Strengthen high-loading operation of wastewater treatment plants by composite micron powder carrier: Microscale control of carbon, nitrogen, and sulfur metabolic pathways.
The concentration of activated sludge is a crucial factor influencing the capacity and efficiency of sewage wastewater treatment plants (WWTPs). However, high sludge concentrations can lead to sludge loss in the secondary sedimentation tank, resulting in reduced processing capacity, particularly during low-temperature stages and sludge bulking. This study investigated the impact of adding composite micron powder carriers (CMPC) in high-concentration powder carrier biofluidized bed (HPB) technology to the biochemical units of WWTPs on sludge concentration and settling performance. For the traditional activated sludge method (ASM), its hydraulic retention time (HRT) was 8 h, with an average effluent total nitrogen (TN) of 15.14 mg/L. Sludge bulking was prone to occur in low-temperature environments, resulting in a high average sludge volume index (SVI) of 560 mL/g. Conversely, with a CMPC dosage of 4 g/L, the HRT of HPB technology was 4.8 h, and the average effluent TN was 11.40 mg/L, with a removal efficiency of 67.43 %. During operation of HPB technology under high sludge concentration conditions (8 g/L), the average SVI remained at 85 mL/g, indicating excellent settling characteristics. Moreover, in the sequencing batch reactor (SBR), the SVI value of bulking sludge decreased from the original 695 to 111 mL/g by the 9th day of operation with the CMPC dosage of 2 g/L. At the same time, the filamentous bacteria almost disappeared, suggesting that CMPC inhibit the growth of filamentous bacteria. Metagenomic analysis demonstrated that CPMC enhance the utilization of small molecular fatty acids in activated sludge and promote electron transfer between nitrate and nitrite, thereby improving wastewater treatment capacity. Additionally, CMPC enhanced the relative abundance of Saprospiraceae in sludge, which accelerate the degradation of polysaccharides in extracellular polymeric substances, weaken sludge's hydrophilic properties, and improve sludge's settling performance. Overall, these findings suggested that CMPC effectively strengthen the high-loading operation of WWTPs by improving sludge concentration and sedimentation performance.


[Interdisciplinary stratification of patients with myoma-related symptoms].
With the establishment of uterine artery embolization (UAE), the individualization of treatment of the symptomatic myomatous uterus showed a general progression. The concrete therapy decision is made in an interactive process between doctor and patient. A series of factors influence the choice of a suitable, operative or non-operative, therapeutic procedure. In the weighting of therapeutic options between surgery or UAE, in addition to current results of studies which compare both techniques,recommendations made by expert committees and guidelines are helpful for a competent counseling of patients and additionally supportive in decision processes such as interdisciplinary stratification.


Novel Mg-Doped SrMoO₃ Perovskites Designed as Anode Materials for Solid Oxide Fuel Cells.
SrMo1-xMxO3-δ (M = Fe and Cr, x = 0.1 and 0.2) oxides have been recently described as excellent anode materials for solid oxide fuel cells at intermediate temperatures (IT-SOFC) with LSGM as the electrolyte. In this work, we have improved their properties by doping with aliovalent Mg ions at the B-site of the parent SrMoO₃ perovskite. SrMo1-xMgxO3-δ (x = 0.1, 0.2) oxides have been prepared, characterized and tested as anode materials in single solid-oxide fuel cells, yielding output powers near 900 mW/cm-2 at 850 °C using pure H₂ as fuel. We have studied its crystal structure with an "in situ" neutron power diffraction (NPD) experiment at temperatures as high as 800 °C, emulating the working conditions of an SOFC. Adequately high oxygen deficiencies, observed by NPD, together with elevated disk-shaped anisotropic displacement factors suggest a high ionic conductivity at the working temperatures. Furthermore, thermal expansion measurements, chemical compatibility with the LSGM electrolyte, electronic conductivity and reversibility upon cycling in oxidizing-reducing atmospheres have been carried out to find out the correlation between the excellent performance as an anode and the structural features.


Microstructure and Tribological Properties of Mo-40Ni-13Si Multiphase Intermetallic Alloy.
Intermetallic compounds are increasingly being expected to be utilized in tribological environments, but to date their implementation is hindered by insufficient ductility at low and medium temperatures. This paper presents a novel multiphase intermetallic alloy with the chemical composition of Mo-40Ni-13Si (at %). Microstructure characterization reveals that a certain amount of ductile Mo phases formed during the solidification process of a ternary Mo-Ni-Si molten alloy, which is beneficial to the improvement of ductility of intermetallic alloys. Tribological properties of the designed alloy-including wear resistance, friction coefficient, and metallic tribological compatibility-were evaluated under dry sliding wear test conditions at room temperature. Results suggest that the multiphase alloy possesses an excellent tribological property, which is attributed to unique microstructural features and thereby a good combination in hardness and ductility. The corresponding wear mechanism is explained by observing the worn surface, subsurface, and wear debris of the alloy, which was found to be soft abrasive wear.


[Diabetic retinopathy: 10 years after light-coagulation (author's transl)].
A retrospective study of 19 patients, who suffered from diabetic retinopathy, were submitted to a xenon-light-coagulation 10 years ago and have been regularly checked, shows better results in the treated eyes than in the untreated fellow-eyes in regard to visual acuity and background morphology. In cases of poorly controlled metabolism, heavy smoking and simultaneous suffering from hypertension and nephropathy the prognosis of the treated eyes is unfavourably affected.


[Studies on the chemical constituents in seeds of Atriplex centralasiatica].
To study the chemical constituents in seeds of Atriplex centralasiatica. The chemical components were isolated by solvents extractions and column chromatography. The chemical structures were identified on the basis of physicochemical constants and spectral data. Six compounds were isolated and identified as isorhamnetin(I), tricin(II), querecetin-7-O-alpha-L-rhamnoside(III), isoorientin(IV), beta-sitosterol(V), beta-daucosterlo(VI). Compound I, II, III, IV are isolated from genus Atriplex for the first time.


Distinct but overlapping binding sites of agonist and antagonist at the relaxin family peptide 3 (RXFP3) receptor.
The relaxin-3 neuropeptide activates the relaxin family peptide 3 (RXFP3) receptor to modulate stress, appetite, and cognition. RXFP3 shows promise as a target for treating neurological disorders, but realization of its clinical potential requires development of smaller RXFP3-specific drugs that can penetrate the blood-brain barrier. Designing such drugs is challenging and requires structural knowledge of agonist- and antagonist-binding modes. Here, we used structure-activity data for relaxin-3 and a peptide RXFP3 antagonist termed R3 B1-22R to guide receptor mutagenesis and develop models of their binding modes. RXFP3 residues were alanine-substituted individually and in combination and tested in cell-based binding and functional assays to refine models of agonist and antagonist binding to active- and inactive-state homology models of RXFP3, respectively. These models suggested that both agonists and antagonists interact with RXFP3 via similar residues in their B-chain central helix. The models further suggested that the B-chain Trp27 inserts into the binding pocket of RXFP3 and interacts with Trp138 and Lys271, the latter through a salt bridge with the C-terminal carboxyl group of Trp27 in relaxin-3. R3 B1-22R, which does not contain Trp27, used a non-native Arg23 residue to form cation-π and salt-bridge interactions with Trp138 and Glu141 in RXFP3, explaining a key contribution of Arg23 to affinity. Overall, relaxin-3 and R3 B1-22R appear to share similar binding residues but may differ in binding modes, leading to active and inactive RXFP3 conformational states, respectively. These mechanistic insights may assist structure-based drug design of smaller relaxin-3 mimetics to manage neurological disorders.


Procalcitonin-a sensitive inflammation marker of febrile episodes in neutropenic children with cancer.
Sensitive parameters of inflammations, are rare or of limited validity in neutropenic patients. Procalcitonin (PCT) proven to be a sensitive inflammatory marker in nonneutropenic patients was evaluated for its diagnostic relevance in febrile episodes of neutropenic patients with cancer Plasma levels of PCT were determined by an immunoluminometric assay in children with febrile neutropenic episodes (n=376) starting at the date of admission until the resolution of fever and were correlated with serum levels of the C-reactive protein (CrP). Febrile episodes were classified as fever of unknown origin (FUO), microbiologically or clinically documented infections and were also differentiated according to the site of the infection (unknown, bacteremia, respiratory, soft tissue, gastrointestinal and urinary tract infection). Independently from the aetiology and the site of infection the PCT peak value occurred mostly on the second hospital day and decreased rapidly in cases of successful antibiotic therapy and with the resolution of fever to the normal range (0.1+/-0.5 microg/l). The highest PCT peak levels at the onset of fever and during the febrile course were observed in patients with gramnegative bacteremia (n = 22, median 12.1 microg/l, range 0.4+/-568.2 microg/l). There was a positive correlation between PCT peak levels and CrP peak levels (r = 0.48, p = 0.001) which mostly were observed 24 h later than for PCT. PCT is a sensitive and specific parameter in the diagnostic and in the sequential assessment of febrile neutropenic episodes, especially in gramnegative infections. Its diagnostic accuracy in neutropenic patients is clearly higher than that of CrP.


Recurrence of Uterine Smooth Muscle Tumor of Uncertain Malignant Potential: A Systematic Review of the Literature.
Background: This study aimed to systematically review the existing literature on uterine smooth muscle tumor of uncertain malignant potential (STUMP) to provide information about characteristics and outcomes of patients and the risk factors for recurrence over a period of 60 years (1960−2021). Methods: According to PRISMA guidelines, we searched for "uterine smooth muscle tumor of uncertain malignant potential" in PubMed (all fields) and Scopus (Title/Abstract/Keywords) databases (accessed on 1 January 2022). Relevant articles were obtained in full-text format and screened for additional references. The only filter used was the English language. Studies including full case description of patients with histopathological diagnosis of STUMP in accordance with Stanford criteria were included. Results: Thirty-four studies, including 189 cases, were included. The median age was 43 years, and in 21.5% of cases there was a recurrence of the disease. Bivariate analysis showed a significant association between use of morcellation without bag and risk of recurrence (p = 0.001). Unprotected morcellation during demolitive or conservative surgery was independently associated with a higher risk of disease recurrence with a relative risk of 2.94 (p < 0.001). A significant progressive decrease in the recurrence rate was observed over time (r = −0.671, p = 0.008). The percentage of patients who underwent surgery followed by in-bag protected morcellation significantly increased after the publication of the U.S. Food and Drug Administration alert about the risk linked to this procedure (p = 0.01). Conclusions: Unprotected morcellation of the lesion is associated with the relapse of the disease. However, this clinical condition showed a drastic decrease over time. This could likely be due to the increased awareness by surgeons of the importance of customizing surgical treatment.


The influence of child-based factors and parental inputs on expressive language abilities in children with autism spectrum disorder.
Language impairment is one of the early signs of Autism Spectrum Disorder (ASD) that alerts parents to take their children for early diagnosis and intervention. Little is known about how children's autism traits, IQ, initial language abilities and parental inputs influence their language abilities. In addition, only a few studies have compared the relative influence of these factors. The present study addressed these issues by examining the structural language in parent-child spontaneous interactions. Forty-two Cantonese (Chinese)-speaking autistic children aged four to eight were recruited. Their expressive language skills grew rapidly more than 9 months, but their development trajectories varied. Initial expressive language ability is the only significant predictor of child language outcomes and language growth trajectories. In contrast, nonverbal cognition, autism traits, and parents' input do not affect language outcomes in children with ASD. Therefore, early language intervention is crucial for autistic children at all severity and IQ levels.


Estimating pediatric cases of COVID-19 over time in the United States: Filling in a gap in public use data.
COVID-19 continues to disturb nearly all aspects of life, leaving us striving to reach herd immunity. Currently, only weekly standardized incidence rate data per age group are publicly available, limiting assessment of herd immunity. Here, we estimate the time-series case counts of COVID-19 among age groups currently ineligible for vaccination in the USA. This was a secondary analysis of publicly available data. COVID-19 case counts by age groups were computed using incidence rate data from the CDC and population estimates from the US Census Bureau. We also created a web-based application to allow on demand analysis. A total of 78 weeks of data were incorporated in the analysis, suggesting the highest peak in cases within the 5-11-year age group on week ending 2021-01-09 (n = 61,095) followed by the 12-15-year age group (n = 58,093). As of July 24, 2021, case counts in the 5-11-year age group have expanded beyond other groups rapidly. This study suggests it is possible to estimate pediatric case counts of COVID-19. National agencies should report COVID-19 time series case counts for pediatric age cohorts. These data will enhance our ability to estimate the population at risk and tailor interventions accordingly.


Mesotrione herbicide promotes biochemical changes and DNA damage in two fish species.
Mesotrione is one of the new herbicides that have emerged as an alternative after the ban of atrazine in the European Union. To our knowledge, any work using genetic or biochemical biomarkers was performed in any kind of fish evaluating the toxicity of this compound. The impact of acute (96 h) exposure to environmentally relevant mesotrione concentrations (1.8, 7, 30, 115 e 460 μg L-1) were evaluated on the liver of Oreochorimis niloticus and Geophagus brasiliensis by assessing the activity of superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione-S- transferase (GST), the levels of reduced glutathione (GSH), carbonyl assays (PCO) and lipid peroxide (LPO) as well as the DNA damage to erithrocytes, liver and gills through the comet assay. We observed an increase in the concentration of GSH and the GPx activity in O. niloticus, and the GST and SOD activity in G. brasiliensis. We found significant increase in DNA damage in all tissues in both species. The results indicated that the acute exposure to mesotrione can induce oxidative stress and DNA damage in both species.


Neuraxial morphine after unintentional dural puncture is not associated with reduced postdural puncture headache in obstetric patients.
To examine the relationship between neuraxial morphine exposure after unintentional dural puncture and the risk for postdural puncture headache in obstetric patients. Retrospective cohort study. Obstetrical unit at a tertiary care referral center. Parturients receiving labor epidural analgesia with recognized unintentional dural puncture. Cases in which neuraxial morphine was given for any reason were compared to cases in which it was not for the outcome of postdural puncture headache. Development of postdural puncture headache, headache severity, number of epidural blood patches, hospital length of stay. Of the 80 cases that were included, 38 women received neuraxial morphine and 42 did not. There was no significant difference in the incidence of headache between the two morphine groups (Headache present: Morphine: 27/56 [48.2%], No morphine: 29/56 [51.8%]; Headache free: Morphine: 11/24 [45.8%], No morphine: 13/24 [54.2%], P = 0.84). There was no difference in the need for epidural blood patch (Morphine: 24/42 [57.1%], No morphine: 18/38 [47.4%], P = 0.50) and headache severity (mean headache pain score: Morphine: 7.9 ± 1.8 vs. No morphine: 7.3 ± 2.4, P = 0.58). Hospital length of stay was higher in the morphine group (4.4 ± 2.9 days vs. 3.0 ± 1.5 days respectively, P = 0.008). Using logistic regression, morphine did not affect headache risk after controlling for covariates (morphine vs. no morphine: adjusted OR 1.24 [0.75]; P = 0.72; pre-eclampsia vs. no pre-eclampsia: adjusted OR 0.56 [0.41], P = 0.42; cesarean vs. normal spontaneous vaginal delivery: adjusted OR 0.97 [0.67]; P = 0.96). In cases of unintentional dural puncture, exposure to neuraxial morphine for any reason may not be protective against the risk of postdural puncture headache. Although an overall protective effect of neuraxial morphine was not observed in this study, its role in specific subsets of patients remains to be investigated.


Safety and Efficacy of Iltamiocel Cellular Therapy for the Treatment of Fecal Incontinence. Results of a Phase 1/2 Study.
To examine the safety and efficacy of iltamiocel, an investigational cellular therapy of autologous muscle-derived cells, as a treatment for fecal incontinence (FI) in adults. Limited therapeutic options are available for patients with FI refractory to conservative treatments. Cell therapy using autologous muscle-derived cells represents a promising, minimally invasive approach for restoring anal sphincter function. In this multicenter, prospective, non-randomized study, 48 participants were treated with a single iltamiocel dose of 250×10 6 cells. The primary outcome was the incidence of product or procedure-related adverse events (AEs) and serious AEs. Secondary outcomes were changes in the number of FI episodes, Cleveland Clinic Incontinence Score, Fecal Incontinence Quality of Life, and anorectal manometry at 3, 6, and 12 months compared to baseline. No serious AEs and only one product-related AE of inflammation at the injection site were reported. At 12 months, there was a reduction in median FI episodes (-6.0; 95% confidence interval (CI): -10.0, -1.0) and days with episodes (-4.0; 95% CI: -8.0, -1.0). A ≥50% reduction in FI episodes was observed in 53.7% of participants, and 24.4% had complete restoration of continence. Symptom severity and quality of life improved with mean Cleveland Clinic Incontinence Score reduction (-2.9; 95% CI: -3.7, -2.1), and Fecal Incontinence Quality of Life increased (2.2; 95% CI:1.4, 2.9). No significant changes were detected in anorectal manometry measurements. A history of episiotomy was significantly associated with treatment response in multivariate analysis. The administration of iltamiocel cellular therapy is safe. Iltamiocel shows promise for significantly improving fecal incontinence symptoms and quality of life.


Cerebral perfusion pressure in giraffe: modelling the effects of head-raising and -lowering.
Loss of consciousness caused by positional changes of the head results from reduced cerebral blood flow (CBF). CBF is related to cerebral perfusion pressure (CPP). CPP is the difference between mean arterial pressure (MAP) at the head and intracranial pressure (ICP). The positional change of the giraffe head between ground level and standing upright is the largest of all animals yet loss of consciousness does not occur. We have investigated the possibility that an increase in CPP protects giraffe from fainting, using a mechanical model that functioned as an anatomical U-tube. It consisted of a rigid ascending "carotid" limb, a collapsible "brain" tube drained by a rigid, "vertebral venous plexus" (VVP) tube, and a collapsible "head" tube drained by a collapsible tube representing the "jugular vein". The descending tubes could be rotated relative to the "carotid" tube to be horizontal, or at 30 degrees , 45 degrees , and 60 degrees to the vertical to simulate changes in head position. Pressure at the top of the "carotid" tube was intracranial MAP, at the top of the "VVP" tube was ICP, and the difference CPP. In the simulated "head-up" position and a fluid flow rate of 4 L min(-1), CPP was approximately 170 mmHg. With the VVP tube horizontal, CPP fell from approximately 170 to 45 mmHg, but increased to approximately 67 mmHg at 30 degrees "down", to approximately 70 mmHg at 45 degrees "down" and to approximately 75 at 60 degrees "down". The fall in CPP in the head-down positions resulted from a decrease in viscous resistance in, and dissipation of pressure to, the "head" and "jugular" tubes. These data provide an estimate of cranial pressure changes in giraffe during positional changes of the head, and suggest that an increase in CPP plays a significant role in maintaining CBF during head-raising and that it may be an important mechanism for preventing fainting in giraffe.


Rate equations and simulation curves for enzymatic reactions which utilize lipids as substrates. II. Effect of adsorption of the substrate or enzyme on the steady-state kinetics.
Theoretical aspects of the kinetics of interaction of enzymes with lipid substrates are presented. Rate equations were written and used to simulate v versus S curves for the following cases: (a) The substrate is adsorbed onto non-catalytic sites of the enzyme or to other proteins accompanying the enzyme. (b) The enzyme is adsorbed, via non-catalytic sites to aggregated forms of the substrate. (c) The substrate is adsorbed onto an externally added protein such as albumin. Although all rate equations are based on the Michaelis-Menten kinetic theory, most of the simulated v vs. S curves were not hyperbolic and some of the v vs. E curves not linear.


Post-extinction selective persistence of large dendritic spines in fear remodeled circuits may serve to reactivate fear.
Memory formation associates with changes in strength and efficacy of existing synapses and with the formation of new synapses. Dendritic spines, the membranous protrusions from neuron dendrites that host the majority of excitatory synapses, are the anatomical sites where neuronal activity reshapes brain networks in response to stimuli. Mounting evidence indicates that structural changes in fear-remodeled circuits undergo partially erasure following extinction, suggesting that the changes that persist may serve to reactivate memory. Here we review data showing how brain circuits are remodeled at the time fear memory is formed and extinguished, with a special focus put on the post-extinction persistence of spine enlargement in relation to memory reactivation.


Health care reform and emergency outpatient use of rural hospitals in Alberta, Canada.
We describe Alberta's publicly funded system of rural hospital emergency outpatient services just before the profound impact of major health care reforms. From a rural physician's perspective, we descriptively analyze a unique government database that contains the number of emergency outpatient visits to all Alberta hospitals in the fiscal year 1992/93. We found that most people in rural Alberta had ready access to an extensive system of physician-based rural hospital emergency outpatient services, that 50% of all emergency visits were made to rural hospitals, and that 70% of physicians providing hospital-based emergency services were rural. There were significant differences in the emergency outpatient use of large urban, regional urban, and rural hospitals, and between rural hospitals that were close, middle, or remote distances from tertiary or secondary care centers. We identify some clinically important factors that are not described by available data, but which should be considered by the reform movement.


Tonotopic organization in human auditory cortex revealed by positron emission tomography.
Positron emission tomography (PET) was used to map alterations in local neuronal activity induced in human primary auditory cortex by pure-tone stimulation. Patterns of blood flow were observed in specific regions on the superior temporal plane showing systematic changes in activity depending on the frequency of a stimulating pure tone. The orientation of these regions agrees well with data for non-human primates.


BRCA1 and NORE1A Form a Her2/Ras Regulated Tumor Suppressor Complex Modulating Senescence.
BRCA1 is a tumor suppressor with a complex mode of action. Hereditary mutations in BRCA1 predispose carriers to breast cancer, and spontaneous breast cancers often exhibit defects in BRCA1 expression. However, haploinsufficiency or suppression of BRCA1 expression leads to defects in DNA repair, which can induce DNA damage responses, leading to senescence. Activating mutation or overexpression of the Her2 oncoprotein are also frequent drivers of breast cancer. Yet, over-activation of Her2, working through the RAS oncoprotein, can also induce senescence. It is thought that additional defects in the p53 and Rb tumor suppressor machinery must occur in such tumors to allow an escape from senescence, thus permitting tumor development. Although BRCA1 mutant breast cancers are usually Her2 negative, a significant percentage of Her2 positive tumors also lose their expression of BRCA1. Such Her2+/BRCA1- tumors might be expected to have a particularly high senescence barrier to overcome. An important RAS senescence effector is the protein NORE1A, which can modulate both p53 and Rb. It is an essential senescence effector of the RAS oncoprotein, and it is often downregulated in breast tumors by promotor methylation. Here we show that NORE1A forms a Her2/RAS regulated, endogenous complex with BRCA1 at sites of replication fork arrest. Suppression of NORE1A blocks senescence induction caused by BRCA1 inactivation and Her2 activation. Thus, NORE1A forms a tumor suppressor complex with BRCA1. Its frequent epigenetic inactivation may facilitate the transformation of Her2+/BRCA1- mediated breast cancer by suppressing senescence.


Body mass index status is effective in identifying metabolic syndrome components and insulin resistance in Pacific Island teenagers living in New Zealand.
Although adults of Pacific ethnicity living in New Zealand have more than double the prevalence of diabetes and cardiovascular disease than the general population, little is known regarding the presence of risk factors for these disorders among young Pacific Islanders. The study aim was to examine relationships between body composition, glucose and lipid metabolism, and components of the metabolic syndrome (MS) in a community sample of Pacific Island (PI) teenagers living in Dunedin. Anthropometry, body composition (dual-energy x-ray absorptiometry), glucose and lipid metabolism, insulin resistance (homeostasis model assessment [HOMA2], McAuley index), and components of MS were assessed in 80 PI teenagers (aged 15-18 years). Results showed that 6 participants had full MS, 2 had high fasting blood glucose values (>7.0 mmol/L), 55 had high adiposity, and 21 had insulin resistance. Assessment of the components of MS by body mass index (BMI) status showed that obese participants (n = 29) had a high prevalence (86.2% had one or more component), whereas only 10.5% of those with healthy BMI status (n = 19) had any MS component. Elevated fat mass had substantial effects on fasting insulin values, HOMA2, and the McAuley index because in data adjusted for age, sex, and lean mass, a 10% greater fat mass was associated with a 4.7% increase in fasting insulin, a 5.3% rise in HOMA2, and a 2.3% decrease in the McAuley index. Our results suggest that the antecedents of cardiovascular disease and type 2 diabetes mellitus occur frequently in young Pacific Islanders having high adiposity. We conclude that community studies of PI adolescents should focus on assessing risk factors whenever BMI values are high.


Evaluation of colchicine therapy in primary biliary cirrhosis.
We have conducted a double-blind controlled trial of colchicine in patients with primary biliary cirrhosis. Fifty-seven patients with biopsy-proven primary biliary cirrhosis were randomized to receive either 0.6 mg of colchicine twice daily or an identically appearing placebo. Patients underwent clinical and laboratory evaluation every 3 mo and liver biopsy annually. Differences in mean alkaline phosphatase and alanine aminotransferase values between the colchicine and placebo recipients were statistically significant at 4 yr. Differences in mean bilirubin and immunoglobulin M values, although lower in the colchicine group, did not reach statistical significance. In colchicine-treated patients, mean alkaline phosphatase values fell significantly compared with controls, from 281 to 112 IU/L (p less than 0.01). Similarly, mean alanine aminotransferase values fell significantly compared with controls, from 129 to 86 IU/L (p less than 0.05). Bilirubin values remained stable in drug-treated patients, even in those patients with initially elevated bilirubin values, whereas they nearly doubled in subjects receiving placebo. Although biochemical parameters of disease activity improved or stabilized in colchicine-treated subjects, no difference in histologic progression was detected between the two treatment groups. We conclude that colchicine is of clinical benefit to patients with primary biliary cirrhosis as judged by improvement in alkaline phosphatase and alanine aminotransferase activities as well as a tendency for stabilization of bilirubin values.


Aerobic degradation of bisphenol A by Pseudomonas sp. LM-1: characteristic and pathway.
Bisphenol A (BPA) has been widely used in the manufacture of polymeric materials. BPA is regarded as an endocrine disrupting chemical, posing a great threat to the public health. In this study, a bacterial strain LM-1, capable of utilizing BPA as the sole carbon and energy source under aerobic conditions, was originally isolated from an activated sludge sample. The isolate was identified as Pseudomonas sp. based on 16S rRNA gene sequence analysis. Strain LM-1 was able to completely degrade 25-100 mg/L BPA within 14-24 h, and it also exhibited high capacity for BPA degradation at a range of pH (6.0-8.0). (NH4)2SO4 and NH4NO3 were the suitable nitrogen sources for its growth and BPA biodegradation, and the BPA degradation could be accelerated when exogenous carbon sources were introduced as the co-substrates. Metal ions such as Zn2+, Cu2+, and Ni2+ could considerably suppress the growth of strain LM-1 and BPA degradation. According to the analysis of liquid chromatography coupled to Q-Exactive high resolution mass spectrometry, hydroquinone, p-hydroxybenzaldehyde, and p-hydroxybenzoate were the predominate metabolites in the BPA biodegradation and the degradation pathways were proposed. This study is important for assessment of the fate of BPA in engineered and natural systems and possibly for designing bioremediation strategies.


Interaction Effects in Health State Valuation Studies: An Optimal Scaling Approach.
This study aimed to introduce a parsimonious modeling approach that enables the estimation of interaction effects in health state valuation studies. Instead of supplementing a main-effects model with interactions between each and every level, a more parsimonious optimal scaling approach is proposed. This approach is based on the mapping of health state levels onto domain-specific continuous scales. The attractiveness of health states is then determined by the importance-weighted optimal scales (ie, main effects) and the interactions between these domain-specific scales (ie, interaction effects). The number of interaction terms only depends on the number of health domains. Therefore, interactions between dimensions can be included with only a few additional parameters. The proposed models with and without interactions are fitted on 3 valuation data sets from 2 different countries, that is, a Dutch latent-scale discrete choice experiment (DCE) data set with 3699 respondents, an Australian time trade-off data set with 400 respondents, and a Dutch DCE with duration data set with 788 respondents. Important interactions between health domains were found in all 3 applications. The results confirm that the accumulation of health problems within health states has a decreasing marginal effect on health state values. A similar effect is obtained when so-called N3 or N5 terms are included in the model specification, but the inclusion of 2-way interactions provides superior model fits. The proposed interaction model is parsimonious, produces estimates that are straightforward to interpret, and accommodates the estimation of interaction effects in health state valuation studies with realistic sample size requirements. Not accounting for interactions is shown to result in biased value sets, particularly in stand-alone DCE with duration studies.


Amine organocatalysts for highly ortho-selective chlorination of anilines with sulfuryl chloride.
A metal catalyst free approach for regioselective ortho-chlorination of anilines has been developed using a secondary amine as the organocatalyst and sulfuryl chloride as the halogen source under mild conditions. A wide range of substrates were compatible with this catalytic system. In addition, this catalytic protocol has been applied to the efficient synthesis of bioactive compounds and modification of drug derivatives. Further studies indicated that the anionic trichloride species was responsible for the ortho-selectivity.


Expression of cell division cycle 2 kinase transcription in chronically rejected cardiac allografts of nonhuman primates.
Accurate diagnosis and prevention of graft arteriosclerosis, known as chronic rejection, is critical to the success of cardiac transplantation, but often is difficult to attain. Expression of cell division cycle (cdc) 2 kinase, which plays a critical role in cell transition through the G2/M phase, is critical to the proliferation of vascular smooth muscle cells. To evaluate the usefulness of cdc2 kinase expression for pathophysiological analysis of chronic rejection, heterotopic cardiac transplantation was performed in Japanese monkeys (n = 7). Standard reverse transcriptase-polymerase chain reaction (RT-PCR) and in situ RT-PCR were performed to evaluate the expression. In the coronary arteries of chronically rejected allografts, enhanced cdc2 kinase expression was observed in thickened intima and media, while none was expressed in native hearts. The cdc2 kinase was also expressed before the intimal thickening occurred. These results indicate that enhanced expression of cdc2 kinase is a sensitive indicator for chronic cardiac rejection; targeting cdc2 kinase may be a viable gene therapy for prevention of this vasculopathy.


Social defeat stress exacerbates atopic dermatitis through downregulation of DNA methyltransferase 1 and upregulation of C-C motif chemokine receptor 7 in skin dendritic cells.
DNA methylation is an epigenetic modification that regulates gene transcription. DNA methyltransferase 1 (DNMT1) plays an important role in DNA methylation. However, the involvement of DNMT1 and DNA methylation in the pathogenesis of atopic dermatitis (AD) remains unclear. In this study, microarray analysis revealed that peripheral blood mononuclear cells of AD patients with low DNMT1 expression (DNMT1-low) highly expressed dendritic cell (DC) activation-related genes. Also, DNMT1-low AD patients exhibited a higher itch score compared to AD patients with high DNMT1 expression (DNMT1-high). By using an AD-like mouse model induced by the application of Dermatophagoides farinae body ointment, we found that Dnmt1 expression was decreased, while the expression of C-C chemokine receptor type 7 (Ccr7) was upregulated in mouse skin DCs. Furthermore, mice exposed to social defeat stress exhibited Dnmt1 downregulation and Ccr7 upregulation in skin DCs. Additionally, dermatitis and itch-related scratching behavior were exacerbated in AD mice exposed to stress. The relationship between low DNMT1 and itch induction was found in both human AD patients and AD mice. In mouse bone marrow-derived DCs, Ccr7 expression was inhibited by 5-aza-2-deoxycytidine, a methylation inhibitor. Furthermore, in mouse skin DCs, methylation of CpG sites in Ccr7 was modified by either AD induction or social defeat stress. Collectively, these findings suggest that social defeat stress exacerbates AD pathology through Dnmt1 downregulation and Ccr7 upregulation in mouse skin DCs. The data also suggest a role of DNMT1 downregulation in the exacerbation of AD pathology.


[Takayashu and pregnancy].
Takayashu arteritis is a chronic inflammatory disease of the large arteries, usually affecting the aorta and its large branches and the pulmonary arteries, with a higher incidence during the childbearing years. We report the case of a 33-year-old patient, primigravida with Takayashu arteritis diagnosed three years ago. At 37 weeks of gestation, she was admitted for a pre-eclampsia and a left ventricular insufficiency. Elective caesarean section under general anesthesia after joint decision between the attending obstetrician and the medical and anesthetic consultants, and allowed the extraction of a hypotrophic baby. The association of pregnancy with Takayashu's arteritis is almost always uneventful. It is associated with high values of maternal blood pressure and severe intra-uterine growth retardation.


Encapsulation of resveratrol using Maillard conjugates and membrane emulsification.
Resveratrol is a stilbene phenolic associated with health-promoting properties such as antioxidant, anti-inflammatory and chemoprevention. Due to its chemical instability and low water solubility, microencapsulation represents a good alternative to provide better results when employing resveratrol as a nutraceutical ingredient. The main purpose of our work was to use low shear membrane emulsification to produce resveratrol-loaded emulsions of low polydispersity and integrate this process to spray drying to produce a powdered product. Resveratrol was dispersed with palm oil in a continuous phase obtained via Maillard reaction. We evaluated the influence of process conditions and phases composition on emulsions properties and performed the characterization of the spray-dried powder. Emulsions droplet size and span decreased as shear stress was increased. Higher dispersed phase fluxes provided increased droplet size polydispersity. Process conditions were set on 60.0 Pa shear stress and 70 L m-2h-1 of dispersed phase flux, obtaining emulsions with mean diameter around 30 μm and span of 0.76. Despite this relatively high droplet size of the infeed emulsions, the spray drying process resulted in particles with high encapsulation efficiency (97.97 ± 0.01%), and water content (~3.6%) and diameter (~10.2 μm) similar to particles obtained from fine emulsions in previously reported works.


Impact of diagnostic laparoscopy on the management of gastric cancer: prospective study of 120 consecutive patients with primary gastric adenocarcinoma.
Peritoneal seeding or liver metastases found at laparotomy usually preclude curative treatment in patients with gastric adenocarcinoma. Such exploratory laparotomies may be avoided by diagnostic laparoscopy. However, routine diagnostic laparoscopy does not benefit those patients who proceed to laparotomy after negative laparoscopy. The aim of this study was to evaluate prospectively the selective use of laparoscopy in uncertain situations. One hundred and twenty consecutive patients with primary gastric adenocarcinoma were studied prospectively. Diagnostic laparoscopy was performed in patients with clinical T4 tumours or suspected metastases, unless laparotomy was required for symptomatic disease. Ninety-six of 120 patients were selected for immediate laparotomy with curative intent (n = 81) or for palliation (n = 15). In two of the 81 patients gastrectomy was abandoned because of unexpected peritoneal carcinomatosis. Fifteen patients underwent diagnostic laparoscopy, which identified intra-abdominal metastases in six; the other nine patients proceeded to laparotomy, which revealed peritoneal metastases not detected at laparoscopy in four patients. The remaining nine patients had overt metastases and were referred for systemic chemotherapy without abdominal exploration. Diagnostic laparoscopy in selected patients effectively limits the number of unnecessary invasive staging procedures. Routine use of diagnostic laparoscopy in all patients with gastric adenocarcinoma is not warranted.


Tyrosine-89 is important for enzymatic activity of S. cerevisiae inorganic pyrophosphatase.
7-Chloro-4-nitro-benzofurazan selectively modifies one PPase Tyr residue per subunit and lowers the enzyme activity. Hydrolysis of the modified protein by trypsin and then by chymotrypsin produces the 82-89 peptide which possesses modified Tyr-89. Substrate analog (CaPPi) and the product of the enzyme reaction, MgPi, protect the enzyme against inactivation. Ions of metal-activators (Mg2+, Zn2+) exert no influence on the inactivation rate. On the contrary, the Ca(2+)-inhibitor of the enzyme accelerates the reaction by binding to the high-affinity site, and effectively decreases it when Ca2+ binds to both sites. Mg2+ competes with Ca2+ for one binding site, which is the low affinity site for Mg2+ and the high-affinity site for Ca2+. The Ca2+ saturation of the high-affinity site decreases the pK2 of Tyr-89, probably due to direct coordination between Tyr and Ca2+. The observed properties of Tyr-89 modification enable us to propose that Tyr-89 serves as a proton donor for phosphate releasing during enzymatic hydrolysis of pyrophosphate. The Ca2+ inhibitory effect on the enzyme activity may be due to the existence of a Tyr-89 bond in the Ca2+ pyrophosphatase complex.


Formation of functional endplates by spinal axons regenerating through a peripheral nerve graft. A study in the adult rat.
Peripheral nerve (PN) autografts were used in the adult rat to join the midcervical spinal cord to a nearby denervated skeletal muscle. Retrograde tracing, morphological and electrophysiological studies indicated the following: 1) a great number of neurons, located bilaterally, between C3 and C7 in most laminae of the grey matter, extended axons into the PN grafts, 2) a lesser number of neurons regenerated up to the reconnected muscle, but most of them were typical motoneurons, 3) neuromuscular junctions were formed in ectopic locations, around the tip of the grafted nerve, and at the sites of original endplates, 4) these junctions were functional and formed by axons that had regenerated into the PN bridges, as muscle contraction was obtained by electrical stimulation of the grafted nerves, 5) they were proved to be cholinergic since endplate potentials, evoked by stimulating the PN graft, were suppressed by curare. These results strongly suggest that spinal neurons, and especially motoneurons, are involved in the formation, through PN bridges, of new functional cholinergic connections with denervated skeletal muscles.


A phase Ib/IIa, randomised, double-blind, multicentre trial to assess the safety and efficacy of expanded Cx611 allogeneic adipose-derived stem cells (eASCs) for the treatment of patients with community-acquired bacterial pneumonia admitted to the intensive care unit.
Community-acquired bacterial pneumonia (CABP) can lead to sepsis and is associated with high mortality rates in patients presenting with shock and/or respiratory failure and who require mechanical ventilation and admission to intensive care units, thus reflecting the limited effectiveness of current therapy. Preclinical studies support the efficacy of expanded allogeneic adipose-derived mesenchymal stem cells (eASCs) in the treatment of sepsis. In this study, we aim to test the safety, tolerability and efficacy of eASCs as adjunctive therapy in patients with severe CABP (sCABP). In addition to standard of care according to local guidelines, we will administer eASCs (Cx611) or placebo intravenously as adjunctive therapy to patients with sCABP. Enrolment is planned for approximately 180 patients who will be randomised to treatment groups in a 1:1 ratio according to a pre-defined randomization list. An equal number of patients is planned for allocation to each group. Cx611 will be administered on Day 1 and on Day 3 at a dose of 160 million cells (2 million cells / mL, total volume 80 mL) through a 20-30 min (240 mL/hr) intravenous (IV) central line infusion after dilution with Ringer Lactate solution. Placebo (Ringer Lactate) will also be administered through a 20-30 min (240 mL/hr) IV central line infusion at the same quantity (total volume of 80 mL) and following the same schedule as the active treatment. The study was initiated in January 2017 and approved by competent authorities and ethics committees in Belgium, Spain, Lithuania, Italy, Norway and France; monitoring will be performed at regular intervals. Funding is from the European Union's Horizon 2020 Research and Innovation Program. SEPCELL is the first trial to assess the effects of eASCs in sCABP. The data generated will advance understanding of the mode of action of Cx611 and will provide evidence on the safety, tolerability and efficacy of Cx611 in patients with sCABP. These data will be critical for the design of future confirmatory clinical investigations and will assist in defining endpoints, key biomarkers of interest and sample size determination. NCT03158727 , retrospectively registered on 9 May 2017.


Advanced tip design for liquid phase vibration mode atomic force microscopy.
We have fabricated polymer tips for atomic force microscopy in order to elucidate the effects of tip length and shape on cantilever vibration damping in liquids. The vibration damping is investigated by measuring the vibration amplitude of cantilevers as a function of tip-sample distance. The cantilever with a short tip provides a higher damping effect over long tip-sample distances. When the vibration amplitude was rescaled to show the effect of the cantilever width on oscillation damping, the vibration amplitude of cantilevers with various tip lengths was similarly obtained in a long distance range over 50 microm. This similarity is explained by an acoustic damping model in which an acoustic wave is generated by the cantilever. Finally, the results indicate a cantilever with a sufficiently long tip compared to the cantilever width can dramatically reduce the long-range damping effect in a liquid environment.


Gonadal dysgenesis with 45,X/46,X,dic(Yp) mosaicism.
A female patient with a gonodal mucinous cystadenoma on the right side and a gonadoblastoma on the left was found to be a 45,X/46,X,dic (Yp) mosaic. This brings the total number of cases with dicentric Y chromosome reported to date to 23. Together with the available evidence, the information derived from this case supports the hypothesis that the gene on the long arm of the Y chromosome is responsible for the initiation of testicular differentiation, whereas that on the short arm is responsible for the maturation of the testes.


Dealing with discounting. An application to the cost-effectiveness of intracoronary thrombolysis with streptokinase.
By introducing discounting in the DEALE method, we reanalyze a recent publication on the cost-effectiveness of early thrombolytic therapy with intracoronary streptokinase after acute myocardial infarction. We show that failure to discount gains in life expectancy results in a serious overestimation of the cost-effectiveness of this technology.


Pregnancy after transcatheter embolization of a uterine arteriovenous malformation.
A 25-year-old woman with a congenital uterine arteriovenous malformation had a long history of repeated excessive vaginal bleeding. She was successfully treated with transarterial embolization. She had normal menstrual periods for 6 months and subsequently conceived. She was delivered of a normally grown baby at 35 weeks. To the best of our knowledge, this is the third pregnancy described after successful embolization of an arteriovenous malformation.


Comparison of bone apatite in osteoporotic and normal Eskimos.
An infrared and x-ray diffraction study of osteoporotic and normal, archaeological Eskimo bones. Osteoporotic bone apatite is greater in crystal size and/or perfection and lower in CO3 than normal bone apatite.


Association of miRNA targetome variants in LAMC1 and GNB3 genes with colorectal cancer and obesity.
Colorectal cancer (CRC) is one of the most common obesity-associated cancers. Inflammation is also considered the most important factor between obesity and CRC. This study aimed to examine miRNAs binding sites variants on inflammatory genes identified using bioinformatics and systematic approach on clinical samples that were collected from CRC patients and controls. The candidate variants related to CRC inflammatory genes were obtained from genome-wide association studies and their population-specific haplotypes. The variants were analyzed according to their genomic position on the miRNA targetome. Targetome variants in inflammation-related genes were selected for genetic association study by TaqMan genotyping assay. The GG genotype of rs7473 decreased the risk of obesity (p < 0.05). Heterozygous genotype (GA) of rs1547715 decreased the risk of CRC (p < 0.05). In the rs7473/rs1547715 genotype and haplotype, the frequencies of AA/GA and GG/AA lessened in CRC and obesity, respectively (p < 0.05). The variants of rs7473 and rs1547715 were associated with obesity and CRC, respectively. The above-mentioned associations could be made based on the interactions of these variants with miRNAs.


Plasma membrane-associated glycohydrolases activation by extracellular acidification due to proton exchangers.
In this paper, we show that the pH optimum for the plasma membrane (PM)-associated activity of four glycohydrolases (conduritol B epoxide sensitive β-glucosidase, β-glucosidase GBA2, β-hexosaminidase and β-galactosidase) measured on intact cells is acidic. Moreover, we show that drugs able to modify the efflux of protons across the PM, thus locally affecting the extracellular proton concentration close to the PM, are able to modulate the activities of these enzymes. These data strongly suggest that pH-dependent modulation of PM-associated glycohydrolases activities could be an effective way to locally modulate the cell surface glycoconjugate composition.


Pharmacogenomic incidental findings in 308 families: The NIH Undiagnosed Diseases Program experience.
Using single-nucleotide polymorphism (SNP) chip and exome sequence data from individuals participating in the National Institutes of Health (NIH) Undiagnosed Diseases Program (UDP), we evaluated the number and therapeutic informativeness of incidental pharmacogenetic variants. Pharmacogenomics Knowledgebase (PharmGKB) annotated sequence variants were identified in 1,101 individuals. Medication records of participants were used to identify individuals prescribed medications with a genetic variant that might alter efficacy. A total of 395 sequence variants, including 19 PharmGKB 1A and 1B variants, were identified in SNP chip sequence data, and 388 variants, including 21 PharmGKB 1A and 1B variants, were identified in the exome sequence data. Nine participants had incidental pharmacogenetic variants associated with altered efficacy of a prescribed medication. Despite the small size of the NIH UDP patient cohort, we identified pharmacogenetic incidental findings potentially useful for guiding therapy. Consequently, groups conducting clinical genomic studies might consider reporting of pharmacogenetic incidental findings.Genet Med 18 12, 1303-1307.


Sensing the position of a single scatterer in an opaque medium by mutual scattering.
We investigate the potential of mutual scattering, i.e., light scattering with multiple properly phased incident beams, as a method to extract structural information from inside an opaque object. In particular, we study how sensitively the displacement of a single scatterer is detected in an optically dense sample of many (up to N = 1000) similar scatterers. By performing exact calculations on ensembles of many point scatterers, we compare the mutual scattering (from two beams) and the well-known differential cross-section (from one beam) in response to the change of location of a single dipole inside a configuration of randomly distributed similar dipoles. Our numerical examples show that mutual scattering provides speckle patterns with an angular sensitivity at least 10 times higher than the traditional one-beam techniques. By studying the "sensitivity" of mutual scattering, we demonstrate the possibility to determine the original depth relative to the incident surface of the displaced dipole in an opaque sample. Furthermore, we show that mutual scattering offers a new approach to determine the complex scattering amplitude.


On the two forms of bacteriorhodopsin.
In our previous work [(1993) FEBS Lett. 313, 248-250; (1993) Biochem. Int. 30, 461-469] M-intermediate formation of wild-type bacteriorhodopsin was shown to involve two components differing in time constants (tau 1 = 60-70 microseconds and tau 2 = 220-250 microseconds), which were suggested to reflect two independent pathways of M-intermediate formation. The contribution of the fast M was 4-times higher than the slow one. Our present research on M-intermediate formation in the D115N bacteriorhodopsin mutant revealed the same components but at a contribution ratio of 1:1. Upon lowering the pH, the slow phase of M-formation vanished at a pK of 6.2, and in the pH region 3.0-5.5 only the M-intermediate with a rise time of 60 microseconds was present. A 5-6 h incubation of D115N bacteriorhodopsin at pH 10.6 resulted in the irreversible transformation of 50% of the protein into a form with a difference absorbance maximum at 460 nm. This form was stable at pH 7.5 and had no photocycle, including M-intermediate formation. The remaining bacteriorhodopsin contained 100% fast M-intermediate. The disappearance of the 250-microseconds phase concomitant with bR460 formation indicates that at neutral pH bacteriorhodopsin exists as two spectroscopically indistinguishable forms.


Recommendations for the treatment of epilepsy in adult patients in general practice in Belgium: an update.
In 2008, a group of Belgian epilepsy experts published recommendations for antiepileptic drug (AED) treatment of epilepsies in adults and children. Selection of compounds was based on the registration and reimbursement status in Belgium, the level of evidence for efficacy, common daily practice and the personal views and experiences of the authors. In November 2011 the validity of these recommendations was reviewed by the same group of Belgian epilepsy experts who contributed to the preparation of the original paper. The recommendations made in 2008 for initial monotherapy in paediatric patients were still considered to be valid, except for the first choice treatment for childhood absence epilepsy. This update therefore focuses on the treatment recommendations for initial monotherapy and add-on treatment in adult patients. Several other relevant aspects of treatment with AEDs are addressed, including considerations for optimal combination of AEDs (rational polytherapy), pharmacokinetic properties, pharmacodynamic and pharmacokinetic interaction profile, adverse effects, comorbidity, treatment of elderly patients, AED treatment during pregnancy, and generic substitution of AEDs.


WITHDRAWN: Stromal Cell-Derived Factor 1 Secreted by Cancer- Associated Fibroblasts Promotes lncRNA Xist through CXCR4 and Facilitates Invasion and Metastasis of Non-Small Cell Lung Cancer
Since the authors are not responding to the editor's requests to fulfill the editorial requirement, therefore, the article has been withdrawn. Bentham Science apologizes to the readers of the journal for any inconvenience this may have caused. The Bentham Editorial Policy on Article Withdrawal can be found at https://benthamscience.com/editorial-policies-main.php. It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.


Delivery of a peptide/microRNA blend via electrospun antimicrobial nanofibres for wound repair.
Downregulation of microRNA-31 (miR-31) and microRNA-132 (miR-132) has been associated with delayed wound healing. Therefore, it was hypothesised that intracellular delivery of miR-31 and miR-132, both as individual and blend formulations, could promote tissue repair. The use of a blend could minimise potential toxicity and achieve synergistic effects, thus maximising the therapeutic effect. miR-31 and miR-132 were condensed with a 30-mer positively charged amphipathic peptide, RALA, to form nanocomplexes with an average size <200 nm and zeta-potential ≥10 designed to facilitate cellular internalisation. This enabled a fold increase in miR-31 and miR-132 expression of ≥100,000 in a murine fibroblast cell line (NCTC-929) and a skin human keratinocyte cell line (HaCaT), with intracellular delivery >70% for individual and blend formulations. Moreover, incubation with the nanocomplexes increased the migration of HaCaT cells ≥25% at 4 and 8 h post-incubation, as well as downregulation of EMP-1 and RASA1 and HB-EGF and RASA1, target genes for miR-31 and miR-132, respectively. Electrospinning was then employed to produce an alginate/polyvinyl alcohol/ciprofloxacin nanofibrous wound patch to facilitate the controlled delivery of the nanocomplexes. Nanofibres were crosslinked with glutaraldehyde to improve stability in aqueous solvents, and they were proven to be biocompatible with antimicrobial activity without cellular attachment to avoid injury upon removal. RALA/miR nanoparticles were incorporated to the nanofibrous wound dressing and in vivo wound healing studies using C57BL/6J mice demonstrated a >60% acceleration in the wound closure rate at Day 7 post-wounding, a ≥1.5 increase in epidermal thickness, and a ≥2 increase in blood vessel count with respect to commercial and untreated controls. Taken together, this data proves that delivery of RALA/miR-31 and RALA/miR-132 from an alginate/polyvinyl alcohol/ciprofloxacin nanofibrous wound dressing constitutes an advanced therapy for wound healing, by accelerating wound closure and improving healed tissue quality. STATEMENT OF SIGNIFICANCE: In this study, we report for the first time the use of the RALA peptide to deliver two miRNA 31 & 132 simultaneously from an electrospun patch. Both miRs have been shown to be downregulated in wounds and this study endeavoured to deliver a blend of the miRs from a nanofibre patch. Electrospinning was used to produce an alginate/polyvinyl alcohol/ciprofloxacin wound patch to enable controlled delivery of the miRs without cellular attachment to the wound with the added benefit of anti-microbial activity. Application of the nanofibre patch loaded with the blended RALA/miR nanoparticles demonstrated a synergistic effect with acceleration of wound closure rate, a significant increase in epidermal thickness and blood vessel count with respect to commercial and untreated controls.


Ars moriendi: Proteases as sculptors of cellular suicide.
The Ars moriendi, which translates to "The Art of Dying," encompasses two Latin texts that gave advice on how to die well and without fear according to the Christian precepts of the late Middle Ages. Given that ten to hundred billion cells die in our bodies every day, it is obvious that the concept of a well and orderly ("regulated") death is also paramount at the cellular level. In apoptosis, as the most well-studied form of regulated cell death, proteases of the caspase family are the central mediators. However, caspases are not the only proteases that act as sculptors of cellular suicide, and therefore, we here provide an overview of the impact of proteases in apoptosis and other forms of regulated cell death.


Congenital cystic adenomatoid malformation of the lung associated with prune belly syndrome.
A case of the rare association of congenital cystic adenomatoid malformation of the lung with prune belly syndrome and brief comments on its pathogenesis is presented.


The ML Cu250; clinical experience in Belgium and The Netherlands.
The ML Cu250, a copper-wired intrauterine contraceptive device, was inserted in 5736 women, at interval or immediately after delivery of the placenta. Forty-eight months after insertion, the data covering 196 214 woman-months were computerized and then analysed according to the life-table method. Interval insertion was more effective than postplacental insertion. In nulligravidas interval insertion did not increase the removal rates for other medical reasons (including pelvic inflammatory disease), but expulsion rates were higher relative to the entire group (a variety of parities).


Oxidant signaling for interleukin-13 gene expression in lung smooth muscle cells.
The growth of airway and vascular smooth muscle cells occurs in various lung diseases including asthma, chronic obstructive pulmonary disease, bronchopulmonary dysplasia, lymphangioleiomyomatosis, and pulmonary hypertension. Although inflammatory responses are critical in these diseases, the relationship between smooth muscle cell growth and inflammatory mediators is poorly understood. This study demonstrates that platelet-derived growth factor (PDGF) promotes the expression of interleukin-13 (IL-13) in lung smooth muscle cells through an oxidant signaling mechanism. Treatment of cultured human airway or pulmonary vascular smooth muscle cells with PDGF promotes IL-13 mRNA and protein expression. IL-13 expression is also detected in smooth muscle of airways and pulmonary vessels in allergen-stimulated mice. PDGF activates the proximal 980-bp region of the IL-13 promoter. PDGF-induced IL-13 expression is suppressed by the inhibition of reactive oxygen species signaling such as by NAD(P)H oxidase inhibition, reactive oxygen species scavenging, and metal chelation. Treatment of cells with hydrogen peroxide at as low as 1 μM also promotes IL-13 gene expression. PDGF-induced cell growth is suppressed by the neutralizing antibody against IL-13 as well as by reactive oxygen inhibitors, and recombinant IL-13 promotes the growth of airway smooth muscle cells. These results demonstrate that oxidant signaling activates IL-13 gene transcription in lung smooth muscle cells and that this signaling mechanism regulates cell growth.


Correction: Investigation of a Measles Outbreak in China to Identify Gaps in Vaccination Coverage, Routes of Transmission, and Interventions.
[This corrects the article DOI: 10.1371/journal.pone.0133983.].


A human homologue of the checkpoint kinase Cds1 directly inhibits Cdc25 phosphatase.
In human cells, the mitosis-inducing kinase Cdc2 is inhibited by phosphorylation on Thr14 and Tyr15. Disruption of these phosphorylation sites abrogates checkpoint-mediated regulation of Cdc2 and renders cells highly sensitive to agents that damage DNA. Phosphorylation of these sites is controlled by the opposing activities of the Wee1/Myt1 kinases and the Cdc25 phosphatase. The regulation of these enzymes is therefore likely to be crucial for the operation of the G2-M DNA-damage checkpoint. Here, we show that the activity of Cdc25 decreased following exposure to ionizing radiation. The irradiation-induced decrease in Cdc25 activity was suppressed by wortmannin, an inhibitor of phosphatidylinositol (PI) 3-kinases, and was dependent on the function of the gene that is mutated in ataxia telangiectasia. We also identified two human kinases that phosphorylate and inactivate Cdc25 in vitro. One is the previously characterized Chk1 kinase. The second is novel and is homologous to the Cds1/Rad53 family of checkpoint kinases in yeast. Human Cds1 was found to be activated in response to DNA damage. These results suggest that, in human cells, the DNA-damage checkpoint involves direct inactivation of Cdc25 catalyzed by Cds1 and/or Chk1.


A simple procedure for surgical repair of vocal cord synechia.
With a simple method performed since 1962 on six patients for the correction of anterior vocal cord synechia, a paladon granule reinforced with a thread is brought into the larynx from outside after severance of the synechia. With convalescent treatment of the cartilaginous frame, it lies in the anterior commissure for 6 weeks. After endoscopic removal, free glottis and good voice. Tracheotomy is not necessary.


Biosynthesis of a rosavin natural product in Escherichia coli by glycosyltransferase rational design and artificial pathway construction.
Phytochemicals are rich resources for pharmaceutical and nutraceutical agents. A key challenge of accessing these precious compounds can present significant bottlenecks for development. The cinnamyl alcohol disaccharides also known as rosavins are the major bioactive ingredients of the notable medicinal plant Rhodiola rosea L. Cinnamyl-(6'-O-β-xylopyranosyl)-O-β-glucopyranoside (rosavin E) is a natural rosavin analogue with the arabinopyranose unit being replaced by its diastereomer xylose, which was only isolated in minute quantity from R. rosea. Herein, we described the de novo production of rosavin E in Escherichia coli. The 1,6-glucosyltransferase CaUGT3 was engineered into a xylosyltransferase converting cinnamyl alcohol monoglucoside (rosin) into rosavin E by replacing the residue T145 with valine. The enzyme activity was further elevated 2.9 times by adding the mutation N375Q. The synthesis of rosavin E from glucose was achieved with a titer of 92.9 mg/L by combining the variant CaUGT3T145V/N375Q, the UDP-xylose synthase from Sinorhizobium meliloti 1021 (SmUXS) and enzymes for rosin biosynthesis into a phenylalanine overproducing E. coli strain. The production of rosavin E was further elevated by co-overexpressing UDP-xylose synthase from Arabidopsis thaliana (AtUXS3) and SmUXS, and the titer in a 5 L bioreactor with fed-batch fermentation reached 782.0 mg/L. This work represents an excellent example of producing a natural product with a disaccharide chain by glycosyltransferase engineering and artificial pathway construction.


Evidence for uptake and synthesis of 5-hydroxytryptamine by a subpopulation of intrinsic neurons in the guinea-pig heart.
Using an indirect immunofluorescence technique, a subpopulation of 5-hydroxytryptamine-like immunoreactive neurons was observed in cell cultures dissociated from the atria and interatrial septum of newborn guinea-pig heart maintained in fetal calf serum-supplemented medium. 5-Hydroxytryptamine has not been demonstrated in intracardiac neurons in situ, and since 5-hydroxytryptamine has been previously shown to be a constituent of fetal calf serum, the 5-hydroxytryptamine-like immunoreactivity seen in culture may have been the result of neuronal uptake of 5-hydroxytryptamine from the growth medium. This was examined by growing the cultures in a serum-free, hormone-supplemented, defined medium. Under these conditions, 5-hydroxytryptamine-like immunoreactive neurons were not present. When cultures were grown in hormone-supplemented, defined medium containing 10(-4) to 10(-6) M 5-hydroxytryptamine, some intracardiac neurons accumulated 5-hydroxytryptamine. This type of neuron also developed 5-hydroxytryptamine-like immunoreactivity after incubation with 5 X 10(-5) M 5-hydroxytryptophan, indicating that the subpopulation of intracardiac neurons which can take up exogenous 5-hydroxytryptamine can also synthesize it from 5-hydroxytryptophan. However, no 5-hydroxytryptamine-like immunoreactive neurons were observed after incubation with L-tryptophan, the other 5-hydroxytryptamine precursor molecule. Under all of the conditions described, some small, 5-hydroxytryptamine-like immunofluorescent cells, very similar to the catecholamine-containing, small intensely fluorescent cells of the heart, were observed in culture. Bright, 5-hydroxytryptamine-like immunoreactive endothelial cells were seen only in cultures maintained in defined medium and loaded with 5-hydroxytryptamine. The present study shows that some intracardiac neurons are amine-handling, and also raises the possibility that 5-hydroxytryptamine is utilized as a neurotransmitter or neuromodulator by these neurons in the mammalian heart. Further, there is evidence to suggest that two populations of small intensely fluorescent cells, one containing 5-hydroxytryptamine, the other a catecholamine, are present in the heart; and to indicate that atrial endothelial cells can take up 5-hydroxytryptamine.


Prevalence and incidence of injuries in para athletes: a systematic review with meta-analysis and GRADE recommendations.
To investigate prevalence, incidence and profile of musculoskeletal injuries in para athletes. Systematic review. Searches were conducted in MEDLINE, EMBASE, AMED, SPORTSDiscus, CINAHL and hand searching. Studies were considered if they reported prevalence or incidence of musculoskeletal injuries in para athletes. Study selection, data extraction and analysis followed the protocol. Meta-analyses were conducted to estimate the prevalence and incidence rate among studies and subgroup analyses investigated whether methodological quality and sample size of the studies influenced on the estimated injury prevalence and incidence. The Grading of Recommendations Assessment, Development and Evaluation system determined the strength of evidence. Forty-two studies were included. The prevalence of musculoskeletal injuries was 40.8% (95% CI 32.5% to 49.8%). Because of imprecision, indirectness and inconsistency, the strength of evidence was very low quality. The incidence of musculoskeletal injuries was 14.3 injuries per 1000 athlete-days (95% CI 11.9 to 16.8). The strength of evidence was low quality because of imprecision and indirectness. The subgroup analyses revealed that the sample size influenced on estimated injury prevalence and methodological quality influenced on estimated incidence. Injuries were more prevalent in the shoulder, for non-ambulant para athletes, and in the lower limbs, for ambulant para athletes. Para athletes show high prevalence and incidence of musculoskeletal injuries. Current very low-quality and low-quality evidence suggests that future high-quality studies with systematic data collection, larger sample size and specificities of para athletes are likely to change estimates of injury prevalence and incidence in para athletes. CRD42020147982.


[Modulation of Renshaw cell activity during scratching].
The activity of the Renshaw cells was recorded during fictitious scratching in 7 decerebrated and 1 spinal curarized cats. The flexor and extensor Renshaw cells were identified according to the responses induced by orthodromic stimulation of muscle nerves. Before the beginning of rhythmical oscillations, the background activity of the flexor Renshaw cells was inhibited. When the rhythmical generation began, both flexor and and extensor cells generated short bursts of spikes at the end of the flexor phase and at the extensor phase of the cycle. The activity of flexor cells began and terminated earlier in the cycle than that of the extensor cells. The results show that the flexor Renshaw cells are active reciprocally with flexor motoneurons, while the extensor cells are coactivated with extensor motoneurons.


Mastectomy with Reconstruction Including Robotic Endoscopic Surgery (MARRES): a prospective cohort study of the Korea Robot-Endoscopy Minimal Access Breast Surgery Study Group (KoREa-BSG) and Korean Breast Cancer Study Group (KBCSG).
Robotic nipple-sparing mastectomy (RNSM) has emerged as a new treatment option for breast cancer and risk-reducing mastectomy (RRM) for women who have a high risk of pathogenic variants. Even though several studies have reported that RNSM is a feasible procedure, some argue that it should only be performed by specialized surgeons, and data on oncologic outcomes and patient-reported outcomes (PROs) are limited. Recently, the United States Food and Drug Administration and several surgeons warned that robotic breast surgery should be performed only by specialized surgeons and recommended that the benefits, risks, and alternatives of all available treatment options be discussed with patients so they can make informed treatment decisions. The Korea Robot-Endoscopy Minimal Access Breast Surgery Study Group (KoREa-BSG) has been established to evaluate, standardize, and teach this state-of-the-art procedure. We have designed a multicenter prospective cohort study entitled Mastectomy with Reconstruction Including Robot Endoscopic Surgery (MARRES) to report surgical, PRO, and oncologic outcomes. MARRES is a multi-institution cohort study prospectively collecting data from patients undergoing mastectomy and reconstruction. The patient inclusion criteria are adult women older than 19 with breast cancer or a high risk of breast cancer (patients with BRCA1/2, TP53, PALB2 mutations, etc.), who have scheduled therapeutic or RRM and want immediate reconstruction. Surgical outcomes, including pre- and postoperative photos, oncologic outcomes, cost-effectiveness, and PRO, are collected. The primary endpoints are postoperative complication rates within 30 postoperative days and the Clavien-Dindo grade of postoperative complications within 180 postoperative days. The secondary endpoints are 5-year postoperative recurrence-free survival and cancer incidence rate (for those who underwent RRM), patient satisfaction with reconstruction expectations preoperative (baseline) and results within 6 to 12 postoperative months, surgeon satisfaction with postoperative results in 6 postoperative months, and cost-effectiveness of the definitive surgery. Patient recruitment will be completed in April 2025, and the target number of enrolled patients is 2000. This study will provide evidence about the surgical outcomes, oncologic outcomes, and patient satisfaction with RNSM and endoscopic nipple-sparing mastectomy (NSM), compared with conventional NSM. ClinicalTrials.gov Identifier NCT04585074. Registered April 8, 2020.


Cell by cell immuno- and cancer marker profiling of non-small cell lung cancer tissue: Checkpoint marker expression on CD103+, CD4+ T-cells predicts circulating tumor cells.
Non-small cell lung cancer (NSCLC) has a poor prognosis. Targeted therapy and immunotherapy in recent years has significantly improved NSCLC patient outcome. In this study, we employed cell-by-cell immune and cancer marker profiling of the primary tumor cells to investigate possible signatures that might predict the presence or absence of circulating tumor cells (CTCs). We performed a comprehensive study on 10 NSCLC patient tissue samples with paired blood samples. The solid tissue biopsy samples were dissociated into single cells by non-enzymatic tissue homogenization and stained with a total 25 immune, cancer markers and DNA content dye and analyzed with high-parameter flow cytometry. CTCs were isolated and analyzed from the paired peripheral blood. We investigated a total of 74 biomarkers for their correlation with CTC number. Strong correlations were observed between CTC number and the frequency of immune checkpoint marker expressing lymphocytes (CTLA-4, LAG3, TIM3, PD-1), within the CD103+CD4+ T lymphocyte subset. CTC number is also correlated with the frequency of PD-L1 expressing cancer cells and cancer cell DNA content. In contrast, CTC number inversely correlated to the frequency of CD44+E-cadherin- cancer cells. Unsupervised clustering analysis based on the biomarker analysis separated the CTC negative patients from the CTC positive patients. Profiling multiple immune and cancer markers on cancer samples with multi-parametric flow cytometry allowed us to obtain protein expression information at the single cell level. Clustering analysis of the proteomic data revealed a signature driven by checkpoint marker expression on CD103+CD4+ T cells that could potentially be predictive of CTCs and targets of therapy.


Id family of helix-loop-helix proteins in cancer.
Over the past few decades, biologists have identified key molecular signatures associated with a wide range of human cancers. Recently, animal models have been particularly useful in establishing whether such signatures have functional relevance; the overexpression of pro-oncogenic or loss of anti-oncogenic factors have been evaluated for their effects on various tumour models. The aim of this review is to analyze the potential role of the inhibitor of DNA binding (Id) proteins in cancer and examine whether deregulated Id activity is tumorigenic and contributes to hallmarks of malignancy, such as loss of differentiation (anaplasia), unrestricted proliferation and neoangiogenesis.


Therapeutic intervention based on circulating tumor cell phenotype in metastatic breast cancer: concept of the DETECT study program.
The aim of the ongoing DETECT study program is to evaluate therapeutic intervention based on phenotypes of circulating tumor cells (CTC) in patients with metastatic breast cancer (MBC). Currently (as of July 2015) more than half of the projected about 2000 patients with MBC have already been screened for CTC. Women with HER2-negative primary tumor and presence of CTC are recruited into different DETECT trials according to the HER2-phenotype of CTC. Patients with HER2-positive CTC are randomized to treatment with physicians' choice therapy (standard chemo- or endocrine therapy) with or without additional HER2-targeted therapy with lapatinib in the DETECT III trial. In DETECT IVa, postmenopausal patients with hormone-receptor positive primary cancer and HER2-negative CTC receive everolimus and standard endocrine therapy. For women with HER2-negative CTC and triple negative MBC or hormone-receptor positive tumor and indication for chemotherapy, a treatment with eribulin is offered (DETECT IVb). The clinical efficacy is investigated by CTC-Clearance and progression-free survival (PFS). The DETECT V/CHEVENDO trial extends the DETECT study program for women with HER2-positive and hormone-receptor positive MBC. The primary objective of this trial is to compare safety and quality of life (QoL) as assessed by the occurrence of adverse events in patients treated with dual (trastuzumab plus pertuzumab) HER2-targeted therapy plus either endocrine or chemotherapy. The translational research projects of the DETECT study program focus on further molecular characterization of CTC and evaluation of markers for their suitability to predict treatment response and to facilitate the development of more personalized treatment options.


PPARβ/δ, a Novel Regulator for Vascular Smooth Muscle Cells Phenotypic Modulation and Vascular Remodeling after Subarachnoid Hemorrhage in Rats.
Cerebral vascular smooth muscle cell (VSMC) phenotypic switch is involved in the pathophysiology of vascular injury after aneurysmal subarachnoid hemorrhage (aSAH), whereas the molecular mechanism underlying it remains largely speculative. Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) has been implicated to modulate the vascular cells proliferation and vascular homeostasis. In the present study, we investigated the potential role of PPARβ/δ in VSMC phenotypic switch following SAH. Activation of PPARβ/δ by GW0742 and adenoviruses PPARβ/δ (Ad-PPARβ/δ) significantly inhibited hemoglobin-induced VSMC phenotypic switch. However, the effects of PPARβ/δ on VSMC phenotypic switch were partly obstacled in the presence of LY294002, a potent inhibitor of Phosphatidyl-Inositol-3 Kinase-AKT (PI3K/AKT). Furthermore, following study demonstrated that PPARβ/δ-induced PI3K/AKT activation can also contribute to Serum Response Factor (SRF) nucleus localization and Myocardin expression, which was highly associated with VSMC phenotypic switch. Finally, we found that Ad-PPARβ/δ positively modulated vascular remodeling in SAH rats, i.e. the diameter of basilar artery and the thickness of vessel wall. In addition, overexpression of PPARβ/δ by adenoviruses significantly improved neurological outcome. Taken together, this study identified PPARβ/δ as a useful regulator for VSMC phenotypic switch and vascular remodeling following SAH, providing novel insights into the therapeutic strategies of delayed cerebral ischemia.


Contribution of reactive oxygen species to thymineless death in Escherichia coli.
Nutrient starvation usually halts cell growth rather than causing death. Thymine starvation is exceptional, because it kills cells rapidly. This phenomenon, called thymineless death (TLD), underlies the action of several antibacterial, antimalarial, anticancer, and immunomodulatory agents. Many explanations for TLD have been advanced, with recent efforts focused on recombination proteins and replication origin (oriC) degradation. Because current proposals account for only part of TLD and because reactive oxygen species (ROS) are implicated in bacterial death due to other forms of harsh stress, we investigated the possible involvement of ROS in TLD. Here, we show that thymine starvation leads to accumulation of both single-stranded DNA regions and intracellular ROS, and interference with either event protects bacteria from double-stranded DNA breakage and TLD. Elevated levels of single-stranded DNA were necessary but insufficient for TLD, whereas reduction of ROS to background levels largely abolished TLD. We conclude that ROS contribute to TLD by converting single-stranded DNA lesions into double-stranded DNA breaks. Participation of ROS in the terminal phases of TLD provides a specific example of how ROS contribute to stress-mediated bacterial self-destruction.


Amikacin Pharmacokinetics in Terminal Stage of Hematological Malignancy.
The influence of cancer cachexia on the pharmacokinetics of and kidney injury caused by amikacin remains unclear. This study investigated whether the pharmacokinetics of amikacin and the risk of kidney injury are altered with the progression of cancer cachexia. A retrospective analysis was conducted using therapeutic drug monitoring data obtained from 52 cancer patients who received amikacin intravenously for infection(s). The patients were classified into 2 groups based on the status of cachexia using a consensus definition: noncachexia group (n = 31) and cachexia group (n = 21). Differences in amikacin pharmacokinetics and occurrence of kidney injury were compared between the 2 groups. Amikacin pharmacokinetics was calculated based on a 1-compartment model using peak and trough concentrations measured clinically for therapeutic drug monitoring. In addition, intrapatient analysis was conducted based on patients who received amikacin treatments more than once during the study period to examine the alteration in amikacin pharmacokinetics with the progression of cancer cachexia. Systemic clearance of amikacin [median (range)] was significantly (P < 0.05) lower in the cachexia group [37.3 (11.2-87.3) (mL/min)] than in the noncachexia group [52.0 (19.1-133.4) (mL/min)]. In contrast, volume of distribution was significantly (P < 0.05) increased in the cachexia group [0.47 (0.20-1.45) L/kg] compared with the noncachexia group [0.32 (0.21-1.00) L/kg]. There was no difference in the occurrence of kidney injuries between the 2 groups. In an intrapatient analysis of the longitudinal alteration of amikacin pharmacokinetics, an approximately 50% reduction in clearance and 30% increase in volume of distribution were observed as cancer cachexia progressed. The present study suggests that progression of cancer cachexia may reduce amikacin clearance and increase the volume of distribution, but cancer cachexia does not increase amikacin-induced kidney injury.


The effect of sleep fragmentation on sleep and performance in younger and older subjects.
Groups of 12 normal 55-70-year-old and young adult subjects had their sleep experimentally disturbed at a rate of approximately 14 times per hour to determine the residual effects of moderate sleep disturbance and to determine any differential impact as a function of age. Normal age-related changes in sleep were seen on baseline and recovery nights. In the second night of sleep disturbance, the older subjects had a smaller increase in total awakenings than young adults. Older subjects had a slower increase in auditory arousal threshold as sleep disturbance progressed. The older subjects also tended to have less performance deterioration on morning testing than did young adults, and this difference was significant for numbers of correctly completed addition problems. These evidences led to the conclusion that, while both age groups were sensitive to moderate sleep disturbance, the older individuals appeared somewhat less sensitive than the young adults.


Simvastatin (MK-733): a potent cholesterol synthesis inhibitor in heterozygous familial hypercholesterolaemia.
Simvastatin (MK-733), a new inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, was administered to 38 patients with heterozygous familial hypercholesterolaemia for 24 weeks. A dose of 40 mg per day produced a mean reduction in low density lipoprotein cholesterol of 43-45% and in triglycerides of 21-31%. Mean high density lipoprotein cholesterol increased significantly by 10-13%. There were no major differences in response whether the drug was taken in one or two doses. MK-733 was tolerated well. Adverse effects were infrequent and limited to slight increases of alanine aminotransferase, creatine phosphokinase and bilirubin. This drug appears to be a potent inhibitor of cholesterol synthesis and has produced the largest therapeutic response as monotherapy in patients with familial hypercholesterolaemia.


Biochemical and biophysical characterization of purified thermophilic xylanase isoforms in Cereus pterogonus plant spp.
Two thermostable xylanase isoforms T₆₀ and T₈₀ were purified to homogeneity from the cladodes of the xerophytic Cereus pterogonus plant species. After three consecutive purification steps, the specific activity of T₆₀ and T₈₀ isoforms were found to be 178.6 and 216.2 U mg⁻¹ respectively. The molecular mass of both isoforms was determined to be 80 kDa. The optimum temperature for T₆₀ and T₈₀ xylanase isoforms were 60 and 80 °C respectively. The pH was 5.0 for both isoforms. The presence of divalent metal ions (10 mM Co²⁺) showed stimulatory effects of both catalytic activities, where as in the presence of Hg²⁺, Cd²⁺, Cu²⁺ showed inhibitory effect on these activities at all concentrations studied. The thermodynamic analysis of xylanase activity using denaturation kinetics and the presence divalent cations at 30-100 °C, showed lower ΔH, ΔS, and ΔG values at all the temperatures investigated. The melting temperature of purified T₈₀ xylanase isoform as determined by TG/DTA analysis and it showed the unfolding temperature was 80 °C. The g value and hyperfine (A) value purified xylanase T₈₀ isoform was 2.017 and 10.80 respectively. Immunoblot analysis with antiserum raised against the purified T₈₀ xylanase isoforms revealed single immunolgically related polypeptides of 80 kDa, identical with the polypeptide band produced on SDS-PAGE. The results of double immunodiffusion against the T₈₀ isoforms showed a single precipitin line indicating that the serum used was specific to these xylanase isoforms. The kinetic and thermodynamic properties suggested that xylanase from C. pterogonus may have a potential usage in various industries.


The Domestic Isolation of Terbinafine- and Itraconazole-Resistant Trichophyton indotineae in Chinese Mainland.
Trichophyton indotineae, a new species of dermatophytes, has become a significant concern in treating dermatophytosis due to the high level of terbinafine resistance reported in India and even worldwide. This study aimed to report the terbinafine- and itraconazole-resistant T. indotineae in Chinese mainland, by identifying the phylogenetic classification of the isolate strain, and detecting the drug resistance, gene mutation and expression. The skin scales of the patient were cultured on SDA and the isolate was authenticated by DNA sequencing and MALDI-TOF MS. Antifungal susceptibility testing was performed following the M38-A2 CLSI protocol to examine the MICs values of terbinafine, itraconazole, fluconazole, etc. The strain was screened for mutations in the squalene epoxidase (SQLE) gene by Sanger sequencing and detected the expression of CYP51A and CYP51B by qRT-PCR. A multi-resistant ITS genotype VIII sibling of the T. mentagrophytes complex (T. indotineae) was isolated in Chinese mainland. The strain harbored high terbinafine MIC of > 32 μg/mL and itraconazole MIC of 1.0 μg/mL, which was identified a mutation in the squalene epoxidase gene with amino acid substitution (Phe397Leu, mutation 1191C > A). In addition, overexpression of CYP51A and CYP51B was observed. With multiple relapses, the patient finally achieved clinical cure by itraconazole pulse therapy and topical clotrimazole cream for 5 weeks. The first domestic strain of terbinafine- and itraconazole-resistant T. indotineae from a patient in Chinese mainland was isolated. Itraconazole pulse therapy can be an effective method for the treatment of T. indotineae.


Inert gas enhancement of superoxide radical production.
Two free radical generating systems, xanthine oxidase/hypoxanthine or phenazine methosulfate/NADH, were exposed to air plus He, N2, or Ar at partial pressures ranging from 0.2 to 6.0 MPa, and the rates of production of superoxide, hydroxyl, singlet O2, and H2O2 were measured. All three inert gases acted similarly to enhance the production of superoxide radicals by facilitating interactions between iron and H2O2, or O2 and organic radicals. These reactions occurred at quite low gas partial pressures, only 0.28 MPa, and hydrostatic pressures of up to 6.0 MPa had no effect on radical reactions. Enhanced radical production may be the basis for the inhibition of cellular growth mediated by inert gases, and inert gas enhancement of O2 toxicity.


Dysnatremias and survival in adult burn patients: a retrospective analysis.
Dysnatremias have been evaluated in many populations and have been found to be significantly associated with mortality. However, this relationship has not been well described in the burn population. Admissions to the burn center at our institution from January 2003 to December 2008 were examined. Independent variables included gender, age, percentage total body surface area burned (%TBSA), percentage of third-degree burn, inhalation injury, injury severity score (ISS), Acute Kidney Injury Network (AKIN) stage, hypernatremia, and hyponatremia. They were examined via Cox proportional hazard regression models against death. Moderate to severe hypo- and hypernatremia were defined as serum sodium <130 and >150 mmol/l, respectively. In 1,969 subjects with a mean age of 36.3 ± 16.4 years, a median %TBSA of 9 (interquartile range 4-20) and a median ISS of 5 (interquartile range 1-16) hypernatremia occurred in 9.9% (n = 194), while hyponatremia occurred in 6.8% (n = 134) with mortality rates of 33.5 and 13.8%, respectively. Patients without a dysnatremia had a mortality rate of 4.3%. On Cox proportional hazard regression age, %TBSA, ISS, and AKIN stage were found to be significant predictors of mortality. Hypernatremia (HR 2.00, 95% CI 1.212-3.31; p = 0.0066), but not hyponatremia (HR 1.72, 95% CI 0.89-3.34; p = 0.1068) was associated with mortality. In the burn population, hypernatremia, but not hyponatremia, is an independent predictor of mortality.


Multivariate sea storm hindcasting and design: the isotropic buoy-ungauged generator procedure.
The present work provides indications for assessment of wave climate and design of structures at sea at ungauged sites, both critical issues in Ocean sciences. The paper is of methodological nature and of global worldwide applicability. It shows how suitable wave hindcasting relations can be exploited in order to provide sea storm scenarios at an ungauged (Target) location useful for design purposes: in particular, only geographical information and the knowledge of another gauged (Source) buoy are used. Several are the novelties introduced. (i) New hindcasting relations are derived. (ii) A full statistical model is set up for the Target area, whereas traditional hindcasting simply transfers time series from a gauged to an ungauged site: this gives the possibility to appropriately deal with design and hazard assessment at the Target location. (iii) The multivariate behavior of non-independent random variables is properly modelled by using the Theory of Copulas. As an illustration, a number of case studies is investigated, involving four pairs of buoys which, given their positions and exposures, are representative of a wide variety of sea states and conditions, as well as of different wave generation mechanisms.


Pancreatic cancer in the remnant pancreas following primary pancreatic resection.
To clarify the clinical features of cancer in the pancreatic remnant. We retrospectively reviewed the clinical and pathological findings of 10 patients who developed remnant pancreatic cancer in our hospital between 2002 and 2012. The KRAS sequences in both the initial pancreatic tumor and remnant pancreatic cancer were examined in two patients. Eight patients underwent a second pancreatectomy for remnant pancreatic cancer (resected group), while two patients were not operated on and underwent chemotherapy (unresected group). The remnant pancreatic cancer developed at the cut end of the pancreas (pancreaticogastrostomy site) in four patients. In the resected group, four patients died 17 months after the emergence of the remnant pancreatic cancer and four patients survived during the median 40.5-month observation period. The median survival of the unresected group after the emergence of the remnant pancreatic cancer was 10 months. The findings of the KRAS sequencing and immunohistological staining of the remnant pancreatic cancer for MUC1 and MUC2 in the two patients were consistent with those of the initial pancreatic tumor in one patient, and not consistent in the other. Our results suggest that both local recurrence and a new primary cancer can develop in the pancreatic remnant, and repeated pancreatectomy can prolong survival.


Microarray analysis reveals increased expression of ΔNp63α in seborrhoeic keratosis.
Seborrhoeic keratoses (SKs) are very common benign epidermal lesions without malignant potential. Ultraviolet radiation, old age and viruses are well-known risk factors for disease development. However, the pathomechanisms of SK are not fully understood. To detect and characterize the genes that are involved in the pathogenesis of SK. We performed a gene expression study using paired lesional and nonlesional skin samples from patients with SK. We identified and validated 19 differentially expressed genes in SK. Of these 19 genes, we focused on p63 transcription factor, which plays a pivotal role in epidermal development by regulating its transcriptional programme. We found by immunofluorescence that the expression of ΔNp63α, the most abundantly expressed p63 isoform, was significantly increased in SK as compared with normal skin. Moreover, siRNA-mediated knockdown of ΔNp63 led to the downregulation of 11 genes, including a member of the tensin family TNS4. Chromatin immunoprecipitation assay revealed that TNS4 was a target gene of p63. We identified upregulated genes in SK using genome-wide cDNA microarray and elucidated the functional contribution of p63 to the disease transcriptome by gene-silencing assay. Taken together, these data may provide a novel insight into the molecular basis of these benign skin lesions.


Guardians of the Living Water: Using a Health Literacy Framework to Evaluate a Child as Change Agent Intervention.
American Indian communities in the United States experience considerable health inequities, including increased exposure to environmental contaminants. Consequently, community members of the Apsáalooke (Crow) Nation identified the lack of water-related environmental knowledge among children as an area of concern. The purpose of this study was to provide a feasibility evaluation of an increasingly sophisticated environmental health literacy program for children. A community-academic partnership developed and piloted the Guardians of the Living Water program to increase environmental health literacy among children and their families on the Crow reservation. Nutbeam's framework for health literacy, a schema based on functional, interactive, and critical literacy, shaped the program evaluation. We used a within-subjects, quasi-experimental design without a control group. Interviews with children and parents were used to assess the feasibility of the program, while pre-/posttests assessed changes in knowledge, skills, and behavior. Compared with preintervention responses, those from postintervention indicated significant increases for selected knowledge and attitude components. Based on qualitative interviews with children and caregivers, the camp was a valuable experience and increased knowledge of water quality science and reinforced cultural knowledge. This success of our program stems from the trust initially built between partners and then expanded throughout the community. The program and the evaluation benefited from both the health literacy framework and from our integration of Apsáalooke values. Our findings suggest that a community-based intervention designed to increase environmental health literacy among youth and their social networks is feasible and acceptable to this American Indian community.