Integrated metabolomics and network pharmacology revealed the key active ingredients for the treatment of ulcerative colitis in the Citrus reticulata 'Dahongpao' peel.
Citrus reticulata pericarpium (CRP), the peel of Citrus reticulata 'Dahongpao' (DHP) is a medicinal herb with significant therapeutic value for treating ulcerative colitis (UC). However, the active therapeutic components of CRP are unclear. This study aims to reveal the metabolites potentially associated with the pharmacological properties of CRP. We performed flavonoid-targeting metabolomics to characterize the components of CRP (anti-UC part), tangerine pith and Citrus reticulata semen (no anti-UC effects parts) of DHP and further screened active components of CRP using network pharmacology and molecular docking. Lipopolysaccharide (LPS)-stimulated RAW 264.7 cells were used to study the anti-inflammatory effect of the selected biologically active components. The therapeutic effects of the selected components were further investigated in a mouse model of UC induced by DSS. Three compounds, namely nobiletin, sinensetin, and hispidulin had the lowest docking scores among all screened ingredients. IL-6 and NO concentrations were significantly decreased in the LPS-stimulated RAW264.7 cells compared with control cells treated with these compounds. Moreover, UC mice treated with these compounds showed a reversal in weight loss, inhibition of shortening of colon length, and amelioration of colon injury. Our results indicated that sinensetin, nobiletin, and hispidulin can be potentially used for the treatment of UC.


Impact Of Incentive-Based Game Therapy And Transporting Children On Toy Vehicle To Operation Theatre On Reducing Anxiety Prior To Induction Of Anesthesia.
To see if transporting paediatric patents to operation theatres using a battery operated vehicle decreases preoperative anxiety and reduce incidents of postoperative adverse events. The study was conducted from May to August 2019 at the Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan, and comprised paediatric patients aged 3-5 years assessed as American Society of Anaesthesiologists grade I and II who were scheduled to undergo elective intrathecal chemotherapy under general anaesthesia. The subjects were randomised into intervention group A and control group B. Patients in group A were part of an incentive-based game in the holding bay area and were transported to the operation theatre using a battery-operated toy vehicle. Those in group B watched a pre-decided cartoon on television screen in the holding bay and were transported further using wheel chair. Induction of anaesthesia was done in the presence of guardians in both the groups. Patient anxiety was assessed using the modified Yale Preoperative Anxiety Scale in holding bay area T0, prior to induction of anaesthesia T1, and postoperative anaesthesia-related recovery T2. Data was analysed using SPSS 22. Of the 36 patients, 18(50%) were in group A; 12(66.6%) boys and 6(33.3%) girls with mean age 4.01±0.48 years. The remaining 18(50%) subjects were in group B; 13(72.2%) boys and 5(27.8%) girls with mean age 3.96 years. The difference in anxiety between the groups at T0 was non-significant (p=0.73). At T1 and T2, the scores were significantly lower group A compared to group B (p<0.05). Group A patients had better bag mask ventilation compliance at induction and remarkably less incidence of hypoxia, bronchospasm, postoperative agitation and early discharge from PACU. Incentive-based game therapy decreased anxiety among paediatric patients preoperatively, made them more compliant and improved postoperative recovery.


[Lung and autoimmune diseases--clinical aspects and diagnosis].
Pulmonary involvement is commonly seen in autoimmune disease. In this review the clinical presentation of pulmonary involvement in vasculitis, rheumatoid arthritis and connective tissue disease is presented. Clinical symptoms and diagnostic approach will be discussed.


Should all pregnant women take calcium supplements in Nepal? GRADE evidence to policy assessment.
The WHO recommends oral calcium supplementation (1.5-2.0 g) in pregnant women to reduce the risk of pre-eclampsia living in areas with low dietary calcium intake. Although maternal mortality is high in Nepal and eclampsia causes at least 20% of maternal deaths, implementing WHO recommendations would be a major undertaking. This review aimed to assess whether the current evidence supports the blanket supplementation of calcium to prevent pre-eclampsia among pregnant women in Nepal. We used a structured approach to appraise the evidence for calcium supplementation in Nepal. We identified what may influence the impact of calcium supplementation in Nepal and conducted a situation analysis in the country covering maternal mortality, pre-eclampsia occurrence, and existing government policy provisions for supplementation. We also consulted with experts and government officials to explore their perspectives and experience on supplementation. We then used AMSTAR (A MeaSurement Tool to Assess Systematic Reviews) to appraise the Cochrane Systematic Review of calcium supplementation. Finally, we used these data in a GRADE (Grading of Recommendations Assessment, Development and Evaluation)-Evidence to Decision framework to reach a policy recommendation. Our assessment of the Cochrane Review showed that the recommendation made by the WHO is based on weak evidence and trial findings that are not consistent between studies. The Cochrane Review found low certainty of the evidence for benefit (reduction in pre-eclampsia and maternal mortality). Conversely, there is a high certainty of the evidence of undesirable effects (HELLP [haemolysis, elevated liver enzymes and low platelets] syndrome) although this is uncommon. The likely absolute reduction in maternal deaths projected to Nepal was estimated to be low, while the implementation costs were high. Stakeholders also raised several concerns regarding feasibility, acceptability, appropriate dosing, and risk communication. This review concludes that the blanket supplementation of calcium cannot be recommended in Nepal. A better approach may be to identify high-risk pregnant women and manage their antenatal visits and delivery to prevent mortality from pre-eclampsia.


Effectiveness and costs of a vocational advice service to improve work outcomes in patients with musculoskeletal pain in primary care: a cluster randomised trial (SWAP trial ISRCTN 52269669).
Musculoskeletal pain is a common cause of work absence, and early intervention is advocated to prevent the adverse health and economic consequences of longer-term absence. This cluster randomised controlled trial investigated the effect of introducing a vocational advice service into primary care to provide occupational support. Six general practices were randomised; patients were eligible if they were consulting their general practitioner with musculoskeletal pain and were employed and struggling at work or absent from work <6 months. Practices in the intervention arm could refer patients to a vocational advisor embedded within the practice providing a case-managed stepwise intervention addressing obstacles to working. The primary outcome was number of days off work, over 4 months. Participants in the intervention arm (n = 158) had fewer days work absence compared with the control arm (n = 180) (mean 9.3 [SD 21·7] vs 14·4 [SD 27·7]) days, incidence rate ratio 0·51 (95% confidence interval 0·26, 0·99), P = 0·048). The net societal benefit of the intervention compared with best care was £733: £748 gain (work absence) vs £15 loss (health care costs). The addition of a vocational advice service to best current primary care for patients consulting with musculoskeletal pain led to reduced absence and cost savings for society. If a similar early intervention to the one tested in this trial was implemented widely, it could potentially reduce days absent over 12 months by 16%, equating to an overall societal cost saving of approximately £500 million (US $6 billion) and requiring an investment of only £10 million.


Availability of Illegal Drugs During the COVID-19 Pandemic in Western Germany.
Background: In response to the COVID-19-pandemic, a lockdown was established in the middle of March 2020 by the German Federal Government resulting in drastic reduction of private and professional traveling in and out of Germany with a reduction of social contacts in public areas. Research Questions: We seek evidence on whether the lockdown has led to a reduced availability of illegal drugs and whether subjects with substance-related problems tried to cope with possible drug availability issues by increasingly obtaining drugs via the internet, replacing their preferred illegal drug with novel psychoactive substances, including new synthetic opioids (NSO), and/or by seeking drug treatment. Methods: A questionnaire was anonymously filled in by subjects with substance-related disorders, typically attending low-threshold settings, drug consumption facilities, and inpatient detoxification wards from a range of locations in the Western part of Germany. Participants had to both identify their main drug of abuse and to answer questions regarding its availability, price, quality, and routes of acquisition. Results: Data were obtained from 362 participants. The most frequent main substances of abuse were cannabis (n = 109), heroin (n = 103), and cocaine (n = 75). A minority of participants reported decreased availability (8.4%), increased price (14.4%), or decreased quality (28.3%) of their main drug. About 81% reported no change in their drug consumption due to the COVID-19 pandemic and the lockdown. A shift to the use of novel psychoactive substances including NSO were reported only by single subjects. Only 1-2% of the participants obtained their main drug via the web. Discussion: Present findings may suggest that recent pandemic-related imposed restrictions may have not been able to substantially influence either acquisition or consumption of drugs within the context of polydrug users (including opiates) attending a range of addiction services in Germany.


Equine Influenza.
Horses are the third major mammalian species, along with humans and swine, long known to be subject to acute upper respiratory disease from influenza A virus infection. The viruses responsible are subtype H7N7, which is believed extinct, and H3N8, which circulates worldwide. The equine influenza lineages are clearly divergent from avian influenza lineages of the same subtypes. Their genetic evolution and potential for interspecies transmission, as well as clinical features and epidemiology, are discussed. Equine influenza is spread internationally and vaccination is central to control efforts. The current mechanism of international surveillance and virus strain recommendations for vaccines is described.


EGF mediates calcium-activated chloride channel activation in the human bronchial epithelial cell line 16HBE14o-: involvement of tyrosine kinase p60c-src.
Particulate atmospheric pollutants interact with the human airway epithelium, which releases cytokines, chemokines, and EGF receptor (EGFR) ligands leading to proinflammatory responses. There is little information concerning the short-term effects of EGFR activation by extracellular ligands on ionic regulation of airway surface lining fluids. We identified in the membrane of human epithelial bronchial cells (16HBE14o(-) line) an endogenous calcium- and voltage-dependent, outwardly rectifying small-conductance chloride channel (CACC), and we examined the effects of EGF on CACC activity. Ion channel currents were recorded with the patch-clamp technique. In cell-attached membrane patches, CACC were activated by exposure of the external surface of the cells to physiological concentrations of EGF without any change in cytosolic Ca(2+) concentration ([Ca(2+)](i)) and inhibited by tyrphostin AG-1478 (an inhibitor of EGFR that also blocks EGF-dependent Src family kinase activation). EGF activation of c-Src protein in 16HBE14o(-) cells was observed, and the signaling pathway elicited by EGFR was blocked by tyrphostin AG-1478. In excised inside-out membrane patches CACC were activated by exposure of the cytoplasmic face of the channels to the human recombinant Src(p60(c-src)) kinase with endogenous or exogenous ATP and inhibited by lambda-protein phosphatase. Secretion of EGFR ligands by epithelial airway cells exposed to pollutants would then elicit a rapid and direct ionic response of CACC mediated by EGFR activation via a Src kinase family-dependent signaling pathway.


Greedy data transportation scheme with hard packet deadlines for wireless ad hoc networks.
We present a greedy data transportation scheme with hard packet deadlines in ad hoc sensor networks of stationary nodes and multiple mobile nodes with scheduled trajectory path and arrival time. In the proposed routing strategy, each stationary ad hoc node en route decides whether to relay a shortest-path stationary node toward destination or a passing-by mobile node that will carry closer to destination. We aim to utilize mobile nodes to minimize the total routing cost as far as the selected route can satisfy the end-to-end packet deadline. We evaluate our proposed routing algorithm in terms of routing cost, packet delivery ratio, packet delivery time, and usability of mobile nodes based on network level simulations. Simulation results show that our proposed algorithm fully exploits the remaining time till packet deadline to turn into networking benefits of reducing the overall routing cost and improving packet delivery performance. Also, we demonstrate that the routing scheme guarantees packet delivery with hard deadlines, contributing to QoS improvement in various network services.


Gene therapy for lysosomal storage disorders.
Lysosomal storage disorders (LSDs) encompass more than 50 distinct diseases, caused by defects in various aspects of lysosomal function. Neurodegeneration and/or dysmyelination are the hallmark of roughly 70% of LSDs. Gene therapy represents a promising approach for the treatment of CNS manifestations in LSDs, as it has the potential to provide a permanent source of the deficient enzyme, either by direct injection of vectors or by transplantation of gene-corrected cells. In this latter approach, the biology of neural stem/progenitor cells and hematopoietic cells might be exploited. Based on an extensive literature search up until March 2011, the author reviews and discusses the progress, the crucial aspects and the major challenges towards the development of novel gene therapy strategies aimed to target the CNS, with particular attention to direct intracerebral gene delivery and transplantation of neural stem/progenitor cells. The implementation of viral vector delivery systems with specific tropism, regulated transgene expression, low immunogenicity and low genotoxic risk and the improvement in isolation and manipulation of relevant cell types to be transplanted, are fundamental challenges to the field. Also, combinatorial strategies might be required to achieve full correction in LSDs with neurological involvement.


Evidence that the human jaw stretch reflex increases the resistance of the mandible to small displacements.
1. Small 'step' or sinusoidal displacements were imposed on the mandible while human subjects maintained an average biting force of 10 N. Phase-related changes in the force resisting sinusoidal displacement were used to determine the mechanical stiffness of the human mandibular system as a function of the frequency of stretching. 2. Jaw-muscle electromyographic (e.m.g.) responses to 'step' stretches were of 8 msec latency and generated a very substantial force response. Jaw-muscle e.m.g. responses having longer latency were not observed. 3. The mechanical stiffness of the human mandible was relatively constant as a function of the frequency of stretching, having a typical magnitude of about 15 N/mm (+/- 200 micrometers stretch) or 10 N/mm (+/- 1500 micrometers stretch) at mean biting forces of 10 N. The force resisting displacement was phase-advanced at all frequencies. 4. Modulation of jaw muscle electrical activity evoked by sinusoidal stretches increased in amplitude as a function of increasing stretch frequency. E.m.g. modulation was 60--100 degrees advanced at frequencies of 1--10 Hz, but the phase decreased at higher frequencies, becoming negative (lagging stretch) at frequencies of 30 Hz and above. These characteristics are consistent with the idea that the jaw stretch reflex is dependent on jaw muscle spindle afferent fibres exciting jaw-closing motoneurones by relatively direct (but not necessarily monosynaptic) connexions. 5. The relationship between jaw-muscle activity and voluntary fluctuations of isometric biting force suggests that human jaw muscles can be modelled as a second-order linear 'filter'. The corner frequency for human jaw muscle is about 3 Hz; thus it would appear to be considerably slower than jaw muscle of monkeys. 6. The reflex stiffness of the human mandible, estimated quantitatively on the assumption that human jaw muscle stiffness is similar to the intrinsic stiffness of the gastrocnemius of the cat, ranges between 5 and 9 N/mm at frequencies between 1 and 8 Hz. Since this reflex stiffness is about the same as muscle stiffness in this frequency range, we conclude that the stretch reflex of the human mandible contributes functionally to its postural stability. 7. Reflex stiffness appears to be greater in the monkey mandible relative to muscle stiffness than in the human mandible. The difference is argued to be a manifestation of the difference in jaw muscle contraction speed between the two species. 8. The fact that the mandibular stretch reflex appears to be stronger than the stretch reflex of the limbs of intact animals and humans is discussed in terms of the special anatomical and functional features of the mandible.


New insights into the (epi)genetics of twinning.
Spontaneous dizygotic (DZ) twins, i.e. twins conceived without the use of ARTs, run in families and their prevalence varies widely around the globe. In contrast, monozygotic (MZ) twins occur at a constant rate across time and geographical regions and, with some rare exceptions, do not cluster in families. The leading hypothesis for MZ twins, which arise when a zygote splits during preimplantation stages of development, is random occurrence. We have found the first series of genes underlying the liability of being the mother of DZ twins and have shown that being an MZ twin is strongly associated with a stable DNA methylation signature in child and adult somatic tissues. Because identical twins keep this molecular signature across the lifespan, this discovery opens up completely new possibilities for the retrospective diagnosis of whether a person is an MZ twin whose co-twin may have vanished in the early stages of pregnancy. Here, we summarize the gene finding results for mothers of DZ twins based on genetic association studies followed by meta-analysis, and further present the striking epigenetic results for MZ twins.


Deep-vein thrombosis in the era of high HIV and tuberculosis prevalence: A prospective review of its diagnosis and treatment in a quaternary centre.
Venous thromboembolic disease (VTE) is a leading cause of morbidity and mortality worldwide. HIV and tuberculosis (TB) infections have an aetiological association with VTE. Implementation of national HIV and TB programmes in South Africa (SA) has changed the burden of these two conditions, with resultant effects on VTE prevalence. Furthermore, with the increased use of direct oral anticoagulants (DOACs), baseline thrombosis data are needed to evaluate the effect of these new agents. To determine real-life baseline VTE characteristics in a pre-DOAC era, and to document the association of HIV and TB infections with VTE. This was a single-centre prospective cohort study performed in a quaternary care centre at Charlotte Maxeke Johannesburg Academic Hospital, SA. Key inclusion criteria included signed informed consent by adults (≥18 years) with a new episode of thrombosis. Procedures included physical examination, thrombosis risk factor assessment, duplex Doppler examination, thrombophilia screening, inpatient treatment and outpatient follow-up. Ninety-nine participants with confirmed thrombosis met the inclusion criteria. Participants were predominantly black (79.8%) and female (64.6%), with a median age of 46 (interquartile range (IQR) 38 - 57) years. The prevalences of HIV and TB were 53.0% and 21.2%, respectively. The most common risk factors for thrombosis were TB (17.2%) and malignancies (14.1%). Thrombophilia screening had a low diagnostic yield. The median time to target international normalised ratio during hospitalisation was 5.5 (IQR 4.0 - 7.0) days and the median duration of hospitalisation was 9 (IQR 7 - 11) days. The overall mortality rate in the cohort at 3 months post hospitalisation was 12.1%. This prospective study provides real-life data on thrombosis diagnosis and management at a quaternary public healthcare facility, providing a valuable baseline against which the effect of new DOAC anticoagulants can be assessed. Further research is required to clarify the aetiological association between thrombosis and HIV and TB.


Clinical Implication of N-Terminal Pro-Brain Natriuretic Peptide Burden in Heart Failure With Reduced Ejection Fraction: From the GUIDE-IT.
This study aimed to explore the prognostic implication of N-terminal pro-brain natriuretic peptide (NT-proBNP) burden on heart failure (HF) with reduced ejection fraction (HFrEF). We performed a post hoc analysis of the GUIDing Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT) trial. NT-proBNP burden was defined as the proportion of days with increased NT-proBNP (≥1,800 pg/ml) to the whole observation time. A Cox proportional hazards regression model was used to evaluate the association with NT-proBNP burden and prognosis. A total of 815 patients with HFrEF were analyzed in our study. Patients were categorized into 4 groups according to the degree of NT-proBNP burden. In the multivariate Cox analysis, NT-proBNP burden was significantly associated with all-cause mortality, cardiovascular mortality, and HF hospitalization. Compared with patients without NT-proBNP burden, the risk for the composite outcome increased by 210% (hazard ratio [HR] 3.10, 95% confidence interval [CI] 1.72 to 5.58, p <0.001) in NT-proBNP burden 1 (mild) group, 432% (HR 5.32, 95% CI 2.93 to 9.67, p <0.001) in NT-proBNP burden 2 (moderate) group, and over 12 times (HR 13.15, 95% CI 7.42 to 23.33, p <0.001) in NT-proBNP burden 3 (severe) group. The sensitivity analyses stratified by age and renal function yielded similar results. A higher NT-proBNP burden was associated with a significant increase in risks of all-cause mortality, cardiovascular mortality, HF hospitalization, and composite outcome. The results suggested that NT-proBNP burden could be an important predictor of the prognosis of patients with HFrEF.


A multimethod screening approach for pediatric depression onset: An incremental validity study.
Screening protocols that rely on a single informant are inadequate in predicting pediatric depression. Multi-informant and risk factor screening approaches are potentially more sensitive methods for identifying depression risk, but the incremental validity of these protocols has not been adequately tested. Using a translational analytic approach and multimethod, longitudinal study design, we simultaneously tested several multi-indicator approaches to depression screening to identify an optimal algorithm for predicting depression onset in youth. Participants were 222 never-depressed children and adolescents (Mage = 10.75 years old, SDage = 1.85; female = 50.45%; 82.88% White), who completed baseline questionnaires for depressive symptoms and cognitive vulnerabilities, in addition to a morphed face task to assess pupil dilation. Mothers, meanwhile, completed baseline questionnaires and a semistructured interview to assess maternal and pediatric depression. Follow-up depression diagnostic assessments with both the mother and youth occurred every 6 months for 2 years. Receiver operating characteristics and reclassification analyses were used to test our aims. Overall, we found moderate support for a multi-informant approach, and convincing evidence that individual differences in pupil dilation uniquely predicted depression onset. Youth with subthreshold depressive symptoms and elevated pupil dilation were over twice as likely to develop a first lifetime episode of depression compared to one's risk rate based on sex and age. Our study provides one of the first screening batteries for detecting first lifetime episodes of depression in youth. The unique and incremental validity provided by pupil dilation suggests feasible biological indicators of depression risk can improve primary prevention efforts that target depression, such as universal pediatric depression screening. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


(S)-9-(2,3-Dihydroxypropyl)adenine: An Aliphatic Nucleoside Analog with Broad-Spectrum Antiviral Activity.
(S)-9-(2,3-Dihydroxypropyl)adenine, a novel nucleoside analog, the sugar moiety of which is replaced by an aliphatic chain, inhibits the replication in vitro of several DNA and RNA viruses, including vaccinia, herpes simplex (types 1 and 2), measles, and vesicular stomatitis. It is also effective in vivo in reducing the mortality rate of mice inoculated intranasally with vesicular stomatitis virus.


Bone marrow transplantation for leukemia after conditioning with busulfan and cyclophosphamide. Bone marrow morphology in the early recovery phase.
The bone marrow morphology of fifty patients with leukemia was analyzed before and two weeks after allogeneic bone marrow transplantation and compared to that of ten normal, healthy control subjects. Conditioning of the marrow graft recipients had been carried out with a combination of 16 mg/kg of Busulfan and 120 mg/kg of cyclophosphamide. The bone marrow at two weeks after transplant showed characteristic features that were unique for this clinical setting. Regenerative precursor cells with a distinct morphology commonly formed clusters or islands. Although mixed, multilinear islands were seen; the majority of islands were unilinear with a homogeneous cell content. These hematopoietic colonies were in direct proximity to degenerated cells of presumed host origin. No damage to the microenvironment was seen, the most characteristic finding being large, uniform, unilocular fat cells in close proximity to regenerative precursor cells. These morphologic changes are indicative of a complete and persistent marrow engraftment.


Positional cloning of the Igl genes controlling rheumatoid factor production and allergic bronchitis in rats.
Rheumatoid factors (RF), autoantibodies that bind the Fc region of IgG, are one of the major diagnostic marker in rheumatoid arthritis (RA) but occur with lower frequency also in other infectious and inflammatory conditions. Through positional cloning of the previously described quantitative trait locus (QTL) Rf1 in congenic and advanced intercrossed rats, we identified the Ig lambda light chain locus as a locus that regulates the production of RF in rats. The congenic rats produce RF-Ig lambda and have significant higher levels of RF-IgG and RF-IgM in serum, while the DA rat has an impaired RF production and does not produces RF-Ig lambda. Thus, we could investigate the role of RF in pristane-induced arthritis (PIA) as well as ovalbumin-induced airway inflammation. We show that there was no difference in the development and severity of PIA between congenic and parental DA rats, suggesting that RF using lambda light chains have no impact on PIA. However, the RF producing congenic rats developed a more severe airway inflammation as indicated in the significantly increased number of eosinophils in bronchoalveolar lavage fluid as well as total IgE in serum. In addition, RF congenic rats had a significantly enhanced immune response toward OVA due to increased OVA-Igk but not OVA-Igl antibodies, suggesting a possible involvement of RF in the regulation of the humoral immune response.


Gas gangrene: potential for hyperbaric oxygen therapy.
Clostridial myonecrosis (gas gangrene) is an uncommon sequela of traumatic injury. Infection with Clostridium perfringens in devitalized tissue is the most common cause. Wide surgical debridement and appropriate antibiotic therapy remain the standard of care. However, the addition of hyperbaric oxygen therapy to standard management has been shown to have a synergistic effect in reducing morbidity and mortality in both canine and murine models. Although no prospective human data are available, retrospective data indicate that concomitant hyperbaric oxygen therapy has resulted in a twofold reduction in mortality. Where feasible, hyperbaric oxygen therapy should routinely be incorporated into the treatment plan for gas gangrene. Primary care physicians are in a unique position not only to make an early diagnosis but also to have a central role in coordinating multidisciplinary care often needed for this potentially fatal infection.


BioMagResBank.
The BioMagResBank (BMRB: www.bmrb.wisc.edu) is a repository for experimental and derived data gathered from nuclear magnetic resonance (NMR) spectroscopic studies of biological molecules. BMRB is a partner in the Worldwide Protein Data Bank (wwPDB). The BMRB archive consists of four main data depositories: (i) quantitative NMR spectral parameters for proteins, peptides, nucleic acids, carbohydrates and ligands or cofactors (assigned chemical shifts, coupling constants and peak lists) and derived data (relaxation parameters, residual dipolar couplings, hydrogen exchange rates, pK(a) values, etc.), (ii) databases for NMR restraints processed from original author depositions available from the Protein Data Bank, (iii) time-domain (raw) spectral data from NMR experiments used to assign spectral resonances and determine the structures of biological macromolecules and (iv) a database of one- and two-dimensional (1)H and (13)C one- and two-dimensional NMR spectra for over 250 metabolites. The BMRB website provides free access to all of these data. BMRB has tools for querying the archive and retrieving information and an ftp site (ftp.bmrb.wisc.edu) where data in the archive can be downloaded in bulk. Two BMRB mirror sites exist: one at the PDBj, Protein Research Institute, Osaka University, Osaka, Japan (bmrb.protein.osaka-u.ac.jp) and the other at CERM, University of Florence, Florence, Italy (bmrb.postgenomicnmr.net/). The site at Osaka also accepts and processes data depositions.


Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds.
Using both confocal immunofluorescence microscopy and biochemical approaches, we have examined the role of beta-arrestins in the activation and targeting of extracellular signal-regulated kinase 2 (ERK2) following stimulation of angiotensin II type 1a receptors (AT1aR). In HEK-293 cells expressing hemagglutinin-tagged AT1aR, angiotensin stimulation triggered beta-arrestin-2 binding to the receptor and internalization of AT1aR-beta-arrestin complexes. Using red fluorescent protein-tagged ERK2 to track the subcellular distribution of ERK2, we found that angiotensin treatment caused the redistribution of activated ERK2 into endosomal vesicles that also contained AT1aR-beta-arrestin complexes. This targeting of ERK2 reflects the formation of multiprotein complexes containing AT1aR, beta-arrestin-2, and the component kinases of the ERK cascade, cRaf-1, MEK1, and ERK2. Myc-tagged cRaf-1, MEK1, and green fluorescent protein-tagged ERK2 coprecipitated with Flag-tagged beta-arrestin-2 from transfected COS-7 cells. Coprecipitation of cRaf-1 with beta-arrestin-2 was independent of MEK1 and ERK2, whereas the coprecipitation of MEK1 and ERK2 with beta-arrestin-2 was significantly enhanced in the presence of overexpressed cRaf-1, suggesting that binding of cRaf-1 to beta-arrestin facilitates the assembly of a cRaf-1, MEK1, ERK2 complex. The phosphorylation of ERK2 in beta-arrestin complexes was markedly enhanced by coexpression of cRaf-1, and this effect is blocked by expression of a catalytically inactive dominant inhibitory mutant of MEK1. Stimulation with angiotensin increased the binding of both cRaf-1 and ERK2 to beta-arrestin-2, and the association of beta-arrestin-2, cRaf-1, and ERK2 with AT1aR. These data suggest that beta-arrestins function both as scaffolds to enhance cRaf-1 and MEK-dependent activation of ERK2, and as targeting proteins that direct activated ERK to specific subcellular locations.


Improvement of contrast sensitivity with practice is not compatible with a sensory threshold account.
In forced-choice detection, incorrect responses are routinely ascribed to internal noise, because experienced psychophysical observers do not act as if they have a sensory threshold, below which all perceived intensities would be identical. To determine whether inexperienced observers have sensory thresholds, we examined psychometric functions (percent correct versus log contrast) for detection and detection in full-screen, dynamic visual noise. Over five days, neither type of psychometric function changed shape, but both shifted leftwards, indicating increased sensitivity. These results are not consistent with a lowered sensory threshold, which would decrease psychometric slope. Our results can be understood within the context of Dosher and Lu's "stochastic" perceptual template model [Vis. Res.40, 1269 (2000)], augmented to allow intrinsic uncertainty. Specifically, our results are consistent with a combination of reduced internal additive noise and improved filtering of external noise.


Application of Epineural Sheath as a Novel Approach for Fat Volume Maintenance.
Various methods have been suggested to improve fat graft survival and decrease graft loss. The exact mechanism of fat graft survival is still unclear, and new strategies are needed to further investigate it. The efficacy of epineural sheath in fat volume maintenance was tested in rat model. Five experimental groups were created: group 1, fat graft without any coverage; group 2, epineural sheath tube alone; group 3, epineural sheath tube filled with fat graft; group 4, fat graft mixed with minced epineural sheath without any coverage; and group 5, fat graft covered with the epineural sheath patch. All grafts were implanted into the dorsal subcutaneous region and were followed for up to 12 weeks, when samples were harvested for hematoxylin and eosin and immunostaining for vascular endothelial growth factor expression and perilipin evaluation of fat viability. In groups 1 and 4, over 25% of graft loss was observed at first week, over 50% at third week, and 100% at sixth week postimplantation. The weight of fat graft within the epineural sheath tube and the weight of epineural tube (ET) alone were maintained up to 12 weeks postimplantation. The weight of fat graft within the epineural patch was maintained up to 6 weeks, but 50% of weight loss was observed between 6 and 12 weeks. Structure of the epineural sheath tubes and patches was intact, and no leakage of fat graft was observed. Based on hematoxylin and eosin staining, normal structure and integrity of the fat graft within the ET were preserved up to 12 weeks postimplantation. Characteristic adipocyte morphology was confirmed by perilipin staining, showing viable fat cells in groups 3 and 5 at 12 weeks. Increased vascular endothelial growth factor expression was observed in groups 2, 3, 4, and 5. Both, the ETs and epineural patches maintained 100% and 50% of fat graft weight at 12 weeks postimplantation, respectively. These results were confirmed by histology and immunostaining showing viable adipocytes within the epineural patches (6 weeks) and tubes (12 weeks). These results are encouraging and justify further evaluation of fat volume maintenance in preclinical large animal model in preparation to clinical application.


Signal-processing-based bioinformatics approach for the identification of influenza A virus subtypes in neuraminidase genes.
Neuraminidase (NA) genes of influenza A virus is a highly potential candidate for antiviral drug development that can only be realized through true identification of its sub-types. In this paper, in order to accurately detect the sub-types, a hybrid predictive model is therefore developed and tested over proteins obtained from the four subtypes of the influenza A virus, namely, H1N1, H2N2, H3N2 and H5N1 that caused major pandemics in the twentieth century. The predictive model is built by the following four main steps; (i) decoding the protein sequences into numerical signals by means of EIIP amino acid scale, (ii) analysing these signals (protein sequences) by using Discrete Fourier Transform (DFT) and extracting DFT-based features, (iii) selecting more influential sub-set of the features by using the F-score statistical feature selection method, and finally (iv) building a predictive model on the feature sub-set by using support vector machine classifier. The protein sequences were chosen as to be of high percentage identity that they demonstrate within individual influenza subtype classes and high variation that they display in the percentage identity. This makes the proteins very difficult to distinguish from each other even they belong to different subtypes. Given this set of the proteins, the predictive model yielded 98.3% accuracy based on a 5-fold cross validation. This also results in a twenty feature sub-set that can also help reveal spectral characteristics of the subtypes. The proposed model is promising and can easily be generalized for other similar studies.


Reduced cortical cannabinoid 1 receptor messenger RNA and protein expression in schizophrenia.
Cannabis use is associated with both impaired cognitive functions, including working memory, and an increased risk of schizophrenia. Schizophrenia is characterized by impairments in working memory that are associated with reduced gamma-aminobutyric acid (GABA) neurotransmission in the dorsolateral prefrontal cortex. The cannabinoid 1 receptor (CB1R) is highly expressed in the dorsolateral prefrontal cortex, is contained in the axon terminals of a subpopulation of perisomatic-targeting GABA neurons, and, when activated, suppresses the release of GABA. To determine the potential relationship between CB1R signaling and altered GABA neurotransmission in schizophrenia by evaluating CB1R messenger RNA (mRNA) and protein expression in the dorsolateral prefrontal cortex. In situ hybridization and immunocytochemistry techniques were used to examine the cortical levels of CB1R mRNA and protein, respectively. Brain specimens were obtained from autopsies conducted at the Allegheny County Medical Examiner's Office, Pittsburgh, Pennsylvania. Postmortem brain specimens from 23 pairs of subjects with schizophrenia and age-, sex-, and postmortem interval-matched comparison subjects, as well as brain specimens from 18 macaque monkeys with long-term exposure to haloperidol, olanzapine, or placebo. Optical density measures of CB1R mRNA expression and protein levels and correlations with previously reported glutamic acid decarboxylase 67 and cholecystokinin mRNA measures. Levels of CB1R mRNA were significantly lower by 14.8% in the subjects with schizophrenia. Similarly, CB1R protein levels, assessed by radioimmunocytochemistry and standard immunocytochemistry, were significantly decreased by 11.6% and 13.9%, respectively. Group differences in CB1R mRNA levels were significantly correlated with those in glutamic acid decarboxylase 67 and cholecystokinin mRNA levels. Expression of CB1R mRNA was not changed in antipsychotic-exposed monkeys, and neither CB1R mRNA levels nor protein levels were affected by potential confounding factors in the subjects with schizophrenia. This combination of findings suggests the testable hypothesis that reduced CB1R mRNA and protein levels in schizophrenia represent a compensatory mechanism to increase GABA transmission from perisomatic-targeting cholecystokinin interneurons with impaired GABA synthesis.


VUS-type alteration in POLD1 and microsatellite instability in a metastatic luminal B breast cancer patient.
Microsatellite instability (MSI) and POLD1 mutations are usually described in colorectal tumours in patients with polyposis syndrome but rarely found in breast tumours. This case describes a metastatic luminal B breast tumour in a young patient with an important family history of cancer. Mutational studies found a Variant of Uncertain Significance (VUS)-type alteration in POLD1 that motivated the study for MSI, which was found positive. Recent data point towards the use of pembrolizumab as a treatment option for tumour presenting with MSI instead of chemotherapy.


Bound H dibaryon in flavor SU(3) limit of lattice QCD.
The flavor-singlet H dibaryon, which has strangeness -2 and baryon number 2, is studied by the approach recently developed for the baryon-baryon interactions in lattice QCD. The flavor-singlet central potential is derived from the spatial and imaginary-time dependence of the Nambu-Bethe-Salpeter wave function measured in N(f)=3 full QCD simulations with the lattice size of L≃2,3,4 fm. The potential is found to be insensitive to the volume, and it leads to a bound H dibaryon with the binding energy of 30-40 MeV for the pseudoscalar meson mass of 673-1015 MeV.


Perspective on the evolution of cell-based bone tissue engineering strategies.
Despite the compelling clinical needs in enhancing bone regeneration and the potential offered by the field of tissue engineering, the adoption of cell-based bone graft substitutes in clinical practice is limited to date. In fact, no study has yet convincingly demonstrated reproducible clinical performance of tissue-engineered implants and at least equivalent cost-effectiveness compared to the current treatment standards. Here, we propose and discuss how tissue engineering strategies could be evolved towards more efficient solutions, depicting three different experimental paradigms: (i) bioreactor-based production; (ii) intraoperative manufacturing, and (iii) developmental engineering. The described approaches reflect the need to streamline graft manufacturing processes while maintaining the potency of osteoprogenitors and recapitulating the sequence of biological steps occurring during bone development, including vascularization. The need to combine the assessment of efficacy of the different strategies with the understanding of their mechanisms of action in the target regenerative processes is highlighted. This will be crucial to identify the necessary and sufficient set of signals that need to be delivered at the injury or defect site and should thus form the basis to define release criteria for reproducibly effective engineered bone graft substitutes.


Computational modeling approaches for developing a synergistic effect prediction model of estrogen agonistic activity.
The concerns regarding the potential health threats caused by estrogenic endocrine-disrupting chemicals (EDCs) and their mixtures manufactured by the chemical industry are increasing worldwide. Conventional experimental tests for understanding the estrogenic activity of mixtures are expensive and time-consuming. Although non-testing methods using computational modeling approaches have been developed to reduce the number of traditional tests, they are unsuitable for predicting synergistic effects because current prediction models consider only a single chemical. Thus, the development of predictive models is essential for predicting the mixture toxicity, including chemical interactions. However, selecting suitable computational modeling approaches to develop a high-performance prediction model requires considerable time and effort. In this study, we provide a suitable computational approach to develop a predictive model for the synergistic effects of estrogenic activity. We collected datasets on mixture toxicity based on the synergistic effect of estrogen agonistic activity in binary mixtures. Using the model deviation ratio approach, we classified the labels of the binary mixtures as synergistic or non-synergistic effects. We assessed five molecular descriptors, four machine learning-based algorithms, and a deep learning-based algorithm to provide a suitable computational modeling approach. Compared with other modeling approaches, the prediction model using the deep learning-based algorithm and chemical-protein network descriptors exhibited the best performance in predicting the synergistic effects. In conclusion, we developed a new high-performance binary classification model using a deep neural network and chemical-protein network-based descriptors. The developed model will be helpful for the preliminary screening of the synergistic effects of binary mixtures during the development process of chemical products.


Does intramuscular thermal feedback modulate eccrine sweating in exercising humans?
Few investigators have considered the possibility that skeletal muscles might contain thermosensitive elements capable of modifying thermoeffector responses. In this experiment, the temporal relationships between dynamic changes in deep-body and intramuscular temperatures and eccrine sweat secretion were explored during rhythmical and reproducible variations in heat production. Eight subjects performed semi-recumbent cycling (25 °C) at a constant load to first establish whole-body thermal and sudomotor steady states (35 min), followed by a 24-min block of sinusoidal workload variations (three, 8-min periods) and then returning to steady-state cycling (20 min). Individual oesophageal, mean skin and intramuscular (vastus lateralis) temperatures were independently cross-correlated with simultaneously measured forehead sweat rates to evaluate the possible thermal modulation of sudomotor activity. Both intramuscular and oesophageal temperatures showed strong correlations with sinusoidal variations in sweating with respective maximal cross-correlation coefficients of 0.807 (±0.044) and 0.845 (±0.035), but these were not different (P = 0.40). However, the phase delay between intramuscular temperature changes and sweat secretion was significantly shorter than the delay between oesophageal temperature and sweating [25.6 s (±12.6) vs. 46.9 s (±11.3); P = 0.03]. The temporal coupling of eccrine sweating to intramuscular temperature, combined with a shorter phase delay, was consistent with the presence of thermosensitive elements within skeletal muscles that appear to participate in the modulation of thermal sweating.


Bulk Nanobubbles from Acoustically Cavitated Aqueous Organic Solvent Mixtures.
We investigate the existence and stability of bulk nanobubbles in various aqueous organic solvent mixtures. Bulk nanobubble suspensions generated via acoustic cavitation are characterized in terms of their bubble size distribution, bubble number density, and zeta potential. We show that bulk nanobubbles exist in pure water but do not exist in pure organic solvents, and they disappear at some organic solvent-water ratio. We monitor the nanobubble suspensions over a period of a few months and propose interpretations for the differences behind their long-term stability in pure water versus their long-term stability in aqueous organic solvent solutions. Bulk nanobubbles in pure water are stabilized by their substantial surface charge arising from the adsorption of hydroxyl ions produced by self-ionization of water. Pure organic solvents do not autoionize, and therefore, nanobubbles cannot exist in concentrated aqueous organic solvent solutions. Because of preferential adsorption of organic solvent molecules at the nanobubble interfaces, the surface charge of the nanobubbles decreases with the solvent content, but the strong hydrogen bonding near their interfaces ensures their stability. The mean bubble size increases monotonically with the solvent content, whereas the surface tension of the mixture is sharply reduced. This is in agreement with literature results on macro- and microbubbles in aqueous organic solutions, but it stands in stark contrast to the behavior of macro- and microbubbles in aqueous surfactant solutions.


On bells, saliva, and abdominal pain or discomfort: Early aversive visceral conditioning and vulnerability for anorexia nervosa.
Gastrointestinal (GI) symptoms are common in anorexia nervosa (AN), can predate illness onset, complicate renourishment, and persist after recovery. We explore how, through processes of aversive visceral conditioning, early GI pain and discomfort may increase vulnerability to AN in some individuals. Processes include enhanced preoccupation with the gut resulting from aversive visceral memories and disruptions in the typical acquisition of self-attunement when children learn to map and interpret interoceptive sensations and develop adaptive actions. We question whether a fear of weight gain, in some cases, may be an epiphenomenon of the recapitulation of actual or perceived GI symptoms that is especially relevant during puberty, especially in girls. This conceptualization has immediate clinical implications and offers ideas for future research. We propose that GI discomfort associated with renourishment may reignite prior aversive visceral experiences. We encourage development of a formulation that organizes the individual's current experience of the body with respect to these prior aversive experiences. Our conceptualization underscores the importance of assessment of GI experiences in individuals with AN; the examination of dietary strategies that minimize GI symptoms and enhance renourishment efficacy; and strategies that attempt to alter this aversive visceral conditioning by mapping sensations to meanings and adaptive actions.


Differential Timing and Coordination of Neurogenesis and Astrogenesis in Developing Mouse Hippocampal Subregions.
Neocortical development has been extensively studied and therefore is the basis of our understanding of mammalian brain development. One fundamental principle of neocortical development is that neurogenesis and gliogenesis are temporally segregated processes. However, it is unclear how neurogenesis and gliogenesis are coordinated in non-neocortical regions of the cerebral cortex, such as the hippocampus, also known as the archicortex. Here, we show that the timing of neurogenesis and astrogenesis in the Cornu Ammonis (CA) 1 and CA3 regions of mouse hippocampus mirrors that of the neocortex; neurogenesis occurs embryonically, followed by astrogenesis during early postnatal development. In contrast, we find that neurogenesis in the dentate gyrus begins embryonically but is a protracted process which peaks neonatally and continues at low levels postnatally. As a result, astrogenesis, which occurs during early postnatal development, overlaps with the process of neurogenesis in the dentate gyrus. During all stages, neurogenesis overwhelms astrogenesis in the dentate gyrus. In addition, we find that the timing of peak astrogenesis varies by hippocampal subregion. Together, our results show differential timing and coordination of neurogenesis and astrogenesis in developing mouse hippocampal subregions and suggest that neurogenesis and gliogenesis occur simultaneously during dentate gyrus development, challenging the conventional principle that neurogenesis and gliogenesis are temporally separated processes.


Craniofacial alterations following electrolytic lesions of the trigeminal motor nucleus in actively growing rats.
The objective of this study was to define further the role of the trigeminal motor nucleus (TMNu) in the postnatal ontogeny of the mammalian craniofacial skeleton. To that end, 42 male Sprague-Dawley rats underwent stereotaxic surgery at 40 days of age; 21 received small electrolytic lesions to their left-side TMNu (lesioned group) while 21 had TMNu stimulation with no actual electrolytic lesion produced (sham group). Seven rats from each group were killed at 28, 56, and 84 days postoperative to analyze trigeminal motoneuron (TMNe) count, masticatory muscle weight, and osteological growth vector data. At all three time periods, lesioned animals showed significant differences 1) between the surgery and nonsurgery sides, and 2) from sham animals. However, sham animals also demonstrated significant between-side differences for medial pterygoid muscle weight (56 days), mandibular height (28 and 56 days), and mandibular length data (84 days); these data suggested that even relatively slight damage to TMNe can create morphological changes within the craniofacial complex. Snout deviation in a lesioned rat towards the opposite side from all other lesioned animals was correlated with unique damage to its pontine reticular formation; this suggested that the observed morphological alterations of the craniofacial complex may have been due not only to TMNu damage, but also to changed expressions of the masticatory central pattern generator (CPG). Morphological alterations of the craniofacial skeleton resulting from lesions to the TMNu were likely due to changed neuromuscular activity patterns of the masticatory muscles and their biomechanical effects upon bone.


Preparedness of elderly long-term care facilities in HSE East for influenza outbreaks.
Abstract We assessed preparedness of HSE East elderly long-term care facilities for an influenza outbreak, and identified Public Health Department support needs. We surveyed 166 facilities based on the HSE checklist document for influenza outbreaks, with 58% response rate. Client flu vaccination rates were > 75%; leading barriers were client anxiety and consent issues. Target flu vaccine uptake of 40% in staff occurred in 43% of facilities and was associated with staff vaccine administration by afacility-attached GP (p = 0.035), having a facility outbreak plan (p = 0.013) and being anon-HSE run facility (p = 0.013). Leading barriers were staff personal anxiety (94%) and lack of awareness of the protective effect on clients (21%). Eighty-nine percent found Public Health helpful, and requested further educational support and advocacy. Staff vaccine uptake focus, organisational leadership, optimal vaccine provision models, outbreak plans and Public Health support are central to the influenza campaign in elderly long-term care facilities.


Cancer-associated mutations in chromatin remodeler hSNF5 promote chromosomal instability by compromising the mitotic checkpoint.
The hSNF5 subunit of human SWI/SNF ATP-dependent chromatin remodeling complexes is a tumor suppressor that is inactivated in malignant rhabdoid tumors (MRTs). Here, we report that loss of hSNF5 function in MRT-derived cells leads to polyploidization and chromosomal instability. Re-expression of hSNF5 restored the coupling between cell cycle progression and ploidy checkpoints. In contrast, cancer-associated hSNF5 mutants harboring specific single amino acid substitutions exacerbated poly- and aneuploidization, due to abrogated chromosome segregation. We found that hSNF5 activates the mitotic checkpoint through the p16INK4a-cyclinD/CDK4-pRb-E2F pathway. These results establish that poly- and aneuploidy of tumor cells can result from mutations in a chromatin remodeler.


[GallRiks 10 years. Quality registry for gallstone surgery have improved health care].
The Swedish Registry for cholecystectomy and endoscopic retrograde cholangiopancreatography (ERCP) (GallRiks) is a validated register with high coverage. The registry started on May 1, 2005 and serves as a base for audit on gallstone disease treatment and also provides a database for clinical research. The aim of this study is to present an overview of the clinical consequences and implementations in patient care that GallRiks research may have contributed to during a 10-year period. Results from studies on GallRiks data have reduced the use of antibiotic and thromboembolic prophylaxis as well as showed the importance of intraoperative cholangiography. Furthermore, the studies on GallRiks data have most probably changed the treatment strategies in ERCP. Studies on GallRiks data have changed and improved the management of patients in Sweden who undergo gallstone surgery or ERCP.


An Efficient Probe-Based Routing for Content-Centric Networking.
With the development of new technologies and applications, such as the Internet of Things, smart cities, 5G, and edge computing, traditional Internet Protocol-based (IP-based) networks have been exposed as having many problems. Information-Centric Networking (ICN), Named Data Networking (NDN), and Content-Centric Networking (CCN) are therefore proposed as an alternative for future networks. However, unlike IP-based networks, CCN routing is non-deterministic and difficult to optimize due to frequent in-network caching replacement. This paper presents a novel probe-based routing algorithm that explores real-time in-network caching to ensure the routing table storing the optimal paths to the nearest content provider is up to date. Effective probe-selections, Pending Interest Table (PIT) probe, and Forwarding Information Base (FIB) probe are discussed and analyzed by simulation with different performance measurements. Compared with the basic CCN, in terms of qualitative analysis, the additional computational overhead of our approach is O(NCS + Nrt + NFIB ∗ NSPT) and O(NFIB) on processing interest packets and data packets, respectively. However, in terms of quantitative analysis, our approach reduces the number of timeout interests by 6% and the average response time by 0.6 s. Furthermore, although basic CCN and our approach belong to the same Quality of Service (QoS) category, our approach outperforms basic CCN in terms of real values. Additionally, our probe-based approach performs better than RECIF+PIF and EEGPR. Owing to speedup FIB updating by probes, our approach provides more reliable interest packet routing when accounting for router failures. In summary, the results demonstrate that compared to basic CCN, our probe-based routing approach raises FIB accuracy and reduces network congestion and response time, resulting in efficient routing.


Endoscopic Mucosal Resection of a Proximal Esophageal Pyogenic Granuloma.
Pyogenic Granuloma (PG), also known as lobular capillary hemangioma, is usually seen as a polypoid red lesion found on the skin or the mucosal surface of the oral cavity. PG of the gastrointestinal tract is rare, in particular involving the esophagus, only 14 cases have been reported in the English literature. We present an 80-year-old male who underwent endoscopy for evaluation of dysphagia and was found to have a single, red, bilobed 10 mm polyp with adherent white exudate approximately 19 cm from the incisors. Endoscopic ultrasound was performed with a 20 mHz miniprobe which showed the lesion contained to the mucosal layer with no muscularis propria invasion. A decision was made to perform endoscopic mucosal resection (EMR). A mixture of saline and methylene blue was injected into the submucosal plane to raise the lesion with subsequent successful mucosal hot snare resection. The resection defect was then approximated and closed with a hemostatic clip to prevent bleeding. Pathology of the specimen revealed small capillary vessels growing in a lobular architecture with an edematous stroma and a florid inflammatory infiltrate representing a pyogenic granuloma. EMR allows for an en bloc resection of mucosal lesions with tumor-free margins, thereby providing both diagnostic and prognostic information. Comparing EMR with the novel technique of endoscopic submucosal dissection (ESD), the incidence of bleeding and perforation is much lower; making EMR the best and safest resection option for this rare hemangioma. In this case, we demonstrate that EMR is a safe technique in removing a pyogenic granuloma in the esophagus.


Rubella reimmunization: comparative analysis of the immunoglobulin G response to rubella virus vaccine in previously seronegative and seropositive individuals.
Rubella virus (RV)-specific immunoglobulin G (IgG) antibodies were studied in military recruits undergoing unselected immunization with live attenuated measles, mumps, and rubella virus (MMR) vaccine. Three different whole-RV enzyme immunoassays (EIAs) and an epitope-specific EIA with a synthetic peptide (BCH-178c) representing a heutralization domain on the RV E1 envelope protein were used. Before vaccination, 84.2, 87.7, and 84.5% of the subjects tested (n = 399) were found to be seropositive (> 10 IU/ml or assay equivalent) by the three whole-RV EIAs, respectively, while only 82.5% were seropositive by the BCH-178c EIA. Although prevaccination seropositivity rates were similar for the whole-RV EIAs (sensitivity, 94 to 100%), many sera considered seropositive by the whole-RV EIAs had E1 peptide EIA antibody levels of < 10 IU/ml (sensitivity, 77.4 to 80.7%). One month after vaccination, 97.8, 97.2, and 93.5% of the subjects who were followed (n = 356) were seropositive by the three whole-RV EIAs, respectively, while 89% had BCH-178c peptide-specific IgG titers of > 10 IU/ml. After vaccination, depending on the assay used, up to 20.6% of initially seropositive individuals exhibited a greater than fourfold increase in RV-specific IgG, while up to 47.3% showed a greater than twofold increase. Increased antibody titers after vaccination (seroboosting) were most frequently associated with low levels of BCH-178c peptide-specific IgG before vaccination. RV protein-specific IgG was also studied by immunoblot assays in a subset (n = 56) of individuals receiving the MMR vaccine. Of these, 89.4 and 91.1% exhibited RV protein (E1, E2, and C protein)-specific IgG before and after vaccination, respectively. Seroboosting (two- to fourfold increase in EIA titers of individuals seropositive by the whole-RV EIA before vaccination) was usually accompanied by a shift in the IgG immunoblot pattern from a single (E1) to multiple (E1-E1, E1-C, or E1-E2-C) specificities, suggesting exposure of new epitopes as a result of viral replication.


Absence of changes in airway responsiveness during the menstrual cycle.
The effect of sex hormones on airway function has not been well studied in spite of much evidence to suggest that they are important. We asked if the normal physiologic variation in hormone levels during the menstrual cycle resulted in changes in airway responsiveness and pulmonary function that were not clinically apparent. Nine women with asthma and with normal menstrual cycles but not taking systemic asthma medication were asked to chart temperatures, asthma attacks, and use of asthma medication for four menstrual cycles. We measured baseline spirograms, skin and airway responsiveness to histamine, and serum levels for estradiol, progesterone, and testosterone on approximately day 7 and day 24 of two consecutive cycles. None of the women reported cyclic asthma symptoms, and review of subjects' charts demonstrated no menstrual variation in asthma attacks or use of asthma medications. We found no differences in forced vital capacity or FEV1 early compared to late in the menstrual cycle. Neither did we find a change in airway responsiveness, as indicated by the histamine dose causing a 15% fall in FEV1 or a 35% fall in specific airway conductance. Skin responsiveness as indicated by the wheal response to intradermal histamine was also unchanged. We conclude that physiologic changes in hormone levels during the menstrual cycle are not in themselves associated with changes in airway or skin responsiveness to histamine.


Vero cells infected with vaccinia viruses expressing Japanese encephalitis virus envelope protein induce polykaryocyte formation under neutral conditions.
Flavivirus membranes fuse with cellular membranes by low pH-induced mechanisms. Although Japanese encephalitis virus (JEV) has similar mechanisms, fusion induced under neutral conditions has been observed. We report herein polykaryocyte formation using Vero cells infected with recombinant vaccinia viruses, vP829 expressing JEV premembrane (prM) and envelope (E), or vP555 expressing prM, E, and the nonstructural proteins NS1 and NS2A. Polykaryocytes were detected under pH 7.0 as early as 9 h after infection. Higher fusion indices were shown with vP555 than vP829. A monoclonal antibody to E suppressed vP829/vP555-induced polykaryocyte formation. Polykaryocytes were also formed under alkaline conditions (pH 8.0).


[Morphology of "resuscitation-induced encephalopathy"].
Two groups of changes in the cerebral substance were revealed by histological examinations of the central nervous system in a case of clinical death followed by respiratory resuscitation for 12 days. Changes of the 1st group consisted in foci of incomplete necrosis in the stage of organization in the cortex and dentate nuclei of the cerebellum, lower olives of the medulla, Zommer sector of the Ammon horn, and caudate nuclei. Their development is due to ischemia and circulatory hypoxia in the early resuscitation period. Changes of the 2nd group included acute disorders of microcirculation and extensive protein and carbohydrate dystrophy of nerve cells of the cortex and subcortical ganglia in the form of hyperchromatosis hydropic degeneration. "alzheimerization", accumulation of glycogen in the cytoplasm of neurons and astrocytes. The degenerative changes were combined with signs of gradual death of neurons and pseudolaminar losses in the cerebral cortex. Changes of the 2nd group may be classified as the so-called secondary nor delayed cerebral hypoxia in the development of which microcirculatory disorders are of importance. The observed morphological changes in the brain after clinical death and prolonged respiratory resuscitation represent morphological expression of "resuscitation-conditioned encephalopathy".


Long-lasting increase in the set point for cocaine self-administration after escalation in rats.
When access time to a continuous schedule of drug self-administration is restricted, animals tend to limit intake to a certain level over time and across doses. This observation suggests an endogenous constraint or set point that determines the individual's preferred level of pharmacological effects. To assess whether the transition to increased levels of drug intake is associated with a change in set point. Two groups of rats were trained on a 1-h continuous schedule of cocaine self-administration (250 microg/injection), after which access to cocaine was increased to 6 h in one group (Long Access or LgA rats) or kept to 1 h in the other group (Short Access or ShA rats). After 22 sessions on this regimen, different doses of cocaine were tested (31.25, 62.5, 125, and 250 microg/injection). For each dose, the post-response time-out period was reduced to 4 s to reduce any temporal limitations on self-injections and subjects were tested several times. In LgA rats, the first hour intake escalated over time and eventually reached a level 200% greater than that of ShA rats. Though all rats maintained relatively constant intake across doses, LgA rats took nearly two times as much cocaine than ShA rats. When access to cocaine for LgA rats was reduced to 1 h, intake returned very slowly toward pre-escalation levels but was still elevated even after 2 months of reduced availability. These data suggest that the transition to escalated levels of intake is associated with a long-lasting change in cocaine set point.


Chelator PBT2 Forms a Ternary Cu2+ Complex with β-Amyloid That Has High Stability but Low Specificity.
The metal chelator PBT2 (5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline) acts as a terdentate ligand capable of forming binary and ternary Cu2+ complexes. It was clinically trialed as an Alzheimer's disease (AD) therapy but failed to progress beyond phase II. The β-amyloid (Aβ) peptide associated with AD was recently concluded to form a unique Cu(Aβ) complex that is inaccessible to PBT2. Herein, it is shown that the species ascribed to this binary Cu(Aβ) complex in fact corresponds to ternary Cu(PBT2)NImAβ complexes formed by the anchoring of Cu(PBT2) on imine nitrogen (NIm) donors of His side chains. The primary site of ternary complex formation is His6, with a conditional stepwise formation constant at pH 7.4 (Kc [M-1]) of logKc = 6.4 ± 0.1, and a second site is supplied by His13 or His14 (logKc = 4.4 ± 0.1). The stability of Cu(PBT2)NImH13/14 is comparable with that of the simplest Cu(PBT2)NIm complexes involving the NIm coordination of free imidazole (logKc = 4.22 ± 0.09) and histamine (logKc = 4.00 ± 0.05). The 100-fold larger formation constant for Cu(PBT2)NImH6 indicates that outer-sphere ligand-peptide interactions strongly stabilize its structure. Despite the relatively high stability of Cu(PBT2)NImH6, PBT2 is a promiscuous chelator capable of forming a ternary Cu(PBT2)NIm complex with any ligand containing an NIm donor. These ligands include histamine, L-His, and ubiquitous His side chains of peptides and proteins in the extracellular milieu, whose combined effect should outweigh that of a single Cu(PBT2)NImH6 complex regardless of its stability. We therefore conclude that PBT2 is capable of accessing Cu(Aβ) complexes with high stability but low specificity. The results have implications for future AD therapeutic strategies and understanding the role of PBT2 in the bulk transport of transition metal ions. Given the repurposing of PBT2 as a drug for breaking antibiotic resistance, ternary Cu(PBT2)NIm and analogous Zn(PBT2)NIm complexes may be relevant to its antimicrobial properties.


Formation and destruction of CH2O in the exhaust system of a gas engine.
A computational study of chemical reactions occurring in the exhaust system of natural gas engines has been conducted, emphasizing the formation and destruction of formaldehyde. The modeling was based on a detailed reaction mechanism, developed for describing oxidation of C1-C2 hydrocarbons and formaldehyde. The mechanism was validated against data from laboratory flow reactors and from the exhaust system of a full-scale gas engine. A parametric study of the exhaust system chemistry was performed, investigating the effect of temperature, stoichiometry, pressure, and exhaust gas composition. The results indicate a complex interaction between unburned hydrocarbons (UHC), formaldehyde, and nitrogen oxides. Above 850 K, partial oxidation of unburned hydrocarbons may occur, resulting in net formation or net destruction of CH2O depending on the unburned hydrocarbons/CH2O ratio and the reaction conditions. At the typical unburned hydrocarbons/CH2O ratio of 1.0-1.5% for gas engines, net formaldehyde formation may occur in the exhaust system if temperatures above 850 K are reached.


Occipital and Cerebellar Theta Burst Stimulation for Mal De Debarquement Syndrome.
Individuals with Mal de Debarquement syndrome (MdDS) experience persistent oscillating vertigo lasting for months or years. Transcranial magnetic stimulation (TMS) can modulate the motion perception of MdDS. Twenty-six TMS naive individuals received single administrations of continuous theta burst stimulation (cTBS) over the occipital cortex, cerebellar vermis, and lateral cerebellar hemisphere, in randomized order. A 0-100 point Visual Analogue Scale was used to assess acute changes in oscillating vertigo severity after each session. Repeated treatments were given over the target that led to the most acute reduction in symptoms. All treatments were performed with neuronavigation using the participant's own brain MRI. The Dizziness Handicap Inventory (DHI), MdDS Balance Rating Scale (MBRS), and Hospital Anxiety and Depression Scale (HADS) were assessed weekly at four pretreatment and six posttreatment time points. Twenty participants chose either the occipital cortex (11) or cerebellar vermis (9) targets as most effective in reducing the oscillating vertigo; one chose lateral cerebellar hemisphere; five chose none. After 10 to 12 sessions of 1,200 pulses over the target of choice, 19 of 25 treatment completers noted ≥ 25% reduction, 12 of 25 ≥50% reduction, and 8 of 25 ≥75% reduction in oscillating vertigo intensity. A one-way repeated measures ANOVA of DHI, MBRS, and HADS scores before and after treatment showed significant reductions in DHI, MBRS, and the HADS Anxiety subscore immediately after treatment with most improvement lasting through posttreatment week 6. There were no significant Depression subscore changes. Participants who had chosen vermis stimulation had comparatively worse balance at baseline than those who had chosen occipital cortex stimulation. cTBS over either the occipital cortex or cerebellar vermis is effective in reducing the oscillating vertigo of MdDS acutely and may confer long-term benefits. Sustained improvement requires more frequent treatments.


Protective effect of tetramethylpyrazine and salvianolic acid B on apoptosis of rat cerebral microvascular endothelial cell under high shear stress.
Apoptosis induced by high shear stress has been reported for the dysfunction of various vascular endothelial cells. We investigated the protective effects of tetramethylpyrazine (TMP) and salvianolic acid B (SAB) from Chinese medicine on the shear-induced early and late stages of apoptosis in cultured rat cerebral microvascular endothelial cells (rCMECs) under pathological high shear stress. Near-confluent cultures of rCMECs were pretreated with TMP or SAB and their combinational dosages, and exposed to high shear stress generated by a rheometer. Apoptotic death rate of rCMECs was assessed by immunofluorescence microscopy of Annexin V-FITC and propidium iodide (PI). We found that early and late stage apoptosis occurred at 3.0 Pa for a short duration of 450 sec but did not occur at 1.5 Pa. SAB inhibited the cells from apoptosis at concentrations from 10 microM to 20 microM in a dose-dependent manner, while effect of TMP at 0.37 mM and 0.73 mM did not significantly differ. Moreover, the combined use of TMP and SAB had synergistic anti-apoptotic effects (P<0.01). The results indicate that the anti-apoptotic effect of TMP and SAB on rheologically induced endothelial injury is likely involved in their efficacy.


Comparative outcomes of total hip and knee arthroplasty: a prospective cohort study.
The comparative outcome of primary hip and knee arthroplasty is not well understood. This study aimed to investigate the outcome and satisfaction of these procedures and determine predictive models for 1 year patient outcome with a view to informing surgical management and patient expectations. Prospective cohort study of all primary hip and knee arthroplasty procedures performed at the Royal Infirmary of Edinburgh between January 2006 and November 2008. General health (SF-12) and joint specific function (Oxford Score) was assessed pre-operatively and at 6 and 12 months post-operatively. Patient satisfaction was assessed at 12 months. 1410 total hip arthroplasty (THA) and 1244 total knee arthroplasty (TKA) procedures were assessed. Oxford Score improved by 4.9 points more in THA patients than in TKA patients. SF-12 physical scores were on average 2.7 points greater in the THA patients at one year. Satisfaction was also greater (91%) following THA compared with TKA (81%). Regression modelling was not able to predict individual patient outcome; however, mean pre-operative Oxford Scores were found to be strong predictors of mean post-operative Oxford Scores for each procedure. Age, gender and pre-operative general health scores did not influence these models. Both THA and TKA confer substantial improvement in patient outcome; however, greater joint specific, general health and satisfaction scores are reported following THA. This difference is physical in nature. Regression models are presented that can be applied to predict mean hip/knee arthroplasty outcome based on preoperative values.


Hypoxia and the energy charge of the cerebral adenylate pool.
A brief period of anoxia in vivo causes a transitory decrease in the size of the adenylate pool in the rat brain. This is probably caused by feedback inhibition by AMP of adenine nucleotide synthesis. Exposing rats to various degrees of hypoxia suggests that the sensitivity of the brain to lack of O(2) results from the brain's limited ability to maintain an adequate energy charge in unfavourable circumstances.


A Tertiary Care Center's Experience with Clinicopathological Characteristics of Gallbladder Carcinoma in Our Population.
Gallbladder cancer (GBC) is the most common malignant biliary tract tumor with the shortest survival from the time of diagnosis. This poor prognosis is due to the destructive biologic behavior of GBC, lack of sensitive screening tests for early detection, and vague nature of first presentation. Here in this study, we will evaluate the baseline characteristics of the patients presenting with gallbladder carcinoma in our population. This retrospective study was conducted in the Department of Gastroenterology at Sindh Institute of Urology and Transplantation (SIUT), Karachi. Patient data were compiled and composed from the in-patient health records, radiology, and operational records. Those patients with suspicion of GBC, but negative at histology, or patients having inconclusive radiologic findings, were excluded. Baseline characteristics were recorded. Results were presented as means ± SD for quantitative data or as numbers with percentages for qualitative data. Continuous variables were analyzed using the Student's t-test, while categorical variables were analyzed using the Chi-square test. A p-value of <0.05 was considered statistically significant. A total of 162 patients were included in our study. Among them, 101 (62.3%) were females. Hypertension was the most common comorbid illness noted in 29 (17.9%) patients while 91 (56.2%) patients had no concurrent comorbidities. Most common risk factor for carcinoma of gallbladder was gallstones seen in 106 (65.1%) patients. The most common presenting complaint was combination of obstructive jaundice, weight loss with right hypochondrial pain seen in 66 (40.7%) patients. On CT abdomen, direct liver infiltration without lymphovascular invasion was noted in 77 (47.5%) patients followed by liver infiltration along with lymphovascular invasion in 26 (16%) patients and distant metastasis in 24 (14.8%) patients. On gallbladder (GB) mass biopsy, 58 (35.8%) patients had well-differentiated, 46 (28.4%) had moderately differentiated, while 33 (20.4%) had poorly differentiated adenocarcinoma. Of 162 patients, 103 (63.6%) patients underwent endoscopic retrograde cholangiopancreatography (ERCP). The most common finding on ERCP was proximal common bile duct (CBD) stricture with intrahepatic biliary system dilatation which was noted in 95 (58.6%) patients. Percutaneous transhepatic cholangiography (PTC) was performed only in 9 (5.6%) patients. Seventeen (10.5%) patients were managed by simple cholecystectomy, 39 (24.1%) patients underwent extended cholecystectomy, 14 (8.6%) patients underwent chemotherapy, while 102 (56.8%) patients were given palliative management. When followed for 1 year, 101 (62.3%) patients died within 6 months. The baseline characteristics, biopsy findings, modes of treatment, and rates of 1 year mortality were studied in patients with gallbladder carcinoma in our population. Advanced age, high white blood cell counts, and serum bilirubin at presentation with low lymphocyte count and presence of comorbid illnesses were the factors independently associated with increased mortality in patients with gallbladder carcinoma. However, further studies with large sample size and stratification with respect to age, gender, and different variables can be done in terms of mortality in patients with gallbladder carcinoma. Akbar N, Yaseen T, Muhammad A, et al. A Tertiary Care Center's Experience with Clinicopathological Characteristics of Gallbladder Carcinoma in Our Population. Euroasian J Hepato-Gastroenterol 2022;12(1):35-39.


Remote origins of tail-anchored proteins.
C-tail-anchored (TA) proteins constitute a heterogeneous group of membrane proteins that are inserted into membranes by unique post-translational mechanisms and that play key roles within cells. During recent years, bioinformatic screens on eukaryotic genomes have helped to obtain comprehensive pictures of the number, intracellular distribution and functions of TA proteins, but similar screens had not yet been carried out on prokaryotic cells. Here, we report the results of a bioinformatic screen of the genomes of two bacteria and one archeon. We find that all three of these prokaryotes contain TA proteins in proportions approaching those found in eukaryotic cells, indicating that this protein group is present in all three domains of life. Although some of our hits correspond to proteins of unknown function, others are enzymes with hydrophobic substrates or have functions carried out at the inner face of the cytoplasmic membrane. To generate hypotheses on the insertion mechanisms of prokaryotic TA proteins, we compared the sequences of the prokaryotic and eukaryotic versions of Asna1/Trc40/GET3, a cytosolic ATPase that plays a key role in TA protein post-translational delivery to membranes in eukaryotic cells. We found that hydrophobic residues involved in TA binding by the eukaryotic chaperone (Mateja et al., Nature 2009;461:361-366) are generally replaced with equally hydrophobic amino acids in the archeal homologue (ArsA), whereas this is not the case for the bacterial protein. Thus, eukaryotes may have inherited the GET3 targeting pathway from our archeal ancestor, while the bacterial homologue may be exclusively dedicated to heavy metal resistance.


Characterization of delta9-tetrahydrocannabinol and anandamide antinociception in nonarthritic and arthritic rats.
Little is known about the effectiveness of delta9-tetrahydrocannabinol (THC) and anandamide in blocking mechanical nociception. Even less is known about their antinociceptive efficacy in chronic inflammatory arthritis induced by Freund's complete adjuvant. The hypothesis was tested that THC and anandamide elicit antinociception in the paw pressure test, and that arthritic rats would exhibit a different response. In nonarthritic rats, THC- and anandamide-induced antinociception lasted 90 min and 15 min, respectively, while antinociception lasted 90 min and 30 min, respectively, in arthritic rats. Area under the curve calculations revealed no effect of arthritis on THC- and anandamide-induced antinociception. Another hypothesis was that paw pressure thresholds in arthritic rats reflect chronic cannabinoid receptor stimulation due to elevations in free anandamide levels. Yet, the CB1 receptor antagonist SR141716A failed to alter paw pressure thresholds in either nonarthritic or arthritic rats. Further investigation revealed that SR141716A significantly blocked THC antinociception, with no effect on anandamide. Thus, anandamide's effects did not result from CB1 receptor stimulation, and any potential contribution of endogenous anandamide in arthritis was not revealed. Finally, THC and anandamide appear to release an as yet unknown endogenous opioid, because naloxone significantly blocked their effects. This study indicates that anandamide and THC may act at different receptor sites to modulate endogenous opioid levels in mechanical nociception.


Querying pathways in protein interaction networks based on hidden Markov models.
High-throughput techniques for measuring protein interactions have enabled the systematic study of complex protein networks. Comparing the networks of different organisms and identifying their common substructures can lead to a better understanding of the regulatory mechanisms underlying various cellular functions. To facilitate such comparisons, we present an efficient framework based on hidden Markov models (HMMs) that can be used for finding homologous pathways in a network of interest. Given a query path, our method identifies the top k matching paths in the network, which may contain any number of consecutive insertions and deletions. We demonstrate that our method is able to identify biologically significant pathways in protein interaction networks obtained from the DIP database, and the retrieved paths are closer to the curated pathways in the KEGG database when compared to the results from previous approaches. Unlike most existing algorithms that suffer from exponential time complexity, our algorithm has a polynomial complexity that grows linearly with the query size. This enables the search for very long paths with more than 10 proteins within a few minutes on a desktop computer. A software program implementing the algorithm is available upon request from the authors.


Fecal Microbiota Transplantation Eliminates Clostridium difficile in a Murine Model of Relapsing Disease.
Recurrent Clostridium difficile infection (CDI) is of particular concern among health care-associated infections. The role of the microbiota in disease recovery is apparent given the success of fecal microbiota transplantation (FMT) for recurrent CDI. Here, we present a murine model of CDI relapse to further define the microbiota recovery following FMT. Cefoperazone-treated mice were infected with C. difficile 630 spores and treated with vancomycin after development of clinical disease. Vancomycin treatment suppressed both C. difficile colonization and cytotoxin titers. However, C. difficile counts increased within 7 days of completing treatment, accompanied by relapse of clinical signs. The administration of FMT immediately after vancomycin cleared C. difficile and decreased cytotoxicity within 1 week. The effects of FMT on the gut microbiota community were detectable in recipients 1-day posttransplant. Conversely, mice not treated with FMT remained persistently colonized with high levels of C. difficile, and the gut microbiota in these mice persisted at low diversity. These results suggest that full recovery of colonization resistance against C. difficile requires the restoration of a specific community structure.


West Nile Virus Infection Blocks Inflammatory Response and T Cell Costimulatory Capacity of Human Monocyte-Derived Dendritic Cells.
West Nile virus (WNV) is a neurotropic flavivirus and the leading cause of mosquito-borne encephalitis in the United States. Recent studies in humans have found that dysfunctional T cell responses strongly correlate with development of severe WNV neuroinvasive disease. However, the contributions of human dendritic cells (DCs) in priming WNV-specific T cell immunity remains poorly understood. Here, we demonstrate that human monocyte derived DCs (moDCs) support productive viral replication following infection with a pathogenic strain of WNV. Antiviral effector gene transcription was strongly induced during the log phase of viral growth, while secretion of type I interferons (IFN) occurred with delayed kinetics. Activation of RIG-I like receptor (RLR) or type I IFN signaling prior to log phase viral growth significantly diminished viral replication, suggesting that early activation of antiviral programs can block WNV infection. In contrast to the induction of antiviral responses, WNV infection did not promote transcription or secretion of proinflammatory (interleukin-6 [IL-6], granulocyte-macrophage colony-stimulating factor [GM-CSF], CCL3, CCL5, and CXCL9) or T cell modulatory (IL-4, IL-12, and IL-15) cytokines. There was also minimal induction of molecules associated with antigen presentation and T cell priming, including the costimulatory molecules CD80, CD86, and CD40. Functionally, WNV-infected moDCs dampened allogenic CD4 and CD8 T cell activation and proliferation. Combining these observations, we propose a model whereby WNV subverts human DC activation to compromise priming of WNV-specific T cell immunity.IMPORTANCE West Nile virus (WNV) is an encephalitic flavivirus that remains endemic in the United States. Previous studies have found dysfunctional T cell responses correlate to severe disease outcomes during human WNV infection. Here, we sought to better understand the ability of WNV to program human dendritic cells (DCs) to prime WNV-specific T cell responses. While productive infection of monocyte-derived DCs activated antiviral and type I interferon responses, molecules associated with inflammation and programming of T cells were minimally induced. Functionally, WNV-infected DCs dampened T cell activation and proliferation during an allogeneic response. Combined, our data support a model whereby WNV infection of human DCs compromises WNV-specific T cell immunity.


Cytoprotective effects of 5 benzophenones and a xanthone from Hypericum annulatum in models of epirubicin-induced cytotoxicity: SAR-analysis and mechanistic investigations.
A new benzophenone O-glucoside neoannulatophenonoside (1) together with the known pinocembrin-7-O-glucoside were isolated from the aerial parts of Hyperium annulatum Moris (Guttiferae). The former was identified as 3',5',6-trihydroxy-4-methoxybenzophenone-2-O-beta-D-glucopyranoside by means of chemical and physical evidence. The cytoprotective effects of the new compound together with the previously isolated from this species hypericophenonoside (2), annulatophenone (3), annulatophenonoside (4), acetylannulatophenonoside (5) and 1,3,7-trihydroxyxanthone (6) were evaluated in a model of epirubicin-induced cellular toxicity in K-562 cells. While the benzophenone O-glycosides 1, 2, 4 and 5 exerted substantial cytoprotective effects against the epirubicin cytotoxicity in K-562 cells the aglycones 3 and 6 lacked any significant cytoprotective activity. Biochemical investigations aimed at evaluating the free-radical scavenging activity of the tested compounds as well as their effects on the cellular glutathione stores were carried out as well, aiming at unravelling the mechanisms of cytoprotection. Finally, the ability of 1, 4 and 5 to ameliorate epirubicin-induced anticlonogenic effects on bone marrow cells colony forming units, in vitro were also evaluated. Taken together, the experimental data indicate that the benzophenone glycosides isolated from H. annulatum have a substantial cytoprotective potential against the toxic effects induced by epirubicin and necessitates further detailed pharmacological evaluation of these compounds as possible chemoprotective/radioprotective agents.


The outcome of terminal liver cirrhosis patients requiring mechanical ventilation.
Liver cirrhosis is a common problem in Taiwan. Without liver transplantation, patients with end-stage liver cirrhosis frequently die of various complications and often require mechanical ventilatory support prior to their death. The purpose of this study was to investigate the in-hospital and short-term outcome of such patients. A retrospective review of 47 medical records of mechanically ventilated patients with primary diagnosis of liver cirrhosis, admitted from November 1990 to September 1993, allowed analysis of disease course and outcome for these patients. Among the 47 patients, a Child-Pugh's class A patient receiving temporary mechanical ventilation (MV) after elective devascularization surgery was excluded from analysis. Among the remaining medically treated 46 patients, there were 33 Child-Pugh's class C patients, 9 class B patients and 4 unclassified patients. Primary reasons for endotracheal intubation and MV included airway protection, acute respiratory distress and shock. Of these patients, shock was present in 39 cases, upper gastrointestinal bleeding in 34, systemic inflammatory response syndrome in 32, renal insufficiency with creatinine greater than 1.3 mg/dl in 32, bacteremia in 14, parenchymal lung disease in 16, spontaneous bacterial peritonitis in 10, and intracerebral hemorrhage in 1 during their hospital courses. Thirty-eight patients (83%) died within 72 hours after being placed on mechanical ventilation. Patients requiring MV with complications of bacteremia, parenchymal lung disease or renal insufficiency during hospitalization were found to have a 100% mortality rate. Successful weaning occurred in only 3 of 46 patients (8.7%). Of these three, two (4.3%) went home alive and had survived over six months after discharge. It was concluded that cirrhotic patients requiring MV have an extremely poor prognosis. Patients and their families should be fully informed of the prognosis, and routine use of MV should not be encouraged in patients with terminal stage liver disease.


Proceedings of the 2022 UAB CRRT Academy: Non-Invasive Hemodynamic Monitoring to Guide Fluid Removal with CRRT and Proliferation of Extracorporeal Blood Purification Devices.
In 2022, we celebrated the 15th anniversary of the University of Alabama at Birmingham (UAB) Continuous Renal Replacement Therapy (CRRT) Academy, a 2-day conference attended yearly by an international audience of over 100 nephrology, critical care, and multidisciplinary trainees and practitioners. This year, we introduce the proceedings of the UAB CRRT Academy, a yearly review of select emerging topics in the field of critical care nephrology that feature prominently in the conference. First, we review the rapidly evolving field of non-invasive hemodynamic monitoring and its potential to guide fluid removal by renal replacement therapy (RRT). We begin by summarizing the accumulating data associating fluid overload with harm in critical illness and the potential for harm from end-organ hypoperfusion caused by excessive fluid removal with RRT, underscoring the importance of accurate, dynamic assessment of volume status. We describe four applications of point-of-care ultrasound used to identify patients in need of urgent fluid removal or likely to tolerate fluid removal: lung ultrasound, inferior vena cava ultrasound, venous excess ultrasonography, and Doppler of the left ventricular outflow track to estimate stroke volume. We briefly introduce other minimally invasive hemodynamic monitoring technologies before concluding that additional prospective data are urgently needed to adapt these technologies to the specific task of fluid removal by RRT and to learn how best to integrate them into practical fluid-management strategies. Second, we focus on the growth of novel extracorporeal blood purification devices, starting with brief reviews of the inflammatory underpinnings of multiorgan dysfunction and the specific applications of pathogen, endotoxin, and/or cytokine removal and immunomodulation. Finally, we review a series of specific adsorptive technologies, several of which have seen substantial clinical use during the COVID-19 pandemic, describing their mechanisms of target removal, the limited existing data supporting their efficacy, ongoing and future studies, and the need for additional prospective trials.


Experiences and Needs of Children Who Have a Parent with Young Onset Dementia: A Meta-ethnographic Review.
Objectives: The aim of the present review was to critically evaluate empirical evidence regarding the needs and experiences of children who have a parent with young onset dementia (YOD).Methods: A systematic search of five databases was carried out and the resulting 16 studies were reviewed using a meta-ethnographic approach.Results: Three main themes arose from the data: 'Dementia Impact", which describes how the child experiences the deterioration in their parent and changes to relationships; "Psychological Impact", comprising the child's private emotional experiences and the psychological consequences of changes in roles; and "Practical Impact", detailing the ways in which children adapt their lives in response to parental YOD, and children's needs for support.Conclusions: These themes synthesize the existing literature and produce a line of argument explaining the experience of children whose parents have YOD.Clinical Implications: Information and policies regarding YOD should take account of the experiences of patients' children and should include targeted support for children of parents with YOD.


Methods for evaluating image quality in magnetic resonance imaging.
A quality control program for magnetic resonance imaging is necessary to evaluate the major imaging characteristics and to monitor image performance constancy. The methods used to evaluate and monitor imaging quality characteristics and image quality variables are discussed. These imaging characteristics and methods may be utilized by the trained radiology technologist to assist in the continuation of a quality control program for magnetic resonance imaging.


Commercial weight-loss diets, greenhouse gas emissions and freshwater consumption.
Weight-loss attempts are widespread in the United States, with many using commercial weight-loss diet plans for guidance and support. Accordingly, dietary suggestions within these plans influence the nation's food-related environmental footprint. We modelled United States (US) per capita greenhouse gas emissions (GHGe) and water footprints associated with seven commercial weight-loss diets, the US baseline, and selected other dietary patterns. We characterised consumption in commercial weight-loss diets both via modelling from provided guidelines and based on specific foods in 1-week meal plans. Cradle-to-farmgate GHGe and water footprints were assessed using a previously developed model. GHGe results were compared to the EAT-Lancet 2050 target. Water footprints were compared to the US baseline. Weight-loss diets had GHGe footprints on average 4.4 times the EAT-Lancet target recommended for planetary health (range: 2.4-8.5 times). Bovine meat was by far the largest contributor of GHGe in most diets that included it. Three commercial diets had water footprints above the US baseline. Low caloric intake in some diets compensated for the relative increases in GHGe- and water-intensive foods. Dietary patterns suggested by marketing materials and guidelines from commercial weight-loss diets can have high GHGe and water footprints, particularly if caloric limits are exceeded. Commercial diet plan guidance can be altered to support planetary and individual health, including describing what dietary patterns can jointly support environmental sustainability and weight loss.