Sentinel Surveillance System Implementation and Evaluation for SARS-CoV-2 Genomic Data, Washington, USA, 2020-2021.

Genomic data provides useful information for public health practice, particularly when combined with epidemiologic data. However, sampling bias is a concern because inferences from nonrandom data can be misleading. In March 2021, the Washington State Department of Health, USA, partnered with submitting and sequencing laboratories to establish sentinel surveillance for SARS-CoV-2 genomic data. We analyzed available genomic and epidemiologic data during presentinel and sentinel periods to assess representativeness and timeliness of availability. Genomic data during the presentinel period was largely unrepresentative of all COVID-19 cases. Data available during the sentinel period improved representativeness for age, death from COVID-19, outbreak association, long-term care facility-affiliated status, and geographic coverage; timeliness of data availability and captured viral diversity also improved. Hospitalized cases were underrepresented, indicating a need to increase inpatient sampling. Our analysis emphasizes the need to understand and quantify sampling bias in phylogenetic studies and continue evaluation and improvement of public health surveillance systems.

Refugees, trade, and FDI.

Humanitarian policies aimed at welcoming forced migrants may yield unexpected economic dividends. This article focuses on the trade and investment links forged by refugees between their countries of resettlement and the origins they fled. We document how such immigrant-links differ in the case of refugees, focusing on why their opportunity sets might differ and the difficulties in establishing economic connections against a backdrop of civil conflict and political unrest. We conclude by discussing a range of policies aimed at engaging refugee diasporas to foster development at refugees' origins.

International Study of the Epidemiology of Paediatric Trauma: PAPSA Research Study.

OBJECTIVES: Trauma is a significant cause of morbidity and mortality worldwide. The literature on paediatric trauma epidemiology in low- and middle-income countries (LMICs) is limited. This study aims to gather epidemiological data on paediatric trauma. METHODS: This is a multicentre prospective cohort study of paediatric trauma admissions, over 1 month, from 15 paediatric surgery centres in 11 countries. Epidemiology, mechanism of injury, injuries sustained, management, morbidity and mortality data were recorded. Statistical analysis compared LMICs and high-income countries (HICs). RESULTS: There were 1377 paediatric trauma admissions over 31 days; 1295 admissions across ten LMIC centres and 84 admissions across five HIC centres. Median number of admissions per centre was 15 in HICs and 43 in LMICs. Mean age was 7 years, and 62% were boys. Common mechanisms included road traffic accidents (41%), falls (41%) and interpersonal violence (11%). Frequent injuries were lacerations, fractures, head injuries and burns. Intra-abdominal and intra-thoracic injuries accounted for 3 and 2% of injuries. The mechanisms and injuries sustained differed significantly between HICs and LMICs. Median length of stay was 1 day and 19% required an operative intervention; this did not differ significantly between HICs and LMICs. No mortality and morbidity was reported from HICs. In LMICs, in-hospital morbidity was 4.0% and mortality was 0.8%. CONCLUSION: The spectrum of paediatric trauma varies significantly, with different injury mechanisms and patterns in LMICs. Healthcare structure, access to paediatric surgery and trauma prevention strategies may account for these differences. Trauma registries are needed in LMICs for future research and to inform local policy.

Glucocorticosteroids for infants with biliary atresia following Kasai portoenterostomy.

BACKGROUND: Biliary atresia is a life-threatening disease characterised by progressive destruction of both intra- and extra-hepatic biliary ducts. The mainstay of treatment is Kasai portoenterostomy, as soon as the disease has been confirmed. Glucocorticosteroids are steroid hormones which act on the glucocorticoid receptor and have a range of metabolic and immunomodulatory effects. Glucocorticosteroids are used to improve the postoperative outcomes in infants who have undergone Kasai portoenterostomy. OBJECTIVES: To assess the beneficial and harmful effects of glucocorticosteroid administration versus placebo or no intervention following Kasai portoenterostomy in infants with biliary atresia. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE Ovid, Embase Ovid, Science Citation Index Expanded (Web of Science), and online trial registries (last search: 20 December 2017) for randomised controlled trials. SELECTION CRITERIA: We included randomised clinical trials which assessed glucocorticosteroids for infants who have undergone Kasai portoenterostomy. For harm, we also considered quasi-randomised studies, observational studies, and case-control studies that were identified amongst the search results. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We assessed the risk of bias for each trial according to prespecified domains. We analysed data using both random-effects and fixed-effect models. We performed the analyses using Review Manager 5.3 and Trial Sequental Analysis software. We considered a P value of 0.025 or less, two-tailed, as statistically significant. We planned to calculate risk ratios (RRs) for dichotomous outcomes, and the mean difference (MD) for continuous outcomes. For all association measures, we planned to use 95% confidence intervals (CIs) as well as Trial Sequential Analysis-adjusted CIs. We used Trial Sequential Analyisis to control the risks of random errors; however, we were often unable to implement this beyond calculating the required information size as there were few trials and data. We assessed the certainty of the evidence using GRADE. MAIN RESULTS: We found two randomised controlled trials fulfilling the inclusion criteria of our review. The trials provided data for meta-analysis. We judged the two trials as trials at low risk of bias. The two trials randomised a total of 213 infants to glucocorticosteroids versus placebo. In our Trial Sequential Analysis, the required information size (that is, the meta-analytic sample size) was not reached for any outcome. Trials were funded by charities, public organisations, and received support from private sector companies, none of which seemed to have an interest in the outcome of the respective trials. The effect of glucocorticosteroids after Kasai portoenterostomy on all-cause mortality is uncertain; the confidence interval is consistent with appreciable benefit and harm (RR 1.00; 95% CI 0.14 to 6.90; low-certainty evidence). The results showed little or no difference in adverse effects between the use of glucocorticosteroids or placebo after Kasai portoenterostomy, however this analysis was based on a single trial and we have low certainty in the result (RR 1.02; 95% CI 0.87 to 1.20;). Available data suggest that the proportions of infants who do not clear their jaundice at six months is similar between the two groups (RR 0.89; 95% CI 0.67 to 1.17; low-certainty evidence). All-cause mortality or liver transplantation did not differ at two years between the two groups (RR 1.00; 95% CI 0.72 to 1.39; low-certainty evidence). There were no data regarding health-related quality of life.Our searches also yielded 19 observational studies, some of them containing limited information on harmful effects of glucocorticosteroid treatment. We presented the extracted information narratively. We identified one further ongoing trial with no currently available results. AUTHORS' CONCLUSIONS: The two meta-analysed randomised clinical trials present insufficient evidence to determine the effects of using glucocorticosteroids versus placebo after Kasai portoenterostomy in infants with biliary atresia on any of the primary or secondary review outcomes. There is insufficient evidence to support glucocorticosteroid use in the postoperative management of infants with biliary atresia for long-term outcomes of all-cause mortality or liver transplantation. It is also unclear if glucocorticosteroids are able to reduce the numbers of infants who did not clear their jaundice by six months. Further randomised, placebo-controlled trials are required to be able to determine if glucocorticosteroids may be of benefit in the postoperative management of infants with biliary atresia treated with Kasai portoenterostomy. Such trials need to be conducted as multicentre trials.

Global phosphorus retention by river damming.

More than 70,000 large dams have been built worldwide. With growing water stress and demand for energy, this number will continue to increase in the foreseeable future. Damming greatly modifies the ecological functioning of river systems. In particular, dam reservoirs sequester nutrient elements and, hence, reduce downstream transfer of nutrients to floodplains, lakes, wetlands, and coastal marine environments. Here, we quantify the global impact of dams on the riverine fluxes and speciation of the limiting nutrient phosphorus (P), using a mechanistic modeling approach that accounts for the in-reservoir biogeochemical transformations of P. According to the model calculations, the mass of total P (TP) trapped in reservoirs nearly doubled between 1970 and 2000, reaching 42 Gmol y(-1), or 12% of the global river TP load in 2000. Because of the current surge in dam building, we project that by 2030, about 17% of the global river TP load will be sequestered in reservoir sediments. The largest projected increases in TP and reactive P (RP) retention by damming will take place in Asia and South America, especially in the Yangtze, Mekong, and Amazon drainage basins. Despite the large P retention capacity of reservoirs, the export of RP from watersheds will continue to grow unless additional measures are taken to curb anthropogenic P emissions.

Arsenic trioxide inhibits EBV reactivation and promotes cell death in EBV-positive lymphoma cells.

BACKGROUND: Epstein-Barr Virus (EBV) is associated with hematopoietic malignancies, such as Burkitt's lymphoma, post-transplantation lymphoproliferative disorder, and diffuse large B-cell lymphoma. The current approach for EBV-associated lymphoma involves chemotherapy to eradicate cancer cells, however, normal cells may be injured and organ dysfunction may occur with currently employed regimens. This research is focused on employing arsenic trioxide (ATO) as EBV-specific cancer therapy takes advantage of the fact the EBV resides within the malignant cells. METHODS AND RESULTS: Our research reveals that low ATO inhibits EBV gene expression and genome replication. EBV spontaneous reactivation starts as early as 6 h after re-suspending EBV-positive Mutu cells in RPMI media in the absence of ATO, however this does not occur in Mutu cells cultured with ATO. ATO's inhibition of EBV spontaneous reactivation is dose dependent. The expression of the EBV immediate early gene Zta and early gene BMRF1 is blocked with low concentrations of ATO (0.5 nM - 2 nM) in EBV latency type I cells and EBV-infected PBMC cells. The combination of ATO and ganciclovir further diminishes EBV gene expression. ATO-mediated reduction of EBV gene expression can be rescued by co-treatment with the proteasome inhibitor MG132, indicating that ATO promotes ubiquitin conjugation and proteasomal degradation of EBV genes. Co-immunoprecipitation assays with antibodies against Zta pulls down more ubiquitin in ATO treated cell lysates. Furthermore, MG132 reverses the inhibitory effect of ATO on anti-IgM-, PMA- and TGF-ß-mediated EBV reactivation. Thus, mechanistically ATO's inhibition of EBV gene expression occurs via the ubiquitin pathway. Moreover, ATO treatment results in increased cell death in EBV-positive cells compared to EBV-negative cells, as demonstrated by both MTT and trypan blue assays. ATO-induced cell death in EBV-positive cells is dose dependent. ATO and ganciclovir in combination further enhances cell death specifically in EBV-positive cells. CONCLUSION: ATO-mediated inhibition of EBV lytic gene expression results in cell death selectively in EBV-positive lymphocytes, suggesting that ATO may potentially serve as a drug to treat EBV-related lymphomas in the clinical setting.

The Gravity of High-Skilled Migration Policies.

Combining unique, annual, bilateral data on labor flows of highly skilled immigrants for 10 OECD destinations between 2000 and 2012, with new databases comprising both unilateral and bilateral policy instruments, we present the first judicious cross-country assessment of policies aimed to attract and select high-skilled workers. Points-based systems are much more effective in attracting and selecting high-skilled migrants than requiring a job offer, labor market tests, and shortage lists. Offers of permanent residency, while attracting the highly skilled, overall reduce the human capital content of labor flows because they prove more attractive to non-high-skilled workers. Bilateral recognition of diploma and social security agreements foster greater flows of high-skilled workers and improve the skill selectivity of immigrant flows. Conversely, double taxation agreements deter high-skilled migrants, although they do not alter overall skill selectivity. Our results are robust to a variety of empirical specifications that account for destination-specific amenities, multilateral resistance to migration, and the endogeneity of immigration policies.

Colonic Perforation: A Medical Complication.

Hypothyroidism is a common comorbidity that on acute presentation is often overlooked. It can be an easily managed condition; however non-compliance can have severe consequences. In the presented case it was requirement for emergency surgery that resulted in stoma formation. This case is a first example of the need to include patient's decision making process with regards to medication adherence in the setting of chronic disease.

HIV-1-Tat Protein Inhibits SC35-mediated Tau Exon 10 Inclusion through Up-regulation of DYRK1A Kinase.

The HIV-1 transactivator protein Tat is implicated in the neuronal damage that contributes to neurocognitive impairment affecting people living with HIV/AIDS. Aberrant splicing of TAU exon 10 results in tauopathies characterized by alterations in the proportion of TAU isoforms containing three (3R) or four (4R) microtubule-binding repeats. The splicing factor SC35/SRSF2 binds to nuclear RNA and facilitates the incorporation of exon 10 in the TAU molecule. Here, we utilized clinical samples, an animal model, and neuronal cell cultures and found that Tat promotes TAU 3R up-regulation through increased levels of phosphorylated SC35, which is retained in nuclear speckles. This mechanism involved Tat-mediated increased expression of DYRK1A and was prevented by DYRK1A silencing. In addition, we found that Tat associates with TAU RNA, further demonstrating that Tat interferes with host RNA metabolism in the absence of viral infection. Altogether, our data unravel a novel mechanism of Tat-mediated neuronal toxicity through dysregulation of the SC35-dependent alternative splicing of TAU exon 10. Furthermore, the increased immunostaining of DYRK1A in HIV+ brains without pathology points at dysregulation of DYRK1A as an early event in the neuronal complications of HIV infection.

Defining Plasma MicroRNAs Associated With Cognitive Impairment In HIV-Infected Patients.

Human Immunodeficiency Virus (HIV)-infected individuals are at increased risk for developing neurocognitive disorders and depression. These conditions collectively affect more than 50% of people living with HIV/AIDS and adversely impact adherence to HIV therapy. Thus, identification of early markers of neurocognitive impairment could lead to interventions that improve psychosocial functioning and slow or reverse disease progression through improved treatment adherence. Evidence has accumulated for the role and function of microRNAs in normal and pathological conditions. We have optimized a protocol to profile microRNAs in body fluids. Using this methodology, we have profiled plasma microRNA expression for 30 age-matched, HIV-infected (HIV(+) ) patients and identified highly sensitive and specific microRNA signatures distinguishing HIV(+) patients with cognitive impairment from those without cognitive impairment. These results justify follow-on studies to determine whether plasma microRNA signatures can be used as a screening or prognostic tool for HIV(+) patients with neurocognitive impairment. J. Cell. Physiol. 231: 829-836, 2016. © 2015 Wiley Periodicals, Inc.

Effects of sarizotan in animal models of ADHD: challenging pharmacokinetic-pharmacodynamic relationships.

Sarizotan 1-[(2R)-3,4-dihydro-2H-chromen-2-yl]-N-[[5-(4-fluorophenyl) pyridin-3-yl]methyl] methenamine, showed an in vivo pharmaco-EEG profile resembling that of methylphenidate which is used in attention deficit/hyperactivity disorder (ADHD). In turn, we tested sarizotan against impulsivity in juvenile rats measuring the choice for large delayed vs. a small immediate reward in a T-maze and obtained encouraging results starting at 0.03 mg/kg (plasma levels of ~11 nM). Results from rats treated neonatally with 6-hydroxydopamine (6-OHDA), also supported anti-ADHD activity although starting at 0.3 mg/kg. However, microdialysis studies revealed that free brain concentration of sarizotan at active doses were below its affinity for 5-HT1A receptors, the assumed primary target. In contrast, electrophysiological experiments in mid-brain Raphé serotonergic cells paralleled by plasma sampling showed that there was ~60% inhibition of firing rate­indicating significant activation of 5-HT1A receptors­at a plasma concentration of 76 nM. In line with this, we observed that sarizotan concentrations in brain homogenates were similar to total blood levels but over 500 fold higher than free extracellular fluid (ECF) concentrations as measured using brain microdialysis. These data suggest that sarizotan may have potential anti-ADHD effects at low doses free of the previously reported side-effects. Moreover, in this case a classical pharmacokinetic-pharmacodynamic relationship based on free brain concentrations seems to be less appropriate than target engagement pharmacodynamic readouts.

On-off mobilization of contaminants in soils during redox oscillations.

Near-surface biogeochemical systems can oscillate between oxic and anoxic conditions. Under such periodic changes many redox-sensitive inorganic contaminants undergo speciation, mobility and toxicity changes. We investigated the changes to chromium (Cr), arsenic (As), selenium (Se), antimony (Sb) and uranium (U) mobility during a series of laboratory experiments where argillaceous substrates were subjected to successive cycles of oxidizing and reducing conditions. The EH oscillated between -320 and +470 mV, induced via both abiotic and microbial forcings. Chemically induced cycles of oxidation and reduction were achieved via a combination of gas (N2:CO2 vs compressed air) and carbon (ethanol) addition, to stimulate the metabolism of a natively present microbial community. The contaminants were added either alone or as contaminant mixtures. Results show clear on-off switch mobility behavior for both major elements such as carbon (C), iron (Fe) and manganese (Mn) and for contaminants. Mn, Fe, and As were mobilized under anoxic conditions, whereas Sb, Se, and U were mobilized under oxic conditions. While As, Sb, and U were reversibly sorbed, Se and Cr were irreversibly sequestered via reductive precipitation. When present in aqueous solutions at high concentrations, Cr(VI) prevented the reduction of Mn and Fe, and inhibited the mobilization of elements with lower EH(o). To improve remediation strategies for multiple contaminants in redox-dynamic environments, we propose a mixed kinetic-equilibrium biogeochemical model that can be forced by oscillating boundary conditions and that uses literature rates and constants to capture the key processes responsible for the mobilization of contaminants in soils.

Mutation of the 5'-untranslated region stem-loop structure inhibits α1(I) collagen expression in vivo.

Type I collagen is a heterotrimeric extracellular matrix protein consisting of two α1(I) chains and one α2(I) chain. During liver fibrosis, activated hepatic stellate cells (HSCs) are the major source of the type I collagen that accumulates in the damaged tissue. Expression of α1(I) and α2(I) collagen mRNA is increased 60-fold compared with quiescent stellate cells and is due predominantly to post-transcriptional message regulation. Specifically, a stem-loop structure in the 5'-untranslated region of α1(I) collagen mRNA may regulate mRNA expression in activated HSCs through its interaction with stem-loop binding proteins. The stem-loop may also be necessary for efficient production and folding of the type I collagen heterotrimer. To assess the role of the stem-loop in type I collagen expression in vivo, we generated a knock-in mouse harboring a mutation that abolished the stem-loop structure. Heterozygous and homozygous knock-in mice exhibited a normal phenotype. However, steady-state levels of α1(I) collagen mRNA decreased significantly in homozygous mutant MEFs as well as HSCs; intracellular and secreted type I collagen protein levels also decreased. Homozygous mutant mice developed less liver fibrosis. These results confirm an important role of the 5' stem-loop in regulating type I collagen mRNA and protein expression and provide a mouse model for further study of collagen-associated diseases.

Characterization of HIV-associated Hodgkin's lymphoma in HIV-infected patients: a single-center experience.

INTRODUCTION: Although the incidence and prevalence of AIDS-defining malignancies has decreased in the era of highly active antiretroviral therapy (HAART), the incidence and prevalence of Hodgkin's lymphoma (HL) in the HIV-infected population continues to rise. Compared with the general population, HIV-infected patients exhibit a 5-10-fold increased risk for developing HL. METHODS: A retrospective review of charts and electronic records from 2000-2010 at the HIV outpatient clinic (HOP)-Louisiana State University in New Orleans was conducted, and pathologically confirmed cases of HIV-HL were identified within this cohort. RESULTS: We found a prevalence of 6.3 cases per 1,000 patients per year of HIV-HL over a period of 10 years in our HIV outpatient clinic. The mean absolute CD4 count before treatment was 284 cells/mm(3) and after treatment was 194 cells/mm(3). The average time from the diagnosis of HIV infection to the diagnosis of HIV-HL was 7.6 years. The most common histopathologic type was mixed cellularity followed by lymphocytic predominance. The majority of patients had 6 cycles delivered. In terms of HL staging 87% presented with advanced stages (III B or IV). To the best of our knowledge 5 out of the 14 patients remain alive. CONCLUSIONS: Patients in our cohort were older than most patients identified in other cohorts. All of our patients had coexisting chronic illnesses associated with inflammation, as well as detectable HIV viral loads and CD4 count >200, suggesting a role for both HIV- and non-HIV-associated inflammation in HIV-HL pathogenesis in this population. The role of HIV virus and other oncogenic viruses (EBV, HPV, and others) in the pathogenesis of Hodgkin's lymphoma in this group of patients needs to be elucidated.

Venous thrombosis, peripheral aneurysm formation, and fever in a feral pig hunter with Brucellosis.

Brucellosis is a systemic bacterial zoonotic disease with potential endovascular complications including endocarditis, although multifocal vasculopathy is rare. Moreover, swine-associated human infections are less common since brucellosis was eradicated in commercial swine in U.S. states and territories. However, feral swine continue to serve as a reservoir for Brucella suis. We describe the case of a feral swine hunter who presented with fever and respiratory symptoms and was diagnosed with pulmonary embolus. Blood cultures revealed growth of Brucella, later confirmed as Brucella suis. Despite initial appropriate antimicrobial therapy, he maintained fever with worsening knee pain, and magnetic resonance imaging and two-dimensional echocardiography subsequently confirmed the presence of a thrombosed popliteal artery aneurysm and mitral valve vegetation, respectively. To our knowledge, this is the first report of contemporaneous venous and arterial thromboembolism attributable to B. suis infection.

Pharmacological characterization of MRZ-8676, a novel negative allosteric modulator of subtype 5 metabotropic glutamate receptors (mGluR5): focus on L: -DOPA-induced dyskinesia.

Subtype 5 metabotropic glutamate receptors (mGluR5) are abundant in the basal ganglia, amygdala, septum, hippocampus, peripheral sensory neurones and dorsal horn of the spinal cord. Thus, mGluR5 has been implicated in central processes underlying movement control, emotion, learning, and nociception. Different negative allosteric modulators (NAMs) of mGluR5 were repeatedly shown to be efficacious in models of L: -DOPA-induced dyskinesia (LID), anxiety, and some forms of pain. MRZ-8676 (6,6-dimethyl-2-phenylethynyl-7,8-dihydro-6H-quinolin-5-one) is a novel proprietary, selective, orally bioavailable mGluR5 NAM. MRZ-8676 (8.33, 25 and 75 mg/kg) showed a high efficacy in the rat model of LID, with the maximal effect size reaching ~80%. The antidyskinetic effects of MRZ-8676 (75 mg/kg) did not show tolerance as assessed after repetitive (6 days) treatment. MRZ-8676 (25 or 75 mg/kg) demonstrated moderate efficacy in two rat models of anxiety-contextual fear conditioning and the elevated plus maze. MRZ-8676 (25 mg/kg) was also effective in the formalin test, a rat model of persistent pain. The efficacious doses of MRZ-8676 did not produce any detrimental effects on motor performance of rats as determined by means of automated open field and rotarod. However, high doses of MRZ-8676 (75 or 150 mg/kg) disrupted learning in an aversive learning paradigm of the contextual fear conditioning test. In conclusion, MRZ-8676 is a new investigational agent with an efficacy profile similar to the widely published reference mGluR5 NAMs. The drug was demonstrated to possess a superior antidyskinetic efficacy with a sufficient therapeutic window. MRZ-8676 has also therapeutic potential as an anxiolytic and analgesic drug.

Inhalational Anesthetics Do Not Deteriorate Amyloid-ß-Derived Pathophysiology in Alzheimer's Disease: Investigations on the Molecular, Neuronal, and Behavioral Level.

BACKGROUND: Studies suggest that general anesthetics like isoflurane and sevoflurane may aggravate Alzheimer's disease (AD) neuropathogenesis, e.g., increased amyloid-ß (Aß) protein aggregation resulting in synaptotoxicity and cognitive dysfunction. Other studies showed neuroprotective effects, e.g., with xenon. OBJECTIVE: In the present study, we want to detail the interactions of inhalational anesthetics with Aß-derived pathology. We hypothesize xenon-mediated beneficial mechanisms regarding Aß oligomerization and Aß-mediated neurotoxicity on processes related to cognition. METHODS: Oligomerization of Aß1-42 in the presence of anesthetics has been analyzed by means of TR-FRET and silver staining. For monitoring changes in neuronal plasticity due to anesthetics and Aß1-42, Aß1-40, pyroglutamate-modified amyloid-(AßpE3), and nitrated Aß (3NTyrAß), we quantified long-term potentiation (LTP) and spine density. We analyzed network activity in the hippocampus via voltage-sensitive dye imaging (VSDI) and cognitive performance and Aß plaque burden in transgenic AD mice (ArcAß) after anesthesia. RESULTS: Whereas isoflurane and sevoflurane did not affect Aß1-42 aggregation, xenon alleviated the propensity for aggregation and partially reversed AßpE3 induced synaptotoxic effects on LTP. Xenon and sevoflurane reversed Aß1-42-induced spine density attenuation. In the presence of Aß1-40 and AßpE3, anesthetic-induced depression of VSDI-monitored signaling recovered after xenon, but not isoflurane and sevoflurane removal. In slices pretreated with Aß1-42 or 3NTyrAß, activity did not recover after washout. Cognitive performance and plaque burden were unaffected after anesthetizing WT and ArcAß mice. CONCLUSION: None of the anesthetics aggravated Aß-derived AD pathology in vivo. However, Aß and anesthetics affected neuronal activity in vitro, whereby xenon showed beneficial effects on Aß1-42 aggregation, LTP, and spine density.

Inhibition of transforming growth factor-beta/Smad signaling improves regeneration of small-for-size rat liver grafts.

Transforming growth factor-beta (TGF-beta) is a potent inhibitor of cell proliferation. This study investigated whether overexpression of Smad7, which blocks TGF-beta-induced activation of Smad2/3, could prevent the suppression of regeneration of small-for-size liver grafts. Rats were intravenously given adenoviruses (2 x 10(10) pfu/rat) carrying the LacZ gene or the Smad7 gene (Ad-Smad7) 3 days prior to liver harvesting. Half-size livers were implanted into recipients of the same weight or twice the donor weight, and this resulted in half-size or quarter-size liver grafts. Cell proliferation, detected by 5-bromo-2'-deoxyuridine (BrdU) incorporation, increased to 23% in half-size grafts at 38 hours after implantation but was only 4% in quarter-size grafts. Graft weight did not increase after 38 hours in full-size and quarter-size grafts but increased 28% in half-size grafts. Ad-Smad7 restored BrdU labeling to 32%, and the graft weight increased to 43% in quarter-size grafts. Serum total bilirubin increased approximately 30-fold after the implantation of quarter-size grafts. Ad-Smad7 blunted hyperbilirubinemia by 80%. The basal hepatic TGF-beta(1) level was 7 ng/g of liver wet weight, and this increased to 30 ng/g at 1.5 hours after the transplantation of full-size grafts but decreased rapidly afterwards. After the transplantation of quarter-size grafts, however, TGF-beta(1) progressively increased to 159 ng/g in 38 hours. Nuclear phosphorylated Smad2/3 was barely detectable, and p21Cip1 expression was negligible in full-size grafts but increased markedly in quarter-size grafts. Ad-Smad7 blocked Smad2/3 activation and expression of p21Cip1. Together, these data show that TGF-beta is responsible, at least in part, for the defective liver regeneration in small-for-size grafts by activating the Smad signaling pathway.

Closure of an iatrogenic ventricular septal defect using a hybrid approach and echocardiographic guidance.

Treatment of postsurgical iatrogenic ventricular septal defects (VSDs) remains a challenge. Surgical closure is associated with significant morbidity and mortality. A peripheral accessed percutaneous approach is faced with difficulties of gaining adequate access and complex positioning in a beating heart. We report a case of using a hybrid approach to treat iatrogenic VSD with surgical right atriotomy and delivery of an Amplatzer system under direct visualization and transesophageal echocardiography guidance.