Cholemic Nephropathy Causes Acute Kidney Injury and Is Accompanied by Loss of Aquaporin 2 in Collecting Ducts.
Impairment of renal function often occurs in patients with liver disease. Hepatorenal syndrome is a significant cause of acute kidney injury (AKI) in patients with cirrhosis (HRS-AKI, type 1). Causes of non-HRS-AKI include cholemic nephropathy (CN), a disease that is characterized by intratubular bile casts and tubular injury. As data on patients with CN are obtained primarily from case reports or autopsy studies, we aimed to investigate the frequency and clinical course of CN. We identified 149 patients who underwent kidney biopsy between 2000 and 2016 at the Department of Gastroenterology, Hepatology and Endocrinology at Hannover Medical School. Of these, 79 had a history of liver disease and deterioration of renal function. When applying recent European Association for the Study of the Liver criteria, 45 of 79 patients (57%) presented with AKI, whereas 34 patients (43%) had chronic kidney disease (CKD). Renal biopsy revealed the diagnosis of CN in 8 of 45 patients with AKI (17.8%), whereas none of the patients with CKD was diagnosed with CN. Univariate analysis identified serum bilirubin, alkaline phosphatase, and urinary bilirubin and urobilinogen as predictive factors for the diagnosis of CN. Histological analysis of AKI patients with normal bilirubin, elevated bilirubin, and the diagnosis of CN revealed loss of aquaporin 2 (AQP2) expression in collecting ducts in patients with elevated bilirubin and CN. Biopsy-related complications requiring medical intervention occurred in 4 of 79 patients (5.1%). Conclusion: CN is a common finding in patients with liver disease, AKI, and highly elevated bilirubin. Loss of AQP2 in AKI patients with elevated bilirubin and CN might be the result of toxic effects of cholestasis and in part be responsible for the impairment of renal function.


Comparative and phylogenetic analyses of Swertia L. (Gentianaceae) medicinal plants (from Qinghai, China) based on complete chloroplast genomes.
Swertia L. is a large genus in Swertiinae (Gentianaceae). In China, many Swertia species are used as traditional Tibetan medicines, known as "Zangyinchen" or "Dida". However, the phylogenetic relationships among Swertia medicinal plants and their wild relatives have remained unclear. In this study, we sequenced and assembled 16 complete chloroplast (cp) genomes of 10 Swertia species, mainly distributed in Qinghai Province, China. The results showed that these species have typical structures and characteristics of plant cp genomes. The sizes of Swertia cp genomes are ranging from 149,488 bp to 154,097 bp. Most Swertia cp genomes presented 134 genes, including 85 protein coding genes, eight rRNA genes, 37 tRNA genes, and four pseudogenes. Furthermore, the GC contents and boundaries of cp genomes are similar among Swertia species. The phylogenetic analyses indicated that Swertia is a complex polyphyletic group. In addition, positive selection was found in psaI and petL genes, indicating the possible adaptation of Qinghai Swertia species to the light environment of the Qinghai-Tibet plateau. These new cp genome data could be further investigated to develop DNA barcodes for Swertia medicinal plants and for additional systematic studies of Swertia and Swertiinae species.


Screening for oral cancer and precancer--a valuable new technique.
Many precancerous or cancerous oral lesions may resemble benign lesions and a definitive diagnosis on clinical grounds alone may be difficult, if not impossible, to make. The introduction of OralCDx, an oral brush biopsy procedure, permits the dental practitioner to determine which lesions contain atypical or dysplastic epithelial cells and require that a conventional scalpel biopsy be performed. This article reviews the features of the test, explains the clinical situations for which its use is recommended, and discusses the interpretation and significance of the biopsy reports.


Cortical Acetylcholine Levels Correlate With Neurophysiologic Complexity During Subanesthetic Ketamine and Nitrous Oxide Exposure in Rats.
Neurophysiologic complexity has been shown to decrease during states characterized by a depressed level of consciousness, such as sleep or anesthesia. Conversely, neurophysiologic complexity is increased during exposure to serotonergic psychedelics or subanesthetic doses of dissociative anesthetics. However, the neurochemical substrates underlying changes in neurophysiologic complexity are poorly characterized. Cortical acetylcholine appears to relate to cortical activation and changes in states of consciousness, but the relationship between cortical acetylcholine and complexity has not been formally studied. We addressed this gap by analyzing simultaneous changes in cortical acetylcholine (prefrontal and parietal) and neurophysiologic complexity before, during, and after subanesthetic ketamine (10 mg/kg/h) or 50% nitrous oxide. Under isoflurane anesthesia, adult Sprague Dawley rats (n = 24, 12 male and 12 female) were implanted with stainless-steel electrodes across the cortex to record monopolar electroencephalogram (0.5-175 Hz; 30 channels) and guide canulae in prefrontal and parietal cortices for local microdialysis quantification of acetylcholine levels. One subgroup of these rats was instrumented with a chronic catheter in jugular vein for ketamine infusion (n = 12, 6 male and 6 female). The electroencephalographic data were analyzed to determine subanesthetic ketamine or nitrous oxide-induced changes in Lempel-Ziv complexity and directed frontoparietal connectivity. Changes in complexity and connectivity were analyzed for correlation with concurrent changes in prefrontal and parietal acetylcholine. Subanesthetic ketamine produced sustained increases in normalized Lempel-Ziv complexity (0.5-175 Hz; P < .001) and high gamma frontoparietal connectivity (125-175 Hz; P < .001). This was accompanied by progressive increases in prefrontal (104%; P < .001) and parietal (159%; P < .001) acetylcholine levels that peaked after 50 minutes of infusion. Nitrous oxide induction produced a transient increase in complexity (P < .05) and high gamma connectivity (P < .001), which was accompanied by increases (P < .001) in prefrontal (56%) and parietal (43%) acetylcholine levels. In contrast, the final 50 minutes of nitrous oxide administration were characterized by a decrease in prefrontal (38%; P < .001) and parietal (45%; P < .001) acetylcholine levels, reduced complexity (P < .001), and comparatively weaker frontoparietal high gamma connectivity (P < .001). Cortical acetylcholine and complexity were correlated with both subanesthetic ketamine (prefrontal: cluster-weighted marginal correlation [CW r] [144] = 0.42, P < .001; parietal: CW r[144] = 0.42, P < .001) and nitrous oxide (prefrontal: CW r[156] = 0.46, P < .001; parietal: CW r[156] = 0.56, P < .001) cohorts. These data bridge changes in cortical acetylcholine with concurrent changes in neurophysiologic complexity, frontoparietal connectivity, and the level of consciousness.


Complete Genome Sequence of Bordetella pertussis Pelita III, the Production Strain for an Indonesian Whole-Cell Pertussis Vaccine.
PT Bio Farma, the sole World Health Organization-approved Indonesian vaccine producer, manufactures a whole-cell whooping cough vaccine (wP) that, as part of a pentavalent diphtheria-tetanus-pertussis/hepatitis B/Haemophilus influenzae b (DTP/HB/Hib) vaccine, is used in Indonesia and many other countries. We report here the whole-genome sequence for Bordetella pertussis Pelita III, PT Bio Farma's wP production strain.


Cerebrospinal fluid shunt infections in children over a 13-year period: anaerobic cultures and comparison of clinical signs of infection with Propionibacterium acnes and with other bacteria.
Shunt infections represent a major problem with risk for sequelae and even death. The aim in this retrospective study was to analyze the incidence, origin, and clinical presentation of shunt infections, with special reference to the results of cultures for anaerobic organisms performed in addition to the usual tests, to prolonged incubation times, and to infections caused by Propionibacterium acnes. The medical records of 237 hydrocephalic children (age range 0-15 years) in whom operations were performed by a pediatric surgeon at Uppsala University Hospital during a 13-year period were reviewed. Thirty-four verified or suspected intraventricular shunt infections and 5 distal catheter infections occurred after 474 operations. Skin bacteria, such as coagulase-negative staphylococci ([CoNS], 19 patients), Staphylococcus aureus (7 patients), and P. acnes (6 patients) predominated. The addition of anaerobic cultures and prolonged incubation times increased the verification of shunt infection by more than one third. Children with P. acnes infection were significantly older, had a lower body temperature, fewer cerebrospinal fluid (CSF) leukocytes, a higher CSF/blood glucose ratio, more distal catheter infections, and other sources of infection. Four had an abdominal pseudocyst. Children < 1 year of age and infected with CoNS were more affected than older children with systemic and local symptoms. In children with distal catheter infection and growth of propionibacteria at the time of the distal catheter and valve replacement, no follow-up antibiotic treatment was necessary. Addition of anaerobic cultures and prolonged incubation times led to an increase in the detection of shunt infections. Infections caused by propionibacteria often result in mild symptoms that may be overlooked if adequate anaerobic cultures are not obtained.


Transfer of ampicillin resistance between strains of Haemophilus influenzae type B.
Haemophilus influenzae type B, strain W-2, is highly resistant to ampicillin (MIC, 12.5 mug/ml). The ampicillin resistance of strain W-2 was transferred to an antibiotic-sensitive strain TF-2 (RifR, SmR) during mixed incubation on membrane filters at 36 C(transfeer frequency, 4.6 times 10(-5) per donor). Resistance was also transferred from the primary recipient to a secondary one (TF-3, EryR, NovR). The transfer frequency between these derivative strains was 10(-4) after incubation for 30 min. Resistance in strain W-2 remained even after growth in the presence of ethidium bromide or at an elevated temperature, although ampicillin resistance was lost from 13%-25% of transcipient cells after growth in broth. Strain W-2 and transcipients of ampicillin resistance had equivalent levels of beta-lactamase activity, while sensitive segregants and recipient strains demonstrated little or no enzyme activity. Transfer of ampicillin resistance between strains of H. influenzae is probably mediated by conjugation since transfer (1) requires cell-to-cell contact, (2) remains unchanged in the presence of DNase I, and (3) occurs in the absence of demonstrable bacteriophage.


MemBuilder: a web-based graphical interface to build heterogeneously mixed membrane bilayers for the GROMACS biomolecular simulation program.
Molecular dynamics (MD) simulations have had a profound impact on studies of membrane proteins during past two decades, but the accuracy of MD simulations of membranes is limited by the quality of membrane models and the applied force fields. Membrane models used in MD simulations mostly contain one kind of lipid molecule. This is far from reality, for biological membranes always contain more than one kind of lipid molecule. Moreover, the lipid composition and their distribution are functionally important. As a result, there is a necessity to prepare more realistic lipid membranes containing different types of lipids at physiological concentrations. To automate and simplify the building process of heterogeneous lipid bilayers as well as providing molecular topologies for included lipids based on both united and all-atom force fields, we provided MemBuilder as a web-based graphical user interface. MemBuilder is a free web server available from www.membuilder.org.


Promoting Protein Intake in an Ageing Population: Product Design Implications for Protein Fortification.
Protein is a macronutrient of interest for an ageing population and intake requirements increase with age. Accordingly, protein is often fortified into products for older adults to help alleviate malnutrition and impede sarcopenia. However, more emphasis needs to be placed upon designing protein-fortified products to ensure suitability for older adults. This study involved a two-stage approach: (1) an initial review of products commonly fortified with protein and (2) two questionnaires for younger and older adults (n = 73; 18-30; 65+) to investigate optimal portion sizes (drinks and cakes) as well as attitudes, consumption habits and preferences towards protein fortification. The initial literature and market review demonstrated protein-fortified products are typically in liquid or snack format; however, there is considerable variability in terms of product types, serving size and protein sources. There were no age-related differences found for ideal cakes portion size whereas there were for liquids. Older adults are typically not consuming protein-fortified products; therefore, more importance should be placed on the consumption moment (breakfast or as snacks between meals) and on cereals, pasta, porridge, cakes, and biscuits. Older adults need increased awareness of, and more education on, the benefits of protein consumption, coupled with products tailored and designed to encourage intake.


Determinants of urea production and mineral retention in parenterally fed preterm infants.
To determine how weight for gestational age affects urea and mineral excretion by preterm infants receiving total parenteral nutrition (TPN). Daily urine samples were collected from all preterm infants given high calcium TPN, providing 30 kcal/g amino acids, during its first 44 months of use, and from all those given standard TPN, providing 25 kcal/g amino acids, over the previous 24 months. Urine urea and mineral excretion were measured as follows: Urea excretion mmol/kg/day = Urine urea/urine creatinine X creatinine production Creatinine production μmol/kg/day = -2.07 + 2.34 X gestational age in weeks Results: High calcium TPN was evaluated in 52 infants. Urea excretion did not rise with increasing TPN intake. During the first week, urea excretion increased with weight for gestational age, with higher rates in above average than below average weight infants. It also increased with gestational age in above average but not below average weight infants. Below average weight infants had lower potassium and phosphate excretion than those above average. Standard TPN was evaluated in 20 infants. Urea excretion increased with TPN intake to higher levels than on high calcium, and also increased with weight for gestational age. Urea excretion was simple to measure, with remarkably consistent daily results in individuals. Below 30 weeks gestation infants on TPN providing 30 kcal/g amino acids had urea excretion < 0.1 g urea N/kg/day, < 3.5 mmol/kg/day if below average weight, and < 0.12 g urea N/kg/day, < 4.3 mmol/kg/day if above average weight. Below average weight infants retained more potassium and phosphate during the first week than those above average, and their greater requirements were provided by the TPN.


Progress in Myelodysplastic Syndromes: Clinicopathologic Correlations and Immune Checkpoints.
Myelodysplastic syndromes (MDS) are a group of clonal neoplasms characterized by ineffective hematopoiesis. Hypomethylating agent (HMA) therapy is one of the mainstays of MDS therapy. Failure of HMA therapy is related to poor outcome; hence, new therapeutic approaches are warranted in these patients. In MDS, the immune system has a pivotal role in modulation of hematopoiesis and clonal expansion. In neoplastic conditions, immune checkpoint (PD-1 and CTLA4 molecules) hide tumor cells from immune surveillance. Identification of the pattern of expression of these molecules in MDS provides an interesting alternative within clinical trials. We describe the clinicopathologic correlations by morphology, immunohistochemistry (PD-L1) and flow cytometry immunophenotypic analysis in an MDS patient treated with immune checkpoint PD-1 inhibitor. Bone marrow (BM) morphology, differential counts and aberrant flow markers were assessed before and after anti PD-1 inhibitor therapy. At baseline, BM showed severe trilineage dysplasia with decreased granulopoiesis; after therapy, BM showed normal trilineage hematopoiesis. A decrease in PD-L1 expression, by manual and automatic analysis, was also noted from 15% to 5% after 26 months of treatment. The findings correlated with the recovery of peripheral blood counts and transfusion independency. BM morphology and PD-L1 expression by immunohistochemistry can be used to assess treatment response in immune checkpoints therapy.


Epicardial mapping in the Wolff-Parkinson-White syndrome.
Epicardial mapping provides a method for defining antegrade and retrograde sites of pre-excitation. It is best undertaken only after a careful, detailed preoperative electrophysiological study has been performed. The potential pitfalls of the technique are many and technical expertise must be constantly available to maintain a functioning system. For these reasons, it is not likely to lend itself to widespread application. The same techniques can be applied to localization of the site of origin of atrial or ventricular dysrhythmias, localization of myocardial ischemia and infarction, as well as to differentiate between epicardial delays due to conduction delay and those caused by intramural myocardial delay.


Repair capacity for UV light induced DNA damage associated with risk of nonmelanoma skin cancer and tumor progression.
To examine the role of suboptimal DNA repair capacity (DRC) for UV light-induced DNA damage in the development of nonmelanoma skin cancer (NMSC) and tumor progression. We conducted a hospital-based case-control study of 255 patients with newly diagnosed NMSC [146 with basal cell carcinoma (BCC) and 109 with squamous cell carcinoma (SCC)] and 333 cancer-free controls. We collected information on demographic variables and risk factors from questionnaires, tumor characteristics from medical records, and lymphocytic DRC phenotype by the host-cell reactivation assay. Multivariable logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (95% CI). Overall, there was a relative 16% reduction in DRC in NMSC patients compared with controls (P < 0.001 for BCC and for SCC, respectively). DRC below the controls' median value was associated with increased risk significantly for BCC (OR, 1.62; 95% CI, 1.07-2.45) but borderline for SCC (OR, 1.63; 95% CI, 0.95-2.79) after adjustment for age, sex, and other assay-related covariates. When the highest tertile of controls' DRC was used as the reference, the intermediate and low DRC were associated with a statistically significant trend for increasing risk for both BCC (P(trend) = 0.007) and SCC (P(trend) = 0.020). However, patients with aggressive or multiple SCC tended to have a higher DRC than those with nonaggressive or single SCC. Reduced DRC is an independent risk factor for BCC and single or nonaggressive SCC but not for multiple primaries, local aggressiveness, or recurrence of NMSC.


Robust spatial ventriloquism effect and trial-by-trial aftereffect under memory interference.
Our brain adapts to discrepancies in the sensory inputs. One example is provided by the ventriloquism effect, experienced when the sight and sound of an object are displaced. Here the discrepant multisensory stimuli not only result in a biased localization of the sound, but also recalibrate the perception of subsequent unisensory acoustic information in the so-called ventriloquism aftereffect. This aftereffect has been linked to memory-related processes based on its parallels to general sequential effects in perceptual decision making experiments and insights obtained in neuroimaging studies. For example, we have recently implied memory-related medial parietal regions in the trial-by-trial ventriloquism aftereffect. Here, we tested the hypothesis that the trial-by-trial (or immediate) ventriloquism aftereffect is indeed susceptible to manipulations interfering with working memory. Across three experiments we systematically manipulated the temporal delays between stimuli and response for either the ventriloquism or the aftereffect trials, or added a sensory-motor masking trial in between. Our data reveal no significant impact of either of these manipulations on the aftereffect, suggesting that the recalibration reflected by the trial-by-trial ventriloquism aftereffect is surprisingly resilient to manipulations interfering with memory-related processes.


Whole Transcriptomic Analysis of Apigenin on TNFα Immuno-activated MDA-MB-231 Breast Cancer Cells.
Triple-negative breast cancer is categorized by a lack of hormone receptors, inefficacy of anti-estrogen or aromatase inhibitor chemotherapies and greater mortality rates in African American populations. Advanced-stage breast tumors have a high concentration of tumor necrosis factor-α (TNFα) throughout the tumor/stroma milieu, prompting sustained release of diverse chemokines (i.e. C-C motif chemokine ligand 2 (CCL2)/CCL5). These potent chemokines can subsequently direct mass infiltration of leukocyte sub-populations to lodge within the tumor, triggering a loss of tumor immune surveillance and subsequent rapid tumor growth. Previously, we demonstrated that in the MDA-MB-231 TNBC cell line, TNFα evoked a rise in immune signaling proteins: CCL2, granulocyte macrophage colony-stimulating factor, interleukin (IL)1α, IL6 and inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKε) all of which were attenuated by apigenin, a dietary flavonoid found in chamomile and parsley. The present work elucidates changes evoked by TNFα in the presence or absence of apigenin by examining the entire transcriptome for mRNA and long intergenic non-coding RNA with Affymetrix Hugene-2.1_ST human microarrays. Differential gene-expression analysis was conducted on 48,226 genes. TNFα caused up-regulation of 75 genes and down-regulation of 10. Of these, apigenin effectively down-regulated 35 of the 75 genes which were up-regulated by TNFα. These findings confirm our previous work, specifically for the TNFα-evoked spike in IL1A vs. untreated controls [+21-fold change (FC), p<0.0001] being attenuated by apigenin in the presence of TNFa (-15 FC vs. TNFα, p<0.0001). Similar trends were seen for apigenin-mediated down-regulation of TNFα-up-regulated transcripts: IKBKE (TNFα: 4.55 FC vs. control, p<0.001; and TNFα plus apigenin: -4.92 FC, p<0.001), CCL2 (2.19 FC, p<0.002; and -2.12 FC, p<0.003), IL6 (3.25 FC, p<0.020; and -2.85 FC, p<0.043) and CSF2 (TNFα +6.04 FC, p<0.001; and -2.36 FC, p<0.007). In addition, these data further establish more than a 65% reduction by apigenin for the following transcripts which were also up-regulated by TNFα: cathepsin S (CTSS), complement C3 (C3), laminin subunit gamma 2 (LAMC2), (TLR2), toll-like receptor 2 G protein-coupled receptor class C group 5 member B (GPRC5B), contactin-associated protein 1 (CNTNAP1), claudin 1 (CLDN1), nuclear factor of activated T-cells 2 (NFATC2), C-X-C motif chemokine ligand 10 (CXCL10), CXCL11, interleukin 1 receptor-associated kinase 3 (IRAK3), nuclear receptor subfamily 3 group C member 2 (NR3C2), interleukin 32 (IL32), IL24, slit guidance ligand 2 (SLIT2), transmembrane protein 132A (TMEM132A), TMEM171, signal transducing adaptor family member 2 (STAP2), mixed lineage kinase domain-like pseudokinase (MLKL), kinase insert domain receptor (KDR), BMP-binding endothelial regulator (BMPER), and kelch-like family member 36 (KLHL36). There is a possible therapeutic role for apigenin in down-regulating diverse genes associated with tumorigenic leukocyte sub-population infiltration by triple-negative breast cancer. The data have been deposited into the Gene Expression Omnibus for public analysis at https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE120550.


Theratyping in cystic fibrosis.
The treatment of cystic fibrosis (CF) with CF transmembrane conductance regulator (CFTR) modulators continues to develop at a fast pace. These compounds are potentially disease modifying but are only available to certain patient subsets based on genotype. This review discusses the role of theratyping in CF and the potential to assess all patients' response to current and emerging therapies. There are limitations to treatment determined by mutation, as variable clinical response to CFTR modulators has been observed within the same genotype. Patients with rare mutations not currently licensed for CFTR modulator therapy have demonstrated response to these medications. Patient-specific cellular models called organoids can be used to demonstrate response to different CFTR modulators in vitro prior to their clinical application and represent a method of theratyping. Theratyping charts patients' clinical response to different treatments on an individual basis. This overcomes the limitations of genotype being used to predict response to individual therapies and includes all patients regardless of mutation. The use of organoids in high throughput screening allows numerous compounds to be tested on patient-specific tissue preclinically. This could lead to the extension of theratyping beyond CFTR modulators.


West Nile Virus Population Structure, Injury, and Interferon-Stimulated Gene Expression in the Brain From a Fatal Case of Encephalitis.
Background. West Nile virus (WNV) infection in humans can result in severe, acute encephalitis typically involving subcortical gray matter brain regions. West Nile virus replication within specific human brain regions from a human case of acute encephalitis has not been studied. Methods. We describe a fatal case of WNV encephalitis in which we obtained tissue from specific brain regions at autopsy to evaluate viral-host interactions using next-generation sequencing and immunohistochemistry analysis. Results. We found that WNV populations in the injured subcortical brain regions exhibited increased amino acid variation and increased expression of specific interferon genes compared with cortical tissues despite similar viral burden. Conclusions. These observational, patient-based data suggest that neuronal injury and the strength of viral selection pressure may be associated with the level of the innate immune responses. Further studies in human and animal models evaluating the role of innate immune responses on injury patterns and viral selection pressure are needed.


Biosynthesis of the iron-transport compound enterochelin: mutants of Escherichia coli unable to synthesize 2,3-dihydroxybenzoate.
Mutants of Escherichia coli K-12 blocked in each of the three enzymatic reactions between chorismate and 2,3-dihydroxybenzoate, in the pathway leading to the iron-sequestering compound enterochelin, have been isolated and biochemically characterized. The three genes concerned (designated entA, entB and entC) have been shown to be clustered on the chromosome between purE and gal and to be located near minute 14 by cotransduction with the purE, lip, and fep genes. entA, entB, and entC were shown to be the structural genes for 2,3-dihydro-2,3-dihydroxybenzoate dehydrogenase, 2,3-dihydro-2,3-dihydroxybenzoate synthetase, and isochorismate synthetase, respectively.


Sulfur Removal from Dibenzothiophene by Newly Isolated Paenibacillus validus Strain PD2 and Process Optimization in Aqueous and Biphasic (Model-Oil) Systems.
Dibenzothiophene (DBT) is an organic sulfur compound which remains in oil after hydrodesulfurization (HDS) process and can be removed by biodesulfurization (BDS). A new strain of Paenibacillus validus (strain PD2) was isolated from oil contaminated soils that is able to desulfurize DBT. HPLC analysis and Gibbs assay showed that this strain was capable to convert DBT to 2-Hydroxybiphenyl (2-HBP) as final product. The presence of dszC gene confirmed that DBT desulfurization occurred through the 4S pathway. Maximum growth and the highest induction in dsz operon obtained in the presence of dimethyl sulfoxide (DMSO) as sole sulfur source. DBT concentration, temperature and pH were optimized statistically for growing and resting cells by using Response Surface Methodology (RSM). All parameters in growing cells had a significant effect on 2-HBP production during BDS of DBT by P. validus PD2, although in resting cells temperature in range of 20-40 degrees C was not a significant factor. Maximum BDS for growing cells was obtained at 0.41 mM DBT concentration, pH 6.92 and temperature 31.23 degrees C. For resting cells, optimum pH, temperature and DBT concentration were 6.62, 27.73 degrees C and 7.86 mM respectively. The results of this study showed that high concentrations of DBT could be desulfurized by P. validus strain PD2 in model-oil. Thus, the isolated strain could be introduced as a proper candidate for biodesulfurization of organic sulfur in the oil industry.


ASK1 inhibitors are potential pan-antiviral drugs, which dampen replication of diverse viruses including SARS-CoV2.
Apoptosis signal-regulating kinase 1 (ASK1)/MAP3K5 is a stress response kinase that is activated by various stimuli. It is known as an upstream activator of p38- Mitogen-activated protein kinase (p38MAPK) and c-Jun N-terminal kinase (JNK) that are reactive oxygen species (ROS)-induced kinases. Accumulating evidence show that ROS accumulate in virus-infected cells. Here, we investigated the relationship between viruses and ASK1/p38MAPK or ASK1/JNK pathways. Our findings suggest that virus infection activates ASK1 related pathways. In parallel, ASK1 inhibition led to a remarkable reduction in the replication of a broad range of viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), vaccinia virus (VV), vesicular stomatitis virus (VSV), Herpes Simplex Virus (HSV), and Human Immunodeficiency virus (HIV) in different human cell lines. Our work demonstrates the potential therapeutic use of Selonsertib, an ASK1 inhibitor, as a pan-antiviral drug in humans. Surprisingly, we observed differential effects of Selonsertib in in vitro and in vivo hamster models, suggesting caution in using rodent models to predict clinical and therapeutic outcomes in humans.


Identification of hepatitis B virus aetiologic antigens, HBx and Pre-S2, in diffuse large B-cell lymphoma.
Diffuse large B-cell lymphoma (DLBCL) has been reported to have a significant association with the hepatitis B virus (HBV) infection. However, there has been no experimental evidence to determine whether the components of the hepatitis B virus are expressed in lymphoid cells. In this study, we used immunohistochemical methods to explore whether the antigens of hepatitis B virus are expressed in DLBCL lymphoma cells in HBsAg-positive DLBCL patients (HBsAg + DLBCL). HBx antigen was detected in 48.9% of HBsAg + DLBCL patients, and the expression rate of the Pre-S2 antigen was 57.2%. HBx expression was significantly associated with high-level expression of c-Myc, while the Pre-S2 antigen was not. In this study, we demonstrated that HBx antigen and Pre-S2 antigen could be detected in lymphoma cells, and HBx expression was related to c-Myc expression. Our findings provide a strong basis for further study of the HBV-infected DLBCL and molecular mechanism underlying the lymphomagenesis.


Fryns syndrome survivors and neurologic outcome.
Fryns syndrome is an autosomal recessive multiple congenital anomaly syndrome characterized by diaphragmatic hernia, unusual facies, and distal limb hypoplasia. It was first reported as a lethal condition. We report on a three-year-old survivor with Fryns syndrome, and provide a review on the outcome of other survivors. Patients who survive the neonatal period represent 14% of reported cases. Characteristics of survivors include less frequent diaphragmatic hernia and milder lung hypoplasia, absence of complex cardiac malformation, and neurologic impairment. Multiple central nervous system abnormalities have been reported in Fryns syndrome, including agenesis of the corpus callosum, Dandy-Walker abnormality, cerebellar heterotopias, cerebellar hypoplasia, enlarged ventricles, and hypoplasia of the olfactory bulbs. Our patient exhibited profound mental retardation. He had malformations of gyration and sulcation, particularly around the central sulcus, and hypoplastic optic tracts beyond the optic chiasm. Understanding of long-term outcome of survivors is important for counseling of families with Fryns syndrome. Careful brain examination is advised; however, a normal radiological brain examination does not preclude developmental delay. The spectrum of individual outcome and of associated anomalies indicates that individual evaluation, including imaging for structural brain malformation, is strongly advised.


Application of the fluorescent probe 1-anilinonaphthalene-8-sulfonate to the measurement of the nonspecific binding of drugs to human liver microsomes.
The fluorescence of 1-anilinonaphthalene-8-sulfonate (ANS) in the presence of human liver microsomes (HLMs) is altered by drugs that bind nonspecifically to the lipid bilayer. The present study characterized the relationship between the nonspecific binding (NSB) of drugs to HLMs as measured by equilibrium dialysis and the magnitude of the change in baseline ANS fluorescence. Fraction unbound in incubations of HLMs (f(u(mic))) was determined for 16 drugs (12 bases, 3 acids, and 1 neutral) with log P values in the range 0.1 to 6.7 at three concentrations (100, 200, and 500 μM). Changes in ANS fluorescence induced by each of the drugs in the presence of HLMs were measured by spectrofluorometry. Values of f(u(mic)) determined by equilibrium dialysis ranged from 0.08 to 1.0. Although NSB of the basic drugs tended to increase with increasing log P, exceptions occurred. Basic drugs generally caused an increase in ANS fluorescence, whereas the acidic and neutral drugs resulted in a decrease in ANS fluorescence. There were highly significant (p < 0.001) linear relationships between the modulus (absolute value) of the increment/decrement in ANS fluorescence and both f(u(mic)) (r = 0.90 to 0.96) and log(1 - f(u(mic))/f(u(mic))) (r = 0.85 to 0.92) at the three drug concentrations. Agreement between measured f(u(mic)) and that predicted by ANS fluorescence was very good (<10% variance) for a validation set of six compounds. The ANS fluorescence method provides an accurate measure of the NSB of drugs to HLMs. Physicochemical determinants other than log P and charge type influence the NSB of drugs to HLMs.


Role of IL28B for chronic hepatitis C treatment toward personalized medicine.
Genome-wide association studies recently revealed that certain interleukin-28B (IL28B) polymorphisms are strongly associated with responses to pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy in patients chronically infected with hepatitis C virus (HCV) genotype 1, as well as with spontaneous clearance of HCV. Subsequent reports revealed that IL28B genotypes also affect treatment efficacy in chronic infection with other HCV genotypes. Furthermore, there have been several reports that implicate IL28B genotypes in inflammatory status, progression of fibrosis and adverse clinical outcomes in chronic hepatitis C (CHC). Therapy of CHC recently entered a new era with the deployment of direct-acting antivirals. These include nonstructural 3/4A protease inhibitors which have shown promise in combination with PEG-IFN/RBV in several clinical trials. IFN-free therapy is expected to be useful especially in IFN-resistant patients and may become the standard of care in the future. Several clinical trials have revealed an association between IL28B genotype and treatment efficacy in triple therapy or IFN-free regimens. On the other hand the mechanism of the effect of IL28B on HCV infection has not yet been elucidated. Recently, it was shown that the polymorphism of IFN-lambda 4 (IFNL4) is in high linkage disequilibrium with that of near IL28B, and more strongly associated with spontaneous or treatment-induced HCV clearance than IL28B genotypes, especially in individuals of African ancestry. This finding provides new insights into the genetic regulation of HCV clearance and its clinical management. IL28B genotyping will be also useful for personalized CHC treatment in the forthcoming era of direct-acting antivirals.


RNP Granule Formation: Lessons from P-Bodies and Stress Granules.
It is now clear that cells form a wide collection of large RNA-protein assemblies, referred to as RNP granules. RNP granules exist in bacterial cells and can be found in both the cytosol and nucleus of eukaryotic cells. Recent approaches have begun to define the RNA and protein composition of a number of RNP granules. Herein, we review the composition and assembly of RNP granules, as well as how RNPs are targeted to RNP granules using stress granules and P-bodies as model systems. Taken together, these reveal that RNP granules form through the summative effects of a combination of protein-protein, protein-RNA, and RNA-RNA interactions. Similarly, the partitioning of individual RNPs into stress granules is determined by the combinatorial effects of multiple elements. Thus, RNP granules are assemblies generally dominated by combinatorial effects, thereby providing rich opportunities for biological regulation.


Cerebral autoregulation dynamics in endurance-trained individuals.
Aerobic fitness may be associated with reduced orthostatic tolerance. To investigate whether trained individuals have less effective regulation of cerebral vascular resistance, we studied the middle cerebral artery (MCA) mean blood velocity (V(mean)) response to a sudden drop in mean arterial pressure (MAP) after 2.5 min of leg ischemia in endurance athletes and untrained subjects (maximal O(2) uptake: 69 ± 7 vs. 42 ± 5 ml O(2)·min(-1)·kg(-1); n = 9 for both, means ± SE). After cuff release when seated, endurance athletes had larger drops in MAP (94 ± 6 to 62 ± 5 mmHg, -39%, vs. 99 ± 5 to 73 ± 4 mmHg, -26%) and MCA V(mean) (53 ± 3 to 37 ± 2 cm/s, -30%, vs. 58 ± 3 to 43 ± 2 cm/s, -25%). The athletes also had a slower recovery to baseline of both MAP (25 ± 2 vs. 16 ± 1 s, P < 0.01) and MCA V(mean) (15 ± 1 vs. 11 ± 1 s, P < 0.05). The onset of autoregulation, determined by the time point of increase in the cerebrovascular conductance index (CVCi = MCA V(mean)/MAP) appeared later in the athletes (3.9 ± 0.4 vs. 2.7 ± 0.4s, P = 0.01). Spectral analysis revealed a normal MAP-to-MCA V(mean) phase in both groups but ~40% higher normalized MAP to MCA V(mean) low-frequency transfer function gain in the trained subjects. No significant differences were detected in the rates of recovery of MAP and MCA V(mean) and the rate of CVCi regulation (18 ± 4 vs. 24 ± 7%/s, P = 0.2). In highly trained endurance athletes, a drop in blood pressure after the release of resting leg ischemia was more pronounced than in untrained subjects and was associated with parallel changes in indexes of cerebral blood flow. Once initiated, the autoregulatory response was similar between the groups. A delayed onset of autoregulation with a larger normalized transfer gain conforms with a less effective dampening of MAP oscillations, indicating that athletes may be more prone to instances of symptomatic cerebral hypoperfusion when MAP declines.


Patients with unsolved congenital disorders of glycosylation type II can be subdivided in six distinct biochemical groups.
Defects in the biosynthesis of N- and core 1 O-glycans may be found by isoelectric focusing (IEF) of plasma transferrin and apolipoprotein C-III (apoC-III). We hypothesized that IEF of transferrin and apoC-III in combination with sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) of apoC-III may provide a classification for congenital disorders of glycosylation (CDG) patients. We analyzed plasma from 22 patients with eight different and well-characterized CDG subtypes and 19 cases with unsolved CDG. Transferrin IEF (TIEF) has been used to distinguish between N-glycan assembly (type 1 profile) and processing (type 2 profile) defects. We differentiated two different CDG type 2 TIEF profiles: The "asialo profile" characterized by elevated levels of asialo- and monosialotransferrin and the "disialo profile" characterized by increased levels of disialo- and trisialotransferrin. ApoC-III IEF gave two abnormal profiles ("apoC-III(0)" and "apoC-III(1)" profiles). The results for the eight established CDG forms exactly matched the theoretical expectations, providing a validation for the study approach. The combination of the three electrophoretic techniques was not additionally informative for the CDG-Ix patients as they had normal apoC-III IEF patterns. However, the CDG-IIx patients could be further subdivided into six biochemical subgroups. The robustness of the methodology was supported by the fact that three patients with similar clinical features ended in the same subgroup and that another patient, classified in the "CDG-IIe subgroup," turned out to have a similar defect. Dividing the CDG-IIx patients in six subgroups narrows down drastically the options of the primary defect in each of the subgroups and will be helpful to define new CDG type II defects.


Preventive health counseling reported by uninsured women with limited access to care.
Low-income women in the childbearing years are at an increasing risk of becoming uninsured as welfare reforms are enacted and women enter minimum-wage jobs without insurance benefits. This study contrasts preventive counseling reported by low-income uninsured mothers and mothers insured through Medicaid. Low-income women attending Women, Infant, and Children (WIC) clinics and human services offices who had received health care during the previous 12 months (N = 406) were asked if they had received counseling from a health provider regarding any of seven types of preventive health behaviors. Uninsured women were less than half as likely to receive counseling on three or more preventive topics (OR = 0.42) as were mothers on Medicaid. Risk estimates were stable on bivariate analyses and logistic regression models. Findings indicate that opportunities for preventive health counseling need to be maximized for this group already experiencing compromised access to care.


Radiographic assessment of the extracranial internal carotid artery.
The accuracy of new (non-invasive) techniques of carotid artery assessment is classically established by comparing the results of the method under study with those of conventional contrast angiography. It is, therefore, important to establish the reproducibility of data acquired from contrast angiograms. Categories of carotid lesion must be chosen such that good reproducibility is likely both on an inter and intra-observer basis. This paper suggests that the smallest useful number of categories be used. It a two category discriminating system (less than 25% and greater than or equal to 25% stenosis), inter-observer agreement was found to be 95% and intra-observer agreement 96%. The principal observer variation occurred at the 0% and greater than 0% level of discrimination and this should be avoided in future studies comparing new arterial assessment techniques with conventional angiography.


Altered glucose metabolism and the invasive tumor phenotype.
Multiple genetic changes are necessary for carcinogenesis, yet a wide range of different genetic changes may give rise to malignant behavior and no set or sequence of defects is seen in all cancers. The similar pattern of invasive growth in malignancy despite the genotypic and phenotypic heterogeneity of tumor populations suggests that a final cellular state common to all cancers may exist. Such a state must be the sequela of many possible genetic changes, and the cellular properties of the state must promote malignant, invasive growth. It is hypothesized that the common denominator of the transformed state is reversion to primitive phenotype, and its invasive properties stem from alteration of metabolic pathways. Increased use of glycolysis and consequent production of acid have been consistently demonstrated in malignant cells in vitro and are seen in the vast majority of clinical tumors imaged with FDG Positron Emission Tomography (PET) and Magnetic Resonance Spectroscopy (MRS). Application of mathematical models from population ecology and competition theory demonstrates that these metabolic changes will alter the local microenvironment in ways that favor tumor growth but are lethal to normal cells. This phenomenon alone appears to provide a simple but sufficient mechanism for invasive tumor growth. This hypothesis is testable experimentally and suggests significant new approaches to tumor therapy.


Organizational factors to optimize mental health nurses' wellbeing in the workplace: An integrative literature review.
Mental health nursing is a privilege and a rewarding profession. There has been a call for transformational change in mental health services to improve outcomes for the people of New Zealand, with mental health nurses integral to this. However, with predicted nursing shortages, high levels of burnout, and increasing demands in the workplace, an organizational focus on wellbeing for mental health nurses is needed to sustain the workforce, implement change and improve outcomes for people using mental health services. An integrative review of the literature was undertaken to explore how organizations can optimize mental health nurses' wellbeing in the workplace and to identify measures for organizations to support mental health nurses' wellbeing with a focus on New Zealand. Seven articles were included in this review after a search, data extraction and evaluation. Data were synthesized and categorized using thematic analysis. The findings indicate organizations can invest in several initiatives to enhance mental health nurses' wellbeing in the workplace. These include professional development, skills to build resilience, enabling time to reflect on practice, enhancing professional supervision, having the right managerial support and focusing on individual's strengths. Organizations need to prioritize mental health nurses' wellbeing by embedding the practical strategies this review identified and by addressing organizational barriers to wellbeing. Organizations should consider implementing multileveled organizational wellbeing initiatives to nurture and grow the New Zealand mental health nursing workforce which in turn will contribute to quality care and enable mental health nurses to have long meaningful careers. Time, investment and resources are essential for these initiatives to be effective.


[Idiopathic orbital inflammatory syndrome (orbital pseudotumors): diagnosis and therapy].
Pseudotumors of the orbit comprise a group of idiopathic inflammatory processes and are, except for endocrine orbitopathy, the most common reason for exophthalmos in adults. Orbital pseudotumors, also called idiopathic orbital inflammatory syndrome (IOIS), can be determined from orbital involvement in systemic fibrosing diseases. Finding the correct diagnosis can be challenging. Due to the topographic relations of the orbit to neighbouring structures, a multidisciplinary cooperation is highly recommended. We report a case of a 42-year-old woman with unilateral exophthalmos. Additionally we found impaired motility of the affected bulbus, ptosis and reduction of visual acuity. Orbital MR imaging demonstrated dense fibrotic masses filling the whole orbita including the extraocular muscles as well as the optic nerve. Tissue specimens were extracted while performing orbital decompression via a lateral orbitotomy. Histological examination revealed a lymphatic infiltration and fibrotically destroyed tissue containing the lacrimal gland. After surgical decompression, oral steroid therapy and immunotherapy, a recovery of the visual loss could be seen. Intraorbital fibrosclerosing pseudotumors often require a difficult long-term treatment. Therapeutic options are steroid therapy, immunotherapy, radiotherapy and surgery. The diagnostic steps include blood tests, ultrasound, CT and/or MRI as well as histological differentiation. Solid tumors and orbital involvement in diseases of the hematopoetic system have to be excluded. Since intraorbital fibrosis can be accompanied by manifestations in various other organs, a complete investigation of the body and thorough follow up are crucial.


A Point-Process Approach for Tracking Valence using a Respiration Belt.
Emotional valence is difficult to be inferred since it is related to several psychological factors and is affected by inter- and intra-subject variability. Changes in emotional valence have been found to cause a physiological response in respiration signals. In this study, we propose a state-space model and decode the valence by analyzing a person's respiration pattern. Particularly, we generate a binary point process based on features that are indicative of changes in respiration pattern as a result of an emotional valence response. High valence is typically associated with faster and deeper breathing. As a result, (i)depth of breath, (ii)rate of respiration, and (iii) breathing cycle time are indicators of high valence and used to generate the binary point process representing underlying neural stimuli associated with changes in valence. We utilize an expectation-maximization (EM) framework to decode a hidden valence state and the associated valence index. This predicted valence state is compared to self-reported valence ratings to optimize the parameters and determine the accuracy of the model. The accuracy of the model in predicting high and low valence events is found to be 77% and 73%, respectively. Our study can be applied towards the long term analysis of valence. Additionally, it has applications in a closed-loop system procedures and wearable design paradigm to track and regulate the emotional valence.


Galangin inhibits human osteosarcoma cells growth by inducing transforming growth factor-β1-dependent osteogenic differentiation.
Osteosarcoma is the most common primary malignancy of the musculoskeletal system, and is associated with excessive proliferation and poor differentiation of osteoblasts. Currently, despite the use of traditional chemotherapy and radiotherapy, no satisfactory and effective agent has been developed to treat the disease. Herein, we found that a flavonoid natural product, galangin, could significantly attenuate human osteosarcoma cells proliferation, without causing obvious cell apoptosis. Moreover, galangin enhanced the expression of osteoblast differentiation markers (collagen type I, alkaline phosphatase, osteocalcin and osteopontin) remarkably and elevated the alkaline phosphatase activity in human osteosarcoma cells. And galangin could also attenuated osteosarcoma growth in vivo. These bioactivities of galangin resulted from its selective activation of the transforming growth factor (TGF)-β1/Smad2/3 signaling pathway, which was demonstrated by pathway blocking experiments. These findings suggested that galangin could be a promising agent to treat osteosarcoma. In addition, targeting TGF-β1 to induce osteogenic differentiation might represent a novel therapeutic strategy to treat osteosarcoma with minimal side effects.


Rehabilitation Program Combined with Local Vibroacoustics Improves Psychophysiological Conditions in Patients with ACL Reconstruction.
Background and objective: This study investigated the therapeutic effect of applying local body vibration (LBV) with built-in vibroacoustic sound on patients who had an anterior cruciate ligament (ACL) reconstruction. Materials and Methods: Twenty-four participants were randomly classified into a LBV group (LBVG; n = 11) or a non-LBV group (nLBVG; n = 13). Both groups received the same program; however, the LBVG received LBV. Psychological measures included pain, anxiety, and symptoms; physiological measures included systolic blood pressure (SBP), diastolic blood pressure, heart rate (HR), breathing rate (BR), sympathetic activation (SA), parasympathetic activation (PSA), range of motion (ROM), and isokinetic muscle strength at Weeks 0, 4, and 8. Results: Among the psychophysiological variables, pain, anxiety, symptoms, SBP, BR, and SA were significantly reduced in both groups, whereas HR, PSA, isokinetic peak torque (PT) of the knee joint, and ROM were significantly improved only in the LBVG. Comparing both groups, a significant difference appeared in pain, symptom, SA, PSA, isokinetic PT, and ROM at Weeks 4 and 8. Conclusions: The results indicate that the LBV intervention mitigated the participants' pain and symptoms and improved their leg strength and ROM, thus highlighting its effectiveness.


Bovine Herpesvirus 1 Invasion of Sensory Neurons by Retrograde Axonal Transport Is Dependent on the pUL37 Region 2 Effector.
Following exposure and replication at mucosal surfaces, most alphaherpesviruses invade the peripheral nervous system by retrograde axonal transport and establish lifelong latent infections in the peripheral ganglia. Reactivation of ganglionic infections is followed by anterograde axonal transport of virions back to body surfaces where viral replication results in disease that can range from moderate to severe in presentation. In the case of bovine herpesvirus 1 (BoHV-1), replication in the epithelial mucosa presents as infectious bovine rhinotracheitis (IBR), a respiratory disease of significant economic impact. In this study, we provide a live-cell analysis of BoHV-1 retrograde axonal transport relative to the model alphaherpesvirus pathogen pseudorabies virus (PRV) and demonstrate that this critical neuroinvasive step is conserved between the two viruses. In addition, we report that the BoHV-1 pUL37 tegument protein supports processive retrograde motion in infected axons and invasion of the calf peripheral nervous system. IMPORTANCE A molecular and cellular understanding of the retrograde axonal transport process that underlies the neuroinvasive properties of the alphaherpesviruses is established from studies of herpes simplex virus and pseudorabies virus. The degree to which this phenotype is conserved in other related viruses has largely not been examined. We provide a time-lapse analysis of the retrograde axonal transport kinetics of bovine herpesvirus 1 and demonstrate that mutation of the pUL37 region 2 effector affords a strategy to produce live-attenuated vaccines for enhanced protection of cattle.


Trauma of the colon: early drop-back of exteriorized repair.
Exteriorized repair of selected colonic injuries has been reported to be successful. Eighty-two colonic injuries were reviewed to determine the indications for primary repair, exteriorized repair, or colostomy and to assess the feasibility of early drop-back of the exteriorized repaired colon. Injuries were graded into three stages: stage 1, good risk; stage 2, moderate risk; and stage 3, bad risk. Sixty-seven percent of patients with stage 1 injuries underwent primary repair, 61% of patients with stage 2 injuries underwent exteriorized repair, and 61% of patients with stage 3 injuries received a colostomy. Of 38 patients who had exteriorized repair, 29 (76%) had their colon successfully dropped back on an average of five days postoperatively. Nine patients had their exteriorized colon converted to a colostomy on an average of 5.5 days postoperatively. The overall mortality was 2.4%; however, the mortality of the patients with exteriorized repair was 0%. Exteriorized repair with early drop-back is safe and economical for most patients with stage 2 injuries and selected patients with stage 3 injuries.


[Immunological status of patients with caries and its complications in combination with parodontitis].
Results of complex clinical and immunological study of patients with caries and pulpitis in combination with periodontitis were presented. It was revealed that high intensity of caries and parodontitis combines with significant disturbances in cellular and humoral parts of immune system.


Partial decellularization eliminates immunogenicity in tracheal allografts.
There is currently no suitable autologous tissue to bridge large tracheal defects. As a result, no standard of care exists for long-segment tracheal reconstruction. Tissue engineering has the potential to create a scaffold from allografts or xenografts that can support neotissue regeneration identical to the native trachea. Recent advances in tissue engineering have led to the idea of partial decellularization that allows for the creation of tracheal scaffolds that supports tracheal epithelial formation while preserving mechanical properties. However, the ability of partial decellularization to eliminate graft immunogenicity remains unknown, and understanding the immunogenic properties of partially decellularized tracheal grafts (PDTG) is a critical step toward clinical translation. Here, we determined that tracheal allograft immunogenicity results in epithelial cell sloughing and replacement with dysplastic columnar epithelium and that partial decellularization creates grafts that are able to support an epithelium without histologic signs of rejection. Moreover, allograft implantation elicits CD8+ T-cell infiltration, a mediator of rejection, while PDTG did not. Hence, we establish that partial decellularization eliminates allograft immunogenicity while creating a scaffold for implantation that can support spatially appropriate airway regeneration.


The Effects of Gender Signals and Performance in Online Product Reviews.
This work quantifies the effects of signaling gender through gender specific user names, on the success of reviews written on the popular amazon.com shopping platform. Highly rated reviews play an important role in e-commerce since they are prominently displayed next to products. Differences in reviews, perceived-consciously or unconsciously-with respect to gender signals, can lead to crucial biases in determining what content and perspectives are represented among top reviews. To investigate this, we extract signals of author gender from user names to select reviews where the author's likely gender can be inferred. Using reviews authored by these gender-signaling authors, we train a deep learning classifier to quantify the gendered writing style (i.e., gendered performance) of reviews written by authors who do not send clear gender signals via their user name. We contrast the effects of gender signaling and performance on the review helpfulness ratings using matching experiments. This is aimed at understanding if an advantage is to be gained by (not) signaling one's gender when posting reviews. While we find no general trend that gendered signals or performances influence overall review success, we find strong context-specific effects. For example, reviews in product categories such as Electronics or Computers are perceived as less helpful when authors signal that they are likely woman, but are received as more helpful in categories such as Beauty or Clothing. In addition to these interesting findings, we believe this general chain of tools could be deployed across various social media platforms.


Radioimmunodetection of cervical carcinoma xenografts with (111)In-labeled MAb Cx-99 detected by a hand-held gamma detector.
To establish a radioimmunodetection (RAID) system for localization of cervical cancer by labeling 111-indium ((111)In) to a monoclonal antibody against cytokeratin 19 (MAb Cx-99), and detecting it with a hand-held gamma detector in an animal model. MAb Cx-99 was labeled with 111-Indium by the DTPA chelating method. From the second day to the seventh day after injection of this immunoconjugate into athymic nude mice bearing cervical cancer cell line CC7T xenografts, the biodistribution ratios of tumor and non-tumor radioactivity were detected by a hand-held gamma detector. Data were also correlated with the data detected by the conventional gamma counter. The labeling efficiency of this (111)In-labeled MAb Cx-99 and (111)In-labeled MOPC was 91.6% and 95.5%, respectively. After injection, the liver, kidney and lung were initially noticed to have high radioactivity, but the localization of tumor/tissue ratios increased progressively as time passed, indicating the effect of delayed detection for distinguishing tumor from non-tumor tissues. Except for the spleen, the range of tumor/tissue ratios was 1.18-32.7 and 1.14-39.35 for the fourth day and the seventh day, respectively. The tumor/spleen ratio remained low until the seventh day after injection, thus indicating that the spleen might have a different excretion rate. This study indicated the feasibility of a hand-held detection system in the localization of cervical cancer after injection of (111)In-labeled MAb Cx-99. The effect of delayed detection was obvious by the decreasing high bindings in the liver, spleen and kidney, with the applicable detection time being four to seven days after injection.


Regulation of the methionine feedback-sensitive enzyme in mutants of Salmonella typhimurium.
Assay of the first enzyme unique to methionine biosynthesis, homoserine-O-transsuccinylase, in metJ and metK regulatory mutants of Salmonella typhimurium showed that synthesis of the enzyme was derepressed seven- and fourfold, respectively. The possibility of noncoordinate regulation of the methionine enzymes is discussed. In metA feedback-resistant mutants, the enzyme activity can be inhibited in vitro by 10 mmS-adenosylmethionine but not by 10 mm l-methionine; hence, the synergistic inhibition found for the wild-type enzyme is not effective in these latter mutants.


Broad-host-range vector system for synthetic biology and biotechnology in cyanobacteria.
Inspired by the developments of synthetic biology and the need for improved genetic tools to exploit cyanobacteria for the production of renewable bioproducts, we developed a versatile platform for the construction of broad-host-range vector systems. This platform includes the following features: (i) an efficient assembly strategy in which modules released from 3 to 4 donor plasmids or produced by polymerase chain reaction are assembled by isothermal assembly guided by short GC-rich overlap sequences. (ii) A growing library of molecular devices categorized in three major groups: (a) replication and chromosomal integration; (b) antibiotic resistance; (c) functional modules. These modules can be assembled in different combinations to construct a variety of autonomously replicating plasmids and suicide plasmids for gene knockout and knockin. (iii) A web service, the CYANO-VECTOR assembly portal, which was built to organize the various modules, facilitate the in silico construction of plasmids, and encourage the use of this system. This work also resulted in the construction of an improved broad-host-range replicon derived from RSF1010, which replicates in several phylogenetically distinct strains including a new experimental model strain Synechocystis sp. WHSyn, and the characterization of nine antibiotic cassettes, four reporter genes, four promoters, and a ribozyme-based insulator in several diverse cyanobacterial strains.


Endothelin receptor a blockade is an ineffective treatment for adriamycin nephropathy.
Endothelin is a vasoconstricting peptide that plays a key role in vascular homeostasis, exerting its biologic effects via two receptors, the endothelin receptor A (ETA) and endothelin receptor B (ETB). Activation of ETA and ETB has opposing actions, in which hyperactive ETA is generally vasoconstrictive and pathologic. Selective ETA blockade has been shown to be beneficial in renal injuries such as diabetic nephropathy and can improve proteinuria. Atrasentan is a selective pharmacologic ETA blocker that preferentially inhibits ETA activation. In this study, we evaluated the efficacy of ETA blockade by atrasentan in ameliorating proteinuria and kidney injury in murine adriamycin nephropathy, a model of human focal segmental glomerulosclerosis. We found that ETA expression was unaltered during the course of adriamycin nephropathy. Whether initiated prior to injury in a prevention protocol (5 mg/kg/day, i.p.) or after injury onset in a therapeutic protocol (7 mg/kg or 20 mg/kg three times a week, i.p.), atrasentan did not significantly affect the initiation and progression of adriamycin-induced albuminuria (as measured by urinary albumin-to-creatinine ratios). Indices of glomerular damage were also not improved in atrasentan-treated groups, in either the prevention or therapeutic protocols. Atrasentan also failed to improve kidney function as determined by serum creatinine, histologic damage, and mRNA expression of numerous fibrosis-related genes such as collagen-I and TGF-β1. Therefore, we conclude that selective blockade of ETA by atrasentan has no effect on preventing or ameliorating proteinuria and kidney injury in adriamycin nephropathy.


Using non-communicable disease clinics for tobacco cessation: A promising perspective.
Globally, non-communicable diseases (NCDs) are responsible for 38 million (68%) of the world's 56 million deaths, of which 28 million occur in low- and middle-income countries. Tobacco use is a major preventable and modifiable behavioural risk factor for NCDs. It takes annually a toll of over 7 million people and by 2030, it is anticipated to kill over 8 million people every year. Internationally, WHO has advocated the Framework Convention on Tobacco Control and MPOWER policy to combat the tobacco epidemic. As part of its global commitment towards tobacco control, the Government of India has enacted a comprehensive law, namely Cigarette and Other Tobacco Products Act, in 2003, for governing tobacco control in the country followed by launching of the National Tobacco Control Programme for its effective implementation along with strengthening of tobacco cessation facilities at national and sub-national levels. As per the National Programme for Prevention and Control of Cancers, Diabetes, Cardiovascular Diseases and Stroke, there is a provision of screening of risk factors for NCDs (including tobacco) besides providing treatment and behavioural advice for NCDs. However, presently, tobacco cessation services for NCD patients are under-utilized, probably due to lack of a skilled and dedicated workforce. Delivery of effective patient-centric, disease-specific, culturally sensitive tobacco cessation services at an NCD clinic might efficiently reduce complications of NCDs among patients using tobacco and might further reduce morbidity and mortality attributable to NCDs in India.


Identification of fall risk predictors in daily life measurements: gait characteristics' reliability and association with self-reported fall history.
Background. Gait characteristics extracted from trunk accelerations during daily life locomotion are complementary to questionnaire- or laboratory-based gait and balance assessments and may help to improve fall risk prediction. Objective. The aim of this study was to identify gait characteristics that are associated with self-reported fall history and that can be reliably assessed based on ambulatory data collected during a single week. Methods. We analyzed 2 weeks of trunk acceleration data (DynaPort MoveMonitor, McRoberts) collected among 113 older adults (age range, 65-97 years). During episodes of locomotion, various gait characteristics were determined, including local dynamic stability, interstride variability, and several spectral features. For each characteristic, we performed a negative binomial regression analysis with the participants' self-reported number of falls in the preceding year as outcome. Reliability of gait characteristics was assessed in terms of intraclass correlations between both measurement weeks. Results. The percentages of spectral power below 0.7 Hz along the vertical and anteroposterior axes and below 10 Hz along the mediolateral axis, as well as local dynamic stability, local dynamic stability per stride, gait smoothness, and the amplitude and slope of the dominant frequency along the vertical axis, were associated with the number of falls in the preceding year and could be reliably assessed (all P < .05, intraclass correlation > 0.75). Conclusions. Daily life gait characteristics are associated with fall history in older adults and can be reliably estimated from a week of ambulatory trunk acceleration measurements.


Inflammation in ESRD: causes and potential consequences.
Malnutrition in end-stage renal disease (ESRD) is characterized by hypoalbuminemia, decreased serum creatinine and prealbumin, and decreased subjective global assessment (SGA) scores. Markers of malnutrition predict mortality and correlate closely with inflammatory markers, including serum cytokines and acute phase proteins. After multiple regression analysis, markers of inflammation become stronger predictors of mortality than nutritional markers, suggesting that malnutrition is a result of inflammation. The etiology of inflammation is variable and includes vascular access infection, bioincompatible dialyzers, back filtration of nonsterile dialysate, periodontal disease, urinary tract infections, and other pyogenic infections. Renal failure also may serve to promote inflammation through protein carbonylation. Differences in care patterns of ESRD patients and genetics may contribute to inflammation as evidenced by lower levels of C-reactive protein (CRP) in Asian populations. Inflammation results in loss of muscle mass and hypoalbuminemia as a consequence of its decreased synthesis and increased catabolism. Vascular disease occurs partly because of changes in lipoprotein structure and function, including oxidation of low-density lipoprotein (LDL) and modification of high-density lipoprotein (HDL) by serum amyloid A (SAA) and loss of apolipoprotein A-I. Leukocyte adhesion is promoted by changes in endothelial structure and function, whereas plasma proteins associated with cardiovascular disease (fibrinogen, lipoprotein[a]; SAA) are increased. Consequences of inflammation in ESRD patients include muscle wasting, erythropoetin resistance, and vascular disease. Whereas improvements in nutrition can increase serum albumin and creatinine levels, identification and removal of the underlying cause of inflammation should be one treatment goal.


Alginic Acid from Padina boryana Abate Particulate Matter-Induced Inflammatory Responses in Keratinocytes and Dermal Fibroblasts.
Particulate matter (PM) is a significant participant in air pollution and is hence an inducer of serious health issues. This study aimed to evaluate the dust protective effects of alginate from Padina boryana (PBA) via inflammatory-associated pathways to develop anti-fine dust skincare products. In between the external and internal environments, the skin is considered to be more than a physical barrier. It was observed that PM stimulates inflammation in the skin via activating NF-κB and MAPK pathways. The potential of PBA to inhibit the studied pathways were evident. The metal ion content of PM was considerably reduced by PBA and thus attributed to its chelation ability. Current research demonstrated the potential of P. boryana alginates to be implemented as a protective barrier against inflammation imposed with heavy metal and bacterial-derived endotoxin bound to the surface of the PM. Concisely, the results suggest that the bioactive components derived from the brown algae Padina boryana increased the cellular resistance to PM-stimulated inflammation-driven skin damage.


Biomechanical evaluation of an atlantoaxial lateral mass fusion cage with C1-C2 pedicle fixation.
A biomechanical testing protocol was used to evaluate atlantoaxial fixation techniques in a human cadaveric model. To compare in vitro biomechanics of atlantoaxial lateral mass fusion cage combined with C1-C2 pedicle screw technique with those of C1-C2 pedicle screw technique alone and C1-C2 transarticular screws combined with Gallie wires. An atlantoaxial lateral mass fusion cage was designed, knowing that the cage, when rigidly combined with C1-C2 pedicle screws, could offer other fusion spots for atlantoaxial stabilization in cases when the posterior arch of the atlas is absent or removed for decompression and a Gallie fixation is impossible. No comparative in vitro biomechanical test has been conducted previously to evaluate the feasibility of this method. Anatomic measurements of the atlantoaxial lateral masses were taken using computed tomography in normal human subjects. Six fresh-frozen human cadaveric cervical spines (C0-C4) were used in the biomechanical study. Specimens were tested in their intact condition, after destabilization via transverse-alar-apical ligament disruption, and after implantation of 3 fixation constructs: (1) transarticular screws combined with Gallie wires, (2) C1-C2 pedicle screws, and (3) atlantoaxial lateral mass fusion cage combined with C1-C2 pedicle screws. Pure moment loading up to 1.5 Nm in flexion/extension, right-left lateral bending, and right-left axial rotation was applied to the occiput, and relative intervertebral rotations were determined using stereophotogrammetry. Range of motion for the intact, destabilized, and 3 fixation scenarios were determined. The anatomic data indicated that feasible cage design were in 3 sizes: 11/8, 12/9, and 13/10 mm for length/width, and 3.5, 4, and 4.5 mm for height. The biomechanical data indicated that transverse-alar-apical ligament disruption significantly increased C1-C2 motion for all directions. All the 3 fixation techniques significantly reduced motion compared with the intact and destabilized cases. There were no statistically significant differences among the 3 fixation techniques. The biomechanical study indicated that, contrary to expectation, addition of a cage did not increase the stability compared with C1-C2 pedicle screw alone. However, the C1 + C2 + Cage technique may be a viable alternative for atlantoaxial stabilization when the posterior arch of the atlas is absent or removed for decompression and a Gallie fixation is impossible.


PGE2-EP3 signaling exacerbates intracerebral hemorrhage outcomes in 24-mo-old mice.
With the population aging at an accelerated rate, the prevalence of stroke and financial burden of stroke-related health care costs are expected to continue to increase. Intracerebral hemorrhage (ICH) is a devastating stroke subtype more commonly affecting the elderly population, who display increased mortality and worse functional outcomes compared with younger patients. This study aimed to investigate the contribution of the prostaglandin E2 (PGE2) E prostanoid (EP) receptor subtype 3 in modulating anatomical outcomes and functional recovery following ICH in 24-mo-old mice. EP3 is the most abundant EP receptor in the brain and we have previously shown that signaling through the PGE2-EP3 axis exacerbates ICH outcomes in young mice. Here, we show that EP3 receptor deletion results in 17.9 ± 6.1% less ICH-induced brain injury (P < 0.05) and improves neurological functional recovery (P < 0.01), as identified by lower neurological deficit scores, decreased resting time, and more gross and fine motor movements. Immunohistological staining was performed to investigate possible mechanisms of EP3-mediated neurotoxicity. Identified mechanisms include reduced blood accumulation and modulation of angiogenic and astroglial responses. Using this aged cohort of mice, we have confirmed and extended our previous results in young mice demonstrating the deleterious role of the PGE2-EP3 signaling axis in modulating brain injury and functional recovery after ICH, further supporting the notion of the EP3 receptor as a putative therapeutic avenue for the treatment of ICH.


"It's Like Being a Parent at Work": Antiviolence Frontline Work, Boundaries, and Intimacy During COVID-19.
COVID-19 profoundly shaped how service providers in the antiviolence sector interact with clients, coworkers, and community stakeholders. In addition to stressors inherent in antiviolence work, service providers negotiated new, challenging social distancing and remote communication strategies. In this paper, we analyze interviews with 23 antiviolence workers in the US Great Plains region, focusing on participants' descriptions of workplace boundaries and intimacy. We demonstrate how COVID-19 both expanded and contracted public/private boundaries and formal/informal connections in antiviolence workers' daily experiences. Pandemic conditions revealed the pressing need for frontline workers to exercise discretion over levels of intimate engagement with coworkers and clients.


Aerosolized medications for altering lung surface active properties.
Surface active material is important in the function of both the infant and adult lung. In the premature infant, surfactant depletion results in the requirement for very high distending pressures to open alveoli. As a consequence, shunt, hypoxemia, and right ventricular dysfunction occur. Surfactant replacement, especially by the direct instillation approach, has been proven effective in improving clinical outcome under these circumstances. Problems with surfactant instillation include the "fluid bolus" effect and concerns about optimal distribution of the instilled material. Recent improvements in aerosol systems have created interest in using aerosol delivery to reduce the total dose of surfactant required to treat RDS. In adult acute lung injury, surfactant dysfunction, rather than depletion, is the problem. Simple phospholipid replacement strategies thus may not be effective. Instead, surfactant delivery strategies aimed at regional targeting with surfactants having the necessary associated proteins may be the goal in ARDS. In adults, several instillation trials are underway, but there is also a hope that an aerosol strategy might also be tried. The aerosol route may be particularly useful if a high-efficiency aerosol system (eg, one distal to an endotracheal tube) can be shown to be effective. Other surface active materials exist and there are small studies showing benefit when large instilled doses of these materials are given. These materials, however, have never been studied as aerosols.


Phase III Randomized Controlled Trial of eRAPID: eHealth Intervention During Chemotherapy.
Electronic patient self-Reporting of Adverse-events: Patient Information and aDvice (eRAPID) is an online eHealth system for patients to self-report symptoms during cancer treatment. It provides automated severity-dependent patient advice guiding self-management or medical contact and displays the reports in electronic patient records. This trial evaluated the impact of eRAPID on symptom control, healthcare use, patient self-efficacy, and quality of life (QOL) in a patient population treated predominantly with curative intent. Patients with colorectal, breast, or gynecological cancers commencing chemotherapy were randomly assigned to usual care (UC) or the addition of eRAPID (weekly online symptom reporting for 18 weeks). Primary outcome was symptom control (Functional Assessment of Cancer Therapy-General, Physical Well-Being subscale [FACT-PWB]) assessed at 6, 12, and 18 weeks. Secondary outcomes were processes of care (admissions or chemotherapy delivery), patient self-efficacy, and global quality of life (Functional Assessment of Cancer Therapy-General, EQ5D-VAS, and EORTC QLQ-C30 summary score). Multivariable mixed-effects repeated-measures models were used for analyses. Trial registration: ISRCTN88520246. Participants were 508 consenting patients (73.6% of 690 eligible) and 55 health professionals. eRAPID compared to UC showed improved physical well-being at 6 (P = .028) and 12 (P = .039) weeks and no difference at 18 weeks (primary end point) (P = .69). Fewer eRAPID patients (47%) had clinically meaningful physical well-being deterioration than UC (56%) at 12 weeks. Subgroup analysis found benefit in the nonmetastatic group at 6 weeks (P = .0426), but not in metastatic disease. There were no differences for admissions or chemotherapy delivery. At 18 weeks, patients using eRAPID reported better self-efficacy (P = .007) and better health on EQ5D-VAS (P = .009). Average patient compliance with weekly symptom reporting was 64.7%. Patient adherence was associated with clinician's data use and improved FACT-PWB at 12 weeks. Real-time monitoring with electronic patient-reported outcomes improved physical well-being (6 and 12 weeks) and self-efficacy (18 weeks) in a patient population predominantly treated with curative intent, without increasing hospital workload.


Promising clinical performance of pretargeted immuno-PET with anti-CEA bispecific antibody and gallium-68-labelled IMP-288 peptide for imaging colorectal cancer metastases: a pilot study.
This pilot study evaluated the imaging performance of pretargeted immunological positron emission tomography (immuno-PET) using an anti-carcinoembryonic antigen (CEA) recombinant bispecific monoclonal antibody (BsMAb), TF2 and the [68Ga]Ga-labelled HSG peptide, IMP288, in patients with metastatic colorectal carcinoma (CRC). Patients requiring diagnostic workup of CRC metastases or in case of elevated CEA for surveillance were prospectively studied. They had to present with elevated CEA serum titre or positive CEA tumour staining by immunohistochemistry of a previous biopsy or surgical specimen. All patients underwent endoscopic ultrasound (EUS), chest-abdominal-pelvic computed tomography (CT), abdominal magnetic resonance imaging (MRI) and positron emission tomography using [18F]fluorodeoxyglucose (FDG-PET). For immuno-PET, patients received intravenously 120 nmol of TF2 followed 30 h later by 150 MBq of [68Ga]Ga-labelled IMP288, both I.V. The gold standard was histology and imaging after 6-month follow-up. Eleven patients were included. No adverse effects were reported after BsMAb and peptide injections. In a per-patient analysis, immuno-PET was positive in 9/11 patients. On a per-lesion analysis, 12 of 14 lesions were positive with immuno-PET. Median SUVmax, MTV and TLG were 7.65 [3.98-13.94, SD 3.37], 8.63 cm3 [1.98-46.64; SD 14.83] and 37.90 cm3 [8.07-127.5; SD 43.47] respectively for immuno-PET lesions. Based on a per-lesion analysis, the sensitivity, specificity, positive-predictive value and negative-predictive value were, respectively, 82%, 25%, 82% and 25% for the combination of EUS/CT/MRI; 76%, 67%, 87% and 33% for FDG-PET; and 88%, 100%, 100% and 67% for immuno-PET. Immuno-PET had an impact on management in 2 patients. This pilot study showed that pretargeted immuno-PET using anti-CEA/anti-IMP288 BsMAb and a [68Ga]Ga-labelled hapten was safe and feasible, with promising diagnostic performance. ClinicalTrials.gov NCT02587247 Registered 27 October 2015.


Spatial and temporal characteristics of the spine muscles activation during walking in patients with lumbar instability due to degenerative lumbar disk disease: Evaluation in pre-surgical setting.
Our purpose was to investigate the spatial and temporal profile of the paraspinal muscle activation during gait in a group of 13 patients with lumbar instability (LI) in a pre-surgical setting compared to the results with those from both 13 healthy controls (HC) and a sample of 7 patients with failed back surgery syndrome (FBSS), which represents a chronic untreatable condition, in which the spine muscles function is expected to be widely impaired. Spatiotemporal gait parameters, trunk kinematics, and muscle activation were measured through a motion analysis system integrated with a surface EMG device. The bilateral paraspinal muscles (longissimus) at L3-L4, L4-L5, and L5-S1 levels and lumbar iliocostalis muscles were evaluated. Statistical analysis revealed significant differences between groups in the step length, step width, and trunk bending and rotation. As regard the EMG analysis, significant differences were found in the cross-correlation, full-width percentage and center of activation values between groups, for all muscles investigated. Patients with LI, showed preserved trunk movements compared to HC but a series of EMG abnormalities of the spinal muscles, in terms of left-right symmetry, top-down synchronization, and spatiotemporal activation and modulation compared to the HC group. In patients with LI some of such EMG abnormalities regarded mainly the segment involved by the instability and were strictly correlated to the pain perception. Conversely, in patients with FBSS the EMG abnormalities regarded all the spinal muscles, irrespective to the segment involved, and were correlated to the disease's severity. Furthermore, patients with FBSS showed reduced lateral bending and rotation of the trunk and a reduced gait performance and balance. Our methodological approach to analyze the functional status of patients with LI due to spine disease with surgical indications, even in more complex conditions such as deformities, could allow to evaluate the biomechanics of the spine in the preoperative conditions and, in the future, to verify whether and which surgical procedure may either preserve or improve the spine muscle function during gait.


A simple and safe volumetric alternative to the method of Miles, Misra and Irwin for counting viable bacteria.
A rapid and simple method for counting viable bacteria is described. The technique involves the use of a semi-automatic micropipette and disposable glass-capillary tubes. Viable counts obtained by this method were not significantly different from those obtained by the Miles, Misra and Irwin method or by a pour-plate method. The micropipette procedure is less hazardous than techniques involving the use of calibrated dropping pipettes.


Evolutionary dynamics of higher-order interactions in social networks.
We live and cooperate in networks. However, links in networks only allow for pairwise interactions, thus making the framework suitable for dyadic games, but not for games that are played in larger groups. Here, we study the evolutionary dynamics of a public goods game in social systems with higher-order interactions. First, we show that the game on uniform hypergraphs corresponds to the replicator dynamics in the well-mixed limit, providing a formal theoretical foundation to study cooperation in networked groups. Second, we unveil how the presence of hubs and the coexistence of interactions in groups of different sizes affects the evolution of cooperation. Finally, we apply the proposed framework to extract the actual dependence of the synergy factor on the size of a group from real-world collaboration data in science and technology. Our work provides a way to implement informed actions to boost cooperation in social groups.


[Interaction of Na,K-ATPase with modifying ATP analogs and chloromethylphosphonic acid].
The interaction of synthetic ATP analogs, containing active groups in the triphosphate moiety and in the 8-position of the nucleotide molecule, with highly purified Na, K-ATPase from the medullar layer of porcine kidney was studied. It was found that 11 out of 17 ATP analogs studied irreversibly inhibit the ATPase activity of the enzyme. The pH optimum of the enzyme inactivation by adenosine-5'-(beta-chloroethylphosphate) and adenosine-5'-(p-fluorosulfonylphenylphosphate) beside the pronounced protective effect of ATP suggests possible covalent blocking of histidine and dicarboxylic amino acid residues in the enzyme active center. The irreversible inhibition of the enzyme by "oxo-ATP" containing aldehyde groups in the modified ribose residue in the presence of sodium borohydride suggests a possible presence of the lysine residue epsilon-amino group in the ATP binding site of the enzyme. Na, K-ATPase was found to possess an inorganic phosphate binding site, which is specifically blocked by chloromethylphosphonic acid. the accessibility of this site for modification depends on ATP, NA+ and K+.


Patients with prior fractures have an increased risk of future fractures: a summary of the literature and statistical synthesis.
Numerous studies have reported increased risks of hip, spine, and other fractures among people who had previous clinically diagnosed fractures, or who have radiographic evidence of vertebral fractures. However, there is some variability in the magnitudes of associations among studies. We summarized the literature and performed a statistical synthesis of the risk of future fracture, given a history of prior fracture. The strongest associations were observed between prior and subsequent vertebral fractures; women with preexisting vertebral fractures (identified at baseline by vertebral morphometry) had approximately 4 times greater risk of subsequent vertebral fractures than those without prior fractures. This risk increases with the number of prior vertebral fractures. Most studies reported relative risks of approximately 2 for other combinations of prior and future fracture sites (hip, spine, wrist, or any site). The confidence profile method was used to derive a single pooled estimate from the studies that provided sufficient data for other combinations of prior and subsequent fracture sites. Studies of peri- and postmenopausal women with prior fractures had 2.0 (95 % CI = 1.8, 2.1) times the risk of subsequent fracture compared with women without prior fractures. For other studies (including men and women of all ages), the risk was increased by 2.2 (1.9, 2.6) times. We conclude that history of prior fracture at any site is an important risk factor for future fractures. Patients with a history of prior fracture, therefore, should receive further evaluation for osteoporosis and fracture risk.


Successful birth following transfer of frozen-thawed embryos produced from in-vitro matured oocytes.
It is well established that ovarian hyperstimulation syndrome (OHSS) is more frequent in patients with polycystic ovarian syndrome. In-vitro maturation (IVM) of immature oocytes presents a potential alternative for the fertility treatment and prevention of OHSS for these patients. This report describes the case of a 26-year old woman with a successful pregnancy and delivery following the transfer of frozen-thawed embryos derived from in-vitro matured oocytes. She had three failed cycles of ovarian stimulation (using low-dose step-up gonadotrophin protocol) with or without intrauterine insemination cycles, an ovulation-induction cycle with luteal long protocol, two fresh IVM cycle and one frozen-thawed IVM cycle. During the IVF cycle, she developed moderate OHSS and required hospitalization for 3 weeks. Following four unsuccessful IVF or IVM cycles, 15 months after the last cryopreservation, six fertilized oocytes were thawed for a scheduled embryo transfer. Following thawing, four fertilized oocytes survived and cleaved. Four frozen-thawed embryos were transferred. Six weeks after embryo transfer an ongoing intrauterine single pregnancy with fetal heartbeat was confirmed by transvaginal ultrasound. An uneventful pregnancy and delivery via Caesarean section at 39 weeks resulted in the birth of a normal healthy infant.


Micro/Nanostructured Coating for Cotton Textiles That Repel Oil, Water, and Chemical Warfare Agents.
Using a lotus leaf as our model, we fabricated an extremely low surface energy micro/nanostructured coating for textiles that repel oil, water, and chemical warfare agents (CWAs) using a simple process that is suitable for large scale production. This coating, called "OmniBlock", consisted of approximately 200-nm silica nanoparticles, tetraethylorthosilicate, 3-glycidoxypropyl trimethoxysilane, and a perfluorooctanoic acid-free fluoropolymer (Fluorolink S10) that was cross-linked between Si-O-Si groups via a sol-gel process. The perfluorooctanoic acid-free fluoropolymer-coated silica nanoparticles were simply applied to the surface of a cotton fabric by a dip-dry-cure process, forming dense, continuous, and uniform layers of OmniBlock coating. OmniBlock modified the surface of the cotton fibers, creating a rough, high surface area uniform coating with many micro-crevasses. As a result, n-dodecane, water, and CWAs beaded up without wetting the surface, exhibiting large contact angles of 154° for water and 121° for n-dodecane, with a small shedding angle of 5° and contact angle hysteresis of 3.2° for water. The designed coating showed excellent liquid repellence properties against three types of CWAs: 129°, 72°, and 87° for sulfur mustard (HD), soman (GD), and VX nerve agents, respectively. Furthermore, OmniBlock coating shows good mechanical properties under tensile strength and wash tests. This remarkable ability to repel CWAs is likely to have potential military applications in personal protective equipment systems requiring self-cleaning functions.


Cardiac sudden death as a result of acute coronary artery thrombosis during chemotherapy for testicular carcinoma.
We report the first acute coronary fibrin thrombus arising upon atherosclerosis detected at autopsy in a man receiving chemotherapy for testicular carcinoma. The decedent was a smoker with no other known atherosclerotic risk factors. Histology revealed superficial atherosclerotic plaque erosion with endothelial necrosis and no intraplaque hemorrhage. A focus of intimal lymphoid infiltrates was noted away from the plaque. These findings raise the possibility of chemotherapy-induced vascular damage as a factor in thrombogenesis. A review of Pubmed was performed which documented clinical reports of an association of chemotherapy with acute cardiac ischemia but no well described autopsy findings. Our case highlights the need for careful assessment of the coronary system in chemotherapy patients dying suddenly, particularly in the absence of significant atherosclerotic risk factors. Such postmortem examination will ensure thorough death investigation and may elucidate the pathogenesis of thrombosis with potential reduction in cardiac ischemic risks of chemotherapy patients.


Capillary column switching restricted-access media-liquid chromatography-electrospray ionization-tandem mass spectrometry system for simultaneous and direct analysis of drugs in biofluids.
Capillary online restricted-access media-liquid chromatography-electrospray ionization-tandem mass spectrometry (RAM-LC-ESI-MS/MS) for direct analysis of drugs and metabolites spiked in biological fluids was developed. Using a column switching setup it was possible to perform effective sample preparation and analysis of raw biological fluids (plasma and urine) without matrix effects in the electrospray mass spectrometric detection step. The peak focusing efficiency of the extraction column was more effective in backflush compared to foreflush mode. The system was able to concentrate diminished samples of polar drugs and their metabolites reaching quantifiable results as low as 1 ng/mL utilizing a sample volume of only 333 nL of biofluids. New column hardware was developed to circumvent clogging problems experienced with plasma injections. The glass fiber filter frit, which is commonly used, was replaced with a short piece of 20 microm i.d. fused silica capillary. The extraction columns were able to handle up to 60 injections and showed a high loading capacity, making the saturation of the MS detector the limiting factor on the linear dynamic range. The simultaneous separation and detection of 10 drugs and metabolites was obtained in 8 min of analysis, including the online sample preparation and enrichment step.


Eudaimonic well-being and tumor norepinephrine in patients with epithelial ovarian cancer.
The impact of psychological well-being on the physiologic processes involved in cancer progression remains unclear. Prior research has implicated adrenergic signaling in tumor growth and metastasis. Given that adrenergic signaling is influenced by both positive and negative factors, the authors examined how 2 different aspects of well-being (eudaimonic and positive affect) and psychological distress were associated with tumor norepinephrine (NE) in patients with ovarian cancer. A total of 365 women with suspected ovarian cancer completed psychosocial assessments before surgery and clinical information was obtained from medical records. Study inclusion was confirmed after histological diagnosis. Tumor NE was measured in frozen tissue samples using high-performance liquid chromatography with electrochemical detection. Confirmatory factor analysis was used to model eudaimonic well-being, positive affect, and psychological distress, and structural equation modeling was used to examine associations between these factors and tumor NE. Eudaimonic well-being, positive affect, and psychological distress, modeled as distinct but correlated constructs, best fit the data (ie, compared with unitary or 2-factor models) (root mean square error of approximation, 0.048; comparative fit index, 0.982; and standardized root-mean-squared residual, 0.035). Structural equation modeling analysis that included physical well-being, stage of disease, histology, psychological treatment history, beta-blocker use, and caffeine use as covariates was found to have good model fit (root mean square error of approximation, 0.052; comparative fit index, 0.955; and standardized root-mean-squared residual, 0.036) and demonstrated that eudaimonic well-being was related to lower tumor NE (β = -.24 [P = .045]). In contrast, no effects were found for positive affect or psychological distress. Eudaimonic well-being was found to be associated with lower tumor NE, independent of positive affect and psychological distress. Because adrenergic signaling is implicated in tumor progression, increasing eudaimonic well-being may improve both psychological and physiologic resilience in patients with ovarian cancer.