Aspects of functional constipation - a trial of an opioid antagonist as a treatment and an investigation of the colonic microbiota associated with the illness

INTRODUCTION Functional constipation (FC) is a common condition which affects patients’ quality of life (QoL), is of uncertain pathophysiology, and is poorly treated. The aims of this research were to conduct a randomised, placebo-controlled trial investigating an opiate antagonist (Naloxone - Nalcol™) on symptom relief in FC and secondly to describe the colonic microbiota in FC and determine the effect of Nalcol™ on it. MATERIAL AND METHODS The trial consisted of; a 2 week screening period (Period I), a 4 week trial period of Nalcol™ vs. Placebo (Period II), and a 4 week open label period with all patients taking Nalcol™ (Period III). The primary outcome was patients’ assessment of ‘satisfactory improvement in the preceding 2 weeks’ after each period. The secondary outcomes were: changes in QoL, stool type and frequency, and transit time. A subset of patients donated stool samples at the end of each period for microbiological analysis which were compared with controls without FC. Faecal samples were analysed using denaturing gradient gel electrophoresis (DGGE), fluorescence in situ hybridisation (FISH), and pyrosequencing. RESULTS 41 females were recruited (median age 45, range 23-76 years) .There were no significant differences in ‘satisfactory improvement in the preceding 2 weeks’, (Nalcol™ vs. Placebo, 20% vs. 24%, p=1.00, n=41) or any secondary outcomes. Nalcol™ use was associated with more bloating (40% vs. 5%, p=0.009). Patients with FC had significant reductions in the Firmicutes phylum (25% vs. 45%, p=0.004) and Bifidiobacteria spp. (0.67 vs. 0.88 log10 cell/g, p=0.03), with increases in the Bacteroidetes phylum (66% vs. 41%, p=0.002) compared to controls. CONCLUSION Nalcol™ had no clinical benefits for managing FC in this trial and cannot be recommended in this group of patients. Differences in the colonic microbiota in FC warrant further investigation to see how it is implicated in the pathophysiology of FC

Complex hidradenitis suppurativa on a background of long‐standing Crohn's disease requiring radical pelvic and perineal reconstruction: A case report

Key Clinical Message: A surgical MDT approach to high‐complexity surgeries can allow maximal resection in order to achieve disease control and excellent functional outcomes, as demonstrated here for a case of hidradenitis suppurativa in a patient with Crohn's disease. Abstract: Hidradenitis suppurativa is an autoimmune disease characterized by abscess and fistula formation with purulent discharge in intertriginous zones, and is associated with inflammatory bowel disease. We present the case of a patient with severe ongoing hidradenitis suppurativa causing osteomyelitis and affecting the perineum, on a background of Crohn's disease previously treated with panprotocolectomy and permanent ileostomy. The hidradenitis suppurativa was having a severe impact on the patient's quality of life, and she had failed to respond to conservative management. The patient opted for a radical two‐step procedure: first her coccyx and sacrum were removed. The second step was a radical bilateral anterior vulvectomy and posterior vaginectomy, with preservation of the uterine body and cervix. An anterolateral thigh flap was used to reconstruct the perineum. This complex procedure required the expertise of multiple surgical specialties, including plastic, general, spinal, and gynecological oncology surgeons to achieve maximal disease resection, minimizing the risk of recurrence

Emergency surgery admissions and the COVID-19 pandemic: did the first wave really change our practice? Results of an ACOI/WSES international retrospective cohort audit on 6263 patients

Introduction The COVID-19 pandemic is having a deep impact on emergency surgical services, with a significant reduction of patients admitted into emergency surgical units world widely. Reliable figures of this reduction have not been produced yet. Our international audit aimed at giving a precise snapshot of the absolute and relative changes of emergency surgical admissions at the outbreak of the pandemic. Materials and methods Datasets of patients admitted as general surgical emergencies into 45 internationally distributed emergency surgical units during the months of March and April 2020 (Covid-19 pandemic outbreak) were collected and compared with those of patients admitted into the same units during the months of March and April 2019 (pre-Covid-19). Primary endpoint was to evaluate the relative variation of the presentation symptoms and discharge diagnoses between the two study periods. Secondary endpoint was to identify the possible change of therapeutic strategy during the same two periods. Results Forty-five centres participated sent their anonymised data to the study hub, for a total of 6263 patients. Of these, 3810 were admitted in the pre-Covid period and 2453 in the Covid period, for a 35.6% absolute reduction. The most common presentation was abdominal pain, whose incidence did not change between the two periods, but in the Covid period patients presented less frequently with anal pain, hernias, anaemia and weight loss. ASA 1 and low frailty patients were admitted less frequently, while ASA>1 and frail patients showed a relative increase. The type of surgical access did not change significantly, but lap-to-open conversion rate halved between the two study periods. Discharge diagnoses of appendicitis and diverticulitis reduced significantly, while bowel ischaemia and perianal ailments had a significant relative increase. Conclusions Our audit demonstrates a significant overall reduction of emergency surgery admissions at the outbreak of the Covid-19 pandemic with a minimal change of the proportions of single presentations, diagnoses and treatments. These findings may open the door to new ways of managing surgical emergencies without engulfing the already busy hospitals

The weekend effect on the provision of Emergency Surgery before and during the COVID-19 pandemic: case-control analysis of a retrospective multicentre database

Introduction The concept of "weekend effect", that is, substandard healthcare during weekends, has never been fully demonstrated, and the different outcomes of emergency surgical patients admitted during weekends may be due to different conditions at admission and/or different therapeutic approaches. Aim of this international audit was to identify any change of pattern of emergency surgical admissions and treatments during weekends. Furthermore, we aimed at investigating the impact of the COVID-19 pandemic on the alleged "weekend effect". Methods The database of the CovidICE-International Study was interrogated, and 6263 patients were selected for analysis. Non-trauma, 18+ yo patients admitted to 45 emergency surgery units in Europe in the months of March-April 2019 and March-April 2020 were included. Demographic and clinical data were anonymised by the referring centre and centrally collected and analysed with a statistical package. This study was endorsed by the Association of Italian Hospital Surgeons (ACOI) and the World Society of Emergency Surgery (WSES). Results Three-quarters of patients have been admitted during workdays and only 25.7% during weekends. There was no difference in the distribution of gender, age, ASA class and diagnosis during weekends with respect to workdays. The first wave of the COVID pandemic caused a one-third reduction of emergency surgical admission both during workdays and weekends but did not change the relation between workdays and weekends. The treatment was more often surgical for patients admitted during weekends, with no difference between 2019 and 2020, and procedures were more often performed by open surgery. However, patients admitted during weekends had a threefold increased risk of laparoscopy-to-laparotomy conversion (1% vs. 3.4%). Hospital stay was longer in patients admitted during weekends, but those patients had a lower risk of readmission. There was no difference of the rate of rescue surgery between weekends and workdays. Subgroup analysis revealed that interventional procedures for hot gallbladder were less frequently performed on patients admitted during weekends. Conclusions Our analysis revealed that demographic and clinical profiles of patients admitted during weekends do not differ significantly from workdays, but the therapeutic strategy may be different probably due to lack of availability of services and skillsets during weekends. The first wave of the COVID-19 pandemic did not impact on this difference

A novel albumin gene mutation (R222I) in familial dysalbuminemic hyperthyroxinemia.

CONTEXT: Familial dysalbuminemic hyperthyroxinemia, characterized by abnormal circulating albumin with increased T4 affinity, causes artefactual elevation of free T4 concentrations in euthyroid individuals. OBJECTIVE: Four unrelated index cases with discordant thyroid function tests in different assay platforms were investigated. DESIGN AND RESULTS: Laboratory biochemical assessment, radiolabeled T4 binding studies, and ALB sequencing were undertaken. (125)I-T4 binding to both serum and albumin in affected individuals was markedly increased, comparable with known familial dysalbuminemic hyperthyroxinemia cases. Sequencing showed heterozygosity for a novel ALB mutation (arginine to isoleucine at codon 222, R222I) in all four cases and segregation of the genetic defect with abnormal biochemical phenotype in one family. Molecular modeling indicates that arginine 222 is located within a high-affinity T4 binding site in albumin, with substitution by isoleucine, which has a smaller side chain predicted to reduce steric hindrance, thereby facilitating T4 and rT3 binding. When tested in current immunoassays, serum free T4 values from R222I heterozygotes were more measurably abnormal in one-step vs two-step assay architectures. Total rT3 measurements were also abnormally elevated. CONCLUSIONS: A novel mutation (R222I) in the ALB gene mediates dominantly inherited dysalbuminemic hyperthyroxinemia. Susceptibility of current free T4 immunoassays to interference by this mutant albumin suggests likely future identification of individuals with this variant binding protein.This work was supported by funding from the Wellcome Trust (Grant 100585/Z/12/Z, to N.S., Grant 095564/Z/11/Z, to K.C.) and National Institute for Health Research Cambridge Biomedical Research Centre (to C.M., and M.G.).This is the final published version of the article. It was originally published in The Journal of Clinical Endocrinology & Metabolism (Nadia Schoenmakers, Carla Moran, Irene Campi, Maura Agostini, Olivia Bacon, Odelia Rajanayagam, John Schwabe, Sonia Bradbury, Timothy Barrett, Frank Geoghegan, Maralyn Druce, Paolo Beck-Peccoz, Angela O'Toole, Penelope Clark, Michelle Bignell, Greta Lyons, David Halsall, Mark Gurnell, Krishna Chatterjee. J Clin Endocrinol Metab 2014 Jul 19;99(7):E1381-6. Epub 2014 Mar 19. http://dx.doi.org/10.1210/jc.2013-4077). A correction to this article was issued because the CC-BY licence was not present on the final published paper (http://dx.doi.org/10.1210/jc.2015-1656)

Comparative genomics of the emerging human pathogen Photorhabdus asymbiotica with the insect pathogen Photorhabdus luminescens

<p>Abstract</p> <p>Background</p> <p>The Gram-negative bacterium <it>Photorhabdus asymbiotica </it>(Pa) has been recovered from human infections in both North America and Australia. Recently, Pa has been shown to have a nematode vector that can also infect insects, like its sister species the insect pathogen <it>P. luminescens </it>(Pl). To understand the relationship between pathogenicity to insects and humans in <it>Photorhabdus </it>we have sequenced the complete genome of Pa strain ATCC43949 from North America. This strain (formerly referred to as <it>Xenorhabdus luminescens </it>strain 2) was isolated in 1977 from the blood of an 80 year old female patient with endocarditis, in Maryland, USA. Here we compare the complete genome of Pa ATCC43949 with that of the previously sequenced insect pathogen <it>P. luminescens </it>strain TT01 which was isolated from its entomopathogenic nematode vector collected from soil in Trinidad and Tobago.</p> <p>Results</p> <p>We found that the human pathogen Pa had a smaller genome (5,064,808 bp) than that of the insect pathogen Pl (5,688,987 bp) but that each pathogen carries approximately one megabase of DNA that is unique to each strain. The reduced size of the Pa genome is associated with a smaller diversity in insecticidal genes such as those encoding the Toxin complexes (Tc's), Makes caterpillars floppy (Mcf) toxins and the <it>Photorhabdus </it>Virulence Cassettes (PVCs). The Pa genome, however, also shows the addition of a plasmid related to pMT1 from <it>Yersinia pestis </it>and several novel pathogenicity islands including a novel Type Three Secretion System (TTSS) encoding island. Together these data suggest that Pa may show virulence against man via the acquisition of the <it>pMT1</it>-like plasmid and specific effectors, such as SopB, that promote its persistence inside human macrophages. Interestingly the loss of insecticidal genes in Pa is not reflected by a loss of pathogenicity towards insects.</p> <p>Conclusion</p> <p>Our results suggest that North American isolates of Pa have acquired virulence against man via the acquisition of a plasmid and specific virulence factors with similarity to those shown to play roles in pathogenicity against humans in other bacteria.</p

New Insights into the mineralogy of the Atlantis II deep metalliferous sediments, Red Sea

The Atlantis II Deep of the Red Sea hosts the largest known hydrothermal ore deposit on the ocean floor and the only modern analog of brine pool-type metal deposition. The deposit consists mainly of chemical-clastic sediments with input from basin-scale hydrothermal and detrital sources. A characteristic feature is the millimeter-scale layering of the sediments, which bears a strong resemblance to banded iron formation (BIF). Quantitative assessment of the mineralogy based on relogging of archived cores, detailed petrography, and sequential leaching experiments shows that Fe-(oxy)hydroxides, hydrothermal carbonates, sulfides, and authigenic clays are the main “ore” minerals. Mn-oxides were mainly deposited when the brine pool was more oxidized than it is today, but detailed logging shows that Fe-deposition and Mn-deposition also alternated at the scale of individual laminae, reflecting short-term fluctuations in the Lower Brine. Previous studies underestimated the importance of nonsulfide metal-bearing components, which formed by metal adsorption onto poorly crystalline Si-Fe-OOH particles. During diagenesis, the crystallinity of all phases increased, and the fine layering of the sediment was enhanced. Within a few meters of burial (corresponding to a few thousand years of deposition), biogenic (Ca)-carbonate was dissolved, manganosiderite formed, and metals originally in poorly crystalline phases or in pore water were incorporated into diagenetic sulfides, clays, and Fe-oxides. Permeable layers with abundant radiolarian tests were the focus for late-stage hydrothermal alteration and replacement, including deposition of amorphous silica and enrichment in elements such as Ba and Au

Treating the placenta to prevent adverse effects of gestational hypoxia on fetal brain development.

Some neuropsychiatric disease, including schizophrenia, may originate during prenatal development, following periods of gestational hypoxia and placental oxidative stress. Here we investigated if gestational hypoxia promotes damaging secretions from the placenta that affect fetal development and whether a mitochondria-targeted antioxidant MitoQ might prevent this. Gestational hypoxia caused low birth-weight and changes in young adult offspring brain, mimicking those in human neuropsychiatric disease. Exposure of cultured neurons to fetal plasma or to secretions from the placenta or from model trophoblast barriers that had been exposed to altered oxygenation caused similar morphological changes. The secretions and plasma contained altered microRNAs whose targets were linked with changes in gene expression in the fetal brain and with human schizophrenia loci. Molecular and morphological changes in vivo and in vitro were prevented by a single dose of MitoQ bound to nanoparticles, which were shown to localise and prevent oxidative stress in the placenta but not in the fetus. We suggest the possibility of developing preventative treatments that target the placenta and not the fetus to reduce risk of psychiatric disease in later life

Organic-rich sediments in brine-filled Shaban- and Kebrit Deeps, Northern Red Sea

The element compositions Si, Ca and Al of up to 2 1.1 ka old sediments in about 10 in long cores from the southern basin of the Shaban and Kebrit deeps in the northern Red Sea allowed a classification of major sediment types in carbonate sands and -muds and siliceous oozes. A FeOOH-enriched sediment horizon and a few samples with high Zn values in the Kebrit core indicate a hydrothermal origin probably near the brine-sea water interface with subsequent transport of hydrothermal compounds into the deep sediments. High organic carbon contents up to 8.4% are positively correlated with the Ba concentrations, which suggests that high bioproductivity, and rapid deposition (C-14 dating suggests a sedimentation rate near 70 cm/ka) led to the formation of sapropelic sediments between 11.8 and 13.6 ka (Younger Dryas). Organic petrological observations showed that the sediment organic material largely consists of <20 gm-sized roundish fecal pellets (intimate mixtures of organic matter and inorganic constituents) and bituminite. Terrestrial organic matter (pollens of land plants, fusinite etc.) is very rare in the sediment cores from both deeps. Organic-geochemical investigations of kerogens and organic extracts show that a significant (hydrothermal) hydrocarbon production did not occur in near-surface sediments of the Shaban and Kebrit deeps. Rock Eval pyrolysis of kerogens characterised the organic matter to be of type II quality. The delta C-13 values of the kerogens from the most prominent sapropel in the Shaban deep indicate an enrichment of(C-12-rich) nutrients in the water column during postglacial sapropel formation in the Younger Dryas. The n-alkane spectra are dominated by short chain lengths between n-C-15 and n-C-25 Prevailing n-C-15 to n-C-25 alkanes in low mature sediments are indicative of algal and microbial source. Pristane/phytane ratios are generally low (< I to similar to 1) which suggests that anoxic conditions prevailed within the anaerobic brine-filled deeps for the whole time covered by the sediments. This again indicates that sapropel formation was caused by high bioproductivity in the northern Red Sea rather than episodic stagnation with better preservation of the organic matter. Long-chain alkenones and sterols are the dominating compounds of the lipid fraction. Cholesterol contents in the sediment cores reflect phases of eukaryotes production in the water column, whereas the positive correlations of dinosterol with TOC and the amounts of total extract suggests that the major organic carbon source in the northern Red Sea during postglacial high-productivity stages were dinoflagellates. Another important carbon source, however, is indicated by the occurrence of 22,29,30-trisnorhopan-21 -one (TNH). Although the formation of TNH from its precursors is not fully understood, this compound probably results from microbial. degradation of intact bacteriohopanepolyols (BHP), which can be used as indicators for bacterial abundances and phyla. TNH is most likely produced at the brine-sea water interface where sedimenting organic matter accumulates and, if the redoxcline corresponds to the density gradient, the organic matter is subjected to efficient aerobic bacterial degradation processes. However, during high bioproductivity stage (Younger Dryas) the redoxcline was probably higher in the water column and thus, a significant TNH production at the brine-sea water interface did not occur at times of sapropel formation in the northern Red Sea deeps. (C) 2007 Elsevier B.V All rights reserved