Effect of Physical activity on Insulin Resistance, Inflammation and Oxidative Stress in Diabetes Mellitus.
Diabetes Mellitus is a growing health concern projected to affect 366 million people worldwide by around 2030. Multiple approaches to address this health concern are documented; amongst which increased the habitual physical activity has been shown to be beneficial. Various mechanisms demonstrated show improvement of cellular insulin sensitivity. The interplay between insulin sensitivity and insulin resistance plays a key role in development and persistence of the diabetic state, which can be directly linked to the levels of physical activity. Regulation of adiponectin and leptin levels are also linked to physical activity via reduction of central obesity. Inflammatory markers, free radical reduction and up-regulation of physiological antioxidant processes are also observed in subjects with increased physical activity schedules, all of which play a significant role in the pathogenesis of Diabetes Mellitus.


Hetero-nanocomposites of magnetic and antifungal nanoparticles as a platform for magnetomechanical stress induction in Saccharomyces cerevisiae.
Copper(i) oxide (Cu2O) nanoparticles (NPs) of 30 nm with antifungal properties have been functionalized with 9 nm nickel ferrite (NiFe2O4) magnetic nanoparticles (MNPs) to construct hetero-nanocomposites (NCs) of a submicron hydrodynamic size for magnetomechanical stress induction in the yeast, Saccharomyces cerevisiae. A post-synthetic approach involving the assembly through hydrophobic interactions of the preformed NPs of non-uniform sizes, albeit coated with the same surfactant (oleylamine), is reported. Solvents of different polarity were implemented during the synthetic procedure resulting in NCs of similar composition consisting mainly of MNPs randomly decorated onto the bigger Cu2O NPs. The antifungal properties of the building NPs and the NCs were studied in terms of fungistatic and fungicidal activity, whereas the ionic leaching was found to be negligible, highlighting the nanosize effect. Although S. cerevisiae cells were found to be resistant to individual NiFe2O4 MNPs because of their small size, their sensitivity to NCs significantly increased upon short-time exposure to a rotating low-frequency magnetic field (10 min, 30 Hz, 35 G) and this arises from the collective properties. The magnetomechanical cell stress induction was accompanied by alteration of cellular membrane integrity and programmed cell death signaling.


A multi-center, Phase II trial of nab-paclitaxel and gemcitabine in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy.
Nanoparticle albumin-bound paclitaxel (nab-PTX) plus gemcitabine (GEM) significantly improved overall survival in patients with metastatic pancreatic adenocarcinoma. Anti-tumor synergy between GEM and nab-PTX was recently demonstrated in a mouse model. We planned to assess the efficacy and safety of the combination of nab-PTX + GEM in patients with non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy. Patients with advanced NSCLC with progressive disease after platinum-based chemotherapy, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, and adequate kidney, liver and bone marrow function were eligible. Treatment consisted of nab-PTX (100 mg/m2) + GEM (1000 mg/m2) on days 1 and 8 of each 3-week cycle until progression disease or unacceptable toxicity occurred. The primary endpoint was progression-free survival (PFS). Of the 28 patients enrolled, all were evaluable for response and toxicity. The median age was 68 years (range 47-79), and 23 were male and 5 female. The histologic subtypes were: adenocarcinoma in 19 patients, and squamous cell carcinoma in 9 patients. Seventeen patients had ECOG PS 1 and 11 patients had PS 0. Twenty-four patients were second line and 4 patients were third line. The median number of cycles administered was 4 (range 1-10). The overall response rate was 17.9%. The disease control rate was 67.9%. The median progression-free survival was 3.1 months (95% confidence interval [CI] =1.6-4.1). Adverse events were generally tolerable except grade 3 interstitial pneumonia with in 4 patients (14.3%). The efficacy of nab-PTX in combination with GEM in advanced second or third-line NSCLC patients was limited and the frequent occurrence of interstitial pneumonia was unacceptable.


Structural reversibility of Cu doped NU-1000 MOFs under hydrogenation conditions.
The metal-organic framework (MOF), NU-1000, and its metalated counterparts have found proof-of-concept application in heterogeneous catalysis and hydrogen storage among others. A vapor-phase technique, akin to atomic layer deposition (ALD), is used to selectively deposit divalent Cu ions on oxo, hydroxo-bridged hexa-zirconium(IV) nodes capped with terminal -OH and -OH2 ligands. The subsequent reaction with steam yields node-anchored, CuII-oxo, hydroxo clusters. We find that cluster installation via AIM (ALD in MOFs) is accompanied by an expansion of the MOF mesopore (channel) diameter. We investigated the behavior of the cluster-modified material, termed Cu-AIM-NU-1000, to heat treatment up to 325 °C at atmospheric pressure with a low flow of H2 into the reaction cell. The response under these conditions revealed two important results: (1) Above 200 °C, the initially installed few-metal-ion clusters reduce to neutral Cu atoms. The neutral atoms migrate from the nodes and aggregate into Cu nanoparticles. While the size of particles formed in the MOF interior is constrained by the width of mesopores (∼3 nm), the size of those formed on the exterior surface of the MOF can grow as large as ∼8 nm. (2) Reduction and release of Cu atoms from the MOFs nodes is accompanied by the dynamic structural transformation of NU-1000 as it reverts back to its original dimension following the release. These results show that while the MOF framework itself remains intact at 325 °C in an H2 atmosphere, the small, AIM-installed CuII-oxo, hydroxo clusters are stable with respect to reduction and conversion to metallic nanoparticles only up to ∼200 °C.


Outcome of treated and untreated asymptomatic bacteriuria in renal transplant recipients.
No guidelines exist concerning treatment of asymptomatic bacteriuria in renal transplant recipients (RTR). Because of scarce clinical symptoms and fear of complications, such episodes are frequently treated based on subjective criteria without clear clinical benefit, with the risk of selecting resistant pathogens. We retrospectively analysed the outcome of 334 asymptomatic Escherichia coli (E. coli) and Enterococcus faecalis (E. faecalis) bacteriuria that occurred in 77 RTR later than 1 month post-transplantation. We distinguished: Type I, high-grade bacteriuria with pyuria; Type II, high-grade bacteriuria without pyuria; Type III, low-grade bacteriuria with pyuria and Type IV, low-grade bacteriuria without pyuria. None of the 334 episodes was followed by acute rejection or chronic pyelonephritis. One hundred and one (30%) episodes were treated [32 (62%) Type I, 38 (45%) Type II, 13 (36%) Type III and 18 (11%) Type IV]. Evolution to symptomatic urinary tract infection (UTI) was similar between treated and untreated episodes (0/101 versus 4/233, P = 0.32). The four UTI resolved favourably without further complication upon treatment. Persistent asymptomatic bacteriuria occurred in 45 (46%) treated episodes (2 Type I, 27 Type II, 8 Type III and 9 Type IV), with selection of resistant pathogen in 35 cases (78%). Spontaneous bacterial clearance occurred in 138 (59%) untreated episodes (15 Type I, 23 Type II, 9 Type III and 91 Type IV). Negative control cultures tended to be more frequent in treated Type I (P = 0.09) and in untreated Type II episodes (P = 0.08). Restricting antibiotic treatments for asymptomatic low-grade bacteriuria and high-grade bacteriuria in the absence of pyuria, occurring later than 1 month posttransplantation, might be safe in RTR.


Relationship between TIM-3 gene polymorphisms and steroid-resistant primary nephrotic syndrome in children.
Nephrotic syndrome, also known as nephrosis, is a collection of symptoms in medicine and urology caused by damage to the basement membrane of the kidney glomeruli and the kidneys excrete a large amount of protein. This experiment was carried out to investigate the association of three single nucleotide polymorphisms (SNPs) of T-cell immunoglobulin and mucin-domain-containing-3 (Tim-3) with childhood primary nephrotic syndrome (PNS) steroid response in Han Chinese. For this purpose, a total of 218 children with steroid-resistant PNS and 189 children with steroid-responsive PNS were enrolled in this case-control study. Three single nucleotide polymorphisms (SNPs) of the TIM-3 gene promoter region (rs4704853, rs1051746, and rs10053538) were analyzed by polymerase chain reaction (PCR) and restriction enzyme digestion. Results showed that there were 124 males and 94 females in the steroid-resistant PNS group and 114 males and 75 females in the steroid-responsive PNS group. The mean ages of the two groups were 7.9 years and 7.7 years, respectively. The distribution of alleles of Rs1051746 and Rs10053538 were significantly different between the steroid-resistant PNS group and the steroid-responsive PNS group (P-value = 0.047 and 0.012, respectively). The distribution of their genotypes was also significantly different between the steroid-resistant PNS group and the steroid-responsive PNS group (P-value = 0.044 and 0.010, respectively). Haplotype G-C-G was less frequent among steroid-resistant PNS children than the steroid-responsive PNS children (P = 0.015). There was no significant difference between the three SNPs of TIM-3 and the clinical features of these PNS children (P>0.05). It concluded that this study provided evidence showing that the polymorphisms of Rs1051746 and Rs10053538 at the TIM-3 gene were related to childhood PNS steroid response. This result provided fundamental support for future studies on the role of TIM-3 in pathogenesis and therapy of childhood PNS.


Two subdomains of negative symptoms in psychotic disorders: established and confirmed in two large cohorts.
Negative symptoms of schizophrenia are normally grouped into a single category. However, the diversity of such symptoms suggests that they are actually made up of more than one dimension. The DSM-V proposes two negative symptom domains, namely expressive deficits and avolition/asociality. We investigated whether the negative symptoms do indeed have two dimensions. An exploratory factor analysis was carried out based on interviews with the PANSS (664 patients). We restricted our analysis to items that had been described as negative symptoms in previous factor analyses. The symptom structure was then tested for stability by performing a confirmatory factor analysis on PANSS interviews from a separate cohort (2172 patients). Exploratory factor analysis yielded a two-factor structure of negative symptoms. The first factor consisted of PANSS items Flat affect, Poor rapport, Lack of spontaneity, Mannerisms and posturing, Motor retardation, and Avolition. The second factor consisted of Emotional withdrawal, Passive/apathetic social withdrawal, and Active social avoidance. The first factor could be related to expressive deficits, reflecting a loss of initiative, and the second factor to social amotivation, related to community interaction. This factor structure supports the DSM-V classification and may be relevant for pathophysiology and treatment of schizophrenia and other psychotic disorders.


Visceral Leishmaniasis Treatment Outcome and Associated Factors in Northern Ethiopia.
Visceral leishmaniasis (VL), one of the most neglected tropical diseases, is placing a huge burden on Ethiopia. Despite the introduction of antileishmanial drugs, treatment outcomes across regions are variable due to drug resistance and other factors. Thus, understanding of VL treatment outcomes and its contributing factors helps decisions on treatment. However, the magnitude and the risk factors of poor treatment outcome are not well studied in our setting. Therefore, our study was designed to assess treatment outcomes and associated factors in patients with VL. A cross-sectional study was conducted in VL patients admitted between June 2016 and April 2018 to Ayder Comprehensive Specialized Hospital, Tigray, Northern Ethiopia. Data was collected through chart review of patient records. Logistic regression analysis was used to identify factors associated with poor treatment outcome. A total of 148 VL patients were included in the study. The mean age (SD) of the patients was 32.86 (11.9) years; most of them (94.6%) were male patients. The proportion of poor treatment outcome was 12.1%. Multivariable logistic regression analysis showed that long duration of illness (> four weeks) (adjusted odds ratio (AOR): 6.1 [95% confidence interval (CI); 1.3-28.6], p=0.02) and concomitant tuberculosis (TB) infection (AOR 4.6 [95% CI; 1.1-19.1], p=0.04) were the independent predictors of poor treatment outcome. Poor treatment outcome was observed in a considerable proportion of VL patients. Long duration of illness and coinfection with TB were associated with poor VL treatment outcome. Hence, early diagnosis and effective prompt treatment are important to improve treatment outcomes among VL patients. Special attention should also be given in the treatment of VL/TB coinfected patients in our setting.


Toremifene to reduce fracture risk in men receiving androgen deprivation therapy for prostate cancer.
Androgen deprivation therapy is associated with fracture risk in men with prostate cancer. We assessed the effects of toremifene, a selective estrogen receptor modulator, on fracture incidence in men receiving androgen deprivation therapy during a 2-year period. In this double-blind, placebo controlled phase III study 646 men receiving androgen deprivation therapy for prostate cancer were assigned to toremifene (80 mg by mouth daily) and 638 were assigned to placebo. Subjects were followed for 2 years. The primary study end point was new vertebral fractures. Secondary end points included fragility fractures, bone mineral density and lipid changes. The 2-year incidence of new vertebral fractures was 4.9% in the placebo group vs 2.5% in the toremifene group, a significant relative risk reduction of 50% (95% CI -1.5 to 75.0, p = 0.05). Toremifene significantly increased bone mineral density at the lumbar spine, hip and femoral neck vs placebo (p <0.0001 for all comparisons). There was a concomitant decrease in markers of bone turnover (p <0.05 for all comparisons). Toremifene also significantly improved lipid profiles. Venous thromboembolic events occurred more frequently with toremifene than placebo with 7 subjects (1.1%) in the placebo group experiencing a venous thromboembolic event vs 17 (2.6%) in the toremifene group. Other adverse events were similar between the groups. Toremifene significantly decreased the incidence of new vertebral fractures in men receiving androgen deprivation therapy for prostate cancer. It also significantly improved bone mineral density, bone turnover markers and serum lipid profiles.


Radiosynthesis of 68Ga-labelled DOTA-biocytin (68Ga-r-BHD) and assessment of its pharmaceutical quality for clinical use.
Biocytin analogues labelled with indium-111, yttrium-90 and lutetium-177 have shown their effectiveness in the imaging of infections/inflammation in patients with osteomyelitis and function as efficient tools in pretargeted antibody-guided radioimmunotherapy. In this study, the labelling of a biocytin analogue coupled with DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), namely, r-BHD, with gallium-68 (68Ga) was optimized, and the quality and stability of the preparations were assessed for clinical use. Synthesis of 68Ga-r-BHD was carried out by heating a fraction of the 68Ge/68Ga eluate in a reactor containing the biocytin analogue with the appropriate buffer. The influence of the precursor amount (from 2.5 to 140 nmol), the pH of the reaction (from 2 to 5.5) and the buffer species (1.5 mol/l sodium acetate, 1.5 mol/l sodium formate, 4.5 mol/l HEPES) on radiochemical yield and radiochemical purity was assessed. Studies on stability and binding to avidin (Av) were also conducted in different media. Under the best labelling condition (56 nmol of precursor, 3.8 pH, sodium formate buffer) synthesis of 68Ga-r-BHD resulted in a yield of 64 ± 3% (not decay corrected). Radiochemical purity was around 95% because a 68Ga-coordinated sulfoxide form of the ligand was detected as a by-product of the reaction (68Ga-r-SBHD). The by-product was identified and characterized by liquid chromatography-electrospray ionization tandem mass spectrometry. At the natural 1 : 4 Av/68Ga-r-BHD molar ratio, affinity results were 62 ± 2 and 80 ± 2% in saline and human serum, respectively. Stability of 68Ga-r-BHD and of the radiotracer/Av complex remains almost constant over 180 min. 68Ga-r-BHD appears to be a good candidate for clinical applications.


Effects of temperature and nutritional conditions on the mitotic cell cycle of Saccharomyces cerevisiae.
Yeast cells were cultivated at different growth rates in a chemostat by alterations in the flow of the limiting nutrient glucose and in batch cultures where variations in growth rate were achieved by alterations in the composition of nutrients. It was observed that the stage in the cycle at which S-phase was completed varied with growth rate. The faster the growth rate, the earlier the stage in the cycle in which completion of S-phase occurred. When stage in the cycle is converted into time before division it was observed that the time from completion of S-phase to cell division varied only slightly with growth rate except at extremely slow growth rates. Expansion of cell cycle transit time as the growth rate was slowed was achieved primarily by an expansion in time of the period from division to the completion of S-phase. In contrast, when cells were grown at different rates by alterations in the temperature of cultivation, completion of S-phase occurred at approximately the same stage in the cell cycle at all growth rates.


The Utility of Data Transformation for Alignment, De Novo Assembly and Classification of Short Read Virus Sequences.
Advances in DNA sequencing technology are facilitating genomic analyses of unprecedented scope and scale, widening the gap between our abilities to generate and fully exploit biological sequence data. Comparable analytical challenges are encountered in other data-intensive fields involving sequential data, such as signal processing, in which dimensionality reduction (i.e., compression) methods are routinely used to lessen the computational burden of analyses. In this work, we explored the application of dimensionality reduction methods to numerically represent high-throughput sequence data for three important biological applications of virus sequence data: reference-based mapping, short sequence classification and de novo assembly. Leveraging highly compressed sequence transformations to accelerate sequence comparison, our approach yielded comparable accuracy to existing approaches, further demonstrating its suitability for sequences originating from diverse virus populations. We assessed the application of our methodology using both synthetic and real viral pathogen sequences. Our results show that the use of highly compressed sequence approximations can provide accurate results, with analytical performance retained and even enhanced through appropriate dimensionality reduction of sequence data.


Clonally diverse T cell homeostasis is maintained by a common program of cell-cycle control.
Lymphopenia induces T cells to undergo cell divisions as part of a homeostatic response mechanism. The clonal response to lymphopenia is extremely diverse, and it is unknown whether this heterogeneity represents distinct mechanisms of cell-cycle control or whether a common mechanism can account for the diversity. We addressed this question by combining in vivo and mathematical modeling of lymphopenia-induced proliferation (LIP) of two distinct T cell clonotypes. OT-I T cells undergo rapid LIP accompanied by differentiation that superficially resembles Ag-induced proliferation, whereas F5 T cells divide slowly and remain naive. Both F5 and OT-I LIP responses were most accurately described by a single stochastic division model where the rate of cell division was exponentially decreased with increasing cell numbers. The model successfully identified key biological parameters of the response and accurately predicted the homeostatic set point of each clone. Significantly, the model was successful in predicting interclonal competition between OT-I and F5 T cells, consistent with competition for the same resource(s) required for homeostatic proliferation. Our results show that diverse and heterogeneous clonal T cell responses can be accounted for by a single common model of homeostasis.


Occupational cannabis exposure and allergy risks.
Cannabis allergy has mainly been described following recreational use but some cases also point to cannabis sensitisation as a result of occupational exposure. As a consequence, little is known on the prevalence and clinical phenotype of occupational cannabis allergy. Therefore, this study aims to explore the allergy-associated health risks of occupational cannabis exposure in Belgian police force personnel. 81 participants, active in the police force, reporting regular occupational cannabis exposure during the past 12 months, were included. History was combined with a standardised questionnaire on allergies and cannabis exposure.Basophil activation tests (BATs) with a crude cannabis extract and rCan s 3 were performed. In addition, specific (s)IgE rCan s 3 as well as sIgE to house dust mite, six pollen and three mould allergens were quantified. Although 42% of the participants reported respiratory and/or cutaneous symptoms on occupational cannabis exposure, all cannabis diagnostics were entirely negative, except one symptomatic case demonstrating a borderline result. Furthermore, there is no significant difference between the groups with and without symptoms on cannabis exposure in terms of allergenic sensitisations. The origins of the reported respiratory and cutaneous symptoms during cannabis exposure remain elusive but are probably due to non-immune reactions. It should be noted that the study was volunteer-based possibly reflecting an excessive number of symptomatic individuals. Nevertheless, as only one participant reported using fully protective gear, much improvement is needed for reducing the number of symptoms reported on duty, independent of their origin.


Effect of food on the oral bioavailability of UFT and leucovorin in cancer patients.
UFT is composed of tegafur (FT), a prodrug of 5-fluorouracil (5-FU), and uracil in a fixed combination (1:4). In conjunction with leucovorin, UFT is being developed for the first-line oral treatment of metastatic colorectal cancer. The effect of food on the oral bioavailability of UFT (2 x 100 mg capsules; dose in terms of FT) and leucovorin (2 x 15 mg tablets) was evaluated in a single-dose, randomized, two-way crossover study. Patients (n = 25) were assigned to receive both drugs after an overnight fast or 5 min after completion of a high-fat meal (721 calories) with a 3-day washout period between treatments; then they were permitted to continue on oral UFT/leucovorin therapy for safety assessment. UFT (300 mg/m2/day as three divided doses) and leucovorin (90 mg/day as three divided doses) were given for 28 days. After a 7-day rest, the 28-day cycle was repeated. Pharmacokinetics (n = 22 patients) were determined for FT, 5-FU, uracil, leucovorin, and 5-methyltetrahydrofolate (an active metabolite of leucovorin). The absence of food-effect on peak plasma concentration (CMAX) and the area under the curve (AUC) was concluded if the 90% confidence interval for the ratio of the treatment means was entirely contained in 0.75-1.33. Administration of UFT with food resulted in a 34% decrease in CMAX of FT, whereas the AUC of FT remained unchanged. Food decreased the CMAX and AUC values of uracil and 5-FU by 37-76%. On the contrary, the CMAX and AUC values of leucovorin and 5-methyltetrahydrofolate were increased by 14-60% with food. Time to reach CMAX for all analytes was significantly (P < or = 0.001) delayed by food. Except for the AUCs of FT, the statistical criterion for concluding a lack of food-effect was not met. These data suggest that UFT/leucovorin should not be dosed simultaneously with food. It is recommended that food should not be consumed for 1 h before and after an oral dose of UFT and leucovorin in a manner similar to pivotal Phase III trials. The 28-day oral regimen of UFT and leucovorin was generally well tolerated in the population studied.


Analysis of functional SNP in ifng/ifngr1 in Chinese Han population with tuberculosis.
Ifng/Ifngr1 are the main genes that are associated with tuberculosis. We continued to search for other functional single nucleotide polymorphisms (SNP) and investigated their influence on patients with tuberculosis in the Chinese population. Seven SNP located in the ifng and ifngr1 genes were genotyped by ligase detection reaction in 222 cases and 188 ethnically matched controls. A significant genetic association between rs7749390 (located on the exon/intron splice site of the ifngr1 gene) and tuberculosis was observed, and the log-additive model was accepted as the best inheritance model to fit these data (OR: 1.35, 95% CI: 1.02-1.80, P = 0.038). Haplotype-specific association analysis revealed that the result was consistent with the individual SNP study. The combination of rs2234711/rs1327474/rs7749390/rs41401746, which was in strong linkage disequilibrium (D' > 0.75), showed a significant association of ifngr1 with tuberculosis (P = 0.00079). Neither the single SNP nor the haplotype analysis showed a significant association between tuberculosis and the ifng gene markers. Our data implied the involvement of the ifngr1 gene in susceptibility to tuberculosis.


Intermittent hypoxia is a key regulator of cancer cell and endothelial cell interplay in tumours.
Solid tumours are complex structures in which the interdependent relationship between tumour and endothelial cells modulates tumour development and metastasis dissemination. The tumour microenvironment plays an important role in this cell interplay, and changes in its features have a major impact on tumour growth as well as on anticancer therapy responsiveness. Different studies have shown irregular blood flow in tumours, which is responsible for hypoxia and reoxygenation phases, also called intermittent hypoxia. Intermittent hypoxia induces transient changes, the impact of which has been underestimated for a long time. Recent in vitro and in vivo studies have shown that intermittent hypoxia could positively modulate tumour development, inducing tumour growth, angiogenic processes, chemoresistance, and radioresistance. In this article, we review the effects of intermittent hypoxia on tumour and endothelial cells as well as its impacts on tumour development.


Exploring Mental Health Presentations in Remote Aboriginal Community Controlled Health Services in the Kimberley Region of Western Australia Using an Audit and File Reviews.
The study aims to explore the role of mental health care in remote Aboriginal health services in the Kimberley region of Western Australia and provide a more nuanced understanding of the patients presenting for care, their needs, and the clinical response. Little is currently known about primary health care presentations for mental health, suicide, and self-harm for remote dwelling Aboriginal residents of the Kimberley region, despite high rates of psychological distress, self-harm, and suicide across the area. This study was progressed through a retrospective, cross-sectional audit of the electronic medical records system used by three remote clinics to explore the interactions recorded by the clinics about a patient's mental health. In addition, an in-depth file review was conducted on a stratified purposive sample of 30 patients identified through the audit. Mental ill-health and psychological distress were found to be prominent within clinical presentations. Psychosocial factors were frequently identified in relation to a patient's mental health presentation. Optimizing patients' recovery and wellness through service improvements, including an enhanced mental health model of care, is an important next step.


Staphylococcal phosphatidylglycerol antigens activate human T cells via CD1a.
Expressed on epidermal Langerhans cells, CD1a presents a range of self-lipid antigens found within the skin; however, the extent to which CD1a presents microbial ligands from bacteria colonizing the skin is unclear. Here we identified CD1a-dependent T cell responses to phosphatidylglycerol (PG), a ubiquitous bacterial membrane phospholipid, as well as to lysylPG, a modified PG, present in several Gram-positive bacteria and highly abundant in Staphylococcus aureus. The crystal structure of the CD1a-PG complex showed that the acyl chains were buried within the A'- and F'-pockets of CD1a, while the phosphoglycerol headgroup remained solvent exposed in the F'-portal and was available for T cell receptor contact. Using lysylPG and PG-loaded CD1a tetramers, we identified T cells in peripheral blood and in skin that respond to these lipids in a dose-dependent manner. Tetramer+CD4+ T cell lines secreted type 2 helper T cell cytokines in response to phosphatidylglycerols as well as to co-cultures of CD1a+ dendritic cells and Staphylococcus bacteria. The expansion in patients with atopic dermatitis of CD4+ CD1a-(lysyl)PG tetramer+ T cells suggests a response to lipids made by bacteria associated with atopic dermatitis and provides a link supporting involvement of PG-based lipid-activated T cells in atopic dermatitis pathogenesis.


Pharmacological treatment of acquired QT prolongation and torsades de pointes.
Torsades de pointes (TdP) is a characteristic polymorphic ventricular arrhythmia associated with delayed ventricular repolarization as evidenced on the surface electrocardiogram by QT interval prolongation. It typically occurs in self-limiting bursts, causing dizziness and syncope, but may occasionally progress to ventricular fibrillation and sudden death. Acquired long QT syndromes are mainly caused by cardiac disease, electrolyte abnormalities or exposure to drugs that block rectifying potassium channels, especially IKr. Management of TdP or marked QT prolongation includes removal or correction of precipitants, including discontinuation of culprit drugs and institution of cardiac monitoring. Electrolyte abnormalities and hypoxia should be corrected, with potassium concentrations maintained in the high normal range. Immediate treatment of TdP is by intravenous administration of magnesium sulphate, terminating prolonged episodes using electrical cardioversion. In refractory cases of recurrent TdP, the arrhythmia can be suppressed by increasing the underlying heart rate using isoproterenol (isoprenaline) or transvenous pacing. Other interventions are rarely needed, but there are case reports of successful use of lidocaine or phenytoin. Anti-arrhythmic drugs that prolong ventricular repolarization should be avoided. Some episodes of TdP could be avoided by careful prescribing of QT prolonging drugs, including an individualized assessment of risks and benefits before use, performing baseline and periodic electrocardiograms and measurement of electrolytes, especially during acute illnesses, using the lowest effective dose for the shortest possible time and avoiding potential drug interactions. These steps are particularly important in those with underlying repolarization abnormalities and those who have previously experienced drug-induced TdP.


Metabolic basis of diethylaminoethoxyhexestrol-induced phospholipid fatty liver.
Diethylaminoethoxyhexestrol caused a foam cell lipidosis in humans characterized by phospholipid storage in the liver, spleen, and other tissues, and this represents the first description of acquired lipidosis caused by a drug. It has been proposed that diethylaminoethoxyhexestrol causes phospholipid fatty liver by concentrating in lysosomes and inhibiting phospholipases but it has not previously been possible to measure the intralysosomal concentration of diethylaminoethoxyhexestrol. In this paper we report for the first time the intralysosomal concentration of this drug in rats. After a single oral dose of diethylaminoethoxyhexestrol (100 mg/kg) the intralysosomal concentration was 7.9 mM at 2.5 h, 15.6 mM at 12 h, and 20.9 mM at 24 h, respectively. The total phospholipid content of lysosomes in drug-treated rats increased 1.9-, 6.0-, and 7.6-fold over control at 2.5, 12, and 24 h, respectively. Purified lysosomal phospholipase A1 was strongly inhibited by diethylaminoethoxyhexestrol in vitro. In phospholipid fatty liver, phospholipid accumulation in lysosomes appears to be caused by the presence of diethylaminoethoxyhexestrol in lysosomes at concentrations estimated to be 7.9-20 mM, because drug levels above 1 mM completely block the activity of purified lysosomal phospholipase A1 in vitro.


General multi-group macroscopic modeling for thermo-chemical non-equilibrium gas mixtures.
This paper opens a new door to macroscopic modeling for thermal and chemical non-equilibrium. In a game-changing approach, we discard conventional theories and practices stemming from the separation of internal energy modes and the Landau-Teller relaxation equation. Instead, we solve the fundamental microscopic equations in their moment forms but seek only optimum representations for the microscopic state distribution function that provides converged and time accurate solutions for certain macroscopic quantities at all times. The modeling makes no ad hoc assumptions or simplifications at the microscopic level and includes all possible collisional and radiative processes; it therefore retains all non-equilibrium fluid physics. We formulate the thermal and chemical non-equilibrium macroscopic equations and rate coefficients in a coupled and unified fashion for gases undergoing completely general transitions. All collisional partners can have internal structures and can change their internal energy states after transitions. The model is based on the reconstruction of the state distribution function. The internal energy space is subdivided into multiple groups in order to better describe non-equilibrium state distributions. The logarithm of the distribution function in each group is expressed as a power series in internal energy based on the maximum entropy principle. The method of weighted residuals is applied to the microscopic equations to obtain macroscopic moment equations and rate coefficients succinctly to any order. The model's accuracy depends only on the assumed expression of the state distribution function and the number of groups used and can be self-checked for accuracy and convergence. We show that the macroscopic internal energy transfer, similar to mass and momentum transfers, occurs through nonlinear collisional processes and is not a simple relaxation process described by, e.g., the Landau-Teller equation. Unlike the classical vibrational energy relaxation model, which can only be applied to molecules, the new model is applicable to atoms, molecules, ions, and their mixtures. Numerical examples and model validations are carried out with two gas mixtures using the maximum entropy linear model: one mixture consists of nitrogen molecules undergoing internal excitation and dissociation and the other consists of nitrogen atoms undergoing internal excitation and ionization. Results show that the original hundreds to thousands of microscopic equations can be reduced to two macroscopic equations with almost perfect agreement for the total number density and total internal energy using only one or two groups. We also obtain good prediction of the microscopic state populations using 5-10 groups in the macroscopic equations.


New Insights into the Mechanism of NO3- Selectivity in the Human Kidney Chloride Channel ClC-Ka and the CLC Protein Family.
The mechanism of anion selectivity in the human kidney chloride channels ClC-Ka and ClC-Kb is unknown. However, it has been thought to be very similar to that of other channels and antiporters of the CLC protein family, and to rely on anions interacting with a conserved Ser residue (Sercen) at the center of three anion binding sites in the permeation pathway Scen. In both CLC channels and antiporters, mutations of Sercen alter the anion selectivity. Structurally, the side chain of Sercen of CLC channels and antiporters typically projects into the pore and coordinates the anion bound at Scen. To investigate the role of several residues in anion selectivity of ClC-Ka, we created mutations that resulted in amino acid substitutions in these residues. We also used electrophysiologic techniques to assess the properties of the mutants. Mutations in ClC-Ka that change Sercen to Gly, Pro, or Thr have only minor effects on anion selectivity, whereas the mutations in residues Y425A, F519A, and Y520A increase the NO3-/Cl- permeability ratio, with Y425A having a particularly strong effect. s ClC-Ka's mechanism of anion selectivity is largely independent of Sercen, and it is therefore unique in the CLC protein family. We identified the residue Y425 in ClC-Ka-and the corresponding residue (A417) in the chloride channel ClC-0-as residues that contribute to NO3- discrimination in these channels. This work provides important and timely insight into the relationship between structure and function for the kidney chloride channels ClC-Ka and ClC-Kb, and for CLC proteins in general.


Patient turnover and nursing staff adequacy.
To assess the relative validity of patient turnover adjustments and the difference in nurse staffing using measures that adjust for patient turnover and severity versus those that do not. Numbers of registered nurses (RNs), adjusted patient days of care (APDC), length of stay, and patient severity information from acute care general hospitals in Pennsylvania 1994-2001, obtained from the Pennsylvania Department of Health, the American Hospital Association, and the Atlas MediQual system. After examining the trends in patient turnover and severity and their relationship to RN staffing, we apply two-patient turnover indices, with and without patient severity adjustments, to RN staffing measures, and test the difference between the original and adjusted measures using paired sample t-tests. Data sets were match merged by hospital ID, and patient turnover and severity indices were created, using 1994 as the base year. RN staffing measures were developed using unadjusted APDC, and APDC adjusted for patient turnover and both patient turnover and severity. Patient turnover increased significantly from 1994 to 2001. The difference between RN staffing measures adjusted for patient turnover and severity and those not adjusted was increasingly significant from 1995 onward. Unadjusted RN staffing showed a 1 percent decline over the 8-year-period compared with decreases of from 9 to 26 percent after adjustments. These results indicate that the assessment of unadjusted RN staffing by RN to patient ratios alone underestimates nursing workload and overstates RN staffing levels. Patient turnover, as well as severity, should be taken into account in staffing assessment and decision making.


Stimulation of rat colonic crypt cell proliferative activity by wheat bran consumption during the stage of 1,2-dimethylhydrazine administration.
The effect on colonic epithelial cytokinetics of feeding a 20% wheat bran dietary supplement, either during and/or after the stage of carcinogen administration with 1,2-dimethylhydrazine, was examined in 48 male Sprague-Dawley rats fed defined diets for up to 31 weeks. Nutrient intake and body weight gain were equivalent in all groups of animals. All subgroups of rats fed bran, either during and/or after carcinogen administration, developed colonic crypt cell hyperplasia (p less than 0.05), this being greater in the proximal than in the distal colon. Autoradiographic studies showed a significant increase in proximal colonic crypt cell-labeling index, proliferation zone size, and migration distance in those rats fed wheat bran during the period of carcinogen administration (p less than 0.05). The increase in epithelial cell proliferation activity was most marked in the upper two-thirds of the crypt. These data show that there is a greater stimulation of crypt cell proliferation activity when wheat bran is consumed during the stage of carcinogen administration as compared to the stage following carcinogen exposure. This alteration in mucosal cytokinetics appears to be the mechanism by which wheat bran consumption enhances rat colon carcinogenesis during the period of dimethylhydrazine treatment.


[Protective properties of antigenic complexes of Proteus].
To determine the possibility of the specific therapy and prevention of Proteus infection, the protective activity of antigenic complexes extracted from Pr. mirabilis cells by various methods was studied. Immunization of mice with these antigens rendered the animals resistant to challenge with a virulent Proteus strain, and the therapeutic injection of the antigens alleviated the infectious process developing as a result of intradermal infection. The blood sera of the treated rabbits acquired capacity of protecting mice from the Proteus infection.


[Sacro-colpoplexy using mersilene: report of 12 cases at the General Hospital Zone 7, Monclova, Coahuila].
The purpose of this study was to describe our experience to be realizing Sacral colpopexia in patients with prolapso of cupola from March 1991 to August 1996 and to compare our results with the written in the National and International literature, cause at least in our country the reports and the number of patients that are included in thus kind of surgery are fex, even in hospitals with great concentration. Twelve women were attended which age were average 52 years old, multiparity in 83.3% of these cases and all of them with the story of hysterectomy. In the 58.3% the symptoms produced by the prolapse were presented was sensation of rare body and to give up the sexual activity in the patients that got in before of the prolapse was emerged. In 5 patients (41.6%) also this symptomatology was accompanied by incontinence urinary of stress because of were demonstrated in them the debility of the anterior vaginal wall and for this reason was realized Sacral colpopexy plus operation of Burch at the same surgical time. A mersilene No. 5 material was used in order to set the vaginal cupola to the anterior ligament of the sacral an a "bridge" of the additional reinforce with the same material. Were not emerged transoperatory complications. The following of our patients after surgery had been from 6 month to 6 years (depending on the year in which was the surgery) and sexual activity reset in the patients has been identified got it before the prolapse, and by the other side a new prolapse is not presented in the patients of the study. We establishes surgical preventive rules to avoid the prolapse of cupola in patients that are emerged to hysterectomy, vaginal or abdominal.


Rheumatoid factors do not preferentially bind to ACPA-IgG or IgG with altered galactosylation.
Recent reports describe interactions between the two most prominent RA-related autoantibodies, RFs and ACPAs. The main aim of the present study was to investigate whether RFs preferentially interact with ACPA-IgG over non-ACPA IgG. Additionally, interactions of RFs with IgG with altered galactose content in the Fc domain were examined, since ACPA-IgGs have been shown to have decreased Fc galactose content in RF+ patients. (Auto)antibody interactions were studied in a surface plasmon resonance imaging assay and with ELISA. Target antibodies were isolated from RA patient plasma (polyclonal ACPA- and non-ACPA-IgG) or recombinantly produced to obtain monoclonal IgG with well-defined Fc galactose content. Interacting autoantibodies were studied using autoantibody positive patient sera and two recombinantly produced IgM-RFs. The sera from 41 RF+ RA patients showed similar RF binding to ACPA- and non-ACPA-IgG and no differences in binding to IgG with normal, high or low levels of Fc galactosylation. Two monoclonal IgM-RFs, one interacting with the CH2-CH3 interface and one binding close to the C-terminal end of the CH3 domain showed no influence of the Fc glycan on IgG binding by IgM-RF. Although interactions between RF and ACPA may play a role in inflammatory processes in RA, RFs do not preferentially interact with ACPA-IgG over non-ACPA-IgG nor with agalatosylated IgG over IgG with normal or high galactosylation.


Suicide and chronic kidney disease: a case-control study.
The association of chronic kidney disease (CKD) and dialysis with suicide is not well established. The objectives of this study were to assess the association of suicide with CKD and dialysis and investigate whether differences exist between dialysis modalities or the durations of dialysis. Data were obtained from the Taiwan National Health Insurance Research Database. A total of 51 642 patients who died from suicide between 2000 and 2012 and 206 568 living control patients matched by age, gender and residency area were examined. Known risk factors included sociodemographic characteristics, physical comorbidities and psychiatric disorders, which were controlled for as covariates in the analysis. The crude odds ratios (ORs) and adjusted ORs (aORs) for various risk factors were obtained using conditional logistic regression. After potential confounders were controlled for, CKD was significantly associated with an increased risk of suicide [aOR = 1.25, 95% confidence interval (CI) = 1.17-1.34]. End-stage renal disease patients on haemodialysis (HD) had an increased risk of suicide compared with controls (aOR = 3.35, 95% CI = 3.02-3.72). Moreover, patients who initially underwent dialysis within 0-3 months had a significantly increased risk of suicide (aOR = 20.26, 95% CI = 15.99-25.67). CKD and HD are positively associated with suicide. Suicide is preventable; therefore, assessing mental and physical disorders is essential and recommended to all physicians, particularly those treating patients in the early phase of HD.


HLA-E and Its Soluble Form as Indicators of a Sex-Specific Immune Response in Patients with Oral Squamous Cell Carcinoma.
The human leukocyte antigene E (HLA-E) is associated with tumorigenesis in various cancers. Immunoncology along with sex-specific aspects in cancer therapy are now in scientific focus. Therefore, immunohistochemical HLA-E expression was retrospectively analysed in a cohort of oral squamous cell carcinomas (OSCC) after surgical therapy. Then, serum concentration of HLA-E (sHLA-E) was quantified in a prospective cohort by enzyme-linked immunosorbent assay. High HLA-E expression was associated with advanced UICC stage (Spearman's correlation: p = 0.002) and worse survival (Cox-regression: progression-free survival: hazard ratio (HR) 3.129, confidence range (CI) 1.443-6.787, p = 0.004; overall survival: HR 2.328, CI 1.071-5.060, p = 0.033). The sHLA-E concentration was significantly higher in the control group than in tumor group (Mann-Whitney U-test (MW-U): p = 0.021). Within the tumor group, women showed significantly higher sHLA-E levels than men (MW-U: p = 0.049). A closer look at the tumor group and the control group showed that gender-specific differences exist: while no differences in sHLA-E concentration were detectable between female subjects of tumor group and control group (MW-U: p = 0.916), male subjects of tumor group had a significantly lower sHLA-E concentration compared to those of control group (MW-U: p = 0.001). In summary, our results provide evidence for sex-specific differences in immune responses in OSCC. This fact should be considered regarding future immunotherapy regimens.


Variation in Seeking Care for Cardiovascular Disease and Ambulance Utilization among Migrants in Australia: Time, Ethnicity, and Delay (TED) Study III.
Insight into differences in seeking medical care for chest pain among migrant populations is limited. This study aimed to determine ethnic differences in seeking care behaviors and using ambulances among migrants compared to an Australian-born group. A total of 607 patients presenting with chest pain to a tertiary hospital between 1 July 2012 and 30 June 2014 were randomly selected. Data from the emergency department dataset and medical record reviews were collected and linked for analysis. The migrant group was stratified into nine ethnic groups for analysis based on the Australian Standard Classification of Cultural and Ethnic Groups. The overall median prehospital delay time was 3.7 (1.5, 10.7) h, which ranged from 2.5 (1.0, 10.7) (Southern and Eastern European group) to 6.0 (2.3, 20.6) (Sub-Saharan African group). The median decision time was 2.0 (0.8, 7.9) h, which ranged from 1.5 (Australian-born group) to 4.5 h (Sub-Saharan African group). Five ethnic groups had significantly longer decision times compared to the Australian-born group. Decision time accounted for 58.4% of pre-hospital delay time. Migrant patients were 60% less likely to seek care for chest pain within one hour (odds ratio 0.40, (0.23-0.68), p = 0.001). There was no significant difference in ambulance utilization between migrant and Australian-born groups. In conclusion, ethnic differences in seeking care for chest pain do exist, and ethnicity plays a vital role in a longer delay in seeking care. To reduce the delays and improve patient outcomes, appropriate health campaigns focusing on ethnic differences among migrant populations and normalizing cultural competency into practice are recommended.


Current progress in the controlled synthesis and biomedical applications of ultrasmall (<10 nm) NaREF4 nanoparticles.
The design and fabrication of rare earth upconversion nanoparticle (UCNP)-based nanomedical platforms have evoked increasing interest. However, their bio-safety is always the most worrisome problem. Most nanoparticles can accumulate in the internal organs, leading to acute toxicity, a long-term inflammatory response, or even fibrosis and cancer. In contrast, ultrasmall (sub-10 nm) nanoparticles have minimal safety risk because they can escape from macrophages, pass biological barriers, and be easily degraded or excreted from the body. In this review, we mainly introduce new progress in preparation strategies, imaging and drug delivery with regards to ultrasmall UCNPs, with an emphasis on rare earth fluorides, NaREF4. Finally, we discuss the future outlook and challenges relating to ultrasmall UCNPs.


Polyamine transporters and polyamines increase furfural tolerance during xylose fermentation with ethanologenic Escherichia coli strain LY180.
Expression of genes encoding polyamine transporters from plasmids and polyamine supplements increased furfural tolerance (growth and ethanol production) in ethanologenic Escherichia coli LY180 (in AM1 mineral salts medium containing xylose). This represents a new approach to increase furfural tolerance and may be useful for other organisms. Microarray comparisons of two furfural-resistant mutants (EMFR9 and EMFR35) provided initial evidence for the importance of polyamine transporters. Each mutant contained a single polyamine transporter gene that was upregulated over 100-fold (microarrays) compared to that in the parent LY180, as well as a mutation that silenced the expression of yqhD. Based on these genetic changes, furfural tolerance was substantially reconstructed in the parent, LY180. Deletion of potE in EMFR9 lowered furfural tolerance to that of the parent. Deletion of potE and puuP in LY180 also decreased furfural tolerance, indicating functional importance of the native genes. Of the 8 polyamine transporters (18 genes) cloned and tested, half were beneficial for furfural tolerance (PotE, PuuP, PlaP, and PotABCD). Supplementing AM1 mineral salts medium with individual polyamines (agmatine, putrescine, and cadaverine) also increased furfural tolerance but to a smaller extent. In pH-controlled fermentations, polyamine transporter plasmids were shown to promote the metabolism of furfural and substantially reduce the time required to complete xylose fermentation. This increase in furfural tolerance is proposed to result from polyamine binding to negatively charged cellular constituents such as nucleic acids and phospholipids, providing protection from damage by furfural.


Chronic intestinal inflammation drives colorectal tumor formation triggered by dietary heme iron in vivo.
The consumption of red meat is associated with an increased risk for colorectal cancer (CRC). Multiple lines of evidence suggest that heme iron as abundant constituent of red meat is responsible for its carcinogenic potential. However, the underlying mechanisms are not fully understood and particularly the role of intestinal inflammation has not been investigated. To address this important issue, we analyzed the impact of heme iron (0.25 µmol/g diet) on the intestinal microbiota, gut inflammation and colorectal tumor formation in mice. An iron-balanced diet with ferric citrate (0.25 µmol/g diet) was used as reference. 16S rRNA sequencing revealed that dietary heme reduced α-diversity and caused a persistent intestinal dysbiosis, with a continuous increase in gram-negative Proteobacteria. This was linked to chronic gut inflammation and hyperproliferation of the intestinal epithelium as attested by mini-endoscopy, histopathology and immunohistochemistry. Dietary heme triggered the infiltration of myeloid cells into colorectal mucosa with an increased level of COX-2 positive cells. Furthermore, flow cytometry-based phenotyping demonstrated an increased number of T cells and B cells in the lamina propria following heme intake, while γδ-T cells were reduced in the intraepithelial compartment. Dietary heme iron catalyzed formation of fecal N-nitroso compounds and was genotoxic in intestinal epithelial cells, yet suppressed intestinal apoptosis as evidenced by confocal microscopy and western blot analysis. Finally, a chemically induced CRC mouse model showed persistent intestinal dysbiosis, chronic gut inflammation and increased colorectal tumorigenesis following heme iron intake. Altogether, this study unveiled intestinal inflammation as important driver in heme iron-associated colorectal carcinogenesis.


Quantum random number generator using a microresonator-based Kerr oscillator.
We demonstrate an all-optical quantum random number generator using a dual-pumped degenerate optical parametric oscillator in a silicon nitride microresonator. The frequency-degenerate bi-phase state output is realized using parametric four-wave mixing in the normal group-velocity dispersion regime with two nondegenerate pumps. We achieve a random number generation rate of 2 MHz and verify the randomness of our output using the National Institute of Standards and Technology Statistical Test Suite. The scheme offers potential for a chip-scale random number generator with gigahertz generation rates and no postprocessing.


Presence of pancreatic hormones in islet cells with MHC-class II antigen expression.
In the normal rat pancreas, only few islet cells express MHC-class II antigens. Their nature and function has not yet been elucidated. We report a method for the purification of Ia-positive islet cells by fluorescence-activated cell sorting. The isolated mononuclear cells appear of nonendocrine origin but contain vacuoles with partially digested secretory vesicles. Both insulin- and glucagon-immunoreactive granules were identified in these vacuoles of varying size and composition. It is suggested that at least part of the rat islet cells with class II antigen expression can exhibit phagocytotic properties leading to the uptake of fragments from damaged endocrine cells. This functional characteristic may implicate this particular islet cell type in the pathology of the endocrine pancreas in type I diabetes.


[Enhanced epitope immunoreactivity of the dominant epitope of Toxoplasma gondii fused at the "N terminus" of HPV16L1].
For improving epitope immunogenicity and achieving the co-immunization, late protein 1 (L1) of HPV type 16 (HPV16L1) was selected as the vector to carry the dominant epitope of Toxoplasma gondii because of the shared common population between Toxoplasma gondii and human papillomavirus (HPV). RSepitope-HPV16L1 (RSepitope fused at the "N-terminus" of HPV16L1) and HPV16L1-RSepitope (RSepitope fused at the "C-terminus" of HPV16L1) chimeras were constructed. After transfection of COS-7 cells with the recombinants, Western blot, RT-PCR, and immunofluorescence experiments confirmed that RSepitope-HPV16L1 could successfully express the corresponding mRNA and protein of RSepitope and HPV16L1, but the HPV16L1-RSepitope construct could not. A "prime-boost" immunization program was applied in mice to further evaluate the immune response elicited by the constructs, and the RSepitope-HPV16L1 immunization group produced the most significantly increased humoral and cellular immune responses (the highest RSepitope-specific IgG antibody level and the highest IFN-γ production, respectively), in which both elevated Th1 and Th2 immune responses were obtained. Moreover, the advantage of HPV16L1 as an epitope carrier was remarkable for RSepitope-HPV16L1, which induced a more prominent immunological response than RSepitope alone (without fusion with HPV16L1). Our research indicated that the N-terminus of HPV16L1 could be a better insertion site for enhancing target epitope immunogenicity, and our study offers a design for epitope vaccine of reasonable combination.


Identifying emerging trends in recreational drug use; outcomes from the Psychonaut Web Mapping Project.
This paper presents the outcomes of the 2-year European Union funded Psychonaut Web Mapping Project which aimed at developing and implementing an integrated web mapping system to promptly identify and learn about novel psychoactive substances (NPS; "legal highs") through the regular monitoring of the Internet. More than 200 discussion forums, social media, online shops, websites and other Internet resources (e.g. YouTube, eBay, Google, Google Insight) have been extensively and regularly monitored in 7 European countries (UK, Finland, Norway, Belgium, Germany, Italy and Spain) for emerging trends of NPS throughout the period of the study. Key online resources have been identified as "leading edge" which have provided accurate and timely information on novel emerging compounds. In total more than 400 substances/products have been recorded. NPS have been noted online before reaching wider audiences. Although a high number of novel psychoactive substances have been identified in the 2-year duration of the project, not all have become trends that needed public health response. Conversely, new recreational drug phenomena such as "spice drugs," mephedrone and naphyrone were all identified as emerging trends in forums and websites. In addition, it has been possible for the first time to collate detailed information on these and several more compounds even though no or limited scientific publications were available. It is therefore recommended that these monitoring activities are to be continued, that more countries, researchers and health professionals are involved, and that the findings are widely shared with all the relevant agencies, health professionals and future research projects. Implications, advantages and limitations of using the Internet as primary source for identifying emerging trends are also discussed.


Type 1- and type 2-like lesional skin-derived Mycobacterium leprae-responsive T cell clones are characterized by coexpression of IFN-gamma/TNF-alpha and IL-4/IL-5/IL-13, respectively.
In an earlier study, we generated a large number of Mycobacterium leprae-responsive and M. leprae-nonresponsive T cell clones (TCC) from the lesional skin of immunologic unstable borderline leprosy patients. In that study, we divided TCC into type 1- and type 2-like on the basis of their IFN-gamma and IL-4 expression. To explore whether other cytokines are coproduced along with IFN-gamma and IL-4, we investigated the secretion of a panel of other cytokines (TNF-alpha, IL-5, IL-6, IL-10, and IL-13) by a large number of these TCC. Upon analysis of 139 M. leprae-responsive TCC, we observed a positive correlation in the coproduction of IFN-gamma/TNF-alpha (r = 0.81), and in that of IL-4/IL-5 (r = 0.83), IL-4/IL-13 (r = 0.80), and IL-5/IL-13 (r = 0.82). Polarized type 1-like TCC produced dominantly IFN-gamma/TNF-alpha, and polarized type 2-like TCC predominantly IL-4/IL-5/IL-13. Most type 0-like TCC produced both sets of cytokines. In contrast, type 1- and type 2-like subsets of M. leprae-nonresponsive TCC (n = 58) did not show the same coexpression of these cytokines. Furthermore, when the differential expression of a broad panel of cytokines by individual M. leprae-responsive TCC is considered, it appeared that additional phenotypes could be recognized. These results suggested that distinct isotypes of type 1- and type 2-like T cells, based on the secretion of a panel of cytokines, may reflect M. leprae-specific characteristics.


A light and electron microscopic analysis of the mossy fibers of the rat dentate gyrus.
The axon collaterals of dentate granule cells have been analyzed with the aid of a computerized microscope, following intracellular injections of horseradish peroxidase in hippocampal slice preparations. The axon of each granule cell gives rise to approximately seven primary collaterals; these collaterals usually divide into secondary and tertiary branches, which form an extensive plexus within the hilar region of the dentate gyrus. Individual axon collaterals vary greatly in length, but most have been found to be between 100 and 300 microns long. On average, the summed lengths of the collaterals (exclusive of the parent mossy fiber) are approximately 2,300 microns. Except for an occasional collateral that is given off by a mossy fiber in the proximal part of field CA3 of the hippocampus, the collaterals of the granule cell axons are confined to the hilar region; they are rarely seen in the granule cell layer itself and have never been observed in the molecular layer. In the longitudinal dimension of the dentate gyrus, most of the collaterals are contained within a zone about 400 microns wide. The distribution of the collaterals within the hilar region is correlated with the location of the granule cell body. Those that arise from cells near the tip of the suprapyramidal blade tend to be confined to the region above field CA3; those from cells nearer the crest and from the infrapyramidal blade ramify widely throughout the hilus. Two types of varicosities are present on the collaterals. Numerous small (approximately 2 microns), round varicosities are distributed unevenly along the collaterals; in electron micrographs these varicosities can be seen to make asymmetric synaptic contacts with dendritic shafts. On average, each granule cell collateral plexus has about 160 of these varicosities. The second type of varicosity is irregular in shape and ranges from 2 to 4 microns in diameter; there is usually only one such varicosity per collateral. In all respects except size, these varicosities resemble the expansions found on the parent mossy fibers. Mossy fiber trajectories in the proximal part of field CA3 were studied after extracellular injections of HRP into localized regions of the granule cell layer. Granule cells at different locations around the blade send their mossy fibers to different depths within the pyramidal cell layer in the proximal part of field CA3. However, further distally, mossy fibers from all parts of the granule cell layer contribute to the suprapyramidal bundle that occupies the stratum lucidum.


Effects of pulsed therapeutic ultrasound on the treatment of people with knee osteoarthritis.
[Purpose] The aim was to evaluate the effect of therapeutic ultrasound on the pain, joint mobility, muscle strength, physical function, and quality of life of people with knee OA. [Subjects and Methods] One-site, one-arm, before-after study that included people with Grade II or III tibiofemoral osteoarthritis. Ten therapeutic ultrasound sessions (duty cycle=20%, ERA=10 cm2, BNR=6:1, SATP=2.2 W/cm2, SATA=0.44 W/cm2, frequency=1 MHz, time=4 minutes) were applied. Assessments of primary outcome variables: pain intensity and function, and secondary variables: joint mobility, muscle strength and quality of life, were performed at onset and end of therapy; an additional intermediate evaluation was included for the primary variables. [Results] Means of repeated measurements of pain intensity (pain at rest, pain on palpation and pain after functional activities) and function showed significant differences. There was a significant reduction in pain intensity at the end of functional activities as well as a significant increase in function and in quadriceps muscle strength. [Conclusion] Therapeutic ultrasound applied in accordance with the parameters used, could be recommended during the treatment of individuals with knee osteoarthritis, because it significantly decreased the intensity of pain after the 5th session, and this reduction was maintained until the end of the intervention.


Prevalence of macrolide and fluoroquinolone resistance-mediating mutations in Mycoplasma genitalium in five cities in Russia and Estonia.
Resistance in the sexually transmitted bacterium Mycoplasma genitalium to all recommended therapeutic antimicrobials have rapidly emerged. However, to date, internationally reported resistance surveillance data for M. genitalium strains circulating in Eastern Europe are entirely lacking. The aim of this study was to estimate the prevalence of macrolide and fluoroquinolone resistance-associated mutations in M. genitalium in four cities in Russia and one in Estonia, 2013-2016. Consecutive urogenital samples found positive for M. genitalium during diagnostic testing were retrospectively analyzed for resistance-associated mutations in the 23S rRNA and parC genes using pyrosequencing and conventional Sanger sequencing, respectively. In total, 867 M. genitalium positive samples from 2013-2016 were analyzed. Macrolide resistance-associated mutations were detected in 4.6% of the samples from Russia (0.7-6.8% in different cities) and in 10% of the samples from Estonia. The mutations A2059G and A2058G were highly predominating in both Russia and Estonia, accounting together for 90.9% of the cases positive for nucleotide substitutions in the 23S rRNA gene. The rates of possible fluoroquinolone resistance-associated mutations were 6.2% in Russia (2.5-7.6% in different cities) and 5% in Estonia. The mutations S83I and S83N were the most frequent ones in Russia (24.4% each), whereas D87N highly predominated in Estonia (83.3% of all fluoroquinolone resistance-associated mutations). Approximately 1% of the samples in both countries harbored both macrolide and possible fluoroquinolone resistance-associated mutations, with A2058G and S83I being the most frequent combination (37.5%). The prevalence of macrolide and fluoroquinolone resistance-associated mutations in M. genitalium was 4.6% and 6.2%, respectively, in Russia, and 10% and 5%, respectively, in Estonia. Despite the relatively low rates of macrolide and fluoroquinolone resistance in these countries, antimicrobial resistance surveillance and testing for resistance-associated mutations in M. genitalium positive cases would be valuable.


Serpinb3 is overexpressed in the liver in presence of iron overload.
Iron overload results in cellular toxicity, tissue injury, organ fibrosis and increased risk of neoplastic transformation. SerpinB3 is a serine protease inhibitor overexpressed in the liver in oxidative stress conditions, able to induce fibrosis and increased risk of malignant transformation. Aim of the present study was to assess the effect of iron overload on SerpinB3 expression in the liver using in vivo and in vitro models.The expression of Serpinb3 was assessed in the liver of hemojuvelin knockout mice (Hjv-/-), an established model of hereditary hemochromatosis, and of wild type control mice, following dietary or pharmacological iron manipulation. To assess the direct effect of iron in vitro, cell lines were treated with different concentration of hemin or with an iron chelator.Hepatic Serpinb3 mRNA and protein were highly expressed in Hjv-/- mice, but not in wild type controls fed with a standard diet. Serpinb3 became detectable in wild type mice fed with a high iron diet or injected with iron dextran; these treatments further induced Serpinb3 expression in Hjv-/- mice. Livers expressing Serpinb3 showed a positive staining also for HIF-2α in the same areas. Hemin promoted induction of SerpinB3 mRNA in HeLa and HA22T/VGH cells, but a mild stimulation of SerpinB3 promoter activity in HeLa and Huh7 cells. In conclusion, Serpinb3 is strongly induced by iron in the mouse liver. The molecular link between iron, ROS and SerpinB3 seems to be HIF-2α, which is induced by iron overload and was previously found capable of up-regulating SerpinB3 at the transcriptional level.


Application of response surface Methodology coupled with Artificial Neural network and genetic algorithm to model and optimize symbiotic interactions between Chlorella vulgaris and Stutzerimonas stutzeri strain J3BG for chlorophyll accumulation.
Research on microalgae has surged due to its diverse biotechnological applications and capacity for accumulating bioactive compounds. Despite considerable advancements, microalgal cultivation remains costly, prompting efforts to reduce expenses while enhancing productivity. This study proposes a cost-effective approach through the coculture of microalgae and bacteria, exploiting mutualistic interactions. An engineered consortium of Chlorella vulgaris and Stutzerimonas stutzeri strain J3BG demonstrated biofilm-like arrangements, indicative of direct cell-to-cell interactions and metabolite exchange. Strain J3BG's enzymatic characterization revealed amylase, lipase, and protease production, sustaining mutual growth. Employing Response Surface Methodology (RSM), Artificial Neural Network (ANN), and Genetic Algorithm (GA) in a hybrid modeling approach resulted in a 2.1-fold increase in chlorophyll production. Optimized conditions included a NaNO3 concentration of 128.52 mg/l, a 1:2 (Algae:Bacteria) ratio, a 6-day cultivation period, and a pH of 5.4, yielding 10.92 ± 0.88 mg/l chlorophyll concentration.


Caenorhabditis elegans VEM-1, a novel membrane protein, regulates the guidance of ventral nerve cord-associated axons.
In the developing CNS, pathfinding growth cones use intermediate target- and pioneer axon-associated guidance cues to navigate along stereotypical trajectories. We previously showed that the novel membrane-associated protein Vema is localized to the floor plate and the optic chiasm, intermediate targets located at the ventral midline of the spinal cord and diencephalon in the developing rodent CNS, respectively. Here, we report that the Caenorhabditis elegans ortholog of vema, vem-1, is expressed by the AVG pioneer midline neuron and by several neurons that extend longitudinally projecting axons into the ventral nerve cord (VNC). In vem-1 mutants and vem-1 (RNAi) animals, a subset of posteriorly projecting interneuron axons either fail to extend ventrally to the VNC and, instead, assume aberrant lateral positions or are inappropriately located in the left tract of the VNC. In addition, ventral motor neuron axons exhibit pathfinding errors within the VNC and along the dorsoventral body axis. The conserved UNC-40/DCC and SAX-3-/Robo receptors mediate signaling events that regulate axon guidance in a wide variety of systems. Double-mutant analyses reveal that vem-1 genetically interacts with unc-40 and is likely to function in parallel with sax-3 to regulate the guidance of a subset of VNC-associated interneuron and motor neuron axons. Consistent with these genetic data, we also show that VEM-1 is capable of physically interacting with UNC-40 but not SAX-3.


Cell fusion contributes to the rescue of apoptotic cardiomyocytes by bone marrow cells.
Cardiomyocyte apoptosis is an important contributor to the progressive cardiac dysfunction that culminates in congestive heart failure. Bone marrow cells (BMCs) restore cardiac function following ischaemia, and transplanted BMCs have been reported to fuse with cells of diverse tissues. We previously demonstrated that the myogenic conversion of bone marrow stromal cells increased nearly twofold when the cells were co-cultured with apoptotic (TNF-α treated) cardiomyocytes. We therefore hypothesized that cell fusion may be a major mechanism by which BMCs rescue cardiomyocytes from apoptosis. We induced cellular apoptosis in neonatal rat cardiomyocytes by treatment with hydrogen peroxide (H(2)O(2)). The TUNEL assay demonstrated an increase in apoptosis from 4.5 ± 1.3% in non-treated cells to 19.0 ± 4.4% (P < 0.05) in treated cells. We subsequently co-cultured the apoptotic cardiomyocytes with BMCs and assessed cell fusion using flow cytometry. Fusion was rare in the non-treated control cardiomyocytes (0.3%), whereas H(2)O(2) treatment led to significantly higher fusion rates than the control group (P < 0.05), with the highest rate of 7.9 ± 0.3% occurring at 25 μM H(2)O(2). We found an inverse correlation between cell fusion and completion of cardiomyocyte apoptosis (R(2) = 0.9863). An in vivo mouse model provided evidence of cell fusion in the infarcted myocardium following the injection of BMCs. The percentage of cells undergoing fusion was significantly higher in mice injected with BMCs following infarction (8.8 ± 1.3%) compared to mice that did not undergo infarction (4.6 ± 0.6%, P < 0.05). Enhancing cell fusion may be one method to preserve cardiomyocytes following myocardial infarction, and this new approach may provide a novel target for cardiac regenerative therapies.


The Warburg Dance Movement Library-The WADAMO Library: A Validation Study.
The Warburg Dance Movement Library is a validated set of 234 video clips of dance movements for empirical research in the fields of cognitive science and neuroscience of action perception, affect perception and neuroaesthetics. The library contains two categories of video clips of dance movement sequences. Of each pair, one version of the movement sequence is emotionally expressive (Clip a), while the other version of the same sequence (Clip b) is not expressive but as technically correct as the expressive version (Clip a). We sought to complement previous dance video stimuli libraries. Facial information, colour and music have been removed, and each clip has been faded in and out. We equalised stimulus length (6 seconds, 8 counts in dance theory), the dancers' clothing and video background and included both male and female dancers, and we controlled for technical correctness of movement execution. The Warburg Dance Movement Library contains both contemporary and ballet movements. Two online surveys ( N = 160) confirmed the classification into the two categories of expressivity. Four additional online surveys ( N = 80) provided beauty and liking ratings for each clip. A correlation matrix illustrates all variables of this norming study (technical correctness, expressivity, beauty, liking, luminance, motion energy).


Actin synthesis in tumorigenic and non-tumorigenic human hybrid cells.
We have previously shown that the total actin content of tumorigenic HeLa/fibroblast somatic cell hybrids is significantly lower than that of the non-tumorigenic hybrid cells. A measure of actin synthesis, relative to total protein synthesis, was obtained for these cells to determine whether the reduced actin content of the tumorigenic cells is due to specific suppression of actin synthesis. Actin synthesis was measured in cells labelled with [35S]methionine using DNase I affinity chromatography to isolate the actin quantitatively. The results show that actin synthesis is not specifically suppressed, since the relative amount of actin synthesized is constant for the tumorigenic and non-tumorigenic cell lines. The reduced actin content of the tumorigenic cells is therefore most likely to be the result of increased degradation of actin.


Long-term treatment effect and adverse events of a modified jailed-balloon technique for side branch protection in patients with coronary bifurcation lesions.
Percutaneous coronary interventions (PCI) of bifurcation lesions is technically challenging and associated with lower success rates and higher frequency of adverse outcomes. In the present study, we aimed to evaluate the immediate and long-term treatment effect and adverse events of a new modified jailed-balloon technique on side branch (SB) during PCI on coronary bifurcation lesions. This was a prospective study of 60 patients (49 males, 11 females, mean age 66 ± 10 years) with coronary bifurcation lesions treated at the Beijing Hospital between September 2014 and October 2015. They underwent main vessel (MV) stenting and modified jailed-balloon technique on the SB. All patients were followed with hospital visits at 9 months. Angiographic success, major adverse cardiac events (MACE), SB occlusion, and angina were evaluated. The majority of the patients had acute coronary syndrome (91.7%) and Medina 1.1.1. bifurcation lesions (71.7%). After MV stenting, thrombolysis in myocardial infarction (TIMI) 3 flow was established 100% of MV and 93.3% of SB. No SB occlusion occurred. The jailed SB balloon and wire could be successfully removed in all patients without damage or entrapment. The majority (91.7%) of patients achieved Canadian Cardiovascular Society I stage. There was no MACE during in-hospital stay and 9-month follow-up. The modified JBT provided high rate of procedural success, excellent SB protection during MV stenting, and excellent immediate and long-term clinical outcomes.


The nature and pollutant role of solids at the water-sediment interface in combined sewer networks.
Solids at the water-sediment interface in combined sewers are known to be important for pollution potential during storm washout via CSOs. They have been investigated in several studies, but nonetheless, little is known about the origins, build-up, transport and nature of these solids. From a review of current knowledge it is apparent that whilst there is general agreement that these solids are largely organic and have high polluting potential, their modes of transport and definition are not generally agreed upon. It is possible that there may be several "types" of these solids, defined as either: "near bed solids" or "fluid sediments/dense undercurrents", possibly representing transport modes in flows with different ranges of ambient (dry weather) velocities and with differing sewerage layouts. Current knowledge is presented and new ideas for resolving the uncertainties regarding the nature, movement and effects of this material are outlined.


IDF Europe's position on mobile applications in diabetes.
Over the last decade, advances in technology and connectivity have led to the boom of Internet-based and mobile applications (Apps) which have rendered access to information easier and faster and have changed our daily lives. With 60 million people living with diabetes (PWD) in Europe and 32 million more at risk, diabetes has been a major target for software companies, with the aim to help people manage their chronic condition, and to prevent diabetes in people at risk. IDF Europe is the voice of 70 national associations, representing PWD and health professionals in 47 European countries, and a strong supporter of innovation in healthcare. Witnessing the emergence of Apps in the field of diabetes, given the general uptake of a connected lifestyle, and recognising the potential in the ability of these Apps to make an impact on the lives of PWD, IDF Europe reflected on Mobile Applications in Diabetes, examining Diabetes and new technology through psychology, motivation and behavioral change in diabetes management; the healthcare professional perspective; potential roles of diabetes-related Apps, pointing to existing evidence and important ethical issues; and finally offering recommendations on four levels: individual, healthcare professional, political and App developers.


Plant secondary compounds as complementary resources: are they always complementary?
Generalist herbivores typically grow better on mixed- than on single-component diets. This response has been attributed to food complementarities that either enhance the utilization of nutrients or dilute the negative impacts of plant secondary compounds (PSC). For instance, when animals choose between foods that contain diverse PSC, they eat more than animals offered a food that contains just one PSC. In addition to their negative impacts on herbivore fitness, recent evidence suggests that at appropriate doses PSC may provide beneficial effects to herbivores (i.e., by reducing parasitic infections). Thus, complementarities among diverse PSC may not only influence an herbivore's ability to consume food but also reduce the incidence of disease. We assessed the complementary effects of two PSC by offering sheep (Ovis aries) a choice of foods containing condensed tannins and saponins while challenged with a parasitic (Haemonchus contortus) infection. Animals offered a choice ate more than animals just offered tannins or saponins in single rations. However, sheep offered choices displayed greater fecal egg counts (an indirect measurement of parasitic burdens) than sheep offered single rations. Thus, saponin- and tannin-containing foods were complementary resources regarding nutrient intake but antagonistic regarding effects on parasitic loads. The nature of the relationship among PSC may depend on the dimension (i.e., nutrient intake, disease) where the interaction occurs. A unifying currency such as growth or reproductive output may help understand the trade-offs between costs (disease) and benefits (nutrient and medicine intake) for herbivores grazing multiple PSC.


Effect of truncated projections on defect detection in attenuation-compensated fanbeam cardiac SPECT.
For some camera systems used in cardiac SPECT, the limited field of view of fanbeam-collimated detectors produces truncation in the projection data. This truncation may generate artifacts and distortions in the transmission CT images and in the attenuation-corrected myocardial SPECT images (that use the transmission CT images as attenuation maps), thus affecting clinical diagnosis. Concern over this problem stimulated us to evaluate the effect of truncation with human observer performance studies. A three-dimensional mathematical cardiac-torso phantom that realistically models the attenuation and 201Tl uptake distributions in different organs of the upper torso was used for the investigation. Five degrees of truncation (from 0% to 40% truncation) in the projection data were simulated by the use of five different detector sizes collimated by fanbeam collimators. The attenuation maps were obtained by reconstructing the truncated transmission data generated from these fanbeam geometries. The emission data obtained with the same fanbeam geometries were reconstructed by using the maximum likelihood-expectation maximization algorithm and were corrected for attenuation using the reconstructed attenuation maps. Two observer performance studies were performed. In Study 1, the images were reconstructed without using the body contour as support, whereas in Study 2, the exact body contour was used in reconstructing both the attenuation maps and the attenuation-corrected SPECT images. The results of the receiver operating characteristics analysis indicate that there is very little difference between detection for the various degrees of truncation, and this difference only becomes noticeable for severe truncation of greater than 40%. Using the acquisition and processing methods, we found the use of the body contour as support in reconstructing truncated transmission CT and SPECT data reduces the loss of defect detectability in attenuation-compensated myocardial SPECT images due to truncated data.


Formalin disinfection of prostate biopsy needles may reduce post-biopsy infectious complications.
We sought to determine whether formalin disinfection of prostate biopsy needles between cores reduces post-biopsy urinary tract infections (UTIs). We reviewed a single-surgeon experience of transrectal prostate biopsies from 2010 to 2014. Biopsies were performed in either an operative suite, where 10% formalin was used to disinfect the needle tip between each biopsy core, or an outpatient clinic, where formalin was not used. Our primary outcome was post-biopsy UTI rates, defined as a positive urine culture within 30 days of biopsy. Infection severity was characterized by the need for admission. Patient demographics, prostate size, prior biopsies, prior UTIs, pre-biopsy antibiotics and cultures and post-biopsy cultures were analyzed. Logistic regression was used to assess predictors of post-biopsy UTIs. Statistical significance was defined as P<0.05. A total of 756 patients were included for analysis, including 253 who received formalin disinfection and 503 who did not. Of these, 32 patients (4.2%) experienced post-biopsy UTIs, with 8 requiring admission (all without formalin use). Infection rates were more than double in the group that did not receive formalin (5.2% vs 2.3%, P=0.085). More patients in the formalin group had undergone prior biopsies (73.9% vs 31.8%, P<0.001). On multivariable analysis, prior UTI (odds ratio (OR) 3.77, P=0.006) was a significant predictor for post-biopsy infection, whereas formalin disinfection trended towards a protective effect (OR 0.41, P=0.055). Infectious complications following prostate biopsy may be mitigated by the use of formalin disinfection of the biopsy needle between cores.


Sclerotherapy for Reticular Veins in the Lower Limbs: A Triple-Blind Randomized Clinical Trial.
Reticular veins are subdermal veins located in the lower limbs and are mainly associated with aesthetic complaints. Although sclerotherapy is the treatment of choice for reticular veins in the lower limbs, no consensus has been reached regarding to the optimal sclerosant. To compare the efficacy and safety of 2 sclerosants used to treat reticular veins: 0.2% polidocanol diluted in 70% hypertonic glucose (HG) (group 1) vs 75% HG alone (group 2). Prospective, randomized, triple-blind, controlled, parallel-group clinical trial with patients randomly assigned in a 1:1 ratio between the 2 treatment groups from March through December 2014, with 2 months' follow-up. The study was conducted in a single academic medical center. Eligible participants were all women, aged 18 to 69 years, who had at least 1 reticular vein with a minimum length of 10 cm in 1 of their lower limbs. The patients underwent sclerotherapy in a single intervention with either 0.2% polidocanol plus 70% HG or 75% HG alone to eliminate reticular veins. The primary efficacy end point was the disappearance of the reticular veins within 60 days after treatment with sclerotherapy. The reticular veins were measured on images obtained before treatment and after treatment using ImageJ software. Safety outcomes were analyzed immediately after treatment and 7 days and 60 days after treatment and included serious adverse events (eg, deep vein thrombosis and systemic complications) and minor adverse events (eg, pigmentation, edema, telangiectatic matting, and hematomas). Ninety-three women completed the study, median (interquartile range) age 43.0 (24.0-61.0) years for group 1 and 41.0 (27.0-62.0) years for group 2. Sclerotherapy with 0.2% polidocanol plus 70% HG was significantly more effective than with 75% HG alone in eliminating reticular veins from the treated area (95.17% vs 85.40%; P < .001). No serious adverse events occurred in either group. Pigmentation was the most common minor adverse event, with a 3.53% treated-vein pigmentation length for group 1 and 7.09% for group 2, with no significant difference between the groups (P = .09). Sclerotherapy with 0.2% polidocanol diluted in 70% HG was superior to 75% HG alone in sclerosing reticular veins, with no statistical difference for complications. Pigmentation occurred in both groups, with no statistical difference between them. No serious adverse events occurred in either group. clinicaltrials.gov Identifier: NCT02054325.


DNA extraction from archival formalin-fixed, paraffin-embedded tissues: heat-induced retrieval in alkaline solution.
Based on the antigen retrieval principle, our previous study has demonstrated that heating archival formalin-fixed, paraffin-embedded (FFPE) tissues at a higher temperature and at higher pH value of the retrieval solution may achieve higher efficiency of extracted DNA, when compared to the traditional enzyme digestion method. Along this line of heat-induced retrieval, this further study is focused on development of a simpler and more effective heat-induced DNA retrieval technique by testing various retrieval solutions. Three major experiments using a high temperature heating method to extract DNA from FFPE human lymphoid and other tissue sections were performed to compare: (1) different concentrations of alkaline solution (NaOH or KOH, pH 11.5-12) versus Britton and Robinson type of buffer solution (BR buffer) of pH 12 that was the only retrieval solution tested in our previous study; (2) several chemical solutions (SDS, Tween 20, and GITC of various concentrations) versus BR buffer or alkaline solution; and (3) alkaline solution mixed with chemicals versus BR buffer or single alkaline solution. Efficiency of DNA extraction was evaluated by measuring yields using spectrophotometry, electrophoretic pattern, semiquantitation of tissue dissolution, PCR amplification, and kinetic thermocycling-PCR methods. Results showed that boiling tissue sections in 0.1 M NaOH or KOH or its complex retrieval solutions produced higher yields and better quality of DNA compared to BR buffer or chemical solutions alone. The conclusion was that boiling FFPE tissue sections in 0.1 M alkaline solution is a simpler and more effective heat-induced retrieval protocol for DNA extraction. Combination with some chemicals (detergents) may further significantly improve efficiency of the heat-induced retrieval technique.


Clinical spectrum and long-term course of sustained ventricular tachycardia in pediatric patients: 10 years of experience.
Pediatric ventricular tachycardias (VTs) have heterogeneous etiology and different clinical features. This study aimed to evaluate the clinical spectrum and long-term course of pediatric sustained VTs. Patients diagnosed as having sustained VT between 2010 and 2020 were evaluated retrospectively. A total of 129 patients with VT were evaluated; 74 patients were male, and the median age was 12.5 years (0.25-18 years). Patients were grouped as having idiopathic VT (IVT) [n=85 (65.9%)], cardiomyopathy-associated VT (CMP-VT) [n=24 (18.6%)], catecholaminergic polymorphic VT [n=17 (13.2%)], and myocarditis-associated VT [n=3, (2.3%)]. Palpitations (n=61) and syncope (n=24) were the most common symptoms. VT originated from the right ventricle in 53.6% of the patients. Half of the patients underwent electrophysiological study, 64 patients received radiofrequency ablation therapy, and 29 patients had implantable cardiac defibrillators. During the follow-up, 70.4% of all patients had complete resolution, whereas 19 patients had a partial resolution and 23 patients (19.5%) had stable disease. Monomorphic VTs and VTs with left bundle bunch block were more thriving controlled (p=0.02 vs. p=0.04). In terms of long-term results, no statistical difference was found among the VT groups (p=0.39). Deaths were observed only in IVT (n=1) and CMP-VT (n=8) groups (p<0.001), and the overall mortality rate of pediatric sustained VT was observed at 6.9% in this study. VTs, which can cause sudden cardiac arrest, are potentially life-threatening arrhythmias. Identifying the heterogeneity of this VT and its peculiar characteristics would facilitate appropriate diagnosis and therapy.


A Functional Model for Unifying Brain Computer Interface Terminology.
Brain Computer Interface (BCI) technology is a critical area both for researchers and clinical practitioners. The IEEE P2731 working group is developing a comprehensive BCI lexicography and a functional model of BCI. The glossary and the functional model are inextricably intertwined. The functional model guides the development of the glossary. Terminology is developed from the basis of a BCI functional model. This paper provides the current status of the P2731 working group's progress towards developing a BCI terminology standard and functional model for the IEEE.


Protein kinase inhibitor β enhances the constitutive activity of G-protein-coupled zinc receptor GPR39.
GPR39 is a G-protein-coupled zinc receptor that protects against diverse effectors of cell death. Its protective activity is mediated via constitutive activation of Gα13 and the RhoA pathway, leading to increased SRE (serum-response element)-dependent transcription; the zinc-dependent immediate activation of GPR39 involves Gq-mediated increases in cytosolic Ca2+ and Gs coupling leading to increased cAMP levels. We used the cytosolic and soluble C-terminus of GPR39 in a Y2H (yeast-2-hybrid) screen for interacting proteins, thus identifying PKIB (protein kinase A inhibitor β). Co-expression of GPR39 with PKIB increased the protective activity of GPR39 via the constitutive, but not the ligand-mediated, pathway. PKIB inhibits protein kinase A by direct interaction with its pseudosubstrate domain; mutation of this domain abolished the inhibitory activity of PKIB on protein kinase A activity, but had no effect on the interaction with GPR39, cell protection and induction of SRE-dependent transcription. Zinc caused dissociation of PKIB from GPR39, thereby liberating it to associate with protein kinase A and inhibit its activity, which would result in a negative-feedback loop with the ability to limit activation of the Gs pathway by zinc.


Lysergic Acid Diethylamide, Psilocybin and Dimethyltryptamine in Depression Treatment: A Systematic Review.
Despite many different kinds of substances available for depression treatment, depression itself still appears to be a clinical challenge. Recently, formerly illicit substances came to scientists' attention, including lysergic acid diethylamide (LSD), psilocybin and dimethyltryptamine (DMT). Some studies suggest that these substances might be effective in depression treatment. The aim of this study was to evaluate the efficiency of LSD, psilocybin and DMT in depression treatment in the light of current medical literature. The authors followed the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines for this systematic review. The authors searched the PubMed and Cochrane Library databases to identify relevant publications. Finally, 10 papers were included. Most of the selected studies showed significant correlation between psilocybin and DMT use and reduction in depression symptom intensity. By analyzing qualified studies, it can be concluded that psilocybin and DMT could be useful in depression treatment, but further observations are still required.


Lagoecia cuminoides L., its antioxidant activity and polyphenolic constituents from Iran.
Lagoecia cuminoides L. belongs to the family of Umbelliferae (Apiaceae), and known also as common wild cumin. The aerial parts of L. cuminoides were collected at the flowering stage and dried, then the methanolic extract was analyzed for polyphenol compounds identified by HPLC-DAD and antioxidant activity (DPPH(2,2-diphenyl-1-picrylhydrazyl) radical scavenging assay). It was found that the predominant phenolic constituents were chlorogenic acid, hesperidin, rosmarinic acid, hesperetin and vanillin. The antioxidant activity of methanolic extract from L. cuminoides was found 1597 μg/mL in DPPH scavenging assay. There is no strict positive relationship between the polyphenolic content and antioxidant activity of extracts.


Alexithymia in personality disorders: correlations with symptoms and interpersonal functioning.
Impairment in the ability to recognize and make sense of emotions has been hypothesized to be present in a sub-sample of people suffering from personality disorder (PD). In particular it is possible that difficulty recognizing and expressing feelings, or alexithymia, is related to many of the symptoms and problems in making sense of social interactions which are hallmarks of PD. In this study we measured levels of alexithymia with the Toronto Alexithymia Scale-20 and explored its correlations with the overall presence of PD and different PD diagnoses, symptoms, and interpersonal difficulties. Results were largely consistent with the hypothesis. Higher levels of alexithymia were related to high levels of global psychopathology and with dysfunctional representation of interpersonal relations. A sub-sample of patients, mostly suffering from avoidant, dependent, passive-aggressive and depressive PD, had alexithymic features and, in particular reported difficulties describing their feelings to others. A patient with cluster B PD featured no alexithymia. Implications of this study for future research and treatment are discussed.