Proteoglycans in neurulation

Glycosaminoglycans are made up of repeating disaccharide subunits consisting of a hexosamine and a hexose or hexuronic acid. They occur freely or as carbohydrate side chains in proteoglycans. Although widely distributed, their importance in embryogenesis is incompletely understood. This thesis investigates their roles in neurulation and neural crest migration. Primary neurulation occurs between E8.5 and E10.5 in the mouse embryo. Neural tube closure in the spinal region is accomplished by bending at the median hinge point and at paired dorsolateral hinge points. Histochemical and immunohistochemical studies show that sulphated glycosaminoglycans are present in the basement membrane of the closing neural tube, as well as elsewhere in the embryo. Culturing E8.5 CD1 mouse embryos in the presence of chlorate, a competitive inhibitor of glycosaminoglycan sulphation, suppressed median hinge point formation. This was associated with increased bending at the dorsolateral hinge points, resulting in accelerated posterior neuropore closure. Suppression of median hinge point formation was prevented by addition of heparan sulphate, but not chondroitin sulphate, de-N- or de-O-sulphated heparan sulphate, to the culture medium. This may be due to the requirement for heparan sulphate in Sonic hedgehog induction of median hinge point formation. Chondroitin sulphate also influenced posterior neuropore closure. Chondroitinase treatment of CD1 mouse embryos in culture retarded closure of the neuropore, whereas exogenous chondroitin sulphate accelerated closure. However, the median and dorsolateral hinge points were unaffected. The mechanism of action of chondroitin sulphate is unknown and requires further investigation. Besides their role in neurulation, chondroitin sulphate proteoglycans are known to inhibit cell migration. Splotch mouse mutants, where mutations in Pax-3 result in deficiencies of neural crest derived structures, have been shown by in situ hybridisation to over-express versican mRNA. To determine whether the glycosaminoglycan component was increased, chondroitin sulphate was quantified in E9.5 splotch embryos photospectroscopically using a 1,9-dimethylmethylene blue binding assay. It was found that mutants contained larger amounts of chondroitin sulphate than wild type embryos. On the other hand, there was no difference in the net synthetic rate, as determined by 35S-labelling of chondroitin sulphate in cultured splotch embryos. This suggests that the defect may lie in the mutants ability to degrade chondroitin sulphate, resulting in its accumulation and inhibition of neural crest migration. These experiments underline the importance of sulphated glycosaminoglycans in mouse development and raise the possibility that these molecules may contribute to development of neural tube defects and neurocristopathies in humans

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

The oncogenic role of KIF21A in breast cancer

Breast cancer pathogenesis is known to be propagated by the differential expression of a group of proteins called the Kinesin Superfamily (KIFs). All KIFs have adenosine triphosphate (ATP )- and microtubule-binding activity, assisting their role in the transport of vesicles and organelles within cells, and chromosomes during mitosis and meiosis. During mitosis, KIFs are strictly regulated through temporal synthesis so that they are only present when needed. However, their misregulation during the cell cycle may contribute to uncontrolled cell growth, highlighting their involvement in tumorigenesis. Furthermore, some KIFs have recently been associated with poor prognosis and chemotherapeutic drug resistance in breast cancer patients and cell lines, respectively. One particular KIF, KIF21A, was recently found to promote lysosomal stability and the survival of human breast cancer cells in vitro. However, how KIF21A influences other cancerous phenotypes requires further investigation. To investigate the possible oncogenic role of KIF21A in breast cancer, KIF21A was silenced in MCF-7 and MDA-MB-231 breast cancer cell lines via siRNA transfection. Migration, invasion, proliferation, and adhesion assays were then performed to measure the effects of KIF21A-silencing on oncogenic behaviour. KIF21A-silencing reduced cell migration and invasion in both cell lines, but had no effect on adhesion or proliferation, suggesting that KIF21A plays an important role in the early stages of breast cancer metastasis. Identifying exactly how KIF21A is involved in breast carcinogenesis may prove pivotal to the development of chemotherapeutic targeting to block its function and improve prognostic outcomes

Targeting cd82/kai1 for precision therapeutics in surmounting metastatic potential in breast cancer

10.3390/cancers13174486Cancers1317448

Biomimetic nanotherapeutics for targeted drug delivery to glioblastoma multiforme

10.1002/btm2.10483BIOENGINEERING & TRANSLATIONAL MEDICINE8