Potent intracellular antibacterial activity of a marine peptide-N6NH2 and its D-enantiomer against multidrug-resistant Aeromonas veronii.
Aeromonas veronii can cause a variety of diseases such as sepsis in humans and animals. However, there has been no effective way to eradicate A. veronii. In this study, the intracellular antibacterial activities of the C-terminal aminated marine peptide N6 (N6NH2) and its D-enantiomer (DN6NH2) against A. veronii were investigated in macrophages and in mice, respectively. The result showed that DN6NH2 with the minimum inhibitory concentration (MIC) of 1.62 μM is more resistant to cathepsin B than N6NH2 (3.23 μM). The penetration percentages of the cells treated with 4-200 μg/mL fluorescein isothiocyanate (FITC)-DN6NH2 were 52.5-99.6%, higher than those of FITC-N6NH2 (27.0-99.1%). Both N6NH2 and DN6NH2 entered macrophages by macropinocytosis and an energy-dependent manner. DN6NH2 reduced intracellular A. veronii by 34.57%, superior to N6NH2 (19.52%). After treatment with 100 μg/mL DN6NH2, the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β were reduced by 53.45%, 58.54%, and 44.62%, respectively, lower than those of N6NH2 (15.65%, 12.88%, and 14.10%, respectively); DN6NH2 increased the IL-10 level (42.94%), higher than N6NH2 (7.67%). In the mice peritonitis model, 5 μmol/kg DN6NH2 reduced intracellular A. veronii colonization by 73.22%, which was superior to N6NH2 (32.45%) or ciprofloxacin (45.67%). This suggests that DN6NH2 may be used as the candidate for treating intracellular multidrug-resistant (MDR) A. veronii. KEY POINTS: • DN6NH2 improved intracellular antibacterial activity against MDR A. veronii. • DN6NH2 entered macrophages by micropinocytosis and enhanced the internalization rates. • DN6NH2 effectively protected the mice from infection with A. veronii.


A Modified Arrestin1 Increases Lactate Production in the Retina and Slows Retinal Degeneration.
Glucose metabolism in the retina is carefully orchestrated, with glucose being delivered to photoreceptors from the choroidal circulation through the retinal pigmented epithelium (RPE). In photoreceptors, glucose is processed principally by aerobic glycolysis, from which the lactate byproduct is provided to the RPE and Müller glia for their energetic needs. In this study, we utilize a modified arrestin1 protein to enhance the glycolytic output of lactate from rod photoreceptors through disinhibition of enolase1 activity with the goal being to use this increased lactate production as a gene-agnostic approach to slowing retinal degeneration. Mouse arrestin1 with E362G/D363G amino acid substitutions (referred to as "ArrGG") was packaged into AAV and tested for safety and for efficacy in increasing retinal lactate production. Overexpression of ArrGG in C57BL/6J mice did not result in any detectable changes in either electroretinogram (ERG) function or photoreceptor survival as measured by outer nuclear layer (ONL) thickness. However, mouse retinas expressing ArrGG showed a ∼25% increase in the rate of lactate secretion. Therefore, AAV-ArrGG was delivered intravitreally to heterozygous P23H rhodopsin knockin mice (RhoP23H/+) to determine if enhancing glycolysis in photoreceptors can slow retinal degeneration in this animal model of retinitis pigmentosa. We found that the expression of ArrGG in these mice slowed the decline of both scotopic and photopic ERG function. Correspondingly, there was significant preservation of ONL thickness in RhoP23H/+ mice treated with ArrGG compared with controls. In conclusion, our studies show that expressing ArrGG in C57BL/6J mouse retina results in an increase in lactate production, consistent with an upregulation of glycolysis. In the P23H rhodopsin model of retinitis pigmentosa, the expression of ArrGG led to significant preservation of photoreceptor function and slowing of retinal degeneration. These findings suggest that enhancing glycolysis by targeting increased enolase1 activity with a modified arrestin1 in photoreceptors may offer a therapeutic approach to slowing retinal degeneration.


Constitutively activated ALK2 and increased SMAD1/5 cooperatively induce bone morphogenetic protein signaling in fibrodysplasia ossificans progressiva.
Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder characterized by congenital malformation of the great toes and by progressive heterotopic bone formation in muscle tissue. Recently, a mutation involving a single amino acid substitution in a bone morphogenetic protein (BMP) type I receptor, ALK2, was identified in patients with FOP. We report here that the identical mutation, R206H, was observed in 19 Japanese patients with sporadic FOP. This mutant receptor, ALK2(R206H), activates BMP signaling without ligand binding. Moreover, expression of Smad1 and Smad5 was up-regulated in response to muscular injury. ALK2(R206H) with Smad1 or Smad5 induced osteoblastic differentiation that could be inhibited by Smad7 or dorsomorphin. Taken together, these findings suggest that the heterotopic bone formation in FOP may be induced by a constitutively activated BMP receptor signaling through Smad1 or Smad5. Gene transfer of Smad7 or inhibition of type I receptors with dorsomorphin may represent strategies for blocking the activity induced by ALK2(R206H) in FOP.


[Experience of surgical treatment of patients with N2 lung cancer].
From January 1987 to December 1993, 426 patients with lung cancer were operated in our hospital, among which 159 patients were diagnosed postoperatively to be N2 disease by pathology including 81 central type and 78 peripheral type lung cancer. Radical operations were performed on 135 cases, palliative operations on 24 cases. Follow up study: one-year survival rate was 71.7%, three-year survival rate 29.0% and five-year survival rate 21.7%. The main factors affecting operative results are tumor cell type, the number and location of metastatic lymph nodes and the thoroughness of dissection. Tumor staging, except T4 tumor is not a main factor influencing prognosis. The indications of operation performed on N2 lung cancer and the necessity of extensive nodal exenteration are also discussed in this article. We consider extensive hilar and mediastinal nodal exenteration necessary in order to achieve radical resection and good prognosis.


[School children poisoning by ornamental trees].
Eleven cases of poisoning of children who had chewed threads from the barks of trees subsequently identified as Robinia pseudo-acacia were detected in Sanlúcar La Mayor (Sevilla). A retrospective study was carried out of all children who had chewed barks of these trees on the days 28, 29 and 30 of January. The data were collected from the daily record of emergencies. From the twenty fulfilled epidemiological questionnaires it was found out that the predominant symptoms were abdominal pain, nausea, "biliary" vomits and some degree of weakness. This fact points to the need to identify and to control the risk factors in a given milieu so as to prevent these occurrences.


Curcumin-coordinated nanoparticles with improved stability for reactive oxygen species-responsive drug delivery in lung cancer therapy.
The natural compound curcumin (Cur) can regulate growth inhibition and apoptosis in various cancer cell lines, although its clinical applications are restricted by extreme water insolubility and instability. To overcome these hurdles, we fabricated a Cur-coordinated reactive oxygen species (ROS)-responsive nanoparticle using the interaction between boronic acid and Cur. We synthesized a highly biocompatible 4-(hydroxymethyl) phenylboronic acid (HPBA)-modified poly(ethylene glycol) (PEG)-grafted poly(acrylic acid) polymer (PPH) and fabricated a Cur-coordinated ROS-responsive nanoparticle (denoted by PPHC) based on the interaction between boronic acid and Cur. The mean diameter of the Cur-coordinated PPHC nanoparticle was 163.8 nm and its zeta potential was -0.31 mV. The Cur-coordinated PPHC nanoparticle improved Cur stability in physiological environment and could timely release Cur in response to hydrogen peroxide (H2O2). PPHC nanoparticles demonstrated potent antiproliferative effect in vitro in A549 cancer cells. Furthermore, the viability of cells treated with PPHC nanoparticles was significantly increased in the presence of N-acetyl-cysteine (NAC), which blocks Cur release through ROS inhibition. Simultaneously, the ROS level measured in A549 cells after incubation with PPHC nanoparticles exhibited an obvious downregulation, which further proved that ROS depression indeed influenced the therapeutic effect of Cur in PPHC nanoparticles. Moreover, pretreatment with phosphate-buffered saline (PBS) significantly impaired the cytotoxic effect of Cur in A549 cells in vitro while causing less damage to the activity of Cur in PPHC nanoparticle. The Cur-coordinated nanoparticles developed in this study improved Cur stability, which could further release Cur in a ROS-dependent manner in cancer cells.


Maturity degree of composts from municipal solid wastes evaluated by differential scanning calorimetry.
Differential scanning calorimetry (DSC) in association with chemical analysis was applied to assess the maturity reached by the organic fraction of Municipal Solid Wastes (MSW) subjected to composting processes with manual and fixed aeration and sampled at different composting times. Thermograms showed that the difference in the treatments, i.e., the manual aeration and the fixed aeration, had no relevant effect on the stabilization and maturation of OM in the substrates. Common thermal effects observed were: a low temperature endotherm assigned to dehydration and/or loss of peripheral polysaccharides chains; a medium temperature exotherm assigned to loss of peptidic structures, and a high temperature exotherm assigned to oxydation and polycondensation of aromatic nuclei of the molecule. Results obtained suggest that in the experimental conditions used, a shorter time of composting (about 30 d) appears adequate, in order to limit the extended mineralization of OM, whereas a prolonged composting time (up to 132 d) would produce a compost of poor quality with high ash content and low OM content.


General control of transition-metal-doped GaN nanowire growth: toward understanding the mechanism of dopant incorporation.
We report the first synthesis and characterization of cobalt- and chromium-doped GaN nanowires (NWs), and compare them to manganese-doped GaN NWs. Samples were synthesized by chemical vapor deposition method, using cobalt(II) chloride and chromium(III) chloride as dopant precursors. For all three impurity dopants hexagonal, triangular, and rectangular NWs were observed. The fraction of NWs having a particular morphology depends on the initial concentration of the dopant precursors. While all three dopant ions have the identical effect on GaN NW growth and faceting, Co and Cr are incorporated at much lower concentrations than Mn. These findings suggest that the doping mechanism involves binding of the transition-metal intermediates to specific NW facets, inhibiting their growth and causing a change in the NW morphology. We discuss the doping concentrations of Mn, Co, and Cr in terms of differences in their crystal-field stabilization energies (DeltaCFSE) in their gas-phase intermediates and in substitutionally doped GaN NWs. Using iron(III) chloride and cobalt(II) acetate as dopant precursors we show that the doping concentration dependence on DeltaCFSE allows for the prediction of achievable doping concentrations for different dopant ions in GaN NWs, and for a rational choice of a suitable dopant-ion precursor. This work further demonstrates a general and rational control of GaN NW growth using transition-metal impurities.


Ovarian response and cumulative live birth rate of women undergoing in-vitro fertilisation who had discordant anti-Mullerian hormone and antral follicle count measurements: a retrospective study.
To evaluate ovarian response and cumulative live birth rate of women undergoing in-vitro fertilization (IVF) treatment who had discordant baseline serum anti-Mullerian hormone (AMH) level and antral follicle count (AFC). This is a retrospective cohort study on 1,046 women undergoing the first IVF cycle in Queen Mary Hospital, Hong Kong. Subjects receiving standard IVF treatment with the GnRH agonist long protocol were classified according to their quartiles of baseline AMH and AFC measurements after GnRH agonist down-regulation and before commencing ovarian stimulation. The number of retrieved oocytes, ovarian sensitivity index (OSI) and cumulative live-birth rate for each classification category were compared. Among our studied subjects, 32.2% were discordant in their AMH and AFC quartiles. Among them, those having higher AMH within the same AFC quartile had higher number of retrieved oocytes and cumulative live-birth rate. Subjects discordant in AMH and AFC had intermediate OSI which differed significantly compared to those concordant in AMH and AFC on either end. OSI of those discordant in AMH and AFC did not differ significantly whether either AMH or AFC quartile was higher than the other. When AMH and AFC are discordant, the ovarian responsiveness is intermediate between that when both are concordant on either end. Women having higher AMH within the same AFC quartile had higher number of retrieved oocytes and cumulative live-birth rate.


Management of Pacemaker Implantation during COVID-19 Infection.
The management of device implantation during the COVID-19 infection has not well defined yet. This is the first case of complete atrioventricular block in a symptomatic patient affected by the COVID-19 infection treated with early pacemaker implantation to minimize the risk of virus contagion.


The regulation of hematopoiesis in max 41 transgenic mice with sustained excess granulopoiesis.
max 41 transgenic mice consistently exhibit elevated numbers of mature granulocytes and monocytes in the peripheral blood and of immature and mature cells of these lineages in the marrow, spleen, lymph nodes and liver. The immature populations are not autonomous and exhibit a normal quantitative responsiveness to proliferative stimulation by the four colony-stimulating factors. The present studies examined three other candidate regulators of granulocyte formation and showed that max 41 cells exhibit normal quantitative responsiveness to stem cell factor, slightly enhanced responsiveness to IL-6 but reduced responsiveness to Flk-ligand. Serum levels of growth factors were not unusually elevated in max 41 mice before or after the injection of endotoxin nor were excessive levels of the four CSFs or IL-6 produced in cultures of max 41 organs. Responses to injected G-CSF were not unusually high in terms of fold-elevations in max 41 mice. Levels of mRNA for various growth factors were not abnormal in max 41 marrow populations although, in crowded cultures, max 41 marrow cells exhibited a higher level of endogenously stimulated colony formation than control cells. max 41 cells also exhibited elevated responsiveness to stimulation by mixtures of growth factors, particularly those in organ-conditioned media. The present observations suggest some possible mechanisms by which a max 41 mouse might achieve a sustained elevation of granulocyte and monocyte production but the data seem insufficient to provide a complete explanation and indicate persisting deficiencies in knowledge of how granulocyte and monocyte production is regulated.


Immediate and Sustained Improvement in Behavior and Life Quality by Adenotonsillectomy in Children With Sleep-Disordered Breathing.
To investigate longitudinal changes in behavior and quality-of-life (QoL) in children with sleep disordered breathing (SDB) after adenotonsillectomy (AT). This study prospectively enrolled 148 children who underwent AT for SDB. Caregivers filled out Korean attention deficit hyperactivity disorder (ADHD) rating scale (K-ARS) and Korean version of the obstructive sleep apnea-18 (KOSA-18) at preoperative 1 day, postoperative 1 month, and postoperative 6 months. Longitudinal changes in K-ARS and KOSA-18 were evaluated and compared among subgroups. Both K-ARS and KOSA-18 scores improved immediately at postoperative 1 month and were maintained at postoperative 6 months. The mean preoperative K-ARS scores of the non-ADHD, ADHD-trait, and overt-ADHD groups showed uniformly immediate and sustained improvements. Also, the mean preoperative KOSA-18 scores of the small, moderate, and large impact groups were significantly improved both at postoperative 1 month and 6 months. The changes in behavior and QoL showed no significant differences with regard to the aforementioned factors. After AT, we may expect immediate and sustained improvements in behavior and QoL in children with SDB regardless of preoperative symptom severity. Moreover, by performing AT, improvements in behavior and QoL are expected regardless of sex, age, allergic trait, or concurrent coblation-assisted turbinoplasty. These findings may help our colleague physicians counselling pediatric SDB patients and their caregivers.


Machine learning discovery of longitudinal patterns of depression and suicidal ideation.
Depression is often accompanied by thoughts of self-harm, which are a strong predictor of subsequent suicide attempt and suicide death. Few empirical data are available regarding the temporal correlation between depression symptoms and suicidal ideation. We investigated the anecdotal concern that suicidal ideation may increase during a period of depression improvement. Longitudinal Patient Health Questionnaire (PHQ)-9 is a questionnaire of 9 multiple-choice questions to assess the frequency of depressive symptoms within the previous two weeks. We analyzed a chronic depression treatment population's electronic health record (EHR) data, containing 610 patients' longitudinal PHQ-9 scores (62% age 45 and older; 68% female) within 40 weeks. The irregular and sparse EHR data were transformed into continuous trajectories using Gaussian process regression. We first estimated the correlations between the symptoms (total score of the first 8 questions; PHQ-8) and suicide ideation (9th question score; Item 9) using the cross-correlation function. We then used an artificial neural network (ANN) to discover subtypes of depression patterns from the fitted depression trajectories. In addition, we conducted a separate analysis using the unfitted raw PHQ scores to examine PHQ-8's and Item 9's pattern changes. Results showed that the majority of patients' PHQ-8 and Item 9 scores displayed strong temporal correlations. We found five patterns in the PHQ-8 and the Item 9 trajectories. We also found 8% - 13% of the patients have experienced an increase in suicidal ideation during the improvement of their PHQ-8. Using a trajectory-based method for subtype pattern detection in depression progression, we provided a better understanding of temporal correlations between depression symptoms over time.


[A case of bilateral 3-lung lesion (metastatic and primary tumour, tumourlet) resected simultaneously].
A 70-year-old male patient underwent right nephrectomy for renal clear cell carcinoma. After 8 years an X-ray showed a nodule on the left lung, and CT scan detected it to be a 15 × 12 mm mass in S1+2 segment of the left lung. CT also detected another 15 × 7 mm mass in the right S3 segment. These lesions had a high FDG accumulation. Pre-operative diagnosis is bilateral pulmonary metastases from renal cell carcinoma, and bilateral lung segmentectomy was performed. Left S1+2 resected tumor was histologically clear cell carcinoma by intra-operative examination, then right S3 segmentectomy was done. And that time, small tumor was found in the middle lung lobe, and a wedge resection was performed. These specimens revealed a primary lung carcinoma of right S3, and tumourlet of middle lobe. It is very rare that three different histlogical types of lung tumor were found.


Nance-Horan syndrome protein, NHS, associates with epithelial cell junctions.
Nance-Horan syndrome, characterized by congenital cataracts, craniofacial, dental abnormalities and mental disturbances, is an X-linked disorder with significant phenotypic heterogeneity. Affected individuals have mutations in the NHS (Nance-Horan syndrome) gene typically resulting in premature truncation of the protein. This report underlines the complexity of the regulation of the NHS gene that transcribes several isoforms. We demonstrate the differential expression of the two NHS isoforms, NHS-A and NHS-1A, and differences in the subcellular localization of the proteins encoded by these isoforms. This may in part explain the pleiotropic features of the syndrome. We show that the endogenous and exogenous NHS-A isoform localizes to the cell membrane of mammalian cells in a cell-type-dependent manner and that it co-localizes with the tight junction (TJ) protein ZO-1 in the apical aspect of cell membrane in epithelial cells. We also show that the NHS-1A isoform is a cytoplasmic protein. In the developing mammalian lens, we found continuous expression of NHS that became restricted to the lens epithelium in pre- and postnatal lens. Consistent with the in vitro findings, the NHS-A isoform associates with the apical cell membrane in the lens epithelium. This study suggests that disturbances in intercellular contacts underlie cataractogenesis in the Nance-Horan syndrome. NHS is the first gene localized at TJs that has been implicated in congenital cataracts.


Relationship among blood indicators of lipomobilization and hepatic function during early lactation in high-yielding dairy cows.
Blood indicators are used as a tool to diagnose metabolic disorders. The present work was conducted to study the relationships among blood indicators of lipomobilization and hepatic function in high-yielding dairy cows. Two groups of Holstein cows were studied: 27 early lactation cows and 14 mid lactation cows from four different herds with similar husbandry characteristics in Galicia, Spain. Blood samples were obtained to measure beta-hydroxybutyrate (BHB), non-esterified fatty acids (NEFA), triglycerides (TG), and the activity of aspartate transaminase (AST) and gamma-glutamyl transferase. Cows in early lactation had higher levels of BHB and NEFA than mid lactation cows. High lipomobilization (NEFA > 400 µmol/L) was detected in 67% and 7% of early lactation and mid lactation cows, respectively, while subclinical ketosis (BHB > 1.2 mmol/L) was detected in 41% and 28% of the early lactation and lactation cows, respectively. TG concentrations were low in all cows suffering subclinical ketosis and in 61% of the cows with high lipomobilization. During early lactation, 30% of cows suffered hepatic lipidosis as detected by levels of AST. Compromised hepatic function was observed in early lactation cows as shown by lower concentrations of glucose, total protein, and urea.


Endothelin-like immunoreactivity and receptor binding in the choroid and retina.
This study has examined the localisation and receptor-binding of the endothelins in retina and choroid of human and rat origin. Immunoreactivity to anti-ET1 and anti-ET3 was investigated in trypsin digests, frozen sections and ultrathin sections using immunocytochemistry and immunogold labelling techniques. In addition, receptor binding of 125I-ET1 and 125I-ET3 was visualised and quantified using autoradiography and image analysis. Intense immunoreactivity to anti-ET1 and anti-ET3 was observed in the photoreceptor inner segments and in the outer plexiform layer (OPL) of human and rat retina. Ultrastructural localisation using immunogold labelling confirmed the presence of ET1 and ET3 in the photoreceptor cells. In retinal vascular digests, ET1 was visualised in the arteries, arterioles and at the pre-arteriolar sphincters, however, immunoreactivity to anti-ET3 was absent in the retinal vasculature. Both ETA and ETB-type receptor binding sites to 125I-ET1 and 125I-ET3 were detected in the vascular smooth muscle of choroidal and retinal vessels with the former being predominant. Extravascular binding sites of the ETB-type were found in the ganglion cell layer.


Airway scope laryngoscopy under manual inline stabilization and cervical collar immobilization: a crossover in vivo cinefluoroscopic study.
Direct laryngoscopy along with manual inline stabilization (MIS) is currently the standard care for patients with suspected neck injuries. However, cervical collar immobilization is more commonly performed in the prehospital environment, and its early removal is necessary before intubation. We hypothesized that if usability of Airway Scope (AWS) in a difficult airway could also bring merits to intubation under cervical collar immobilization, unnecessary risk caused by the removal of a neck collar may be prevented. In this crossover study, 30 consenting patients presenting for surgery were assigned to undergo intubation using AWS. Neck was stabilized manually and by a neck collar in a random order before laryngoscopy was performed by the same anesthesiologist. Measurements include interincisor distance (IID), success rate, intubation time, and fluoroscopic examination of the upper and middle cervical spine. IID was notably narrower after application of a neck collar (mean ± SE: MIS, 19 mm ± 1 mm; collar, 10 mm ± 1 mm; p < 0.01). One and 9 failures were encountered in MIS and collar groups, respectively (p = 0.012). Intubation time proved no statistical significance. Extension of craniocervical junction was observed in both groups, but occipitoatlantal joint was significantly more extended in collar group (median [range]: AWS, 10-degree angle [-1 to 20-degree angle]; collar, 14-degree angle [5 to 26-degree angle]; p < 0.01). AWS laryngoscopy under cervical collar immobilization fails to meet our expectation. Intubation failed in 30% of the cases in collar group whereas only 3.3% of the cases in MIS group. Significant difference of mouth opening limitation is probably the major reason, as 7 of 9 failed cases in collar group had IID <10 mm. This was insufficient to insert the 18-mm blade of AWS. In addition, occipitoatlantal joint suffered a greater extension when wearing a neck collar. Differences in the method to stabilize the neck may be the reason. When compared with cervical collar immobilization, AWS laryngoscopy along with MIS seems to be a safer and more definite method to secure airway of neck-injured trauma patients because it limits less mouth opening and upper cervical spine movement.


[Ultrasonographic diagnosis in inflammatory-rheumatic changes of the shoulder joint].
Inflammatory rheumatoid changes of the shoulder joint are often diagnosed rather late, so therapy is largely directed towards pain reduction and less towards maintenance of full joint function. When considering the mutilating type of chronic polyarthritis, it becomes evident how important the role of the shoulder joint is in the patients performance of basic everyday activities. In this paper the important structures of the shoulder joint that can be visualized by ultrasound are described as to their rheumatological significance, and pathological findings are discussed along with the appropriate therapy.


Testosterone Recovery after Androgen Deprivation Therapy in Prostate Cancer: Building a Predictive Model.
To analyze the variability, associated actors, and the design of nomograms for individualized testosterone recovery after cessation of androgen deprivation therapy (ADT). A longitudinal study was carried out with 208 patients in the period 2003 to 2019. Castrated and normogonadic testosterone levels were defined as 0.5 and 3.5 ng/mL, respectively. The cumulative incidence curve described the recovery of testosterone. Univariate and multivariate analyzes were performed to predict testosterone recovery with candidate prognostic factors prostate-specific antigen at diagnosis, clinical stage, Gleason score from biopsy, age at cessation of ADT, duration of ADT, primary therapy and use of LHRH (luteinizing hormone-releasing hormone) agonists. The median follow-up duration in the study was 80 months (interquartile range, 49-99 mo). Twenty-five percent and 81% of patients did not recover the castrate and normogonadic levels, respectively. Duration of ADT and age at ADT cessation were significant predictors of testosterone recovery. We built two nomograms for testosterone recovery at 12, 24, 36, and 60 months. The castration recovery model had good calibration. The C-index was 0.677, with area under the receiver operating characteristic curve (AUC-ROC) of 0.736, 0.783, 0.782, and 0.780 at 12, 24, 36, and 60 months, respectively. The normogonadic recovery model overestimated the higher values of probability of recovery. The Cindex was 0.683, with AUC values of 0.812, 0.711, 0.708 and 0.693 at 12, 24, 36, and 60 months, respectively. Depending on the age of the patient and the length of treatment, clinicians may stop ADT and the castrated testosterone level will be maintained or, if the course of treatment has been short, we can estimate if it will return to normogonadic levels.


Prognostic factors for relapse and outcome in pediatric acute transverse myelitis.
It may be difficult for clinicians to estimate the prognosis of pediatric acute transverse myelitis (ATM). The aim of this study was to define prognostic factors for relapsing disease and poor outcome in pediatric ATM. This prospective cohort study included 49 children, 18 boys and 31 girls (median age 13.1 years, IQR 6.5-16.2) with a first episode of ATM. Factors associated with relapsing disease and poor outcome (Expanded Disability Status Scale (EDSS) ≥ 4) were assessed during a median follow-up of 37 months (IQR 18-75). In total, 14 patients (29%) experienced ≥ 1 relapse(s) and nine patients (18%) had a poor outcome. Factors at onset associated with relapsing disease included higher age (16.1 vs. 11.6 years, p = 0.002), longer time to maximum severity of symptoms (5.5 vs. 3 days, p = 0.01), lower maximum EDSS score (4.0 vs. 6.5, p = 0.003), short lesion on spinal MRI (64 vs. 21%, p = 0.006), abnormalities on brain MRI (93 vs. 44%, p = 0.002) and presence of oligoclonal bands in cerebrospinal fluid (67 vs. 14%, p = 0.004). The only factor associated with poor outcome was presence of a spinal cord lesion on MRI without cervical involvement (56 vs. 14%, p = 0.02). Pediatric ATM patients presenting with clinical, radiological and laboratory features associated with multiple sclerosis (MS) are at risk for relapsing disease. In absence of these known MS risk factors at onset of disease these patients are at low risk for relapses. Only a minority of pediatric ATM patients in this cohort have a poor outcome.


Sphingosine 1-phosphate in metabolic syndrome (Review).
Metabolic syndrome (MetS), a clustering of components, is closely associated with the development and prognosis of cardiovascular disease and diabetes. Sphingosine 1-phosphate (S1P) is a lysophospholipid with paracrine and autocrine effects, which is associated with obesity, insulin resistance, hyperglycemia, dyslipidemia and hypertension through extracellular and intracellular signals to achieve a variety of biological functions. However, there is controversy regarding the role of S1P in MetS; the specific role played by S1P remains unclear. It ameliorates abnormal energy metabolism and deviant adipogenesis and mediates inflammation in obesity. Despite the fact that sphingosine kinase (SphK)2/S1P increases the glucose‑stimulated insulin secretion of β-cells, more evidence showed that activation of the SphK1/S1P/S1P2R pathway inhibited the feedback loop of insulin secretion and sensitivity. The majority of S1P1R activation improves diabetes whereas S1P2R activation worsens the condition. In hyperlipidemia, S1P binds to high-density lipoprotein, low‑density lipoprotein and very low-density lipoprotein exerting different effects. Moreover, low concentrations of S1P lead to vasodilation whereas high concentrations of S1P result in vasocontraction of isolated arterioles. This review discusses the means by which different SphKs, S1P concentrations or S1P receptor subtypes results to diverse result in MetS, and then examines the role of S1P in MetS.


Asymptomatic Clostridium difficile colonization in two Australian tertiary hospitals, 2012-2014: prospective, repeated cross-sectional study.
To investigate the prevalence and risk factors for asymptomatic toxigenic (TCD) and nontoxigenic Clostridium difficile (NTCD) colonization in a broad cross section of the general hospital population over a 3-year period. Patients without diarrhoea admitted to two Australian tertiary hospitals were randomly selected through six repeated cross-sectional surveys conducted between 2012 and 2014. Stool specimens were cultured under anaerobic conditions, and C. difficile isolates were tested for the presence of toxin genes and ribotyped. Patients were then grouped into noncolonized, TCD colonized or NTCD colonized for identifying risk factors using multinomial logistic regression models. A total of 1380 asymptomatic patients were enrolled; 76 patients (5.5%) were TCD colonized and 28 (2.0%) were NTCD colonized. There was a decreasing annual trend in TCD colonization, and asymptomatic colonization was more prevalent during the summer than winter months. TCD colonization was associated with gastro-oesophageal reflux disease (relative risk ratio (RRR) = 2.20; 95% confidence interval (CI) 1.17-4.14), higher number of admissions in the previous year (RRR = 1.24; 95% CI 1.10-1.39) and antimicrobial exposure during the current admission (RRR = 2.78; 95% CI 1.23-6.28). NTCD colonization was associated with chronic obstructive pulmonary disease (RRR = 3.88; 95% CI 1.66-9.07) and chronic kidney failure (RRR = 5.78; 95% CI 2.29-14.59). Forty-eight different ribotypes were identified, with 014/020 (n = 23), 018 (n = 10) and 056 (n = 6) being the most commonly isolated. Risk factors differ between patients with asymptomatic colonization by toxigenic and nontoxigenic strains. Given that morbidity is largely driven by toxigenic strains, this novel finding has important implications for disease control and prevention.


Infantile leukocoria caused by posterior lenticonus.
Posterior lenticonus--a bulging of the posterior capsule and cortex--is an acquired lens abnormality, which becomes increasingly opaque. We report an unusual case of bilateral posterior lenticonus in an infant, who initially presented with leukocoria and was referred with a diagnosis of retinoblastoma. Careful physical examination and ultrasound analysis were important in the diagnosis. Ultrasound also aids the surgeon in planning therapy. Posterior lenticonus should be considered in the differential diagnosis of retinoblastoma.


Controversial aspects of the concept of health needs and their impact on the accessibility of medicine and health services.
This article aimed to present the problems related to accessibility of health services by re-reading four case studies which illustrate the different dimensions of the definition of health needs and their impact on the accessibility of medicine and health services. The theoretical model of Vargas-Peláez et al.1, which allows a better understanding of the complexity of the definition of health needs and its impact on the demand for medicines and services, was adopted to re-read the case studies on the prices of patented medicines, the models of public provision, hemodynamic services, and prescription of anxiolytics. The results may shed some light on the complexity of the challenges to achieve health rights in a peripheral capitalist society where the production and distribution of goods and services is organized from the perspective of the market, even though public policies seek to regulate them. In this sense, it seems essential that the State plays a major role in guaranteeing equality in the achievement of social rights, not only influencing the industrial sector in reducing the prices of medicines and improving their supply, but also guaranteeing access to medicine and health services.


Antimicrobial Carvacrol-Containing Polypropylene Films: Composition, Structure and Function.
Significant research has been directed toward the incorporation of bioactive plant extracts or essential oils (EOs) into polymers to endow the latter with antimicrobial functionality. EOs offer a unique combination of having broad antimicrobial activity from a natural source, generally recognized as safe (GRAS) recognition in the US, and a volatile nature. However, their volatility also presents a major challenge in their incorporation into polymers by conventional high-temperature-processing techniques. Herein, antimicrobial polypropylene (PP) cast films were produced by incorporating carvacrol (a model EO) or carvacrol, loaded into halloysite nanotubes (HNTs), via melt compounding. We studied the composition-structure-property relationships in these systems, focusing on the effect of carvacrol on the composition of the films, the PP crystalline phase and its morphology and the films' mechanical and antimicrobial properties. For the first time, molecular dynamics simulations were applied to reveal the complex interactions between the components of these carvacrol-containing systems. We show that strong molecular interactions between PP and carvacrol minimize the loss of this highly-volatile EO during high-temperature polymer processing, enabling semi-industrial scale production. The resulting films exhibit outstanding antimicrobial properties against model microorganisms (Escherichia coli and Alternaria alternata). The PP/(HNTs-carvacrol) nanocomposite films, containing the carvacrol-loaded HNTs, display a higher level of crystalline order, superior mechanical properties and prolonged release of carvacrol, in comparison to PP/carvacrol blends. These properties are ascribed to the role of HNTs in these nanocomposites and their effect on the PP matrix and retained carvacrol content.


Healthy colon, healthy life (colon sano, vida sana): colorectal cancer screening among Latinos in Santa Clara, California.
Colorectal cancer (CRC) screening rates are low among Latinos. To identify factors associated with CRC screening, we conducted a telephone survey of Latino primary care patients aged 50-79 years. Among 1,013 participants, 38% were up-to-date (UTD) with fecal occult blood test (FOBT); 66% were UTD with any CRC screening (FOBT, sigmoidoscopy, or colonoscopy). Individuals less than 65, females, those less acculturated, and patients of female physicians were more likely to be UTD with FOBT. CRC screening among Latinos is low. Younger patients, women, and patients of female physicians receive more screening.


[Viral etiology of acute respiratory infection in children from Wenzhou between 2007 and 2008].
To study the viral etiology of acute respiratory infection (ARI)in children from Wenzhou, Zhejiang between 2007 and 2008. The nasopharyngeal aspirate samples were obtained from 5 097 hospitalized children with ARI. Seven common respiratory viruses, including respiratory syncytial virus (RSV), influenza virus A and B, parainfluenza viruses 1, 2 and 3 and adenovirus, were detected using direct immunofluorescence. Viral agents were identified in 2 209 cases (43.3%).Of the 2 209, RSV was the most frequent (78.1%), followed by parainfluenza 3 (12.4%), influenza virus A (3.0%), adenovirus (2.8%), parainfluenza 1 (1.7%), influenza B (0.5%) and parainfluenza 2 (0.3%). The infants at ages of <3 months and <6 months had higher detection rate of viruses (53.6% and 49.2%, respectively). A highest detection rate of viruses was found in winter. RSV is the leading pathogen of ARI in children from Wenzhou, Zhejiang between 2007 and 2008. The children at age of less than 6 months are susceptible to respiratory viruses. The viral activity peaks in winter.


Alterations in CDK1 expression and nuclear/nucleolar localization following induction in a spontaneous canine mammary cancer model.
Transcription of CDK1 is induced as cells re-enter the cell cycle from quiescence and these early cell cycle re-entry events have been modeled by okadaic acid treatment due to its activity on specific enhancer sequences in the human CDK1 promoter. To investigate heterogeneity of control of this mechanism in the context of neoplastic transformation, a cellular model derived from spontaneous canine mammary cancer (CMT) was developed that includes six cell lines derived from different animals. Notable heterogeneity in response to okadaic acid was observed in expression of CDK1 mRNA and protein. In response to okadaic acid treatment, two CMT cell lines exhibited a CDK1 mRNA induction while one cell line exhibited CDK1 mRNA suppression, and three remained unchanged. Despite this variability, three CMT cell lines arrested in S or G2/M phase and five exhibited marked increases in apoptosis. Moderation of some of these differences were observed at the level of CDK1 protein as three of six CMT cell lines exhibited only moderate enhancement in CDK1 protein levels while three remained essentially unchanged. Some additional differences in distribution of CDK1 protein, favoring enhanced nuclear over cytoplasmic CDK1 localization, were observed in treated cells in the form of concentrated nuclear CDK1 labeled foci. Confocal microscopy revealed the presence of brightly labeled punctate foci containing CDK1 protein within nuclei as well as nucleoli in okadaic acid treated non-mitotic cells suggesting a role for this kinase outside the normal G2/mitotic phase of the cell cycle and suggesting a possible new function within the nucleolus.


Efficacy of a functional food ingredient from Ensete superbum Roxb. Cheesman peel in reducing the severity of ulcerative colitis in a murine model.
Ulcerative colitis is a recurrent inflammatory illness of the colon with an elevated risk of developing colon cancer. The drugs presently used to treat UC cause adverse effects and are limited to symptomatic treatments. To overcome these constraints, naturally derived novel alternative therapies are being tested. Ensete superbum Roxb. Cheesman (wild banana) is used as a folk medicinal plant to treat stomach aches, diarrhea, and dysentery. Previous research has shown that a peel dioxane (PD) fraction obtained from a ripe peel aqueous extract of E. superbum Roxb. Cheesman possesses in vitro antioxidant, anti-inflammatory and anti-colon cancer effects. Furthermore, it has been shown to alleviate 2,4,6-trinitrobenzene sulfonic acid (TNBS) induced ulcerative colitis (UC) in rats. The current study intended to evaluate its efficacy as a functional dietary component added to cold pressed orange juice in colitic rats, and deduce the molecular processes involved in UC amelioration. The PD fraction in orange juice ameliorated colitis by modulating the oxidative stress and inflammatory parameters in the damaged tissue with improved healing activity as indicated by a lower disease activity index (DAI) score. The ameliorative effect was related to the inhibition of the nuclear factor-κB (NF-κB) signaling pathway by downregulating the expression levels of NFκBp65, TNF-α, IL-6 and IL-1β, followed by the recovery of epithelial barrier integrity. The ameliorating effects were statistically similar (p > 0.05) to those of the standard sulfasalazine treated population. The results suggest that PD fractions can be used as a new functional food and as an adjuvant to prevent IBDs due to their anti-colitic effect; however, it needs to be confirmed in clinical trials.


Long-Term Cardiac Sequelae in Patients Referred into a Diagnostic Post-COVID-19 Pathway: The Different Impacts on the Right and Left Ventricles.
Most patients who had COVID-19 are still symptomatic after many months post infection, but the long-term outcomes are not yet well defined. The aim of our prospective/retrospective study was to define the cardiac sequelae of COVID-19 infection. This monocentric cohort study included 160 consecutive patients who had been discharged from the ward or from the outpatient clinic after a diagnosis of COVID-19 and subsequently referred for a follow-up visit. Clinical features' data about the acute phase along with information about the follow-up visit, including ECG and Echocardiographic parameters, were recorded. At an average follow-up of 5 months, echocardiography showed morpho-functional characteristics of both right (RV) and left (LV) ventricles, such as RV dilation, increased pressure in the pulmonary circulation, and bi-ventricular systolic-diastolic dysfunction. When examined using multivariate analysis, independent of age, sex, and co-morbidities, RV and LV changes were significantly associated with chest High-Resolution computed tomography score and hemodynamic Instability (HI), and with C-reactive protein, respectively. Our results suggest that COVID-19 may impact RV and LV differently. Notably, the extent of the pneumonia and HI may affect RV, whereas the inflammatory status may influence LV. A long-term follow-up is warranted to refine and customize the most appropriate therapeutic strategies.


Alternation in the coronary blood flow velocity pattern in patients with no reflow and reperfused acute myocardial infarction.
Experimental and clinical evidence indicates that myocardial ischemia often damages the coronary microvasculature ("no-reflow" phenomenon). In this study, we examined the effect of this phenomenon on the coronary blood flow velocity pattern in patients with reperfused acute myocardial infarction. We measured coronary blood flow velocity after coronary angioplasty in 42 patients with acute myocardial infarction using a Doppler guidewire. Myocardial contrast echocardiography (MCE) was also performed before and after angioplasty. Thirty-one patients showed good contrast reperfusion (MCE reflow), whereas the other 11 showed no reflow (MCE no reflow). Peak velocity and duration of systolic coronary flow were significantly less in patients with MCE no reflow than in those with MCE reflow (8 +/- 4 versus 17 +/- 10 cm/s and 207 +/- 79 versus 289 +/- 55 ms, respectively; P < .01). Early systolic retrograde flow was frequently observed in patients with MCE no reflow, whereas it was observed in only 1 patient among those with MCE reflow (95% versus 3%; P < .001). Although peak diastolic flow velocity was similar between the two subsets, diastolic deceleration rate was significantly higher in patients with MCE no reflow than in those with MCE reflow (107 +/- 76 versus 56 +/- 31 cm/s2; P < .01). The coronary flow velocity pattern in patients with the no-reflow phenomenon was characterized by the appearance of systolic retrograde flow, diminished systolic antegrade flow, and rapid deceleration of diastolic flow. Thus, the Doppler guidewire allows us to assess the presence of microvascular dysfunction in AMI.


Adaptation of internet-based multiple mini-interviews in a limited-resource medical school during the coronavirus disease 2019 pandemic.
The coronavirus disease 2019 pandemic has affected many aspects of life, including medical education. The selection of students using multiple mini-interviews (MMI) should be adapted promptly as internet-based MMI (iMMI) in the current setting. The current transition from MMI to iMMI is supported by experience in conducting conventional MMI in previous years; hence, the station and assessor preparation could be completed without significant issues. The greater challenges to the use of iMMI are due to technical issues, including poor internet connections and adaptations necessary for assessing candidates' nonverbal expressions. This paper aims to describe the experience of conducting iMMI in the current pandemic situation, with further highlights on contextual challenges in a limited-resource setting.


Vibrational spectroscopic study of glutathione complexation in aqueous solutions.
A spectroscopic study of glutathione (GSH) and glutathione disulfide (GSSG) has been performed using Fourier-transformed infrared absorption and Raman scattering in order to pinpoint the sites of complexation of these two species with water and particularly with H2O2. Molecules of GSH and GSSG were studied in KBr pellets, and in aqueous solutions of H2O, D2O, and H2O with H2O2 (1 mol L(-1)) to characterize the specific influence of the solvent molecules. A time-resolved Raman study was performed for GSH/H2O2, in aqueous solution at 1:1 molar ratio in order to observe the formation of GSSG and to discuss the mechanism of this redox reaction.


[Inverted urothelial papilloma and resembling tumors].
Two cases of inverted papilloma, developed on the bladder neck in 36- and 23-year old males, are presented. From the Japanese literature, 40 cases of inverted papillomas have been collected and are reviewed. In addition, a review of the consecutive series of 173 pathological specimens, obtained by bladder biopsy and at the time of bladder surgery over the past 5 years disclosed a resembling lesion in two cases of bladder tumors. An inverted growth of transitional-cell carcinoma was observed in one case. Transitional-cell carcinoma with abundant microcysts was covered by the non-neoplastic transitional-cell epithelium in the other case. In conclusion, the inverted urothelial papilloma is more likely an inverted growth of the neoplastic epithelium with epithelial metaplasia and microcyst formation, much as is observed in so-called chronic proliferative cystitis, than a neoplastic transformation from chronic proliferative cystitis.


The structure of an LIM-only protein 4 (LMO4) and Deformed epidermal autoregulatory factor-1 (DEAF1) complex reveals a common mode of binding to LMO4.
LIM-domain only protein 4 (LMO4) is a widely expressed protein with important roles in embryonic development and breast cancer. It has been reported to bind many partners, including the transcription factor Deformed epidermal autoregulatory factor-1 (DEAF1), with which LMO4 shares many biological parallels. We used yeast two-hybrid assays to show that DEAF1 binds both LIM domains of LMO4 and that DEAF1 binds the same face on LMO4 as two other LMO4-binding partners, namely LIM domain binding protein 1 (LDB1) and C-terminal binding protein interacting protein (CtIP/RBBP8). Mutagenic screening analysed by the same method, indicates that the key residues in the interaction lie in LMO4LIM2 and the N-terminal half of the LMO4-binding domain in DEAF1. We generated a stable LMO4LIM2-DEAF1 complex and determined the solution structure of that complex. Although the LMO4-binding domain from DEAF1 is intrinsically disordered, it becomes structured on binding. The structure confirms that LDB1, CtIP and DEAF1 all bind to the same face on LMO4. LMO4 appears to form a hub in protein-protein interaction networks, linking numerous pathways within cells. Competitive binding for LMO4 therefore most likely provides a level of regulation between those different pathways.


Gaming Technology for Pediatric Neurorehabilitation: A Systematic Review.
The emergence of gaming technologies, such as videogames and virtual reality, provides a wide variety of possibilities in intensively and enjoyably performing rehabilitation for children with neurological disorders. Solid evidence-based results are however required to promote the use of different gaming technologies in pediatric neurorehabilitation, while simultaneously exploring new related directions concerning neuro-monitoring and rehabilitation in familiar settings. In order to analyze the state of the art regarding the available gaming technologies for pediatric neurorehabilitation, Scopus and Pubmed Databases have been searched by following: PRISMA statements, PICOs classification, and PEDro scoring. 43 studies have been collected and classified as follows: 11 feasibility studies; six studies proposing home-system solutions; nine studies presenting gamified robotic devices; nine longitudinal intervention trials; and eight reviews. Most of them rely on feasibility or pilot trials characterized by small sample sizes and short durations; different methodologies, outcome assessments and terminologies are involved; the explored spectrum of neurological conditions turns out to be scanty, mainly including the most common and wider debilitating groups of conditions in pediatric neurology: cerebral palsy, brain injuries and autism. Even though it highlights reduced possibilities of drawing evidence-based conclusions due to the above outlined biases, this systematic review raises awareness among pediatricians and other health professionals about gaming technologies. Such a review also points out a definite need of rigorous studies that clearly refer to the underlying neuroscientific principles.


Virus-like particle-display of the enterotoxigenic Escherichia coli heat-stable toxoid STh-A14T elicits neutralizing antibodies in mice.
Enterotoxigenic Escherichia coli (ETEC) causes diarrhoea by secreting enterotoxins into the small intestine. Human ETEC strains may secrete any combination of three enterotoxins: the heat-labile toxin (LT) and the heat-stable toxins (ST), of which there are two variants, called human ST (STh) and porcine ST (STp). Strains expressing STh, either alone or in combination with LT and/or STp, are among the four most important diarrhoea-causing pathogens affecting children in low- and middle-income countries. ST is therefore an attractive target for ETEC vaccine development. To produce a safe ST-based vaccine, several challenges must be solved. ST must be rendered immunogenic and non-toxic, and antibodies elicited by an ST vaccine should neutralize ST but not cross-react with the endogenous ligands uroguanylin and guanylin. Virus-like particles (VLPs) tend to be highly immunogenic and are increasingly being used as carriers for presenting heterologous antigens in new vaccines. In this study, we have coupled native STh and the STh-A14T toxoid to the coat protein of Acinetobacter phage AP205 by using the SpyCatcher system and immunized mice with these VLPs without the use of adjuvants. We found that both STs were efficiently coupled to the VLP, that both the STh and STh-A14T VLPs were immunogenic in mice, and that the resulting serum antibodies could completely neutralize the toxic activities of native STh. The serum antibodies showed a high degree of immunological cross-reaction to STp, while there was little or no unwanted cross-reaction to uroguanylin and guanylin. Moreover, compared to native STh, the STh-A14T mutation did not seem to negatively impact the immunogenicity of the construct or the neutralizing ability of the resulting sera. Taken together, these findings demonstrate that VLPs are suitable carriers for making STs immunogenic, and that the STh-A14T-coupled AP205 VLP represents a promising ETEC vaccine candidate.


[Netherton syndrome].
The case of a 8 years old girl, who since the delivery had suffered from a generalized, erythematous and scaling eruption of the skin is reported. She also had a sparse, short and brittle hair. Abnormalities such as trichorrhexis nodosa and pilo torti were observed. The finding of a generalized increase of the urinary aminoacids, excretion especially for Glycine and Serine, is added to this features.


A Novel Predictive-Coding-Inspired Variational RNN Model for Online Prediction and Recognition.
This study introduces PV-RNN, a novel variational RNN inspired by predictive-coding ideas. The model learns to extract the probabilistic structures hidden in fluctuating temporal patterns by dynamically changing the stochasticity of its latent states. Its architecture attempts to address two major concerns of variational Bayes RNNs: how latent variables can learn meaningful representations and how the inference model can transfer future observations to the latent variables. PV-RNN does both by introducing adaptive vectors mirroring the training data, whose values can then be adapted differently during evaluation. Moreover, prediction errors during backpropagation-rather than external inputs during the forward computation-are used to convey information to the network about the external data. For testing, we introduce error regression for predicting unseen sequences as inspired by predictive coding that leverages those mechanisms. As in other variational Bayes RNNs, our model learns by maximizing a lower bound on the marginal likelihood of the sequential data, which is composed of two terms: the negative of the expectation of prediction errors and the negative of the Kullback-Leibler divergence between the prior and the approximate posterior distributions. The model introduces a weighting parameter, the meta-prior, to balance the optimization pressure placed on those two terms. We test the model on two data sets with probabilistic structures and show that with high values of the meta-prior, the network develops deterministic chaos through which the randomness of the data is imitated. For low values, the model behaves as a random process. The network performs best on intermediate values and is able to capture the latent probabilistic structure with good generalization. Analyzing the meta-prior's impact on the network allows us to precisely study the theoretical value and practical benefits of incorporating stochastic dynamics in our model. We demonstrate better prediction performance on a robot imitation task with our model using error regression compared to a standard variational Bayes model lacking such a procedure.


Multiscale simulation of thin-film lubrication: free-energy-corrected coarse graining.
The quasicontinuum method was previously extended to the nonzero temperature conditions by implementing a free-energy correction on non-nodal atoms in coarse-grained solid systems to avoid the dynamical constraint, [Diestler, Wu, and Zeng, J. Chem. Phys. 121, 9279 (2004)]. In this paper, we combine the extended quasicontinuum method and an atomistic simulation to treat the monolayer film lubrication with elastic (nonrigid) substrates. It is shown that the multiscale method with the coarse-graining local elements in the merging regions between the atomistic and continuous descriptions of the substrates can reasonably predict the shear stress profile, the mean separation curve, and the transverse stress profile in the fully atomistic simulation for the tribological system. Moreover, when the nonlocal elements are placed in the merging regions, the inhomogeneous solid atoms in the near regions covered by the cut-off circles of the nonlocal elements replace the homogeneous ones at the equilibrium configuration for the free-energy correction on the non-nodal atoms. The treatment can cause an unphysical sliding between the near and far regions of the upper substrate. It is shown that if the free-energy correction on the non-nodal atoms in the coarse-grained merging regions is removed, the multiscale method can still well reproduce the shear stress profile, the mean separation curve, and the transverse stress profile obtained from the fully atomistic simulation for the system.


Therapeutic effect and mechanism of 4-phenyl butyric acid on renal ischemia-reperfusion injury in mice.
The aim of the present study was to explore the effects and possible mechanism of 4-phenylbutyric acid (4-PBA) on renal ischemia-reperfusion injury (RIRI) in mice. A RIRI model of HK-2 cells was constructed using hypoxia/reoxygenation (H/R) treatment. Dexmedetomidine and 4-PBA were used to treat the cells before and after modeling. Apoptosis and expression levels of cyclophilin D (CypD), cytochrome c, eukaryotic translation initiation factor 2α (eIF2α), glucose-regulated protein 78 (GRP78), intercellular adhesion molecule (ICAM)-1 and vascular adhesion molecule (VCAM)-1 were measured using flow cytometry, western blotting and immunohistochemistry. The renal volume, weight and renal arterial resistance index (RRI) were determined using the renal ischemia model. Compared with untreated model cells, 4-PBA treatment significantly decreased apoptosis and the expression levels of CypD, Cytochrome c, eIF2α and GRP78 in HK-2 cells. There was no significant change in renal volume and weight after modeling, but RRI was significantly decreased after 4-PBA treatments in the model. Western blotting and immunohistochemistry analysis demonstrated that 4-PBA treatment also significantly decreased the expression of ICAM-1 and VCAM-1. Overall, 4-PBA had a therapeutic effect on RIRI in mice. This protection may be mediated by decreasing the expression levels of CypD, Cytochrome c, eIF2α and GRP78, and subsequent reduction of cellular oxygen free radicals and apoptosis, leading to an alleviated endoplasmic reticulum stress response and RIRI.


Physical analysis of the region deleted in the tw18 allele of the mouse tcl-4 complementation group.
We have generated a YAC contig of at least 3.3 Mb from the proximal region of In(17)4 of mouse chromosome 17. This region corresponds to DNA lost in the gastrulation mutant tw18, which belongs to the tcl-4 complementation group. Our most proximal and distal probes lie within the deletion-3.3 Mb apart-indicating that we have not cloned the entire region. The deleted region is contained in a genetic interval of less than 1 cM, suggesting that some suppression of recombination must occur.


Adsorption of DNA Oligonucleotides by Self-Assembled Metalloporphyrin Nanomaterials.
Porphyrin assemblies have controllable morphology, high biocompatibility, and good optical properties and were widely used in biomedical diagnosis and treatment. With the development of DNA biotechnology, combining DNA with porphyrin assemblies can broaden the biological applications of porphyrins. Porphyrin assemblies can serve as nanocarriers for DNA, although the fundamental interactions between them are not well understood. In this work, zinc meso-tetra(4-pyridyl)porphyrin (ZnTPyP) assemblies were prepared in the presence of various surfactants and at different pH values, yielding a variety of aggregation forms. Among them, the hexagonal stacking form exposes more pyridine substituents, and the hydrogen bonding force between the substituents and the DNA bases allows the DNA to be quickly adsorbed on the surface of the assemblies. The effects of DNA sequence and length were systematically tested. In particular, the adsorption of duplex DNA was less efficient compared to the adsorption of single-stranded DNA. This fundamental study is useful for the further combination of DNA and porphyrin assemblies to prepare new functional hybrid nanomaterials.


Pharmacologic therapy for intermittent claudication.
Peripheral artery disease, defined as atherosclerosis in the lower extremities, affects nearly 8.5 million people in the United States. Due to the frequent asymptomatic manifestation of peripheral artery disease, diagnosis may be delayed and its true incidence underestimated. However, some patients may experience aching pain, numbness, weakness, or fatigue, a condition termed intermittent claudication. Peripheral atherosclerosis is associated with cardiovascular risk and physical impairment; therefore, treatment goals are aimed at decreasing cardiovascular risk, as well as improving quality of life. Little debate exists regarding the management of cardiovascular risk reduction, which consists of both antiplatelet therapy and risk factor modification. Despite recently published guidelines, the treatment of intermittent claudication is less well established and the management remains controversial and uncertain. Exercise remains the first-line therapy for intermittent claudication; however, pharmacologic treatment is often necessary. Although only two prescription drugs have been approved by the U.S. Food and Drug Administration for the treatment of intermittent claudication, several supplements and investigational agents have been evaluated. Therapeutic optimization should balance the anticipated improvements in quality of life with the potential safety risks.


Optimization of Sacrificial Layer Etching in Single-Crystal Silicon Nano-Films Transfer Printing for Heterogeneous Integration Application.
As one of the important technologies in the field of heterogeneous integration, transfer technology has broad application prospects and unique technical advantages. This transfer technology includes the wet chemical etching of a sacrificial layer, such that silicon nano-film devices are released from the donor substrate and can be transferred. However, in the process of wet etching the SiO2 sacrificial layer present underneath the single-crystal silicon nano-film by using the transfer technology, the etching is often incomplete, which seriously affects the efficiency and quality of the transfer and makes the device preparation impossible. This article analyzes the principle of incomplete etching, and compares the four factors that affect the etching process, including the size of Si nano-film on top of the sacrificial layer, the location of the anchor point, the shape of Si nano-film on top of the sacrificial layer, and the thickness of the sacrificial layer. Finally, the etching conditions are obtained to avoid the phenomenon of incomplete etching of the sacrificial layer, so that the transfer technology can be better applied in the field of heterogeneous integration. Additionally, Si MOSFETs (Metal-Oxide-Semiconductor Field Effect Transistors) on sapphire substrate were fabricated by using the optimized transfer technology.


Mucormycosis co-infection in COVID-19 patients: An update.
Mucormycosis (MCM) is a rare fungal disorder that has recently been increased in parallel with novel COVID-19 infection. MCM with COVID-19 is extremely lethal, particularly in immunocompromised individuals. The collection of available scientific information helps in the management of this co-infection, but still, the main question on COVID-19, whether it is occasional, participatory, concurrent, or coincidental needs to be addressed. Several case reports of these co-infections have been explained as causal associations, but the direct contribution in immunocompromised individuals remains to be explored completely. This review aims to provide an update that serves as a guide for the diagnosis and treatment of MCM patients' co-infection with COVID-19. The initial report has suggested that COVID-19 patients might be susceptible to developing invasive fungal infections by different species, including MCM as a co-infection. In spite of this, co-infection has been explored only in severe cases with common triangles: diabetes, diabetes ketoacidosis, and corticosteroids. Pathogenic mechanisms in the aggressiveness of MCM infection involves the reduction of phagocytic activity, attainable quantities of ferritin attributed with transferrin in diabetic ketoacidosis, and fungal heme oxygenase, which enhances iron absorption for its metabolism. Therefore, severe COVID-19 cases are associated with increased risk factors of invasive fungal co-infections. In addition, COVID-19 infection leads to reduction in cluster of differentiation, especially CD4+ and CD8+ T cell counts, which may be highly implicated in fungal co-infections. Thus, the progress in MCM management is dependent on a different strategy, including reduction or stopping of implicit predisposing factors, early intake of active antifungal drugs at appropriate doses, and complete elimination via surgical debridement of infected tissues.


The effect of nanofiber-guided cell alignment on the preferential differentiation of neural stem cells.
Stem cells display sensitivity to substrate presentation of topographical cues via changes in cell morphology. These biomechanical responses may be transmitted to the nucleus through cytoskeletal-linked signaling pathways. Here we investigate the influence of aligned substratum topography on the cell morphology and subsequently, the neuronal differentiation capabilities of adult neural stem cells (ANSCs). ANSCs that were cultured on aligned fibers elongated along the major fiber axis. Upon induction of differentiation with retinoic acid, a higher fraction of cells on aligned fibers exhibited markers of neuronal differentiation as compared with cells on random fiber or unpatterned surfaces. This effect was in part due to substrate selectivity, whereby aligned fiber substrates were less receptive to the attachment and continued survival of oligodendrocytes than random fiber or unpatterned substrates. Substrate-induced elongation alone was also effective in upregulating canonical Wnt signaling in ANSCs, which was further potentiated by retinoic acid treatment. These findings suggest a mechanism by which morphological control of stem cells operates in concert with biochemical cues for cell fate determination.


Characterisation of three novel β-1,3 glucanases from the medically important house dust mite Dermatophagoides pteronyssinus (airmid).
The European house dust mite, Dermatophagoides pteronyssinus is a major source of airborne allergens worldwide and is found in half of European homes. Interactions between microbes and house dust mites (HDM) are considered important factors that allow them to persist in the home. Laboratory studies indicate the European HDM, D. pteronyssinus is a mycophagous mite, capable of utilising a variety of fungi for nutrients, however specific mycolytic digestive enzymes are unknown. Our previous work identified a number of putative glycosyl hydrolases present in the predicted proteome of D. pteronyssinus airmid and validated the expression of 42 of these. Of note, three GH16 proteins with predicted β-1,3 glucanase activity were found to be consistently present in the mite body and excretome. Here, we performed an extensive bioinformatic, proteomic and biochemical study to characterize three-novel β-1,3 glucanases from this medically important house dust mite. The genes encoding novel β-1,3 glucanases designated Glu1, Glu2 and Glu3 were identified in D. pteronyssinus airmid, each exhibited more than 59% amino acid identity to one another. These enzymes are encoded by Glu genes present in a tri-gene cluster and protein homologs are found in other acari. The patchy phyletic distribution of Glu proteins means their evolutionary history remains elusive, however horizontal gene transfer cannot be completely excluded. Recombinant Glu1 and Glu2 exhibit hydrolytic activity toward laminarin, pachyman and barley glucan. Excreted β-1,3 glucanase activity was increased in response to D. pteronyssinus airmid feeding on baker's yeast. Active β-1,3 glucanases are expressed and excreted in the faeces of D. pteronyssinus airmid indicating they are digestive enzymes capable of breaking down β-1,3 glucans of fungi present in house dust.


Taking into account latency, amplitude, and morphology: improved estimation of single-trial ERPs by wavelet filtering and multiple linear regression.
Across-trial averaging is a widely used approach to enhance the signal-to-noise ratio (SNR) of event-related potentials (ERPs). However, across-trial variability of ERP latency and amplitude may contain physiologically relevant information that is lost by across-trial averaging. Hence, we aimed to develop a novel method that uses 1) wavelet filtering (WF) to enhance the SNR of ERPs and 2) a multiple linear regression with a dispersion term (MLR(d)) that takes into account shape distortions to estimate the single-trial latency and amplitude of ERP peaks. Using simulated ERP data sets containing different levels of noise, we provide evidence that, compared with other approaches, the proposed WF+MLR(d) method yields the most accurate estimate of single-trial ERP features. When applied to a real laser-evoked potential data set, the WF+MLR(d) approach provides reliable estimation of single-trial latency, amplitude, and morphology of ERPs and thereby allows performing meaningful correlations at single-trial level. We obtained three main findings. First, WF significantly enhances the SNR of single-trial ERPs. Second, MLR(d) effectively captures and measures the variability in the morphology of single-trial ERPs, thus providing an accurate and unbiased estimate of their peak latency and amplitude. Third, intensity of pain perception significantly correlates with the single-trial estimates of N2 and P2 amplitude. These results indicate that WF+MLR(d) can be used to explore the dynamics between different ERP features, behavioral variables, and other neuroimaging measures of brain activity, thus providing new insights into the functional significance of the different brain processes underlying the brain responses to sensory stimuli.


Severe nonendemic pemphigus foliaceus presenting in the postpartum period.
The new onset of pemphigus in the postpartum period is exceedingly rare with only 1 case previously reported in the literature. We describe a 31-year-old woman who developed extensive denudation of her skin shortly after delivering her second child. Histologic examination, immunofluorescence testing, and immunoprecipitation with desmoglein 1 confirmed the diagnosis of pemphigus foliaceus. The patient responded to treatment with prednisone, cyclophosphamide, and plasmapheresis. The effect of the postpartum period on the onset and exacerbation of immune-mediated bullous diseases is discussed.


Components in Plasma-Derived Factor VIII, But Not in Recombinant Factor VIII Downregulate Anti-Inflammatory Surface Marker CD163 in Human Macrophages through Release of CXCL4 (Platelet Factor 4).
Hemarthrosis, or bleeding into the joints, is a hallmark of hemophilia. Heme triggers oxidative stress, inflammation, and destruction of cartilage and bone. The haptoglobin-CD163-heme oxygenase-1 (HO-1) pathway circumvents heme toxicity through enzymatic degradation of heme and transcription of antioxidant genes. Plasma-derived factor concentrates contain many proteins that might impact on cellular pathways in joints, blood, and vessels. Activation of platelets from healthy volunteers was assessed by flow cytometry analysis of fibrinogen binding and CD62P expression. Platelet CXCL4 release was measured by ELISA. Human peripheral blood mononuclear cells were exposed to CXCL4 or platelet supernatants (untreated or pre-stimulated with factor VIII (FVIII) products) during their differentiation to macrophages and analyzed for CD163 expression. Some macrophage cultures were additionally incubated with autologous hemoglobin for 18 h for analysis of HO-1 expression. Platelet CXCL4 release was increased by all 8 tested plasma-derived FVIII products but not the 3 recombinant products. Macrophages exposed to supernatant from platelets treated with some plasma-derived FVIII products downregulated CD163 surface expression and failed to upregulate the athero- and joint protective enzyme HO-1 in response to hemoglobin. Plasma-derived FVIII products might promote bleeding-induced joint injury via generation of macrophages that are unable to counteract redox stress.


[Patent protection of biotechnological developments].
Patents can be granted with respect to microbiological processes and products therefrom. In principle it is necessary to deposit a culture of the microorganisms at a recognized depository institution. The deposited culture is available upon request to any person from the date of publication of the patent application. Consequently, there is a great risk that the applicant's product is used by other people.


Quantification of the preexisting CD4 T-cell repertoire specific for human erythropoietin reveals its immunogenicity potential.
Antibody-mediated pure red cell aplasia is a rare but serious event resulting from the induction of neutralizing erythropoietin (Epo)-specific antibodies provoked by treatment with recombinant Epo. Because of the crucial role of CD4 T cells in humoral response, we have quantified the number of Epo-specific CD4 T cells in the blood of normal donors by in vitro stimulation. An important repertoire of preexisting Epo-specific T cells was observed in almost half of the donors, comparable with that of non-self-proteins. This observation suggests that, at the steady state, endogenous Epo weakly contributes to tolerance induction and may be ignored by the immune system. As a result, circulating Epo-specific CD4 T cells could be prone to be activated by altered batches of Epo, providing them with costimulatory signals. Our data also highlight the relevance of T-cell assays performed with normal donors to evaluate the potential immunogenicity of therapeutic proteins.


Electromyographic assessment of the neuromuscular blockade produced in vivo by anatoxin-a in the rat.
The indirectly evoked compound action potentials (ECAP) of the plantar muscles of the rat were used to investigate the pharmacodynamics in vivo of the neuromuscular blockade produced by anatoxin-a. Onset time to maximum depression and the magnitude of maximum depression in amplitude of the ECAP were dose-dependent. The mean maximum percent depression (+/- S.D.) of the ECAP induced by single, supramaximal stimulations of the posterior tibial nerve after i.v. doses of (+)anatoxin-a hydrochloride at 0, 50, 100, 200 and 800 micrograms/kg were 3 (4), 53 (15), 82 (7), 95 (2), and 100 (1), respectively. The ED50 (95% confidence limits) for depression of the ECAP was 47 mg/kg (39-57 micrograms/kg). Rats administered 200 micrograms/kg or less of (+)anatoxin-a hydrochloride had 75% return of the pretoxin amplitude of the ECAP within 93 min. Animals dosed at 800 micrograms/kg did not have return of neuromuscular function and died despite mechanical ventilation, suggesting a lethal mechanism(s) of action in addition to respiratory paralysis. Percent decrements (+/- S.D.) in the amplitude of the fourth ECAP following repetitive stimulation at 10 Hz were 6 (5), 13 (22), 46 (18) and 59 (8) from (+)anatoxin-a hydrochloride given i.v. at 0, 50, 100 and 200 micrograms/kg, respectively. The decrement observed following repetitive stimulation was attributed to a presynaptic site of action. No change in maximal motor nerve conduction velocity or latency of the ECAP was observed after i.v. administration of (+)anatoxin-a hydrochloride at 100 micrograms/kg. LD50 values (95% confidence limits) for anatoxin-a administered i.v. to mice were 386 micrograms/kg (365-408 micrograms/kg, for (+)anatoxin-a hydrochloride and 913 micrograms/kg (846-985 micrograms/kg) for racemic anatoxin-a hydrochloride. No deaths were observed in mice after i.p. administration of (-)anatoxin-a hydrochloride at doses up to 73 mg/kg.


Thermochromic Magnetic Ionic Liquids from Cationic Nickel(II) Complexes Exhibiting Intramolecular Coordination Equilibrium.
Among the various thermochromic materials, liquid thermochromic materials are comparatively rare. To produce functional thermochromic liquids, we have designed ionic liquids based on cationic nickel complexes with ether side chains, [Ni(acac)(Me2 NC2 H4 NR1 R2 )]Tf2 N ([1]Tf2 N: R1 =C3 H6 OEt, R2 =Me; [2]Tf2 N: R1 =C3 H6 OMe, R2 =Me; [3]Tf2 N: R1 =R2 =C3 H6 OMe), where acac=acetylacetonate and Tf2 N=(F3 CSO2 )2 N- . The side chains (R1 , R2 ) can moderately coordinate to the metal center, enabling temperature-dependent coordination equilibria in the liquid state. [1]Tf2 N is a liquid at room temperature. [2]Tf2 N is obtained as a solid (Tm =352.7 K) but remains liquid at room temperature after melting. [3]Tf2 N is a solid with a high melting point (Tm =422.3 K). These salts display thermochromism in the liquid state, appearing red at high temperatures and orange, light-blue, or bluish-green at lower temperatures, and exhibiting concomitant changes in their magnetic properties. This phenomenon is based on temperature-dependent equilibrium between a square-planar diamagnetic species and a paramagnetic species with intramolecular ether coordination.


Establishing an integrated multiprofessional skills training programme.
Opportunities to learn and practice skills are becoming less with changes in the health care environment. Responses to this have included curriculum change and the development of skills programmes. Although the skills programmes, often taught in simulated settings in skills Centres have been frequently described, such a model may not be appropriate for all Universities or have the best outcomes. Firstly access to a centre may not be available and secondly, the training may not alter students' behaviour in the workplace in terms of applying and practicing these skills. This paper offers tips for developing a centrally coordinated, integrated, multidisciplinary skills training programme. These 12 tips are based upon current literature, discussion with other skills training providers and reflection on local experiences of establishing and maintaining a skills training programme. The programme, outlined here, used a multidisciplinary, multiprofessional group to design and run a skills programme, which was clearly linked back to clinical attachments, emphasising ongoing practice with feedback. The twelve tips highlight the importance of broad ownership of the programme; separate funding and good evaluation are essential if the programme is to be continued in the absence of a specific Centre or a School to run it.


Apoptotic cell debris and phosphatidylserine-containing lipid vesicles induce apolipoprotein J (clusterin) gene expression in vital fibroblasts.
The molecular events in cells undergoing programmed cell death (apoptosis) are well studied; however, the response of the surviving neighbor cells to local cell death is largely uncharacterized. Apolipoprotein J (clusterin) is an 80-kDa glycoprotein that has been implied in cytoprotection of the vital cells, presumably by assisting in the clearance of apoptotic vesicles and membrane remnants. Its mRNA is specifically up-regulated in the vital cells of apoptotic tissues. The molecular mechanisms, however, leading to this response are not known. We here show that exposure of vital fibroblasts to apoptotic vesicles, disrupted vital cells, and trypsin-treated membrane remnants induces apoJ mRNA. Moreover, lipid vesicles consisting of phosphatidylserine (PtSer) and dimyristoylphosphatidylcholine (PC), but not liposomes with PC alone nor with dimyristoylphosphatidylethanolamine or phosphatidic acid, did elevate apoJ mRNA level. These results suggest that, apart from mediating the endocytic uptake of the apoptotic vesicles, PtSer also serves as a trigger to stimulate the expression of genes that might be involved in the cellular clearance process.


The analysis of an overstimulated child.
This paper shows how environmental and medical overstimulation affected a latency girl in all her developmental phases, leading to severe impairment of object relationships. These factors are seen against the background of an acrimonious parental divorce. Suzie's negative body image was inextricably interwoven with anxieties about her masturbation activities and castration fantasies and this was fueled by her physical condition (lichen sclerosis et atrophicis). She was in a constant state either of withdrawness or excitement. The initial task of the treatment was to provide Suzie with a holding environment so that she could find alternative means of gratification and control in order to manage within a more organized secondary process mode. When her difficulties around excitation abated, she could begin to make analytic use of verbalization, clarification, and interpretations.


Looks are (almost) everything: where drivers look to get information.
To describe the impact of Rockwell's early eye movements research. The advent of a new technology enabling measurements of eye movements in natural environments launched the seminal research of a Human Factors pioneer, Tom Rockwell, into how drivers process visual information. In two seminal Human Factors articles -"Mapping Eye-Movement Pattern to the Visual Scene in Driving: An Exploratory Study" (Mourant & Rockwell, 1970) and "Strategies of Visual Search by Novice and Experienced Drivers" (Mourant & Rockwell, 1972)- Rockwell and his student, Ron Mourant, examined drivers' eye movements in naturalistic driving environments. The analyses of the visual fixations revealed systematic relationships between the sources of information the drivers needed to drive safely and the spatial distributions of their visual fixations. In addition, they showed that as drivers gain skill and experience, their pattern of fixations changes in a systematic manner. The research demonstrated that fixations and saccadic eye movements provide important insights into drivers' visual search behavior, information needs, and information acquisition processes. This research has been a cornerstone for a myriad of driving-related studies, by Rockwell and other researchers. Building on Rockwell's pioneering work, these studies used eye-tracking systems to describe cognitive aspects of skill acquisition, and the effects of fatigue and other impairments on the process of attention and information gathering. A novel and potentially revolutionary application of this research is to use eye movement recordings for vehicle control and activation of in-vehicle safety systems.


Six-minute walk test and respiratory muscle strength in patients with uncontrolled severe asthma: a pilot study.
To evaluate respiratory muscle strength and six-minute walk test (6MWT) variables in patients with uncontrolled severe asthma (UCSA). This was a cross-sectional study involving UCSA patients followed at a university hospital. The patients underwent 6MWT, spirometry, and measurements of respiratory muscle strength, as well as completing the Asthma Control Test (ACT). The Mann-Whitney test was used in order to analyze 6MWT variables, whereas the Kruskal-Wallis test was used to determine whether there was an association between the use of oral corticosteroids and respiratory muscle strength. We included 25 patients. Mean FEV1 was 58.8 ± 21.8% of predicted, and mean ACT score was 14.0 ± 3.9 points. No significant difference was found between the median six-minute walk distance recorded for the UCSA patients and that predicted for healthy Brazilians (512 m and 534 m, respectively; p = 0.14). During the 6MWT, there was no significant drop in SpO2. Mean MIP and MEP were normal (72.9 ± 15.2% and 67.6 ± 22.2%, respectively). Comparing the patients treated with at least four courses of oral corticosteroids per year and those treated with three or fewer, we found no significant differences in MIP (p = 0.15) or MEP (p = 0.45). Our findings suggest that UCSA patients are similar to normal subjects in terms of 6MWT variables and respiratory muscle strength. The use of oral corticosteroids has no apparent impact on respiratory muscle strength.


Genome-wide de novo prediction of cis-regulatory binding sites in prokaryotes.
Although cis-regulatory binding sites (CRBSs) are at least as important as the coding sequences in a genome, our general understanding of them in most sequenced genomes is very limited due to the lack of efficient and accurate experimental and computational methods for their characterization, which has largely hindered our understanding of many important biological processes. In this article, we describe a novel algorithm for genome-wide de novo prediction of CRBSs with high accuracy. We designed our algorithm to circumvent three identified difficulties for CRBS prediction using comparative genomics principles based on a new method for the selection of reference genomes, a new metric for measuring the similarity of CRBSs, and a new graph clustering procedure. When operon structures are correctly predicted, our algorithm can predict 81% of known individual binding sites belonging to 94% of known cis-regulatory motifs in the Escherichia coli K12 genome, while achieving high prediction specificity. Our algorithm has also achieved similar prediction accuracy in the Bacillus subtilis genome, suggesting that it is very robust, and thus can be applied to any other sequenced prokaryotic genome. When compared with the prior state-of-the-art algorithms, our algorithm outperforms them in both prediction sensitivity and specificity.


Fecal microbiota transplantation in the treatment of Crohn disease.
Fecal microbiota transplantation (FMT) is an alternative treatment option with minimal risk for patients with Crohn disease. This article explains FMT and how it effectively targets the gut microbiota changes associated with the pathogenesis of Crohn disease.


Inflation from quantum geometry.
Quantum geometry predicts that a universe evolves through an inflationary phase at small volume before exiting gracefully into a standard Friedmann phase. This does not require the introduction of additional matter fields with ad hoc potentials; rather, it occurs because of a quantum gravity modification of the kinetic part of ordinary matter Hamiltonians. An application of the same mechanism can explain why the present day cosmological acceleration is so tiny.


A Genomics-Based Model for Prediction of Severe Bioprosthetic Mitral Valve Calcification.
Severe bioprosthetic mitral valve calcification is a significant problem in cardiovascular surgery. Unfortunately, clinical markers did not demonstrate efficacy in prediction of severe bioprosthetic mitral valve calcification. Here, we examined whether a genomics-based approach is efficient in predicting the risk of severe bioprosthetic mitral valve calcification. A total of 124 consecutive Russian patients who underwent mitral valve replacement surgery were recruited. We investigated the associations of the inherited variation in innate immunity, lipid metabolism and calcium metabolism genes with severe bioprosthetic mitral valve calcification. Genotyping was conducted utilizing the TaqMan assay. Eight gene polymorphisms were significantly associated with severe bioprosthetic mitral valve calcification and were therefore included into stepwise logistic regression which identified male gender, the T/T genotype of the rs3775073 polymorphism within the TLR6 gene, the C/T genotype of the rs2229238 polymorphism within the IL6R gene, and the A/A genotype of the rs10455872 polymorphism within the LPA gene as independent predictors of severe bioprosthetic mitral valve calcification. The developed genomics-based model had fair predictive value with area under the receiver operating characteristic (ROC) curve of 0.73. In conclusion, our genomics-based approach is efficient for the prediction of severe bioprosthetic mitral valve calcification.


Gastric dysplasia. Significance and pathologic criteria.
In view of uncertainty regarding the criteria and significance of gastric dysplasia as a precancerous lesion, members of the Pathology Panel of the International Study Group on Gastric Cancer (ISGGC) reviewed microslides of 93 gastric lesions showing varying degrees of mucosal abnormality, and reached the following consensus: (1) immature and proliferating gastric epithelium can be divided into two categories: hyperplastic and dysplastic; (2) the term dysplasia, especially of high-grade type, should be restricted to precancerous lesions, and hyperplasia is applied to regenerative changes; (3) regenerative hyperplasia may be simple or atypical, but dysplasia includes both moderate and severe abnormalities, since they often coexist and can not be sharply separated; and (4) occasionally the possibility of malignancy can not be excluded in a severely dysplastic epithelium; in such a case rebiopsy and diligent follow-up are necessary to establish the diagnosis. Criteria for diagnosing dysplasia and hyperplasia are presented and discussed. The opinions are offered as guidelines for establishing the diagnosis of gastric dysplasia and for prospective studies.


Cost minimization analysis comparing enteral N-acetylcysteine to intravenous acetylcysteine in the management of acute acetaminophen toxicity.
Acetaminophen poisoning is one of the most common exposures and causes of poisoning-related fatalities as reported to U.S. poison information centers. Acetylcysteine is indicated for the antidotal treatment of acetaminophen poisoning to prevent or minimize acetaminophen-related hepatotoxicity. Available as either an enteral or intravenous (IV) formulation, both forms of acetylcysteine have been proven to be efficacious. Because of the differences in the acquisition costs and the length of treatment, it is unclear which treatment route is the most cost-effective. The purpose of this study was to compare the total hospitalization charges associated with patients who received either enteral or IV acetylcysteine therapy. A retrospective, IRB-approved cohort study of patients treated with either enteral or IV acetylcysteine at a university-related hospital for the treatment of acute acetaminophen overdose was conducted. Patients included were over 18 years of age, admitted during the 5-year periods of 1996-2000 (enteral) and 2004-2008 (IV), had an ICD-9 discharge diagnosis for acetaminophen overdose, had no transplant history, and were admitted within 24 h of the overdose. The primary endpoint was the total cost associated with the hospital stay. The Consumer Price Index (CPI) inflation calculator from the U.S. Bureau of Labor Statistics was used to adjust all monetary values to 2008 dollars. Of a total of 1,647 patients, 261 met the inclusion criteria with 70 patients being treated with enteral acetylcysteine and 191 patients treated with IV acetylcysteine. The associated cost was greater in the enteral group than in the IV group ($18,287.63 vs. $7,607.82; p < 0.001). The average length of stay was longer in the enteral group compared to the IV group (7 days vs. 4 days; p < 0.001). Patients who were treated with IV acetylcysteine had a decreased length of stay and cost of hospitalization compared with those patients who were treated with enteral acetylcysteine.


Xenograft rejection of porcine islet-like cell clusters in normal and natural killer cell-depleted mice.
Fetal porcine islet-like cell clusters (ICC) were transplanted under the renal capsule of normoglycemic normal or athymic (nu/nu) C57BL/6 mice. Control animals were implanted with allogeneic minced kidney tissue from C57BL/Ks mice. The animals were killed 6 or 14 days after transplantation and the grafts were processed for flow cytometric analyses or immunohistochemistry. Xenograft destruction was evident in normal mice on day 6 after transplantation. The majority of infiltrating cells were macrophage-like cells expressing the F4/80 antigen. Lymphocytes expressing the CD3 antigen were in minority and mainly located in the peripheral parts of the ICC xenograft. The frequency and distribution of CD4+ cells were found to resemble those of the CD3+ cells. A large number of infiltrating cells, including several macrophage-like cells, expressed the Thy 1.2 antigen. Flow cytometry of infiltrating cells in the ICC xenograft revealed that approximately half of the cells expressing the F4/80 antigen also expressed Thy 1.2 and/or CD4. No cells were found expressing both the F4/80 and CD8 antigens. Both the F4/80 single-positive and the F4/80, CD4 double-positive cells were found to be larger and more granular than the CD4 single-positive cells. No co-expression of CD4 or Thy 1.2 with the F4/80 antigen was detected on cells infiltrating allogeneic tissue grafts. Moreover, a relative large number of cells (approximately 15%) in the xenograft expressed the NK 1.1 antigen as determined by flow cytometry. The role of natural killer (NK) cells in islet xenograft rejection was further evaluated in mice depleted of NK cells, using intraperitoneal injections of the monoclonal antibody NK 1.1. The simultaneous inoculation and subsequent growth of the NK cell-sensitive beta 2-microglobulin-deficient mutant, C4.4-25-, lymphoma cell line EL-4 served as an in vivo control of NK cell depletion. However, all NK cell-depleted mice rejected the ICC xenograft. In contrast, athymic mice permanently accepted the porcine ICC xenograft but, readily rejected the NK cell-sensitive lymphoma cell line. Taken together, ICC xenograft rejection in mice seems to be T cell dependent, as evidenced in the nude mice model, while the main effector cell appears to be a macrophage with a unique phenotype.


How relatives look back at suicide risk after their close one's death by suicide.
The aim of the current study is to analyze how relatives understand in retrospect the suicide risk of their next of kin who died by suicide. We interviewed 103 adult relatives who lost their significant others to suicide, using qualitative content analysis to explore the data. Participants expressed difficulties understanding suicide risk by identifying personal traits incompatible with suicide, reasons to doubt the risk, life oriented actions, the situation seemed better than it was, or that the loved one denied suicide risk; only a few recognized suicide risk. Prevalent myths about suicide and denial are possible explanations for these findings.