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Addison Mizner : architect of fantasy and romance
The go-to architect for the Jazz Age elite of South Florida and beyond, Addison Mizner created a new architectural style and a new lifestyle for the wealthy and socially prominent of Palm Beach America s preeminent winter resort town of the time. Building mansions, clubs, hotels and apartment houses with a bent toward fantasy and romance, Mizner established a design vocabulary and tradition that to this day influences architects, designers, and builders. Evocative of old Spain, Venice, and the Moorish capitals of Granada and Seville, Mizner s work is a dream realized: courtyards with fountains, trellises with climbing bougainvillea, arched windows, glazed tile floors, spiraling marble columns, expansive interiors with grand proportions. This book explores Mizner s legacy through the extraordinary houses and other structures he built, including such storied homes as La Guerida, an 11-bedroom Spanish Revival mansion, best known now as the Kennedy Estate the place where JFK he composed his Inaugural Address. Known for their beauty, opulence, fantastic detail, as well as the stories of those individuals who have lived or played in them, the houses and buildings of Addison Mizner stand as monuments to grand living and romance made in stone and iron, stucco and tile.
Book
Improved Urinary Cortisol Metabolome in Addison Disease: A Prospective Trial of Dual-Release Hydrocortisone
Abstract
Context
Oral once-daily dual-release hydrocortisone (DR-HC) replacement therapy has demonstrated an improved metabolic profile compared to conventional 3-times-daily (TID-HC) therapy among patients with primary adrenal insufficiency. This effect might be related to a more physiological cortisol profile, but also to a modified pattern of cortisol metabolism.
Objective
This work aimed to study cortisol metabolism during DR-HC and TID-HC.
Design
A randomized, 12-week, crossover study was conducted.
Intervention and Participants
DC-HC and same daily dose of TID-HC were administered to patients with primary adrenal insufficiency (n = 50) vs healthy individuals (n = 124) as controls.
Main Outcome Measures
Urinary corticosteroid metabolites were measured by gas chromatography/mass spectrometry at 24-hour urinary collections.
Results
Total cortisol metabolites decreased during DR-HC compared to TID-HC (P < .001) and reached control values (P = .089). During DR-HC, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity measured by tetrahydrocortisol + 5α-tetrahydrocortisol/tetrahydrocortisone ratio was reduced compared to TID-HC (P < .05), but remained increased vs controls (P < .001). 11β-HSD2 activity measured by urinary free cortisone/free cortisol ratio was decreased with TID-HC vs controls (P < .01) but normalized with DR-HC (P = .358). 5α- and 5β-reduced metabolites were decreased with DR-HC compared to TID-HC. Tetrahydrocortisol/5α-tetrahydrocortisol ratio was increased during both treatments, suggesting increased 5β-reductase activity.
Conclusions
The urinary cortisol metabolome shows striking abnormalities in patients receiving conventional TID-HC replacement therapy, with increased 11β-HSD1 activity that may account for the unfavorable metabolic phenotype in primary adrenal insufficiency. Its change toward normalization with DR-HC may mediate beneficial metabolic effects. The urinary cortisol metabolome may serve as a tool to assess optimal cortisol replacement therapy.
Journal Article
Clinical and Immunological Characteristics of Autoimmune Addison Disease: A Nationwide Swedish Multicenter Study
Context:Studies of the clinical and immunological features of autoimmune Addison disease (AAD) are needed to understand the disease burden and increased mortality.Objective:To provide upgraded data on autoimmune comorbidities, replacement therapy, autoantibody profiles, and cardiovascular risk factors.Design, Setting, and Participants:A cross-sectional, population-based study that included 660 AAD patients from the Swedish Addison Registry (2008–2014). When analyzing the cardiovascular risk factors, 3594 individuals from the population-based survey in Northern Sweden, MONICA (monitoring of trends and determinants of cardiovascular disease), served as controls.Main Outcome Measures:The endpoints were the prevalence of autoimmune comorbidities and cardiovascular risk factors. Autoantibodies against 13 autoantigens were determined.Results:The proportion of 21-hydroxylase autoantibody-positive patients was 83%, and 62% of patients had ≥1 associated autoimmune diseases, more frequently coexisting in females (P < 0.0001). AAD patients had a lower body mass index (P < 0.0001) and prevalence of hypertension (P = 0.027) compared with controls. Conventional hydrocortisone tablets were used by 89% of the patients, with a mean dose of 28.1 ± 8.5 mg/d. The mean hydrocortisone equivalent dose normalized to the body surface was 14.8 ± 4.4 mg/m2/d. A greater hydrocortisone equivalent dose was associated with a greater incidence of hypertension (P = 0.046).Conclusions:Careful monitoring of AAD patients is warranted to detect associated autoimmune diseases. Contemporary Swedish AAD patients did not have an increased prevalence of overweight, hypertension, type 2 diabetes mellitus, or hyperlipidemia. However, high glucocorticoid replacement doses could be a risk factor for hypertension.Upgraded data regarding autoimmune comorbidities, autoantibody profiles, replacement therapy and cardiovascular risk factors revealing a need to carefully monitor AAD patients.
Journal Article
Does vitamin D play a role in autoimmune endocrine disorders? A proof of concept
In the last few years, more attention has been given to the “non-calcemic” effect of vitamin D. Several observational studies and meta-analyses demonstrated an association between circulating levels of vitamin D and outcome of many common diseases, including endocrine diseases, chronic diseases, cancer progression, and autoimmune diseases. In particular, cells of the immune system (B cells, T cells, and antigen presenting cells), due to the expression of 1α-hydroxylase (CYP27B1), are able to synthesize the active metabolite of vitamin D, which shows immunomodulatory properties. Moreover, the expression of the vitamin D receptor (VDR) in these cells suggests a local action of vitamin D in the immune response. These findings are supported by the correlation between the polymorphisms of the
VDR
or the
CYP27B1
gene and the pathogenesis of several autoimmune diseases. Currently, the optimal plasma 25-hydroxyvitamin D concentration that is necessary to prevent or treat autoimmune diseases is still under debate. However, experimental studies in humans have suggested beneficial effects of vitamin D supplementation in reducing the severity of disease activity. In this review, we summarize the evidence regarding the role of vitamin D in the pathogenesis of autoimmune endocrine diseases, including type 1 diabetes mellitus, Addison’s disease, Hashimoto’s thyroiditis, Graves’ disease and autoimmune polyendocrine syndromes. Furthermore, we discuss the supplementation with vitamin D to prevent or treat autoimmune diseases.
Journal Article
Visceral Fat and Novel Biomarkers of Cardiovascular Disease in Patients With Addison’s Disease: A Case-Control Study
ContextPatients with Addison’s disease (AD) have increased cardiovascular mortality.ObjectiveTo study visceral fat and conventional and exploratory cardiovascular risk factors in patients with AD.DesignA cross-sectional, single-center, case-control study.SubjectsPatients (n = 76; n = 51 women) with AD and 76 healthy control subjects were matched for sex, age, body mass index (BMI), and smoking habits.Main outcome measuresThe primary outcome variable was visceral abdominal adipose tissue (VAT) measured using computed tomography. Secondary outcome variables were prevalence of metabolic syndrome (MetS) and 92 biomarkers of cardiovascular disease.ResultsThe mean ± standard deviation age of all subjects was 53 ± 14 years; mean BMI, 25 ± 4 kg/m2; and mean duration of AD, 17 ± 12 years. The median (range) daily hydrocortisone dose was 30 mg (10 to 50 mg). Median (interquartile range) 24-hour urinary free cortisol excretion was increased in patients vs controls [359 nmol (193 to 601 nmol) vs 175 nmol (140 to 244 nmol); P < 0.001]. VAT did not differ between groups. After correction for multiple testing, 17 of the 92 studied biomarkers differed significantly between patients and control subjects. Inflammatory, proinflammatory, and proatherogenic risk biomarkers were increased in patients [fold change (FC), >1] and vasodilatory protective marker was decreased (FC, <1). Twenty-six patients (34%) vs 12 control subjects (16%) fulfilled the criteria for MetS (P = 0.01).ConclusionDespite higher cortisol exposure, VAT was not increased in patients with AD. The prevalence of MetS was increased and several biomarkers of cardiovascular disease were adversely affected in patients with AD.In this study, patients with Addison’s disease had increased prevalence of the metabolic syndrome compared with matched control subjects, and several cardiovascular biomarkers were adversely affected.
Journal Article
Circadian Rhythm of Glucocorticoid Administration Entrains Clock Genes in Immune Cells: A DREAM Trial Ancillary Study
Abstract
Context
Adrenal insufficiency (AI) requires lifelong glucocorticoid (GC) replacement. Conventional therapies do not mimic the endogenous cortisol circadian rhythm. Clock genes are essential components of the machinery controlling circadian functions and are influenced by GCs. However, clock gene expression has never been investigated in patients with AI.
Objective
To evaluate the effect of the timing of GC administration on circadian gene expression in peripheral blood mononuclear cells (PBMCs) of patients from the Dual Release Hydrocortisone vs Conventional Glucocorticoid Replacement in Hypocortisolism (DREAM) trial.
Design
Outcome assessor–blinded, randomized, active comparator clinical trial.
Participants and Intervention
Eighty-nine patients with AI were randomly assigned to continue their multiple daily GC doses or switch to an equivalent dose of once-daily modified-release hydrocortisone and were compared with 25 healthy controls; 65 patients with AI and 18 controls consented to gene expression analysis.
Results
Compared with healthy controls, 19 of the 68 genes were found modulated in patients with AI at baseline, 18 of which were restored to control levels 12 weeks after therapy was switched: ARNTL [BMAL] (P = 0.024), CLOCK (P = 0.016), AANAT (P = 0.021), CREB1 (P = 0.010), CREB3 (P = 0.037), MAT2A (P = 0.013); PRKAR1A, PRKAR2A, and PRKCB (all P < 0.010) and PER3, TIMELESS, CAMK2D, MAPK1, SP1, WEE1, CSNK1A1, ONP3, and PRF1 (all P < 0.001). Changes in WEE1, PRF1, and PER3 expression correlated with glycated hemoglobin, inflammatory monocytes, and CD16+ natural killer cells.
Conclusions
Patients with AI on standard therapy exhibit a dysregulation of circadian genes in PBMCs. The once-daily administration reconditions peripheral tissue gene expression to levels close to controls, paralleling the clinical outcomes of the DREAM trial (NCT02277587).
We compared multiple-times-a-day vs once-daily modified-release hydrocortisone in adrenal insufficiency and found a significant effect on the expression of several clock-related genes.
Journal Article
Primary adrenocortical insufficiency in patients with AIDS in Wuhan, China: 3 cases report and literature review
Background
Primary adrenal insufficiency (PAI) is a common endocrine complication in AIDS patients, but the diagnosis is often delayed due to the atypical clinic symptoms, which may result in a life-threatening adrenal crisis.
Result
In this report we present the clinical data of three patients with AIDS and PAI, summarizing the etiology, clinical characteristics, treatment and prognosis. All enrolled three patients were male, aged between 32 and 54 years. Their CD4
+
T lymphocyte count (CD4 count) were 58 cells/µL, 378 cells/µL and 35 cells/µL respectively. Two patients had cytomegalovirus (CMV) infection and one had tuberculosis (TB), which were considered to be the main etiologies for PAI. The reported cases exhibited nonspecific clinical symptoms, including fatigue, weight loss, vomiting, diarrhea, anorexia, and fever. All three patients had skin and mucous membrane hyperpigmentation, and two experienced adrenal crisis characterized by intractable hypotension and hyponatremia. Laboratory results revealed low cortisol and higher adrenocorticotropic hormone (ACTH) in serum. All patients responded well to glucocorticoid replacement therapy. By follow-up, their CD4 counts increased steadily.
Conclusions
In patients with AIDS, especially those with opportunistic infection such as CMV infection or TB, PAI should be considered when symptoms of glucocorticoid deficiency are present. Conversely, in AIDS patients diagnosed with PAI, potential underlying infections such as CMV or TB should be actively investigated.
Journal Article
GDF15 Is Elevated in Conditions of Glucocorticoid Deficiency and Is Modulated by Glucocorticoid Replacement
Abstract
Context
GDF15 is a stress-induced hormone acting in the hindbrain that activates neural circuitry involved in establishing aversive responses and reducing food intake and body weight in animal models. Anorexia, weight loss, nausea and vomiting are common manifestations of glucocorticoid deficiency, and we hypothesized that glucocorticoid deficiency may be associated with elevated levels of GDF15.
Objective
To determine the impact of primary adrenal insufficiency (PAI) and glucocorticoid replacement on circulating GDF15 levels.
Methods and Results
We measured circulating concentrations of GDF15 in a cohort of healthy volunteers and Addison’s disease patients following steroid withdrawal. Significantly higher GDF15 (mean ± standard deviation [SD]) was observed in the Addison’s cohort, 739.1 ± 225.8 pg/mL compared to healthy controls, 497.9 ± 167.7 pg/mL (P = 0.01). The effect of hydrocortisone replacement on GDF15 was assessed in 3 independent PAI cohorts with classical congenital adrenal hyperplasia or Addison’s disease; intravenous hydrocortisone replacement reduced GDF15 in all groups. We examined the response of GDF15 to increasing doses of glucocorticoid replacement in healthy volunteers with pharmacologically mediated cortisol deficiency. A dose-dependent difference in GDF15 (mean ± SD) was observed between the groups with values of 491.0 ± 157.7 pg/mL, 427.0 ± 152.1 pg/mL and 360 ± 143.1 pg/mL, in the low, medium and high glucocorticoid replacement groups, respectively, P < .0001.
Conclusions
GDF15 is increased in states of glucocorticoid deficiency and restored by glucocorticoid replacement. Given the site of action of GDF15 in the hindbrain and its effects on appetite, further study is required to determine the effect of GDF15 in mediating the anorexia and nausea that is a common feature of glucocorticoid deficiency.
Journal Article