionalized pyrrole derivatives 7 in one step. In a similar manner, a novel functionalized dihydropyrrolizine derivative 9 was directly synthesized starting from (S)-7-(pyrrolidin-2-yl)trideca-5,8-diyn-7-ol 8.


Sustainability of community-led total sanitation outcomes: Evidence from Ethiopia and Ghana.
We conducted a study to evaluate the sustainability of community-led total sanitation (CLTS) outcomes in Ethiopia and Ghana. Plan International, with local actors, implemented four CLTS interventions from 2012 to 2014: health extension worker-facilitated CLTS and teacher-facilitated CLTS in Ethiopia, and NGO-facilitated CLTS with and without training for natural leaders in Ghana. We previously evaluated these interventions using survey data collected immediately after implementation ended, and concluded that in Ethiopia health extension workers were more effective facilitators than teachers, and that in Ghana training natural leaders improved CLTS outcomes. For this study, we resurveyed 3831 households one year after implementation ended, and analyzed latrine use and quality to assess post-intervention changes in sanitation outcomes, to determine if our original conclusions were robust. In one of four interventions evaluated (health extension worker-facilitated CLTS in Ethiopia), there was an 8 percentage point increase in open defecation in the year after implementation ended, challenging our prior conclusion on their effectiveness. For the other three interventions, the initial decreases in open defecation of 8-24 percentage points were sustained, with no significant changes occurring in the year after implementation. On average, latrines in Ethiopia were lower quality than those in Ghana. In the year following implementation, forty-five percent of households in Ethiopia repaired or rebuilt latrines that had become unusable, while only 6% did in Ghana possibly due to higher latrine quality. Across all four interventions and three survey rounds, most latrines remained unimproved. Regardless of the intervention, households in villages higher latrine use were more likely to have sustained latrine use, which together with the high latrine repair rates indicates a potential social norm. There are few studies that revisit villages after an initial evaluation to assess sustainability of sanitation outcomes. This study provides new evidence that CLTS outcomes can be sustained in the presence of training provided to local actors, and strengthens previous recommendations that CLTS is not appropriate in all settings and should be combined with efforts to address barriers households face to building higher quality latrines.


Kinetic Study on Clogging of a Geothermal Pumping Well Triggered by Mixing-Induced Biogeochemical Reactions.
The sustainability of ground-source geothermal systems can be severely impacted by microbially mediated clogging processes. Biofouling of water wells by hydrous ferric oxide is a widespread problem. Although the mechanisms and critical environmental factors associated with clogging development are widely recognized, effects of mixing processes within the wells and time scales for clogging processes are not well characterized. Here we report insights from a joint hydrological, geochemical, and metagenomics characterization of a geothermal doublet in which hydrous ferric oxide and hydrous manganese oxide deposits had formed as a consequence of mixing shallow groundwater containing dissolved oxygen and nitrate with deeper, anoxic groundwater containing dissolved iron (FeII) and manganese (MnII). Metagenomics identify distinct bacteria consortia in the pumping well oxic and anoxic zones, including autotrophic iron-oxidizing bacteria. Batch mixing experiments and geochemical kinetics modeling of the associated reactions indicate that FeII and MnII oxidation are slow compared to the residence time of water in the pumping well; however, adsorption of FeII and MnII by accumulated hydrous ferric oxide and hydrous manganese oxide in the well bore and pump riser provides "infinite" time for surface-catalyzed oxidation and a convenient source of energy for iron-oxidizing bacteria, which colonize the surfaces and also catalyze oxidation. Thus, rapid clogging is caused by mixing-induced redox reactions and is exacerbated by microbial activity on accumulated hydrous oxide surfaces.


Angiotensin II increases periostin expression via Ras/p38 MAPK/CREB and ERK1/2/TGF-β1 pathways in cardiac fibroblasts.
Angiotensin II (AngII) is involved in extracellular matrix (ECM) accumulation contributing to heart failure. Periostin, a 90 kDa ECM protein, is a key regulator of cardiac fibrosis, and its expression is significantly higher in failing hearts. We determined the modulatory effect of AngII on periostin level and explored the possible signal transduction mechanism. AngII (400 ng/kg/min) or normal saline was infused subcutaneously for 28 days into rats; AngII antagonism was with losartan (10 mg/kg/day orally). AngII infusion induced cardiac fibrosis and increased periostin expression, which was attenuated by losartan. In cultured adult rat cardiac fibroblasts, AngII promoted the mRNA and protein expression of periostin. AngII provoked activation of cAMP response element-binding protein (CREB), and CREB small interfering RNA (siRNA) suppressed AngII-induced periostin expression. Inhibition of p38 mitogen-activated protein kinase (p38 MAPK) with SB202190 attenuated AngII-induced CREB activation and periostin expression. Transfection with Ras guanyl-releasing protein 1 siRNA or RasN17 dominant-negative plasmid prevented AngII-induced p38 MAPK phosphorylation and periostin expression. Transforming growth factor (TGF)-β1 antibody decreased the stimulatory effect of AngII on periostin expression. The extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor PD98059 attenuated AngII-induced TGF-β1 expression, Smad2/3 nuclear accumulation, and periostin expression. The activation of the Ras/p38 MAPK/CREB pathway is required for AngII-induced periostin expression. ERK1/2 also participates in AngII-induced periostin expression by regulating TGF-β1/Smad signalling.


Toxicosis in sows and their pigs caused by feeding rations containing polybrominated biphenyls to sows during pregnancy and lactation.
The toxicity and the distribution of polybrominated biphenyls (PBB) were investigated by feeding rations containing different concentrations of PBB to sows during pregnancy and lactation. Sows and newborn pigs were clinically unaffected. Mortality was increased among pigs nursing sows fed rations containing PBB. Although transplacental passage of PBB resulted in an appreciable amount of PBB in tissues of newborn pigs, far more PBB were transferred to the pigs through the milk. On a body-weight basis, nursing pigs consumed PBB in concentrations similar to the concentrations given to the sows. The highest tissue concentrations of PBB (fat basis) were found in the liver, followed by the adipose tissue, kidney, and brain. Dietary concentrations of 10 mg of PBB/kg of feed increased serum concentrations of alkaline phosphatase, alanine aminotransferase, and thyroid hormones of pigs, whereas dietary concentrations of 100 or 200 mg of PBB/kg of feed caused those values to decrease. Gross pathologic changes consisted of increased weight of the thyroid gland of newborn pigs and increased weight of the liver of 4-week-old pigs. Histologically, thyroid glands of newborn pigs were slightly hyperplastic, and the colloid was scant and vacuolated. In the liver, lesions consisted of fatty change and centrolobular necrosis; changes were more severe in the sows than in the pigs nursing those sows. Measuring serum concentrations of ornithine carbamoyltransferase was the most effective clinical test in assessing the degree of liver damage in the pigs.


Application of self-organising maps towards segmentation of soybean samples by determination of inorganic compounds content.
In this study, 20 samples of soybean, both transgenic and conventional cultivars, which were planted in two different regions, Londrina and Ponta Grossa, both located at Paraná, Brazil, were analysed. In order to verify whether the inorganic compound levels in soybeans varied with the region of planting, K, P, Ca, Mg, S, Zn, Mn, Fe, Cu and B contents were analysed by an artificial neural network self-organising map. It was observed that with a topology 10 × 10, 8000 epochs, initial learning rate of 0.1 and initial neighbourhood ratio of 4.5, the network was able to differentiate samples according to region of origin. Among all of the variables analysed by the artificial neural network, the elements Zn, Ca and Mn were those which most contributed to the classification of the samples. The results indicated that samples planted in these two regions differ in their mineral content; however, conventional and transgenic samples grown in the same region show no difference in mineral contents in the grain.


ATP-dependent transport of glutathione conjugate of 7beta, 8alpha-dihydroxy-9alpha,10alpha-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene in murine hepatic canalicular plasma membrane vesicles.
Glutathione (GSH) S-transferases (GSTs) have an important role in the detoxification of (+)-anti-7,8-dihydroxy-9,10-oxy-7,8,9, 10-tetrahydrobenzo[a]pyrene [(+)-anti-BPDE], which is the ultimate carcinogen of benzo[a]pyrene. However, the fate and/or biological activity of the GSH conjugate of (+)-anti-BPDE [(-)-anti-BPD-SG] is not known. We now report that (-)-anti-BPD-SG is a competitive inhibitor (Ki 19 microM) of Pi-class isoenzyme mGSTP1-1, which among murine hepatic GSTs is most efficient in the GSH conjugation of (+)-anti-BPDE. Thus the inhibition of mGSTP1-1 activity by (-)-anti-BPD-SG might interfere with the GST-catalysed GSH conjugation of (+)-anti-BPDE unless one or more mechanisms exist for the removal of the conjugate. The results of the present study indicate that (-)-anti-BPD-SG is transported across canalicular liver plasma membrane (cLPM) in an ATP-dependent manner. The ATP-dependent transport of (-)-anti-[3H]BPD-SG followed Michaelis-Menten kinetics (Km 46 microM). The ATP dependence of the (-)-anti-BPD-SG transport was confirmed by measuring the stimulation of ATP hydrolysis (ATPase activity) by the conjugate in the presence of cLPM protein, which also followed Michaelis-Menten kinetics. In contrast, a kinetic analysis of ATP-dependent uptake of the model conjugate S-[3H](2,4-dinitrophenyl)-glutathione ([3H]DNP-SG) revealed the presence of a high-affinity and a low-affinity transport system in mouse cLPM, with apparent Km values of 18 and 500 microM respectively. The ATP-dependent transport of (-)-anti-BPD-SG was inhibited competitively by DNP-SG (Ki 1.65 microM). Likewise, (-)-anti-BPD-SG was found to be a potent competitive inhibitor of the high-affinity component of DNP-SG transport (Ki 6.3 microM). Our results suggest that GST-catalysed conjugation of (+)-anti-BPDE with GSH, coupled with ATP-dependent transport of the resultant conjugate across cLPM, might be the ultimate detoxification pathway for this carcinogen.


Vegetarian diets and diets which restrict animal-source foods during childhood in high-income countries.
Increasing numbers of populations in the West are restricting their intake of meat and other animal products for reasons relating to health or ethics; in many countries, these restrictions are already common for cultural, religious, or socio-economic reasons. By following their parent's diet, children are exposed in parallel. This narrative review aims at assessing current data regarding vegetarian diets in children from birth to 18 years of age, which include, by increasing degree of restriction, flexitarian, lacto-ovo-vegetarian, lacto-vegetarian, pescatarian, vegan and macrobiotic diets. The 202 references include 45 studies in children. The more restrictive the diet and the younger the child, the greater the risk of nutritional deficiency. Of particular concern are vitamin B12, iron, zinc, calcium, n-3 long-chain polyunsaturated fatty acids, and protein and energy intake, especially in pregnant and nursing women, infants and young children. Providing an adequate lacto-ovo-vegetarian diet is relatively easy, whereas the maintenance of more restrictive diets may be challenging. The benefits and risks of vegetarian diets in adults are relatively well documented, but data for children are scarce. Vegan and macrobiotic diets should be discouraged in pregnant and lactating mothers as well as in young children, who, otherwise, should pay careful attention to ensuring nutritional adequacy, blood testing and appropriate supplementation. The health consequences of a chosen diet should be discussed with parents and adolescents to ensure the best possible adherence to advice and prescriptions. There is a need for well conducted studies in children but also for better knowledge of nutrition in healthcare professionals.Abbreviations: ALA: α-linolenic acid; ARA: arachidonic acid; ASF: animal source foods; BMC: bone mineral content; BMD: bone mineral density; DHA: docosahexaenoic acid; DRV: dietary reference value; EPA: eicosapentaenoic acid; FLD: flexitarian diet; LA: linoleic acid; LC-PUFA: long-chain polyunsaturated fatty acids; LOVD: lacto-ovo-vegetarian diet; LVD: lacto-vegetarian diet; MAD: macrobiotic diet; OMD: omnivorous diet; PSF: plant-source foods; SFA: saturated fatty acids; VGD: vegetarian diets; VND: vegan diet.


Hydroxyapatite paste Ostim, without elevation of full-thickness flaps, improves alveolar healing stimulating BMP- and VEGF-mediated signal pathways: an experimental study in humans.
Tooth extraction is considered as the starting point of jaw atrophy via osteoclast activity stimulation. The maintenance of dental alveolar bone depends on surgery procedure and use of materials to maintain prior space favoring bone regeneration. Among substitutes used in dentistry to fill bone defects, Ostim-Pastes (Ostim) is a nanocrystalline paste tested for treatment of severe clinical conditions. This research first investigated the effect of Ostim on alveolar healing, comparing in the same healthy subjects, an Ostim-filled socket with a not-filled one. Moreover, it also proposed a new surgical protocol for the post-extractive socket treatment using the graft materials without elevation of full-thickness flaps. Fourteen patients were enrolled to bilateral maxillary or mandibular extraction that was performed without elevation of full-thickness flaps. In each patient, one socket was filled using Ostim, and the other one was allowed to undergo natural healing. No suture was carried out. Clinical and biologic parameters were screened at 1, 7, and 14 days. Obtained results evidenced that nanocrystalline hydroxyapatite supports bone regeneration, increasing the synthesis of pro-osteogenic factors as bone morphogenetics protein (BMP)-4, BMP-7, alkaline phosphatase, and osteocalcin. Moreover, filling post-extractive socket with nanocrystalline hydroxyapatite paste leads to a complete epithelialization already at 7 days after extraction, despite the fact that the teeth were extracted without elevation of full-thickness flaps . The improved epithelialization is mediated by increased vascular endothelial growth factor (VEGF) expression. No significant change was observed in inflammatory parameters, with exception of an early and transient IL-1β induction, that could trigger and improve alveolar healing. Clinical and biomolecular observations of this explorative study evidenced that nanocrystalline hydroxyapatite improves alveolar socket healing, increasing angiogenesis, epithelialization, and osteogenesis, also in absence of elevation of full-thickness flaps.


Effect of single doses of methoxypolyethylene glycol-epoetin beta (CERA, Mircera™) and epoetin delta (Dynepo™) on isoelectric erythropoietin profiles and haematological parameters.
Erythropoietin (EPO) has been misused in sports for many years due to its performance-enhancing effect. In the last decade, detection of abuse has been possible with isoelectric focusing (IEF) based on the different isoform profiles of endogenous and recombinant EPO. The release of new EPOs on the market, such as the recombinant erythropoietin epoetin delta (Dynepo™) and the chemically modified EPO, CERA (Mircera™) potentially represents analytical challenges to the fight against doping. This study set out to investigate the possibility of and the time window for detecting the administration of a single dose of Dynepo™ and CERA. Our results are in agreement with earlier findings that detection of Dynepo™ is best achieved by combining IEF with SDS-PAGE. Haematological parameters were monitored for possible effects due to the long half-life (130 hours) of CERA in blood. Interestingly, although several haematological parameters were significantly changed after the injection of CERA, the endogenous EPO signal was still present in all collected samples. Due to the long half-life and the large size of the CERA molecule (about 60 kDa), it was uncertain whether CERA would be excreted into urine in detectable amounts unless urine collection was preceded by strenuous physical exercise. We find that CERA can be detected in urine without prior exercise in several, but not all, subjects. CERA is nevertheless best detected in serum with regard to both probability and length of detection, in addition to stability in matrix over time.


Activin A suppresses neuroblastoma xenograft tumor growth via antimitotic and antiangiogenic mechanisms.
The tumor suppressor function of activin A, together with our findings that activin A is an inhibitor of angiogenesis, which is down-regulated by the N-MYC oncogene, prompted us to investigate in more detail its role in the malignant transformation process of neuroblastomas. Indeed, neuroblastoma cells with restored activin A expression exhibited a diminished proliferation rate and formed smaller xenograft tumors with reduced vascularity, whereas lung metastasis rate remained unchanged. In agreement with the decreased vascularity of the xenograft tumors, activin A inhibited several crucial angiogenic responses of cultured endothelial cells, such as proteolytic activity, migration, and proliferation. Endothelial cell proliferation, activin A, or its constitutively active activin receptor-like kinase 4 receptor (ALK4T206D), increased the expression of CDKN1A (p21), CDKN2B (p15), and CDKN1B (p27) CDK inhibitors and down-regulated the expression of vascular endothelial growth factor receptor-2, the receptor of a key angiogenic factor in cancer. The constitutively active forms of SMAD2 and SMAD3 were both capable of inhibiting endothelial cell proliferation, whereas the dominant-negative forms of SMAD3 and SMAD4 released the inhibitory effect of activin A on endothelial cell proliferation by only 20%. Thus, the effects of activin A on endothelial cell proliferation seem to be conveyed via the ALK4/SMAD2-SMAD3 pathways, however, non-SMAD cascades may also contribute. These results provide novel information regarding the role of activin A in the malignant transformation process of neuroblastomas and the molecular mechanisms involved in regulating angiogenesis thereof.


Bioaccumulation of organic contaminants in humans: a multimedia perspective and the importance of biotransformation.
Bioaccumulation is an important component of the exposure hazard assessment and risk assessment of organic chemicals. Screening criteria for chemical hazard used in national and international regulations are based on the paradigm that partitioning properties are the primary chemical determinants of bioaccumulation. We use a holistic multimedia perspective to evaluate the partitioning property paradigm with respect to assessing human bioaccumulation. Multimedia bioaccumulation factors (mmBAFs) for humans were modeled for hypothetical chemicals with a wide range of physical-chemical properties. Varying partitioning properties over 12 orders of magnitude (a plausible range for nonionizing organics) resulted in only modest changes in mmBAFs (a factor of ∼ 10) for all but very volatile or hydrophilic chemicals. In contrast, varying biotransformation rate constants over 6 orders of magnitude resulted in substantial differences in mmBAFs (greater than a factor of 10(9)). Our model results are supported by empirical observations of well characterized pollutants, which demonstrate that chemicals with similar partitioning properties can have very different bioaccumulation behavior. Susceptibility to biotransformation clearly determines bioaccumulation in humans for many chemicals. We conclude that a holistic multimedia perspective for bioaccumulation assessment is necessary to develop regulations, criteria, and policies that are protective of human health and the environment.


Enterococcal colonization of the gastro-intestinal tract: role of biofilm and environmental oligosaccharides.
Biofilm formation in E. faecalis is presumed to play an important role in a number of enterococcal infections. We have previously identified a genetic locus provisionally named bop that is involved in maltose metabolism and biofilm formation. A transposon insertion into the second gene of the locus (bopB) resulted in loss of biofilm formation, while the non-polar deletion of this gene, together with parts of the flanking genes (bopA and bopC) resulted in increased biofilm formation. A polar effect of the transposon insertion on a transcriptional regulator (bopD) was responsible for the reduced biofilm formation of the transposon mutant. The amount of biofilm formed is related to the presence of maltose or glucose in the growth medium. While the wild-type strain was able to produce biofilm in medium containing either glucose or maltose, two mutants of this locus showed opposite effects. When grown in medium containing 1% glucose, the transposon mutant showed reduced biofilm formation (9%), while the deletion mutant produced more biofilm (110%) than the wild-type. When grown in medium containing 1% maltose, the transposon mutant was able to produce more biofilm than the wild-type strain (111%), while the deletion mutant did not produce biofilm (4%). Biofilm formation was not affected by the presence of several other sugar sources. In a gastrointestinal colonization model, the biofilm-negative mutant was delayed in colonization of the mouse intestinal tract. The biofilm-positive phenotype of the wild-type strain seems to be associated with colonization of enterococci in the gut and the presence of oligosaccharides in food may influence biofilm formation and therefore colonization of enterococci in the gastrointestinal system.


Speeding up chemical database searches using a proximity filter based on the logical exclusive or.
In many large chemoinformatics database systems, molecules are represented by long binary fingerprint vectors whose components record the presence or absence in the molecular graphs of particular functional groups or combinatorial features, such as labeled paths or labeled trees. To speed up database searches, we propose to store with each fingerprint a small header vector containing primarily the result of applying the logical exclusive OR (XOR) operator to the fingerprint vector after modulo wrapping to a smaller number of bits, such as 128 bits. From the XOR headers of two molecules, tight bounds on the intersection and union of their fingerprint vectors can be rapidly obtained, yielding tight bounds on derived similarity measures, such as the Tanimoto measure. During a database search, every time these bounds are unfavorable, the corresponding molecule can be rapidly discarded with no need for further inspection. We derive probabilistic models that allow us to estimate precisely the behavior of the XOR headers and the level of pruning under different conditions in terms of similarity threshold and fingerprint density. These theoretical results are corroborated by experimental results on a large set of molecules. For a Tanimoto threshold of 0.5 (respectively 0.9), this approach requires searching less than 50% (respectively 10%) of the database, leading to typical search speedups of 2 to 3 times over the previous state-of-the-art.


An epidemiological perspective on dietary electrolytes and hypertension.
This review of epidemiological studies has several general implications. First, the most relevant population data for extrapolation in providing public health or medical advice should come from intra-population studies, either observational or interventional. Second, the observational studies require follow-up with long-term intervention trials in representative segments of the population before broad pronouncements are made. Third, not all people respond uniformly to changes in the intake of a single electrolyte, at the levels that can be safely achieved in our society. Finally, there are clear indications of useful directions in which to alter dietary electrolytes, either singly or multiply, but the most effective, safe and achievable combinations of dietary change remain to be defined and tested over prolonged periods in naturalistic settings.


Loss of imprinting of IGF2 sense and antisense transcripts in Wilms' tumor.
Human insulin-like growth factor II gene (IGF2) is overexpressed, and its imprinting is disrupted in many tumors, including Wilms' tumor. A transcript that is antisense to IGF2, IGF2-antisense (IGF2-AS), is transcribed from within IGF2 in a reverse orientation. This transcript is also maternally imprinted and overexpressed in Wilms' tumor. IGF2-AS was detected as a 2.2 kb mRNA in Hep 3B cells by Northern blotting, and it encodes a putative 168 amino acid peptide. An alternative splicing mRNA observed predominantly in adult liver encodes an additional putative 199 amino acid peptide. We have examined the expression of IGF2 and IGF2-AS in normal tissue, breast and ovarian tumors, and 25 informative, well-characterized Wilms' tumors and determined the relationship between IGF2 and IGF2-AS imprinting. IGF2-AS was expressed at levels comparable with IGF2 sense expression derived from promoters P1 and P2 in normal tissue and in breast, ovarian, and Wilms' tumor tissues. In Wilms' tumors that demonstrate maintenance of imprinting of IGF2, IGF2-AS was imprinted. In contrast, in tumors which demonstrate LOI of IGF2, only two of six tumors showed loss of imprinting of IGF2-AS, whereas four of six tumors demonstrated maintenance of imprinting for IGF2-AS. The discrepancy between IGF2 and IGF2-AS loss of imprinting in some tumors demonstrates the control complexity of the imprinting status of the various transcripts derived from the IGF2 gene.


Home-Based Telemedicine in Patients with Chronic Neck Pain.
To investigate if a structured physician-directed, nurse-managed, home-based telemedicine (HBT) program, consisting of scheduled/unscheduled phone surveillance, can reduce pain in patients with chronic neck pain. This is a prospective randomized controlled study conducted on outpatients. Following outpatient rehabilitation, patients (n = 100) were consecutively randomized to a 6-month HBT program (HBT group) or no HBT but only the recommendation to continue exercising at home (control group). At baseline and after 6 months, pain severity (visual analog scale) and disability (Neck Disability Index) were evaluated. At 6 months, neck pain and disability declined in both groups (P < 0.001 for both groups, both parameters), but the decline was significantly more marked in the HBT group (P = 0.001, both parameters). At 6 months, 87.2% of HBT patients and 65.9% of control subjects were performing home exercises (in the range of 2-7 exercise sessions/wk). Pain and disability scores were correlated to participation in the HBT program, patients' perception of HBT, and adherence to home exercises. Home-based telemedicine may be a useful additional tool to help physicians in the management of chronic neck pain.


Tumor radiosensitization by monomethyl auristatin E: mechanism of action and targeted delivery.
Intrinsic tumor resistance to radiotherapy limits the efficacy of ionizing radiation (IR). Sensitizing cancer cells specifically to IR would improve tumor control and decrease normal tissue toxicity. The development of tumor-targeting technologies allows for developing potent radiosensitizing drugs. We hypothesized that the anti-tubulin agent monomethyl auristatin E (MMAE), a component of a clinically approved antibody-directed conjugate, could function as a potent radiosensitizer and be selectively delivered to tumors using an activatable cell-penetrating peptide targeting matrix metalloproteinases and RGD-binding integrins (ACPP-cRGD-MMAE). We evaluated the ability of MMAE to radiosensitize both established cancer cells and a low-passage cultured human pancreatic tumor cell line using clonogenic and DNA damage assays. MMAE sensitized colorectal and pancreatic cancer cells to IR in a schedule- and dose-dependent manner, correlating with mitotic arrest. Radiosensitization was evidenced by decreased clonogenic survival and increased DNA double-strand breaks in irradiated cells treated with MMAE. MMAE in combination with IR resulted in increased DNA damage signaling and activation of CHK1. To test a therapeutic strategy of MMAE and IR, PANC-1 or HCT-116 murine tumor xenografts were treated with nontargeted free MMAE or tumor-targeted MMAE (ACPP-cRGD-MMAE). While free MMAE in combination with IR resulted in tumor growth delay, tumor-targeted ACPP-cRGD-MMAE with IR produced a more robust and significantly prolonged tumor regression in xenograft models. Our studies identify MMAE as a potent radiosensitizer. Importantly, MMAE radiosensitization can be localized to tumors by targeted activatable cell-penetrating peptides.


Task-dependent recurrent dynamics in visual cortex.
The capacity for flexible sensory-action association in animals has been related to context-dependent attractor dynamics outside the sensory cortices. Here, we report a line of evidence that flexibly modulated attractor dynamics during task switching are already present in the higher visual cortex in macaque monkeys. With a nonlinear decoding approach, we can extract the particular aspect of the neural population response that reflects the task-induced emergence of bistable attractor dynamics in a neural population, which could be obscured by standard unsupervised dimensionality reductions such as PCA. The dynamical modulation selectively increases the information relevant to task demands, indicating that such modulation is beneficial for perceptual decisions. A computational model that features nonlinear recurrent interaction among neurons with a task-dependent background input replicates the key properties observed in the experimental data. These results suggest that the context-dependent attractor dynamics involving the sensory cortex can underlie flexible perceptual abilities.


Mechanism of mitochondrial dysfunction in diabetic sensory neuropathy.
Symmetrical sensory polyneuropathy, the most common form of diabetic neuropathy in humans, is associated with a spectrum of structural changes in peripheral nerve that includes axonal degeneration, paranodal demyelination, and loss of myelinated fibers--the latter probably the result of a dying-back of distal axons. Mitochondrial dysfunction has recently been proposed as an etiological factor in this degenerative disease of the peripheral nervous system. Lack of neurotrophic support has been proposed as a contributing factor in the etiology of diabetic neuropathy based on studies in animal models of Type I diabetes. We have recently demonstrated that insulin and neurotrophin-3 (NT-3) modulate mitochondrial membrane potential in cultured adult sensory neurons. We therefore tested the hypothesis that diabetes-induced mitochondrial dysfunction is caused by impairments in neurotrophic support. We have used real-time fluorescence video microscopy to analyze mitochondrial membrane potential in cultured adult sensory neurons isolated from normal and diabetic rats. Diabetes caused a significant loss of mitochondrial membrane potential in all sub-populations of sensory neurons which can be prevented by in vivo treatment with insulin or NT-3. The mechanism of insulin and NT-3-dependent modulation of mitochondrial membrane potential involves the activation of the phosphoinositide 3 kinase (PI 3 kinase) pathway. Downstream targets of PI 3 kinase, such as Akt and the transcription factor cAMP response element-binding protein (CREB), are activated by insulin and NT-3 and regulate sensory neuron gene expression. These alterations in gene expression modulate critical components of metabolite pathways and the electron transport chain associated with the neuronal mitochondrion. Our results show that in adult sensory neurons, treatment with insulin can elevate the input of reducing equivalents into the mitochondrial electron transport chain, which leads to greater mitochondrial membrane polarization and enhanced ATP synthesis.


CDK11 requires a critical activator SAP30BP to regulate pre-mRNA splicing.
CDK11 is an emerging druggable target for cancer therapy due to its prevalent roles in phosphorylating critical transcription and splicing factors and in facilitating cell cycle progression in cancer cells. Like other cyclin-dependent kinases, CDK11 requires its cognate cyclin, cyclin L1 or cyclin L2, for activation. However, little is known about how CDK11 activities might be modulated by other regulators. In this study, we show that CDK11 forms a tight complex with cyclins L1/L2 and SAP30BP, the latter of which is a poorly characterized factor. Acute degradation of SAP30BP mirrors that of CDK11 in causing widespread and strong defects in pre-mRNA splicing. Furthermore, we demonstrate that SAP30BP facilitates CDK11 kinase activities in vitro and in vivo, through ensuring the stabilities and the assembly of cyclins L1/L2 with CDK11. Together, these findings uncover SAP30BP as a critical CDK11 activator that regulates global pre-mRNA splicing.


A nonsense variant in Rap Guanine Nucleotide Exchange Factor 5 (RAPGEF5) is associated with equine familial isolated hypoparathyroidism in Thoroughbred foals.
Idiopathic hypocalcemia in Thoroughbred (TB) foals causes tetany and seizures and is invariably fatal. Based upon the similarity of this disease with human familial hypoparathyroidism and occurrence only in the TB breed, we conducted a genetic investigation on two affected TB foals. Familial hypoparathyroidism was identified, and pedigree analysis suggested an autosomal recessive (AR) mode of inheritance. We performed whole-genome sequencing of the two foals, their unaffected dams and four unaffected, unrelated TB horses. Both homozygosity mapping and an association analysis were used to prioritize potential genetic variants. Of the 2,808 variants that significantly associated with the phenotype using an AR mode of inheritance (P<0.02) and located within a region of homozygosity, 1,507 (54%) were located in a 9.7 Mb region on chr4 (44.9-54.6 Mb). Within this region, a nonsense variant (RAPGEF5 c.2624C>A,p.Ser875*) was significantly associated with the hypoparathyroid phenotype (Pallelic = 0.008). Affected foals were homozygous for the variant, with two additional affected foals subsequently confirmed in 2019. Necropsies of all affected foals failed to identify any histologically normal parathyroid glands. Because the nonsense mutation in RAPGEF5 was near the C-terminal end of the protein, the impact on protein function was unclear. Therefore, we tested the variant in our Xenopus overexpression model and demonstrated RAPGEF5 loss-of-function. This RAPGEF5 variant represents the first genetic variant for hypoparathyroidism identified in any domestic animal species.


Effect of fabric washing on the presumptive identification of bloodstains.
The purpose of this study was to investigate the retention of blood stains on twelve different types of fabrics after washing at various drying times. The findings of this study, supported by chi-square analysis, indicate that the retention of bloodstains on washed fabrics depends upon the particular fiber composition of the fabric, the specific blood screening test used, and whether or not a detergent was used in the wash. The results of this research did not reveal a significant effect of the drying time on the retention of bloodstains, as tested during the 48-h limit of this experiment. The author concludes that the forensic serologist should consider the factors investigated in this study before rendering an opinion on the retention of bloodstains on washed garments.


Happy Despite Pain: A Randomized Controlled Trial of an 8-Week Internet-delivered Positive Psychology Intervention for Enhancing Well-being in Patients With Chronic Pain.
There is preliminary evidence for the efficacy of positive psychology interventions for pain management. The current study examined the effects of an internet-based positive psychology self-help program for patients with chronic musculoskeletal pain and compared it with an internet-based cognitive-behavioral program. A randomized controlled trial was carried out with 3 conditions: an internet-delivered positive psychology program, an internet-delivered cognitive-behavioral program and waitlist control. A total of 276 patients were randomized to 1 of the 3 conditions and posttreatment data were obtained from 206 patients. Primary outcomes were happiness, depression, and physical impairments at posttreatment and at 6-month follow-up. Intention-to-treat analyses were carried out using mixed regression analyses. Both treatments led to significant increases in happiness and decreases in depression. Physical impairments did not significantly decrease compared with waitlist. Improvements in happiness and depression were maintained until 6-month follow-up. There were no overall differences in the efficacy of the 2 active interventions but effects seemed to be moderated by education. Patients with a higher level of education profited slightly more from the positive psychology intervention than from the cognitive-behavioral program. The results suggest that an internet-based positive psychology and cognitive-behavioral self-help interventions for the management of chronic pain are clinically useful. Because the self-help exercises as used in the current program do not require therapist involvement, dissemination potential is large. Further studies should examine whether it can best be used as stand-alone or add-on treatment combined with established pain treatment programs.


Polysaccharides isolated from Açaí fruit induce innate immune responses.
The Açaí (Acai) fruit is a popular nutritional supplement that purportedly enhances immune system function. These anecdotal claims are supported by limited studies describing immune responses to the Acai polyphenol fraction. Previously, we characterized γδ T cell responses to both polyphenol and polysaccharide fractions from several plant-derived nutritional supplements. Similar polyphenol and polysaccharide fractions are found in Acai fruit. Thus, we hypothesized that one or both of these fractions could activate γδ T cells. Contrary to previous reports, we did not identify agonist activity in the polyphenol fraction; however, the Acai polysaccharide fraction induced robust γδ T cell stimulatory activity in human, mouse, and bovine PBMC cultures. To characterize the immune response to Acai polysaccharides, we fractionated the crude polysaccharide preparation and tested these fractions for activity in human PBMC cultures. The largest Acai polysaccharides were the most active in vitro as indicated by activation of myeloid and γδ T cells. When delivered in vivo, Acai polysaccharide induced myeloid cell recruitment and IL-12 production. These results define innate immune responses induced by the polysaccharide component of Acai and have implications for the treatment of asthma and infectious disease.


Doppler ultrasonography of the pectinis oculi artery in harpy eagles (Harpia harpyja).
Twenty harpy eagles (Harpia harpyja) without systemic or ocular diseases were examined to measure blood velocity parameters of the pectinis oculi artery using Doppler ultrasonography. Pectinate artery resistive index (RI) and pulsatility index (PI) were investigated using ocular Doppler ultrasonography. The mean RI and PI values across all eyes were 0.44±0.10 and 0.62±0.20 respectively. Low RI and PI values found in the harpy eagle´s pectinis oculi artery compared with the American pekin ducks one and other tissue suggest indeed a high metabolic activity in pecten oculi and corroborates the hypothesis of a nutritional function and/or intraocular pressure regulation.


[Diagnosis and treatment of high-flow vascular malformation of the jaws].
To report our experience on diagnosis and treatment of the high-flow vascular malformation of the jaws. Thirty-seven cases of high-flow vascular malformation of the jaws (6 cases in maxilla and 31 in mandible) were comprised this study. Twenty-one patients were embolized with coils and N-buty1-2-cyanoacrylate, and 16 cases underwent surgery. The embolization was carried out with both arterial and venous route. Different signs of the lesions were demonstrated on X-ray plain film, such as locular, rough of bone trabecula and soap bubble-like changes, frequently accompanied by dilatation of the mandibular nerve canal. CT scan showed unilocular and multilocular radiolucency. T(1)WI and T(2)WI on MRI exhibited low signal, and varix was found on DSA. The high-flow vascular malformation of the jaws classified into two groups: arterial malformation and arteriovenous malformation according to CT and DSA. The acute bleeding of 16 cases was effectively controlled by embolization. The chronic bleeding in the other 5 cases stopped after the 4 - 59 months and new bone formation was found in the follow-up radiography. The characteristic signs were not unique on X-ray plain film, and MRI and DSA had diagnostic value. Arteriovenous malformation of the jaws should be embolized by direct puncture in conjunction with endovascular therapy, and arterial malformation be superselectively embolized with NBCA.


[Purification, heterogeneity and some properties of T2 bacteriophage lysozyme].
Free T2 bacteriophage lysozyme is isolated and purified from 80 l portion of phagolysate by means of ballast protein and bacterial debris precipitation with rivanol, two-stage fractionation on amberlit IRC-50 and chromatography on CM-Sephadex C-50. Purified enzyme is homogenous under polyacrylamide gel electrophoresis in the presence of sodium dodecylsulphate, it has a molecular weight value similar to that in the literature. A presence of two active enzyme forms (I and II) is demonstrated. They can be separated by means of analytical electrophoresis in polyacrylamide gel at pH 4,5 and of ion-exchange chromatography on Amberlite IRC-50. T2 lysozymes I and II do not differ in their amino acid composition, ORD parameters, and they are not interconversible. Heterogeneity of phage lysozyme is shown not to be an artefact and to be due neither to heterogeneity of the initial phage poluation, nor to aggregation and to oxidation of enzyme SH-groups. The content of alpha-helix regions, as estimated by ORD is higher in phage lysozyme than in hen egg-white lysozyme, which evidences that these proteins are non-homologous.


Regulation of macrophage lysosomal enzyme secretion: role of arachidonate metabolites, divalent cations and cyclic AMP.
We have investigated the role in macrophage lysosomal enzyme release of arachidonate metabolites, extracellular divalent cations and cyclic AMP (cAMP) which modulate secretion in other cell types. Lysosomal enzyme secretion induced by zymosan was accompanied by release of malondialdehyde (MDA), which is derived from arachidonic acid via prostaglandin synthase. Blockade of MDA formation, by aspirin or indomethacin, was associated with only a small inhibitory effect on lysosomal enzyme release by zymosan: arachidonate metabolites thus play only a minor role in mediating macrophage lysosomal enzyme release. Zymosan-induced secretion of lysosomal enzymes from macrophages did not require extracellular magnesium or calcium although release was enhanced by magnesium and inhibited by calcium. These effects may be related to an influence of the ions on phagocytosis. Elevation of intracellular divalent cation concentrations, by ionophore A23187, induced release of lysosomal enzymes but this was a result of cell lysis. Adenylate cyclase stimulants and dibutyryl cAMP produced slight inhibition of zymosan-induced lysosomal enzyme release. Aminophylline and papaverine caused more marked inhibition but their effects may be due to actions independent of phosphodiesterase inhibition. Our data indicate that arachidonate metabolites and cAMP do not play a major role in regulating zymosan-induced enzyme release from macrophages. Extracellular calcium and magnesium may modulate secretion but the role of intracellular divalent cations remains to be established. We conclude that macrophage lysosomal enzyme secretion is controlled by regulatory mechanisms different from those which control similar degranulation processes in other cell types.


Treatment of mycosis fungoides with recombinant interferon-alpha 2a2 alone and in combination with etretinate.
Eleven patients with mycosis fungoides (MF) were treated with recombinant alpha-interferon (rIFN-alpha 2a2) in combination with etretinate (seven patients) or alone. One patient, who also received etretinate, went into complete remission and remained without signs of MF after 18 months. Six patients experienced partial remission; one of these was treated with rIFN-alpha 2a alone and was clinically in complete remission, but had still a pleomorphic skin infiltrate. Two patients were non-evaluable, and two stopped therapy due to progressive disease. Five patients discontinued therapy due to side-effects although three had partial remission of their disease. Only four patients received 12 months therapy. The study shows that rIFN-alpha 2a in combination with etretinate or alone can induce remission of MF.


Emerging vs Time-Tested Methods of Facial Grading Among Patients With Facial Paralysis.
Most rehabilitation specialists and many facial reanimation surgeons use the Sunnybrook Facial Grading System (FGS) to measure and detect changes in facial function. The eFACE, an electronic and digitally graded facial measurement scale, was recently created to provide similar information to the Sunnybrook FGS, but with scaling uniformity across all categories of facial function, graphical outputs, and easy-to-use visual analog scales. To establish the correlation between the scores on the eFACE and the Sunnybrook FGS among patients with facial paralysis and to compare the reliability of the 2 scales. A retrospective review of medical records identified 109 patients who were evaluated at a facial nerve center by physical therapists using the eFACE and the Sunnybrook FGS on the same day, between November 1, 2014, and May 31, 2015. The level of facial function predicted using the 2 scales was compared to study correlation between the scales. Data analysis was conducted from June 1 to September 1, 2015. Correlation between the Sunnybrook FGS and the eFACE grading scale. Two independent physical therapists evaluated patients using both the eFACE and the Sunnybrook FGS. Scores were compared and the Spearman rank correlation coefficient was calculated between the total scores and each of the 3 subscores, including static, dynamic, and synkinesis scores. The total Sunnybrook FGS synkinesis score (worst score, 15; perfect score, 0) and static score (worst score, 20; perfect score, 0) were normalized to a 100-point scale with the eFACE (perfect score, 100; worst score, 1). eFACE scores ranged from 48 to 100, and Sunnybrook FGS scores ranged from 0 to 100. Among 109 patients, there was a moderately strong correlation between eFACE and Sunnybrook FGS scores in both total and subcategory scores. The Spearman rank correlation coefficient of the total eFACE and Sunnybrook FGS was 0.75 (r < 0.0001). For the static scores, the correlation coefficient was -0.71 (r < 0.0001). The correlation coefficients for the dynamic and synkinesis scores were 0.77 (r < 0.0001) and -0.78 (r < 0.0001), respectively. There is moderately good agreement between the Sunnybrook FGS and the eFACE. Given the ease of using the eFACE on mobile devices, as well as its additional functionality, it may represent a reasonable facial grading option across disciplines in the future. NA.


Absent or Excessive Corpus Luteum Number Is Associated With Altered Maternal Vascular Health in Early Pregnancy.
Identifying modifiable factors that contribute to preeclampsia risk associated with assisted reproduction can improve maternal health. Vascular dysfunction predates clinical presentation of preeclampsia. Therefore, we examined if a nonphysiological hormonal milieu, a modifiable state, affects maternal vascular health in early pregnancy. Blood pressure, endothelial function, circulating endothelial progenitor cell numbers, lipid levels, and corpus luteum (CL) hormones were compared in a prospective cohort of women with infertility history based on number of CL: 0 CL (programmed frozen embryo transfer [FET], N=18); 1 CL (spontaneous conception [N=16] and natural cycle FET [N=12]); or >3 CL associated with in vitro fertilization [N=11]. Women with 0 or >3 CL lacked the drop in mean arterial blood pressure compared with those with 1 CL (both P=0.05). Reactive hyperemia index was impaired in women with 0 CL compared with 1 CL ( P=0.04) while baseline pulse wave amplitude was higher with > 3 CL compared with 1 CL ( P=0.01) or 0 CL ( P=0.01). Comparing only FET cycles, a lower reactive hyperemia index and a higher augmentation index is noted in FETs with suppressed CL compared with FETs in a natural cycle (both P=0.03). The number of angiogenic and nonangiogenic circulating endothelial progenitor cell numbers was lower in the absence of a CL in FETs ( P=0.01 and P=0.03). Vascular health in early pregnancy is altered in women with aberrant numbers of CL (0 or >3) and might represent insufficient cardiovascular adaptation contributing to an increased risk of preeclampsia.


Isolation of F' plasmids carrying a portion of the Salmonella typhimurium histidine transport operon.
The transposable drug resistance element Tn10 was employed as a region of homology to direct the insertion of Tn10-containing derivatives of F'ts114 lac into the chromosome of a Salmonella typhimurium strain that carries a Tn10 insertion in the histidine transport operon. Based on the direction of transfer of the resulting Hfr strains, the chromosomal Tn10 insertion was determined to be in orientation "A." New F' plasmids were selectively generated from one of the Hfr strains. The F' factors carry an intact dhuA hisJ portion of the histidine transport operon. A Southern hybridization revealed that one of the F' plasmids was formed by a type II excision event.


Understanding policy persistence-The case of police drug detection dog policy in NSW, Australia.
Significant research attention has been given to understanding the processes of drug policy reform. However, there has been surprisingly little analysis of the persistence of policy in the face of opposition and evidence of ineffectiveness. In this article we analysed just such a case - police drug detection dog policy in NSW, Australia. We sought to identify factors which may account for the continuation of this policy, in spite of counter-evidence and concerted advocacy. The analysis was conducted using the Advocacy Coalition Framework (ACF). We collated documents relating to NSW drug detection dog policy from 1995 to 2016, including parliamentary records (NSW Parliament Hansard), government and institutional reports, legislation, police procedures, books, media, and academic publications. Texts were then read, coded and classified against the core dimensions of the ACF, including subsystem actors and coalitions, their belief systems and resources and venues employed for policy debate. Three coalitions were identified as competing in the policy subsystem: security/law and order, civil liberties and harm reduction. Factors that aided policy stability were the continued dominance of the security/law and order coalition since they introduced the drug dog policy; a power imbalance enabling the ruling coalition to limit when and where the policy was discussed; and a highly adversarial policy subsystem. In this context even technical knowledge that dogs infringed civil liberties and increased risks of overdose were readily downplayed, leading to only incremental changes in implementation rather than policy cessation or wholesale revision. The analysis provides new insights into why the accumulation of new evidence and advocacy efforts can be insufficient to drive significant policy change. It poses a challenge for the evidence-based paradigm suggesting that in highly adversarial policy subsystems new evidence is unlikely to generate policy change without broader subsystem change, such as reducing the adversarial nature and/or providing new avenues for cross-coalition learning.


Patient information leaflets: friend or foe?
Every registered medication has an information insert in its package. This patient leaflet provides information on the product, which includes clinical pharmacology, recommended dose, mode of administration, how supplied, and a large section contains warnings and contraindications, adverse reactions, and precautions. Most of the prescribers do not read the patient information leaflets and do not discuss it with the users, whereas some patients do read it thoroughly. This may create worries and uncertainties resulting in reduced compliance to treatment. With easy access of patients to information on drugs that they use, mainly through the electronic media, it is very important that the text and contents of these patient leaflets are simple to understand and readable. Although information from official health agencies is superior to net-based sources, the patient information leaflets should be improved and become more user-friendly and less frightening.


p24 and p26, structurally related cell surface molecules identified by monoclonal antibody BA-2.
This paper describes additional structural analyses of the p24 cell surface molecule recognized by monoclonal antibody BA-2. Since BA-2 is broadly reactive with a variety of normal and malignant lymphohematopoietic and nonlymphohematopoietic cells, we examined the structure of p24 expressed on different cell types. Tryptic peptide mapping and 2-dimensional gel electrophoresis of p24 isolated from colon carcinoma cells, fresh leukemic cells, leukemic cell lines, and activated T-cells indicated that p24 exhibits no structural polymorphism within the cells examined. As has recently been demonstrated with several other cell surface molecules, p24 is shown to possess a covalently-attached fatty acid, based on the incorporation of [3H]palmitate. We have also identified an additional protein, designated p26, that is coprecipitated with p24. The p26 molecule is not disulfide-linked to p24, and can be immunoprecipitated from a variety of 125I- or [35S]methionine-labeled cells. V8 protease peptide mapping indicated that p24 and p26 are structurally homologous. Pulse-chase analysis using [35S]methionine and digestion with endoglycosidase-F indicated that p24 and p26 are probably derived from a p23 precursor, but no precursor-product relationship exists between p24 and p26. Based on this data we propose that p24 and p26 are most likely differentially-processed protein products of the same gene.


Mitochondrial permeability transition in pH-dependent reperfusion injury to rat hepatocytes.
To simulate ischemia and reperfusion, cultured rat hepatocytes were incubated in anoxic buffer at pH 6.2 for 4 h and reoxygenated at pH 7.4. During anoxia, intracellular pH (pHi) decreased to 6.3, mitochondria depolarized, and ATP decreased to < 1% of basal values, but the mitochondrial permeability transition (MPT) did not occur as assessed by confocal microscopy from the redistribution of cytosolic calcein into mitochondria. Moreover, cell viability remained > 90%. After reperfusion at pH 7.4, pHi returned to pH 7.2, the MPT occurred, and most hepatocytes lost viability. In contrast, after reperfusion at pH 6.2 or with Na(+)-free buffer at pH 7.4, pHi did not rise and cell viability remained > 80%. After acidotic reperfusion, the MPT did not occur. When hepatocytes were reperfused with cyclosporin A (0.5-1 microM) at pH 7.4, the MPT was prevented and cell viability remained > 80%, although pHi increased to 7.2. Reperfusion with glycine (5 mM) also prevented cell killing but did not block recovery of pHi or the MPT. Retention of cell viability was associated with recovery of 30-40% of ATP. In conclusion, preventing the rise of pHi after reperfusion blocked the MPT, improved ATP recovery, and prevented cell death. Cyclosporin A also prevented cell killing by blocking the MPT without blocking recovery of pHi. Glycine prevented cell killing but did not inhibit recovery of pHi or the MPT.


A qualitative study of younger men's experience of heart attack (myocardial infarction).
The effects of heart attack, or myocardial infarction (MI), across psychosocial domains may be particularly acute in younger adults, for whom serious health events are non-normative. MI morbidity is declining in Western countries, but in England MI numbers have plateaued for the under-45 cohort, where approximately 90% of patients are male. Qualitative research on younger adults' experience of MI is limited, and no study has sampled exclusively under-45s. This study aimed to understand how a sample of men under 45 adjusted to and made sense of MI. Qualitative research design based on semi-structured in-depth interviews. Ten men aged under 45 who had experienced MI in the past 3-6 months were purposively recruited and interviewed. Interviews were transcribed verbatim and analysed using interpretative phenomenological analysis. Seven superordinate themes were identified. This article focuses in depth on the three most original themes: (1) 'I'm less of a man', which described experiences of losing 'maleness' (strength, independence, ability to provide) post-MI; (2) 'Shortened horizons', which covered participants' sense of foreshortened future and consequent reprioritization; and (3) 'Life loses its colour', describing the loss of pleasure from lifestyle-related changes. Themes broadly overlapped with the qualitative literature on younger adult MI. However, some themes (e.g., loss of 'maleness' post-MI, and ambivalence towards MI risk factors) appeared unique to this study. Themes were also discussed in relation to risk factors for anxiety and depression and how this might inform clinical care for a younger, male population. Statement of contribution What is already known on this subject? Myocardial infarction (MI) morbidity is not declining in England for under-45s. Adjustment to MI is particularly challenging for younger adults, perhaps because it is non-normative. However, little is known about the experience of MI in younger adults. What does this study add? This is the first qualitative study to sample MI patients exclusively under 45, thereby mapping to epidemiological trends. Further support is provided for some themes identified in the existing young adult MI literature. New themes are identified here which can provide insights relevant to clinical care in this population.


Myolipoma of Soft Tissue: Clinicopathologic Analysis of 34 Cases.
Myolipoma of soft tissue, which was first described by Meis and Enzinger (1991), is a rare benign neoplasm characterized by the admixture of mature adipocytes and well-differentiated smooth muscle cells. Recently, cytogenetic alteration of the HMGA2 gene has been reported in 2 myolipomas. We present the clinicopathologic features of 34 cases of myolipoma of soft tissue, study immunoreactivity for HMGA2, and review the previous literature. In our series, there were 32 women and 2 men, with age at presentation ranging from 35 to 94 years (median, 55 y). The most frequently affected site was retroperitoneum (47%), followed by pelvis (15%), abdominal wall (12%), and intra-abdominal sites (9%). Follow-up information was available for 17 patients (50%), ranging from 1 to 202 months (mean, 41 mo). None has developed local recurrence or metastasis. Grossly, tumors were well circumscribed, and the cut surface showed an admixture of yellowish adipose tissue and tan-whitish nodules. The size ranged from 2.4 to 60 cm (median 10.5 cm). Histologically, the tumors were composed of an intimate admixture of mature fat cells and bland spindle-shaped cells with brightly eosinophilic cytoplasm, arranged in fascicles. Some cases showed the following unusual features focally: hypercellular fascicular pattern (N=2), degenerative nuclear atypia (N=1), round cell morphology (N=1), hemosiderin deposition (N=1), metaplastic cartilage (N=1), metaplastic bone (N=1), and eosinophil infiltrates (N=1). Immunohistochemically, spindle cells showed strong and diffuse positivity for desmin (26/26 cases), SMA (20/21), and ER (13/15). Nuclear positivity for HMGA2 was identified in 15 of 25 cases (60%). MDM2 and CDK4 were usually negative (14/15, 8/9, respectively). In summary, myolipoma of soft tissue is a distinctive benign tumor composed of mature fat cells and smooth muscle cells and arises most commonly in deep-seated locations of middle-aged women. In our study, 60% of cases showed nuclear staining for HMGA2 by immunohistochemistry, which supports the possibility that these tumors harbor aberration of the HMGA2 gene, as seen in lipomas and leiomyomas elsewhere.


Deficient coordination of associated postural adjustments during a lifting task in children with neurodevelopmental disorders.
Precision grip and concomitant anticipatory postural adjustments were investigated in 11 children (three females, eight males; mean age 9 years 1 month, SD 11 months) with attention-deficit-hyperactivity disorder (ADHD); 12 children (three females, nine males; mean age 9 years, SD 7 months) with developmental coordination disorder (DCD), and 13 children (two females, 11 males; mean age 9 years 9 months, SD 11 months) with a combination of ADHD and DCD (ADHD+). There were two comparison groups: an age-matched group (four females, 11 males; mean age 9 years 1 month, SD 14 months) and a younger age group (five females, six males; mean age 6 years 5 months, SD 8 months). Adaptation to different weights was evaluated by lifting a specialized grip instrument monitoring grip force, load force, and centre of foot pressure displacements. Children with ADHD+ showed: (1) excessive grip forces, (2) decreased amplitude and prolonged onset of postural adjustments, and (3) reduced ability to adapt the motor output. Children with ADHD and DCD did not scale manual and postural forces in amplitude and time domains. Children with DCD also differed in delayed timing of postural adjustments. Results indicate that children with ADHD and DCD show a spectrum of neural dysfunctions underlying poor motor coordination, which are not specific to the clinical disorder.


Serum potassium testing in diuretic-treated outpatients. A multivariate approach.
We evaluated risk factors for abnormal serum potassium (K+) concentrations in 5817 outpatients on chronic diuretic therapy. Hypokalemia (K+ less than 3.5 meq/L) occurred in 18.8 percent at the last clinic measurement. Hyperkalemia (K+ greater than 5.5) was rare (0.5%) and was even less common in those also taking KCl or a K+ sparing drug (0.2%). Hypokalemic patients were younger, healthier, more often hypertensive, more commonly taking a thiazide diuretic, and more likely to have been hypokalemic in the past. Hyperkalemic patients were older, more often suffering from heart or renal failure, and more commonly taking furosemide. Logistic regression analysis yielded eight variables that contributed significantly to the prediction of hypokalemia: mean and most recent serum K+, thiazide use, the use and duration of use of potassium-sparing diuretics, age, and most recent serum sodium and bicarbonate determinations. The regression equation allowed us to identify a group of patients (63% of the total) at low risk for hypokalemia (K+ less than 3.5 in 9.4%; K+ less than 3.0 in 0.5%) and another group (37% of the total) at high risk for hypokalemia (K+ less than 3.5 in 35%; K+ less than 3.0 in 5%). Information about the risk of hypokalemia can be used to decide when to measure serum potassium concentration in individual diuretic-treated outpatients.


Management of elderly patients with urothelial carcinoma of the bladder: guideline concordance and predictors of overall survival.
To study guideline recommendation (GR)-concordance rates of treatment in elderly patients with urothelial carcinoma of the bladder (UCB) and to identify predictors of survival. The records of 206 consecutive patients aged ≥ 75 years (median age 79 years; range 75-95) were reviewed. All patients underwent transurethral resection (TUR) or biopsy of UCB. The European Association of Urology and American Urological Association guidelines were used as reference when evaluating concordance with GRs and clinical outcome. Univariable and multivariable analyses were performed to identify predictors of survival. The overall GR-concordance rate of treatment was 88.8% (183 of 206 patients). Patients who were older (P = 0.017), who underwent prior treatment for UCB (P = 0.010), and had greater comorbidities (P = 0.001) were less likely to undergo treatment following GRs. With a median (mean; range) follow-up of 14.7 (22.6; 0.3-111.5) months, 79 patients died (38.3%). More comorbidities (unadjusted Charlson comorbidity index; P = 0.007), a Karnofsky performance status (KPS) score of ≤ 80 (P = 0.001) and more advanced initial pathological tumour stage (P = 0.019) independently predicted reduced overall survival (OS). In the subgroup of patients with indication for cystectomy (n = 99), there was a trend for longer OS in patients treated with curative intent (cystectomy or radio-chemotherapy) compared with conservative treatment with TUR ± intravesical therapy only (P = 0.095). The vast majority of elderly patients with UCB received adequate treatment at our tertiary institution. The KPS score, more comorbidities and more advanced pathological tumour stage are predictors for reduced OS and should be considered to optimize patient care.


What do I need to know about gout?
Many patients with gout present with an acute attack (flare) of gouty arthritis. In its early stages, gout is a chronic, often silent disorder punctuated by acute, extremely painful arthritic flares. Over time, untreated or insufficiently treated gout may progress, with more frequent flares and formation of urate crystal deposits (tophi) and associated chronic, deforming arthritis (gouty arthropathy). About 20% of patients with gout have urinary tract stones and can develop an interstitial urate nephropathy. Gout (also called urate crystal deposition disease) is characterized by reduced renal clearance or, less frequently, an overproduction of uric acid. When the serum urate acid (sUA) level persistently exceeds 6.8 mg/dL, extracellular fluids become saturated and hyperuricemia occurs. Hyperuricemia is also very common among adult men and postmenopausal women, most of whom remain asymptomatic with respect to gout throughout their lives. Nevertheless, hyperuricemia is the major risk factor for gout because it predisposes to urate crystal formation and deposition, particularly in and around joints and in other soft tissue structures. The symptoms and signs of gout result from acute and chronic inflammatory responses of the body to urate crystal deposits. Although any joint may be affected, the metatarsophalangeal (MTP) joint of the great toe (podagra) is the first joint affected in half of all cases. One major goal in managing gout is to treat the pain of acute flares aggressively with anti-inflammatory agents to reduce flare intensity and duration. In addition, most patients with gout eventually require long-term treatment with urate-lowering therapy (ULT) to reverse the chronic urate crystal deposition and to prevent recurrent flares that can cause permanent joint damage.


Observation of vortex-ring "discrete" solitons in 2D photonic lattices.
We present the experimental observation of both on-site and off-site vortex-ring solitons of unity topological charge in a nonlinear photonic lattice, along with a theoretical study of their propagation dynamics and stability.


Sugar sweetened beverage consumption during pregnancy is associated with lower diet quality and greater total energy intake.
Identify the socio-economic correlates of sugar sweetened beverage (SSB) consumption among pregnant women and analyze to what extent SSB consumption is associated with diet quality and total energy intake. Additionally, we aim to predict how diet quality scores and totally energy intakes would change if SSB consumption was artificially set to 0. Repeated Cross Sectional Study. United States. SSB consumption was estimated from 1-2 24-hour dietary recalls from 1,154 pregnant women who participated in the 1999-2006 National Health and Nutrition Examination Survey. Linear regression models were used to identify socioeconomic and demographic factors associated with SSB consumption and to assess the associations between SSB consumption and diet quality and total energy intake. Diet quality was measured with the Alternate Healthy Eating Index modified for Pregnancy (AHEI-P). The mean SSB intake was 1.3 servings per day (sd 1.5). Having a household income ≤100% of the Federal Poverty Level, being born in the United States, and not being married or living with a partner were positively associated with SSB consumption. Every 12 oz. of SSBs consumed was associated with a 2.3 lower AHEI-P score (95% CI: 1.6, 2.9) and the consumption of 124 more calories (95% CI: 85, 163), after adjusting for age, country of birth, race/ethnicity, educational attainment, marital status, household income, survey year and day/s of the week the recall/s were collected. Our predictive models indicated that average AHEI-P would be 6.4 (5.4, 7.6) higher and average total energy intakes would be 203.5 calories (122.2, 284.8) lower if SSB intake was set to 0. SSB consumption is associated with poorer diet quality and higher total energy intake among pregnant women.


Matrix metalloproteinases process the laminin-5 gamma 2-chain and regulate epithelial cell migration.
Matrix metalloproteinase (MMP)-2 and membrane type 1-MMP can process the laminin-5 (Ln-5) gamma2-chain, revealing a cryptic site inducing epithelial cell migration. We investigated whether other MMPs process the Ln-5 gamma2-chain and related their ability to induce epithelial cell migration. The N-terminal sequences of the MMP-3, -12, -13, and -20 processed 80kDa Ln-5 gamma2x-chains were identical whereas the N-terminus of the 80kDa(MMP-8) Ln-5 gamma2x-chain was not. MMP-3, -13, -14, and -20 induced MCF-7 cell migration over Ln-5 while MMP-8 was a poor inducer of MCF-7 cell migration. In conclusion, several MMPs can process the Ln-5 gamma2-chain and induce epithelial cell migration.