Semi-empirical (AM1 and PM3) and DFT (B3LYP/6-31G(d)) calculations were employed to study the tautomeric equilibrium between the aminequinone
A
and hydroxylquinoneimine
B
forms of ...4-(4-R-phenylamino)naphthalene-1,2-diones. Substituent effects on the tautomeric equilibrium as well as on geometric and electronic parameters were also determined. In the gas phase the hydroxylquinoneimine
B
form is the most stable, whereas in water the aminequinone
A
form becomes more stable. The substituents do not modify the relative energies of the two tautomers. These results are in accordance with experimental data reported in the literature.
Figure
The hydroxylquinoneimine form B1 is the most stable tautomer in the gas-phase. In a polar solvent the aminequinone form A1 becomes the most stable. Substituents have only marginal influence on the relative stabilities of the two tautomers
DFT calculations using the B3LYP and PBE1PBE functionals with the standard 6-31G(d) and 6-311+G(2d,p) basis sets were carried out for the 3-(2-phenylhydrazone)-naphthalene-1,2,4-trione system in ...solution (dmso) and in the gas phase, and showed the keto-hydrazone forms (rotamers Ia and Ib) to be more stable than the enol-azo forms (rotamers IIa and IIb, by about 14 kcal mol-1) and III (by approximately 6 kcal mol-1), independently of the nature of the substituent in the phenylene ring. These results were confirmed by spectroscopic data on the derivatives HL1-HL13, obtained from 2-hydroxy-1,4-naphthoquinone and arylamines (R = 4-OMe, 4-N2-C6H5, 4-Cl, 4-I, 3-I, 2-I, 4-COOH, 3-COOH, 4-CN, 3-CN, 4-NO2, 3-NO2, 2-NO2). The in vitro antitumor (against SF-295, HCT-8, MDAMB-435 and HL-60 cancer cell lines) and antibacterial activities (Bacillus cereus, Bacillus subtilis, Enterococcus faecalis, Staphylococcus aureus, Escherichia coli, Klebsiella pneumonia and Pseudomonas aeruginosa) of compounds HL1-HL13 and of their respective copper(II) complexes, Cu(L1-13)2, were tested. In general, these compounds exhibited low antibacterial activity, except for HL5 (R = 3-I), more active than the control; however, the corresponding complex was inactive. In contrast, increased cytotoxicity was observed upon complexation. Complex Cu(L13)2 (R = 3-NO2) presented moderate cytotoxicity against human leukemia (HL-60).
Semi-empirical (AM1 and PM3) and DFT (B3LYP/6-31G(d)) calculations were employed to study the tautomeric equilibrium between the aminequinone A and hydroxylquinoneimine B forms of ...4-(4-R-phenylamino)naphthalene-1,2-diones. Substituent effects on the tautomeric equilibrium as well as on geometric and electronic parameters were also determined. In the gas phase the hydroxylquinoneimine B form is the most stable, whereas in water the aminequinone A form becomes more stable. The substituents do not modify the relative energies of the two tautomers. These results are in accordance with experimental data reported in the literature. graphic removed
Abstract
Context
Primary aldosteronism (PA) is the most common cause of endocrine hypertension (HT). HT remission (defined as blood pressure <140/90 mm Hg without antihypertensive drugs) has been ...reported in approximately 50% of patients with unilateral PA after adrenalectomy. HT duration and severity are predictors of blood pressure response, but the prognostic role of somatic KCNJ5 mutations is unclear.
Objective
To determine clinical and molecular features associated with HT remission after adrenalectomy in patients with unilateral PA.
Methods
We retrospectively evaluated 100 patients with PA (60 women; median age at diagnosis 48 years with a median follow-up of 26 months). Anatomopathological analysis revealed 90 aldosterone-producing adenomas, 1 carcinoma, and 9 unilateral adrenal hyperplasias. All patients had biochemical cure after unilateral adrenalectomy. KCNJ5 gene was sequenced in 76 cases.
Results
KCNJ5 mutations were identified in 33 of 76 (43.4%) tumors: p.Gly151Arg (n = 17), p.Leu168Arg (n = 15), and p.Glu145Gln (n = 1). HT remission was reported in 37 of 100 (37%) patients. Among patients with HT remission, 73% were women (P = 0.04), 48.6% used more than three antihypertensive medications (P = 0.0001), and 64.9% had HT duration <10 years (P = 0.0015) compared with those without HT remission. Somatic KCNJ5 mutations were associated with female sex (P = 0.004), larger nodules (P = 0.001), and HT remission (P = 0.0001). In multivariate analysis, only a somatic KCNJ5 mutation was an independent predictor of HT remission after adrenalectomy (P = 0.004).
Conclusion
The presence of a KCNJ5 somatic mutation is an independent predictor of HT remission after unilateral adrenalectomy in patients with unilateral PA.
The impact of KCNJ5 somatic mutations on hypertension remission after adrenalectomy brings new insight into the postoperative follow-up of patients with PA.
Abstract
Context
Primary aldosteronism (PA) screening relies on an elevated aldosterone to renin ratio with a minimum aldosterone level, which varies from 10 to 15 ng/dL (277-415.5 pmol/L) using ...immunoassay.
Objective
To evaluate intra-individual coefficient of variation (CV) of aldosterone and aldosterone to direct renin concentration ratio (A/DRC) and its impact on PA screening.
Methods
A total of 671 aldosterone and DRC measurements were performed by the same chemiluminescence assays in a large cohort of 216 patients with confirmed PA and at least 2 screenings.
Results
The median intra-individual CV of aldosterone and A/DRC was 26.8% and 26.7%. Almost 40% of the patients had at least one aldosterone level <15 ng/dL, 19.9% had at least 2 aldosterone levels <15 ng/dL, and 16.2% had mean aldosterone levels <15 ng/dL. A lower cutoff of 10 ng/dL was associated with false negative rates for PA screening of 14.3% for a single aldosterone measurement, 4.6% for 2 aldosterone measurements, and only 2.3% for mean aldosterone levels. Considering the minimum aldosterone, true positive rate of aldosterone thresholds was 85.7% for 10 ng/dL and 61.6% for 15 ng/dL. An A/DRC >2 ng/dL/µIU/mL had a true positive rate for PA diagnosis of 94.4% and 98.4% when based on 1 or 2 assessments, respectively. CV of aldosterone and A/DRC were not affected by sex, use of interfering antihypertensive medications, PA lateralization, hypokalemia, age, and number of hormone measurements.
Conclusion
Aldosterone concentrations had a high CV in PA patients, which results in an elevated rate of false negatives in a single screening for PA. Therefore, PA screening should be based on at least 2 screenings with concomitant aldosterone and renin measurements.
Many vertebrate species undergo population fluctuations that may be random or regularly cyclic in nature. Vertebrate population cycles in northern latitudes are driven by both endogenous and ...exogenous factors. Suggested causes of mysterious disappearances documented for populations of the Neotropical, herd-forming, white-lipped peccary (Tayassu pecari, henceforth "WLP") include large-scale movements, overhunting, extreme floods, or disease outbreaks. By analyzing 43 disappearance events across the Neotropics and 88 years of commercial and subsistence harvest data for the Amazon, we show that WLP disappearances are widespread and occur regularly and at large spatiotemporal scales throughout the species' range. We present evidence that the disappearances represent 7-12-year troughs in 20-30-year WLP population cycles occurring synchronously at regional and perhaps continent-wide spatial scales as large as 10,000-5 million km.sup.2 . This may represent the first documented case of natural population cyclicity in a Neotropical mammal. Because WLP populations often increase dramatically prior to a disappearance, we posit that their population cycles result from over-compensatory, density-dependent mortality. Our data also suggest that the increase phase of a WLP cycle is partly dependent on recolonization from proximal, unfragmented and undisturbed forests. This highlights the importance of very large, continuous natural areas that enable source-sink population dynamics and ensure re-colonization and local population persistence in time and space.
Confirmatory tests represent a fundamental step in primary aldosteronism (PA) diagnosis, but they are laborious and often require a hospital environment due to the risks involved.
To evaluate the ...efficacy of oral furosemide as a new confirmatory test for PA diagnosis.
We prospectively evaluated the diagnostic performance of 80 mg of oral furosemide in 64 patients with PA and 22 with primary hypertension (controls). Direct renin concentration (DRC) was measured before, and 2 hours and 3 hours after the oral furosemide. In addition, the oral furosemide test was compared with 2 other confirmatory tests: the furosemide upright test (FUT) and saline infusion test (SIT) or captopril challenge test (CCT) in all patients with PA.
The cut-off of 7.6 µU/mL for DRC at 2 hours after oral furosemide had a sensitivity of 92%, specificity of 82%, and accuracy of 90% for PA diagnosis. In 5 out of 6 controls with low-renin hypertension, which might represent a PA spectrum, renin remained suppressed. Excluding these 6 controls with low-renin hypertension, the DRC cut-off of 10 µU/mL at 2 hours after oral furosemide had a sensitivity of 95.3%, specificity of 93.7% and accuracy of 95% for PA diagnosis. DRC after 3 hours of oral furosemide did not improve diagnostic performance. Using the cut-off of 10 µU/mL, the oral furosemide test and the FUT were concordant in 62 out of 64 (97%) patients with PA. Only 4 out of 64 cases with PA (6.4%) ended the oral furosemide test with potassium <3.5 mEq/L. Hypotension was not evidenced in any patient with PA during the test.
The oral furosemide test was safe, well-tolerated and represents an effective strategy for PA investigation.
This study presents the Trypanosoma rangeli gene expression profile as determined by the generation of ESTs and ORESTES of both epimastigote and trypomastigote forms.
Two species of the genus ...Trypanosoma infective to humans have been extensively studied at a cell and molecular level, but study of the third, Trypanosoma rangeli, remains in relative infancy. T. rangeli is non-pathogenic, but is frequently mistaken for the related Chagas disease agent Trypanosoma cruzi with which it shares vectors, hosts, significant antigenicity and a sympatric distribution over a wide geographical area. In this study, we present the T. rangeli gene expression profile as determined by the generation of ESTs (Expressed Sequence Tags) and ORESTES (Open Reading Frame ESTs). A total of 4208 unique high quality sequences were analyzed, composed from epimastigote and trypomastigote forms of SC-58 and Choachí strains, representing the two major phylogenetic lineages of this species. Comparative analyses with T. cruzi and other parasitic kinetoplastid species allowed the assignment of putative biological functions to most of the sequences generated and the establishment of an annotated T. rangeli gene expression database. Even though T. rangeli is apathogenic to mammals, genes associated with virulence in other pathogenic kinetoplastids were found. Transposable elements and genes associated mitochondrial gene expression, specifically RNA editing components, are also described for the first time. Our studies confirm the close phylogenetic relationship between T. cruzi and T. rangeli and enable us to make an estimate for the size of the T. rangeli genome repertoire (∼8500 genes).
Abstract
Background: Primary aldosteronism (PA) is the most common cause of endocrine hypertension (HT). PA subtypes include aldosterone-producing adenomas (APA) and bilateral adrenal hyperplasia. To ...date, few PA patients with bilateral adenomas have been reported, but only one case was well characterized by anatomopathological analysis and clinical outcome after adrenal sparing surgery (1).
Clinical case: A 53-year-old woman was referred to investigate resistant HT and hypokalemia. (3.0 mEq/L). PA screening revealed aldosterone (A) of 37.9 ng/dL, renin (R) < 1.6 (4.4-46.1 mUI/L), A/R ratio of 24.8. Confirmatory testing confirmed PA diagnosis: seated saline infusion test (A= 83.3 ng/dL) and intravenous furosemide test (R= 3.1 mUI/L; positive test <13 mUI/L). Hypercortisolism investigation revealed a non-suppressible cortisol after an overnight 1 mg low-dose dexamethasone suppression cortisol (C)= 2.9 μg/dL and dexamethasone= 701 (˃130 ng/dL), and normal urinary free cortisol, midnight salivary cortisol, plasma DHEAS and ACTH levels. Computed tomography demonstrated bilateral adrenal nodules without adrenal thickening: 3.5 cm right nodule (pre-contrast density of 7UH density; absolute wash-out of 71%) and 2.5 cm left nodule (pre-contrast density of 8UH density; absolute wash-out of 78%). Sequential adrenal venous (AV) sampling (AVS) under continuous cosyntropin infusion showed a lateralization index of 3.4 (bilateral disease <4). Then, the patient underwent right adrenalectomy and left nodulectomy. In the postoperative period, she presented normalization of K+ levels and complete HT remission. She remained under hydrocortisone replacement for 2 months. After 2 months, biochemical evaluation revealed normal basal cortisol levels (13.3 µg/dL) and biochemical cure of PA (A= 3.1 ng/dL and R= 15.3 mUI/L). Currently, she doesn’t have symptoms of adrenal insufficiency after discontinuation of hydrocortisone. Anatomopathological analysis showed bilateral adenomas (Weiss score of 0) in both sides without adjacent hyperplasia. CYP11B2 immunohistochemistry displayed a strong staining in 50% of cells in the right adenoma and in 30% of cells in the left adenoma. Few aldosterone-producing cell clusters (APCC) were identified in the right zona glomerulosa, which is a frequent finding in normal adrenals.
Conclusion: We herein described a very rare case of PA caused by bilateral-producing adenomas, confirmed by AVS and CYP11B2 staining after adrenal sparing surgery.
Abstract
Primary aldosteronism (PA) is the most common cause of endocrine hypertension. PA subtypes include bilateral hyperplasia and unilateral PA, typically aldosterone-producing adenomas. Adrenal ...venous (AV) sampling (AVS) is a key step to define PA subtype and guide PA management. According current PA guidelines, most PA patients should undergo AVS, which is a challenging procedure, especially in terms of successfully cannulating the right AV. The aim of this study was to report a single tertiary center experience with AVS in PA patients. We retrospectively evaluated 84 AVS from 1984 to 2019. Sequential AVS was performed by an experienced interventional radiologist. AV and inferior vena cava (IVC) samples were obtained under cosyntropin continuous infusion. Successful catheterization was defined by a selectivity index SI= AV/IVC cortisol (C) concentrations ≥5. Unilateral disease was defined by a lateralization index LI= aldosterone (A)/C ratio in the dominant AV divided by A/C in the non-dominant AV ≥4. The relative aldosterone secretion index (RASI= A/C ratio in AV divided by A/C in IVC) was calculated in each side. A RASI <1 was defined as contralateral suppression (CS). In patients with unsuccessful AV catheterization (mostly right AV) or undetermined LI (3-4), CS was used to indicate adrenalectomy. The biochemical cure of PA after adrenalectomy was defined as the gold standard parameter to confirm unilateral disease. Successful bilateral AV catheterization was achieved in 75% of the cases. After 2015, the use of intra-procedural rapid cortisol assay improved angiographer experience and increased AVS successful rate from 52 to 80%. LI revealed unilateral and bilateral aldosterone excess in 68 and 32% of the cases, respectively. A LI ≥4 had a sensitivity of 100% and specificity of 98% to define unilateral PA among patients with successful catheterization. In addition, RASI in the non-dominant AV was significantly lower in unilateral PA according the LI when compared to bilateral cases 0.12 (0.03 to 1.18) vs. 1.1 (0.04 to 4.56), p= 0.0001. RASI in the non-dominant AV was inversely correlated with LI (r= -0.81, p= 0.0001). A CS index ≤0.5 had a high sensitivity (90%) and specificity (94%) to define unilateral aldosterone excess. In conclusion, the LI is the most valuable parameter in AVS for PA subtyping. Additionally, CS (cut-off of 0.5) is very useful to define lateralization and can be used in cases of borderline LI or unsuccessful AV catheterization.CAPES Grant to Freitas TC.
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