STUDY OF THE LEUKOCYTE MIGRATION INHIBITORY FACTOR IN HUMAN GLOMERULONEPHRITIS FROM THE ASPECT OF THE PROGNOSIS

No abstrac

Bicyclic Boronate β-Lactamase Inhibitors: The Present Hope against Deadly Bacterial Pathogens

The use of β-lactamase inhibitors in combination with β-lactam antibiotics is an emerging area in drug discovery. This strategy allows the restoration of the therapeutic efficacy of these antibiotics in clinical use against multiresistant bacteria. These pathogens are drug resistant because they express β-lactamase enzymes, which prevent the antibiotic therapeutic action by catalyzing the hydrolysis of the β-lactam ring. These enzymes are quite diverse in both their structural architecture and hydrolytic capability, as well as in the mechanism of action. The ever-increasing emergence of pathogens that are capable of coproducing different types of β-lactamases has triggered the search for ultrabroad-spectrum inhibitors capable of deactivating both serine- and metallo-β-lactamases. A recent breakthrough in this long-pursued and unmet need is the discovery of bicyclic boronate inhibitors, specifically taniborbactam, VNRX-7145, and QPX7728, which are currently under clinical development in combination with cefepime, ceftibuten, and QPX2014, respectively. The present article highlights the therapeutic potential of these inhibitors and their spectrum of efficacy is compared with those of other β-lactam/β-lactamase inhibitor combinations recently approved by the food and drug administration. The molecular basis of the ultrabroad-spectrum of activity of boron-based inhibitors is also discussed, on the basis of the available crystal structures and the results of computational studiesinancial support from the Spanish Ministry of Economy and Competiveness (SAF2016-75638-R, PID2019-105512RB-I00), the Xunta de Galicia [ED431B 2018/04 and Centro singular de investigación de Galicia accreditation 2019–2022 (ED431G 2019/03)], and the European Regional Development Fund (ERDF) is gratefully acknowledgedS

UK experience of liver transplantation for erythropoietic protoporphyria

Erythropoietic protoporphyria (EPP) is characterised by excess production of free protoporphyrin from the bone marrow, most commonly due to deficiency of the enzyme ferrochelatase. Excess protoporphyrin gives rise to the cutaneous photosensitivity characteristic of the disease, and in a minority of patients leads to end-stage liver disease necessitating liver transplantation (LT). There is limited information regarding the timing, impact and long-term outcome of LT in such patients, thus we aimed to identify the indications and outcomes of all transplants performed for EPP in the UK using data from the UK Transplant Registry. Between 1987 and 2009, five patients underwent LT for EPP liver disease. Median follow-up was 60 months, and there were two deaths at 44 and 95 months from causes unrelated to liver disease. The remaining recipients are alive at 22.4 years, 61 months and 55 months after transplant. A high rate of postoperative biliary stricturing requiring multiple biliary interventions was observed. Recurrent EPP-liver disease occurred in 4/5 (80%) of patients but graft failure has not been observed. Given the role of biliary obstruction in inducing EPP-mediated liver damage, we suggest that consideration should be given for construction of a Roux loop at the time of transplant. Thus we demonstrate that although EPP liver transplant recipients have a good long-term survival, comparable to patients undergoing LT for other indications, biliary complications and disease recurrence are almost universal, and bone marrow transplantation should be considered where possible

Thematic Working Group 5: Formative assessment supported by technology.

The future of assessment faces major challenges including the use of IT to facilitate formative assessment that is important for improving learners’ development, motivation and engagement in learning. In many countries, in recent years, a renewed focus on assessments to support learning has been pushing against the burgeoning of testing for accountability, which in some countries, renders effective formative assessment practices almost impossible. Moreover, a systematic review by Harlen and Deakin Crick (2002) revealed that a strong focus on summative assessment for accountability can reduce motivation and disengage many learners. At the same time use of IT‐enabled assessments has been increasing rapidly, as they offer promise of cheaper ways of delivering and marking assessments as well as access to vast amounts of assessment data from which a wide range of judgements might be made about students, teachers, schools and education systems (Gibson & Webb, 2015). These opportunities also extend to assessment of complex collaborative work (Webb & Gibson, 2015). Current opportunities for using IT, including for harnessing the data that is being collected automatically, for formative assessment are underexplored and less well understood than those for summative assessments. Opportunities for learning with IT and perhaps with less teacher input are increasing but this depends on students developing as autonomous or independent learners. Research in formative assessment including effective feedback has emphasised the value of peer assessment practices for developing self‐assessment capabilities and hence independent learners (Black, Harrison, Lee, Marshall, & William, 2003). At previous EDUsummITs the possibilities and challenges for IT‐enabled assessments to support simultaneously both formative and summative purposes were analysed (Webb, Gibson, & Forkosh‐Baruch, 2013). While these challenges remain, at EDUsummIT 2017 we focused on the opportunities and challenges of IT supporting formative assessment because effective formative assessment is known to be extremely important for learning.RETHINKING LEARNING IN A DIGITAL AGE, EDUsummIT 2017 Summary Reports 18-20 september, Bulgari

Erythropoietic protoporphyria

Erythropoietic protoporphyria (EPP) is an inherited disorder of the haem metabolic pathway characterised by accumulation of protoporphyrin in blood, erythrocytes and tissues, and cutaneous manifestations of photosensitivity. EPP has been reported worldwide, with prevalence between 1:75,000 and 1:200,000. It usually manifests in early infancy upon the first sun exposures. EPP is characterised by cutaneous manifestations of acute painful photosensitivity with erythema and oedema, sometimes with petechiae, together with stinging and burning sensations upon exposure to sunlight, without blisters. These episodes have a variable severity depending on the exposure duration and may result in chronic permanent lesions on exposed skin. As protoporphyrin is a lipophilic molecule that is excreted by the liver, EPP patients are at risk of cholelithiasis with obstructive episodes, and chronic liver disease that might evolve to rapid acute liver failure. In most patients, EPP results from a partial deficiency of the last enzyme of the haem biosynthetic pathway, ferrochelatase, EC 4.99.1.1/FECH (encoded by the FECH gene). EPP appears to be inherited as an autosomal dominant disease, the clinical expression of which is modulated by the presence of the hypomorphic FECH IVS3-48C allele trans, but recessive inheritance with two mutated FECH alleles has also been described. In about 2% of patients, overt disease was recently shown to be caused by gain-of-function mutations in the erythroid-specific aminolevulinic acid synthase 2 (ALAS2/ALAS, EC 2.3.1.27) gene and named X-linked dominant protoporphyria. Diagnosis is established by finding increased levels of protoporphyrin in plasma and red blood cells, and detection of a plasma fluorescence peak at 634 nm. Investigations for hepatic involvement, ferrochelatase activity level, genetic analysis (FECH mutations, presence of the hypomorphic FECH IVS3-48C allele trans and ALAS2 mutations) and family studies are advisable. Differential diagnosis includes phototoxic drug reactions, hydroa vacciniforme, solar urticaria, contact dermatitis, angio-oedema and, in some cases, other types of porphyria. Management includes avoidance of exposure to light, reduction of protoporphyrin levels and prevention of progression of possible liver disease to liver failure. As the major risk in EPP patients is liver disease, a regular follow-up of hepatic involvement is essential. Sequential hepatic and bone marrow transplantation should be considered as a suitable treatment for most severe cases of EPP with hepatic involvement. EPP is a lifelong disorder whose prognosis depends on the evolution of the hepatic disease. However, photosensitivity may have a significant impact on quality of life of EPP patients

A systematic review showing the lack of diagnostic criteria and tools developed for lower-limb cellulitis

BACKGROUND: Cellulitis can be a difficult diagnosis to make. Furthermore, 31% of patients admitted from the emergency department with suspected lower-limb cellulitis have been misdiagnosed, with incorrect treatment potentially resulting in avoidable hospital admission and the prescription of unnecessary antibiotics. OBJECTIVES: We sought to identify diagnostic criteria or tools that have been developed for lower-limb cellulitis. METHODS: We conducted a systematic review using Ovid MEDLINE and Embase databases in May 2018, with the aim of describing diagnostic criteria and tools developed for lower-limb cellulitis, and we assessed the quality of the studies identified using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. We included all types of study that described diagnostic criteria or tools. RESULTS: Eight observational studies were included. Five studies examined biochemical markers, two studies assessed imaging and one study developed a diagnostic decision model. All eight studies were considered to have a high risk for bias in at least one domain. The quantity and quality of available data was low and results could not be pooled owing to the heterogeneity of the findings. CONCLUSIONS: There is a lack of high-quality publications describing criteria or tools for diagnosing lower-limb cellulitis. Future studies using prospective designs, validated in both primary and secondary care settings, are needed. What's already known about this topic? Diagnosing lower-limb cellulitis on first presentation is challenging. Approximately one in three patients admitted from the emergency department with suspected lower-limb cellulitis do not have cellulitis and are given another diagnosis on discharge. Consequently, this results in potentially avoidable hospital admissions and the prescription of unnecessary antibiotics. There are no diagnostic criteria available for lower-limb cellulitis in the U.K. What does this study add? This systematic review has identified a key research gap in the diagnosis of lower-limb cellulitis. There is a current lack of robustly developed and validated diagnostic criteria or tools for use in clinical practice

Complementary and alternative medicine: attitudes, knowledge and use among surgeons and anaesthesiologists in Hungary

BACKGROUND: Despite their worldwide popularity the question of using non-conventional treatments is a source of controversy among medical professionals. Although these methods may have potential benefits it presents a problem when patients use non-conventional treatments in the perioperative period without informing their attending physician about it and this may cause adverse events and complications. To prevent this, physicians need to have a profound knowledge about non-conventional treatments. METHODS: An anonymous questionnaire was distributed among surgeons and anaesthesiologists working in Hungarian university clinics and in selected city or county hospitals. Questionnaires were distributed by post, online or in person. Altogether 258 questionnaires were received from 22 clinical and hospital departments. RESULTS: Anaesthesiologists and surgeons use reflexology, Traditional Chinese Medicine, herbal medicine and manual therapy most frequently in their clinical practice. Traditional Chinese Medicine was considered to be the most scientifically sound method, while homeopathy was perceived as the least well-grounded method. Neural therapy was the least well-known method among our subjects. Among the subjects of our survey only 3.1 % of perioperative care physicians had some qualifications in non-conventional medicine, 12.4 % considered themselves to be well-informed in this topic and 48.4 % would like to study some complementary method. Women were significantly more interested in alternative treatments than men, p = 0.001427; OR: 2.2765. Anaesthesiologists would be significantly more willing to learn non-conventional methods than surgeons. 86.4 % of the participants thought that non-conventional treatments should be evaluated from the point of view of evidence. Both surgeons and anaesthesiologists accept the application of integrative medicine and they also approve of the idea of teaching these methods at universities. CONCLUSIONS: According to perioperative care physicians, non-conventional methods should be evaluated based on evidence. They also expressed a willingness to learn about those treatments that meet the criteria of evidence and apply these in their clinical practice

The Pre-designed Lesson: Teaching with Transdisciplinary Pedagogical Templates (Tpts)

An ongoing challenge in higher education is the support of educators in their development of effective pedagogies. The field of educational research and practice referred to as Learning Design may be able to help educators with no or limited pedagogical training deliver highly interactive and contemporary teaching and learning offerings. The present study reported the findings from a trial of new technologically supported Learning Designs. These pre-designed lessons are referred to as Transdisciplinary Pedagogical Templates (TPTs). These templates contain prepopulated pedagogical instructions to educators and students, but are free of subject specific content allowing them to be used in discipline areas as diverse as teacher education, accounting, engineering or medicine. These TPTs have been designed to assist educators provide constructivist learning experiences, without the need for pedagogical upskilling. This research explored the practical efficacy of the de Bono LAMS template model, documenting educator and student engagement patterns and issues arising from the trial of the five de Bono LAMS sequences. The findings suggest an interest in TPTs by educators and students, but also a reluctance to engage with research, citing mainly a lack of time. The findings also point to a need to better understand students’ affective states and the role of emotional intelligence in technology enhanced learning and teaching provision

Innate Immune Functions of the Keratinocytes

Human keratinocytes are known to kill living microbes. They express different pattern recognition receptors (PRRs) such as the Toll-like receptor 2 (TLR2), TLR4, the CD1d molecule and a keratinocyte mannose-binding receptor (KcMR). In response to challenge with microbes or microbial-derived substances the activation and nuclear translocation of NF-kB, the production of nitric oxide (NO) and inflammatory cytokines occur in keratinocytes, in a TLR-dependent manner. Blocking of NF-kB activation or NO production inhibit the Candida albicans-killing activity of keratinocytes. This Candida killing activity could be inhibited by blocking of KcMR. Recognition of invading pathogens in the epidermis triggers cytokine production in keratinocytes leading to elimination of pathogens and the activation of the adaptive immune system. These findings stress the importance of the role of keratinocytes in innate immunity