Irbesartan in Marfan syndrome (AIMS): a double-blind, placebo-controlled randomised trial

BACKGROUND: Irbesartan, a long acting selective angiotensin-1 receptor inhibitor, in Marfan syndrome might reduce aortic dilatation, which is associated with dissection and rupture. We aimed to determine the effects of irbesartan on the rate of aortic dilatation in children and adults with Marfan syndrome. METHODS: We did a placebo-controlled, double-blind randomised trial at 22 centres in the UK. Individuals aged 6-40 years with clinically confirmed Marfan syndrome were eligible for inclusion. Study participants were all given 75 mg open label irbesartan once daily, then randomly assigned to 150 mg of irbesartan (increased to 300 mg as tolerated) or matching placebo. Aortic diameter was measured by echocardiography at baseline and then annually. All images were analysed by a core laboratory blinded to treatment allocation. The primary endpoint was the rate of aortic root dilatation. This trial is registered with ISRCTN, number ISRCTN90011794. FINDINGS: Between March 14, 2012, and May 1, 2015, 192 participants were recruited and randomly assigned to irbesartan (n=104) or placebo (n=88), and all were followed for up to 5 years. Median age at recruitment was 18 years (IQR 12-28), 99 (52%) were female, mean blood pressure was 110/65 mm Hg (SDs 16 and 12), and 108 (56%) were taking β blockers. Mean baseline aortic root diameter was 34·4 mm in the irbesartan group (SD 5·8) and placebo group (5·5). The mean rate of aortic root dilatation was 0·53 mm per year (95% CI 0·39 to 0·67) in the irbesartan group compared with 0·74 mm per year (0·60 to 0·89) in the placebo group, with a difference in means of -0·22 mm per year (-0·41 to -0·02, p=0·030). The rate of change in aortic Z score was also reduced by irbesartan (difference in means -0·10 per year, 95% CI -0·19 to -0·01, p=0·035). Irbesartan was well tolerated with no observed differences in rates of serious adverse events. INTERPRETATION: Irbesartan is associated with a reduction in the rate of aortic dilatation in children and young adults with Marfan syndrome and could reduce the incidence of aortic complications

Sickness behaviour pushed too far – the basis of the syndrome seen in severe protozoal, bacterial and viral diseases and post-trauma

Certain distinctive components of the severe systemic inflammatory syndrome are now well-recognized to be common to malaria, sepsis, viral infections, and post-trauma illness. While their connection with cytokines has been appreciated for some time, the constellation of changes that comprise the syndrome has simply been accepted as an empirical observation, with no theory to explain why they should coexist. New data on the effects of the main pro-inflammatory cytokines on the genetic control of sickness behaviour can be extended to provide a rationale for why this syndrome contains many of its accustomed components, such as reversible encephalopathy, gene silencing, dyserythropoiesis, seizures, coagulopathy, hypoalbuminaemia and hypertriglyceridaemia. It is thus proposed that the pattern of pathology that comprises much of the systemic inflammatory syndrome occurs when one of the usually advantageous roles of pro-inflammatory cytokines – generating sickness behaviour by moderately repressing genes (Dbp, Tef, Hlf, Per1, Per2 and Per3, and the nuclear receptor Rev-erbα) that control circadian rhythm – becomes excessive. Although reversible encephalopathy and gene silencing are severe events with potentially fatal consequences, they can be viewed as having survival advantages through lowering energy demand. In contrast, dyserythropoiesis, seizures, coagulopathy, hypoalbuminaemia and hypertriglyceridaemia may best be viewed as unfortunate consequences of extreme repression of these same genetic controls when the pro-inflammatory cytokines that cause sickness behaviour are produced excessively. As well as casting a new light on the previously unrationalized coexistence of these aspects of systemic inflammatory diseases, this concept is consistent with the case for a primary role for inflammatory cytokines in their pathogenesis across this range of diseases

The impact of inversions across 33,924 families with rare disease from a national genome sequencing project

Detection of structural variants (SVs) is currently biased toward those that alter copy number. The relative contribution of inversions toward genetic disease is unclear. In this study, we analyzed genome sequencing data for 33,924 families with rare disease from the 100,000 Genomes Project. From a database hosting >500 million SVs, we focused on 351 genes where haploinsufficiency is a confirmed disease mechanism and identified 47 ultra-rare rearrangements that included an inversion (24 bp to 36.4 Mb, 20/47 de novo). Validation utilized a number of orthogonal approaches, including retrospective exome analysis. RNA-seq data supported the respective diagnoses for six participants. Phenotypic blending was apparent in four probands. Diagnostic odysseys were a common theme (>50 years for one individual), and targeted analysis for the specific gene had already been performed for 30% of these individuals but with no findings. We provide formal confirmation of a European founder origin for an intragenic MSH2 inversion. For two individuals with complex SVs involving the MECP2 mutational hotspot, ambiguous SV structures were resolved using long-read sequencing, influencing clinical interpretation. A de novo inversion of HOXD11-13 was uncovered in a family with Kantaputra-type mesomelic dysplasia. Lastly, a complex translocation disrupting APC and involving nine rearranged segments confirmed a clinical diagnosis for three family members and resolved a conundrum for a sibling with a single polyp. Overall, inversions play a small but notable role in rare disease, likely explaining the etiology in around 1/750 families across heterogeneous clinical cohorts

Locational Analysis of Filling Stations in Portharcourt Local Government Area, River State, Nigeria Using GIS Approach

The rapid growth of urbanization has created greater demand for vehicles, which results in more fuel consumption and has given rise to the establishment of filling stations in other to satisfy those needs. A petrol filling station is important but meanwhile it is a hazardous facility, so special attention is paid on its location. The paper is aimed at location analysis of filling stations in Port Harcourt local government area of rivers state using GIS approach through acquisition of primary and secondary datasets of the study area, creation of a functional spatial database and spatial attribute queries that will aid in the location analysis of filling stations in compliance with petroleum safety rules and regulations. The result shows that About 7 filling stations were located close to residential buildings, 14 out of 38 filling stations do not have adequate fire extinguishers, 14 filling stations have its pumping machine close to the road and 15 filling station lie in electricity high tension right of way. It is recommended that the regulating bodies should frequently inspect these filling stations to ensure that all the safety measures are properly observed and equipments are put in place

Evaluation of Anti-diabetics and Cardiovascular Effects of Parinari curatellifolia Seed Extract and Anthoclista vogelli Root Extract Individually and Combined on Postprandial and Alloxan-Induced Diabetic Albino Rats

Objective: To study toxicity, anti-diabetic and cardiovascular effects of hydro-ethanolic extracts of Parinari curatellifolia seed extract and Aristolochia vogelii roots extract and (1:1) mixture of the above two extracts. Materials and Methods: Twenty Wister strain albino rats were randomly assigned to four groups; A, B, C and D with each consisting of five animals received extracts as follows: Group I, P. curatellifolia and A. vogelli mixture (1:1) (500 mg/kg bwt); Group II, A. vogelli (500 mg/kg bwt); Group III, P. curatellifolia seed extract (500 mg/kg bwt); Group IV, 0.5 ml (2% w/v) acacia solution and served as control. After 30 min, the animals were each administered orally with 40% (w/v) glucose at a dose of 1ml /100 g bwt. Blood glucose levels were then monitored at 30, 60, and 120 min. intervals and reported as the average glucose level of each group. Another set of twenty five rats (diabetic rats) were randomly distributed into five groups of five animals each while the additional sixth group was the positive control consisting of five normal rats. Treatments were as follows: Group I, diabetic treated with A. vogelli at a dose of 500 mg/kg bwt; Group II, diabetic treated with P. curatellifolia at a dose of 500 mg/kg bwt; Group III, diabetic treated with glibenclamide 600μg /kg bwt; Group IV, diabetic treated with mixture of Parinari curatellifolia and A. vogelli (1:1) (500 mg/kg bwt); Group V, diabetic untreated (control negative) while group VI was the positive control. Results: A significant reduction in postprandial sugar level was observed after 30 min in all treatments. The extracts individually and in combined form also showed effective decrease in plasma glucose levels on the diabetic rats. There were significant reductions (p<0.05) in low density lipoprotein (LDL)-cholesterol levels and significant increase (p<0.05) in high density lipoprotein (HDL)–cholesterol in the treated diabetic group compared to the negative control. Furthermore, significant reductions in aspartate aminotransferases (AST) and alanine aminotransferases (ALT) levels were observed in the treated diabetic animals compared to the untreated. Also significant reduction in the creatinine and increase in the protein levels respectively were observed in the treated diabetic groups. Conclusion: The results showed that the respective extracts and the extract mixture had both good hypoglycaemic activity and beneficial effects on cardiovascular risk factors

Molecular characterization of non-aureus staphylococci and Mammaliicoccus from Hipposideros bats in Southwest Nigeria

Abstract Bats are not only ecologically valuable mammals but also reservoirs of zoonotic pathogens. Their vast population, ability to fly, and inhabit diverse ecological niches could play some role in the spread of antibiotic resistance. This study investigated non-aureus staphylococci and Mammaliicoccus colonization in the Hipposideros bats at Obafemi Awolowo University, Ile-Ife, Nigeria. Pharyngeal samples (n = 23) of the insectivorous bats were analyzed, and the presumptive non-aureus staphylococcal and Mammaliicoccus isolates were confirmed by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). The isolates were characterized based on antibiotic susceptibility testing and whole-genome sequencing (WGS). Six bacterial genomes were assembled, and three species were identified, including Mammaliicoccus sciuri (n = 4), Staphylococcus gallinarum (n = 1), and Staphylococcus nepalensis (n = 1). All the isolates were resistant to clindamycin, while the M. sciuri and S. gallinarum isolates were also resistant to fusidic acid. WGS analysis revealed that the M. sciuri and S. gallinarum isolates were mecA-positive. In addition, the M. sciuri isolates possessed some virulence (icaA, icaB, icaC, and sspA) genes. Multi-locus sequence typing identified two new M. sciuri sequence types (STs) 233 and ST234. The identification of these new STs in a migratory mammal deserves close monitoring because previously known ST57, ST60, and ST65 sharing ack (8), ftsZ (13), glpK (14), gmk (6), and tpiA (10) alleles with ST233 and ST234 have been linked to mastitis in animals. Moreover, the broad host range of M. sciuri could facilitate the dispersal of antibiotic resistance genes. This study provides evidence of the importance of including migratory animals in monitoring the development and spread of antibiotic resistance