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Bone density and bone health alteration in boys with Duchenne Muscular Dystrophy: a prospective observational study.
Suthar, R, Reddy, BVC, Malviya, M, Sirari, T, Attri, SV, Patial, A, Tageja, M, Didwal, G, Khandelwal, NK, Saini, AG, et al
Journal of pediatric endocrinology & metabolism : JPEM. 2021;(5):573-581
Abstract
OBJECTIVES Boys with Duchenne Muscular Dystrophy (DMD) are at increased risk for compromised bone health, manifesting as low-impact trauma long bone fractures and vertebral compression fractures. METHODS In a prospective observational study, we studied bone health parameters in North Indian boys with DMD. We consecutively enrolled ambulatory boys with DMD on glucocorticoid therapy. Bone health was evaluated with X-ray spine, Dual-energy X-ray absorptiometry (DXA), serum calcium, vitamin D3 (25[OH]D), 1,25-dihyroxyvitamin D3 (1,25[OH]2D3), serum osteocalcin, osteopontin, and N terminal telopeptide of type 1 collagen (Ntx) levels. RESULTS A total of 76 boys with DMD were enrolled. The median age was 8.5 (interquartile range [IQR] 7.04-10.77) years. Among these, seven (9.2%) boys had long bone fractures, and four (5.3%) had vertebral compression fractures. Fifty-four (71%) boys underwent DXA scan, and among these 31 (57%) had low bone mineral density (BMD, ≤-2 z-score) at the lumbar spine. The mean BMD z-score at the lumbar spine was -2.3 (95% confidence interval [CI] = -1.8, -2.8), and at the femoral neck was -2.5 (95% CI = -2, -2.9). 25(OH)D levels were deficient in 68 (89.5%, n=76) boys, and 1,25(OH)2D3 levels were deficient in all. Mean serum osteocalcin levels were 0.68 ± 0.38 ng/mL (n=54), serum osteopontin levels were 8.6 ± 4.6 pg/mL (n=54) and serum Ntx levels were 891 ± 476 nmol/L (n=54). Boys with low BMD received glucocorticoids for longer duration, in comparison to those with normal BMD (median, IQR [16.9 (6-34) months vs. 7.8 (4.8-13.4) months]; p=0.04). CONCLUSIONS Bone health is compromised in North Indian boys with DMD. BMD at the lumbar spine is reduced in more than half of boys with DMD and nearly all had vitamin D deficiency on regular vitamin D supplements. Longer duration of glucocorticoid therapy is a risk factor for low BMD in our cohort.
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Lung macrophages drive mucus production and steroid-resistant inflammation in chronic bronchitis.
Andelid, K, Öst, K, Andersson, A, Mohamed, E, Jevnikar, Z, Vanfleteren, LEGW, Göransson, M
Respiratory research. 2021;(1):172
Abstract
BACKGROUND Patients with chronic obstructive pulmonary disease (COPD) frequently suffer from chronic bronchitis (CB) and display steroid-resistant inflammation with increased sputum neutrophils and macrophages. Recently, a causal link between mucus hyper-concentration and disease progression of CB has been suggested. METHODS In this study, we have evaluated the steroid sensitivity of purified, patient-derived sputum and alveolar macrophages and used a novel mechanistic cross-talk assay to examine how macrophages and bronchial epithelial cells cross-talk to regulate MUC5B production. RESULTS We demonstrate that sputum plug macrophages isolated from COPD patients with chronic bronchitis (COPD/CB) are chronically activated and only partially respond to ex vivo corticosteroid treatment compared to alveolar macrophages isolated from lung resections. Further, we show that pseudo-stratified bronchial epithelial cells grown in air-liquid-interface are inert to direct bacterial lipopolysaccharide stimulation and that macrophages are able to relay this signal and activate the CREB/AP-1 transcription factor complex and subsequent MUC5B expression in epithelial cells through a soluble mediator. Using recombinant protein and neutralizing antibodies, we identified a key role for TNFα in this cross-talk. CONCLUSIONS For the first time, we describe ex vivo pharmacology in purified human sputum macrophages isolated from chronic bronchitis COPD patients and identify a possible basis for the steroid resistance frequently seen in this population. Our data pinpoint a critical role for chronically activated sputum macrophages in perpetuating TNFα-dependent signals driving mucus hyper-production. Targeting the chronically activated mucus plug macrophage phenotype and interfering with aberrant macrophage-epithelial cross-talk may provide a novel strategy to resolve chronic inflammatory lung disease.
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Identification of human glucocorticoid response markers using integrated multi-omic analysis from a randomized crossover trial.
Chantzichristos, D, Svensson, PA, Garner, T, Glad, CA, Walker, BR, Bergthorsdottir, R, Ragnarsson, O, Trimpou, P, Stimson, RH, Borresen, SW, et al
eLife. 2021
Abstract
BACKGROUND Glucocorticoids are among the most commonly prescribed drugs, but there is no biomarker that can quantify their action. The aim of the study was to identify and validate circulating biomarkers of glucocorticoid action. METHODS In a randomized, crossover, single-blind, discovery study, 10 subjects with primary adrenal insufficiency (and no other endocrinopathies) were admitted at the in-patient clinic and studied during physiological glucocorticoid exposure and withdrawal. A randomization plan before the first intervention was used. Besides mild physical and/or mental fatigue and salt craving, no serious adverse events were observed. The transcriptome in peripheral blood mononuclear cells and adipose tissue, plasma miRNAomic, and serum metabolomics were compared between the interventions using integrated multi-omic analysis. RESULTS We identified a transcriptomic profile derived from two tissues and a multi-omic cluster, both predictive of glucocorticoid exposure. A microRNA (miR-122-5p) that was correlated with genes and metabolites regulated by glucocorticoid exposure was identified (p=0.009) and replicated in independent studies with varying glucocorticoid exposure (0.01 ≤ p≤0.05). CONCLUSIONS We have generated results that construct the basis for successful discovery of biomarker(s) to measure effects of glucocorticoids, allowing strategies to individualize and optimize glucocorticoid therapy, and shedding light on disease etiology related to unphysiological glucocorticoid exposure, such as in cardiovascular disease and obesity. FUNDING The Swedish Research Council (Grant 2015-02561 and 2019-01112); The Swedish federal government under the LUA/ALF agreement (Grant ALFGBG-719531); The Swedish Endocrinology Association; The Gothenburg Medical Society; Wellcome Trust; The Medical Research Council, UK; The Chief Scientist Office, UK; The Eva Madura's Foundation; The Research Foundation of Copenhagen University Hospital; and The Danish Rheumatism Association. CLINICAL TRIAL NUMBER NCT02152553.
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Augmentation index, a predictor of cardiovascular events, is increased in children and adolescents with primary nephrotic syndrome.
Alves, C, Pinho, JF, Dos Santos, LM, Magalhães, G, da Silva, JM, Fontes, FL, Caligiorne, SM, Pinheiro, S, Rodrigues-Machado, MG
Pediatric nephrology (Berlin, Germany). 2020;(5):815-827
Abstract
BACKGROUND Arterial stiffness is associated with an increased risk of cardiovascular diseases. Augmentation index (AIx@75), a measure of arterial stiffness and wave reflection, has not been evaluated in patients with primary nephrotic syndrome (PNS). We investigated whether central and peripheral vascular profiles, hemodynamic parameters, and biochemical tests are associated with AIx@75 in PNS patients. METHODS This observational study involved 38 children and adolescents with PNS (12.14 ± 3.65 years) and 37 healthy controls (13.28 ± 2.80 years). Arterial stiffness and vascular and hemodynamic parameters were measured noninvasively using the Mobil-O-Graph® (IEM, Stolberg, Germany). In the PNS group, biochemical tests and corticosteroid dosage/treatment time were analyzed. RESULTS Peripheral and central systolic blood pressure (SBPp, SBPc) Z-scores were significantly higher in the PNS patients. AIx@75 was significantly higher in the PNS patients (25.14 ± 9.93%) than in controls (20.84 ± 7.18%). In the control group, AIx@75 negatively correlated with weight (r = - 0.369; p = 0.025), height (r = - 0.370; p = 0.024), and systolic volume/body surface (r = - 0.448; p = 0.006). In the PNS group, a univariate linear correlation showed that AIx@75 negatively correlated with weight (r = - 0.360; p = 0.027), height (r = 0.381; p = 0.18), and systolic volume/body surface (r = - 0.447; p < 0.002) and positively with the Z-score of SBPp (r = 0.407; p = 0.011), peripheral diastolic blood pressure (DBPp, r = 0.452; p = 0.004), SBPc (r = 0.416; p = 0.009), DBPc (r = 0.407; p = 0.011), triglycerides (r = 0.525; p = 0.001), and cholesterol [total (r = 0.539; p < 0.001), LDLc (r = 0.420; p = 0.010), and non-HDLc (r = 0.511; p = 0.001)]. CONCLUSIONS Early abnormalities of AIx@75 and vascular parameters suggest that patients with PNS, even in stable condition, present subclinical indicators for the development of cardiovascular disease.
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Anatomic Response to Intravitreal Dexamethasone Implant and Baseline Aqueous Humor Cytokine Levels in Diabetic Macular Edema.
Figueras-Roca, M, Sala-Puigdollers, A, Zarranz-Ventura, J, Alba-Linero, C, Alforja, S, Esquinas, C, Molins, B, Adán, A
Investigative ophthalmology & visual science. 2019;(5):1336-1343
Abstract
PURPOSE To determine whether baseline cytokine aqueous humor (AH) levels are associated with diabetic macular edema (DME) anatomic response to dexamethasone intravitreal implant (DEX) injection. METHODS This was a prospective cohort study of DME cases receiving DEX treatment. Seventy patients were recruited with center-involving DME with spectral-domain (SD) optical coherence tomography (OCT) detection of central macular thickness (CMT) ≥300 μm on macular cube 518 × 128-μm scan protocol (Cirrus SD-OCT). DEX injection and anterior chamber tap to obtain an AH sample were performed at the same time. Multiplex immunoassay was carried out for interleukin (IL)-1β, IL-3, IL-6, IL-8, IL-10; monocyte chemoattractant protein (MCP)-1; interferon gamma-induced protein (IP)-10; tumor necrosis factor (TNF)-α; and vascular endothelial growth factor (VEGF). A follow-up visit and OCT exam were undertaken 6 to 8 weeks afterward. The association between AH cytokine baseline levels and change in CMT and macular volume (MV) was defined as main outcome measure. RESULTS Multivariate linear regression analysis showed a higher decrease in MV to be associated (Rs of 0.512) with four baseline items: higher MCP-1 (β = -0.4; P = 0.028), higher CMT (β = -0.003; P = 0.024), decreased visual acuity (β = -0.7; P = 0.040), and a diffuse retinal thickening (DRT) OCT pattern (β = -1.3; P < 0.001). Logistic regression found DRT also to be associated with higher odds of a good MV response (odds ratio, 31.96; 95% confidence interval [CI] 7.11-143.72; P < 0.001). CONCLUSIONS Even though visual acuity response and anatomic effect are not always correlated in DME, we found that baseline elevated MCP-1 AH levels and DRT pattern were biomarkers that predicted a future favorable anatomic response to DEX.
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Real-World Assessment of Dexamethasone Intravitreal Implant in DME: Findings of the Prospective, Multicenter REINFORCE Study.
Singer, MA, Dugel, PU, Fine, HF, Capone, A, Maltman, J
Ophthalmic surgery, lasers & imaging retina. 2018;(6):425-435
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Abstract
BACKGROUND AND OBJECTIVE Dexamethasone intravitreal implant (DEX) (Ozurdex; Allergan plc, Dublin, Ireland) is approved for the treatment of diabetic macular edema (DME). This study assessed the real-world effectiveness, safety, and reinjection interval of DEX in adult patients with DME. PATIENTS AND METHODS This was a phase 4, prospective, multicenter (18 U.S. sites), observational study. RESULTS The study population comprised 177 patients (180 eyes; 93.8% previously treated). Baseline mean best-corrected visual acuity (BCVA) and central retinal thickness (CRT) were 54.4 letters and 424.6 μm, respectively. DEX was administered as monotherapy or with other DME therapy (55%/45%). The mean reinjection interval was 5.0 months. Mean maximum BCVA change from baseline after the first three DEX injections was +9.1 letters, +7.7 letters, and +7.0 letters, respectively (P < .001); 36.0% of eyes achieved 15-letter or greater BCVA improvement. Mean maximum CRT change from baseline was -137.7 μm (P < .001). CONCLUSION DEX used alone or with other DME therapy improved visual and anatomic outcomes in DME patients in clinical practice, with no new safety concerns. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:425-435.].
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Impact of Preterm Birth on Glucocorticoid Variability in Human Milk.
Pundir, S, Mitchell, CJ, Thorstensen, EB, Wall, CR, Perrella, SL, Geddes, DT, Cameron-Smith, D
Journal of human lactation : official journal of International Lactation Consultant Association. 2018;(1):130-136
Abstract
BACKGROUND Preterm birth is a stressful event for both the mother and infant. Whereas the initiation of breastfeeding is important for preterm infant health, little is known of the glucocorticoid hormones (cortisol and cortisone) in human milk following preterm birth. Research aim: The aim of this study was to investigate the relationship between human milk glucocorticoid concentrations and preterm birth. METHODS Human milk was sampled weekly for up to 6 weeks from 22 women who delivered a preterm infant at 28 to 32 weeks' gestation. Human milk was analyzed for total and free cortisol and cortisone concentrations using liquid chromatography-tandem mass spectrometry. RESULTS Milk sampled from mothers of preterm infants had more cortisone than cortisol ( p < .001), with a strong correlation between both hormones ( p = .001, r = .85). The cortisone was significantly higher in the milk of mothers who delivered infants after 30 weeks compared with those who delivered before 30 weeks of gestation ( p = .02). Glucocorticoid concentrations did not change over the sampling time (weeks 1 to 6 postpartum) and did not differ by infant gender. CONCLUSION Glucocorticoids were present in all milk samples following preterm birth. Cortisone concentration tended to be higher in those who delivered after 30 weeks' gestation but did not increase further over the weeks following birth.
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Vitamin D Deficiency as a Factor Influencing Asthma Control in Children.
Kaaviyaa, AT, Krishna, V, Arunprasath, TS, Ramanan, PV
Indian pediatrics. 2018;(11):969-971
Abstract
OBJECTIVE To study the association between asthma control and serum 25OH Vitamin D levels in children with moderate persistent asthma on preventer therapy. METHODS Children aged 6-18 years, with moderate persistent asthma, on preventer therapy for ≥2 months were included. Control was categorized as good, partial or poor as per GINA guidelines. Serum 25 (OH) Vitamin D levels were measured and their relationship with the level of control was studied. RESULTS Out of 50 children enrolled, 22 had well-controlled asthma, and 21 had partially controlled asthma. Vitamin D was deficient in 30 children and insufficient in 18 children. Children with vitamin D deficiency had significantly less well-controlled asthma as compared to those with insufficient or sufficient levels of 25 (OH) vitamin D (13.3% vs 88.9% vs 100%). CONCLUSIONS Vitamin D deficiency is associated with suboptimal asthma control.
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Trends and Determinants of Osteoporosis Treatment and Screening in Patients With Rheumatoid Arthritis Compared to Osteoarthritis.
Ozen, G, Kamen, DL, Mikuls, TR, England, BR, Wolfe, F, Michaud, K
Arthritis care & research. 2018;(5):713-723
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Abstract
OBJECTIVE To profile osteoporosis (OP) care in patients with rheumatoid arthritis (RA) over the past decade. METHODS Patients with RA or osteoarthritis (OA) were followed from 2003 through 2014. OP care was defined as receipt of OP treatment (with the exception of calcium/vitamin D) or screening (OPTS). Adjusted trends over followup, and the factors associated with OP care, were examined using multivariable Cox proportional hazards. RESULTS OPTS was reported in 67.4% of 11,669 RA patients and in 64.6% of 2,829 OA patients during a median (interquartile range) 5.5 (2-9) years of followup. In patients for whom treatment was recommended by the 2010 American College of Rheumatology (ACR) glucocorticoid-induced OP (GIOP) guidelines (48.4% of RA patients and 17.6% of OA patients), approximately 55% overall reported OP medication use. RA patients were not more likely to undergo OPTS compared to OA patients (hazard ratio 1.04 [95% confidence interval 0.94-1.15]). Adjusted models showed a stable trend for OPTS between 2004 and 2008 compared to 2003, with a significant downward trend after 2008 in both RA and OA patients. Factors associated with receipt of OP care in RA patients were older age, postmenopausal state, prior fragility fracture or diagnosis of OP, any duration of glucocorticoid treatment, and use of biologic agents. CONCLUSION Approximately half of RA patients for whom treatment was indicated never received an OP medication. OP care in RA patients was not better than in OA patients, and the relative risk of the application of this care has been decreasing in RA and OA patients since 2008 without improvement after the release of the 2010 ACR GIOP guideline.
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Effectiveness and safety of dexamethasone implants for postsurgical macular oedema including Irvine-Gass syndrome: the EPISODIC-2 study.
Bellocq, D, Pierre-Kahn, V, Matonti, F, Burillon, C, Voirin, N, Dot, C, Akesbi, J, Milazzo, S, Baillif, S, Soler, V, et al
The British journal of ophthalmology. 2017;(3):333-341
Abstract
AIM: To assess the effectiveness of intravitreal dexamethasone implants for treating postsurgical macular oedema (PSMO) including Irvine-Gass syndrome and determining the predictive factors of treatment response. METHODS Descriptive, observational, retrospective, consecutive, uncontrolled, multicentre, national case series. One hundred patients were included between April 2011 and June 2014, with a minimum of 1-year follow-up. Patients received dexamethasone implant 0.7 mg at baseline. Clinical characteristics, best-corrected visual acuity (BCVA), central subfield macular thickness (CSMT) and intraocular pressure were measured at each visit. The main outcome measure was the change in BCVA (Early Treatment of Diabetic Retinopathy Study (ETDRS) letters: L). An analysis of predictive factors of treatment response is also provided. RESULTS Mean improvement in BCVA was 9.6 (±10.6) L at month 6 and 10.3 (±10.7) L at month 12 (p<0.001). The proportion of eyes with gains in BCVA of 15 or more letters was 32.5% and 37.5% at months 6 and 12, respectively. The mean reduction in CSMT was 135.2 and 160.9 µm at months 6 and 12, respectively (p<0.001). Thirty-seven per cent of patients did not need a second injection after the first injection during follow-up. The presence of at least one PSMO risk factor decreases the probability of a gain in visual acuity (VA) ≥10 L (p=0.006). Initial VA ≤50 L at baseline and non-naïve status decrease the probability of having only one injection during follow-up (p=0.044). CONCLUSIONS The significant gain in BCVA from baseline achieved at month 6 was maintained at month 12 after intravitreal injection of dexamethasone implant. Naïve status seems to be a good predictive factor of treatment response.