UPR Responsive Genes Manf and Xbp1 in Stroke

Stroke is a devastating medical condition with no treatment to hasten recovery. Its abrupt nature results in cataclysmic changes in the affected tissues. Resident cells fail to cope with the cellular stress resulting in massive cell death, which cannot be endogenously repaired. A potential strategy to improve stroke outcomes is to boost endogenous pro-survival pathways. The unfolded protein response (UPR), an evolutionarily conserved stress response, provides a promising opportunity to ameliorate the survival of stressed cells. Recent studies from us and others have pointed toward mesencephalic astrocyte-derived neurotrophic factor (MANF) being a UPR responsive gene with an active role in maintaining proteostasis. Its pro-survival effects have been demonstrated in several disease models such as diabetes, neurodegeneration, and stroke. MANF has an ER-signal peptide and an ER-retention signal; it is secreted by ER calcium depletion and exits cells upon cell death. Although its functions remain elusive, conducted experiments suggest that the endogenous MANF in the ER lumen and exogenously administered MANF protein have different mechanisms of action. Here, we will revisit recent and older bodies of literature aiming to delineate the expression profile of MANF. We will focus on its neuroprotective roles in regulating neurogenesis and inflammation upon post-stroke administration. At the same time, we will investigate commonalities and differences with another UPR responsive gene, X-box binding protein 1 (XBP1), which has recently been associated with MANF's function. This will be the first systematic comparison of these two UPR responsive genes aiming at revealing previously uncovered associations between them. Overall, understanding the mode of action of these UPR responsive genes could provide novel approaches to promote cell survival.Peer reviewe

Minimally Invasive Spinal Stabilization Using Fluoroscopic-Guided Percutaneous Screws as a Form of Palliative Surgery in Patients with Spinal Metastasis

Study DesignProspective cohort study.PurposeTo report the outcome of 50 patients with spinal metastases treated with minimally invasive stabilization (MISt) using fluoroscopic guided percutaneous pedicle screws with/without minimally invasive decompression.Overview of LiteratureThe advent of minimally invasive percutaneous pedicle screw stabilization system has revolutionized the treatment of spinal metastasis.MethodsBetween 2008 and 2013, 50 cases of spinal metastasis with pathological fracture(s) with/without neurology deficit were treated by MISt at our institution. The patients were assessed by Tomita score, pain score, operation time, blood loss, neurological recovery, time to ambulation and survival.ResultsThe mean Tomita score was 6.3±2.4. Thirty seven patients (74.0%) required minimally invasive decompression in addition to MISt. The mean operating time was 2.3±0.5 hours for MISt alone and 3.4±1.2 hours for MISt with decompression. Mean blood loss for MISt alone and MISt with decompression was 0.4±0.2 L and 1.7±0.9 L, respectively. MISt provided a statistically significant reduction in visual analog scale pain score with mean preoperative score of 7.9±1.4 that was significantly decreased to 2.5±1.2 postoperatively (p=0.000). For patients with neurological deficit, 70% displayed improvement of one Frankel grade and 5% had an improvement of 2 Frankel grades. No patient was bed-ridden postoperatively, with the average time to ambulation of 3.4±1.8 days. The mean overall survival time was 11.3 months (range, 2–51 months). Those with a Tomita score <8 survived significantly longer than those a Tomita score ≥8 with a mean survival of 14.1±12.5 months and 6.8±4.9 months, respectively (p=0.019). There were no surgical complications, except one case of implant failure.ConclusionsMISt is an acceptable treatment option for spinal metastatic patients, providing good relief of instability back pain with no major complications

Surgical Morphometry of C1 and C2 Vertebrae: A Three-Dimensional Computed Tomography Analysis of 180 Chinese, Indian, and Malay Patients

Study DesignClinical imaging study.PurposeTo study the surgical morphometry of C1 and C2 vertebrae in Chinese, Indian, and Malay patients.Overview of LiteratureC1 lateral mass and C2 pedicle screw fixation is gaining popularity. However, there is a lack of C1–C2 morphometric data for the Asian population.MethodsComputed tomography analysis of 180 subjects (60 subjects each belonging to Chinese, Indian, and Malay populations) using simulation software was performed. Length and angulations of C1 lateral mass (C1LM) and C2 pedicle (C2P) screws were assessed.ResultsThe predicted C1LM screw length was between 23.2 and 30.2 mm. The safe zone of trajectories was within 11.0°±7.7° laterally to 29.1°±6.2° medially in the axial plane and 37.0°±10.2° caudally to 20.9°±7.8° cephalically in the sagittal plane. The shortest and longest predicted C2P screw lengths were 22.1±2.8 mm and 28.5±3.2 mm, respectively. The safe trajectories were from 25.1° to 39.3° medially in the axial plane and 32.3° to 45.9° cephalically in the sagittal plane.ConclusionsC1LM screw length was 23–30 mm with the axial safe zone from 11° laterally to 29° medially and sagittal safe zone at 21° cephalically. C2P screw length was 22–28 mm with axial safe zone from 26° to 40° medially and sagittal safe zone from 32° to 46° cephalically. These data serve as an important reference for Chinese, Indian, and Malay populations during C1–C2 instrumentation

Microstructure and Discharge Performance of Aluminum Al 6061 Alloy as Anode for Electrolyte Activated Battery

Electrolyte activated battery finds its important use during natural disaster emergencies, such as floods and typhoons. Nevertheless, high corrosion rate will deteriorate the discharge performance of the battery and it is influenced by the type of electrolyte and discharge current. In this study, the corrosion and discharge performance of a commercial Al 6061 aluminum alloy as an anode are investigated at different discharge currents (0.001, 0.01, and 1 mA) and in different electrolytes, namely salt water, urea, and distilled water. Scanning electron microscopy results show that electrode in salt water has the most serious corrosion, followed by that of in urea and in distilled water. These electrodeelectrolyte combinations are further investigated with potentiodynamic polarization, galvanostatic discharge, and electrochemical impedance spectroscopy (EIS) to understand their discharge potential, discharge behavior, and corrosion mechanism. Among all combinations, aluminum in water is found to have the highest discharge performance with discharge potentials ranging from 716 to 744 mV, regardless of discharge current

Augmenting hematoma-scavenging capacity of innate immune cells by CDNF reduces brain injury and promotes functional recovery after intracerebral hemorrhage

During intracerebral hemorrhage (ICH), hematoma formation at the site of blood vessel damage results in local mechanical injury. Subsequently, erythrocytes lyse to release hemoglobin and heme, which act as neurotoxins and induce inflammation and secondary brain injury, resulting in severe neurological deficits. Accelerating hematoma resorption and mitigating hematoma-induced brain edema by modulating immune cells has potential as a novel therapeutic strategy for functional recovery after ICH. Here, we show that intracerebroventricular administration of recombinant human cerebral dopamine neurotrophic factor (rhCDNF) accelerates hemorrhagic lesion resolution, reduces peri-focal edema, and improves neurological outcomes in an animal model of collagenase-induced ICH. We demonstrate that CDNF acts on microglia/macrophages in the hemorrhagic striatum by promoting scavenger receptor expression, enhancing erythrophagocytosis and increasing anti-inflammatory mediators while suppressing the production of pro-inflammatory cytokines. Administration of rhCDNF results in upregulation of the Nrf2-HO-1 pathway, but alleviation of oxidative stress and unfolded protein responses in the perihematomal area. Finally, we demonstrate that intravenous delivery of rhCDNF has beneficial effects in an animal model of ICH and that systemic application promotes scavenging by the brain's myeloid cells for the treatment of ICH.Peer reviewe

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Tailored Approaches in Drug Development and Diagnostics: From Molecular Design to Biological Model Systems

Approaches to increase the efficiency in developing drugs and diagnostics tools, including new drug delivery and diagnostic technologies, are needed for improved diagnosis and treatment of major diseases and health problems such as cancer, inflammatory diseases, chronic wounds, and antibiotic resistance. Development within several areas of research ranging from computational sciences, material sciences, bioengineering to biomedical sciences and bioimaging is needed to realize innovative drug development and diagnostic (DDD) approaches. Here, an overview of recent progresses within key areas that can provide customizable solutions to improve processes and the approaches taken within DDD is provided. Due to the broadness of the area, unfortunately all relevant aspects such as pharmacokinetics of bioactive molecules and delivery systems cannot be covered. Tailored approaches within (i) bioinformatics and computer-aided drug design, (ii) nanotechnology, (iii) novel materials and technologies for drug delivery and diagnostic systems, and (iv) disease models to predict safety and efficacy of medicines under development are focused on. Current developments and challenges ahead are discussed. The broad scope reflects the multidisciplinary nature of the field of DDD and aims to highlight the convergence of biological, pharmaceutical, and medical disciplines needed to meet the societal challenges of the 21st century