Role of histone acetylation in the activity-dependent regulation of sulfiredoxin and sestrin 2.
Peroxiredoxins are neuroprotective antioxidant enzymes that reduce hydroperoxides and protect neurons against oxidative stress. However, they can be inactivated through hyperoxidation of their active site cysteine, an event that can take place in the brain in response to oxidative insults such as stroke and also normal aging. Synaptic activity promotes the reduction of hyperoxidized peroxiredoxins in neurons, and induces the expression of sulfiredoxin (Srxn1) and sestrin 2 (Sesn2) which have been reported to mediate this. We have investigated the importance of histone acetylation in the regulation of these genes, to understand more about how these genes are regulated by synaptic activity. We show that the sestrin 2 promoter undergoes activity-dependent histone acetylation, which contributes to its transcriptional activation. In contrast, promoter-proximal histone acetylation is not involved in the activity-dependent induction of sulfiredoxin. Nevertheless, expression of both sestrin 2 and sulfiredoxin can be induced by enhancing histone acetylation through treatment of neurons with the histone deacetylase inhibitor trichostatin A (TSA). Furthermore, protective doses of TSA inhibit the formation of hyperoxidized peroxiredoxins in neurons exposed to oxidative insults. Histone deacetylases are emerging therapeutic targets in neurodegenerative disorders associated with oxidative stress. Our results indicate that manipulating the histone acetylase-deacetylase balance in neurons may mimic the effects of synaptic activity in preventing the oxidative inactivation of peroxiredoxins.


In Vivo Response of Acellular Porcine Pericardial for Tissue Engineered Transcatheter Aortic Valves.
Current heart valve prostheses have limitations that include durability, inability to grow in pediatric patients, and lifelong anticoagulation. Transcatheter aortic valve replacements are minimally invasive procedures, and therefore have emerged as an alternative to traditional valve prostheses. In this experiment, the regenerative capacity of potential tissue engineered transcatheter valve scaffolds (1) acellular porcine pericardium and (2) mesenchymal stem cell-seeded acellular porcine pericardium were compared to native porcine aortic valve cusps in a rat subcutaneous model for up to 8 weeks. Immunohistochemistry, extracellular matrix evaluation, and tissue biomechanics were evaluated on the explanted tissue. Acellular valve scaffolds expressed CD163, CD31, alpha smooth muscle actin, and vimentin at each time point indicating host cell recellularization; however, MSC-seeded tissue showed greater recellularization. Inflammatory cells were observed with CD3 biomarker in native porcine pericardial tissue throughout the study. No inflammation was observed in either acellular or MSC-seeded scaffolds. There was no mechanical advantage observed in MSC-seeded tissue; however after the first week post-explant, there was a decrease in mechanical properties in all groups (p < 0.05). MSC-seeded and acellular porcine pericardium expressed decreased inflammatory response and better host-cell recellularization compared to the native porcine aortic valve cusps.


Painful and provocative events: Determining which events are associated with increased odds of attempting suicide.
The present study sought to determine which painful and provocative events differentiated those with suicidal ideation from those who attempted suicide. Additionally, it presents a novel way of utilizing the Painful and Provocative Scale (PPES) by looking at items dichotomously as experienced or not experienced, instead of the frequency at which they are experienced. Participants (N = 666) were recruited as part of a large online study seeking to understand suicide risk across multiple high-risk groups (i.e., veterinarians, military service members, transgender individuals, and gun owners) for suicide. Participants in the present study were predominately white, female, and heterosexual. First, the PPES was examined as a dichotomous measure and results indicate that experiencing physical or sexual abuse, tying a noose, using intravenous drugs, or having injuries that required medical attention were associated with greater odds of attempting suicide; shooting a gun was associated with decreased odds. Next, the PPES was examined as a scale measure and findings indicate that increased exposure to rock climbing, experiencing physical or sexual abuse, or using intravenous drug were associated with increased odds of attempting suicide; while increased exposure to shooting a gun was associated with decreased odds. The present study adds to the literature on the ideation-to-action framework and provides evidence considering the frequency of experiences using the Painful and Provocative Event Scale may not provide substantial information beyond dichotomous scoring.


[Role of myocardial micropump function in the pathogenesis of ischemic heart disease].
Myocardial vibrational activity examined in 40 patients with functional classes II-III coronary heart disease and in 20 apparently healthy individuals, which indirectly reflects the status of its micropump function has been studied by using a spectral analysis of the first heart sound. Inhibition of the micropump function of the myocardium with its higher oxygen demands has been found to substantially contribute to the pathogenesis of myocardial ischemia.


Mannose binding lectin genotypes influence recovery from hepatitis B virus infection.
Mannose binding lectin (MBL) is a central component of the innate immune response and thus may be important for determining hepatitis B virus (HBV) persistence. Since single-nucleotide polymorphisms (SNPs) in the gene encoding MBL (mbl2) alter the level of functional MBL, we hypothesized that mbl2 genotypes are a determinant of HBV persistence or recovery from viral infection. We tested this hypothesis by using a nested case control design with 189 persons with HBV persistence matched to 338 individuals who had naturally recovered from HBV infection. We determined genotypes of two promoter and three exon 1 SNPs in mbl2 and grouped these genotypes according to the amount of functional MBL production. We found that the promoter SNP -221C, which leads to deficient MBL production, was more common in those subjects with viral persistence (odds ratio [OR], 1.38; 95% confidence interval [CI], 1.01 to 1.89; P = 0.04). Those subjects homozygous for the combination of promoter and exon 1 genotypes associated with the highest amount of functional MBL had significantly increased odds of recovery from infection (OR, 0.55; 95% CI, 0.37 to 0.84; P = 0.005). Conversely, those homozygous for the combination of promoter and exon 1 genotypes which produce the lowest amount of functional MBL were more likely to have viral persistence (OR, 1.76; 95% CI, 1.02 to 3.01; P = 0.04). These data are consistent with the hypothesis that functional MBL plays a central role in the pathogenesis of acute hepatitis B.


Enzymatic stabilization of gelatin-based scaffolds.
The definitive goal of this research is to develop protein-based scaffolds for use in soft tissue regeneration, particularly in the field of dermal healing. The premise of this investigation was to characterize the mechanical properties of gelatin cross-linked with microbial transglutaminase (mTGase) and to investigate the cytocompatibility of mTGase cross-linked gelatin. Dynamic rheological analysis revealed a significant increase in the storage modulus and thermal stability of gelatin after cross-linking with mTGase. Static, unconfined compression tests showed an increase in Young's modulus of gelatin gels after mTGase cross-linking. A comparable increase in gel strength was observed with 0.03% mTGase and 0.25% glutaraldehyde cross-linked gelatin gels. In vitro studies using 3T3 fibroblasts indicated cytotoxicity at a concentration of 0.05% mTGase after 72 h. However, no significant inhibition of cell proliferation was seen with cells grown on lower concentrations of mTGase cross-linked gelatin substrates. The mechanical improvement and cytocompatibility of mTGase cross-linked gelatin suggests mTGase has potential for use in stabilizing gelatin gels for tissue-engineering applications.


Characterization of glycolytic metabolism and ion transport of Candida albicans.
The main energetic pathways, fermentation and respiration, and the general ion transport properties of Candida albicans were studied. Compared to Saccharomyces cerevisiae, we found that in C. albicans: (a) the cell mass yield when grown in YPD was significantly larger; (b) it required longer times to be starved of endogenous substrates; (c) ethanol production was lower but significant; (d) respiration was also lower; (e) it showed a small activity of an alternative oxidase; (f) fermentation and oxidative phosphorylation seemed to compete for both ADP and NADH; and (g) NADH levels were lower. Regarding ion transport and compared to S. cerevisiae: (a) the general mechanism was similar, with a plasma membrane H(+) -ATPase that generates both a plasma membrane ΔpH and a ΔΨ, the latter being responsible for driving K(+) inside; (b) its acidification capacity is slightly smaller and less sensitive to activation by high pH; and (c) the presence of K(+) results in a large activation of both respiration and fermentation, most probably due to the energy required in the process. ADP produced by H(+) -ATPase stimulation by high pH or the addition of K(+) at low pH results in the increase of both respiration and fermentation.


Integrated PPI- and WGCNA-Retrieval of Hub Gene Signatures Shared Between Barrett's Esophagus and Esophageal Adenocarcinoma.
Esophageal adenocarcinoma (EAC) is a deadly cancer with high mortality rate, especially in economically advanced countries, while Barrett's esophagus (BE) is reported to be a precursor that strongly increases the risk of EAC. Due to the complexity of these diseases, their molecular mechanisms have not been revealed clearly. This study aims to explore the gene signatures shared between BE and EAC based on integrated network analysis. We obtained EAC- and BE-associated microarray datasets GSE26886, GSE1420, GSE37200, and GSE37203 from the Gene Expression Omnibus and ArrayExpress using systematic meta-analysis. These data were accompanied by clinical data and RNAseq data from The Cancer Genome Atlas (TCGA). Weighted gene co-expression network analysis (WGCNA) and differentially expressed gene (DEG) analysis were conducted to explore the relationship between gene sets and clinical traits as well as to discover the key relationships behind the co-expression modules. A differentially expressed gene-based protein-protein interaction (PPI) complex was used to extract hub genes through Cytoscape plugins. As a result, 403 DEGs were excavated, comprising 236 upregulated and 167 downregulated genes, which are involved in the cell cycle and replication pathways. Forty key genes were identified using modules of MCODE, CytoHubba, and CytoNCA with different algorithms. A dark-gray module with 207 genes was identified which having a high correlation with phenotype (gender) in the WGCNA. Furthermore, five shared hub gene signatures (SHGS), namely, pre-mRNA processing factor 4 (PRPF4), serine and arginine-rich splicing factor 1 (SRSF1), heterogeneous nuclear ribonucleoprotein M (HNRNPM), DExH-Box Helicase 9 (DHX9), and origin recognition complex subunit 2 (ORC2), were identified between BE and EAC. SHGS enrichment denotes that RNA metabolism and splicosomes play a key role in esophageal cancer development and progress. We conclude that the PPI complex and WGCNA co-expression network highlight the importance of phenotypic identifying hub gene signatures for BE and EAC.


The CSF tap test in normal pressure hydrocephalus: evaluation time, reliability and the influence of pain.
The cerebrospinal fluid tap test (TT) is a diagnostic tool used to select patients with idiopathic normal pressure hydrocephalus (iNPH) for shunt surgery. The procedure and the evaluation of the TT vary between centres. We aimed to describe the evaluation time after the TT, to assess the variability between repeated measurements, the interrater agreement of the gait tests chosen and finally to investigate whether pain affects the gait performance post-TT. Forty patients (21 men and 19 women) under evaluation for iNPH underwent a TT. Standardized gait analyses were performed before and 2, 4, 6, 8 and 24 h after the TT and repeated twice on every occasion. Independent of each other, two investigators evaluated the quality of gait. At each assessment time, the patients graded headache and back pain on a visual analogue scale. Twenty-seven patients (15 men and 12 women) responded to TT. Improvements in gait speed and number of steps were significant at every assessment time post-TT. The variability between two measurements was low (Intra class correlation coefficient=0.97), and the inter-rater agreement was good with a κ=0.74. Pain correlated negatively with improvement in gait speed (r=-0.40, P<0.05). We suggest that the TT can be evaluated at any time within the first 24 h and should be repeated if the patient does not initially improve. Gait analysis appears reliable between two evaluators. Further, it is indicated that post-lumbar puncture pain negatively affects the gait and should be minimized.


Atorvastatin inhibits hypercholesterolemia-induced calcification in the aortic valves via the Lrp5 receptor pathway.
Calcific aortic valve disease is the most common indication for surgical valve replacement in the United States. The cellular mechanisms of valve calcification are not well understood. We have previously shown that cellular proliferation and osteoblastogenesis are important in the development of valvular heart disease. Lrp5, a known low-density receptor-related protein, plays an essential role in cellular proliferation and osteoblastogenesis via the beta-catenin signaling pathway. We hypothesize that Lrp5 also plays a role in aortic valve (AV) calcification in experimental hypercholesterolemia. We examined the effects of cholesterol and atorvastatin in Watanabe rabbits (n=54). Group I (n=18) received a normal diet, group II (n=18) a 0.25% cholesterol diet, and group III (n=18) a 0.25% (w/w) cholesterol diet with atorvastatin for the development of calcification. The AVs were examined for cellular proliferation, Lrp5/beta-catenin, and bone matrix markers. Bone formation was assessed by micro-computed tomography, calcein injection, and osteopontin expression. Low-density lipoprotein with and without atorvastatin was also tested in AV myofibroblasts for cellular proliferation and regulation of the Lrp5/beta-catenin pathway. Our results demonstrate that the cholesterol diet induced complex bone formations in the calcified AVs with an increase in the Lrp5 receptors, osteopontin, and p42/44 expression. Atorvastatin reduced bone formation, cellular proliferation, and Lrp5/beta-catenin protein levels in the AVs. In vitro analysis confirmed the Lrp5/beta-catenin expression in myofibroblast cell proliferation. Hypercholesterolemic AV calcification is attenuated by atorvastatin and is mediated in part by the Lrp5/beta-catenin pathway. This developmental pathway may be important in the signaling pathway of this disease.


Polyp of the external ear canal arising from the temporomandibular joint: a case report.
A polypoid mass of granulation tissue in the external auditory meatus was found to be arising from the ipsilateral temporomandibular joint (TMJ). The origin of the lesion was suspected clinically and was confirmed by a CT scan study. As the patient showed signs of psoriatic arthritis, it seems likely that this was the underlying pathological process in the joint. A patent foramen of Huschke allowed herniation of synovial tissue from the joint into the external auditory canal.


Is Triamcinolone an Easy and Efficient Way to Treat Meralgia Paresthetica? A Cohort Study.
Meralgia paresthetica (MP) is a painful mononeuropathy of the lateral femoral cutaneous nerve. It is usually idiopathic and can be treated with drugs used for neuropathic pain such as pregabalin, gabapentin, and amitriptyline. This study was done to study the effect of triamcinolone acetonide on drug refractory MP. This study was a retrospective case file review. Eight patients were treated with local injections of triamcinolone. The patients were followed up for a period of 4 months to 54 months. There was significant symptomatic improvement with six patients having complete improvement and all patients reporting >50% improvement. Patients who had recurrence of symptoms on follow up received up to four injections as per their requirement and repeated injections also produced >50% symptom relief. Triamcinolone acetonide injected locally seems to be an effective and safe treatment for refractory MP. A randomized control trial has been planned to look for efficacy and safety.


The contractile and control sites of natural actomyosin.
The various contractile and control sites of natural actomyosin gel were studied by comparing the kinetics of ATP hydrolysis with those of gel contraction, measured as an increase in turbidity. Contraction of actomyosin gel seems to require the cooperative reaction of ATP (with Mg) at two different sites. One of these sites catalyzes the hydrolysis of ATP and most probably contributes the driving force for contraction; the binding of ATP to the other site appears to break certain links that retard movement of the gel components. At limiting concentrations of ATP, the rate of contraction seems to depend on the rate of breaking these links as well as on the rate of ATP hydrolysis. But when both sites are saturated, the rate of contraction appears to be limited only by the rate of ATP hydrolysis. In addition to these two contractile sites, there are also two different control sites. At one, the relaxing site, the binding of ATP with Mg inhibits ATP hydrolysis and gel contraction. At the other, the binding of calcium activates contraction by overcoming the inhibitory action of Mg and ATP at the relaxing site. This control system-inhibition by substrate and disinhibition by calcium-can be selectively inactivated by heat and reactivated by dithiothreitol, a disulfide-reducing agent. These observations on the isolated contractile system are discussed in relation to the contraction and relaxation of muscle.


Understanding Grain Boundary Electrical Resistivity in Cu: The Effect of Boundary Structure.
Grain boundaries (GBs) in metals usually increase electrical resistivity due to their distinct atomic arrangement compared to the grain interior. While the GB structure has a crucial influence on the electrical properties, its relationship with resistivity is poorly understood. Here, we perform a systematic study on the resistivity-structure relationship in Cu tilt GBs, employing high-resolution in situ electrical measurements coupled with atomic structure analysis of the GBs. Excess volume and energies of selected GBs are calculated using molecular dynamics simulations. We find a consistent relation between the coincidence site lattice (CSL) type of the GB and its resistivity. The most resistive GBs are in the high range of low-angle GBs (14°-18°) with twice the resistivity of high angle tilt GBs, due to the high dislocation density and corresponding strain fields. Regarding the atomistic structure, GB resistivity approximately correlates with the GB excess volume. Moreover, we show that GB curvature increases resistivity by ∼80%, while phase variations and defects within the same CSL type do not considerably change it.


Physical and psychosocial demand at work: inequities related to race/skin color.
This cross-sectional study investigated the association between self-reported race/skin color and two outcomes - psychosocial demand and physical demand at work - in 1,032 workers in an urban cleaning services company and two footwear manufacturers, located in the State of Bahia, Brazil. Psychosocial demand was measured through the Job Content Questionnaire and physical demand was measured through questions about postures and cargo handling. A Cox regression analysis provided prevalence ratios (PR) adjusted by age, gender, and educational level. Among blacks, there is a higher proportion of garbage collectors and a lower proportion of supervisory positions. Black workers are more subject to high psychological demand and low job control and, consequently, to high strain (PR=1.65). Also, they are more exposed to work with arms above shoulder level (PR=1.93), and material handling (PR=1.62), compared to white workers. Brown workers are more exposed to low job control (PR=1.36), work with arms above shoulder level (PR=1.48), and material handling (PR=1.25), also compared with whites. Social support is lower among blacks and brown. The study demonstrated inequities in psychosocial and physical exposures at work that are in line with the structural conception of racism. This evidence can contribute to the adoption of practices that increase equity in the world of work.


The effect of visual and/or auditory distraction techniques on children's pain, anxiety and medical fear in invasive procedures: A randomized controlled trial.
This study was conducted to determine the effects of visual and/or auditory distraction techniques applied to children aged 7-12 during invasive procedures on pain, anxiety, and medical fear. This single-blinded, randomized controlled trial was carried out in the pediatric emergency department of a public hospital between November 2021 and March 2022. In the study, 144 children were assigned to three different intervention groups, in which a kaleidoscope, music, and virtual reality were applied during invasive procedures, and the control group in which the standard invasive procedure was applied, by using the stratified block randomization method. The data were collected using a Personal Information Form, Wong-Baker Faces Pain Rating Scale, Children's Anxiety Meter-State, and Child Medical Fear Scale. In the study, the levels of pain, anxiety, and medical fear after the invasive procedure were lower in the intervention groups than in the control group. In addition, there was no difference between the three different distraction techniques in terms of reducing pain and medical fear, but the virtual reality application was more effective in reducing the level of anxiety. Visual and/or auditory distraction techniques are effective methods that can be used by nurses in pediatric healthcare to reduce invasive procedure-related pain, anxiety, and medical fear. This study provides evidence that can guide the use of non-pharmacological methods such as distraction to prevent the traumatic effects of invasive procedures in children.


The Feasibility of Home-Based Treatment Using Vibratory Stimulation in Chronic Severe Dysphagia.
Previously, externally placed vibratory laryngeal stimulation increased rates of swallowing in persons with and without dysphagia. This study examined the feasibility of using a vibratory device on the skin over the thyroid cartilage for home-based swallowing rehabilitation in long-standing dysphagia. Only participants with long-standing dysphagia (> 6 months) following cerebrovascular accident or head/neck cancer who had not previously benefited from dysphagia therapy participated. The device had two modes used daily for 90 days. In automatic mode, participants wore the device when awake, which vibrated for 4-8 s every 5 min to trigger a volitional swallow. In manual mode, participants practiced by activating vibration while swallowing rapidly. Study-related adverse events, such as pneumonia, and device-recorded adherence were tracked. Swallowing function on a modified barium swallow study was assessed at baseline and after 3 months of device use. Outcome measures included the Dysphagia Outcome and Severity Scale (DOSS), Penetration-Aspiration Scale (PAS), and swallowing timing measures. Participants' perceptions of the vibratory device and training were obtained. The intent to treat analysis showed seven of 11 participants completed the study, all with severe chronic dysphagia. Of those seven participants completing the study, two developed respiratory complications (possibly due to pneumonia) that cleared after antibiotic intervention. For prescribed practice trials, adherence was 80% or greater in four of seven participants (57%) whereas prescribed automatic stimulations were met in only two of seven participants (29%). Three participants (43%) had a modest benefit on DOSS. The time to vestibule closure after the bolus passed the ramus was reduced in five participants (71%) on the modified barium swallow study. Overall, the results have indicated that intensive home-based practice with stimulation may provide limited functional benefits in severe chronic dysphagia. https://doi.org/10.23641/asha.21498591.


Does deinstitutionalization increase suicide?
(1) To test whether public psychiatric bed reduction may increase suicide rates; (2) to investigate whether the supply of private hospital psychiatric beds-separately for not-for-profit and for-profit-can substitute for public bed reduction without increasing suicides; and (3) to examine whether the level of community mental health resources moderates the relationship between public bed reduction and suicide rates. We examined state-level variation in suicide rates in relation to psychiatric beds and community mental health spending in the United States for the years 1982-1998. We categorize psychiatric beds separately for public, not-for-profit, and for-profit hospitals. Reduced public psychiatric bed supply was found to increase suicide rates. We found no evidence that not-for-profit or for-profit bed supply compensates for public bed reductions. However, greater community mental health spending buffers the adverse effect of public bed reductions on suicide. We estimate that in 2008, an additional decline in public psychiatric hospital beds would raise suicide rates for almost all states. Downsizing of public inpatient mental health services may increase suicide rates. Nevertheless, an increase in community mental health funding may be promising.


Specificity of Phosphorylation Responses to Mitogen Activated Protein (MAP) Kinase Pathway Inhibitors in Melanoma Cells.
The BRAF-MKK1/2-ERK1/2 pathway is constitutively activated in response to oncogenic mutations of BRAF in many cancer types, including melanoma. Although small molecules that inhibit oncogenic BRAF and MAP kinase kinase (MKK)1/2 have been successful in clinical settings, resistance invariably develops. High affinity inhibitors of ERK1/2 have been shown in preclinical studies to bypass the resistance of melanoma and colon cancer cells to BRAF and MKK1/2 inhibitors, and are thus promising additions to current treatment protocols. But still unknown is how molecular responses to ERK1/2 inhibitors compare with inhibitors currently in clinical use. Here, we employ quantitative phosphoproteomics to evaluate changes in phosphorylation in response to the ERK inhibitors, SCH772984 and GDC0994, and compare these to the clinically used MKK1/2 inhibitor, trametinib. Combined with previous studies measuring phosphoproteomic responses to the MKK1/2 inhibitor, selumetinib, and the BRAF inhibitor, vemurafenib, the outcomes reveal key insights into pathway organization, phosphorylation specificity and off-target effects of these inhibitors. The results demonstrate linearity in signaling from BRAF to MKK1/2 and from MKK1/2 to ERK1/2. They identify likely targets of direct phosphorylation by ERK1/2, as well as inhibitor off-targets, including an off-target regulation of the p38α mitogen activated protein kinase (MAPK) pathway by the MKK1/2 inhibitor, trametinib, at concentrations used in the literature but higher than in vivo drug concentrations. In addition, several known phosphorylation targets of ERK1/2 are insensitive to MKK or ERK inhibitors, revealing variability in canonical pathway responses between different cell systems. By comparing multiple inhibitors targeted to multiple tiers of protein kinases in the MAPK pathway, we gain insight into regulation and new targets of the oncogenic BRAF driver pathway in cancer cells, and a useful approach for evaluating the specificity of drugs and drug candidates.


NAD(P)H : quinone oxidoreductase 1 inducer activity of some Saudi Arabian medicinal plants.
Medicinal plants are a rich source of biologically-active phytochemicals and have been used in traditional medicine for centuries. Specific phytochemicals and extracts of their plant sources have the ability to reduce the risk for chronic degenerative diseases by induction of enzymes involved in xenobiotic metabolism, many of which also have antioxidant and anti-inflammatory functions. One such multifunctional cytoprotective enzyme is NAD(P)H : quinone oxidoreductase. In this study, we prepared extracts of 27 Saudi Arabian medicinal plants which belong to 18 different plant families and tested their ability to induce NAD(P)H : quinone oxidoreductase in murine hepatoma cells grown in microtiter plate wells. In addition to the Brassicaceae, a known source of NAD(P)H : quinone oxidoreductase inducer activity, we found substantial inducer activity in extracts from the Apiaceae, Apocynaceae, and the Asteraceae families. Five out of a total of eight active extracts are from plants which belong to the Asteraceae family. We further show that artemisinin, an agent which is used clinically for the treatment of malaria, contributes but does not fully account for the inducer activity of the extract of Artemisia monosperma. In contrast to artemisinin, deoxyartemisinin is inactive in this assay, demonstrating the critical role of the endoperoxide moiety of artemisinin for inducer activity. Thus, the NAD(P)H : quinone oxidoreductase inducer activity of extracts of some Saudi Arabian medicinal plants indicates the presence of specific phytochemicals which have the potential to protect against chronic degenerative diseases.


A new fast response cryogenic evaporative calorimeter.
We present the principle and implementation of a new type of fast response evaporative calorimeter designed to work at cryogenic temperatures and above-ambient pressures. It is capable of measuring input energy from an electric pulse and the thermal output energy by measuring the evaporation of liquid nitrogen through a mass flow meter. This system may be used to measure either the steady heat output from the system submersed under the cryogen or the heat output that results from a fast square-wave profile electrical pulse of duration from 10 µs or longer. The energy output of metal capillary-wire composite systems has been measured calorimetrically. A four-wire measurement was used to monitor the input electric energy with an uncertainty less than 5% for a typical pulse. Mass flow meters and pressure regulation systems were used to monitor the rate of evaporation of liquid nitrogen with a typical precision of 2 std.-ml/min. For a typical pulse, the integrated mass flow of nitrogen could be determined with an uncertainty less than 3%. The pressure controllers and ballast compliance volumes allow the system to return to a steady state of mass flow in less than 2 min following an electric pulse. The system is capable of housing and measuring four separate wire-capillary systems in a single Dewar. On average, a calibration resulted in 3.9 std. ml evaporated per joule of input energy. This corresponds to a 97% efficiency for this calorimeter.


Revisiting the COP9 signalosome as a transcriptional regulator.
The COP9 signalosome (CSN) is a highly conserved protein complex that was originally described as a repressor of light-dependent growth and transcription in Arabidopsis. The most studied CSN function is the regulation of protein degradation, which occurs primarily through the removal of the ubiquitin-like modifier Nedd8 from cullin-based E3 ubiquitin ligases. This activity can regulate transcription-factor stability and, therefore, transcriptional activity. Recent data suggest that the CSN also regulates transcription on the chromatin by mechanisms that are not yet clearly understood. Furthermore, the CSN subunits CSN5 and CSN2 seem to act as transcriptional coactivators and corepressors, respectively. Here, I re-evaluate the mechanisms by which the CSN acts as a transcriptional regulator, and suggest that they could extend beyond the regulation of protein stability.


Techniques for retrievability and for registering screw access holes in cement-retained implant-supported prostheses: A scoping review of the literature.
After implant rehabilitation, clinicians may need to remove a restoration because of technical and biological complications. For cement-retained implant-supported prostheses (ISPs), the retrievability process may damage the components of the prosthesis, the intaglio surface of the implant, or the abutment screw. To avoid that, the screw access hole (SAH) of the dental implant abutment (DIA) should be registered. Although several clinical reports and dental techniques have been proposed, a review of existing techniques is lacking. The purpose of this scoping review was to evaluate the different techniques described for retrievability and for registering the SAH of cement-retained ISPs. An electronic search of English language dental literature in the PubMed, Scopus, Google Scholar, and SciELO databases was conducted from 1980 to December 2017 with appropriate keywords and phrases. A hand search of relevant dental journals was also completed, and exclusion criteria were applied after full-text evaluation. The electronic and hand search revealed 325 articles. However, 252 publications were discarded after duplicates were removed. After reading the title and abstracts, 15 studies were excluded, and the full text of 64 publications was screened for inclusion and exclusion criteria. Forty studies were selected and included for final evaluation. The evaluation revealed 6 techniques for retrievability and 9 techniques for registering the position of the SAH, divided into 2-dimensional (2D) and 3-dimensional (3D) techniques. Cement-retained ISPs can be effectively retrieved by using interim cements and possibly by using a combined cement- and screw-retained design. Vacuum guides with guiding sleeves and computer-aided design and computer-aided manufacturing (CAD-CAM) guide templates are possible effective 3D techniques for registering the screw access channel (SAC) location and angulation.


Production of bone-resorbing activity corresponding to interleukin-1 alpha by adult T-cell leukemia cells in humans.
The physicochemical properties and relationship of bone-resorbing activity and interleukin 1 (IL-1) produced by adult T-cell leukemia (ATL) cells and cell line were studied in vitro. The culture supernatant of ATL cell line, MT2, and peripheral blood lymphocytes freshly obtained from ATL patients had both IL-1 activity detected by the stimulation of murine thymocyte-proliferative responses and bone-resorbing activity detected by the stimulation of 45Ca release from prelabeled murine fetal bones. By Sephacryl S-200 column chromatography, both activities were eluted as a single peak at approximately Mr 15,000. By the chromatofocusing technique, the isoelectric point values of both activities were estimated as pH 4.8 and 5.2. Furthermore, both activities were absorbed with rabbit anti-IL-1 alpha antiserum, but not with anti-IL-1 beta antiserum. These results suggest that ATL cells and cell line produce bone-resorbing activity which corresponds to IL-1 alpha and that this IL-1 alpha is one of the most important causes of hypercalcemia in ATL patients.


Fulminant myocarditis in adults: a narrative review.
Fulminant myocarditis (FM) is an uncommon syndrome characterized by sudden and severe hemodynamic compromise secondary to acute myocardial inflammation, often presenting as profound cardiogenic shock, life-threatening ventricular arrhythmias and/or electrical storm. FM may be refractory to conventional therapies and require mechanical circulatory support (MCS). The immune system has been recognized as playing a pivotal role in the pathophysiology of myocarditis, leading to an increased focus on immunosuppressive treatment strategies. Recent data have highlighted not only the fact that FM has significantly worse outcomes than non-FM, but that prognosis and management strategies of FM are heavily dependent on histological subtype, placing greater emphasis on the role of endomyocardial biopsy in diagnosis. The impact of subtype on severity and prognosis will likewise influence how aggressively the myocarditis is managed, including whether MCS is warranted. Many patients with refractory cardiogenic shock secondary to FM end up requiring MCS, with venoarterial extracorporeal membrane oxygenation demonstrating favorable survival rates, particularly when initiated prior to the development of multiorgan failure. Among the challenges facing the field are the need to more precisely identify immunopathophysiological pathways in order to develop targeted therapies, and the need to better optimize the timing and management of MCS to minimize complications and maximize outcomes.


A Paneth cell analogue in Xenopus small intestine expresses antimicrobial peptide genes: conservation of an intestinal host-defense system.
Antimicrobial peptides are a widespread component of host defense. We characterized the tissue distribution and cellular localization of expression of the magainin family of antimicrobial peptide genes in Xenopus laevis. Two genes from this family, magainin and PGLa, are expressed at high levels in the skin and throughout the gastrointestinal tract. Magainin and PGLa mRNAs are synthesized in the granular multinucleated cell (GMC) of the gastric mucosa, a cell shown previously to contain magainin and PGLa peptides by immunohistochemical methods. In addition, we have localized magainin and PGLa mRNAs to distinct cells of Xenopus small intestine. Further characterization of this large, granule-filled cell by electron microscopy demonstrates features in common with the Paneth cell of mammalian small intestine, previously identified as a site of expression of antimicrobial peptide genes of the defensin family in mouse and human. Our identification of granule-laden, eosinophilic intestinal cells in Xenopus as a site of magainin and PGLa antimicrobial peptide gene expression suggests that these cells are functional analogues of mammalian Paneth cells and further supports a conserved role of antimicrobial peptides in host defense of the vertebrate small intestine.


Effect of health education on the uptake of HIV counseling and testing among long distance drivers in Jos North Local Government Areas of Plateau State.
The impact of HIV/AIDS has been felt in virtually all aspects of life. Long distance drivers are of particular concern to HIV prevention and care programs because they constitute a high risk group. HIV Counseling and Testing (HCT) is an intervention, which gives the client an opportunity to confidentially discuss his or her HIV risks and be assisted to learn his/her HIV status for purposes of prevention, treatment, care and support. The objective of this study was to determine the effect of health education on the uptake of HCT among Long Distance Drivers (LDDs) in Plateau State. This was a quasi-experimental study with a pre and post intervention phase carried out among 161 LDDs in Jos North Local Government Areas. Health education intervention was provided using a structured health education guide in the form of lecture and discussion. Epi-info™ statistical software version 3.5.4 developed by Centre for Disease and Control and Prevention (CDC) 1600 Clifton Rd. Atlanta, GA 30333 usa was used for data analysis and 95% confidence interval was used for the study and P ≤ 0.05 was considered as statistically significant. The mean age of the respondent in this study was 41.0 ± 7.9 years with majority (92.5%) of the LDDs married and 91.3% resident within the state. Knowledge and uptake of HCT among LDDs improved significantly from 4.17 ± 1.43 to 6.70 ± 1.55 and 18.6-57.2% following the intervention (P < 0.001) respectively. This study has shown that health education is an effective tool in improving the uptake of HCT among long distance drivers. Therefore, it should be used to improve HCT uptake among high risk groups.


PhyloFisher: A phylogenomic package for resolving eukaryotic relationships.
Phylogenomic analyses of hundreds of protein-coding genes aimed at resolving phylogenetic relationships is now a common practice. However, no software currently exists that includes tools for dataset construction and subsequent analysis with diverse validation strategies to assess robustness. Furthermore, there are no publicly available high-quality curated databases designed to assess deep (>100 million years) relationships in the tree of eukaryotes. To address these issues, we developed an easy-to-use software package, PhyloFisher (https://github.com/TheBrownLab/PhyloFisher), written in Python 3. PhyloFisher includes a manually curated database of 240 protein-coding genes from 304 eukaryotic taxa covering known eukaryotic diversity, a novel tool for ortholog selection, and utilities that will perform diverse analyses required by state-of-the-art phylogenomic investigations. Through phylogenetic reconstructions of the tree of eukaryotes and of the Saccharomycetaceae clade of budding yeasts, we demonstrate the utility of the PhyloFisher workflow and the provided starting database to address phylogenetic questions across a large range of evolutionary time points for diverse groups of organisms. We also demonstrate that undetected paralogy can remain in phylogenomic "single-copy orthogroup" datasets constructed using widely accepted methods such as all vs. all BLAST searches followed by Markov Cluster Algorithm (MCL) clustering and application of automated tree pruning algorithms. Finally, we show how the PhyloFisher workflow helps detect inadvertent paralog inclusions, allowing the user to make more informed decisions regarding orthology assignments, leading to a more accurate final dataset.


Functional class and type of pulmonary hypertension determinate severity of cardiac autonomic dysfunction assessed by heart rate variability and turbulence.
Heart rate variability (HRV) and turbulence (HRT) are validated methods of evaluation of cardiac autonomic nervous system (cANS) dysfunction which is associated with sudden cardiac death. There is limited data on cANS imbalance and its significance,in patients with pulmonary hypertension (PH), so we assessed HRV and especially HRT alterations in PH. Thirty-three out of 41 PH patients were enrolled in the study: 22 (66.7%) with pulmonary arterial hypertension (PAH) and 11 (33.3%) with chronic thromboembolic PH (CTEPH), 11 patients were in World Health Organization Functional Class (WHO-FC) I-II, and 22 others in WHO-FC III-IV. The control group consisted of 25 healthy persons. Routine evaluations, echocardiography, right heart catheterization and 24-hour Holter monitoring with time-domain HRV and HRT evaluation were performed. Most of HRV indices and both of HRT parameters were significantly impaired in PH patients, as compared to control subjects. Abnormal HRT (turbulence onset 0.0% and/or turbulence slope 2.5 ms/RR) was found in 36.4% WHO-FC I-II and in 77.3% WHO-FC III-IV patients (P=0.05). Patients in WHO-FC III-IV or with CTEPH presented compromised HRV and HRT values when compared to patients in WHO-FC I-II or with PAH, respectively. Multivariate analysis showed that abnormal HRT occurrence in PH was influenced by higher WHO-FC only (odds ratio 5.3, 95% CI 1.4-19.9, P= 0.01). Higher WHO-FC and probably type of pulmonary hypertension (CTEPH more than PAH) determinate the severity of cANS dysfunction assessed by heart rate variability and turbulence. Potential clinical consequences of our findings need further investigations.


Current Challenges in Breast Implantation.
Breast implantation (BI) is the most common plastic surgery worldwide performed among women. Generally, BI is performed both in aesthetic and oncoplastic procedures. Recently, the prevalence of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) or breast implant illness (BII) has aroused concerns. As a result, several countries, like Australia, Korea or the United Kingdom, introduced national registries dedicated to the safety and quality of BI surgeries. This narrative review aimed to focus on the clinical challenges, management and the current state of knowledge of BI. Both short and long-term outcomes of BI are determined by various alternatives and differences, which surgeons must consider during the planning and performing breast augmentation along with further complications or risk of reoperation. Proper preoperative decisions and aspects of surgical technique emerged to be equally important. The number of performed breast reconstructions is increasing, providing the finest aesthetic results and improving patient's quality of life. Choice of prosthesis varies according to individual preferences and anatomical variables. A newly diagnosed cases of BIA-ALCL with lacking data on prevention, diagnosis, and treatment are placing it as a compelling medical challenge. Similarly, BII remains one of the most controversial subjects in reconstructive breast surgery due to unspecified diagnostic procedures, and recommendations.


Reduced plasma nonesterified fatty acid levels and the advent of an acute lung injury in mice after intravenous or enteral oleic acid administration.
Although exerting valuable functions in living organisms, nonesterified fatty acids (NEFAs) can be toxic to cells. Increased blood concentration of oleic acid (OLA) and other fatty acids is detected in many pathological conditions. In sepsis and leptospirosis, high plasma levels of NEFA and low albumin concentrations are correlated to the disease severity. Surprisingly, 24 h after intravenous or intragastric administration of OLA, main NEFA levels (OLA inclusive) were dose dependently decreased. However, lung injury was detected in intravenously treated mice, and highest dose killed all mice. When administered by the enteral route, OLA was not toxic in any tested conditions. Results indicate that OLA has important regulatory properties on fatty acid metabolism, possibly lowering circulating fatty acid through activation of peroxisome proliferator-activated receptors. The significant reduction in blood NEFA levels detected after OLA enteral administration can contribute to the already known health benefits brought about by unsaturated-fatty-acid-enriched diets.


An essential role of phosphatidylinositol 3-kinase in myogenic differentiation.
The oncogene p3k, coding for a constitutively active form of phosphatidylinositol 3-kinase (PI 3-kinase; EC 184.108.40.206), strongly enhances myogenic differentiation in cultures of chicken-embryo myoblasts. It increases the size of the myotubes and induces elevated levels of the muscle-specific proteins MyoD, myosin heavy chain, creatine kinase, and desmin. Inhibition of PI 3-kinase activity with LY294002 or with dominant-negative mutants of PI 3-kinase interferes with myogenic differentiation and with the induction of muscle-specific genes. PI 3-kinase is therefore an upstream mediator for the expression of the muscle-specific genes and is both necessary and rate-limiting for the process of myogenesis.


Phosphorylation of HDM2 by Akt.
The HDM2 protein is a key regulator of the tumour suppressor, p53. Control of HDM2 function is critical for normal cell proliferation and stress responses, and it is becoming evident that multiple modifications of HDM2 can regulate its function within cells. In this study we show that HDM2 associated with the serine-threonine kinase, Akt, in response to growth factor stimulation of human primary cells. This association was concurrent with phosphorylation of Akt (at Ser 473), and resulted in elevated expression of HDM2 and enhanced nuclear localization. However, analysis of HDM2 proteins mutated at the consensus Akt recognition sites at serines 166 and 186 indicated that modification at these residues was not sufficient for the increased expression of the protein, which was blocked by the PI3 kinase inhibitor LY294002. Tryptic peptide and mutational analyses revealed evidence for an Akt phosphorylation site in HDM2 additional to the two consensus sites.


Does the use of indirect calorimetry change outcome in the ICU? Yes it does.
To review the recent findings on metabolic monitoring and possible beneficial effects of an adequate nutrition therapy, based on indirect calorimetry as the golden standard to predict energy expenditure. in the last decades, major steps are taken in the field of metabolism and nutrition, evolving from nutrition as a baseline support to a therapeutic intervention. The aspect of energy expenditure is of cardinal importance, and technical possibilities have impressively improved: from the first 'calorimetre' in 1789 to the new generation, clinical applicable indirect calorimeters and the high accuracy and easy use model reaching high technology readiness level [Oshima et al. (2017). Clin Nutr 36:651]. Several recent studies provide information on the technique of metabolic monitoring itself and the positive effects of implementation of the tool in a high-end nutritional care plan [Oshima et al. (2017). Clin Nutr 36:651]. The combination of correct energy provision and protein prescription has shown benefits, and mortality of ICU patients is related to the amount of energy provided [Zusman et al. (2016). Crit Care 20:367]. The use of a monitor per se will not change outcome. Optimal dosing of artificial nutrition can be achieved by the use of a parameter acquired by a measurement instead of by inaccurate equations. In the era of precision medicine, this approach has shown positive effects on outcome. Moreover, above all, the concept of metabolic monitoring of the critically ill is just an issue of common sense. Metabolic monitoring by indirect calorimetry is achieving a level in which it can be implemented in critical care practice. Evidence is available to prove that by guiding your nutritional therapy by measured values, it will change outcome of critically ill patients.


Simulation of ventilatory-induced stone movement and its effect on stone fracture during extracorporeal shock wave lithotripsy.
Because ventilation influences renal movement, we investigated the effect of stone motion on the efficiency of extracorporeal shock-wave lithotripsy (ESWL). Comparisons of the rates of fragmentation of an experimental model of renal calculi were made between simulated high-frequency jet ventilation at 100 breaths/min. with four-mm. stone movement as measured from the fluoroscope screen, conventional mechanical ventilation at 10 breaths/min. with 32-mm. stone movement as measured from the fluoroscope screen, and a static control. Fragmentation did not differ significantly between high-frequency jet ventilation and no ventilation (static control), but was significantly greater with high-frequency jet ventilation than with conventional ventilation.


Effects of remifentanil on the recovery quality among pediatric candidates for dental procedures under general anesthesia.
Remifentanil is a short-acting synthetic opioid, seems to facilitate hospital discharge, induce less agitation and better recovery quality. The aim of this study was to investigate the effects of remifentanil on the quality of recovery among healthy children who were candidate for dental procedures under general anesthesia. This study was a double blind randomized controlled clinical trial on healthy children who referred to the Department of Pediatric dentistry, School of Dentistry, Isfahan University of Medical Sciences. Both groups were anaesthetized using 5 mg/kg thiopental sodium, 1 μg/kg fentanyl and 0.6 μg/kg atracurium. The first group received propofol to maintain anesthesia and the second group was given remifentanil along with propofol. Then, the time span to regain consciousness, level of agitation during recovery and time of discharge were monitored and compared between the two groups. Data were analyzed using the Mann-Whitney U-test, and the Kruskal-Wallis test at P < 0.05 level of significance. Findings showed that the propofol + remifentanil group recovered faster than the propofol group. Chi-square test showed a significant difference in recovery time between the two groups (P < 0.05). About 45 min after regaining consciousness, the mean pediatric anesthesia emergence delirium score in the propofol group was 4.02 ± 2.19 and was significantly higher than the propofol + remifentanil group (3.02 ± 2.83) (P < 0.05). In addition, the mean Postanesthetic Discharge Scoring System score in the propofol group was 6.04 ± 1.74 and was significantly higher than the propofol + remifentanil group (7.58 ± 2.14) (P < 0.05). Combination of propofol and remifentanil significantly reduced the time taken for recovery, discharge and agitation level compared to propofol.


Electrophysiological signatures of conceptual and lexical retrieval from semantic memory.
Retrieval from semantic memory of conceptual and lexical information is essential for producing speech. It is unclear whether there are differences in the neural mechanisms of conceptual and lexical retrieval when spreading activation through semantic memory is initiated by verbal or nonverbal settings. The same twenty participants took part in two EEG experiments. The first experiment examined conceptual and lexical retrieval following nonverbal settings, whereas the second experiment was a replication of previous studies examining conceptual and lexical retrieval following verbal settings. Target pictures were presented after constraining and nonconstraining contexts. In the nonverbal settings, contexts were provided as two priming pictures (e.g., constraining: nest, feather; nonconstraining: anchor, lipstick; target picture: BIRD). In the verbal settings, contexts were provided as sentences (e.g., constraining: "The farmer milked a …"; nonconstraining: "The child drew a …"; target picture: COW). Target pictures were named faster following constraining contexts in both experiments, indicating that conceptual preparation starts before target picture onset in constraining conditions. In the verbal experiment, we replicated the alpha-beta power decreases in constraining relative to nonconstraining conditions before target picture onset. No such power decreases were found in the nonverbal experiment. Power decreases in constraining relative to nonconstraining conditions were significantly different between experiments. Our findings suggest that participants engage in conceptual preparation following verbal and nonverbal settings, albeit differently. The retrieval of a target word, initiated by verbal settings, is associated with alpha-beta power decreases. By contrast, broad conceptual preparation alone, prompted by nonverbal settings, does not seem enough to elicit alpha-beta power decreases. These findings have implications for theories of oscillations and semantic memory.


Structural and dynamic study of the transmembrane domain of the amyloid precursor protein.
Alzheimer's disease affects people all over the world, regardless of nationality, gender or social status. An adequate study of the disease requires essential understanding of the molecular fundamentals of the pathogenesis. The amyloid β-peptide, which forms amyloid plaques in the brain of people with Alzheimer's disease, is the product of sequential cleavage of a single-span membrane amyloid precursor protein (APP). More than half of the APP mutations found to be associated with familial forms of Alzheimer's disease are located in its transmembrane domain. The pathogenic mutations presumably affect the structural-dynamic properties of the APP transmembrane domain by changing its conformational stability and/or lateral dimerization. In the present study, the structure and dynamics of the recombinant peptide corresponding to the APP fragment, Gln686-Lys726, which comprises the APP transmembrane domain with an adjacent N-terminal juxtamembrane sequence, were determined in the membrane mimetic environment composed of detergent micelles using NMR spectroscopy. The structure obtained in dodecylphosphocholine micelles consists of two α-helices: a short surface-associated juxtamembrane helix (Lys687-Asp694) and a long transmembrane helix (Gly700-Leu723), both connected via a mobile loop region. A minor bend of the transmembrane α-helix is observed near the paired residues Gly708-Gly709. A cholesterol-binding hydrophobic cavity is apparently formed under the loop region, where the juxtamembrane α-helix comes into contact with the membrane surface near the N-terminus of the transmembrane α-helix.


CD40 ligand trimer enhances the response of CD8+ T cells to Mycobacterium tuberculosis.
We investigated the effect of recombinant CD40 ligand trimer (CD40LT) on the functional capacity of peripheral blood CD8(+) T cells from healthy tuberculin reactors that were cultured with Mycobacterium tuberculosis-infected autologous monocytes. CD40LT enhanced the capacity of M. tuberculosis-responsive CD8(+) T cells to produce IFN-gamma by increasing the number of IFN-gamma-producing CD8(+) T cells and the amount of IFN-gamma produced per cell. CD40LT-induced IFN-gamma production was dependent on production of IL-12 and IL-18, but did not require IL-15. CD40LT up-regulated expression of the transcription factors phosphorylated CREB and c-Jun, both of which have been previously shown to stimulate IFN-gamma mRNA transcription by binding to the IFN-gamma promoter. CD40LT also enhanced the capacity of CD8(+) T cells to lyse M. tuberculosis-infected monocytes, and increased CTL activity was associated with higher expression of perforin and granulysin, but not of Fas ligand. We conclude that CD40LT can enhance CD8(+) T cell effector function in response to M. tuberculosis.


[Diversity of terrestrial gastropod mollusks in the Pacific region of Nicaragua, and their habitat preferences].
Diversity of terrestrial gastropod mollusks in the Pacific region of Nicaragua, and their habitat preferences. Landsnail communities of the Nicaraguan Pacific Slope were studied. The study area was subdivided into 21 quadrats (ca. 40 x 40 km). A high taxonomic richness was found: 79 species, 43 genera and 23 families. Species richness (S) per quadrat ranged from 17 through 50. The biogeographic index presented higher values on quadrats 5 (3.04), 6 (3.03), 8 (2.96) and 11(2.96). Quadrat 11 had the highest species richness (S=50), and one of the highest biogeographic index values (IB=2.96). Gastropod mollusk communities are favored by sites with an illumination of filtered sun, associated to riparian forests and with a susbtratum of wet soils and leaf litter.


Primary immune responses by cord blood CD4(+) T cells and NK cells inhibit Epstein-Barr virus B-cell transformation in vitro.
Epstein-Barr virus (EBV) transformation of B cells from fetal cord blood in vitro varies depending on the individual sample. When a single preparation of EBV was simultaneously used to transform fetal cord blood samples from six different individuals, the virus transformation titer varied from less than zero to 10(5.9). We show that this variation in EBV transformation is associated with a marked primary immune response in cord blood samples predominately involving CD4(+) T cells and CD16(+) CD56(+) NK cells. After virus challenge both CD4(+) T cells and NK cells in fetal cord blood cultures expressed the lymphocyte activation marker CD69. The cytotoxic response against autologous EBV-infected lymphoblastoid cell line (LCL) targets correlated with the number of CD16(+) CD69(+) cells and was inversely correlated with the virus transformation titer. Although NK activity was detected in fresh cord blood and increased following activation by the virus, killing of autologous LCLs was detected only following activation by exposure to the virus. Both activated CD4(+) T cells and CD16(+) NK cells were independently able to kill autologous LCLs. Both interleukin-2 and gamma interferon were produced by CD4(+) T cells after virus challenge. The titer of EBV was lower when purified B cells were used than when whole cord blood was used. Addition of monocytes restored the virus titer, while addition of resting T cells or EBV-activated CD4(+) T-cell blasts reduced the virus titer. We conclude that there are primary NK-cell and Th1-type CD4(+) T-cell responses to EBV in fetal cord blood that limit the expansion of EBV-infected cells and in some cases eliminate virus infection in vitro.


The use of small intestinal segments to replace diseased bilharzial ureters--a prospective study.
Five male patients mean age 31.8 years with lower ureteric obstruction from urinary tract schistosomiasis have been treated by bilateral uretero-ileocystoplasty. All the 5 patients had bilateral hydroureters and hydronephrosts and 3 had reversible chronic renal failure whilst one patient presented with anuria and acute renal failure. Fibrosis of lower 1/4th to 1/3rd of the Ureters was present in the 5 patients. Four patients survived the operation for a mean of 3.4 years (range 1-7 years). The post-operative complications were hypernatraemic hyperchloraemic metabolic acidosis in 3 and incisional hernia in one. There was one death from septicaemia complicating infected bilateral nephrostomies performed before ureteroileocystoplasty. Ureteroileocystoplasty is recommended for replacement of damaged ureters where the extent of the damage precludes ureteroneocystostomy or where previous ureteroneocystostomy has failed.


Complex intervention modelling should capture the dynamics of adaptation.
Complexity has been linked to health interventions in two ways: first as a property of the intervention, and secondly as a property of the system into which the intervention is implemented. The former recognizes that interventions may consist of multiple components that act both independently and interdependently, making it difficult to identify the components or combinations of components (and their contexts) that are important mechanisms of change. The latter recognizes that interventions are implemented in complex adaptive systems comprised of intelligent agents who modify their behaviour (including any actions required to implement the intervention) in an effort to improve outcomes relative to their own perspective and objectives. Although an intervention may be intended to take a particular form, its implementation and impact within the system may deviate from its original intentions as a result of adaptation. Complexity highlights the challenge in developing interventions as effective health solutions. The UK Medical Research Council provides guidelines on the development and evaluation of complex interventions. While mathematical modelling is included in the guidelines, there is potential for mathematical modeling to play a greater role. The dynamic non-linear nature of complex adaptive systems makes mathematical modelling crucial. However, the tendency is for models of interventions to limit focus on the ecology of the system - the 'real-time' operation of the system and impacts of the intervention. These models are deficient by not modelling the way the system reacts to the intervention via agent adaptation. Complex intervention modelling needs to capture the consequences of adaptation through the inclusion of an evolutionary dynamic to describe the long-term emergent outcomes that result as agents respond to the ecological changes introduced by intervention in an effort to produce better outcomes for themselves. Mathematical approaches such as those found in economics in evolutionary game theory and mechanism design can inform the design and evaluation of health interventions. As an illustration, the introduction of a central screening clinic is modeled as an example of a health services delivery intervention. Complexity necessitates a greater role for mathematical models, especially those that capture the dynamics of human actions and interactions.


Optical and magnetic properties of hexagonal arrays of subwavelength holes in optically thin cobalt films.
In this study, we present our experimental results on the optical, magnetic, as well as magneto-optic properties of hexagonal arrays of subwavelength holes in optically thin cobalt films. Different meshes were used with hole diameters ranging between 220 and 330 nm while the interhole distance has been kept constant at 470 nm. The hole pattern modifies completely the magnetic behavior of the cobalt films; it gives rise to an increase of the coercive field of the in-plane magnetization with increasing hole diameter and to the appearance of out-of-plane magnetization components. Magneto-optic measurements show a spectacular magneto-optic response at wavelengths where surface plasmon-polaritons are supported by the structure as deduced in optical measurements. The experiments demonstrate the ability to artificially control the magnetic and thus the magneto-optic properties in hole array structures.


Impact of N-glycosylation site variants during human PrP aggregation and fibril nucleation.
Misfolding and aggregation of the human prion protein (PrP) cause neurodegenerative transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease. Mature native PrP is composed of 209 residues and is folded into a C-terminal globular domain (residues 125-209) comprising a small two-stranded β-sheet and three α-helices. The N-terminal domain (residues 23-124) is intrinsically disordered. Expression of truncated PrP (residues 90-231) is sufficient to cause prion disease and residues 90/100-231 is comprising the amyloid-like fibril core of misfolded infectious PrP. During PrP fibril formation under native conditions in vitro, the disordered N-terminal domain slows down fibril formation likely due to a mechanism of initial aggregation forming morphologically disordered aggregates. The morphological disordered aggregate is a transient phase. Nucleation of fibrils occurs from this initial aggregate. The aggregate phase is largely circumvented by seeding with preformed PrP fibrils. In vivo PrP is N-glycosylated at positions Asn181 and Asn197. Little is known about the importance of these positions and their glycans for PrP stability, aggregation and fibril formation. We have in this study taken a step towards that goal by mutating residues 181 and 197 for cysteines to study the positional impact on these processes. We have further by organic synthetic chemistry and chemical modification generated synthetic glycosylations in these positions. Our data shows that residue 181 when mutated to a cysteine is a key residue for self-chaperoning, rendering a trap in the initial aggregate preventing conformational changes towards amyloid fibril formation. Position 197 is less involved in the aggregate trapping and is more geared towards β-sheet structure conversion within amyloid fibrils. As expected, synthetic glycosylated 197 is less affected towards fibril formation compared to glycosylated 181. Our data are rather compatible with the parallel in-register intermolecular β-sheet model structure of the PrP90-231 fibril and sheds light on the misfolding transitions of PrP in vitro. We hypothesize that glycosylation of position 181 is a key site for prion strain differentiation in vivo.


Estimated plasma volume status (ePVS) could be an easy-to-use clinical tool to determine the risk of sepsis or death in patients with fever.
Capillary permeability can be increased in patients with sepsis. Indirect estimation of plasma volume status (ePVS) could identify more severely ill patients with fever. 1502 patients evaluated for fever at the Emergency Department (ED) of Merano General Hospital (Italy) between June 1, 2018 and May 30, 2019. The ePVS value registered on ED admission and derived from complete blood count was considered. Associations between the ePVS value and the two outcomes of the study (30-day mortality and sepsis diagnosis) were studied. Fifty-one of 1502 patients (3.4%) died at 30 days and 5.3% (80/1502) had a diagnosis of sepsis. The median ePVS in patients who died was higher than in those who survived (6.01 dL/g vs 4.49 dL/g, p < .001). In the multivariate analysis, ePVS higher than 4.52 dL/g presented an OR of 2.717 (CI95% 1.103-6.692, p = .020) for 30-day mortality and 1.824 (CI95% 1.055-3.154, p = .030) for the diagnosis of sepsis. ePVS presented a significant improvement in reclassification of the usual evaluation of patients with fever (NRI 21.6% for 30-day mortality and NRI 19.7 for sepsis diagnosis, p < .001). The ePVS value was a useful additional predictive tool to assess the severity of illness in patients with fever.


Effect of fetal hemoglobin on the determination of neonatal cerebral oxygenation by near-infrared spectroscopy.
Near-infrared spectroscopy has been applied to the study of cerebral oxygenation and hemodynamics in the newborn. Fetal Hb is present in high concentrations in these infants. Because spectral absorption curves in the near-infrared range for fetal Hb are not identical to those for adult Hb, there is a potential for the measurements to be affected. This possibility has not previously been investigated. A quantitative analysis of cerebral oxygenation was undertaken in six newborn infants. The analysis used near-infrared spectroscopy multiplier coefficients derived from the absorption coefficients of both fetal and adult deoxygenated and oxygenated Hb. The results of both analyses were compared. It was concluded that the error in near-infrared spectroscopy analysis of neonatal cerebral oxygenation arising from the use of absorption coefficients derived from adult Hb is inconsequential, even in the presence of high concentrations of fetal Hb.


Nephrosplenic entrapment of the large colon in 142 horses (2000-2009): analysis of factors associated with decision of treatment and short-term survival.
Previous studies indicate similar overall survival of horses with nephrosplenic entrapment of the large colon (NSE), regardless of treatment strategy. Short-term survival of a primarily conservative treatment strategy without rolling under general anaesthesia (GA) and a low proportion of surgical intervention as well as indicators of short-term nonsurvival has not been documented. To document short-term survival of horses with NSE treated in a university referral hospital with a low rate of surgical interventions and to determine factors associated with the decision of treatment and short-term nonsurvival. A retrospective review of medical records of 142 horses diagnosed with NSE between January 2000 and October 2009 was undertaken. Case details and clinical parameters from the initial examination, treatment and outcome were recorded. Factors associated with decision of treatment and short-term survival were identified by multiple logistic regression analysis. Warmblood breeds were over-represented in comparison to the general colic population. Overall short-term survival was 91.5% (130/142) which is similar to previous studies. Three horses considered to be in need of surgery were subjected to euthanasia for economical reasons before treatment. Of 114 conservatively treated horses, 110 (96.5%) survived, as did 20/25 (80%) of surgically treated horses. Nine conservatively managed horses were treated with phenylephrine. Gastric reflux (P = 0.0077), pain (P = 0.024) and abdominal distension (P = 0.05) were associated with the decision to treat surgically. Increased heart rate (P<0.001), and surgery (P = 0.032) were associated with reduced likelihood of short-term survival. Overall short-term survival was similar to that reported in previous studies with higher proportions of surgically managed cases. Consequently, horses with NSE should be managed by a primarily conservative treatment strategy, with the decision to treat surgically based on specific evidence based criteria.


Cholinergic innervation of the primate hippocampal formation. I. Distribution of choline acetyltransferase immunoreactivity in the Macaca fascicularis and Macaca mulatta monkeys.
The cholinergic innervation of the hippocampal formation of Macaca fascicularis (cynomolgus) and Macaca mulatta (rhesus) monkeys was investigated by immunohistochemical procedures using a monoclonal antibody directed against choline acetyltransferase. The distribution of choline acetyltransferase in the monkey demonstrated both similarities and differences with the staining patterns observed in the rat or with acetylcholinesterase in the monkey. While both of these latter preparations demonstrated labeled cells, for example, no choline acetyltransferase labeled neurons were observed in the monkey hippocampal formation. Choline acetyltransferase activity was restricted to fibers which varied in thickness and number of varicosities and in their regional and laminar distribution. The highest densities of labeled fibers were observed in the uncal portion of the hippocampus, in the parasubiculum, and in the entorhinal cortex; the lowest densities of labeled fibers were observed in CA1 and in midrostrocaudal levels of the dentate gyrus. In the dentate gyrus, immunoreactive fibers were densely distributed in the molecular layer and in an infragranular plexus. One of the few striking noticeable interspecies differences was observed in the dentate gyrus. In the rhesus monkey, labeled fibers in the molecular layer were divided into a superficial denser and an inner lighter lamina, whereas in M. fascicularis, the cholinergic fibers were distributed more homogeneously throughout the molecular layer. In the hippocampus proper, there was a progressive decrease in the density of ChAT-immunoreactive fibers from CA3/CA2 into CA1. The subiculum also demonstrated modest labeling which was nonetheless higher than in CA1; the border of these fields demonstrated increased fiber labeling. The density of choline acetyltransferase staining was high in the presubiculum and parasubiculum. In the entorhinal cortex, a relatively clear boundary was observed between the more heavily stained superficial layers (I, II, and III) and the more weakly labeled deep layers (V and VI), especially in the intermediate and caudal fields. A transverse decreasing gradient was observed with the densest plexus of cholinergic fibers found in the medially situated olfactory field of the entorhinal cortex and the lowest density in the laterally located caudal and lateral fields.


Extracellular matrix and its therapeutic potential for cancer treatment.
The extracellular matrix (ECM) is one of the major components of tumors that plays multiple crucial roles, including mechanical support, modulation of the microenvironment, and a source of signaling molecules. The quantity and cross-linking status of ECM components are major factors determining tissue stiffness. During tumorigenesis, the interplay between cancer cells and the tumor microenvironment (TME) often results in the stiffness of the ECM, leading to aberrant mechanotransduction and further malignant transformation. Therefore, a comprehensive understanding of ECM dysregulation in the TME would contribute to the discovery of promising therapeutic targets for cancer treatment. Herein, we summarized the knowledge concerning the following: (1) major ECM constituents and their functions in both normal and malignant conditions; (2) the interplay between cancer cells and the ECM in the TME; (3) key receptors for mechanotransduction and their alteration during carcinogenesis; and (4) the current therapeutic strategies targeting aberrant ECM for cancer treatment.


Endocrine regulation of mitochondrial activity: involvement of truncated RXRalpha and c-Erb Aalpha1 proteins.
The importance of mitochondrial activity has recently been extended to the regulation of developmental processes. Numerous pathologies associated with organelle's dysfunctions emphasize their physiological importance. However, regulation of mitochondrial genome transcription, a key element for organelle's function, remains poorly understood. After characterization in the organelle of a truncated form of the triiodothyronine nuclear receptor (p43), a T3-dependent transcription factor of the mitochondrial genome, our purpose was to search for other mitochondrial receptors involved in the regulation of organelle transcription. We show that a 44 kDa protein related to RXRalpha (mt-RXR), another nuclear receptor, is located in the mitochondrial matrix. We found that mt-RXR is produced after cytosolic or intramitochondrial enzymatic cleavage of the RXRalpha nuclear receptor. After mitochondrial import and binding to specific sequences of the organelle genome, mt-RXR induces a ligand-dependent increase in mitochondrial RNA levels. mt-RXR physically interacts with p43 and acts alone or through a heterodimerical complex activated by 9-cis-retinoic acid and T3 to increase RNA levels. These data indicate that hormonal regulation of mitochondrial transcription occurs through pathways similar to those that take place in the nucleus and open a new way to better understand hormone and vitamin action at the cellular level.


Isolation of neuronal progenitor cells from the adult human neocortex.
The reliability of harvesting neuronal progenitor cells (NPCs) from the adult human neocortex has not been established, with respect to preparing autologous cell cultures for transplantation in stroke and traumatic brain injured patients. Enriched NPC cultures have been generated from nonneurogenic regions of the adult rodent brain by buoyancy-dependent fractionation, but the feasibility of using such a method to isolate NPCs from the adult human cortex has not been reported previously. To determine if a starter population of human adult cortical NPCs could be isolated for in vitro expansion using this method, tissue samples from five patients undergoing cortical resection for either epilepsy or trauma were assayed. Cultured cells generated from all patients predominately expressed both the NPC marker nestin and neuron-specific beta-tubulin III. The presence of NPCs was verified by in vitro BrdU/beta-tubulin III co-labeling and increasing beta-tubulin expression in differentiating conditions. Despite the formation of aggregates in monolayer culture, cell proliferation as measured by BrdU incorporation was not as prevalent as that reported from rodent cultures generated by this protocol. NPCs isolated from the adult human neocortex using this method expressed beta-tubulin III in larger percentages than has been previously reported for NPCs isolated using other methods. As such, these data suggest the possibility of culturing dividing neuroblasts from the adult neocortex for further manipulation as transplantable cells.


Accuracy of identification of the cricothyroid membrane in female subjects using palpation: an observational study.
The cricothyroid membrane (CTM) is the recommended site of access to the airway during cricothyroidotomy to provide emergency oxygenation. Despite the apparent simplicity of the technique, this rescue maneuver frequently fails to achieve its goals and complications are numerous. The reasons for this failure are unclear. We sought to determine the ability of physicians to correctly identify the CTM in female patients. Using fluorescent "invisible" ink, the physician was asked to mark the CTM with the patient in the supine neutral position and then with the head extended. The actual level was identified using ultrasound and the distance between the actual and estimated margin of the CTM was measured. A correct estimation was defined as a mark made between the upper and lower limits of the membrane and within 5 mm of midline. Participants were also asked to assess the ease of CTM palpation using a 10-cm visual analog scoring (VAS) scale. Fifty-six patients participated of whom 15 were obese. In the supine neutral neck position, the CTM was identified in 10/41 vs 0/15 (P = 0.048) in nonobese versus obese, respectively. Of the 46 incorrectly identified CTMs in this position, 24 were above (maximum 3 cm) and 22 below (maximum 3 cm) the actual level. Similar results were observed when the patients were placed with the neck in the extended position; the CTM was identified correctly in 12/41 vs 1/15 nonobese and obese patients, respectively. The range of values was also extensive; the estimation of the position of the membrane was as high as 2.5 cm above and 4 cm below the actual level, and up to 1.6 cm laterally. Participating doctors found palpation of the CTM subjectively more difficult in the obese than nonobese groups; VAS score for palpation difficulty was 5.25 ± 2.5 vs 3.3 ± 2.5, respectively, P = 0.005. Using multiple linear regression, VAS scores for palpation correlated negatively with increased patient height (P < 0.001) and greater thyromental distance (P = 0.006), and correlated positively with increased sternomental distance (P = 0.011) and neck circumference (P = 0.001). Misidentification of the CTM in female patients is common and its localization is less precise in those who are obese. This has implications for the likely success of invasive airway access via the CTM.


Variability of treatment for gouty arthritis between rheumatologists and primary care physicians.
Wide variability exists in the treatment of gout. We compared the treatment practices of rheumatologists with those of primary care physicians (PCPs) in the management of gout. Pharmacy records were reviewed to identify patients treated with colchicine, allopurinol, probenecid, or sulfinpyrazone. Forty PCP patients were compared with 33 patients followed by rheumatologists. Rheumatologists were three times more likely to confirm the diagnosis with joint aspiration and guide therapy with 24-h urine uric acid collections than were PCPs. Rheumatologists were more likely to use prophylaxis in acute gout before initiating uric acid-lowering therapy than were PCPs. All PCP patients were treated with allopurinol compared with 65% of rheumatology patients. Mean posttreatment uric acid levels were lower for rheumatology patients (5.0 mg/dL) compared with PCP patients (6.0 mg/dL). Previous studies have reported poor symptom control and increased toxicity in gouty patients with suboptimal treatment. With the vast majority of patients being treated by PCPs in a man-aged care setting, further studies will be necessary to determine whether treatment variability affects outcome between the two groups.


Selected transient receptor potential channel genes' expression in peripheral blood mononuclear cells of multiple sclerosis.
Transient receptor potential channels have responsibilities in many cellular processes such as cytokine production, cell differentiation, and cytotoxicity by affecting intracellular cation levels or intracellular signal pathways. Multiple sclerosis is a chronic autoimmune central nervous system (CNS) disease caused by environmental and genetic factors. In this study, we aim to investigate TRPV1-TRPV4, TRPM2, TRPM4, TRPM7, TRPC6, and TRPA1 mRNA expression levels, which are associated with the inflammatory process, in the peripheral blood mononuclear cells (PBMCs) of relapsing-remitting multiple sclerosis (RRMS) patients. Thirty-five healthy controls and age-gender matched thirty patients with RRMS were involved in the study. TRPC6, TRPA1, TRPM2, TRPM4, TRPM7, TRPV1, TRPV2, TRPV3, and TRPV4 PBMCs mRNA expression levels were determined by qPCR. In the present study, the TRPC6, TRPM7, TRPV1, TRPV3, and TRPV4 mRNA expressions of RRMS patients in PBMCs decreased at a significant level compared to the healthy control group (p = .000, p = .000, p = .044, p = .000, p = .004, respectively). The decreased expression of TRPC6, TRPM7, TRPV1, TRPV3, and TRPV4 in PBMCs may be associated with the pathogenesis of MS. Further studies are required to understand the mechanism of the relation between these TRP channels and MS and other autoimmune diseases.


Factors controlling plasma renin and aldosterone during pregnancy.
The response of plasma renin activity (PRA) and plasma aldosterone (PA) to change in sodium intake was evaluated in pregnant women during the third trimester. After 7 days on a 10 mEq sodium diet, PRA rose from 20.6 +/- 6.2 to 59.6 +/- 11.6 ng/ml/hr and PA from 47 +/- 11 to 127 +/- 27 ng% in pregnant women compared to PRA from 5 +/- 1.2 to 18.9 +/- 5.2 ng/ml/hr and PA from 7.7 +/- 1 to 42 +/- 3 ng% in nonpregnant controls. Pregnant women conserved sodium normally with urinary sodium excretion and weight loss similar to nonpregnant women. After 6 days on a 300 mEq sodium intake, PRA and PA in pregnant women were significantly higher, 10.2 +/- 1.4 ng/ml/hr and 22 +/- 3 ng%, respectively, compared to 1.5 +/- 0.3 ng/ml/hr and 7.3 +/- 1 ng% in controls. On both low- and high sodium intake there was a positive correlation between PRA and PA in pregnant women. Plasma prostaglandin E (PGE) was 0.45 +/- 0.06 ng/ml in pregnant women compared to 0.1 +/- 0.01 ng/ml in control women (p less than 0.01) and urinary PGE excretion was 2780 +/- 357 ng/24 hr in 28 pregnant women compared to 1191 +/- 142 ng/24 hrs (p less than 0.01) in 14 nonpregnant controls. These findings indicate that although renin and aldosterone secretion respond to change in sodium intake in pregnancy, the cause of the increased renin secretion of pregnancy may be secondary to the increase that occurs in prostaglandin synthesis.


Label-free imaging of mammalian cell nucleoli by Raman microspectroscopy.
The nucleolus is a prominent subnuclear structure whose major function is the transcription and assembly of ribosome subunits. The size of the nucleolus varies with the cell cycle, proliferation rate and stress. Changes in nucleolar size, number, chemical composition, and shape can be used to characterize malignant cells. We used spontaneous Raman microscopy as a label-free technique to examine nucleolar spatial and chemical features. Raman images of the 1003 cm(-1) phenylalanine band revealed large, well-defined subnuclear protein structures in MFC-7 breast cancer cells. The 783 cm(-1) images showed that nucleic acids were similarly distributed, but varied more in intensity, forming observable high-intensity regions. High subnuclear RNA concentrations were observed within some of these regions as shown by 809 cm(-1) Raman band images. Principal component analyses of sub-images and library spectra validated the subnuclear presence of RNA. They also revealed that an actin-like protein covaried with DNA within the nucleolus, a combination that accounted for 64% or more of the spectral variance. Embryonic stem cells are another rapidly proliferating cell type, but their nucleoli were not as large or well defined. Estimating the size of the larger MCF-7 nucleolus was used to show the utility of Raman microscopy for morphometric analyses. It was concluded that imaging based on Raman microscopy provides a promising new method for the study of nucleolar function and organization, in the evaluation of drug and experimental effects on the nucleolus, and in clinical diagnostics and prognostics.


Potential and Challenges of Induced Pluripotent Stem Cells in Liver Diseases Treatment.
Tens of millions of patients are affected by liver disease worldwide. Many of these patients can benefit from cell therapy involving living metabolically active cells, either by treatment of their liver disease, or by prevention of their disease phenotype. Cell therapies, including hepatocyte transplantation and bioartificial liver (BAL) devices, have been proposed as therapeutic alternatives to the shortage of transplantable livers. Both BAL and hepatocyte transplantation are cellular therapies that avoid use of a whole liver. Hepatocytes are also widely used in drug screening and liver disease modelling. However, the demand for human hepatocytes, heavily outweighs their availability by conventional means. Induced pluripotent stem cells (iPSCs) technology brings together the potential benefits of embryonic stem cells (ESCs) (i.e., self-renewal, pluripotency) and addresses the major ethical and scientific concerns of ESCs: embryo destruction and immune-incompatibility. It has been shown that hepatocyte-like cells (HLCs) can be generated from iPSCs. Furthermore, human iPSCs (hiPSCs) can provide an unlimited source of human hepatocytes and hold great promise for applications in regenerative medicine, drug screening and liver diseases modelling. Despite steady progress, there are still several major obstacles that need to be overcome before iPSCs will reach the bedside. This review will focus on the current state of efforts to derive hiPSCs for potential use in modelling and treatment of liver disease.


[The results of treating pulmonary tuberculosis patients with different concomitant diseases by using millimeter-wave resonance therapy].
The authors investigated the clinical and biochemical efficacy of millimeter-wave resonance therapy in patients with destructive pulmonary tuberculosis associated with different concomitant diseases. It was established that inclusion of millimeter-wave resonance therapy in the complex treatment of this patient category favoured the efficacy of tuberculosis treatment. The treatment produced also a favourable effect on concomitant diseases.


Natural Products: Review for Their Effects of Anti-HBV.
Hepatitis B is a global infectious disease, seriously endangering human health. Currently, there are mainly interferons and nucleoside analogues treatment of hepatitis B in the clinic, which have certain therapeutic effects on hepatitis B, but their side effects and drug resistance are increasingly prominent. Therefore, it is urgently needed to discover and develop new anti-HBV drugs, especially natural products, which have novel, high efficiency, and low toxicity anti-HBV compounds with novel antiviral mechanisms. In this manuscript, the natural products (polysaccharides and 165 compounds) with the activity of antihepatitis B virus are discussed according to their chemical classes, including 14 phenylpropanoids, 8 flavonoids,12 xanthones, 13 anthroquinones, 47 terpenoids, 6 alkaloids, 15 enediynes, 11 aromatics, 18 phenylalanine dipeptides compounds, and 13 others. In addition, the anti-HBV mechanism and targets of natural product were also discussed. The aim of this review is to report new discoveries about anti-HBV natural products and to provide reference for researchers.


Distribution of drug resistance mutations in type 3 poliovirus identifies three regions involved in uncoating functions.
We have previously described the use of an uncoating inhibitor, WIN 51711, to select drug-resistant mutants of the Sabin strain of poliovirus type 3. Two-thirds of the mutants proved to be dependent on the drug for plaque formation because of extreme thermolability (A. G. Mosser and R. R. Rueckert, J. Virol. 67:1246-1254, 1993). Here we report the responsible mutations; all were traced to single amino acid substitutions. Mutations conferring dependence and thermolability occurred in all four capsid proteins (VP1 to VP4), but all were clustered near residue 53 of VP4 at the inner capsid surface. Amino acid substitutions of the remaining non-drug-dependent mutants were mapped to three distinct loci: (i) on or near the inner capsid surface, at VP4 residue 46 or VP1 residue 129, in the vicinity of the drug dependence substitutions; (ii) at residues 192, 194, and 260 in the lining of the VP1 beta barrel, which is the drug-binding site; and (iii) at VP1 residue 105 on the edge of the canyon surrounding the fivefold axis of symmetry, the putative receptor-binding site. All of the mutations increased the eclipse rate of cell-attached virus. Such mutants help identify parts of the capsid that play a role in viral uncoating functions.


HIV behavioural surveillance among refugees and surrounding host communities in Uganda, 2006.
We used a standardised behavioural surveillance survey (BSS), modified to be directly relevant to populations in conflict and post-conflict settings as well as to their surrounding host populations, to survey the populations of a refugee settlement in south-western Uganda and its surrounding area. Two-stage probability sampling was used to conduct 800 interviews in each population. The BSS questionnaire adapted for displaced populations was administered to adults aged 15-59 years. It collected information on HIV knowledge, attitudes and practices; issues before, during and after displacement; level of interaction and sexual exploitation among the refugees and host communities (i.e., nationals). Population parameters were compared and 95% confidence intervals were calculated for core HIV indicators. The demographic characteristics were similar (except for educational achievement), and HIV awareness was very high (>95%) in both populations. The refugees reported more-accepting attitudes towards persons with HIV than did nationals (19% versus 13%; p < 0.01). More refugees than nationals reported ever having had transactional sex (10% versus 6%; p < 0.01), which mostly occurred post-displacement. Five percent of females among both the refugees and nationals reported experiencing forced sex, which mostly occurred post-displacement and after the arrival of refugees, respectively. Nationals reported more frequent travel to refugee settlements than reported by refugees to national villages (22% versus 11%; p < 0.01). The high mobility and frequent interactions of these two populations suggest that integrated HIV programmes should be developed and would be an efficient use of resources. Evidence suggesting that female refugees may be at elevated risk for HIV infection, due to forced sex, transactional sex and other vulnerabilities, warrants further examination through qualitative research. The findings indicate a need for additional, focused HIV-prevention programmes, such as youth education, for both refugees and Ugandan nationals.


Venous thromboembolic prophylaxis for transurethral prostatectomy: practice among British urologists.
Venous thromboembolism (VTE) is an occasional cause of death after transurethral prostatectomy but there are no established guidelines for its prevention in relation to this operation. We assessed practice in the UK by mailing a questionnaire to 460 consultant members of the British Association of Urological Surgeons. 362 (79%) completed questionnaires were received. 280 of 362 (77%) respondents routinely used VTE prophylaxis with transurethral prostatectomy; 82 (23%) did not. 230 of the 280 urologists who took precautions used mechanical methods; 50 used low dose heparin, either with stockings or alone. This survey indicates that, despite a lack of clear evidence, most British urologists favour some form of precaution against VTE in patients undergoing transurethral prostatectomy.


Structure and genetic stability of mitochondrial genomes vary among yeasts of the genus Saccharomyces.
Several yeast species/isolates belonging to the genus Saccharomyces were examined for the organization of their mtDNAs and ability to generate petite mutants. A general characteristic for all of the mtDNAs tested was that they were very A+T-rich. However, restriction patterns and inducibility of petite mutations revealed a great diversity in the organization and genetic behaviour of mtDNAs. One group of yeasts, Saccharomyces sensu stricto, contains mtDNA ranging in size from 64 to 85 kb. mtDNAs form these yeasts contain a high number of restriction sites that are recognized by the enzymes Haelll and Mspl, which cut specifically in G+C clusters. There are three to nine ori/rep sequences per genome. These yeasts spontaneously generate respiration deficient mutants. Ethidium bromide (Et-Br), at low concentrations, induces a majority of cells to give rise to petites. A second group of yeasts, Saccharomyces sensu lato, contains smaller mtDNAs, ranging in size from 23 to 48 kb, and probably only a few intergenic G+C clusters and no ori/rep sequences. These yeasts also generate petite clones spontaneously. but Et-Br, even when present at high concentrations, does not substantially increase the frequency of petites. In most petite clones from these yeasts only a small fragment of the wild-type molecule is retained and apparently multiplied. A third group, represented by Saccharomyces kluyveri, does not give rise to petite mutants either spontaneously or after induction.


Short-Axis Methyl Substitution Approach on Indacenodithiophene: A New Multi-Fused Ladder-Type Arene for Organic Solar Cells.
Indacenodithiophene (IDT) is a promising building block for designing organic semiconductors. In this work, a new pentacyclic ladder-type arene IDMe was designed and synthesized by introducing methyl substitution on the short-axis of IDT. Two non-fullerene electron acceptors (IDIC and ID-MeIC) without and with methyl substitution were designed and synthesized for further study. Compared with IDIC, ID-MeIC with methyl substitution on the short-axis of IDT shows smaller bandgap, stronger extinction coefficient, and better crystallinity. Besides, PBDB-T: ID-MeIC blend film shows more efficient exciton generation and dissociation and more balanced charge transport mobility. Therefore, polymer solar cells based on PBDB-T: ID-MeIC can achieve better photovoltaic performance with a PCE of 6.46% and substantial increase in J SC to 14.13 mA cm-2 compared to 4.94% and 9.10 mA cm-2 of PBDB-T: IDIC. These results suggest that short-axis substitution on multi-fused ladder-type arenes, such as IDT is an effective way to change the optical and electronic properties of the organic semiconductors for high-performance OPVs.