Inshore and offshore marine migration pathways of Atlantic salmon post-smolts from multiple rivers in Scotland, England, Northern Ireland, and Ireland.

The migratory behavior of Atlantic salmon (Salmo salar) post-smolts in coastal waters is poorly understood. In this collaborative study, 1914 smolts, from 25 rivers, in four countries were tagged with acoustic transmitters during a single seasonal migration. In total, 1105 post-smolts entered the marine study areas and 438 (39.6%) were detected on a network of 414 marine acoustic receivers and an autonomous underwater vehicle. Migration pathways (defined as the shortest distance between two detections) of up to 575 km and over 100 days at sea were described for all 25 populations. Post-smolts from different rivers, as well as individuals from the same river, used different pathways in coastal waters. Although difficult to generalize to all rivers, at least during the year of this study, no tagged post-smolts from rivers draining into the Irish Sea were detected entering the areas of sea between the Hebrides and mainland Scotland, which is associated with a high density of finfish aquaculture. An important outcome of this study is that a high proportion of post-smolts crossed through multiple legislative jurisdictions and boundaries during their migration. This study provides the basis for spatially explicit assessment of the impact risk of coastal pressures on salmon during their first migration to sea.

Spondyloarthropathies That Mimic Ankylosing Spondylitis: A Narrative Review.

Ankylosing spondylitis is the most common type of seronegative inflammatory spondyloarthropathy often presenting with low back or neck pain, stiffness, kyphosis and fractures that are initially missed on presentation; however, there are other spondyloarthropathies that may present similarly making it a challenge to establish the correct diagnosis. Here, we will highlight the similarities and unique features of the epidemiology, pathophysiology, presentation, radiographic findings, and management of seronegative inflammatory and metabolic spondyloarthropathies as they affect the axial skeleton and mimic ankylosing spondylitis. Seronegative inflammatory spondyloarthropathies such as psoriatic arthritis, reactive arthritis, noninflammatory spondyloarthropathies such as diffuse idiopathic skeletal hyperostosis, and ochronotic arthritis resulting from alkaptonuria can affect the axial skeleton and present with symptoms similar those of ankylosing spondylitis. These similarities can create a challenge for providers as they attempt to identify a patient's condition. However, there are characteristic radiographic findings and laboratory tests that may help in the differential diagnosis. Axial presentations of seronegative inflammatory, non-inflammatory, and metabolic spondyloarthropathies occur more often than previously thought. Identification of their associated symptoms and radiographic findings are imperative to effectively diagnose and properly manage patients with these diseases.

Ultrafast Preparation of Nonequilibrium FeNi Spinels by Magnetic Induction Heating for Unprecedented Oxygen Evolution Electrocatalysis.

Carbon-supported nanocomposites are attracting particular attention as high-performance, low-cost electrocatalysts for electrochemical water splitting. These are mostly prepared by pyrolysis and hydrothermal procedures that are time-consuming (from hours to days) and typically difficult to produce a nonequilibrium phase. Herein, for the first time ever, we exploit magnetic induction heating-quenching for ultrafast production of carbon-FeNi spinel oxide nanocomposites (within seconds), which exhibit an unprecedentedly high performance towards oxygen evolution reaction (OER), with an ultralow overpotential of only +260 mV to reach the high current density of 100 mA cm-2. Experimental and theoretical studies show that the rapid heating and quenching process (ca. 103 K s-1) impedes the Ni and Fe phase segregation and produces a Cl-rich surface, both contributing to the remarkable catalytic activity. Results from this study highlight the unique advantage of ultrafast heating/quenching in the structural engineering of functional nanocomposites to achieve high electrocatalytic performance towards important electrochemical reactions.

Modulation of 11ß-hydroxysteroid dehydrogenase functions by the cloud of endogenous metabolites in a local microenvironment: The glycyrrhetinic acid-like factor (GALF) hypothesis.

11ß-Hydroxysteroid dehydrogenase (11ß-HSD)-dependent conversion of cortisol to cortisone and corticosterone to 11-dehydrocorticosterone are essential in regulating transcriptional activities of mineralocorticoid receptors (MR) and glucocorticoid receptors (GR). Inhibition of 11ß-HSD by glycyrrhetinic acid metabolites, bioactive components of licorice, causes sodium retention and potassium loss, with hypertension characterized by low renin and aldosterone. Essential hypertension is a major disease, mostly with unknown underlying mechanisms. Here, we discuss a putative mechanism for essential hypertension, the concept that endogenous steroidal compounds acting as glycyrrhetinic acid-like factors (GALFs) inhibit 11ß-HSD dehydrogenase, and allow for glucocorticoid-induced MR and GR activation with resulting hypertension. Initially, several metabolites of adrenally produced glucocorticoids and mineralocorticoids were shown to be potent 11ß-HSD inhibitors. Such GALFs include modifications in the A-ring and/or at positions 3, 7 and 21 of the steroid backbone. These metabolites may be formed in peripheral tissues or by gut microbiota. More recently, metabolites of 11ß-hydroxy-Δ4androstene-3,17-dione and 7-oxygenated oxysterols have been identified as potent 11ß-HSD inhibitors. In a living system, 11ß-HSD isoforms are not exposed to a single substrate but to several substrates, cofactors, and various inhibitors simultaneously, all at different concentrations depending on physical state, tissue and cell type. We propose that this "cloud" of steroids and steroid-like substances in the microenvironment determines the 11ß-HSD-dependent control of MR and GR activity. A dysregulated composition of this cloud of metabolites in the respective microenvironment needs to be taken into account when investigating disease mechanisms, for forms of low renin, low aldosterone hypertension.

Bacterial steroid-17,20-desmolase is a taxonomically rare enzymatic pathway that converts prednisone to 1,4-androstanediene-3,11,17-trione, a metabolite that causes proliferation of prostate cancer cells.

The adrenal gland has traditionally been viewed as a source of "weak androgens"; however, emerging evidence indicates 11-oxy-androgens of adrenal origin are metabolized in peripheral tissues to potent androgens. Also emerging is the role of gut bacteria in the conversion of C21 glucocorticoids to 11-oxygenated C19 androgens. Clostridium scindens ATCC 35,704 is a gut microbe capable of converting cortisol into 11-oxy-androgens by cleaving the side-chain. The desA and desB genes encode steroid-17,20-desmolase. Our prior study indicated that the urinary tract bacterium, Propionimicrobium lymphophilum ACS-093-V-SCH5 encodes desAB and converts cortisol to 11ß-hydroxyandrostenedione. We wanted to determine how widespread this function occurs in the human microbiome. Phylogenetic and sequence similarity network analyses indicated that the steroid-17,20-desmolase pathway is taxonomically rare and located in gut and urogenital microbiomes. Two microbes from each of these niches, C. scindens and Propionimicrobium lymphophilum, respectively, were screened for activity against endogenous (cortisol, cortisone, and allotetrahydrocortisol) and exogenous (prednisone, prednisolone, dexamethasone, and 9-fluorocortisol) glucocorticoids. LC/MS analysis showed that both microbes were able to side-chain cleave all glucocorticoids, forming 11-oxy-androgens. Pure recombinant DesAB from C. scindens showed the highest activity against prednisone, a commonly prescribed glucocorticoid. In addition, 0.1 nM 1,4-androstadiene-3,11,17-trione, bacterial side-chain cleavage product of prednisone, showed significant proliferation relative to vehicle in androgen-dependent growth LNCaP prostate cancer cells after 24 h (2.3 fold; P <  0.01) and 72 h (1.6 fold; P < 0.01). Taken together, DesAB-expressing microbes may be an overlooked source of androgens in the body, potentially contributing to various disease states, such as prostate cancer.

Au130-x Agx Nanoclusters with Non-Metallicity: A Drum of Silver-Rich Sites Enclosed in a Marks-Decahedral Cage of Gold-Rich Sites.

The synthesis and structure of atomically precise Au130-x Agx (average x=98) alloy nanoclusters protected by 55 ligands of 4-tert-butylbenzenethiolate are reported. This large alloy structure has a decahedral M54 (M=Au/Ag) core. The Au atoms are localized in the truncated Marks decahedron. In the core, a drum of Ag-rich sites is found, which is enclosed by a Marks decahedral cage of Au-rich sites. The surface is exclusively Ag-SR; X-ray absorption fine structure analysis supports the absence of Au-S bonds. The optical absorption spectrum shows a strong peak at 523 nm, seemingly a plasmon peak, but fs spectroscopic analysis indicates its non-plasmon nature. The non-metallicity of the Au130-x Agx nanocluster has set up a benchmark to study the transition to metallic state in the size evolution of bimetallic nanoclusters. The localized Au/Ag binary architecture in such a large alloy nanocluster provides atomic-level insights into the Au-Ag bonds in bimetallic nanoclusters.

Role of gut metabolism of adrenal corticosteroids and hypertension: clues gut-cleansing antibiotics give us.

Intestinal bacteria can metabolize sterols, bile acids, steroid hormones, dietary proteins, fiber, foodstuffs, and short chain fatty acids. The metabolic products generated by some of these intestinal bacteria have been linked to a number of systemic diseases including obesity with Type 2 diabetes mellitus, some forms of inflammation, and more recently, systemic hypertension. In this review, we primarily focus on the potential role selected gut bacteria play in metabolizing the endogenous glucocorticoids corticosterone and cortisol. Those generated steroid metabolites, when reabsorbed in the intestine back into the circulation, produce biological effects most notably as inhibitors of 11ß-hydroxysteroid dehydrogenase (11ß-HSD) types 1 and 2. Inhibition of the dehydrogenase actions of 11ß-HSD, particularly in kidney and vascular tissue, allows both corticosterone and cortisol the ability to bind to and activate mineralocorticoid receptors with attended changes in sodium handling and vascular resistance leading to increases in blood pressure. In several animal models of hypertension, administration of gut-cleansing antibiotics results in transient resolution of hypertension and transfer of intestinal contents from a hypertensive animal to a normotensive animal produces hypertension in the recipient. Moreover, fecal samples from hypertensive humans transplanted into germ-free mice resulted in hypertension in the recipient mice. Thus, it appears that the intestinal microbiome may not just be an innocent bystander but certain perturbations in the type and number of bacteria may directly or indirectly affect hypertension and other diseases.

Reversible Control of Chemoselectivity in Au38(SR)24 Nanocluster-Catalyzed Transfer Hydrogenation of Nitrobenzaldehyde Derivatives.

Chemoselective hydrogenation of nitrobenzaldehyde derivatives is one of the important catalytic processes being studied in hydrogenation catalysis. In this work, we report for the first time the catalytic reaction over atomically precise gold nanocluster catalysts (Au25, Au38, Au52, and Au144) using potassium formate as the hydrogen source. A complete selectivity for hydrogenation of the aldehyde group, instead of the nitro group, is obtained. A distinct dependence on the size of nanocluster catalysts is also observed, in which the Au38(SCH2CH2Ph)24 gives rise to the highest catalytic activity. The catalyst also shows good versatility and recyclability. Interestingly, the ligand-off nanocluster changes its catalytic selectivity to the nitro hydrogenation, which is in contrast with the ligand-on catalyst. In addition, the selectivity can be restored by treating the ligand-off nanocluster catalyst with thiol. This reversible control of chemoselectivity is remarkable and may stimulate future work on the exploitation of such nanoclusters for hydrogenation catalysis with control over selectivity.

Sensitive X-ray Absorption Near Edge Structure Analysis on the Bonding Properties of Au30(SR)18 Nanoclusters.

Au nanoclusters (NCs) with organothiolate protecting ligands are a field of great interest and X-ray absorption spectroscopy is a useful tool for the structure and property studies of these Au NCs. However, the Au NCs normally show broad and low-intensity features in the gold X-ray absorption near-edge structure (XANES) region, lowering the sensitivity of the technique and making it difficult to use for the analysis of Au NCs. In this work we report a sensitive gold L3-edge XANES study on the bonding properties of the newly discovered Au30(SR)18 NCs utilizing a combined approach of the first derivative XANES spectra and quantum simulations. First derivative XANES spectra are compared with the well-studied Au25(SR)18 with the aim of determining the unique features of Au30(SR)18. It is found that the early XANES region of the Au NCs is significantly influenced by the gold-gold bonding environment in the surface sites, as the varying surface Au-Au bond lengths in Au25(SR)18 and Au30(SR)18 result in pronounced difference in the first derivative XANES. These findings can be consistently explained using site-selective quantum simulations of the XANES spectra based on the Au NC structural models. The XANES method presented in this work offers a useful tool for the sensitive analysis on structure and bonding properties of Au NCs.

How Children Perceive the Acoustic Environment of Their School.

OBJECTIVE: Children's own ratings and opinions on their schools sound environments add important information on noise sources. They can also provide information on how to further improve and optimize children's learning situation in their classrooms. This study reports on the Swedish translation and application of an evidence-based questionnaire that measures how children perceive the acoustic environment of their school. STUDY DESIGN: The Swedish version was made using a back-to-back translation. Responses on the questionnaire along with demographic data were collected for 149 children aged 9-13 years of age. RESULTS: The Swedish translation of the questionnaire can be reduced from 93 to 27 items. The 27 items were distributed over five separate factors measuring different underlying constructs with high internal consistency and high inter-item correlations. The responses demonstrated that the dining hall/canteen and the corridors are the school spaces with the poorest listening conditions. The highest annoyance was reported for tests and reading; next, student-generated sounds occur more frequently within the classroom than any sudden unexpected sounds, and finally, road traffic noise and teachers in adjoining classrooms are the most frequently occurring sounds from outside the classroom. Several demographic characteristics could be used to predict the outcome on these factors. CONCLUSION: The findings suggest that crowded spaces are most challenging; the children themselves generate most of the noise inside the classroom, but it is also common to hear road traffic noise and teachers in adjoining classrooms. The extent of annoyance that noise causes depends on the task but seems most detrimental in tasks, wherein the demands of verbal processing are higher. Finally, children with special support seem to report that they are more susceptible to noise than the typical child.

Glucocorticoids and gut bacteria: "The GALF Hypothesis" in the metagenomic era.

A new concept is emerging in biomedical sciences: the gut microbiota is a virtual 'organ' with endocrine function. Here, we explore the literature pertaining to the role of gut microbial metabolism of endogenous adrenocorticosteroids as a contributing factor in the etiology of essential hypertension. A body of literature demonstrates that bacterial products of glucocorticoid metabolism are absorbed into the portal circulation, and pass through the kidney before excretion into urine. Apparent mineralocorticoid excess (AME) syndrome patients were found to have congenital mutations resulting in non-functional renal 11ß-hydroxysteroid dehydrogenase-2 (11ß-HSD2) and severe hypertension often lethal in childhood. 11ß-HSD2 acts as a "guardian" enzyme protecting the mineralocorticoid receptor from excess cortisol, preventing sodium and water retention in the normotensive state. Licorice root, whose active ingredient, glycerrhetinic acid (GA), inhibits renal 11ß-HSD2, and thereby causes hypertension in some individuals. Bacterially derived glucocorticoid metabolites may cause hypertension in some patients by a similar mechanism. Parallel observations in gut microbiology coupled with screening of endogenous steroids as inhibitors of 11ß-HSD2 have implicated particular gut bacteria in essential hypertension through the production of glycerrhetinic acid-like factors (GALFs). A protective role of GALFs produced by gut bacteria in the etiology of colorectal cancer is also explored.

Description and experimental transmission of Tetracapsuloides vermiformis n. sp. (Cnidaria: Myxozoa) and guidelines for describing malacosporean species including reinstatement of Buddenbrockia bryozoides n. comb. (syn. Tetracapsula bryozoides).

This paper provides the first detailed description of a Tetracapsuloides species, Tetracapsuloides vermiformis n. sp., with vermiform stages in the bryozoan host, Fredericella sultana, and its experimental transmission from F. sultana to Cyprinus carpio. The suitability of morphological, biological and 18S rDNA sequence data for discrimination between malacosporean species is reviewed and recommendations are given for future descriptions. Presently, malacosporean species cannot be differentiated morphologically due to their cryptic nature and the lack of differential characters of spores and spore-forming stages in both hosts. We examined biological, morphological and molecular characters for the present description and for revising malacosporean taxonomy in general. As a result, Buddenbrockia plumatellae was split into two species, with its sac-like stages being ascribed to Buddenbrockia bryozoides n. comb. In addition to ribosomal DNA sequences multiple biological features rather than morphological characters are considered essential tools to improve malacosporean taxonomy in the future according to our analysis of the limited traits presently available.

Auditory event-related responses to diphthongs in different attention conditions.

The modulation of auditory event-related potentials (ERP) by attention generally results in larger amplitudes when stimuli are attended. We measured the P1-N1-P2 acoustic change complex elicited with synthetic overt (second formant, F2Δ=1000Hz) and subtle (F2Δ=100Hz) diphthongs, while subjects (i) attended to the auditory stimuli, (ii) ignored the auditory stimuli and watched a film, and (iii) diverted their attention to a visual discrimination task. Responses elicited by diphthongs where F2 values rose and fell were found to be different and this precluded their combined analysis. Multivariate analysis of ERP components from the rising F2 changes showed main effects of attention on P2 amplitude and latency, and N1-P2 amplitude. P2 amplitude decreased by 40% between the attend and ignore conditions, and by 60% between the attend and divert conditions. The effect of diphthong magnitude was significant for components from a broader temporal window which included P1 latency and N1 amplitude. N1 latency did not vary between attention conditions, a finding that may be related to stimulation with a continuous vowel. These data show that a discernible P1-N1-P2 response can be observed to subtle vowel quality transitions, even when the attention of a subject is diverted to an unrelated visual task.

Metabolic Coupling Determines the Activity: Comparison of 11ß-Hydroxysteroid Dehydrogenase 1 and Its Coupling between Liver Parenchymal Cells and Testicular Leydig Cells.

BACKGROUND: 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) interconverts active 11ß-hydroxyl glucocorticoids and inactive 11keto forms. However, its directionality is determined by availability of NADP+/NADPH. In liver cells, 11ß-HSD1 behaves as a primary reductase, while in Leydig cells it acts as a primary oxidase. However, the exact mechanism is not clear. The direction of 11ß-HSD1 has been proposed to be regulated by hexose-6-phosphate dehydrogenase (H6PDH), which catalyzes glucose-6-phosphate (G6P) to generate NADPH that drives 11ß-HSD1 towards reduction. METHODOLOGY: To examine the coupling between 11ß-HSD1 and H6PDH, we added G6P to rat and human liver and testis or Leydig cell microsomes, and 11ß-HSD1 activity was measured by radiometry. RESULTS AND CONCLUSIONS: G6P stimulated 11ß-HSD1 reductase activity in rat (3 fold) or human liver (1.5 fold), but not at all in testis. S3483, a G6P transporter inhibitor, reversed the G6P-mediated increases of 11ß-HSD1 reductase activity. We compared the extent to which 11ß-HSD1 in rat Leydig and liver cells might be coupled to H6PDH. In order to clarify the location of H6PDH within the testis, we used the Leydig cell toxicant ethane dimethanesulfonate (EDS) to selectively deplete Leydig cells. The depletion of Leydig cells eliminated Hsd11b1 (encoding 11ß-HSD1) expression but did not affect the expression of H6pd (encoding H6PDH) and Slc37a4 (encoding G6P transporter). H6pd mRNA level and H6PDH activity were barely detectable in purified rat Leydig cells. In conclusion, the availability of H6PDH determines the different direction of 11ß-HSD1 in liver and Leydig cells.

Parental comparison of the prosodic and paralinguistic ability of children with cochlear implants and their normal hearing siblings.

The everyday communication of children is commonly observed by their parents. This paper examines the responses of parents (n=18) who had both a Cochlear Implant (CI) and a Normal Hearing (NH) child. Through an online questionnaire, parents rated the ability of their children on a gamut of speech communication competencies encountered in everyday settings. Comparative parental ratings of the CI children were significantly poorer than those of their NH siblings in speaker recognition, happy and sad emotion, and question versus statement identification. Parents also reported that they changed the vocal effort and the enunciation of their speech when they addressed their CI child and that their CI child consistently responded when their name was called in normal, but not in noisy backgrounds. Demographic factors were not found to be linked to the parental impressions.

Why do humans have two glucocorticoids: A question of intestinal fortitude.

The main purpose of this review article is threefold (a) to try to address the question "why are two adrenal glucocorticoids, cortisol and corticosterone, secreted by humans and other mammalian species?", (b) to outline a hypothesis that under certain physiological conditions, corticosterone has additional biochemical functions over and above those of cortisol, and (c) to emphasize the role of gastrointestinal bacteria in chemically transforming corticosterone into metabolites and that these re-cycled metabolites can be reabsorbed from the enterohepatic circuit. Cortisol and its metabolites are not secreted into the bile and thus are excluded from the enterohepatic circuit. Corticosterone was the first steroid hormone isolated from adrenal gland extracts. Many believe that corticosterone functions identically to cortisol. Yet, corticosterone causes significant sodium retention and potassium secretion in Addisonian patients, unlike cortisol. In humans, corticosterone and its metabolite, 3α,5α-TH-corticosterone, are excreted via the bile in humans where they are transformed in the intestine by anaerobic bacteria into 21-dehydroxylated products: 11ß-OH-progesterone or 11ß-OH-(allo)-5α-preganolones. These metabolites inhibit 11ß-HSD2 and 11ß-HSD1 dehydrogenase, being many-fold more potent than 3α,5α-TH-cortisol. Corticosterone has significantly lower Km's for both 11ß-HSD2 and 11ß-HSD1 enzymatic dehydrogenase activity, compared to cortisol. Patients diagnosed with 17α-hydroxylase deficiency have elevated blood pressure and high levels of circulating corticosterone, 3α,5α-TH-corticosterone, and their 21-dehydroxlated corticosterone derivatives. In humans, these 5α-corticosterone metabolites are likely to influence blood pressure regulation and Na(+) retention by inhibiting the rate of deactivation of cortisol by 11ß-HSD isoforms.

Cascading ecological effects of eliminating fishery discards.

Discarding by fisheries is perceived as contrary to responsible harvesting. Legislation seeking to end the practice is being introduced in many jurisdictions. However, discarded fish are food for a range of scavenging species; so, ending discarding may have ecological consequences. Here we investigate the sensitivity of ecological effects to discarding policies using an ecosystem model of the North Sea--a region where 30-40% of trawled fish catch is currently discarded. We show that landing the entire catch while fishing as usual has conservation penalties for seabirds, marine mammals and seabed fauna, and no benefit to fish stocks. However, combining landing obligations with changes in fishing practices to limit the capture of unwanted fish results in trophic cascades that can benefit birds, mammals and most fish stocks. Our results highlight the importance of considering the broader ecosystem consequences of fishery management policy, since species interactions may dissipate or negate intended benefits.

Rotor stability separates sustained ventricular fibrillation from self-terminating episodes in humans.

OBJECTIVES: This study mapped human ventricular fibrillation (VF) to define mechanistic differences between episodes requiring defibrillation versus those that spontaneously terminate. BACKGROUND: VF is a leading cause of mortality; yet, episodes may also self-terminate. We hypothesized that the initial maintenance of human VF is dependent upon the formation and stability of VF rotors. METHODS: We enrolled 26 consecutive patients (age 64 ± 10 years, n = 13 with left ventricular dysfunction) during ablation procedures for ventricular arrhythmias, using 64-electrode basket catheters in both ventricles to map VF prior to prompt defibrillation per the institutional review board-approved protocol. A total of 52 inductions were attempted, and 36 VF episodes were observed. Phase analysis was applied to identify biventricular rotors in the first 10 s or until VF terminated, whichever came first (11.4 ± 2.9 s to defibrillator charging). RESULTS: Rotors were present in 16 of 19 patients with VF and in all patients with sustained VF. Sustained, but not self-limiting VF, was characterized by greater rotor stability: 1) rotors were present in 68 ± 17% of cycles in sustained VF versus 11 ± 18% of cycles in self-limiting VF (p < 0.001); and 2) maximum continuous rotations were greater in sustained (17 ± 11, range 7 to 48) versus self-limiting VF (1.1 ± 1.4, range 0 to 4, p < 0.001). Additionally, biventricular rotor locations in sustained VF were conserved across multiple inductions (7 of 7 patients, p = 0.025). CONCLUSIONS: In patients with and without structural heart disease, the formation of stable rotors identifies individuals whose VF requires defibrillation from those in whom VF spontaneously self-terminates. Future work should define the mechanisms that stabilize rotors and evaluate whether rotor modulation may reduce subsequent VF risk.

An alternative explanation of hypertension associated with 17α-hydroxylase deficiency syndrome.

The syndrome of 17α-hydroxylase deficiency is due to the inability to synthesize cortisol and is associated with enhanced secretion of both corticosterone and 11-deoxy-corticosterone (DOC). In humans, corticosterone and its 5α-Ring A-reduced metabolites are excreted via the bile into the intestine and transformed by anaerobic bacteria to 21-dehydroxylated products: 11ß-OH-progesterone or 11ß-OH-(allo)-5α-preganolones (potent inhibitors of 11ß-HSD2 and 11ß-HSD1 dehydrogenase). Neomycin blocks the formation of these steroid metabolites and can blunt the hypertension in rats induced by either ACTH or corticosterone. 3α,5α-Tetrahydro-corticosterone, 11ß-hydroxy-progesterone, and 3α,5α-tetrahydro-11ß-hydroxy-progesterone strongly inhibit 11ß-HSD2 and 11ß-HSD1 dehydrogenase activity; all these compounds are hypertensinogenic when infused in adrenally intact rats. Urine obtained from a patient with 17α-hydroxylase deficiency demonstrated markedly elevated levels of endogenous glycyrrhetinic acid-like factors (GALFs) that inhibit 11ß-HSD2 and 11ß-HSD1 dehydrogenase activity (>300 times greater, and >400 times greater, respectively, than those in normotensive controls). Thus, in addition to DOC, corticosterone and its 5α-pathway products as well as the 11-oxygenated progesterone derivatives may play a previously unrecognized role in the increased Na(+) retention and BP associated with patients with 17α-hydroxylase deficiency.

Adrenalectomy amplifies aldosterone induced injury in cardiovascular tissue: an effect attenuated by adrenally derived steroids.

Aldosterone induces fibrotic changes in cardiovascular tissues but its effects have usually been demonstrated in models of pre-existing renal injury and/or hypertension. This study tests the hypothesis that aldosterone can directly induce vascular fibrotic changes in the absence of prior renal injury or hypertension. Experiments were conducted in intact or adrenalectomized (ADX) mice. Mice were divided into groups and treated for 1 week with vehicle or aldosterone (8 µg/kg/day)± inhibitor (800 µg/kg/day): CONTROLS, mice treated with aldosterone, ADX-CONTROLS, ADX+corticosterone (CORT 8 µg/kg/day), ADX with aldosterone, ADX with aldosterone plus the mineralocorticoid receptor (MR) antagonist RU-318, ADX with aldosterone+CORT (CORT inhibitor dose), and ADX with aldosterone+11-dehydro-CORT. Aortic smooth muscle to collagen ratio, aorta intimal thickness (µm), heart weight/body weight ratio (mg/gm), and left ventricular collagen (%) were measured. Prior to sacrifice, blood pressures were normal in all animals. Lower dose CORT alone had no effect on any of the variables examined. Aldosterone exposure was associated with extra-cellular matrix accumulation in cardiovascular tissues in intact mice and adrenalectomy exacerbated these effects. RU-318, CORT (inhibitor dose), and 11-deydro-CORT each attenuated the early fibrotic changes induced by aldosterone. In the heart, aldosterone exposure affected all the parameters measured and caused intimal hypercellularity with monocytes adhering to endothelial cells lining coronary vessels. Cultured endothelial cells exposed to aldosterone (10nM) released E-selectin, produced collagen, and promoted monocyte adhesion. These effects were inhibited by RU-318 and 11-deydro-CORT but not by CORT. Thus, adrenalectomy enhances aldosterone induced early fibrotic changes in heart and aorta. Aldosterone initially targets vascular endothelial cells. MR antagonists and 11-dehydro-CORT, an 11ß-HSD dehydrogenase end-product, directly attenuate these effects.