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Background: An early diagnosis of a postpartum hemorrhage (PPH) can be challenging. The Shock Index (SI), the ratio of heart rate to systolic blood pressure, appears to be a useful indicator for the early diagnosis of severe PPH after vaginal delivery. Our primary aim was to evaluate if the SI has a predictive value for severe PPH following cesarean section (C-section) under spinal anesthesia (SA) and its best predictive threshold., Methods: Retrospective single-center trial including women scheduled for C-section under SA with prevention of maternal hypotension by phenylephrine, and complicated by PPH between 2019 and 2021. Women were divided into two groups: non-severe PPH (blood loss <1000 mL) versus severe PPH (blood loss ≥1000 mL). SI was calculated and compared between the groups at four different time points: T0: prior to C-section; T1: at incision; T2: 15 minutes from start of PPH; T3: end of PPH management. Using receiver operating characteristic curve, we calculated the area under the curve (AUC) and the best diagnostic threshold (sensitivity and specificity) for predicting severe PPH., Results: Overall, 129 patients were included, 26 (20.2%) with severe PPH. Median SI was significantly higher at T2 in the severe PPH group (1.14 (1.10-1.25) versus 1.0 (0.85-1.10), P<0.001), but not at other times of management. An SI value of ≥1.17 was the best threshold with an AUC of 0.81 (95% CI 0.72 to 0.90), a sensitivity of 0.42 and a specificity of 0.88., Conclusions: SI may be an early indicator of severe PPH during C-section under SA.

Background: Children with autism spectrum disorder (ASD) often require multiple interventions receiving general anesthesia during their lifetimes. However, a single negative experience may trigger and/or aggravate anxiety and subsequent development of unwanted behavior. This monocentric study assessed the compliance with mask induction of children with ASD who followed a preoperative preparation using behavioral training with positive reinforcement technique and use of mirroring technique., Methods: Prospective observational study including all children with ASD scheduled for day case treatment receiving general anesthesia, from November 2019 to August 2022. The primary outcome was Induction Compliance Checklist (ICC) score. The secondary outcomes were child's anxiety in the operating room assessed by the modified Yale Anxiety Scale (mYPAS), the comportment of the child in the recovery room, parental satisfaction about perioperative management (0 to 10 numerical scale) and the satisfaction of the caregivers about anesthetic management (0 to 10 numerical scale). Behavioral changes were assessed one month after the procedure when possible., Results: In total, 43 children from one to 17 years old were included. Median ICC score was 3 [1-6]. Induction Compliance was considered as excellent in 18.6% of patients, good in 39.5%, fair in 14.0% and poor in 27.9%. Seven patients (16.3%) needed restraint during induction., Conclusions: The use of behavioral and mirroring techniques implemented as a preparation program for children with ASD could facilitate mask induction of anesthesia. Such a preparation achieves good to excellent compliance in almost 60% of patients.

Objective: To describe and compare clinical and microbiological features, surgical and medical management, and outcomes of children with otogenic and sinogenic intracranial empyema (IE) in an institution with an established multidisciplinary protocol. To use the study findings to inform and update the institutional algorithm., Methods: Retrospective analysis was carried out on the electronic healthcare records of all children with oto-sinogenic IE admitted in a 5-year period., Results: A total of 76 patients were identified and treated according to an institutional protocol. Two distinct groups were identified: intracranial empyema related to otogenic infection (OI-IE, n = 36) or sinogenic infection (SI-IE, n = 40). SI-IE was seen in older children and had a significantly higher morbidity. Sub-dural IE was seen in a minority (n = 16) and only in SI-IE and required urgent collaborative ENT-neurosurgery. Extra-dural IE occurred more frequently and was seen in both SI-IE and OI-IE. No death and overall low morbidity were observed. Particularities found in SI-IE and OI-IE groups (as thrombosis, microbiology, antibiotic treatment, duration and outcome) permitted the delineation of these groups in our updated algorithm., Conclusion: The presence of a collaborative multidisciplinary protocol permits the step-wise co-ordination of care for these complex patients in our institution. All patients received prompt imaging, urgent surgical intervention, and antibiotic treatment. Microbiological identification was possible for each patient and antibiotic rationalization was permitted through use of Polymerase chain reaction (PCR) testing in cases of sterile cultures. Of note, intracranial empyema related to sinogenic infection is shown to have significantly more severe clinical presentation, a higher morbidity, and a longer duration of antibiotic therapy than that related to otogenic infection. Study findings allowed for the update and clarification of the institutional protocol, which now clearly demarcates the clinical presentation, biological evidence, radiology, surgical and medical treatments in children with oto-sinogenic IE., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: As advance healthcare directives gain clarity in state legislation in Ireland, anaesthesiologists will come across patients with resuscitation orders that will demand interpretation when encountered perioperatively. Studies show variable perceptions among anaesthesiologists towards the binding nature of resuscitation orders in the context of anaesthesia provision. Currently, knowledge, perceptions and practices of anaesthesiologists in Ireland towards such orders are not known., Methods: A cross-sectional online survey was distributed to anaesthesiologists in adult teaching hospitals., Results: In this cohort, 65.9% of those surveyed did not know if there was a local hospital policy advance healthcare directive containing, do not attempt resuscitation, decisions in the perioperative period in their current hospital; 57.7% did not know if there was a policy for not for resuscitation orders; 74.8% did not know if there are guidelines for the management of patients with resuscitation orders. Irrespective of the presence of an order stating otherwise, 43.9% would initiate resuscitation in the event of any arrest occurring in theatre, with 66.7% initiating resuscitation if secondary to iatrogenesis., Conclusions: By uncovering low self-perceived levels of knowledge and mixed perceptions towards resuscitation orders, the authors hope that the study initiates much-needed conversations on the topic, particularly at a time when advance healthcare directives find a more firm legal footing in Ireland.

Cerebral near infrared spectroscopy (NIRS) monitoring has been extensively applied in neonatology and in cardiac surgery, becoming a standard in many pediatric cardiac centers. However, compensatory physiological mechanisms favor cerebral perfusion to the detriment of peripheral tissue oxygenation. Therefore, simultaneous measurement of cerebral and somatic oxygen saturation has been advocated to ease the differential diagnosis between central and peripheral sources of hypoperfusion, which may go undetected by standard monitoring and not mirrored by cerebral NIRS alone. A clinical algorithm already exists in cardiac surgery, aimed to correct intraoperative cerebral oxygen desaturations. A similar algorithm still lacks in noncardiac pediatric surgery. The goal of this paper is to propose a clinical algorithm for the combined use of cerebral and somatic NIRS monitoring during anesthesia in the pediatric population undergoing noncardiac surgery. A panel of experienced pediatric anesthetists developed the algorithm that is based on the clinical experience and intraoperative observations. It aims to lessen the current variability in interpreting NIRS measurement. Multisite NIRS monitoring was achieved applying one pediatric sensor to the forehead for cerebral tissue perfusion reading and a second one to the decumbent lumbar region for recording somatic renal tissue perfusion. The algorithm describes a sequence of acts aimed to identify the putative cause of intraoperative organ tissue desaturation and suggests clinical interventions expected to restore adequate tissue perfusion. It is composed of two arms: the main arm includes patients with an observed decrease in cerebral perfusion (CrO2), the second one includes those with a stable CrSO2 with declining RrSO2. Described also are five clinical cases of infants and neonates in whom pathological alterations of organ perfusion were detected using intraoperative multisite NIRS monitoring, portrayed in the accompanying figures (Annex)., (© 2022 John Wiley & Sons Ltd.)

Mycobacterium abscessus , an opportunistic pathogen responsible for pulmonary infections, contains genes predicted to encode two steroid catabolic pathways: a cholesterol catabolic pathway similar to that of Mycobacterium tuberculosis and a 4-androstenedione (4-AD) catabolic pathway. Consistent with this prediction, M. abscessus grew on both steroids. In contrast to M. tuberculosis , Rhodococcus jostii RHA1, and other Actinobacteria, the cholesterol and 4-AD catabolic gene clusters of the M. abscessus complex lack genes encoding HsaD, the meta -cleavage product (MCP) hydrolase. However, M. abscessus ATCC 19977 harbors two hsaD homologs elsewhere in its genome. Only one of the encoded enzymes detectably transformed steroid metabolites. Among tested substrates, HsaD Mab and HsaD Mtb of M. tuberculosis had highest substrate specificities for MCPs with partially degraded side chains thioesterified with coenzyme A ( k cat / K M = 1.9 × 10 4 and 5.7 × 10 3 mM -1 s -1 , respectively). Consistent with a dual role in cholesterol and 4-AD catabolism, HsaD Mab also transformed nonthioesterified substrates efficiently, and a Δ hsaD mutant of M. abscessus grew on neither steroid. Interestingly, both steroids prevented growth of the mutant on acetate. The Δ hsaD mutant of M. abscessus excreted cholesterol metabolites with a fully degraded side chain, while the corresponding RHA1 mutant excreted metabolites with partially degraded side chains. Finally, the Δ hsaD mutant was not viable in macrophages. Overall, our data establish that the cholesterol and 4-AD catabolic pathways of M. abscessus are unique in that they converge upstream of where this occurs in characterized steroid-catabolizing bacteria. The data further indicate that cholesterol is a substrate for intracellular bacteria and that cholesterol-dependent toxicity is not strictly dependent on coenzyme A sequestration.

A 6-day-old, 4.0 kg neonate presented with intestinal malrotation, necessitating laparotomy. Intra-operatively, an ultrasound-guided erector spinae plane block was performed under general anesthesia with administration of 1 mg/kg levobupivacaine. Minutes following this, acute cardiac compromise was evident from a tapering end-tidal carbon dioxide, falling oxygen saturations, and low blood pressure. Intravenous epinephrine 1 mcg/kg was administered, with some hemodynamic improvement. Intralipid (1.5 ml/kg) was given, with a return to normal hemodynamic parameters. This is the first case report of suspected local anesthetic toxicity in a neonate following an erector spinae plane block., (© 2021 John Wiley & Sons Ltd.)

Steroid-degrading bacteria, including Mycobacterium tuberculosis ( Mtb ), utilize an architecturally distinct subfamily of acyl coenzyme A dehydrogenases (ACADs) for steroid catabolism. These ACADs are α 2 β 2 heterotetramers that are usually encoded by adjacent fadE- like genes. In mycobacteria, ipdE1 and ipdE2 (formerly fadE30 and fadE33 ) occur in divergently transcribed operons associated with the catabolism of 3aα- H -4α(3'-propanoate)-7aβ-methylhexahydro-1,5-indanedione (HIP), a steroid metabolite. In Mycobacterium smegmatis , Δ ipdE1 and Δ ipdE2 mutants had similar phenotypes, showing impaired growth on cholesterol and accumulating 5-OH HIP in the culture supernatant. Bioinformatic analyses revealed that IpdE1 and IpdE2 share many of the features of the α- and β-subunits, respectively, of heterotetrameric ACADs that are encoded by adjacent genes in many steroid-degrading proteobacteria. When coproduced in a rhodococcal strain, IpdE1 and IpdE2 of Mtb formed a complex that catalyzed the dehydrogenation of 5OH-HIP coenzyme A (5OH-HIP-CoA) to 5OH-3aα- H -4α(3'-prop-1-enoate)-7aβ-methylhexa-hydro-1,5-indanedione coenzyme A (( E ) - 5OH-HIPE-CoA). This corresponds to the initial step in the pathway that leads to degradation of steroid C and D rings via β-oxidation. Small-angle X-ray scattering revealed that the IpdE1-IpdE2 complex was an α 2 β 2 heterotetramer typical of other ACADs involved in steroid catabolism. These results provide insight into an important class of steroid catabolic enzymes and a potential virulence determinant in Mtb .

Mycobacterium tuberculosis ( Mtb ) grows on host-derived cholesterol during infection. IpdAB, found in all steroid-degrading bacteria and a determinant of pathogenicity, has been implicated in the hydrolysis of the last steroid ring. Phylogenetic analyses revealed that IpdAB orthologs form a clade of CoA transferases (CoTs). In a coupled assay with a thiolase, IpdAB transformed the cholesterol catabolite ( R )-2-(2-carboxyethyl)-3-methyl-6-oxocyclohex-1-ene-1-carboxyl-CoA (COCHEA-CoA) and CoASH to 4-methyl-5-oxo-octanedioyl-CoA (MOODA-CoA) and acetyl-CoA with high specificity ( k cat / K m = 5.8 ± 0.8 × 10 4 M -1 ⋅s -1 ). The structure of MOODA-CoA was consistent with IpdAB hydrolyzing COCHEA-CoA to a β-keto-thioester, a thiolase substrate. Contrary to characterized CoTs, IpdAB exhibited no activity toward small CoA thioesters. Further, IpdAB lacks the catalytic glutamate residue that is conserved in the β-subunit of characterized CoTs and a glutamyl-CoA intermediate was not trapped during turnover. By contrast, Glu105 A , conserved in the α-subunit of IpdAB, was essential for catalysis. A crystal structure of the IpdAB·COCHEA-CoA complex, solved to 1.4 Å, revealed that Glu105 A is positioned to act as a catalytic base. Upon titration with COCHEA-CoA, the E105A A variant accumulated a yellow-colored species (λ max = 310 nm; K d = 0.4 ± 0.2 μM) typical of β-keto enolates. In the presence of D 2 O, IpdAB catalyzed the deuteration of COCHEA-CoA adjacent to the hydroxylation site at rates consistent with k cat Based on these data and additional IpdAB variants, we propose a retro-Claisen condensation-like mechanism for the IpdAB-mediated hydrolysis of COCHEA-CoA. This study expands the range of known reactions catalyzed by the CoT superfamily and provides mechanistic insight into an important determinant of Mtb pathogenesis., Competing Interests: The authors declare no conflict of interest.

Most mycolic acid-containing actinobacteria and some proteobacteria use steroids as growth substrates, but the catabolism of the last two steroid rings has yet to be elucidated. In Mycobacterium tuberculosis , this pathway includes virulence determinants and has been proposed to be encoded by the KstR2-regulated genes, which include a predicted coenzyme A (CoA) transferase gene ( ipdAB ) and an acyl-CoA reductase gene ( ipdC ). In the presence of cholesterol, Δ ipdC and Δ ipdAB mutants of either M. tuberculosis or Rhodococcus jostii strain RHA1 accumulated previously undescribed metabolites: 3aα- H -4α(carboxyl-CoA)-5-hydroxy-7aβ-methylhexahydro-1-indanone (5-OH HIC-CoA) and ( R )-2-(2-carboxyethyl)-3-methyl-6-oxocyclohex-1-ene-1-carboxyl-CoA (COCHEA-CoA), respectively. A Δ fadE32 mutant of Mycobacterium smegmatis accumulated 4-methyl-5-oxo-octanedioic acid (MOODA). Incubation of synthetic 5-OH HIC-CoA with purified IpdF, IpdC, and enoyl-CoA hydratase 20 (EchA20), a crotonase superfamily member, yielded COCHEA-CoA and, upon further incubation with IpdAB and a CoA thiolase, yielded MOODA-CoA. Based on these studies, we propose a pathway for the final steps of steroid catabolism in which the 5-member ring is hydrolyzed by EchA20, followed by hydrolysis of the 6-member ring by IpdAB. Metabolites accumulated by Δ ipdF and Δ echA20 mutants support the model. The conservation of these genes in known steroid-degrading bacteria suggests that the pathway is shared. This pathway further predicts that cholesterol catabolism yields four propionyl-CoAs, four acetyl-CoAs, one pyruvate, and one succinyl-CoA. Finally, a Δ ipdAB M. tuberculosis mutant did not survive in macrophages and displayed severely depleted CoASH levels that correlated with a cholesterol-dependent toxicity. Our results together with the developed tools provide a basis for further elucidating bacterial steroid catabolism and virulence determinants in M. tuberculosis. IMPORTANCE Bacteria are the only known steroid degraders, but the pathway responsible for degrading the last two steroid rings has yet to be elucidated. In Mycobacterium tuberculosis , this pathway includes virulence determinants. Using a series of mutants in M. tuberculosis and related bacteria, we identified a number of novel CoA thioesters as pathway intermediates. Analysis of the metabolites combined with enzymological studies establishes how the last two steroid rings are hydrolytically opened by enzymes encoded by the KstR2 regulon. Our results provide experimental evidence for novel ring-degrading enzymes, significantly advance our understanding of bacterial steroid catabolism, and identify a previously uncharacterized cholesterol-dependent toxicity that may facilitate the development of novel tuberculosis therapeutics., (Copyright © 2017 Crowe et al.)

Purpose: Post-surgical adhesions remain a significant concern following abdominopelvic surgery. This study was to assess safety, manageability and explore preliminary efficacy of applying a degradable hydrogel adhesion barrier to areas of surgical trauma following gynecologic laparoscopic abdominopelvic surgery., Methods: This first-in-human, prospective, randomized, multicenter, subject- and reviewer-blinded clinical study was conducted in 78 premenopausal women (18-46 years) wishing to maintain fertility and undergoing gynecologic laparoscopic abdominopelvic surgery with planned clinically indicated second-look laparoscopy (SLL) at 4-12 weeks. The first two patients of each surgeon received hydrogel, up to 30 mL sprayed over all sites of surgical trauma, and were assessed for safety and application only (n = 12). Subsequent subjects (n = 66) were randomized 1:1 to receive either hydrogel (Treatment, n = 35) or not (Control, n = 31); 63 completed the SLL., Results: No adverse event was assessed as serious, or possibly device related. None was severe or fatal. Adverse events were reported for 17 treated subjects (17/47, 36.2%) and 13 Controls (13/31, 41.9%). For 95.7% of treated subjects, surgeons found the device "easy" or "very easy" to use; in 54.5%, some residual material was evident at SLL. For 63 randomized subjects who completed the SLL, adjusted between-group difference in the change from baseline adhesion score demonstrated a 41.4% reduction for Treatment compared with Controls (p = 0.017), with a 49.5% reduction (p = 0.008) among myomectomy subjects (n = 34)., Conclusion: Spray application of a degradable hydrogel adhesion barrier during gynecologic laparoscopic abdominopelvic surgery was performed easily and safely, without evidence of clinically significant adverse outcomes. Data suggest the hydrogel was effective in reducing postoperative adhesion development, particularly following myomectomy., Competing Interests: Compliance with ethical standards All authors have completed the journal conflict of interest form and a declaration has been made within the manuscript. The study was reviewed and approved by the national Competent Authority in Germany (BfArM Federal Institute for Drugs & Medical Devices) and in Greece (National Organization for Medicines), and received approval from the Independent Ethics Committee in Germany (Ethics Committee of the Medical Association of Lower Saxony) and the National Ethics Committee in Greece. The study was conducted to be compliant with the Declaration of Helsinki (2008) and the requirements and guidance provided in ISO 14155 (2011), US and International Standards of Good Clinical Practice (FDA Title 21 CFR part 812 and International equivalent guidelines), and to meet the requirements of the national regulators in Germany and Greece as well as the designated ethical committee in Germany and the national ethics committee in Greece. All patients gave written informed consent to participate in the study prior to any protocol-related procedures. Conflict of interest GHT and MPD received consultancy funding as clinical advisers to the study and to Actamax. Corvus Communications Limited (AMC) was retained as clinical study coordinator and adhesion consultant. TDE is the Clinical and Regulatory Director of Actamax. In accordance with the journal’s policy, full declarations on funding and potential conflicts of interest for all authors have been declared on the journal’s COI form. Funding Actamax Surgical Materials LLC as study Sponsor provided funding to all institutions and organizations involved in the study.

Cholesterol can be a major carbon source forMycobacterium tuberculosisduring infection, both at an early stage in the macrophage phagosome and later within the necrotic granuloma. KstR is a highly conserved TetR family transcriptional repressor that regulates a large set of genes responsible for cholesterol catabolism. Many genes in this regulon, includingkstR, are either induced during infection or are essential for survival ofM. tuberculosis in vivo In this study, we identified two ligands for KstR, both of which are CoA thioester cholesterol metabolites with four intact steroid rings. A metabolite in which one of the rings was cleaved was not a ligand. We confirmed the ligand-protein interactions using intrinsic tryptophan fluorescence and showed that ligand binding strongly inhibited KstR-DNA binding using surface plasmon resonance (IC50for ligand = 25 nm). Crystal structures of the ligand-free form of KstR show variability in the position of the DNA-binding domain. In contrast, structures of KstR·ligand complexes are highly similar to each other and demonstrate a position of the DNA-binding domain that is unfavorable for DNA binding. Comparison of ligand-bound and ligand-free structures identifies residues involved in ligand specificity and reveals a distinctive mechanism by which the ligand-induced conformational change mediates DNA release., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

Purpose: Risk factors for post-surgical adhesions following gynaecological surgery have been identified, but their relative importance has not been precisely determined. No practical tool exists to help gynaecological surgeons evaluate the risk of adhesions in their patients. The purpose of the study was to develop an Adhesion Risk Score to provide a simple tool that will enable gynaecological surgeons to routinely quantify the risk of post-surgical adhesions in individual patients., Methods: A group of European gynaecological surgeons searched the literature to identify the risk factors and the surgical operations reported as carrying a risk of post-surgical adhesions. Through consensus process of meetings and communication, a four-point scale was then used by each surgeon to attribute a specific weight to each item and collective agreement reached on identified risk factors and their relative importance to allow construct of a useable risk score., Results: Ten preoperative and 10 intraoperative risk factors were identified and weighed, leading to the creation of two sub-scores to identify women at risk prior to and during surgery. The Preoperative Risk Score can range from 0 to 36, and the Intraoperative Risk Score from 3 to 31. Several thresholds between these limits may be used to identify women with low, medium, and high risk of post-surgical adhesions., Conclusions: Gynaecological surgeons are encouraged to use this Adhesion Risk Score to identify the risk of adhesions in their patients. This will allow better informed use of available resources to target preventive measures in women at high risk of post-surgical adhesions.

Aim: Symptomatic diverticular disease (DD) may be increasing in incidence in western society particularly in younger age groups. This study aimed to describe hospital admission rates and management for DD in Scotland between 2000 and 2010., Method: Data were obtained from the Scottish Morbidity Records (SMR01). The study cohort included all patients with a hospital admission and a primary diagnosis of DD of the large intestine (ICD-10 primary code K57)., Results: Scottish NHS hospitals reported 90 990 admissions for DD (in 87 314 patients) from 2000 to 2010. The annual number of admissions increased by 55.2% from 6591 in 2000 to 10,228 in 2010, an average annual increase per year of 4.5%. Most of the increase attributable to DD was due to elective day cases (3618 in 2000; 6925 in 2010) a likely consequence of a greater proportion of the population accessing colonoscopy over that time period. There was an 11% increase in inpatient admissions (2973-3303), 60% of these patients being women. Admissions in younger age groups increased proportionally in the later years of the study, and there was an association between DD admissions and greater deprivation. Despite an increase in complicated DD from 22.9% in 2000 to 27.1% in 2010 and a 16.8% increase in emergency inpatient admissions, the rate of surgery fell during the period of study., Conclusion: This report supports findings of other population-based studies of western countries indicating that DD is an increasing burden on health service resources, particularly in younger age groups., (Colorectal Disease © 2014 The Association of Coloproctology of Great Britain and Ireland.)

Mycobacterium tuberculosis (Mtb) relies on a specialized set of metabolic pathways to support growth in macrophages. By conducting an extensive, unbiased chemical screen to identify small molecules that inhibit Mtb metabolism within macrophages, we identified a significant number of novel compounds that limit Mtb growth in macrophages and in medium containing cholesterol as the principle carbon source. Based on this observation, we developed a chemical-rescue strategy to identify compounds that target metabolic enzymes involved in cholesterol metabolism. This approach identified two compounds that inhibit the HsaAB enzyme complex, which is required for complete degradation of the cholesterol A/B rings. The strategy also identified an inhibitor of PrpC, the 2-methylcitrate synthase, which is required for assimilation of cholesterol-derived propionyl-CoA into the TCA cycle. These chemical probes represent new classes of inhibitors with novel modes of action, and target metabolic pathways required to support growth of Mtb in its host cell. The screen also revealed a structurally-diverse set of compounds that target additional stage(s) of cholesterol utilization. Mutants resistant to this class of compounds are defective in the bacterial adenylate cyclase Rv1625/Cya. These data implicate cyclic-AMP (cAMP) in regulating cholesterol utilization in Mtb, and are consistent with published reports indicating that propionate metabolism is regulated by cAMP levels. Intriguingly, reversal of the cholesterol-dependent growth inhibition caused by this subset of compounds could be achieved by supplementing the media with acetate, but not with glucose, indicating that Mtb is subject to a unique form of metabolic constraint induced by the presence of cholesterol.

Catabolism of host cholesterol is critical to the virulence of Mycobacterium tuberculosis and is a potential target for novel therapeutics. KstR2, a TetR family repressor (TFR), regulates the expression of 15 genes encoding enzymes that catabolize the last half of the cholesterol molecule, represented by 3aα-H-4α(3'-propanoate)-7aβ-methylhexahydro-1,5-indane-dione (HIP). Binding of KstR2 to its operator sequences is relieved upon binding of HIP-CoA. A 1.6-Å resolution crystal structure of the KstR2(Mtb)·HIP-CoA complex reveals that the KstR2(Mtb) dimer accommodates two molecules of HIP-CoA. Each ligand binds in an elongated cleft spanning the dimerization interface such that the HIP and CoA moieties interact with different KstR2(Mtb) protomers. In isothermal titration calorimetry studies, the dimer bound 2 eq of HIP-CoA with high affinity (K(d) = 80 ± 10 nm) but bound neither HIP nor CoASH. Substitution of Arg-162 or Trp-166, residues that interact, respectively, with the diphosphate and HIP moieties of HIP-CoA, dramatically decreased the affinity of KstR2(Mtb) for HIP-CoA but not for its operator sequence. The variant of R162M that decreased the affinity for HIP-CoA (ΔΔG = 13 kJ mol(-1)) is consistent with the loss of three hydrogen bonds as indicated in the structural data. A 24-bp operator sequence bound two dimers of KstR2. Structural comparisons with a ligand-free rhodococcal homologue and a DNA-bound homologue suggest that HIP-CoA induces conformational changes of the DNA-binding domains of the dimer that preclude their proper positioning in the major groove of DNA. The results provide insight into KstR2-mediated regulation of expression of steroid catabolic genes and the determinants of ligand binding in TFRs., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

Pseudomonas putida DOC21, a soil-dwelling proteobacterium, catabolizes a variety of steroids and bile acids. Transposon mutagenesis and bioinformatics analyses identified four clusters of steroid degradation (std) genes encoding a single catabolic pathway. The latter includes three predicted acyl-CoA synthetases encoded by stdA1, stdA2 and stdA3 respectively. The ΔstdA1 and ΔstdA2 deletion mutants were unable to assimilate cholate or other bile acids but grew well on testosterone or 4-androstene-3,17-dione (AD). In contrast, a ΔstdA3 mutant grew poorly in media containing either testosterone or AD. When cells were grown with succinate in the presence of cholate, ΔstdA1 accumulated Δ(1/4) -3-ketocholate and Δ(1,4) -3-ketocholate, whereas ΔstdA2 only accumulated 7α,12α-dihydroxy-3-oxopregna-1,4-diene-20-carboxylate (DHOPDC). When incubated with testosterone or bile acids, ΔstdA3 accumulated 3aα-H-4α(3'propanoate)-7aβ-methylhexahydro-1,5-indanedione (HIP) or the corresponding hydroxylated derivative. Biochemical analyses revealed that StdA1 converted cholate, 3-ketocholate, Δ(1/4) -3-ketocholate, and Δ(1,4) -3-ketocholate to their CoA thioesters, while StdA2 transformed DHOPDC to DHOPDC-CoA. In contrast, purified StdA3 catalysed the CoA thioesterification of HIP and its hydroxylated derivatives. Overall, StdA1, StdA2 and StdA3 are acyl-CoA synthetases required for the complete degradation of bile acids: StdA1 and StdA2 are involved in degrading the C-17 acyl chain, whereas StdA3 initiates degradation of the last two steroid rings. The study highlights differences in steroid catabolism between Proteobacteria and Actinobacteria., (© 2014 Society for Applied Microbiology and John Wiley & Sons Ltd.)

Background: National Scottish data were used to compare 3-year mortality in patients hospitalized for Crohn's disease (CD) between 1998-2000 and 2007-2009., Methods: The linked Scottish Morbidity Records database was used to identify patients admitted with CD during two periods: Period 1 (1998-2000) and Period 2 (2007-2009). 3-year mortality and standardized mortality ratio (SMR) were determined and multivariable logistic regression analysis of associated factors was performed. Mortality was determined following four admission types: surgery-elective, surgery-emergency, medical-elective and medical-emergency. 3-year mortality was compared between study periods using age-standardized rates., Results: The number of patients per 100,000 population hospitalized with CD per year was unchanged (15.7 [Period 1]; 14.4 [Period 2]). Overall crude and adjusted 3-year mortality rates were also unchanged (crude mortality 9.0%-9.1%, adjusted mortality odds ratio [OR]=0.87, 95% confidence interval [CI] 0.65-1.17; p=0.36). The adjusted 3-year mortality increased following elective surgery (Period 1: 1/303 [0.3%]; Period 2: 9/261 [3.4%]); OR=13.5 [CI 1.66-109.99]) and decreased following emergency medical admission (Period 1: 99/779 [12.7%]; Period 2:86/802 [10.7%]; OR=0.68 [CI 0.47-0.97]). Directly age-standardized mortality rates were similar (Period 1:338/10,000 person years [CI 282-394]; Period 2:333/10,000 person years [CI 276-390], p=0.2). On multivariable regression, age, deprivation status, comorbidity and the length of hospital stay were associated with mortality in both periods. High 3-year mortality was observed during both periods in patients between 50 and 64years (Period 1: 33/298 [11.1%, SMR=4.8 [CI 3.44-6.63], Period 2: 33/296 [11.1%, SMR=5.9 [4.14-8.22]) and over 65years(Period 1: 94/275 [34.2%, SMR=2.78 [CI 2.42-3.62], Period 2: 78/251 [31.1%, SMR=3.31 [2.64-4.11])., Conclusion: Nationwide linkage data demonstrate that overall 3-year mortality after hospitalization for CD is high, especially in patients over 50years, and has not altered between the time periods 1998-2000 and 2007-2009., (Crown Copyright © 2014. Published by Elsevier B.V. All rights reserved.)

Background: Scottish nationwide linkage data from 1998 to 2000 demonstrated high 3-year mortality in patients hospitalised with ulcerative colitis (UC)., Aim: To compare 3-year mortality, and factors related to mortality, in Scottish patients hospitalised with UC between 1998-2000 and 2007-2009., Methods: The Scottish Morbidity Records and linked datasets were used to assess 3-year mortality, standardised mortality ratio (SMR) and multivariate analyses of factors associated with 3-year mortality. The 3-year mortality was determined after four admission types: surgery-elective or emergency; medical-elective or emergency. Age-standardised mortality rates (ASR) were used to compare mortality rates between periods., Results: Ulcerative colitis admissions increased from 10.6 in Period 1 to 11.6 per 100 000 population per year in Period 2 (P = 0.046). Crude and adjusted 3-year mortality fell between time periods (crude 12.2% to 8.3%; adjusted OR 0.59, CI 0.42-0.81, P = 0.04). Adjusted 3-year mortality following emergency medical admission (OR 0.58, CI 0.39-0.87, P = 0.003) and in patients >65 years (38.8% to 28.7%, P = 0.02) was lower in Period 2. The SMR in period 1 was 3.04 and 2.96 in Period 2. Directly age-standardised mortality decreased from 373 (CI 309-437) to 264 (CI 212-316) per 10 000 person-years. On multivariate analysis, increasing age (50-64 years OR 7.11 (CI 2.77-18.27, P < 0.05); 65-74 years OR 14.70 (CI 5.65-38.25 P < 0.05); >75 years OR 46.42 (CI 18.29-117.78, P < 0.001) and co-morbidity (OR 3.02, CI 1.72-5.28, P < 0.001) were significantly associated with 3-year mortality in Period 2., Conclusions: Comparisons of crude and adjusted mortality rates suggest significant improvement in outcome over the last decade - however, mortality remains high, and older age and co-morbidity are important predictors of outcome., (© 2014 John Wiley & Sons Ltd.)

Bacterial steroid catabolism is an important component of the global carbon cycle and has applications in drug synthesis. Pathways for this catabolism involve multiple acyl coenzyme A (CoA) synthetases, which activate alkanoate substituents for β-oxidation. The functions of these synthetases are poorly understood. We enzymatically characterized four distinct acyl-CoA synthetases from the cholate catabolic pathway of Rhodococcus jostii RHA1 and the cholesterol catabolic pathway of Mycobacterium tuberculosis. Phylogenetic analysis of 70 acyl-CoA synthetases predicted to be involved in steroid metabolism revealed that the characterized synthetases each represent an orthologous class with a distinct function in steroid side-chain degradation. The synthetases were specific for the length of alkanoate substituent. FadD19 from M. tuberculosis H37Rv (FadD19Mtb) transformed 3-oxo-4-cholesten-26-oate (kcat/Km = 0.33 × 10(5) ± 0.03 × 10(5) M(-1) s(-1)) and represents orthologs that activate the C8 side chain of cholesterol. Both CasGRHA1 and FadD17Mtb are steroid-24-oyl-CoA synthetases. CasG and its orthologs activate the C5 side chain of cholate, while FadD17 and its orthologs appear to activate the C5 side chain of one or more cholesterol metabolites. CasIRHA1 is a steroid-22-oyl-CoA synthetase, representing orthologs that activate metabolites with a C3 side chain, which accumulate during cholate catabolism. CasI had similar apparent specificities for substrates with intact or extensively degraded steroid nuclei, exemplified by 3-oxo-23,24-bisnorchol-4-en-22-oate and 1β(2'-propanoate)-3aα-H-4α(3″-propanoate)-7aβ-methylhexahydro-5-indanone (kcat/Km = 2.4 × 10(5) ± 0.1 × 10(5) M(-1) s(-1) and 3.2 × 10(5) ± 0.3 × 10(5) M(-1) s(-1), respectively). Acyl-CoA synthetase classes involved in cholate catabolism were found in both Actinobacteria and Proteobacteria. Overall, this study provides insight into the physiological roles of acyl-CoA synthetases in steroid catabolism and a phylogenetic classification enabling prediction of specific functions of related enzymes.

The cholesterol catabolic pathway occurs in most mycolic acid-containing actinobacteria, such as Rhodococcus jostii RHA1, and is critical for Mycobacterium tuberculosis (Mtb) during infection. FadD3 is one of four predicted acyl-CoA synthetases potentially involved in cholesterol catabolism. A ΔfadD3 mutant of RHA1 grew on cholesterol to half the yield of wild-type and accumulated 3aα-H-4α(3'-propanoate)-7aβ-methylhexahydro-1,5-indanedione (HIP), consistent with the catabolism of half the steroid molecule. This phenotype was rescued by fadD3 of Mtb. Moreover, RHA1 but not ΔfadD3 grew on HIP. Purified FadD3(Mtb) catalysed the ATP-dependent CoA thioesterification of HIP and its hydroxylated analogues, 5α-OH HIP and 1β-OH HIP. The apparent specificity constant (k(cat) /K(m) ) of FadD3(Mtb) for HIP was 7.3 ± 0.3 × 10(5)  M(-1)  s(-1) , 165 times higher than for 5α-OH HIP, while the apparent K(m) for CoASH was 110 ± 10 μM. In contrast to enzymes involved in the catabolism of rings A and B, FadD3(Mtb) did not detectably transform a metabolite with a partially degraded C17 side-chain. Overall, these results indicate that FadD3 is a HIP-CoA synthetase that initiates catabolism of steroid rings C and D after side-chain degradation is complete. These findings are consistent with the actinobacterial kstR2 regulon encoding ring C/D degradation enzymes., (© 2012 Blackwell Publishing Ltd.)

Background: Although population-based studies of patients with Crohn's disease (CD) suggest only a modestly increased mortality, recent data have raised concerns regarding the outcome of CD patients requiring hospitalisation., Aim: To determine the mortality and contributory factors in 1595 patients hospitalised for CD in Scotland between 1998 and 2000., Methods: The Scottish Morbidity Records database and linked datasets were used to assess longitudinal patient outcome, and to explore associations between 3-year mortality and age, sex, comorbidity, admission type and social deprivation. The standardised mortality ratio (SMR) at 3 years from admission was calculated with reference to the Scottish population., Results: The SMR was 3.31 (95% confidence interval 2.80-3.89). This was increased in all patients, other than those <30 years at presentation, and was highest in patients aged 50-64 years (SMR 4.84 [3.44-6.63]). On multivariate analysis, age >50, admission type, comorbidity, social deprivation and length of admission were significantly associated with mortality. Other than age, admission type was the strongest factor predictive of death. Three-year crude mortality was 0.3% for elective surgical, 8.7% for emergency surgical, 8.3% for elective nonsurgical and 12.7% for emergency nonsurgical admission (P < 0.001)., Conclusions: The study demonstrates high mortality rates in patients hospitalised during 1998-2000 for CD, especially in patients over 50. Elective surgery is associated with lower mortality than emergency surgery or medical therapy. Further study is needed to determine whether these patterns have changed following the introduction of biological treatment., (© 2011 Blackwell Publishing Ltd.)

Background: Recent data associated higher mortality with medical rather than surgical intervention in patients with ulcerative colitis who require hospitalization., Aim: To examine factors influencing UC-related mortality in Scotland., Method: Using the national record linkage database 1998-2000, 3-year mortality was determined after four admission types: colectomy-elective or emergency; no colectomy-elective or emergency., Results: Of 1078 patients, crude 3-year mortality rates were: colectomy elective 5.6% (n = 177) and emergency 9.0% (100); no colectomy elective 9.8% (244) and emergency 16.0% (557). Using elective colectomy as reference, multivariate analysis [OR (95% CI)] showed that admission age >50 years [OR 5.46 (2.29-11.95)], male gender [OR 1.92 (1.23-3.02)], comorbidity [OR 2.2 (1.38-3.51)], length of stay >15 days [OR 2.04 (1.08-3.84)] and prior IBD admission [OR 1.66 (1.06-2.61)] were independently related to mortality. Age was the strongest determinant. No patient <30 years died. Mortality of patients aged <50 years [10/587 (1.7%)] was significantly lower than mortality of those aged 50-64 years [26/246 (10.6%)] (chi(2) = 32.91; P < 0.0000001) and >65 [96/245 (39.2%)] (chi(2) = 218.2; P < 0.0000001). For those patients aged more than 65 years, mortality in the four groups was 29.4%, 33.3%, 28.1% and 44.7%- all greater than expected in the Scottish population on assessment of standardized mortality ratios., Conclusion: Hospital admission in UC patients >65 is associated with high mortality. Management strategies should consider this by treatment in specialist units, early investigation, focused medical treatment and earlier surgical referral.

Purpose: The objective of this study is to quantify the overall burden (operative and nonoperative) of small bowel obstruction caused by adhesions after laparotomy in children., Methods: Data from the Scottish National Health Service Medical Record Linkage database were used to assess risk of an adhesion-related readmission in the 5 years after open abdominal surgery in children and adolescents younger than 16 years from April 1996 to March 1997., Results: A total of 1581 children underwent abdominal surgery (ie, from duodenum downward). Patients undergoing surgery on the ileum had the highest risk of readmission because of adhesions in the subsequent 5 years after surgery (9.2%)--formation/closure of ileostomy had the greatest risk (25%); 6.5% of children were readmitted after general laparotomy, 4.7% after duodenal surgery, and 2.1% after colonic surgery. The incidence of readmissions was 0.3% after appendicectomy. The overall readmission rate was 5.3% (if appendicectomy was excluded) and 1.1% (if appendicectomy was included)., Conclusion: This population-based study has demonstrated that children have a high incidence of readmissions owing to adhesions after lower abdominal surgery. The risks are related to the site and the type of the original surgery. The risk of further readmissions was highest in the first year but continued with time. The data enable surgeons to target antiadhesion strategies at procedures that lead to a high risk of adhesions.

Purpose: The aim of this study was to quantify the risk of adhesion-related readmissions after abdominal surgery in children., Methods: This was a population-based study. One thousand five hundred eighty-one children younger than 16 years underwent laparotomy in 1996. Patients were identified from the Scottish Morbidity Records database and followed up for 4 years., Results: In children younger than 5 years, 4.2% had a readmission "directly" owing to adhesions. In children younger than 16 years, 1.1% had a readmission directly owing to adhesions. The highest risk of readmission followed surgery on the small intestine (9.3%), followed by abdominal wall surgery (5.8%), duodenal surgery (2.6%), colonic surgery (2.1%), and appendicectomy (0.3%). 55% of all readmissions occurred in the first year., Conclusion: There was no difference in readmission rates between younger and older children when comparing the organ on which surgery was initially performed. The highest readmission rate followed small intestinal surgery and the lowest followed appendicectomy. The risk of readmission was highest in the first year.

Objective: The Surgical and Clinical Adhesions Research (SCAR) and SCAR-2 studies demonstrated that the burden of adhesions following lower abdominal surgery is considerable and appears to remain unchanged despite advances in strategies to prevent adhesions. In this study, we assessed the adhesion-related readmission risk directly associated with common lower abdominal surgical procedures, taking into account the effect of previous surgery, demography and concomitant disease., Methods: Data from the Scottish National Health Service medical record linkage database were used to assess the risk of an adhesion-related readmission following open lower abdominal surgery during April 1996-March 1997., Results: Patients undergoing lower abdominal surgery (excluding appendicectomy) had a 5% risk of readmission directly related to adhesions in the 5 years following surgery. Appendicectomy was associated with a lower rate of readmission (0.9%), but contributed over 7% of the total lower abdominal surgery patient readmission burden. Panproctocolectomy (15.4%), total colectomy (8.8%) and ileostomy surgery (10.6%) were associated with the highest risk of an adhesion-related readmission. Overall, the risk of readmission was doubled in patients who had undergone abdominal or pelvic surgery within 5 years of the incident operation. A higher risk of readmission was also recorded in patients aged < 60 years compared with those aged > or = 60 yrs. The effect of gender was assessed. However, as the surgical codes used were found to be skewed towards women, these data have not been reported. Readmission risk was slightly higher in patients with concomitant peritonitis compared with patients without peritonitis. In contrast, Crohn's disease had no effect on risk. Patients with colorectal cancer had a lower risk of adhesion formation. However, this may have been due to the type of surgery performed in this patient group., Conclusion: The identification of high-risk patient subgroups may assist in effectively targeting adhesion-prevention strategies and the proffering of preoperative advice on adhesion risk.

Objectives: Adhesions are associated with serious medical complications. This study examines the real-time burden of adhesion-related readmissions following colorectal surgery and assesses the impact of previous surgery on adhesion-related outcomes., Patients and Methods: The study used data from the Scottish National Health Service Medical Record Linkage Database to identify three cohorts of patients who had undergone open colorectal surgery during the financial years 1996-97, 1997-98 and 1998-99. Each cohort was followed up for at least 2 years and the number and category of adhesion-related readmissions was recorded. The influence of any previous operations on adhesion-related readmissions was also determined by performing a subanalysis within the 1996-97 cohort of patients who had no record of abdominal surgery within either the previous 5 or 15 years. The relative risk of adhesion-related readmissions was also assessed., Results: In the 1996-97 cohort, 9.0% of patients were readmitted within a year after surgery; 2.1% had complications directly related to adhesions and 6.9% had complications that were possibly related. After 4 years, 19.0% of patients were readmitted for reasons directly or possibly related to adhesions. Many patients were readmitted on more than one occasion and the relative risk of adhesion-related complications was 29.7 per 100 initial procedures over 4 years. In the subgroups that had no record of abdominal surgery within the previous 5 or 15 years, the relative risks of adhesion-related complications were 24.8% and 23.5%, respectively. There was no change in the rate of adhesion-related readmissions following colorectal surgery between 1996 and 1999., Conclusion: Colorectal surgery is associated with a considerable rate of adhesion-related readmissions. Preventative measures should be considered to reduce this risk.

Background: Gynaecological laparotomies are associated with considerable adhesion-related burdens; however, few data are available concerning laparoscopic surgery. This study evaluated the epidemiology of adhesion-related readmissions following open and laparoscopic procedures., Methods: Records from 24,046 patients undergoing gynaecological surgery in Scottish National Health Service hospitals during 1996 were assessed retrospectively. Cohorts comprised 15,197 patients undergoing laparoscopic surgery and 8849 patients undergoing laparotomies. Adhesion-related readmission episodes (directly and possibly related) were assessed over 4 years following initial surgery and were expressed as percentages of the number of initial procedures., Results: Directly adhesion-related readmissions 1 year after initial laparoscopic surgery were: in the high-risk group (adhesiolysis and cyst drainage) 1.3%; medium-risk (therapeutic and diagnostic procedures not categorized as high- or low-risk) 1.5%; and low-risk (Fallopian tube sterilizations) 0.2%. Readmissions for laparotomy following surgery on the Fallopian tubes were 0.9%, ovaries 2.1%, uterus 0.6% and vagina 0%. Readmissions occurred at reduced rates in the second, third and fourth years after surgery. Exclusion of patients who underwent surgery within the previous 5 years resulted in reduced readmission rates following laparotomy and high-risk laparoscopy., Conclusions: With the exception of laparoscopic sterilizations, open and laparoscopic gynaecological surgery are associated with comparable risks of adhesion-related readmissions., (Copyright 2004 European Society of Human Reproduction and Embryology)

OBJECTIVE: To examine the feasibility of conducting Randomized Controlled Trials (RCT) in lower abdominal surgery to demonstrate a reduction in adhesion-related admissions following use of an adhesion reduction product, and to model the cost effectiveness of such products. METHODS: The number of patients in each limb of a RCT comparing an adhesion reduction product to a control has been estimated based on 25% and 50% reductions in adhesion-related readmissions one year after surgery, for P = 0.05 at a power of 80% and P=0.01 at a power of 90%. A cost effectiveness model based on the Surgical and Clinical Adhesions Research Group (SCAR) database has been developed which calculates the percentage reduction in readmissions required of an adhesion reduction product to return the cost of investment. It also estimates the cumulative costs of adhesion-related readmissions for lower abdominal surgery and the cost savings associated with an adhesion reduction policy using a low or high cost product. RESULTS: 7.2% of patients undergoing lower abdominal surgery will readmit due to adhesions in the first year after surgery. To demonstrate a 25% reduction in readmissions one year after surgery, it is calculated that a RCT would require between 5686 (P = 0.05, power=80%) and 7766 (P = 0.01, power = 90%) lower abdominal surgery patients followed-up for one year. A cost effectiveness analysis demonstrates that routine use of adhesion reduction products costing pound 50 per patient will payback the cost of such investment if they reduce adhesion-related readmissions by 16% after 3 years. A product costing pound 200 will need to offer a 64.1% reduction in readmissions after 3 years. For the estimated 158 000 lower abdominal surgery operations conducted in the UK each year, the cumulative costs of adhesion-related readmissions over 10 years are estimated at pound 569 Million. CONCLUSION: Demonstrating the clinical effectiveness of adhesion reduction products in the RCT setting is unlikely to be feasible due to the large number of patients required. Products costing pound 200 or more are unlikely to payback their direct costs.

Purpose: Postoperative adhesions are a significant problem after colorectal surgery. However, the basic epidemiology and clinical burden are unknown. The Surgical and Clinical Adhesions Research Study has investigated the scale of the problem in a population of 5 million., Methods: Validated data from the Scottish National Health Service Medical Record Linkage Database were used to define a cohort of 12,584 patients undergoing open lower abdominal surgery in 1986. Readmissions for potential adhesion-related disease in the subsequent ten years were analyzed. The methodology was conservative in interpreting adhesion-related disease., Results: In the study cohort 32.6 percent of patients were readmitted a mean of 2.2 times in the subsequent ten years for a potential adhesion-related problem. Although 25.4 percent of readmissions were in the first postoperative year, they continued steadily throughout the study period. After open lower abdominal surgery 7.3 percent (643) of readmissions (8,861) were directly related to adhesions. This varied according to operation site: colon (7.1 percent), rectum (8.8 percent), and small intestine (7.6 percent). The readmission rate was assessed to provide an indicator of relative risk of adhesion-related problems after initial surgery. The overall average rate of readmissions was 70.4 per 100 initial operations, with 5.1 directly related to adhesions. This rose to 116.4 and 116.5, respectively, after colonic or rectal surgery-with 8.2 and 10.3 directly related to adhesions., Conclusions: There is a high relative risk of adhesion-related problems after open lower abdominal surgery and a correspondingly high workload associated with these readmissions. This is influenced by the initial site of surgery, colon and rectum having both the greatest impact on workload and highest relative risk of directly adhesion-related problems. The study provides sound justification for improved adhesion prevention strategies.

Objective: To investigate the epidemiology of, and the clinical burden related to, adhesions following gynaecological surgery., Population: The Scottish National Health Service Medical Record Linkage Database was used to define a cohort of 8849 women undergoing open gynaecological surgery in 1986., Methods: All readmissions for potential adhesion related disease in the subsequent 10 years were reviewed., Main Outcome Measures: Readmissions and the degree of adhesion involvement gave an indication of clinical burden and workload. The rate of readmission following the initial surgery determined the relative risk of disease related to adhesions., Results: Two hundred and forty-five (4.5%) of 5433 readmissions following open gynaecological surgery were directly related to adhesions. 34.5% of patients were readmitted, on average 1.9 times, for a problem potentially related to adhesions or for further intra-abdominal surgery that could be complicated by adhesions. Readmissions related to adhesions continued throughout the 10 year period of the study. The overall rate of readmission was 64.0/100 initial operations. For readmissions directly related to adhesions, the rate was 2.9/100 initial operations. Operations on the ovary had the highest rate directly related to adhesions (7.5/100 initial operations), with an overall rate of readmission of 106.4/100 initial operations., Conclusions: Despite the conservative approach taken in this study, the clinical burden, workload and relative risk of readmissions related to adhesions following open gynaecological surgery was considerable. Post-operative adhesions have important consequences for patients, surgeons and the healthcare system. These results emphasise the need for more effective strategies to prevent adhesions.

The phenomenon of religation of single-strand DNA breaks (nicks) in mitogenically stimulated human T lymphocytes is an event occurring within 8 h of mitogen stimulation. Many later events in lymphocyte activation are known to be dependent on accessory cells, whereas earlier events are often accessory-cell independent. To establish whether nick religation is dependent or independent of accessory-cell function, lymphocytes were stimulated with PHA in the presence of inhibitors thought to act, in part at least, on accessory cells (methylprednisolone and cyclosporine A), or under conditions in which accessory-cell function is limited (low-density culture, adherent-cell depleted populations). In each case DNA synthesis was inhibited but the religation process was retained, indicating that it is independent of accessory-cell function. Inhibition of DNA synthesis in these cells was shown to be readily reversible on addition of conditioned medium containing accessory-cell products, but there was no further change in ligation.