Peri-operative COVID-19 infection in urgent elective surgery during a pandemic surge period: a retrospective observational cohort study.

Maintaining safe elective surgical activity during the global coronavirus disease 2019 (COVID-19) pandemic is challenging and it is not clear how COVID-19 may impact peri-operative morbidity and mortality in this population. Therefore, adaptations to normal care pathways are required. Here, we establish if implementation of a bespoke peri-operative care bundle for urgent elective surgery during a pandemic surge period can deliver a low COVID-19-associated complication profile. We present a single-centre retrospective cohort study from a tertiary care hospital of patients planned for urgent elective surgery during the initial COVID-19 surge in the UK between 29 March and 12 June 2020. Patients asymptomatic for COVID-19 were screened by oronasal swab and chest imaging (chest X-ray or computed tomography if aged ≥ 18 years), proceeding to surgery if negative. COVID-19 positive patients at screening were delayed. Postoperatively, patients transitioning to COVID-19 positive status by reverse transcriptase polymerase chain reaction testing were identified by an in-house tracking system and monitored for complications and death within 30 days of surgery. Out of 557 patients referred for surgery (230 (41.3%) women; median (IQR [range]) age 61 (48-72 [1-89])), 535 patients (96%) had COVID-19 screening, of which 13 were positive (2.4%, 95%CI 1.4-4.1%). Out of 512 patients subsequently undergoing surgery, 7 (1.4%) developed COVID-19 positive status (1.4%, 95%CI 0.7-2.8%) with one COVID-19-related death (0.2%, 95%CI 0.0-1.1%) within 30 days. Out of these seven patients, four developed pneumonia, of which two required invasive ventilation including one patient with acute respiratory distress syndrome. Low rates of COVID-19 infection and mortality in the elective surgical population can be achieved within a targeted care bundle. This should provide reassurance that elective surgery can continue, where possible, despite high community rates of COVID-19.

Succinate dehydrogenase mutations: paraganglioma imaging and at-risk population screening.

Paragangliomas are rare vascular tumours of the autonomic nervous system. They can be classified as sympathetic or parasympathetic. Sympathetic paragangliomas, which include phaeochromocytomas, tend to be functional and symptomatic. Parasympathetic paragangliomas are usually non-functional and may present with mass effect. Forty percent of paragangliomas are linked to genetic syndromes, most commonly due to mutations of the succinate dehydrogenase (SDH) enzyme complex and are collectively known as paraganglioma syndromes, of which five are described. Genetic testing is recommended for all patients, and their first-degree relatives, diagnosed with paragangliomas. When SDH mutations are discovered, biochemical screening and imaging surveillance is indicated. There is currently no consensus on imaging surveillance protocols. Most advocate full-body imaging, but the choice of technique and frequency varies. If paragangliomas are demonstrated, functional imaging to look for synchronous tumours or metastases is indicated. 2-[18F]-fluoro-2-deoxy-d-glucose (18F-FDG) positron-emission tomography (PET)-computed tomography (CT) is the technique of choice for metastatic evaluation, but [123I]-metaiodobenzylguanidine or [111In]-DTPA-octreotide scintigraphy are also utilised. Current research into emerging positron-emitting radiolabelled somatostatin analogues have yielded promising results, which is likely to be reflected in future guidelines. As genetic testing becomes increasingly prevalent, the need to answer the remaining questions regarding surveillance imaging is paramount.

Global lessons: developing military trauma care and lessons for civilian practice.

The wars in Iraq and Afghanistan have helped to shape the modern Defence Medical Services. Many lessons were learnt including the need for rapid haemorrhage control, senior decision-making and the evolution of deployed transfusion support. These changes were implemented simultaneously with a coherent, end-to-end medical plan from point of wounding through to rehabilitation. Implementation of the medical plan is harmonious with the NHS trauma pathway, and is key to ensuring effective delivery. Military anaesthetists have a long pre-deployment training pathway starting with a Certificate of Completion of Training (CCT) in anaesthesia and/or critical care, and with an emphasis on military skills related to their specific role. Pre-deployment training includes additional skill training, team training and finally whole hospital collective training. This pathway ensures ongoing and continuing competence on an individual basis, and assurance that hospital management systems and clinical staff can function effectively as a deploying unit.

Who are we missing? Too few skeletal surveys for children with humeral and femoral fractures.

AIM: To determine the potential shortfall in skeletal survey referral for children presenting with an acute non-supracondylar humeral or femoral fracture. MATERIALS AND METHODS: Plain radiograph reports were reviewed retrospectively using the radiology information system database over a 5 year study period (May 2008-2013) in children under 18 months of age who presented with an acute fracture. Subsequent skeletal survey referral was used as a surrogate marker for further investigation of child abuse. Application of robust meta-analysis derived probability data regarding likelihood of child abuse as a cause of non-supracondylar humeral or femoral fracture was applied. An estimation of the expected number of cases of abuse, with shortfall in skeletal survey referrals, was then calculated. RESULTS: There were 288 fractures in 281 children. Three children presented with multiple fractures and were considered separately in the present data. The mean patient age was 10.5 months. Nine (3%) non-supracondylar humeral fractures were identified of which four cases may have been due to non-accidental injury (NAI). One (11%) of these patients was referred for a skeletal survey indicating a potential shortfall of three referrals. Twenty-five (9%) femoral fractures were identified of which 13 cases may have been due to NAI, with six (24%) referrals for skeletal surveys generated. This indicates a potential shortfall of seven referrals. CONCLUSION: The present study serves as a current analysis of practice within a tertiary paediatric referral centre. There appeared to be local under-investigation of NAI. Improved child protection education and awareness programmes have now been introduced.

Use of thromboelastometry in the assessment of coagulation before epidural insertion after massive transfusion.

A British soldier presented to the UK Field Hospital, Afghanistan with bilateral traumatic lower limb amputations. Resuscitation and surgery followed accepted damage control principles. Blood component therapy was in keeping with UK military guidelines and included platelets and cryoprecipitate. The patient's trachea was extubated following insertion of an effective epidural. Ten days later, in the UK, he developed neurological symptoms and the presence of a subdural haematoma was confirmed on magnetic resonance imaging. Conventional laboratory coagulation results in this patient were above accepted limits for epidural insertion; however, thromboelastometry before insertion was suggestive of reduced platelet function. This case highlights the risk of relying solely on platelet count as a marker of platelet function following massive transfusion. Thromboelastometry provides additional information for the assessment of coagulation and should form part of the assessment of coagulation following massive transfusion before epidural insertion.

Role for Drs2p, a P-type ATPase and potential aminophospholipid translocase, in yeast late Golgi function.

ADP-ribosylation factor appears to regulate the budding of both COPI and clathrin-coated transport vesicles from Golgi membranes. An arf1Delta synthetic lethal screen identified SWA3/DRS2, which encodes an integral membrane P-type ATPase and potential aminophospholipid translocase (or flippase). The drs2 null allele is also synthetically lethal with clathrin heavy chain (chc1) temperature-sensitive alleles, but not with mutations in COPI subunits or other SEC genes tested. Consistent with these genetic analyses, we found that the drs2Delta mutant exhibits late Golgi defects that may result from a loss of clathrin function at this compartment. These include a defect in the Kex2-dependent processing of pro-alpha-factor and the accumulation of abnormal Golgi cisternae. Moreover, we observed a marked reduction in clathrin-coated vesicles that can be isolated from the drs2Delta cells. Subcellular fractionation and immunofluorescence analysis indicate that Drs2p localizes to late Golgi membranes containing Kex2p. These observations indicate a novel role for a P-type ATPase in late Golgi function and suggest a possible link between membrane asymmetry and clathrin function at the Golgi complex.

Effect of variation in CYP11B1 and CYP11B2 on corticosteroid phenotype and hypothalamic-pituitary-adrenal axis activity in hypertensive and normotensive subjects.

BACKGROUND: Aldosterone is important in the development of hypertension. We have shown that a single nucleotide polymorphism (SNP) (-344T) in the 5' regulatory region (UTR) of the gene encoding aldosterone synthase (CYP11B2) associates with aldosterone excess and hypertension as well as altered adrenal 11-hydroxylation efficiency (deoxycortisol to cortisol). This conversion is carried out by the enzyme 11beta-hydroxylase, encoded by the adjacent gene, CYP11B1. We proposed that the effects of CYP11B2 are explained by linkage disequilibrium (LD) across the CYP11B locus. We have demonstrated high LD across this locus and identified two SNPs in the 5' UTR of CYP11B1 (-1859 G/T, -1889 A/G) that associate with reduced transcription in vitro and altered 11-hydroxylation efficiency in vivo. Accordingly, we hypothesized that the reduced adrenal 11-hydroxylation may lead to chronic resetting of the pituitary-adrenal axis, with chronically increased ACTH drive resulting in aldosterone excess. METHODS: To test this, we examined hypothalamic-pituitary-adrenal (HPA) axis activity in hypertensive and normotensive individuals stratified according to genotype at CYP11B2 (-344T/C) and CYP11B1 (-1859 G/T, -1889 A/G). Fifty-six subjects homozygous for CYP11B2 SNP (27 TT, 12 CC), and 38 homozygous for CYP11B1 SNPs (18 TTGG, 20 GGAA) were recruited. Diurnal variation and the effects of dexamethasone suppression and ACTH stimulation on plasma aldosterone, cortisol and ACTH under controlled conditions were studied. RESULTS: Subjects with SNPs associated with reduced 11-hydroxylation efficiency (-344T CYP11B2; TTGG CYP11B1) showed reduced inhibition of ACTH after dexamethasone (P = 0.05) and an altered cortisol-ACTH relationship (decreased cortisol-ACTH ratio, P < 0.02). The same individuals also demonstrated close correlations between plasma cortisol and aldosterone (-344T CYP11B2 r = 0.508, P < 0.004; TTGG CYP11B1 r = 0.563, P < 0.003) suggesting that there was common regulation (possibly ACTH) of these hormones in genetically susceptible subjects. CONCLUSIONS: Variation in CYP11B2 and CYP11B1 associates with chronic up-regulation of the HPA axis. These novel data support the suggestion that chronic aldosterone excess, in genetically susceptible individuals, may be a consequence of increased ACTH drive to the adrenal and identify novel molecular mechanisms that may lead to the development of hypertension within the general population.

Evaluation of the upper urinary tract using transureteric ultrasound--a review of the technique and typical imaging appearances.

Ureteric strictures and pelviureteric junction obstruction often present a diagnostic conundrum to radiologists, particularly after the first-line investigations have failed to provide a definitive answer. Transureteric ultrasonography (TUU) is a relatively novel technique performed by the radiologist, which uses a miniature endoluminal ultrasound probe to interrogate the ureteric anatomy and peri-ureteric soft tissues. In this review, we discuss how TUU is performed, and the normal imaging appearances of the ureter and surrounding anatomical structures. We also focus on the various pathological processes that can be accurately evaluated or diagnosed using TUU including lymphadenopathy, calculi, ureteric neoplasms, ureteritis, crossing vessels and aneurysms. As TUU is not well established in UK practice as yet, we suggest possible indications for its use in the diagnostic work-up of urological patients and future applications.

Thermal Desorption Analysis of Hydrogen in Non-hydrogen-Charged Rolling Contact Fatigue-Tested 100Cr6 Steel.

Hydrogen diffusion during rolling contact fatigue (RCF) is considered a potential root cause or accelerator of white etching cracks (WECs) in wind turbine gearbox bearing steels. Hydrogen entry into the bearing steel during operation is thought to occur either through the contact surface itself or through cracks that breach the contact surface, in both cases by the decomposition of lubricant through catalytic reactions and/or tribochemical reactions of water. Thermal desorption analysis (TDA) using two experimental set-ups has been used to measure the hydrogen concentration in non-hydrogen-charged bearings over increasing RCF test durations for the first time. TDA on both instruments revealed that hydrogen diffused into the rolling elements, increasing concentrations being measured for longer test durations, with numerous WECs having formed. On the other hand, across all test durations, negligible concentrations of hydrogen were measured in the raceways, and correspondingly no WECs formed. Evidence for a relationship between hydrogen concentration and either the formation or the acceleration of WECs is shown in the rollers, as WECs increased in number and severity with increasing test duration. It is assumed that hydrogen diffusion occurred at wear-induced nascent surfaces or areas of heterogeneous/patchy tribofilm, since most WECs did not breach the contact surface, and those that did only had very small crack volumes for entry of lubricant to have occurred.

The Evolution of White Etching Cracks (WECs) in Rolling Contact Fatigue-Tested 100Cr6 Steel.

The formation of white etching cracks (WECs) in steel rolling element bearings can lead to the premature rolling contact fatigue (RCF) failure mode called white structure flaking. Driving mechanisms are still debated but are proposed to be combinations of mechanical, tribochemical and electrical effects. A number of studies have been conducted to record and map WECs in RCF-tested samples and bearings failed from the field. For the first time, this study uses serial sectioning metallography techniques on non-hydrogen charged test samples over a range of test durations to capture the evolution of WEC formation from their initiation to final flaking. Clear evidence for subsurface initiation at non-metallic inclusions was observed at the early stages of WEC formation, and with increasing test duration the propagation of these cracks from the subsurface region to the contact surface eventually causing flaking. In addition, an increase in the amount of associated microstructural changes adjacent to the cracks is observed, this being indicative of the crack being a prerequisite of the microstructural alteration.

The auxilin-like phosphoprotein Swa2p is required for clathrin function in yeast.

BACKGROUND: In eukaryotic cells, clathrin-coated vesicles transport specific cargo from the plasma membrane and trans-Golgi network to the endosomal system. Removal of the clathrin coat in vitro requires the uncoating ATPase Hsc70 and its DnaJ cofactor auxilin. To date, a requirement for auxilin and Hsc70 in clathrin function in vivo has not been demonstrated. RESULTS: The Saccharomyces cerevisiae SWA2 gene, previously identified in a synthetic lethal screen with arf1, was cloned and found to encode a protein with a carboxy-terminal DnaJ domain which is homologous to that of auxilin. Like auxilin, Swa2p has a clathrin-binding domain and is able to stimulate the ATPase activity of Hsc70. The swa2-1 allele recovered from the original screen carries a point mutation in its tetratricopeptide repeat (TPR) domain, a motif not found in auxilin but known in other proteins to mediate interaction with heat-shock proteins. Swa2p fractionates in the cytosol and appears to be heavily phosphorylated. Disruption of SWA2 causes slow growth and several phenotypes that are very similar to those exhibited by clathrin mutants. Furthermore, the swa2Delta mutant exhibits a significant increase in membrane- associated or -assembled clathrin relative to a wild-type strain. CONCLUSIONS: These results indicate that Swa2p is a clathrin-binding protein required for normal clathrin function in vivo. They suggest that Swa2p is the yeast ortholog of auxilin and has a role in disassembling clathrin, not only in uncoating clathrin-coated vesicles but perhaps in preventing unproductive clathrin assembly in vivo.

Phenotypic consequences of variation across the aldosterone synthase and 11-beta hydroxylase locus in a hypertensive cohort: data from the MRC BRIGHT Study.

BACKGROUND: Aldosterone is an important cardiovascular hormone; 15% of hypertensive subjects have alteration in aldosterone regulation, defined by a raised ratio of aldosterone to renin (ARR). Studies of the aldosterone synthase gene (CYP11B2) have focused on a single nucleotide polymorphism in the 5'promoter region (-344 C/T). In normotensive subjects, the T allele associates with raised levels of the 11-deoxysteroids, deoxycorticosterone and 11-deoxycortisol which are substrates for 11beta-hydroxylase, encoded by the adjacent and homologous gene, CYP11B1. We have speculated that this altered 11beta-hydroxylase efficiency leads to increased ACTH drive to the adrenal gland to maintain cortisol production and reported herein the association between the -344 C/T single nucleotide polymorphism (SNP) and adrenal steroid production in subjects with essential hypertension. METHODS: The CYP11B2-344 C/T polymorphism was genotyped and urinary excretion of adrenal steroid metabolites was measured (by GCMS) in 511 unrelated hypertensives from the Medical Research Council (MRC) British Genetics of Hypertension (BRIGHT) study. RESULTS: Thirty-five per cent of subjects were homozygous for the -344T allele whilst 16% were CC homozygotes. There was no difference in cortisol excretion rate between the two genotype groups but the index of adrenal 11beta-hydroxylation (ratio of tetrahydrodeoxycortisol/total cortisol) was significantly higher in the TT group (P < 0.005) than in the CC group. Excretion rates of the major urinary metabolite of aldosterone (tetrahydroaldosterone) correlated strongly with the ACTH-regulated steroids, cortisol (r = 0.437, P < 0.0001) and total androgen metabolites (r = 0.4, P < 0.0001) in TT but not CC subjects. CONCLUSIONS: Hypertensives homozygous for the -344 T allele of CYP11B2 demonstrate altered 11beta-hydroxylase efficiency (CYP11B1); this is consistent with the hypothesis of a genetically determined increase in adrenal ACTH drive in these subjects. The correlation between excretion of aldosterone and cortisol metabolites and suggests that, in TT subjects, ACTH exerts an important common regulatory influence on adrenal corticosteroid production in subjects with hypertension.

Pressure-dependent diffusion coefficients and haven ratios in cation-conducting glasses.

The influence of hydrostatic pressure on diffusion and ionic conduction is providing deeper insights into the atomistic mechanisms of ionic motion in glasses. We have studied the tracer diffusion of 22Na in a sodium borate glass and of 86Rb in a rubidium borate glass as functions of hydrostatic pressures. The activation volumes of tracer diffusion are DeltaVD(Rb) = 33.5 cm3 mol-1 and DeltaVD(Na) = 6.1 cm3 mol-1. In comparison, the activation volumes of charge diffusion obtained recently from the pressure dependence of conductivity are smaller: DeltaVsigma(Rb) = 7.2 cm3 mol(-1) and DeltaVsigma(Na) = 2.8 cm3 mol(-1). These differences, where (DeltaVD - DeltaVsigma) > 0, imply that the Haven ratios decrease with pressure. This effect is particularly significant for the rubidium borate glass. Starting from basic equations of linear response theory for mass and charge transport, we develop a model that accounts for these experimental findings. The difference between the activation volumes, DeltaVD and DeltaVsigma, and the pressure-dependent Haven ratios are consequences of collective movements of ions in glass, implying a concerted motion of ions in a chain- or caterpillar-like fashion. In our treatment, it is a vacant site (with ions jumping into it successively) that moves along an extended pathway. Hence, we regard vacant sites as the carriers of charge and ions as the carriers of diffusing matter. The decrease of the Haven ratio with pressure is attributed to the influence of pressure on the topology of the conduction pathways, which are progressively straightened out with increasing pressure.

Establishment and cell cycle kinetics of a human squamous cell carcinoma in nude mice and in vitro.

A human squamous cell carcinoma of the virus was xenografted to athymic, nude mice. A tissue culture cell line designated SqCaVu-1H was derived from a second-passage xenograft. The growth characteristics and cell cycle kinetics in the xenografts and in SqCaVu-1H cells were compared. Approximately 80% of the tumor implants produced growing xenografts which had a 2-week latent period followed by Gompertzian growth with a doubling time of 5 to 30 days at 35 days postimplantation. The cell cycle kinetics of the xenografts revealed a heterogeneity from region to region within the tumor. G2 phase and S phase in the xenografts are approximately 8 and 13 hr, respectively. The SqCaVu-1H cells contain only human chromosomes. The modal chromosome number was 64. SqCaVu-1H cells produce plasminogen activator during logarithmic growth, and they produce tumors when injected s.c. into athymic, nude mice. Logarithmically growing SqCaVu-1H cells have a population-doubling time of 21.8 hr in tissue culture. In vitro, their cell cycle duration is approximately 16.0 hr, with G2 phase at 5.6 hr and S phase at 8.6 hr. Comparison of the growth of the same human tumor cells under in vivo and in vitro conditions serves to emphasize that tumor cell proliferation depends strongly on the microenvironment. The varied proliferation characteristics are correlated with their varied inhibition of deoxyuridine incorporation into DNA because of exposure to methotrexate. Logarithmically growing SqVaCu-1H cells had a 50% inhibitory dose of 2.2 X 10(-6) M. Plateau-phase cells in vitro had a 50% inhibitory dose of 9 X 10(-6) M, while the inhibition of cells from the xenografts was nearly dose independent.

Preparation of rat islet B-cell-enriched fractions by light-scatter flow cytometry.

Flow cytometry has been examined as a method to separate islet cells into homogeneous subpopulations. Collagenase-isolated rat islets were dissociated into single cells and these were analyzed and sorted according to their low forward angle light scattering properties by using automated flow cytometry. Light scatter histograms showed two peaks of viable cells. Radioimmunoassay of hormone content in cell fractions collected across the the two peaks showed that glucagon-containing cells were concentrated towards the left side of the left peak and somatostatin-containing cells were concentrated towards the right side of the left peak, whereas insulin-containing cells were clearly enriched in the right peak. The B-cell-enriched fraction (90% B cells, 3% A cells, 2% D cells) exhibited significant insulin secretory responses to glucose (16.7 mM), and 3-isobutyl-1-methylxanthine (0.1 mM), during a 24-h culture period, and these responses were slightly greater than those observed in the original mixed islet cell preparation (66% B cells, 14% A cells, and 4% D cells). These results indicate that flow cytometry can be applied to sort pancreatic islet cells into populations enriched in specific endocrine cell types for further study of the functions of individual cell types.

Early activation of microglia and astrocytes in mouse models of spinocerebellar ataxia type 1.

Spinocerebellar ataxia type 1 (SCA1) is an incurable, dominantly inherited neurodegenerative disease of the cerebellum caused by a polyglutamine-repeat expansion in the protein ataxin-1 (ATXN1). While analysis of human autopsy material indicates significant glial pathology in SCA1, previous research has focused on characterizing neuronal dysfunction. In this study, we characterized astrocytic and microglial response in SCA1 using a comprehensive array of mouse models. We have discovered that astrocytes and microglia are activated very early in SCA1 pathogenesis even when mutant ATXN1 expression was limited to Purkinje neurons. Glial activation occurred in the absence of neuronal death, suggesting that glial activation results from signals emanating from dysfunctional neurons. Finally, in all different models examined glial activation closely correlated with disease progression, supporting the development of glial-based biomarkers to follow disease progression.

Evidence of coexisting changes in 11 beta-hydroxysteroid dehydrogenase and 5 beta-reductase activity in subjects with untreated essential hypertension.

We compared corticosteroid metabolite excretion rates and patterns in a group of 68 subjects with untreated essential hypertension and a matched group of 48 normotensive control subjects. The ratio of tetrahydrocortisol plus allotetrahydrocortisol to tetrahydrocortisone and the ratio of allotetrahydrocortisol to tetrahydrocortisol were significantly higher in the hypertensive group. This is qualitatively similar to the situation found in patients with the syndrome of apparent mineralocorticoid excess or subjects treated with licorice or carbenoxolone where hypertension is known to arise from deficiencies of 11 beta-hydroxysteroid dehydrogenase and 5 beta-reductase activities. The equivalent ratios for corticosterone metabolites were not different between groups, but total corticosterone metabolite excretion was higher in the hypertensive group. Plasma cortisol levels were lower in hypertensive than in control subjects, but corticosterone levels were higher. This evidence supports a previous suggestion that the activities of these two enzymes may be reduced in essential hypertension, but the contribution of these changes to hypertension is not known.

Altered 11 beta-hydroxylase activity in glucocorticoid-suppressible hyperaldosteronism.

Corticosteroid 11 beta-hydroxylation is catalyzed by 11 beta-hydroxylase and aldosterone synthase. Using plasma steroid ratios, the level of this process in patients with glucocorticoid-suppressible hyperaldosteronism (GSH) was compared with that in unaffected control subjects and patients with Conn's syndrome. Based on both 11-deoxycortisol/cortisol (S:F) and 11-deoxycorticosterone/corticosterone (DOC:B) ratios, patients with GSH showed impaired resting 11 beta-hydroxylase activity. In GSH, but not in the other groups, the S:F ratio was significantly correlated with the basal plasma aldosterone concentration. ACTH infusion increased the S:F ratio in all of these patient groups, suggesting a common partial deficiency. The results also indicate that 11 beta-hydroxylation may be rate limiting in normal subjects. In control subjects and patients with Conn's syndrome, the DOC:B ratio was not affected by ACTH. However, in GSH patients, this ratio fell markedly, indicating an increased efficiency of 11 beta-hydroxylation of DOC (but not S). This may be due to the activation by ACTH of the zona fasciculata chimeric aldosterone synthase characteristic of this disease. Plasma aldosterone, corticosterone, and DOC concentrations appeared to be more sensitive to ACTH in GSH than in the other groups. The defect in 11 beta-hydroxylation in GSH accounts for the increased levels of DOC reported in this condition and may contribute to the phenotype variability.

Cortisol effects on body mass, blood pressure, and cholesterol in the general population.

The effects of excess cortisol secretion on blood pressure and fat deposition are well documented, but the importance of this glucocorticoid in controlling these processes in normal individuals is less clear. We studied the relationship between cortisol excretion rate (tetrahydrocortisol [THF]+allo-THF+tetrahydrocortisone [THE]) and a range of important cardiovascular risk factors in 439 normal subjects (238 male) sampled from the North of Glasgow (Scotland) population. There were marked gender differences: female subjects were lighter and had lower blood pressures and cortisol levels, whereas HDL cholesterol was higher. The pattern of cortisol metabolism was also different; the index of 11beta-hydroxysteroid dehydrogenase activity (THF+allo-THF/THE) was lower and that of 5alpha-reductase (allo-THF/THF) was higher. There was a strong correlation of blood pressure (positive), cholesterol (positive), and HDL cholesterol (negative in women, positive in men) with age. Cortisol excretion rate did not correlate with blood pressure but correlated strongly with parameters of body habitus (body mass index and waist and hip measurements [positive]) and HDL cholesterol (negative). With multiple regression analysis, there remained a significant association of cortisol excretion rate with HDL cholesterol in men and women and with body mass index in men. These results suggest that glucocorticoids regulate key components of cardiovascular risk.

Evidence of abnormalities in corticosteroid secretion leading to volume-dependent hypertension in Milan rats.

We examined corticosteroid secretory patterns and their relation to altered salt and water metabolism in Milan hypertensive and normotensive rats. Hypertensive rats had significantly higher blood pressures, exchangeable sodium (hypertensive, 41.2 +/- 0.3 mmol.kg-1; normotensive, 38.4 +/- 0.03 mmol.kg-1, P < .001), plasma volume (hypertensive, 5.39 +/- 0.12 mL.100 g-1; normotensive, 4.84 +/- 0.10 mL.100 g-1, P < .001), and plasma concentrations of atrial natriuretic peptide (hypertensive, 38.8 +/- 4.0 pg.mL-1, normotensive, 22.4 +/- 3.1 pg.mL-1, P < .02). These features coincide with those of mineralocorticoid-induced hypertension. Adrenal venous secretory rates (picomoles per minute) of corticosterone (hypertensive, 1696 +/- 202; normotensive, 873 +/- 139), 18-hydroxycorticosterone (hypertensive, 49.7 +/- 8.3; normotensive, 25.7 +/- 3.3), and aldosterone (hypertensive, 1.16 +/- 0.17; normotensive, 0.52 +/- 0.08) were higher in the hypertensive than the normotensive strain, but that of 11-deoxycorticosterone (DOC) (hypertensive, 94.4 +/- 14.9; normotensive, 114.3 +/- 33.9) was similar in the two strains. The corticosterone-DOC, 18-hydroxycorticosterone-DOC, and aldosterone-DOC ratios were higher in the hypertensive than the normotensive strain (P < .02), but the 18-hydroxycorticosterone-corticosterone and aldosterone-18-hydroxycorticosterone ratios were not. These results indicate increased activity of the "late" aldosterone biosynthetic pathway in the hypertensive compared with the normotensive strain caused by an increased conversion rate of DOC to corticosterone. The comparison of corticosterone secretion between the two strains indicates that 11 beta-hydroxylase rather than aldosterone synthase activity is more active in the hypertensive than the normotensive rats.