Phosphorylation of the Human Papillomavirus E2 Protein at Tyrosine 138 Regulates Episomal Replication.
The papillomavirus (PV) E2 protein is a critical regulator of viral transcription and genome replication. We previously reported that tyrosine (Y) 138 of HPV-31 E2 is phosphorylated by the fibroblast growth factor receptor 3 (FGFR3) kinase. In this study, we generated quasiviruses containing G418-selectable HPV-31 genomes with phosphodeficient phenylalanine mutant E2 Y138F and phosphomimetic glutamic acid mutant Y138E. We observed significantly fewer early viral transcripts immediately after infection with these Y138 mutant genomes even though E2 occupancy at the viral origin was equivalent to that of wild-type E2. Keratinocytes infected with Y138F quasiviruses formed stable colonies, and the genomes were maintained as episomes, while those infected with Y138E quasiviruses did not. We previously reported that the HPV-31 E2 Y138 mutation to glutamic acid did not bind to the Brd4 C-terminal motif (CTM). Here, we demonstrate that HPV-16 E2 Y138E bound to full-length Brd4 but not to the Brd4 CTM. We conclude that association of E2 with the Brd4 CTM is necessary for viral genome replication and suggest that this interaction can be regulated by phosphorylation of E2 Y138.IMPORTANCE Papillomavirus (PV) is a double-stranded DNA tumor virus infecting the cutaneous and mucosal epithelium. The PV E2 protein associates with a number of cellular factors to mediate replication of the HPV genome. Fibroblast growth factor receptor 3 (FGFR3) regulates HPV replication through phosphorylation of tyrosine 138 in the HPV E2 protein. Employing a quasivirus infection model and selection for G418 resistant genomes, we demonstrated that Y138 is a critical residue for Brd4 association and that inability to complex with Brd4 does not support episomal replication.


Distinguishing the nonlinear propagation regimes of vortex femtosecond pulses in fused silica by evaluating the broadened spectrum.
The nonlinear propagation dynamics of vortex femtosecond laser pulses in optical media is a topic with significant importance in various fields, such as nonlinear optics, micromachining, light bullet generation, vortex air lasing, air waveguide and supercontinuum generation. However, how to distinguish the various regimes of nonlinear propagation of vortex femtosecond pulses remains challenging. This study presents a simple method for distinguishing the regimes of nonlinear propagation of femtosecond pulses in fused silica by evaluating the broadening of the laser spectrum as the input pulse power gradually increases. The linear, self-focusing and mature filamentation regimes for Gaussian and vortex femtosecond pulses in fused silica are distinguished. The critical powers for self-focusing and mature filamentation of both types of laser pulses are obtained. Our work provides a rapid and convenient method for distinguishing different regimes of nonlinear propagation and determining the critical powers for self-focusing and mature filamentation of Gaussian and structured laser pulses in optical media.


In vitro performance of near infrared light transillumination at 780-nm and digital radiography for detection of non-cavitated approximal caries.
To evaluate the ability of a Near Infrared Light Transillumination (NILT) device to detect non-cavitated approximal caries lesions; and to compare its performance to Digital Radiography (DR). Thirty human extracted premolars (sound to lesions into the outer one-third of dentin) were selected. Lesion depth was confirmed by micro-computed tomography (μ-CT). Teeth were mounted in a custom-made device to simulate approximal contact. DR and NILT (CariVu™, DEXIS, LLC, Hatfield, PA, USA) examinations were performed and repeated by three trained and calibrated examiners. Sensitivity, specificity, area under ROC curve (Az), inter- and intra-class correlation coefficients (ICCs) for each method, and correlation among the methods were determined. ICCs for intra-/inter-examiner agreement were substantial for NILT (0.69/0.64), and moderate for DR (0.52/0.48). Sensitivity/specificity for NILT and DR were 0.68/0.93 and 0.50/0.64, respectively. Az for NILT was 0.81, while for DR it was 0.61. Spearman correlation coefficient with μ-CT for NILT (0.65, p<0.001) demonstrated moderate association, while that of DR suggested no association (0.19, p=0.289). Within the limitations of this in vitro study, NILT demonstrated a potential for early approximal caries detection. NILT and DR performed the same regarding the accuracy for non-cavitated approximal caries detection; however, NILT was superior to DR in terms of repeatability, agreement and correlation with μ-CT. A commercial version of NILT was recently introduced as a non-irradiative adjunctive caries detection method. It uses near infrared (NIR) light at 780-nm to transilluminate teeth and captures live images from the occlusal surface. This study demonstrates that NILT can be used as an alternative to radiography for non-cavitated approximal caries detection.


[Importance of vaccination against influenza in individuals with cardiovascular disease].
Influenza is one of the most common causes of human morbidity and mortality. Analysis of severe cases of influenza during the influenza season 2012/2013 found that 84 % of patients had at least one risk factor and the cohort of patients had lower influenza vaccine coverage in comparison with the general population. Influenza vaccine reduces the risk for cardiovascular disease and, therefore, should be recommended particularly to patients with chronic conditions who suffer more often from severe influenza. The education of physicians specialists is also desirable.


Resolution of phylogenetic position of Nigrofomitaceae within Hymenochaetales (Basidiomycota) and Nigrofomes sinomelanoporus sp. nov. (Nigrofomitaceae) from China.
The family Nigrofomitaceae has been considered to be a member of Polyporales and a synonym of Polyporaceae for a long time. However, no molecular evidence supports this taxonomic opinion. For the first time, Nigrofomitaceae is included in a phylogenetic analysis, which shows that this family is separated from Polyporales and nested within Hymenochaetales as a distinct lineage from four well-known families, viz. Hymenochaetaceae, Neoantrodiellaceae, Oxyporaceae and Schizoporaceae. Therefore, Nigrofomitaceae is treated as the fifth family of Hymenochaetales. Nigrofomes melanoporus, the type species of Nigrofomitaceae, was considered to have a pantropical distribution. However, from both morphological and phylogenetic perspectives, the Chinese specimens labelled as N. melanoporus are found not to be conspecific with the specimens of N. melanoporus from Costa Rica, close to the type locality in Cuba. These Chinese specimens are thus described as a new species Nigrofomes sinomelanoporus. The species diversity of Nigrofomes in pantropical region is discussed.


Small-molecule inhibitors of Slack potassium channels as potential therapeutics for childhood epilepsies.
Slack channels are sodium-activated potassium channels that are encoded by the KCNT1 gene. Several KCNT1 gain of function mutations have been linked to malignant migrating partial seizures of infancy. Quinidine is an anti-arrhythmic drug that functions as a moderately potent inhibitor of Slack channels; however, quinidine use is limited by its poor selectivity, safety and pharmacokinetic profile. Slack channels represent an interesting target for developing novel therapeutics for the treatment of malignant migrating partial seizures of infancy and other childhood epilepsies; thus, ongoing efforts are directed toward the discovery of small-molecules that inhibit Slack currents. This review summarizes patent applications published in 2020-2021 that describe the discovery of novel small-molecule Slack inhibitors.


Paediatric hospital visit with laboratory-confirmed influenza improved family members' influenza vaccination.
Vaccination is the primary intervention to prevent influenza infection, yet vaccine uptake remains low among children and other at-risk patients. The aim of the study is to investigate the impact of a paediatric hospital visit with laboratory-confirmed influenza on the influenza vaccination behaviour of participants and their family members in the subsequent influenza season. This study compared the influenza vaccination coverage for participants < 18 years of age with a clinical suspicion of influenza in 2017-2018 during a hospital visit, in two subsequent influenza seasons. Data was retrieved from the hospital electronic medical record and a follow-up questionnaire (2018-2019) to ascertain the common reason(s) that families did not vaccinate their children the following year (2018-2019). The children were distributed into positive- (antigen and/or PCR) and negative-influenza groups. A total of 133 children were enrolled in our study. Participants' mean age was 4.6 years and 74 (55.6%) were males. Overall, 47 (35.3%) had confirmed influenza virus. A significant increase in influenza immunization was found among both positive- and negative-influenza participants between 2017-2018 and 2018-2019 (6.4% vs. 27.7%, p < 0.001; 8.1% vs. 29.1%, p < 0.001, respectively), as well as among family members of positive-influenza participants - siblings and parents (6.4% vs. 19.6%, p = 0.003; 0% vs. 17%, p < 0.001, respectively). Common reasons for failure to vaccinate included doubt in vaccine effectiveness, unlikely to get "flu", busy, and side effects. Our findings suggest that a paediatric hospital visit with laboratory-confirmed influenza increases vaccine uptake among families. Future studies should aim to evaluate evidence-based interventions to improve influenza vaccine uptake among children.


Constitutive endocytosis of CD163 mediates hemoglobin-heme uptake and determines the noninflammatory and protective transcriptional response of macrophages to hemoglobin.
Heme toxicity contributes to the pathogenesis of chronic inflammatory diseases, atherosclerosis, and hemolysis associated vasculopathy. Macrophage clearance of cell free hemoglobin (Hb) is thus an essential homeostatic function of these cells. We examined the transcriptional response of human PBMC derived macrophages to Hb by gene array analysis. The observed noninflammatory macrophage response was characterized by induction of an antioxidative and antiinflammatory gene expression pattern with most prominent induction of the inducible heme oxygenase (HO-1). The metabolically active Hb-CD163-HO-1 pathway resulted in synthesis of ferritin-1 of the antioxidative and antiinflammatory end products linked to heme breakdown by HO-1. This response was mediated by the Hb scavenger receptor CD163 and heme and was not related to Hb mediated depletion of reduced glutathione. In contrast to other cellular responses induced by CD163, there was no role of protein phosphorylation dependent CD163 signaling in the protective macrophage response to Hb. Instead, CD163 acted as an Hb transporter, which undergoes constitutive and ligand independent internalization and recycling between the cell surface and early endosomes. The expression of CD163 and HO-1 in macrophages of neovascularized atherosclerotic lesions suggests that the pathway described herein is active in vivo. Noninflammatory Hb clearance and intimately linked HO-1 expression may provide the long sought-after explanation for the antiinflammatory activity associated with CD163-positive macrophages.


[Birth control in antiquity].
Challenges of the overpopulation has been handled by two different ways by ancient Greeks: on the level of the individual and on that of the community respectively. Regarding the so-called micro-social strategies various preventive methods (getting married late, contraception, homosexuality, prostitution, zoophily and the one-child system) but also those of correctional methods were used as well: abortion, killing the new-born or selling him or her as a slave. The author, who is a well-known researcher of the polis system, gives an overview of all these methods. He focuses-by the help of contemporary texts-on the problem of putting out the child, single-child system, late marriage, contraception and abortion.


Fe(x)Pb(4-x)Sb4Se10: a new class of ferromagnetic semiconductors with quasi 1D {Fe2Se10} ladders.
A new family of quasi-one-dimensional ferromagnetic selenides with general formula Fe(x)Pb(4-x)Sb(4)Se(10) (0 < or = x < or = 2) was generated by isoelectronic substitution in octahedral positions of Pb atoms by Fe within the structure of Pb(4)Sb(4)Se(10). Two members of this family with x = 0.75 and x = 1 were synthesized as a single phase through direct combination of the elements at 823 K. Single crystal X-ray diffraction revealed that Fe(0.75)Pb(3.25)Sb(4)Se(10) crystallizes with the orthorhombic space group Pnma, whereas Fe(0.96)Pb(3.04)Sb(4)Se(10) adopts the lower symmetry monoclinic subgroup P2(1)/m (#11). Both compounds are isomorphous with Pb(4)Sb(4)Se(10), and their crystal structures consist of corrugated layers of edge-sharing bicapped trigonal prisms and octahedra around Pb atoms. Adjacent layers are interconnected by NaCl-type {SbSe} ribbons. The voids left by this arrangement are filled by the novel one-dimensional {Fe(2)Se(10)} double chains (ladder) of edge-sharing octahedra running along [010]. Temperature dependent magnetic susceptibility as well as field dependent magnetization isotherms showed that both Fe(0.75)Pb(3.25)Sb(4)Se(10) and FePb(3)Sb(4)Se(10) are ferromagnetic below 300 K and exhibit superparamagnetism at higher temperatures. A dramatic reduction in the magnetic moment per Fe(2+), approximately 0.40 micro(B), was observed in Fe(0.75)Pb(3.25)Sb(4)Se(10) and FePb(3)Sb(4)Se(10) suggesting that the Fe(x)Pb(4-x)Sb(4)Se(10) (0 < or = x < or = 2) phases are not ordinary ferromagnets where all the magnetic spins are parallel at low temperatures. Analysis of the magnetic coupling of spins located on adjacent Fe atoms (within a localized Fe(2+) moment picture) using Goodenough-Kanamori rules suggested that the magnetism within the ladder and ladder-single chain systems in Fe(x)Pb(4-x)Sb(4)Se(10) phases is controlled by competing interactions.


Amperometric method for quantitative determination of proteins.
The amperometric method is suggested for the quantitative determination of proteins. The method is based on ability of copper to form the intracomplex compounds with proteins and hardly soluble compounds with potassium ferrocyanide. The sensitivity of the method is 10 micrograms of protein per 1 ml. Main advantages of the method are as follows: a) the accuracy of the method is higher than that of the Lawry method and is 5%; b) possibility to determine proteins at any pH; c) possibility to determine stained proteins.


Effects of ethanol on the activity of brain enzymes.
Ethanol alters, in a selective manner, the activity of several membrane-bound enzymes in the central nervous system (CNS) which are important for neuronal transmission of information. Ethanol inhibits Na+/K+-transporting ATPase activity, while adenylate cyclase (AC) activity is stimulated by ethanol added in vitro. Ethanol's effects on AC activity are mediated primarily via effects on proteins that regulate AC activity. Ethanol has selective effects on monoamine oxidase activity, in that the B form of the enzyme is more sensitive to inhibition by ethanol added in vitro. The selective effects of ethanol on different membrane-bound CNS enzymes may result from differing membrane lipid microenvironments of the enzymes, or from differences in the enzyme proteins per se.


The anti-arthritic and immunosuppressive effects of cyclosporine on arthritis induced in the rat by type II collagen.
The influence of cyclosporine (CsA) on the induction and pathogenesis of type II collagen-induced arthritis has been investigated in inbred and outbred Wistar rats. The proportion of animals developing disease and the severity of disease they developed were both diminished by treatment with CsA. These effects were accompanied by a marked suppression of the antibody response to both the immunizing collagen and also to rat type II collagen. CsA treatment also resulted in a decreased accumulation of lymphocytes in arthritic joints. The results indicate that the anti-arthritic and immunosuppressive effects of CsA probably result from a modification of both systemic antibody-mediated and local cell-mediated immunity.


Genome-wide identification of nuclear receptor (NR) superfamily genes in the copepod Tigriopus japonicus.
Nuclear receptors (NRs) are a large superfamily of proteins defined by a DNA-binding domain (DBD) and a ligand-binding domain (LBD). They function as transcriptional regulators to control expression of genes involved in development, homeostasis, and metabolism. The number of NRs differs from species to species, because of gene duplications and/or lineage-specific gene losses during metazoan evolution. Many NRs in arthropods interact with the ecdysteroid hormone and are involved in ecdysone-mediated signaling in arthropods. The nuclear receptor superfamily complement has been reported in several arthropods, including crustaceans, but not in copepods. We identified the entire NR repertoire of the copepod Tigriopus japonicus, which is an important marine model species for ecotoxicology and environmental genomics. Using whole genome and transcriptome sequences, we identified a total of 31 nuclear receptors in the genome of T. japonicus. Nomenclature of the nuclear receptors was determined based on the sequence similarities of the DNA-binding domain (DBD) and ligand-binding domain (LBD). The 7 subfamilies of NRs separate into five major clades (subfamilies NR1, NR2, NR3, NR4, and NR5/6). Although the repertoire of NR members in, T. japonicus was similar to that reported for other arthropods, there was an expansion of the NR1 subfamily in Tigriopus japonicus. The twelve unique nuclear receptors identified in T. japonicus are members of NR1L. This expansion may be a unique lineage-specific feature of crustaceans. Interestingly, E78 and HR83, which are present in other arthropods, were absent from the genomes of T. japonicus and two congeneric copepod species (T. japonicus and Tigriopus californicus), suggesting copepod lineage-specific gene loss. We identified all NR receptors present in the copepod, T. japonicus. Knowledge of the copepod nuclear receptor repertoire will contribute to a better understanding of copepod- and crustacean-specific NR evolution.


Selective catalytic oxidation of ethanol to acetic acid on dispersed Mo-V-Nb mixed oxides.
The direct oxidation of ethanol to acetic acid is catalyzed by multicomponent metal oxides (Mo-V-NbO(x)) prepared by precipitation in the presence of colloidal TiO(2) (Mo(0.61)V(0.31)Nb(0.08)O(x)/TiO(2)). Acetic acid synthesis rates and selectivities (~95 % even at 100 % ethanol conversion) were much higher than in previous reports. The presence of TiO(2) during synthesis led to more highly active surface areas without detectable changes in the reactivity or selectivity of exposed active oxide surfaces. Ethanol oxidation proceeds via acetaldehyde intermediates that are converted to acetic acid. Water increases acetic acid selectivity by inhibiting acetaldehyde synthesis more strongly than its oxidation to acetic acid, thus minimizing prevalent acetaldehyde concentrations and its intervening conversion to CO(x). Kinetic and isotopic effects indicate that C-H bond activation in chemisorbed ethoxide species limits acetaldehyde synthesis rates and overall rates of ethanol conversion to acetic acid. The VO(x) component in Mo-V-Nb is responsible for the high reactivity of these materials. Mo and Nb oxide components increase the accessibility and reducibility of VO(x) domains, while concurrently decreasing the number of unselective V-O-Ti linkages in VO(x) domains dispersed on TiO(2).


Small-Molecule Allosteric Modulators of the Protein Kinase PDK1 from Structure-Based Docking.
Finding small molecules that target allosteric sites remains a grand challenge for ligand discovery. In the protein kinase field, only a handful of highly selective allosteric modulators have been found. Thus, more general methods are needed to discover allosteric modulators for additional kinases. Here, we use virtual screening against an ensemble of both crystal structures and comparative models to identify ligands for an allosteric peptide-binding site on the protein kinase PDK1 (the PIF pocket). We optimized these ligands through an analog-by-catalog search that yielded compound 4, which binds to PDK1 with 8 μM affinity. We confirmed the docking poses by determining a crystal structure of PDK1 in complex with 4. Because the PIF pocket appears to be a recurring structural feature of the kinase fold, known generally as the helix αC patch, this approach may enable the discovery of allosteric modulators for other kinases.


Filamentous phage fs1 of Vibrio cholerae O139.
Filamentous phage, fs1, was obtained from Vibrio cholerae O139. The lysogenized strains produced a large amount of fs1 phage in the culture supernatant. This phage was previously reported as novel fimbriae of that organism. The genome of the phage was a 6.5 kb single-stranded DNA. The capsid of fsl consists of a small molecule peptide (about 2.5 kDa).


Age-related changes in secretion and metabolic effects of a trial natriuretic factor in rats.
The effects of aging on the secretion of and renal sensitivity to atrial natriuretic factor (ANF) were studied concomitantly in both senescent (25- to 34-month-old) and in adult (7- to 13 month-old) female and male Long-Evans rats. The plasma concentrations of ANF, measured in response to either a mild stimulation induced by a hypertonic volume expansion (i.e., 20 min after the onset of a continuous infusion during 15 min of a 2.5% NaCl solution; n = 18 old and 23 adult rats) or an intense stimulation produced by morphine injection (i.e., 30 min after an intraperitoneal injection of 5 mg morphine/100 g body weight; n = 11 old and 12 adult rats), were significantly lower (approximately -34 and -80%, respectively) in old as compared with adult animals. Acute intravenous injection of exogenous rat ANF (0.10 and 0.40 mu g/100 g body weight) induced similar natriuretic, diuretic, and kaliuretic effects in aged (n = 18) and in adult (n = 23) rats. The present data suggest that the significantly reduced (about -20%) natriuretic and kaliuretic responses of the aged rat, observed 20 min after the onset of hypertonic volume expansion, could be partly due to a primary defect in cardiac production and/or release of ANF rather than to a reduction of renal responsivity to ANF.


Hyperactivation and acrosome reaction in vitro in spermatozoa ejaculated by cryptorchid dogs after orchiopexy.
Orchiopexy of the cryptorchid (CR) testis and castration of the scrotal testis were performed in three unilaterally CR beagles at six months of age. Induction rates for ejaculated sperm hyperactivation (HA) and the acrosome reaction (AR) in vitro in these orchiopexied dogs were compared with five those in normal beagles one year later. Canine spermatozoa were incubated for 9 hr at 38 degrees C under 5% CO2 in air in canine capacitation medium at a concentration of 30 x 10(6) sperm/ml. HA was observed using high-speed videomicrography. The AR spermatozoa were evaluated by the triple stain technique. As a result, there was no significant difference between 'the CR dogs after orchiopexy' (CDO) and the normal dogs (ND) with respect to sperm motility just after ejaculation. However, sperm motility of CDO decreased markedly during incubation. There was a significant difference in sperm motility between CDO (Mean +/- SD; 47 +/- 12%) and ND (80 +/- 9%) after three hours of incubation (p less than 0.01). No significant difference was observed between CDO and ND with respect to the HA rate of motile spermatozoa throughout the incubation period. The peak of HA rate was found in both CDO (58 +/- 5%) and ND (61 +/- 16%) after seven hours of incubation. The AR rate of spermatozoa in CDO was lower than that in ND after six hours of incubation. The AR rate of CDO (26 +/- 4%) was significantly lower than ND (46 +/- 5%) after eight hours of incubation (p less than 0.01). It is assumed that there might be relation between a rapid decrease of motility and low AR rate in spermatozoa of CDO during incubation.


Liver blood flow after major hepatic resection.
The factors involved in liver regeneration are poorly understood, but it has been suggested that blood flow plays a role. This paper documents the changes in liver blood flow (LBF) that occur after major hepatic resection. Eight patients, ranging in age from 37 to 76 years, underwent liver resection. Liver blood flow was measured preoperatively and on days 1, 4 and 7 postoperatively by low-dose galactose clearance. There was a significant (p less than 0.01) fall in LBF on day 1 compared with the baseline value, followed by a significant (p less than 0.01) rise from the baseline value by day 4. By day 7, LBF had returned to baseline levels and was significantly (p less than 0.01) lower than on day 4. These changes in LBF may be related to the stimulus for liver regeneration and increased functional demands during the early regenerative phase.


Variations in Post-Operative Electrolyte in Coronary Artery Intervention.
Low volume change and minimal trauma observed during angiography are the reason why physicians often overlook any changes affecting pre-operative electrolytes levels after coronary intervention. However, few studies have addressed the issue of electrolyte changes after the coronary intervention. Therefore, our study investigates coronary angiography's effect on electrolytes and provides the quick identification of groups more prone to electrolyte changes. From the department of cardiology of the second affiliated hospital of Shandong's first medical university, 374 patients undergoing coronary angiography were selected. Pre-intervention and post-intervention serums, sodium (Na+), potassium (K+), chloride (Cl-), magnesium (Mg2+) and renal function were analyzed. The correlation between influential factors was also assessed. The association of hypokalemia with short-major adverse cardiac events (MACE) and arrhythmia was evaluated. Among the 374 subjects including 264 patients who had a simple angiography and 110 patients who received coronary artery interventional therapy. A decrease in potassium levels was found in 81.8% of the patients, and post-interventional hypokalemia was observed in 15.0%. After the intervention, the hypokalemia among males was 2.18 times than that of females, and the pre-operative serum potassium level was 3.5mmol/L≤K+<4.0mmol/L and was 2.09 times than that of K+≥4.0 mmol/L, but was not associated with age and either simple coronary angiography or PCI (percutaneous coronary intervention). Hypernatremia was also prevalent in males under 60 years and with pre-operative hypernatremia. Significant variations were found between hypokalemia and influential factors like hypertension, diabetes, and gastrointestinal disease. We also found that there was no obvious correlation between hypokalemia and recurrent angina, heart failure and death, but significantly increased the risk of some arrhythmias. Male patients are more likely to suffer from electrolyte disturbance after coronary intervention. There is a need to emphasize monitoring and managing electrolyte changes to prevent severe complications in the peri-operative period.


[Several heart conditions are related to increased risk of ischemic stroke and TIA].
Several heart conditions have been related to increased risk of ischemic stroke and TIA. Some require primary prophylaxis with antithrombotic treatment and often the indication for prophylaxis is further increased after an ischemic cerebrovascular event. Oral anticoagulants have an important role in these situations, but also other treatments such as closure of patent foramen ovale, may be useful. Left atrial appendage occlusion in patients with atrial fibrillation and stroke is being evaluated in several ongoing studies. It should be kept in mind that other pathophysiological mechanisms associated with ischemic stroke may occur simultaneously with heart disease and an individual assessment of patients is needed. Here we provide information about current concepts and treatment options in patients with suspected cardioembolic stroke.


Self-assembly of gradient copolymers synthesized in semi-batch mode by nitroxide mediated polymerization.
The effect of diffuse compositional interfaces on copolymer self-assembly was studied via gradient copolymers (GCP). Poly(methyl methacrylate)-grad-(styrene) (PMMA-grad-PSt) copolymers were synthesized in semi-batch mode using nitroxide-mediated polymerization (NMP) with varied monomer injection protocols to produce varied diffuse interfaces (number average molecular weights (Mn) ranged from 62 000 g mol-1 to 94 000 g mol-1 with dispersities (Đ) between 1.35 and 1.59). The GCPs were spun into thin films on substrates made neutral by (St-ran-MMA-ran-hydroxyethyl methacrylate) terpolymers and annealed at elevated temperature to produce vertically oriented microphase-separated domains. The GCPs were found to have domain spacing larger than equivalent monodisperse BCPs, due to their polydisperse nature. This effect was partially offset by the decrease in χ due to the gradient. GCPs synthesized with a single-injection protocol (i.e. less diffuse interfaces) were found to self-assemble into ordered domains. However, GCPs synthesized with long injection times (i.e. more diffuse interfaces) exhibited poor self-assembly attributed to their predicted statistical-copolymer-like middle sequence, which caused a reduction of the effective enthalpic interaction parameter.


The association between sleep disturbances and tooth loss among post-stroke patients.
Loss of teeth has been associated with neurological and sleep disorders. It is considered to be a predictor of stroke and leads to modifications of airway patency and predisposition to obstructive sleep apnea. To investigate sleep quality, risk of obstructive sleep apnea and excessive sleepiness among post-stroke patients with tooth loss attending the Neurovascular Clinic of the Federal University of São Paulo. The prevalence rates of different types of stroke were assessed among 130 patients with different degrees of tooth loss, along with the presence of sleep disturbances, risk of obstructive sleep apnea and excessive daytime sleepiness. The prevalence of ischemic stroke was 94.6%, with either no significant disability or slight disability. Our sample had poor sleep quality, and a high risk of obstructive sleep apnea, but without excessive daytime sleepiness. Half of our sample had lost between 9 and 31 teeth, and more than 25% had edentulism. The majority used full removable dental prostheses, and more than half of these individuals slept without removing the prosthesis. We found high prevalence of poor sleep quality and high risk of obstructive sleep apnea among post-stroke patients with tooth loss. This indicates the need for further studies on treating and preventing sleep disturbances in stroke patients with tooth loss.


The Role of the Registered Nurse Working in Substance Use Disorder Treatment: A Hermeneutic Study.
Substance Use Disorders (SUDs) are a national public health crisis. However, there is minimal existing research literature on the role of the nurse working in SUD treatment. The purpose of this study was to describe the meaning of the professional role of the registered nurse working in the SUD setting. The study utilized a Heideggerian Phenomenological approach with a modified Colaizzi method for analysis and interpretation. The nine study participants, two males and seven females, aged 27-60 had worked in SUD treatment for 1-37 years. Three major themes, with sub-themes, emerged: Defining the Role for Self; Learning the Role; and Navigating with Ease in an Unchangeable Culture. Findings demonstrated that nurses in SUD treatment value their role and the care of patients with SUDs. Patient recovery or relapse influenced job satisfaction. Significantly, the findings highlighted an outdated role with rigid boundaries and no real contemporary identity. Findings can be used to address the need for a contemporary SUD nursing identity and to support ongoing involvement of nurses in health policy related to SUDs.


The Newest Generation of Drug-eluting Stents and Beyond.
There has been a great evolution in the development of coronary stents in order to avoid both restenosis and thrombosis. Improvements have led to improvements in the design and conformation of metallic or resorbable structures, with an adequate balance between trackability and radial force, the development of antiproliferative drugs and the polymers to control release and allow adequate endothelialisation and an optimal duration of the antiplatelet regimen. Some suggestions are provided about the ideal characteristics of future coronary stents.


The luteinizing hormone-releasing hormone (LHRH) agonist, [D-Trp6, des-Gly-NH2(10)]-LHRH ethylamide, has no direct effect on spermatogenesis in the rat.
Treatment of intact rats with luteinizing hormone-releasing hormone (LHRH) agonists has been shown to produce atrophy of a variable number of testicular seminiferous tubules. These findings raised the question of a possible direct versus indirect action of LHRH agonists on spermatogenesis. To answer this question, we treated hypophysectomized rats with the LHRH agonist [D-Trp6, des-Gly-NH2(10)]-LHRH ethylamide, dihydrotestosterone (DHT), or a combination of these two compounds for a period of 1 mo. Treatment of hypophysectomized animals with the LHRH agonist alone had no significant effect on the atrophy of seminiferous tubules found after hypophysectomy. DHT, however, maintained spermatogenesis at 80% of the level seen in intact animals. When DHT and the LHRH agonist were administered in combination, the stimulatory effects of DHT were observed with no significant interference caused by the LHRH agonist. This study shows that an LHRH agonist has no direct effect on the morphology of the seminiferous tubules in the absence of the pituitary gland and strongly suggests that the atrophy observed in the testis after LHRH agonist treatment in intact animals is mediated by the LHRH agonist-induced changes in luteinizing hormone secretion and/or direct action of the peptide on Leydig cells.


B12-dependent photoresponsive protein hydrogels for controlled stem cell/protein release.
Thanks to the precise control over their structural and functional properties, genetically engineered protein-based hydrogels have emerged as a promising candidate for biomedical applications. Given the growing demand for creating stimuli-responsive "smart" hydrogels, here we show the synthesis of entirely protein-based photoresponsive hydrogels by covalently polymerizing the adenosylcobalamin (AdoB12)-dependent photoreceptor C-terminal adenosylcobalamin binding domain (CarHC) proteins using genetically encoded SpyTag-SpyCatcher chemistry under mild physiological conditions. The resulting hydrogel composed of physically self-assembled CarHC polymers exhibited a rapid gel-sol transition on light exposure, which enabled the facile release/recovery of 3T3 fibroblasts and human mesenchymal stem cells (hMSCs) from 3D cultures while maintaining their viability. A covalently cross-linked CarHC hydrogel was also designed to encapsulate and release bulky globular proteins, such as mCherry, in a light-dependent manner. The direct assembly of stimuli-responsive proteins into hydrogels represents a versatile strategy for designing dynamically tunable materials.


Novel strategies for clinical investigation and biomarker discovery: a guide to applied metabolomics.
Metabolomics is an emerging technology that is increasing both in basic science and in human applications, providing a physiological snapshot. It has been highlighted as one of the most wide ranging and reliable tools for the investigation of physiological status, the discovery of new biomarkers and the analysis of metabolic pathways. Metabolomics uses innovative mass spectrometry (MS) allied to chromatography or nuclear magnetic resonance (NMR). The recent advances in bioinformatics, databases and statistics, have provided a unique perception of metabolites interaction and the dynamics of metabolic pathways at a system level. In this context, several studies have applied metabolomics in physiology- and disease-related works. The application of metabolomics includes, physiological and metabolic evaluation/monitoring, individual response to different exercise, nutritional interventions, pathological processes, responses to pharmacological interventions, biomarker discovery and monitoring for distinct aspects, such as: physiological capacity, fatigue/recovery and aging among other applications. For metabolomic analyses, despite huge improvements in the field, several complex methodological steps must be taken into consideration. In this regard, the present article aims to summarize the novel aspects of metabolomics and provide a guide for metabolomics for professionals related to physiologist and medical applications.


The prognostic significance of elevated serum alkaline phosphatase levels preoperatively in patients with carcinoma of the colon and rectum.
Two hundred and eighty-three patients were observed for a minimum of 38 months after undergoing resection of Dukes' B2, C1 or C2 classification for carcinoma of the colon and rectum. Cumulative recurrence rates were higher in patients with elevated preoperative serum alkaline phosphatase levels. Site specific recurrence rates revealed a lower incidence of metastases to the liver in patients with elevated preoperative alkaline phosphatase levels. Elevated serum alkaline phosphatase values in patients with carcinoma of the colon may reflect hepatic metastases, but when metastases to the liver are not detected at laparotomy, patients with elevated levels of alkaline phosphatase are at no greater risk of having metastases to the liver develop than patients with normal levels.


Experiment protocols for brain-body imaging of locomotion: A systematic review.
Human locomotion is affected by several factors, such as growth and aging, health conditions, and physical activity levels for maintaining overall health and well-being. Notably, impaired locomotion is a prevalent cause of disability, significantly impacting the quality of life of individuals. The uniqueness and high prevalence of human locomotion have led to a surge of research to develop experimental protocols for studying the brain substrates, muscle responses, and motion signatures associated with locomotion. However, from a technical perspective, reproducing locomotion experiments has been challenging due to the lack of standardized protocols and benchmarking tools, which impairs the evaluation of research quality and the validation of previous findings. This paper addresses the challenges by conducting a systematic review of existing neuroimaging studies on human locomotion, focusing on the settings of experimental protocols, such as locomotion intensity, duration, distance, adopted brain imaging technologies, and corresponding brain activation patterns. Also, this study provides practical recommendations for future experiment protocols. The findings indicate that EEG is the preferred neuroimaging sensor for detecting brain activity patterns, compared to fMRI, fNIRS, and PET. Walking is the most studied human locomotion task, likely due to its fundamental nature and status as a reference task. In contrast, running has received little attention in research. Additionally, cycling on an ergometer at a speed of 60 rpm using fNIRS has provided some research basis. Dual-task walking tasks are typically used to observe changes in cognitive function. Moreover, research on locomotion has primarily focused on healthy individuals, as this is the scenario most closely resembling free-living activity in real-world environments. Finally, the paper outlines the standards and recommendations for setting up future experiment protocols based on the review findings. It discusses the impact of neurological and musculoskeletal factors, as well as the cognitive and locomotive demands, on the experiment design. It also considers the limitations imposed by the sensing techniques used, including the acceptable level of motion artifacts in brain-body imaging experiments and the effects of spatial and temporal resolutions on brain sensor performance. Additionally, various experiment protocol constraints that need to be addressed and analyzed are explained.


Influence of PUVA and UVB radiation on delayed hypersensitivity in the guinea pig.
Exposure of guinea pigs to UVA (320--400 nm) radiation following administration of 8-methoxypsoralen by gavage (referred to by the acronym, PUVA) or exposure to UVB (290--320 nm) radiation, produced suppression of the cutaneous delayed hypersensitivity reaction at the site of exposure to radiation and at distant nonexposed sites. In these experiments, the animals were immunized by injection of dinitrophenyl-bovine gamma-globulin (DNP-BGG) in complete Freund's adjuvant and delayed hypersensitivity responses were provoked by intradermal injections of DNP-BGG, DNP and BGG on the flanks. Exposure to erythemogenic doses of either PUVA or UVB radiation for 7 days prior to immunization and for the 7 days between immunization and challenge (total period of radiation: 14 days) produced inhibiton of responses to each of the test substances. In addition, treatment with erythemogenic doses of PUVA either for 7 days prior to immunization or during the interval between immunization and challenge with DNP-BGG, inhibited the delayed hypersensitivity responses at the site of irradiation and at a nonexposed site. These findings suggest that in vivo exposure to nonionizing radiation leads to both local and systemic alteration of certain immune responses.


Retinal changes and tumorigenesis in Ramon syndrome: follow-up of a Brazilian family.
We report on the clinical evolution of the Brazilian family with Ramon syndrome described by de Pina-Neto et al. [1986, Am J Med Genet 25:441-443]. Three members (patients IV-2, IV-18, and IV-19) have developed pigmentary changes in the retina and paleness of the optic disk. Patient IV-18 also has developed giant hypertrophy of the labia minora that, when examined histopathologically, was found to be due to neoplastic fibroblast and epithelial proliferation caused by a fibromatous process similar to that reported in the gingivae of the patients with this syndrome. Audiologic function of patient IV-2 was normal, and no skin lesions were detected. The articular signs and symptoms show that the affected relatives developed rheumatoid arthritis, which is currently inactive in patient IV-18, whereas patient IV-2 did not develop these alterations.


Is Redshirting Beneficial for Reading Acquisition Success?
The controversy around the effect of academic redshirting on reading acquisition continues receiving attention in the international literature. However, few studies are known with non-English speaking children. In this study we intend to understand this phenomenon with 698 Portuguese speaking first graders, 360 girls (51.6%), aged between 5 years old and 8 months and 7 years old and 6 months (M = 6.3 months, SD = 3.9 months). Reading acquisition precursors were assessed namely phonemic awareness and letter-sound knowledge. Results reveal that 5.9% of first graders are redshirted. Clusters analysis indicated two clusters per variable. Cluster 1 with low phonemic awareness and letter-sound knowledge and low socioeconomic status, cluster 2 with high phonemic awareness and letter-sound knowledge and medium-high socioeconomic status. The cluster results suggest a prevalence of 24.5% children at risk of having learning difficulties. The MANOVA indicated that only socioeconomic status has an effect on phonemic awareness and letter-sound knowledge, with children from medium-high level presenting higher results. It is concluded that redshirting did not bring additional advantages for reading acquisition success. Implications about the importance of education in order to lessen those differences, as well as prevent difficulties are presented.


Recent developments of insecticide resistance in some Turkish anophelines.
Susceptibility tests carried out since 1974 in both the field and the laboratory with Anopheles sacharovi, A. hyrcanus and A. maculipennis from Turkey have revealed resistance to organophosphate and carbamate insecticides in all three species, in the first two in the southern Chukurova plain and in the third in the northern area around Osmanjik. Resistance was indicated by significant survivals when exposed to dosages killing presumed susceptible strains of these and other anopheline species. The temperature at which the susceptibility tests were carried out had a marked influence on mortalities. Broad spectra of resistance were shown by all three species, though with interspecific differences, and are attributed to the extensive and intensive use of a wide range of chemicals for agricultural pest control. Of the insecticides readily available for house-spraying for malaria control, malathion would appear to be the one with the greatest potential usefulness.


[Diagnosis and treatment of pancreatogenic portal hypertension: analysis of 26 cases].
To investigate the diagnostic and treatment methods of pancreatogenic portal hypertension and to summarize the experience in surgical treatment of these patients, especially in dealing with the complications and sophisticated cases. Twenty-six patients with pancreatogenic portal hypertension, 19 males and 7 females, aged 37 (29 - 57), underwent pericardial vessel ligation and splenectomy during the period from January 1990 to November 2006 and were followed up for 8 years (2 - 15 years). The clinical data were analyzed. Seven patients received Roux-en-Y operation for huge pancreatogenic cysts and 3 patients received regional dissection operation of diaphragmatic muscle for severe adhesion. One died of acute myocardial infarction 5 days after the operation, and 25 patients were cured without recurrence during the follow-up. Pericardial vessel ligation and splenectomy are rational and reliable methods to treat pancreatogenic portal hypertension. The key issue is how to diagnose pancreatogenic portal hypertension correctly and deal with its complications reasonably.


New directions in the treatment of atypical depression.
Atypical depression, one of the 4 historically important ways of subdividing depression, was first used by West and Dally to describe a patient subgroup that was nonresponsive to imipramine but responsive to iproniazid. The definition was later refined to include reverse vegetative and hysteroid dysphoria symptoms, presaging adoption of the current DSM definition in 1984. However, focusing on hysteroid dysphoria symptoms drew attention away from anxiety symptoms, some of which are more strongly linked to atypical depression. Studies that have attempted to validate atypical depression have reinforced reverse vegetative symptoms criteria and have shown that atypical depression is probably more common than melancholia. Studies suggest that atypical depression is not preferentially responsive to monoamine oxidase inhibitors, but rather less responsive to tricyclic antidepressants.


A new family of diprotodontian marsupials from the latest Oligocene of Australia and the evolution of wombats, koalas, and their relatives (Vombatiformes).
We describe the partial cranium and skeleton of a new diprotodontian marsupial from the late Oligocene (~26-25 Ma) Namba Formation of South Australia. This is one of the oldest Australian marsupial fossils known from an associated skeleton and it reveals previously unsuspected morphological diversity within Vombatiformes, the clade that includes wombats (Vombatidae), koalas (Phascolarctidae) and several extinct families. Several aspects of the skull and teeth of the new taxon, which we refer to a new family, are intermediate between members of the fossil family Wynyardiidae and wombats. Its postcranial skeleton exhibits features associated with scratch-digging, but it is unlikely to have been a true burrower. Body mass estimates based on postcranial dimensions range between 143 and 171 kg, suggesting that it was ~5 times larger than living wombats. Phylogenetic analysis based on 79 craniodental and 20 postcranial characters places the new taxon as sister to vombatids, with which it forms the superfamily Vombatoidea as defined here. It suggests that the highly derived vombatids evolved from wynyardiid-like ancestors, and that scratch-digging adaptations evolved in vombatoids prior to the appearance of the ever-growing (hypselodont) molars that are a characteristic feature of all post-Miocene vombatids. Ancestral state reconstructions on our preferred phylogeny suggest that bunolophodont molars are plesiomorphic for vombatiforms, with full lophodonty (characteristic of diprotodontoids) evolving from a selenodont morphology that was retained by phascolarctids and ilariids, and wynyardiids and vombatoids retaining an intermediate selenolophodont condition. There appear to have been at least six independent acquisitions of very large (>100 kg) body size within Vombatiformes, several having already occurred by the late Oligocene.


Census and evaluation of p53 target genes.
The tumor suppressor p53 functions primarily as a transcription factor. Mutation of the TP53 gene alters its response pathway, and is central to the development of many cancers. The discovery of a large number of p53 target genes, which confer p53's tumor suppressor function, has led to increasingly complex models of p53 function. Recent meta-analysis approaches, however, are simplifying our understanding of how p53 functions as a transcription factor. In the survey presented here, a total set of 3661 direct p53 target genes is identified that comprise 3509 potential targets from 13 high-throughput studies, and 346 target genes from individual gene analyses. Comparison of the p53 target genes reported in individual studies with those identified in 13 high-throughput studies reveals limited consistency. Here, p53 target genes have been evaluated based on the meta-analysis data, and the results show that high-confidence p53 target genes are involved in multiple cellular responses, including cell cycle arrest, DNA repair, apoptosis, metabolism, autophagy, mRNA translation and feedback mechanisms. However, many p53 target genes are identified only in a small number of studies and have a higher likelihood of being false positives. While numerous mechanisms have been proposed for mediating gene regulation in response to p53, recent advances in our understanding of p53 function show that p53 itself is solely an activator of transcription, and gene downregulation by p53 is indirect and requires p21. Taking into account the function of p53 as an activator of transcription, recent results point to an unsophisticated means of regulation.


Surgical management of pivot-shift phenomenon in a dog.
CASE DESCRIPTION A 6.8-year-old neutered male Labrador Retriever-Poodle mix was evaluated because of continued left pelvic limb lameness unresponsive to conservative management 1 year after undergoing tibial plateau leveling osteotomy (TPLO). CLINICAL FINDINGS A jerking lateral movement of the left stifle joint was detected during walking. Orthopedic examination revealed a pivot-shift phenomenon (PSP). Palpation elicited no signs of discomfort over the TPLO plate or caudomedial aspect of the stifle joint. Radiography revealed complete bone fusion at the osteotomy site and only mild joint effusion. TREATMENT AND OUTCOME Arthrotomy was performed at the medial aspect of the stifle joint, revealing no meniscal tears. The previously applied plate was removed, and an extracapsular, synthetic, ligament-like biomaterial was placed to counteract internal tibial rotation, thereby eliminating the PSP. Six weeks later, lameness had improved considerably with no evidence of PSP; 8 weeks after surgery, the dog was assessed for sudden-onset lameness in the right pelvic limb. Cranial cruciate ligament rupture was suspected, and TPLO was performed. The PSP was identified intraoperatively, so an extracapsular implant was placed. Six weeks later, the dog had only mild lameness and no evidence of PSP in either pelvic limb. In a follow-up telephone conversation 1 year later, the owner reported no obvious lameness or gait abnormalities. CLINICAL RELEVANCE Use of an extracapsular implant effectively eliminated the PSP following TPLO in the dog of this report and can be considered as an intra- or postoperative option for dogs with PSP that responds poorly to conservative management.


Distribution of immunoglobulins in squamous cell carcinoma of the head and neck.
The immune response with respect to immunoglobulin production in the tumor was investigated in 23 patients with advanced squamous cell carcinomas of the head and neck. Immunohistochemical staining with monoclonal antibodies against IgG, IgM, IgA, IgD and IgE in the tumor was compared to normal hypopharyngeal mucosa. For IgG, IgA and IgM no significant differences between tumor and control tissues could be found. In contrast, a high number of IgE-positive cells was counted in most squamous cell carcinomas compared to normal mucosa. Most of these cells appeared as plasma cells. Regarding IgD the differences between tumor and control tissues, were less pronounced but also significant.


[Immunotherapy in allergology].
The current state of knowledge is presented of allergenic immunotherapy of atopic allergic diseases emphasizing the fact that desensitisation is an effective and safe method of treatment. Allergenic vaccines, altering the immune profile of patients, correct the deviated immune reactions in atopy. Immunotherapy prevents development of new allergies and the clinical effect is maintained longer than the administered treatment. The technological progress increases the availability of better and ever better standardised vaccines that provide high specificity of administered therapy.


Increased dermal carotenoid levels assessed by noninvasive reflection spectrophotometry correlate with serum levels in women ingesting Betatene.
beta-Carotene is being used as an oral sun protectant, and evidence indicates that carotenoids may protect human skin from light-induced lesions. However, limited information is available on the distribution and accumulation of beta-carotene in skin, especially with respect to various skin regions. With the use of reflection spectroscopy, we investigated the accumulation of total carotenoids in human skin after repeated supplementation of 12 women with beta-carotene from a natural source Betatene, an algal extract. After daily ingestion of 24 mg beta-carotene (in Betatene) for 12 wk, an increase in carotenoid skin levels was observed. Highest basal values were measured in skin of the forehead, palm of the hand and dorsal skin, with lower levels measured in skin of the arm and back of the hand. Upon treatment, increases in carotenoid skin levels were found in all areas as follows: 2.4-fold in forehead, 0.7-fold in dorsal skin, 2.2-fold in the palm of the hand, 17-fold on the back of the hand and 1.7-fold on the inside of the arm. After cessation of treatment, the carotenoid levels decreased in all skin areas. Serum beta-carotene levels were elevated upon treatment and correlated with carotenoid skin levels. Correlations for serum vs. skin from the palm of the hand (r = 0.94) and skin from the forehead (r = 0.89) were calculated, indicating that serum levels appeared to be a suitable indicator for carotenoid accumulation in specific regions of the skin. With doses of approximately 20-25 mg carotenoids/d, it is possible to raise dermal carotenoid levels.


Technical note: assay of cell quantity in the fibroblast-populated collagen matrix with a tetrazolium reagent.
Determination of cell quantity in three-dimensional culture systems, such as the fibroblast-populated collagen matrix, can be difficult secondary to the abundance of extracellular collagen. The WST-1 assay, which can quantitate cellular processes in monolayer culture, was tested as a measure of relative cell quantity in a three dimensional culture system, the fibroblast-populated collagen matrix. The assay had acceptable accuracy and precision, and was not affected by the extracellular matrix. It was concluded that the assay was a reasonable alternative to other measures of cell quantity in the fibroblast-populated collagen matrix.


Choline Kinase Alpha Is a Novel Transcriptional Target of the Brg1 in Hepatocyte: Implication in Liver Regeneration.
Liver regeneration is a key compensatory process in response to liver injury serving to contain damages and to rescue liver functions. Hepatocytes, having temporarily exited the cell cycle after embryogenesis, resume proliferation to regenerate the injured liver parenchyma. In the present study we investigated the transcriptional regulation of choline kinase alpha (Chka) in hepatocytes in the context of liver regeneration. We report that Chka expression was significantly up-regulated in the regenerating livers in the partial hepatectomy (PHx) model and the acetaminophen (APAP) injection model. In addition, treatment with hepatocyte growth factor (HGF), a strong pro-proliferative cue, stimulated Chka expression in primary hepatocytes. Chka depletion attenuated HGF-induced proliferation of hepatocytes as evidenced by quantitative PCR and Western blotting measurements of pro-proliferative genes as well as EdU incorporation into replicating DNA. Of interest, deletion of Brahma-related gene 1 (Brg1), a chromatin remodeling protein, attenuated Chka induction in the regenerating livers in mice and in cultured hepatocytes. Further analysis revealed that Brg1 interacted with hypoxia-inducible factor 1 alpha (HIF-1α) to directly bind to the Chka promoter and activate Chka transcription. Finally, examination of human acute liver failure (ALF) specimens identified a positive correlation between Chka expression and Brg1 expression. In conclusion, our data suggest that Brg1-dependent trans-activation of Chka expression may contribute to liver regeneration.


The PilB-PilZ-FimX regulatory complex of the Type IV pilus from Xanthomonas citri.
Type IV pili (T4P) are thin and flexible filaments found on the surface of a wide range of Gram-negative bacteria that undergo cycles of extension and retraction and participate in a variety of important functions related to lifestyle, defense and pathogenesis. During pilus extensions, the PilB ATPase energizes the polymerization of pilin monomers from the inner membrane. In Xanthomonas citri, two cytosolic proteins, PilZ and the c-di-GMP receptor FimX, are involved in the regulation of T4P biogenesis through interactions with PilB. In vivo fluorescence microscopy studies show that PilB, PilZ and FimX all colocalize to the leading poles of X. citri cells during twitching motility and that this colocalization is dependent on the presence of all three proteins. We demonstrate that full-length PilB, PilZ and FimX can interact to form a stable complex as can PilB N-terminal, PilZ and FimX C-terminal fragments. We present the crystal structures of two binary complexes: i) that of the PilB N-terminal domain, encompassing sub-domains ND0 and ND1, bound to PilZ and ii) PilZ bound to the FimX EAL domain within a larger fragment containing both GGDEF and EAL domains. Evaluation of PilZ interactions with PilB and the FimX EAL domain in these and previously published structures, in conjunction with mutagenesis studies and functional assays, allow us to propose an internally consistent model for the PilB-PilZ-FimX complex and its interactions with the PilM-PilN complex in the context of the inner membrane platform of the X. citri Type IV pilus.


A comparison of the Snellen chart and the S-chart for visual acuity assessment in amblyopia.
A standard Snellen chart and a chart that controls contour interaction effects and gives equal numbers of acuity trials for all letter sizes (the S-chart) were used to compare visual acuities for 30 amblyopic patients (17 with central fixation, 13 with eccentric fixation). No statistically significant difference appeared between S-chart and Snellen acuity in the acuity range 20/30 to 20/80. When amblyopic acuity was below 20/100, S-chart and Snellen acuities differed significantly.


In-Situ Growth of Urchin Manganese Sulfide Anchored Three-Dimensional Graphene (γ-MnS@3DG) on Carbon Cloth as a Flexible Asymmetric Supercapacitor.
In energy storage-device it is highly crucial to develop durable electrode materials having high specific capacitance and superior energy density without disturbing its inherent flexibility. Herein, we demonstrate three-dimensional graphene oxide decorated monodispersed hollow urchin γ-MnS (γ-MnS@3DG) via proficient one-step solvothermal method. The designed material delivers a remarkable capacitance of 858 F g-1 at 1 A g-1. A flexible solid state asymmetric supercapacitor (ASCs) device assembled using surface activated carbon cloth (CC) decorated with γ-MnS@3DG as positive and three-dimension graphene on carbon cloth (3DG@CC) as negative electrode, (γ-MnS@3DG//3DG). The device delivers 26 Wh kg-1 energy density at power density 500 W kg-1 @ 1A g-1 and retains favorable energy density 17.8 Wh kg-1 at an ultrahigh power density of 1500 W kg-1@3 A g-1. This carbon embedded transition-metal sulfide (TMS) based ASC demonstrates eminent mechanical flexibility under rigorous bending states maintaining invariant performance.


Characterization of a dominant negative C. elegans Twist mutant protein with implications for human Saethre-Chotzen syndrome.
Twist is a transcription factor that is required for mesodermal cell fates in all animals studied to date. Mutations of this locus in humans have been identified as the cause of the craniofacial disorder Saethre-Chotzen syndrome. The Caenorhabditis elegans Twist homolog is required for the development of a subset of the mesoderm. A semidominant allele of the gene that codes for CeTwist, hlh-8, has defects that occur earlier in the mesodermal lineage than a previously studied null allele of the gene. The semidominant allele has a charge change (E29K) in the basic DNA-binding domain of CeTwist. Surprisingly, the mutant protein retains DNA-binding activity as both a homodimer and a heterodimer with its partner E/Daughterless (CeE/DA). However, the mutant protein blocks the activation of the promoter of a target gene. Therefore, the mutant CeTwist may cause cellular defects as a dominant negative protein by binding to target promoters as a homo- or heterodimer and then blocking transcription. Similar phenotypes as those caused by the E29K mutation were observed when amino acid substitutions in the DNA-binding domain that are associated with the human Saethre-Chotzen syndrome were engineered into the C. elegans protein. These data suggest that Saethre-Chotzen syndrome may be caused, in some cases, by dominant negative proteins, rather than by haploinsufficiency of the locus.


A zinc-dependent adhesion module is responsible for intercellular adhesion in staphylococcal biofilms.
Hospital-acquired bacterial infections are an increasingly important cause of morbidity and mortality worldwide. Staphylococcal species are responsible for the majority of hospital-acquired infections, which are often complicated by the ability of staphylococci to grow as biofilms. Biofilm formation by Staphylococcus epidermidis and Staphylococcus aureus requires cell-surface proteins (Aap and SasG) containing sequence repeats known as G5 domains; however, the precise role of these proteins in biofilm formation is unclear. We show here, using analytical ultracentrifugation (AUC) and circular dichroism (CD), that G5 domains from Aap are zinc (Zn(2+))-dependent adhesion modules analogous to mammalian cadherin domains. The G5 domain dimerizes in the presence of Zn(2+), incorporating 2-3 Zn(2+) ions in the dimer interface. Tandem G5 domains associate in a modular fashion, suggesting a "zinc zipper" mechanism for G5 domain-based intercellular adhesion in staphylococcal biofilms. We demonstrate, using a biofilm plate assay, that Zn(2+) chelation specifically prevents biofilm formation by S. epidermidis and methicillin-resistant S. aureus (MRSA). Furthermore, individual soluble G5 domains inhibit biofilm formation in a dose-dependent manner. Thus, the complex three-dimensional architecture of staphylococcal biofilms results from the self-association of a single type of protein domain. Surface proteins with tandem G5 domains are also found in other bacterial species, suggesting that this mechanism for intercellular adhesion in biofilms may be conserved among staphylococci and other Gram-positive bacteria. Zn(2+) chelation represents a potential therapeutic approach for combating biofilm growth in a wide range of bacterial biofilm-related infections.


Stray light and tolerance analysis of an ultrathin waveguide display.
Waveguides are becoming increasingly popular in the field of near-eye display because of their low thickness and light weight. However, ghost stray light generated in the waveguide and the double-image problem caused by low parallelism precision seriously degrade the display quality. In this study, the causes of stray light are investigated, an effective solution is proposed, and a coupling-in structure is designed to suppress stray light. The Monte Carlo tolerances on the parallelism errors based on the visual acuity for the two substrates and the partially reflective mirror array (PRMA) of the waveguide are implemented. Results show that the fabrication accuracy of the substrates and the PRMA should be controlled within 6'' and 9'', respectively. A 2.4 mm thick waveguide with stray light of less than 1% is designed. The field of view is 36° in the pupil-expanding direction, and the diameter of the exit pupil is 11.6 mm at an eye relief of 20 mm. Finally, a proof-of-concept prototype is fabricated and demonstrated.


Implementing WHO DOTS strategy in the Russian Federation: stakeholder attitudes.
Russia has the ninth highest tuberculosis burden in the world. After a period of decline starting in the 1960s, the case notification rate tripled during the 1990s. Historically, case-finding, treatment and reporting practices in Russia have differed from those advocated by WHO and the international community: Directly Observed Therapy--short course (DOTS). By 2003, approximately 26% of the population in Russia was covered by the DOTS strategy. By contrast, the average coverage in the 22 high-burden countries is 61%. The reasons for this low rate in Russia have not been systematically examined. Using qualitative research methods we explored, in depth, the attitudes of key stakeholders involved in tuberculosis control to introduction of DOTS in a region of Russia. Six focus groups and 128 in depth interviews were held with clinicians, managers, policy-makers and patients. The results show negative attitude to change due to inadequate understanding of DOTS; perceived 'directiveness' of the 'externally developed' DOTS strategy and the standardized nature of the treatment regimen. The doctors, managers and patients saw that prolonged periods of hospitalisation (the traditional way of managing TB in Russia) was advantageous because treatment routines could be ensured, medical expertise was readily available, and other needs such as shelter and food were provided. Respondents felt that the patients were unlikely to adhere to treatment in the community. Cultural issues and capacity constraints, especially in laboratory equipment and personnel, would impede introduction and sustainability of the DOTS strategy.


New nanoparticles obtained by co-assembly of amphiphilic cyclodextrins and nonlamellar single-chain lipids: Preparation and characterization.
This work aimed at preparing new nanoscale assemblies based on an amphiphilic bio-esterified β-cyclodextrin (β-CD), substituted at the secondary face with n-decanoic fatty acid chains (β-CD-C10), and monoolein (MO) as new carriers for parenteral drug delivery. Stable binary (β-CD-C10/MO) and ternary (β-CD-C10/MO/stabilizer) nanoscale assemblies close to 100nm in size were successfully prepared in water by the solvent displacement method. The generated nanoparticles were fully characterized by dynamic light scattering, transmission electron microscopy, small-angle X-ray scattering, residual solvent analysis, complement activation and the contribution of each formulation parameter was determined by principal component analysis. The β-CD-C10 units were shown to self-organize into nanoparticles with a hexagonal supramolecular packing that was significantly modulated by the molar ratio of the constituents and the presence of a steric or electrostatic stabilizer (DOPE-PEG2000 or DOPA/POPA, respectively). Indeed, nanoparticles differing in morphology and in hexagonal lattice parameters were obtained while the co-existence of multiple mesophases was observed in some formulations, in particular for the β-CD-C10/MO/DOPA and β-CD-C10/MO/POPA systems. The mixed β-CD-C10/MO/DOPE-PEG2000 nanoparticles (49:49:2 in mol%) appeared to be the most suitable for use as a drug delivery system since they contained a very low amount of residual solvent and showed a low level of complement C3 activation.


Cost-effectiveness of posaconazole tablets versus fluconazole as prophylaxis for invasive fungal diseases in patients with graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.
The cost-effectiveness of posaconazole oral suspension versus fluconazole capsules for the prophylaxis of invasive fungal diseases (IFDs) in immunosuppressed allogeneic hematopoietic stem cell transplantation (HSCT) recipients has already been proven. Now, a new solid oral tablet formulation for posaconazole has been developed with improved bioavailability, allowing a reduced daily dosage that can be taken independently of food intake. However, the efficacy of this new formulation should be evaluated since it is associated with a higher cost than the posaconazole oral suspension. To evaluate the cost-effectiveness of solid oral tablets of posaconazole versus fluconazole capsules for the prophylaxis of IFDs in allogeneic HSCT recipients with graft-versus-host disease (GVHD) in Spain. A mathematical model comparing the efficacy and costs of posaconazole versus fluconazole was adapted to the Spanish National Healthcare System. Clinical data were obtained from the pivotal clinical trial of posaconazole oral suspension for allogeneic HSCT recipients, while pharmacological costs and use of resources were obtained from national sources. Deterministic and probabilistic sensitivity analyses (PSA), as well as two alternative scenarios, were run to evaluate the robustness of the results under varying input values. Posaconazole tablets reduced the number of IFD events and enhanced overall survival, while maintaining a controlled budget. When compared to fluconazole, it was found to be a cost-effective alternative, with an incremental cost-effectiveness ratio of €13,193/life years gained. The PSA showed that posaconazole remained cost-effective in 74.6% of the cases, while alternatives scenarios yielded similar results as the base case. Posaconazole tablets are a cost-effective alternative to fluconazole and may show better results than the oral suspension formulation.


High frequency of Gag- and envelope-specific cytotoxic T lymphocyte precursors in children with vertically acquired human immunodeficiency virus type 1 infection.
Circulating human immunodeficiency virus type 1 (HIV-1)-specific cytotoxic T lymphocytes (CTL) are seen less frequently in unstimulated peripheral blood mononuclear cells (PBMC) from children with vertically acquired HIV infection than in PBMC from HIV-infected adults. HIV-1 Gag-, reverse transcriptase (RT)-, and envelope (Env)-specific cytotoxic activity was studied in PBMC from HIV-infected children. Only 9% of subjects had Gag- or RT-specific CTL in unstimulated PBMC. However, in PBMC studied after CD3 stimulation, Gag- and Env-specific CTL were found in PBMC from 91% and 78% of HIV-infected children, respectively. Limiting dilution analysis of precursor CTL (pCTL) frequencies in PBMC from children > 12 months old demonstrated Gag- and Env-specific pCTL frequencies from 0.5 to 6.3/10,000 PBMC and from 0.66 to 33.0/10,000 PBMC, respectively. Thus, children with vertically acquired HIV infection have high frequencies of HIV-specific pCTL.


The Inflamed Niche: A Double-Edged Sword in AML?
Although inflammation has long been recognized as a hallmark of many cancers, including acute myeloid leukemia (AML), how it affects individual cells of the tumor microenvironment and their interaction with normal and neoplastic cells is incompletely understood. A comprehensive single-cell transcriptomic analysis of human bone marrow from patients with AML and healthy individuals identified skewing of stem cell and stromal cell populations in AML toward proinflammatory states associated with reduced risk of relapse, paralleling previous findings in mouse models and suggesting that inflamed bone marrow mesenchymal stromal cells might be a double-edged sword in AML by hampering normal hematopoiesis (while AML cells appear comparatively more resilient) but also rendering AML cells more susceptible to chemotherapy or immune attack. See related article by Chen et al., p. 394 (7) .


Abnormal Peripheral Neutrophil Transcriptome in Newly Diagnosed Type 2 Diabetes Patients.
There are increasing evidence demonstrating that neutrophil-mediated inflammation plays a role in the etiology of type 2 diabetes. However, the molecular mechanisms by which neutrophils contribute to type 2 diabetes remain largely unknown. The aim of the present work was to identify possible changes in circulating neutrophils to better elucidate neutrophil involvement in human type 2 diabetes. Patients newly diagnosed with type 2 diabetes (n = 5) and age- and sex-matched healthy controls (n = 5) were recruited. Neutrophils were purified from type 2 diabetes patients and controls, and RNA sequencing (RNA-seq) was used for comprehensive transcriptome analysis. Differentially expressed genes (DEGs) were screened, and Gene Ontology (GO) and KEGG pathway enrichment analyses were performed. Real-time polymerase chain reaction (qPCR) was used for validation in external samples of type 2 diabetes patients (n = 8) and healthy controls (n = 8). Gene expression analysis showed that, compared with neutrophils from healthy controls, there were 1990 upregulated DEGs and 1314 downregulated DEGs in neutrophils from type 2 diabetes patients. GO analysis demonstrated that the DEGs were mainly involved in myeloid leukocyte activation, T cell activation, adaptive immunity, and cytokine production. The top 20 enriched KEGG pathways included the cytokine-cytokine receptor interaction pathway, NF-κB signaling pathway, cell adhesion molecules, and chemokine signaling pathway. Furthermore, qPCR of genes related to neutrophil activation revealed that the expression of SELL, SELP, CXCR1, and S100A8 was significantly increased in neutrophils from type 2 diabetes patients compared with that in neutrophils from controls. Our study reveals an abnormal activation of circulating neutrophils at the transcriptome level in type 2 diabetes patients. These findings suggest a potential involvement of neutrophil dysfunction in the pathologic process of type 2 diabetes and provide insight into potential therapeutic targets for type 2 diabetes.


Synthetic biology's self-fulfilling prophecy--dangers of confinement from within and outside.
A too narrow focus on engineering and application may confine the development of synthetic biology: this Forum article provides reasons to suggest that knowledge could remain related to intended functions and applications, and not flow back from application to (deeper biological) understanding. Concurrently, such an engineering/application focus may 'attract' and feed strategic policy schemes, in turn enhancing the need for applicability as a prerequisite of knowledge production. This self-reinforcing loop--driven from within and outside the field--could ultimately restrict future knowledge and benefits from synthetic biology.


SQSTM1/p62: A Potential Target for Neurodegenerative Disease.
Neurodegenerative diseases, characterized by a progressive loss of brain function, affect the lives of millions of individuals worldwide. The complexity of the brain poses a challenge for scientists trying to map the biochemical and physiological pathways to identify areas of pathological errors. Brain samples of patients with neurodegenerative diseases have been shown to contain large amounts of misfolded and abnormally aggregated proteins, resulting in dysfunction in certain brain centers. Removal of these abnormal molecules is essential in maintaining protein homeostasis and overall neuronal health. Macroautophagy is a major route by which cells achieve this. Administration of certain autophagy-enhancing compounds has been shown to provide therapeutic effects for individuals with neurodegenerative conditions. SQSTM1/p62 is a scaffold protein closely involved in the macroautophagy process. p62 functions to anchor the ubiquitinated proteins to the autophagosome membrane, promoting degradation of unwanted molecules. Modulators targeting p62 to induce autophagy and promote its protective pathways for aggregate protein clearance have high potential in the treatment of these conditions. Additionally, causal relationships have been found between errors in regulation of SQSTM1/p62 and the development of a variety of neurodegenerative disorders, including Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, and frontotemporal lobar degeneration. Furthermore, SQSTM1/p62 also serves as a signaling hub for multiple pathways associated with neurodegeneration, providing a potential therapeutic target in the treatment of neurodegenerative diseases. However, rational design of a p62-oriented autophagy modulator that can balance the negative and positive functions of multiple domains in p62 requires further efforts in the exploration of the protein structure and pathological basis.


THE HAEMAGGLUTINATION INHIBITION AND THE HOGBEN TEST IN PREGNANCY.
Haemagglutination inhibition tests are easy to perform and easy to read. The results are reproducible and are not subject to the vagaries of supply and temperament inherent in tests using living creatures. In a series of tests with Prepuerin done in parallel with the Hogben test the former has shown a higher sensitivity. There have been three false positive results with Prepuerin tests in the series but it was not established on general grounds that pregnancy was not in fact present.


Histone deacetylase inhibitors promote eNOS expression in vascular smooth muscle cells and suppress hypoxia-induced cell growth.
Hypoxia stimulates excessive growth of vascular smooth muscle cells (VSMCs) contributing to vascular remodelling. Recent studies have shown that histone deacetylase inhibitors (HDIs) suppress VSMC proliferation and activate eNOS expression. However, the effects of HDI on hypoxia-induced VSMC growth and the role of activated eNOS in VSMCs are unclear. Using an EdU incorporation assay and flow cytometry analysis, we found that the HDIs, butyrate (Bur) and suberoylanilide hydroxamic acid (SAHA) significantly suppressed the proliferation of hypoxic VSMC lines and induced apoptosis. Remarkable induction of cleaved caspase 3, p21 expression and reduction of PCNA expression were also observed. Increased eNOS expression and enhanced NO secretion by hypoxic VSMC lines were detected using Bur or SAHA treatment. Knockdown of eNOS by siRNA transfection or exposure of hypoxic VSMCs to NO scavengers weakened the effects of Bur and SAHA on the growth of hypoxic VSMCs. In animal experiments, administration of Bur to Wistar rats exposed to hypobaric hypoxia for 28 days ameliorated the thickness and collagen deposition in pulmonary artery walls. Although the mean pulmonary arterial pressure (mPAP) was not obviously decreased with Bur in hypoxic rats, right ventricle hypertrophy index (RVHI) was decreased and the oxygen partial pressure of arterial blood was elevated. Furthermore, cell viability was decreased and eNOS and cleaved caspase 3 were induced in HDI-treated rat pulmonary arterial SMCs. These findings imply that HDIs prevent hypoxia-induced VSMC growth, in correlation with activated eNOS expression and activity in hypoxic VSMCs.


Molecular investigation of distal renal tubular acidosis in Tunisia, evidence for founder mutations.
Distal renal tubular acidosis (dRTA) is a rare genetic disease caused by mutations in different genes involved in the secretion of H+ ions in the intercalated cells of the collecting duct. Both autosomal dominant and recessive forms have been described; the latter is also associated with sensorineural hearing loss. Twenty-two Tunisian families were analyzed for mutations in the ATP6V1B1 and ATP6V0A4 genes by direct sequencing. Dating of the founder mutations was performed. Two founder mutations in the ATP6V1B1 gene were found in 16/27 dRTA cases. The p.Ile386Hisfs*56 founder mutation was estimated to be older than 2400 years and no correlations were found with deafness. For the remaining patients, two mutations in the ATP6V0A4 gene, one of them being novel, were found in three Tunisian cases. The presence of a heterozygous missense mutation p.T30I, of the ATP6V1B1 gene, was identified in six patients, while no mutations of the second gene were detected. No deleterious mutations of either ATP6V1B1 or ATP6V0A were found for the two probands. Our study gives evidence of phenotypic and genotypic heterogeneity of dRTA in the Tunisian population. Five different mutations were found, two of them were due to a founder effect, and screening of these mutations could provide a rapid and valuable tool for diagnosis of dRTA.


Separation and characterization of polyphenolics from underutilized byproducts of fruit production (Choerospondias axillaris peels): inhibitory activity of proanthocyanidins against glycolysis enzymes.
Bioactive proanthocyanidins were isolated from the peel of Choerospondias axillaris fruit, which is a waste product of the food processing industry. Compositional analysis indicated that the proanthocyanidins had extension units mainly consisting of epicatechin gallate or epicatechin, and terminal units mainly consisting of catechin. Numerous polymeric forms of the molecules were detected, including monomers, dimers, and trimers. Certain fractions exhibited strong α-amylase or α-glucosidase inhibition in a dose-dependent manner. Furthermore, their inhibitory activities depended on their degree of polymerization and galloylation. For example, the most bioactive fraction had α-amylase and α-glucosidase inhibitory activities (IC50 values) of 541 and 3.1 μg mL(-1), respectively. This study demonstrates that proanthocyanidins from C. axillaris peels can inhibit carbohydrate digestive enzymes in vitro and may therefore serve as antidiabetic ingredients in functional or medical foods.


High yield synthesis of matchstick-like PbS nanocrystals using mesoporous organosilica as template.
A simple hard template method has been developed to prepare uniform matchstick-like PbS nanocrystals. The approach combines functionalization of the mesoporous walls and channel surface with thioether groups, adsorption of Pb2+, and heating in an N2 atmosphere at high temperature. The structure, morphology and composition of the nanocrystals have been characterized by X-ray powder diffraction (XRD), transmission electron microscopy (TEM), high-resolution TEM (HRTEM), energy dispersive X-ray spectroscopy (EDS), and X-ray photoelectron spectroscopy (XPS). The optical properties of the matchstick-like PbS nanocrystals have been systematically investigated by Raman spectroscopy, UV-visible absorption spectroscopy (UV-vis), and photoluminescence spectroscopy (PL). These results demonstrate that these matchstick-like PbS nanocrystals are single crystals and possess novel optical properties, suggesting that they may have many potential applications. A large blue shift is observed in the photoluminescence spectrum, and this clearly shows the quantum size effects of the matchstick-like PbS . Furthermore, a growth mechanism of the PbS heteronanostructure is proposed.


Molecular architecture of the neuromuscular junction.
The neuromuscular junction (NMJ) is a complex structure that serves to efficiently communicate the electrical impulse from the motor neuron to the skeletal muscle to signal contraction. Over the last 200 years, technological advances in microscopy allowed visualization of the existence of a gap between the motor neuron and skeletal muscle that necessitated the existence of a messenger, which proved to be acetylcholine. Ultrastructural analysis identified vesicles in the presynaptic nerve terminal, which provided a beautiful structural correlate for the quantal nature of neuromuscular transmission, and the imaging of synaptic folds on the muscle surface demonstrated that specializations of the underlying protein scaffold were required. Molecular analysis in the last 20 years has confirmed the preferential expression of synaptic proteins, which is guided by a precise developmental program and maintained by signals from nerve. Although often overlooked, the Schwann cell that caps the NMJ and the basal lamina is proving to be critical in maintenance of the junction. Genetic and autoimmune disorders are known that compromise neuromuscular transmission and provide further insights into the complexities of NMJ function as well as the subtle differences that exist among NMJ that may underlie the differential susceptibility of muscle groups to neuromuscular transmission diseases. In this review we summarize the synaptic physiology, architecture, and variations in synaptic structure among muscle types. The important roles of specific signaling pathways involved in NMJ development and acetylcholine receptor (AChR) clustering are reviewed. Finally, genetic and autoimmune disorders and their effects on NMJ architecture and neuromuscular transmission are examined.


Genetic profiling of the Plasmodium falciparum population using antigenic molecular markers.
About 50% of malaria infections in India are attributed to Plasmodium falciparum but relatively little is known about the genetic structure of the parasite populations. The molecular genotyping of the parasite populations by merozoite surface protein (msp1 and msp2) and glutamate-rich protein (glurp) genes identifies the existing parasite population in the regions which help in understanding the molecular mechanisms involved in the parasite's drive for survival. This study reveals the genetic profile of the parasite population in selected regions across the country with varying degree of endemicity among them. We also report the prevalence of Pfcrt mutations in this parasite population to evaluate the pattern of drug resistance development in them.


Quality of Newspaper Reporting of Suicide in Kashmir: Adherence to World Health Organization Guidelines.
Background: Sensible media reporting of suicide is one of the important prevention strategies. However, there has been no report assessing the quality of media reporting of suicide in Kashmir, India.Aim: We aimed to assess the quality of newspaper reporting of suicide in Kashmir, India against the World Health Organization (WHO) reporting guidelines.Methods: We searched the available contents in four English and two Urdu newspapers of Jammu Kashmir and assessed the adherence to the WHO media guidelines. We collected the reports between 25 January 2016 and 18 September 2020.Results: A total of 152 reports were scrutinized. Almost all the reports mentioned the name of the person and the method of suicide (99.34%), occupation (85.53%) of the person. The life events were mentioned in 35.53% of the reports. Among the reports, 38.82% explained suicide on the basis of the mono-causality, and 3.95% mentioned suicide notes. Only 3.29% of reports had traced mental illness, and none of the reports mentioned evidence of substance abuse. Only three reports mentioned expert opinion, and none of the reports mentioned any research findings, statistics, prevention programs, educational information, and contact information for help.Conclusion: The study revealed that news reports of suicide in Kashmir adhere poorly to the WHO media reporting guidelines. Identifying information of the deceased was explicitly mentioned in almost every report while almost none of the reports mentioned educational information.


Utility of the balloon-overtube-assisted modified over-the-wire stenting technique to treat post-sleeve gastrectomy complications.
To describe a modified technique of deployment of stents using the overtube developed for balloon-assisted enteroscopy in post-sleeve gastrectomy (SG) complications. Between January 2010 and December 2015, all patients submitted to an endoscopic stenting procedure to treat a post-SG stenosis or leakage were retrospectively collected. Procedures from patients in which the stent was deployed using the balloon-overtube-assisted modified over-the-wire (OTW) stenting technique were described. The technical success, corresponding to proper placement of the stent in the stomach resulting in exclusion of the SG leak or the stenosis, was evaluated. Complications related to stenting were also reported. Five procedures were included to treat 2 staple line leaks and 3 stenoses. Two types of stents were used, including a fully covered self-expandable metal stent designed for the SG anatomy (Hanarostent, ECBB-30-240-090; M.I. Tech, Co., Ltd, Seoul, South Korea) in 4 procedures and a biodegradable stent (BD stent 019-10A-25/20/25-080, SX-ELLA, Hradec Kralove, Czech Republic) in the remaining procedure. In all cases, an overtube was advanced with the endoscope through the SG to the duodenum. After placement of the guidewire and removal of the endoscope, the stent was easily advanced through the overtube. The overtube was pulled back and the stent was successfully deployed under fluoroscopic guidance. Technical success was achieved in all patients. The adoption of a modified technique of deployment of OTW stents using an overtube may represent an effective option in the approach of SG complications.


Rethinking global mental health and its priorities.
Global mental health (GMH) seems to enjoy increasing visibility in the global health and development discourse. However, this visibility implies also the urgency of addressing few questions about new priority setting in the domains of policy, care delivery, service organisation and research. Even before trying to answer these questions, rethinking more deeply the notion and implications of GMH seems to be a useful collective exercise. Some unanswered questions should be at the core of this exercise: Is GMH really global or rather Western? Is GMH concerned enough with local context? Is GMH too unbalanced towards a biomedical model? What are the consequences of the predominant emphasis given by GMH on common mental disorders and primary care level on people with severe mental disabilities? GMH is not global but rather it is hegemonised by western institutions. It would be useful to have an independent and very inclusive think tank which should promote a global debate on these issues and offer an unbiased support to WHO.


Thrombectomy vs. medical management for large vessel occlusion strokes with minimal symptoms.
Patients with acute ischemic stroke (AIS) presenting mild symptoms with a low National Institutes of Health Stroke Scale (NIHSS) score ≤8 and also found to have an intracranial large vessel occlusion (LVO) undergo endovascular thrombolysis (ET) or medical management alone. The current study aimed to evaluate the safety and effectiveness of medical management vs. ET therapy among patients with mild AIS symptoms (NIHSS score ≤8) accompanied by LVO. The present meta-analysis included articles involving mild AIS, LVO, thrombectomy/ET and medical management alone published in full-text form (from 1980 to 2022). Collected variables included: First author name, covered study period, publication year, the total number of patients and age, number of males, presence of diabetes mellitus, hypertension, atrial fibrillation, prior ischemic stroke, location, NIHSS of admission, modified Rankin scale, bleeding, morbidity and mortality. After the initial search and applying all exclusion and inclusion criteria, eight articles were left in the final article pool. The total number of patients who underwent ET was 569, compared with 1097 with medical management for LVO strokes with minimal symptoms. The findings of the present meta-analysis study point out that ET management may be associated with a high risk of bleeding and mortality in patients with LVO presenting with mild symptoms (NIHSS score ≤8).


Pancreatic necrosis and ventricular erosion in adenovirus-associated hydropericardium syndrome of broilers.
Seven 19-day-old broiler chickens affected with hydropericardium syndrome (HPS) with pancreatic necrosis and gizzard erosions were investigated pathologically and virologically. Mortality increased after 13 days of age in a flock on a broiler farm. The mortality rate of the flock reached 10% by 19 days of age. Macroscopically, the chickens had hydropericardium (the characteristic gross change of HPS), pinpoint white foci in the pancreas, and ventricular erosions. Histologically, the chickens had multifocal hepatic necrosis with intranuclear inclusions in hepatocytes, a marked increase of macrophages in the spleen and lung, mild epicardial edema, multifocal necrosis of pancreatic acinar cells with intranuclear inclusions, focal necrosis of the ventricular koilin layer, and degeneration of the ventricular glandular epithelium with intranuclear inclusions. Immunohistochemically, intranuclear inclusions in the liver, pancreas, and ventriculi were stained positively against group I avian adenovirus (GIAAV) antigens. Ultrastructurally, 67-nm diameter viral particles were present in intranuclear inclusions. Virologically, serotype 4 of GIAAV was isolated from the liver, heart, and kidney of affected chickens. The pathologic changes of the present cases differ from previous cases of HPS; therefore, the present strain of GIAAV may have different pathogenicity for chickens than the previous virus strain of HPS.


An assessment of the incidence of maternal mortality in the United States.
Recent studies in several states have found that the incidence of maternal mortality is higher than traditional vital statistics reports indicate. Since no comprehensive national study has been done to evaluate the completeness of maternal mortality ascertainment through the national vital statistics reporting system, the Centers for Disease Control (CDC) undertook such a study with the assistance of the National Center for Health Statistics and state health departments. The state health departments provided CDC with death certificates for all pregnancy-related deaths occurring during 1974-78. We reviewed and classified these certificates using both International Classification of Diseases, Adapted, Eighth Revision (ICDA-8) and International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) maternal death codes. We found that the actual incidence of maternal mortality for 1974-78 was approximately 20 per cent and 30 per cent greater than that published in national vital statistics reports using ICDA-8 and ICD-9-CM, respectively.


LncRNA ALMS1-IT1 is a novel prognostic biomarker and correlated with immune infiltrates in colon adenocarcinoma.
Colon adenocarcinoma (COAD) is one of the most serious cancers. It is important to accurately predict prognosis and provide individualized treatment. Evidence suggests that clinicopathological features and immune status of the body are related to the occurrence and development of cancer. Expression of long non-coding RNA (LncRNA) ALMS1 intronic transcript 1 (ALMS1-IT1) is observed in some cancer types, and we believe that it may have the potential to serve as a marker of COAD. Therefore, we used the data obtained from the cancer genome atlas (TCGA) database to prove the relationship between ALMS1-IT1 and COAD. Wilcoxon rank sum test, Chi-square test, Fisher exact test and logistic regression were used to evaluate relationships between clinical-pathologic features and ALMS1-IT1 expression. Receiver operating characteristic curves were used to describe binary classifier value of ALMS1-IT1 using area under curve score. Kaplan-Meier method and Cox regression analysis were used to evaluate factors contributing to prognosis. Gene oncology (GO) and (Kyoto Encyclopedia of Genes and Genomes) KEGG enrichment analysis were used to predict the function of differentially expressed genes associated with ALMS1-IT1. Gene set enrichment analysis (GSEA) was used to predict canonical pathways associated with ALMS1-IT1.Immune infiltration analysis was performed to identify the significantly involved functions of ALMS1-IT1. Starbase database was used to predict miRNAs and RNA binding proteins (RBPs) that may interact with ALMS1-IT1. Increased ALMS1-IT1 expression in COAD was associated with N stage (P < .001), M stage (P = .003), Pathologic stage (P = .002), and Primary therapy outcome (P = .009). Receiver operating characteristic curve suggested the significant diagnostic and prognostic ability of ALMS1-IT1 (area under curve = 0.857). High ALMS1-IT1 expression predicted a poorer overall-survival (P = .005) and poorer progression-free interval (PFI) (P = .012), and ALMS1-IT1 expression was independently correlated with PFI in COAD patients (hazard ratio (HR) :1.468; 95% CI: 1.029-2.093; P =.034) (HR: 1.468; 95% CI: 1.029-2.093; P = .034). GO, KEGG, GSEA, and immune infiltration analysis showed that ALMS1-IT1 expression was correlated with regulating the function of DNA and some types of immune infiltrating cells. ALMS1-IT1 expression was significantly correlated with poor survival and immune infiltrations in COAD, and it may be a promising prognostic biomarker in COAD.


Need for liver biopsy in pediatric nonalcoholic steatohepatitis diagnosis regardless of improvement in liver damage through weight loss.
Liver biopsy is recommended for obese children with fatty liver disease to ensure that nonalcoholic steatohepatitis (NASH) is not overlooked. Even in pediatric cases, regardless of the improvement in liver damage through weight loss, children should be tested and treated with the possibility of NASH in mind.