Bone Mineral Density in Patients with Hepatic Glycogen Storage Diseases.

The association between bone mineral density (BMD) and hepatic glycogen storage diseases (GSDs) is still unclear. To evaluate the BMD of patients with GSD I, IIIa and IXα, a cross-sectional study was performed, including 23 patients (GSD Ia = 13, Ib = 5, IIIa = 2 and IXα = 3; median age = 11.9 years; IQ = 10.9-20.1) who underwent a dual-energy X-ray absorptiometry (DXA). Osteocalcin (OC, n = 18), procollagen type 1 N-terminal propeptide (P1NP, n = 19), collagen type 1 C-terminal telopeptide (CTX, n = 18) and 25-OH Vitamin D (n = 23) were also measured. The participants completed a 3-day food diary (n = 20). Low BMD was defined as a Z-score ≤ -2.0. All participants were receiving uncooked cornstarch (median dosage = 6.3 g/kg/day) at inclusion, and 11 (47.8%) presented good metabolic control. Three (13%) patients (GSD Ia = 1, with poor metabolic control; IIIa = 2, both with high CPK levels) had a BMD ≤ -2.0. CTX, OC and P1NP correlated negatively with body weight and age. 25-OH Vitamin D concentration was decreased in seven (30.4%) patients. Our data suggest that patients with hepatic GSDs may have low BMD, especially in the presence of muscular involvement and poor metabolic control. Systematic nutritional monitoring of these patients is essential.

Comparative efficacy of bone anabolic therapies in women with postmenopausal osteoporosis: A systematic review and network meta-analysis of randomized controlled trials.

OBJECTIVE: To systematically evaluate the effects of bone anabolic therapies (BATs) - specifically, drug therapy with teriparatide, abaloparatide or romosozumab - on fractures, bone mineral density (BMD), and bone metabolites in postmenopausal osteoporosis. METHODS: Six computerized engines were searched through to November 2018. We selected randomized controlled trials (RCTs) evaluating the effect of BATs on postmenopausal osteoporosis and with at least 6 months of follow-up. Controls were placebo, no treatment, or bisphosphonates. Primary outcomes were vertebral and non-vertebral fractures. Secondary outcomes were: BMD determined by dual energy X-ray absorptiometry at total hip, lumbar spine, and femoral neck; N-terminal propeptide of type I procollagen (PINP); C-terminal telopeptide of type I collagen (CTX); and severe adverse events (SAE). We followed the PRISMA guidelines for reporting, and used version 2 of the Cochrane risk-of-bias tool. Frequentist network meta-analyses were performed per outcome. Effects for dichotomous and continuous outcomes were expressed as relative risks and mean differences and their 95% confidence intervals. We used p-scores to rank best treatments per outcome. RESULTS: Sixteen RCTs (n = 18,940) were evaluated. Mean ages ranged between 61 and 74 years, and follow-up times between 6 and 30 months. Four RCTs (n = 971) excluded patients with previous fractures. In contrast to placebo/no treatment, all BATs significantly reduced the risk of vertebral fractures, but no intervention significantly reduced the risk of non-vertebral fractures; abaloparatide ranked better than other interventions for both fracture types (p-scores: 0.95, and 0.89, respectively). All BATs significantly increased BMD at all locations in comparison with placebo/no treatment; romosozumab consistently ranked better than other interventions at all BMD locations (p-scores >0.86). Teriparatide ranked better than other interventions for increasing PINP. No differences in SAE were observed among treatments. CONCLUSIONS: Abaloparatide, romosozumab, and teriparatide are the best treatments, respectively, to reduce vertebral/non-vertebral fractures, increase BMD, and increase bone formation.

Appraising diagnostic performance of ELF test by pathological staging and digital quantification of liver fibrosis.

INTRODUCTION AND OBJECTIVES: A crucial issue when appraising the performance of non-invasive markers is the limitations of the reference standard they are compared to. Digital image analysis (DIA) was suggested as a reproducible approach expressing fibrosis numerically as a proportionate area (PA) (%). We aimed to evaluate ELF test with direct reference to PA (%), thereby explore the improvement in accuracy to discriminate significant fibrosis which may actually have been underestimated by categorical pathological staging. MATERIALS AND METHODS: PA (%) data were obtained by DIA of trichrome-stained liver biopsies of 52 chronic hepatitis patients. Paired serum samples of patients and additional 36 controls were performed to measure ELF test. Diagnostic performance characteristics of ELF test was derived in predicting significant fibrosis in the patient cohort, and also, in distinguishing healthy controls from patients with significant fibrosis. RESULTS: We found an AUROC value of 0.73 for ELF to predict significant fibrosis as assessed by DIA and a lower AUROC value of 0.66 when assessed by conventional pathology. Importantly, ELF test provided considerably high diagnostic accuracy to discriminate healthy controls from patients with significant fibrosis defined by Ishak F≥2 and TPA≥5% (AUROCs 0.93 and 0.94, respectively) with optimal ELF cut-off point of 8.4 for both. CONCLUSIONS: Digital quantification could represent a better reference standard than conventional pathology allowing a better discriminatory capability for ELF test. ELF test provided high diagnostic accuracy to discriminate healthy controls from patients with significant fibrosis suggesting a role as a screening strategy in the community setting.

Prediction of bone mass changes after successful parathyroidectomy using biochemical markers of bone metabolism in primary hyperparathyroidism: is it clinically useful?

OBJECTIVE: To measure type 1 serum amino-terminal propeptide procollagen (P1NP) and type 1 cross-linked C-terminal telopeptide collagen (CTX) before parathyroidectomy (PTX) in PHPT patients, correlating these measurements with bone mineral density (BMD) changes. SUBJECTS AND METHODS: 31 primary hyperparathyroidism (HPTP) were followed from diagnosis up to 12-18 months after surgery. Serum levels of calcium, parathyroid hormone (PTH) vitamin D, CTX, P1NP, and BMD were measured before and 1 year after surgery. RESULTS: One year after PTX, the mean BMD increased by 8.6%, 5.5%, 5.5%, and 2.2% in the lumbar spine, femoral neck (FN), total hip (TH), and distal third of the nondominant radius (R33%), respectively. There was a significant correlation between BMD change 1 year after the PTX and CTX (L1-L4: r = 0.614, p < 0.0003; FN: r = 0.497, p < 0.0051; TH: r = 0.595, p < 0.0005; R33%: r = 0.364, p < 0.043) and P1NP (L1-L4: r = 0,687, p < 0,0001; FN: r = 0,533, p < 0,0024; TH: r = 0,642, p < 0,0001; R33%: r = 0,467, p < 0,0079) preoperative levels. The increase in 25(OH)D levels has no correlation with BMD increase (r = -0.135; p = 0.4816). On linear regression, a minimum preoperative CTX value of 0.331 ng/mL or P1NP of 37.9 ng/mL was associated with a minimum 4% increase in L1-L4 BMD. In TH, minimum preoperative values of 0.684 ng/mL for CTX and 76.0 ng/mL for P1NP were associated with a ≥ 4% increase in BMD. CONCLUSION: PHPT patients presented a significant correlation between preoperative levels of turnover markers and BMD improvement 1 year after PTX.

Prediction of bone mass changes after successful parathyroidectomy using biochemical markers of bone metabolism in primary hyperparathyroidism: is it clinically useful?

ABSTRACT Objective To measure type 1 serum amino-terminal propeptide procollagen (P1NP) and type 1 cross-linked C-terminal telopeptide collagen (CTX) before parathyroidectomy (PTX) in PHPT patients, correlating these measurements with bone mineral density (BMD) changes. Subjects and methods 31 primary hyperparathyroidism (HPTP) were followed from diagnosis up to 12-18 months after surgery. Serum levels of calcium, parathyroid hormone (PTH) vitamin D, CTX, P1NP, and BMD were measured before and 1 year after surgery. Results One year after PTX, the mean BMD increased by 8.6%, 5.5%, 5.5%, and 2.2% in the lumbar spine, femoral neck (FN), total hip (TH), and distal third of the nondominant radius (R33%), respectively. There was a significant correlation between BMD change 1 year after the PTX and CTX (L1-L4: r = 0.614, p < 0.0003; FN: r = 0.497, p < 0.0051; TH: r = 0.595, p < 0.0005; R33%: r = 0.364, p < 0.043) and P1NP (L1-L4: r = 0,687, p < 0,0001; FN: r = 0,533, p < 0,0024; TH: r = 0,642, p < 0,0001; R33%: r = 0,467, p < 0,0079) preoperative levels. The increase in 25(OH)D levels has no correlation with BMD increase (r = -0.135; p = 0.4816). On linear regression, a minimum preoperative CTX value of 0.331 ng/mL or P1NP of 37.9 ng/mL was associated with a minimum 4% increase in L1-L4 BMD. In TH, minimum preoperative values of 0.684 ng/mL for CTX and 76.0 ng/mL for P1NP were associated with a ≥ 4% increase in BMD. Conclusion PHPT patients presented a significant correlation between preoperative levels of turnover markers and BMD improvement 1 year after PTX.

Biomarcadores de fibrosis y función ventricular derecha en maratonistas con distinto grado de entrenamiento: estudio en la maratón de Santiago / Fibrosis and right ventricular function biomarkers in marathon runners: a study at the Santiago, Chile marathon

Resumen: Introducción: Atletas altamente entrenados muestran cambios cardíacos estructurales como adaptación a la sobrecarga, producto del ejercicio repetitivo y extenuante. Se han evidenciado elevación de biomarcadores de remodelado y fibrosis miocárdica posterior al ejercicio intenso en atletas. Sin embargo, el comportamiento de estos biomarcadores según el nivel de entrenamiento previo no se ha evaluado. Objetivo: Investigar biomarcadores de fibrosis y función ventricular derecha en maratonistas con distinto nivel de entrenamiento previo. Métodos: Se incluyeron 36 maratonistas hombres, sanos, que completaron 42 km en la maratón de Santiago. Se dividieron según entrenamiento previo en dos grupos, Grupo 1 (G1): ≥100 km/semana y Grupo 2 (G2): <100 km/semana. Se realizó ecocardiografía transtorácica y se evaluaron niveles plasmáticos de galectina-3 y del propéptido amino terminal del procolágeno tipo III (PIIINP) en la semana previa a la carrera e inmediatamente posterior a ésta. Resultados: Posterior a la maratón, la función sistólica del ventrículo derecho disminuyó en el grupo G2 junto con un aumento significativo de los niveles plasmáticos de PIIIPNP (61±16 a 94±24 ng/mL, p=0,01). Estos cambios no se observaron en el grupo G1 (65 ± 11 a 90±29 ng/mL, p=0,10). Los niveles plasmáticos de galectina-3 aumentaron significativamente en ambos grupos posterior al ejercicio (6,8±2,2 a 19,7±4,9 ng/mL, p 0,012 y 6,0±1,1 a 19,4 ± 5,9 ng/mL, p 0,01) en los grupos G1 y G2, respectivamente). Conclusiones: Atletas con menor grado de entrenamiento, presentan posterior a una maratón un significativo aumento de productos de degradación del colágeno (PIIIPNP) asociado a disminución de la función del ventrículo derecho. Los niveles de galectina-3 plasmática aumentan significativamente en ambos grupos post-esfuerzo independiente del entrenamiento previo.

Abstracts: Introduction: Highly trained athletes show structural cardiac changes as adaptation to overload. Rise in remodeling biomarkers and myocardial fibrosis after intense exercise in athletes has been evidenced; however, the behavior of these biomarkers according to pre-competition training level has not been evaluated. Objective: To evaluate fibrosis biomarkers levels and right ventricle function in marathon runners according to their previous training level, in the period prior to a marathon race and immediately after it. Methods: Thirty-six healthy male marathon runners were included. Subjects were grouped according to their previous training level: Group 1 (G1): ≥100 km/week and Group 2 (G2): <100 km/week. Transthoracic echocardiography along with plasmatic levels of galectin-3 and amino terminal propeptide of type III procollagen (PIIINP) were measured one week previous and immediately after the marathon. Results: Post-effort right ventricle systolic function decreased in G2, together with a significant elevation of PIIIPNP (61±16 to 94±24 ng/mL, p=0.01). These changes were not observed in G1 (from 65±11 to 90±29 ng/mL, p=0.10). Plasma galectin-3 increased significantly in both groups immediately post-exercise (6.8±2.2 to 19.7±4.9 ng/mL, p=0.012, and 6.0±1.1 to 19.4±5.9 ng/mL, p=0.01, in G1 and G2. respectively). Conclusion: Less trained athletes evidenced higher post marathon levels of PIIIPNP which is associated with a decreased global right ventricle function. Plasma galectin-3 levels increased significantly after intense exertion regardless of the intensity of previous training.

Monocytes from male patients with ankylosing spondylitis display decreased osteoclastogenesis and decreased RANKL/OPG ratio.

The present study investigates the osteoclastogenic capacity of peripheral blood mononuclear cells (PBMCs) in male patients with ankylosing spondylitis (AS). We demonstrated that monocytes from these patients display a lower capacity to generate osteoclasts compared to cells from healthy controls, and osteoclastogenesis was negatively correlated with disease duration. INTRODUCTION: Ankylosing spondylitis (AS) is a disease characterized by new bone growth that leads to syndesmophyte formation but AS patients frequently present with low bone mineral density/fractures. Osteoclastogenesis in AS patients is poorly studied and controversial. The aim of this study is to determine if the osteoclastogenic capacity of PBMCs is different in AS patients compared to controls and the relationship between osteoclastogenesis and clinical/laboratory parameters. METHODS: PBMCs from 85 male AS patients and 59 controls were tested for CD16+ cells and induced to differentiate into osteoclasts over 3 weeks in vitro. Serum levels of RANKL, osteoprotegerin (OPG), C-terminal telopeptide of type I collagen (CTX), and amino-terminal pro-peptide of type I collagen (P1NP) were also evaluated. RESULTS: PBMCs from AS patients had fewer CD16+ cells and produced fewer osteoclasts compared to controls. Apoptosis occurred less frequently in osteoclasts obtained from AS patients than in osteoclasts from the controls. A lower RANKL/OPG and CTX/P1NP were observed in AS patients compared to controls. AS patients taking NSAIDs presented no difference regarding the number of OCs produced and the percentage of CD16+ cells compared to controls. However, patients taking TNF inhibitors (TNFi) presented lower OC numbers than controls. A negative correlation was demonstrated between the number of osteoclasts generated from PBMCs of AS patients and disease duration. CONCLUSION: Monocytes from male AS patients display a lower capacity to generate osteoclasts in vitro compared to cells from controls. Osteoclastogenesis was negatively correlated with disease duration. This finding supports the idea that osteoclasts play a role in the physiopathology of bone disease in AS patients.

[Association of inflammatory cytokines with bone turnover markers in type 1 diabetes]. / Asociación de citocinas inflamatorias con marcadores de recambio óseo en diabetes tipo 1.

BACKGROUND: Diabetes mellitus (DM) adversely affects the skeleton and the physiological mechanisms implicated have not been explained sufficiently. Thus, the objective was to identify inflammatory cytokines (IL-1, IL-6 and TNF-alpha) in patients with T1DM and their association with markers of bone formation (sPINP) and markers of bone resorption (sCTX). METHODS: We studied 62 patients of 18 years of age or more with T1DM. We determined the values of HbA1c, vitamin D, inflammatory cytokines, as well as those of markers of bone formation and of markers of bone resorption. RESULTS: 49 patients were female with a mean age of 33.5 years. We found values of HbA1c > 7.5 in 83 %, vitamin D of 16 ng/mL. In patients with HbA1c >7.5 we found a positive correlation between TNF-alpha and sCTX (r = 0.43, p = 0.05), IL-6 and sCTX (r = 0.48, p = 0.037). With a model of simple linear regression between IL-6 and sCTX, it was found a beta coefficient of 23.8 with a p = 0.030 (95 % CI = 2-45.6), ie.: for every unit increase in IL-6 there is a sCTX increase of 23.8 pg/mL. CONCLUSIONS: We found a positive association between TNF-alpha and IL-6 with the marker of bone resorption (sCTX) in the group of patients with HbA1c > 7.5. The loss of metabolic control was associated with TNF-alpha and IL-6.

Introducción: la diabetes mellitus afecta de una manera adversa al esqueleto y esos mecanismos fisiopatológicos continúan sin entenderse completamente. Por lo tanto, el objetivo de este estudio es identificar citocinas inflamatorias (IL-1, IL-6 y TNFα) en pacientes con DM1 y su asociación con marcadores de formación (sPINP) y resorción (sCTX) óseas. Métodos: Se estudiaron 62 pacientes con DM1, mayores de 18 años. Se determinaron los valores de la HbA1c, la vitamina D, las citocinas inflamatorias, así como los de los marcadores de formación y resorción óseas. Resultados: 49 pacientes fueron del sexo femenino con una edad media de 33.5 años, HbA1c > 7.5 en 83%, vitamina D 16 ng/mL. En los pacientes con HbA1c > 7.5 hubo correlación positiva entre el TNFa y sCTX (r = 0.43, p = 0.05), IL-6 y sCTX (r = 0.48, p = 0.037). Posterior a un modelo de regresión lineal simple entre el sCTX y la IL-6 se encontró un coeficiente beta de 23.8, p = 0.030 (IC 2-45.6), es decir, por cada unidad de elevación de IL-6 hay un incremento de sCTX de 23.8 pg/mL. Conclusiones: encontramos una asociación positiva entre TNF-alfa e IL-6 con el marcador de resorción ósea (sCTX) en pacientes con HbA1c > 7.5 %. El descontrol metabólico se asoció con la elevación de citocinas inflamatorias TNF-alfa e IL-6.

Effect of age and sex on bone markers in Chlorocebus aethiops raised in captivity.

BACKGROUND: The objective was to evaluate the procollagen type I N-propeptide (PINP), osteocalcin (OC), ß-crosslaps (ß-CTX), and parathyroid hormone (PTH) in relation to age and sex of Chlorocebus aethiops in captivity. METHODS: Seventy-three monkeys were divided into four age groups: AG1 (juvenile); AG2 (young adult); AG3 (adult); and AG4 (senile). An electrochemiluminescence immunoassay with an Elecsys 2010 analyzer was used to determine the serum markers of bone. RESULTS AND CONCLUSIONS: Sex did not influence the results of the markers. However, the variables PINP, OC, and ß-CTX were negatively correlated with age (r = -0.643; r = -0.711; r = -0.488; P < 0.001, respectively), and PTH was correlated positively with age (r = 0.418, P < 0.001). The data obtained can be used as biomarkers of bone metabolism reference intervals in healthy C. aethiops in captivity.

Lower P1NP serum levels: a predictive marker of bone loss after 1 year follow-up in premenopausal systemic lupus erythematosus patients.

SUMMARY: Predictors of bone mineral density (BMD) loss are additional tools in the management of osteoporosis in premenopausal women with systemic lupus erythematosus (SLE). This study provides original evidence that N-terminal propeptide of type 1 collagen (P1NP), the most specific bone formation marker, is a predictor of BMD loss in this group of women. INTRODUCTION: SLE is associated with a high risk of low bone mass/fractures but this risk is still controversial in premenopausal women. Our aim was to determine the 1 year incidence of BMD loss in premenopausal SLE women and the value of bone turnover markers as predictors of this complication. METHODS: This study enrolled a convenience sample of 63 premenopausal SLE patients. BMD was evaluated by dual X-ray absorptiometry at lumbar spine and hip at baseline and after 12 months. BMD changes above the least significant change were considered significant. Serum levels of P1NP and CTX (electrochemiluminescence), OPG, and RANKL (ELISA) were determined at baseline. RESULTS: Mean age was 31.1±6.8 years, and disease duration was 5.25±3.8 years. 36.5 % of patients presented BMD loss and 17.5 % BMD gain at lumbar spine and/or hip. Patients were divided in three groups: BMD loss (BL), no BMD change (NC), and BMD gain (BG). Patients with BL and NC received similar cumulative/mean/maximum glucocorticoid doses during the study, but patients with BG received lower doses (p<0.05). Baseline P1NP levels were different in the groups (BL: 36.95±23.37 vs. NC: 54.63±30.82 vs. BG: 84.09±43.85 ng/mL; p=0.031 BL vs. NC, p<0.001 BL vs. BG, and p=0.039 NC vs. BG). There was no difference in CTX, OPG, or RANKL levels. After multivariate analysis, P1NP remained as an independent risk factor for BMD loss (p<0.03). CONCLUSIONS: This study provides original evidence that lower levels of P1NP, the most specific bone formation marker, are predictive of BMD loss over 12 months in premenopausal SLE patients.

Enhanced liver fibrosis panel as a predictor of liver fibrosis in chronic hepatitis C patients.

BACKGROUND: Evaluation of fibrosis is crucial in the assessment of chronic hepatitis C (CHC). The enhanced liver fibrosis (ELF) is a serological panel including hyaluronic acid (HA), tissue inhibitor of matrix metalloproteinases-1 (TIMP-1), and amino-terminal propeptide of type III procollagen (PIIINP) that has shown good results in predicting liver fibrosis in distinct scenarios of chronic liver diseases. AIMS: We aimed to assess the performance of ELF on the detection of fibrosis and cirrhosis in a CHC patient cohort and to compare the results of ELF and transient elastography (TE-Fibroscan) using liver biopsy as reference. PATIENTS AND METHODS: One hundred twenty patients were prospectively evaluated by TE and ELF using an ADVIA Centaur automated system. The ELF score was calculated using the manufacturer's algorithm. Biopsies were classified according to the METAVIR score. Receiver operator characteristic curve analyses were performed to evaluate the accuracy of ELF and TE. RESULTS: The area under the receiver operator characteristic curve (AUROC) of ELF for the diagnosis of significant fibrosis was 0.81 [95% confidence interval (CI), 0.73-0.87], for advanced fibrosis was 0.82 (95% CI, 0.74-0.88), and for cirrhosis was 0.78 (95% CI, 0.70-0.85). Using the proposed cutoffs, ELF overestimated fibrosis in 66% (81/120) of cases and underestimated in 3% (3/120). We found no statistically significant difference when comparing the AUROC of ELF and TE for diagnosing fibrosis or cirrhosis. CONCLUSIONS: ELF panel is a good noninvasive fibrosis marker and showed similar results to TE in CHC patients. However, new cutoff points need to be established to improve its performance on patients with CHC.

Procollagen Type I and III Aminoterminal Propeptide Levels and Severity of Interstitial Lung Disease in Mexican Women With Progressive Systemic Sclerosis.

BACKGROUND: Interstitial lung disease (ILD) is a frequent complication in progressive systemic sclerosis (SSc), being present in 25% to 90% of cases. OBJECTIVES: To evaluate whether serum levels of procollagen typei and iii aminoterminal propeptide (PINP and PIIINP) correlate with severity and patterns of ILD in Mexican women with SSc. METHODS: Thirty three SSc patients were assessed for disease characteristics and anti-topoisomerase antibodies (topoi), and also underwent pulmonary function tests and high-resolution computed tomography (HRCT). Nineteen patients had ILD+SSc, and 14 had no lung involvement (no ILD-SSc); data were compared with those from 45 healthy controls. PINP and PIIINP were assessed in all 3 groups. RESULTS: Patients with SSc had higher PINP and PIIINP vs controls (P=.001, P<.001, respectively). Compared to no ILD-SSc patients, those with ILD+SSc had longer disease duration in years (P=.005), higher modified Rodnan skin score (P<.001), higher Health Assessment Questionnaire-Disability-Index scores (P<.001), higher topoi U/mL (P<.001), PINP (49.28±28.63 vs. 32.12±18.58µg/L, P=.05), and PIIINP (4.33±1.03 vs. 2.67±1.26µg/L, P<.001) levels. ILD severity based on total HRCT correlated with PINP (r=.388, P=.03) and PIIINP (P=.594, P<.001). On adjusted analysis, ILD severity was associated with disease duration (P=.037), PIIINP (P=.038), and topoi (P=.045). CONCLUSIONS: PINP and PIIINP are useful markers for severe ILD+SSc, suggesting they could play a role in the follow-up of this complication in SSc.

Correlation Between Radiographic Area and Immunolocation of MMP-2 and MMP-9 in Unilocular Radiographic Lesions

Unilocular bone cysts are the most common entities affecting the maxillofacial region. The mechanism of proliferation and expansion remains unclear. Metalloproteinases (MMPs) are associated to diverse pathological conditions. The aim of the present study was to correlate the radiographic aspect (area) and the presence of MMP-2 and MMP-9 in dentigerous cysts, radicular cysts and keratocystic odontogenic tumors. The radiographic area of each lesion was calculated using the mathematical formula of the ellipse area. All specimens were subjected to immunohistochemical analysis for these enzymes. The average radiographic area was 284.17 mm2, 235.81 mm2 and 381.81 mm2, respectively. Statistical analyses revealed no association between the immunoreactivity of MMPs and radiographic area of the lesions in all pathologies studied, except for MMP-2 and radicular cysts, for which smaller lesions had increased immunostaining for this enzyme. The results demonstrate that quantities of MMP-2 and MMP-9 are especially involved with dentigerous and radicular cysts in expansion, whereas these enzymes seem to be related to the biological behavior of keratocystic odontogenic tumors, indicating invasion and cell proliferation. Moreover, there is an inverse association between MMP-2 and MMP-9 in keratocystic odontogenic tumors (p=0.03; rs=-0.660), indicating activity in different regions.

Cistos ósseos uniloculares são as entidades mais comuns que afetam a região maxilofacial. O mecanismo de proliferação e expansão permanece obscuro. As metaloproteinases (MMPs) estão associadas a diversas condições patológicas. O objetivo do presente estudo foi correlacionar o aspecto radiográfico (área) e a presença de MMP-2 e MMP-9 em cistos dentígeros, cistos radiculares e tumores odontogênicos queratocísticos. A área radiográfica de cada lesão foi calculada usando a fórmula matemática da área de elipse. Todas as amostras foram submetidas à análise imunoistoquímica para estas enzimas. A área radiográfica média foi de 284,17 mm2, 235,81 mm2 e 381,81 mm2, respectivamente. As análises estatísticas não mostraram associação entre a imunorreatividade de MMPs e área radiográfica das lesões em todas as patologias estudadas, exceto para MMP-2 e cistos radiculares, nas quais as lesões menores tinham maior imunomarcação para esta enzima. Os resultados demonstraram que a quantidade de imunomarcação da MMP-2 e MMP-9 estão envolvidos com cistos dentígeros e radiculares na expansão óssea, ao passo que estas enzimas parecem estar relacionados com o comportamento biológico dos tumores odontogénicos queratocísticos, indicando invasão e proliferação celular. Além disso, há uma relação inversa entre a MMP-2 e MMP-9 em tumores odontogénicos queratocísticos (p=0,03; rs= -0,660), indicando atividade em diferentes regiões.

Performance of diagnostic biomarkers in predicting liver fibrosis among hepatitis C virus-infected Egyptian children

The aim of the present study was to identify specific markers that mirror liver fibrosis progression as an alternative to biopsy when biopsy is contraindicated, especially in children. After liver biopsies were performed, serum samples from 30 hepatitis C virus (HCV) paediatric patients (8-14 years) were analysed and compared with samples from 30 healthy subjects. All subjects were tested for the presence of serum anti-HCV antibodies. Direct biomarkers for liver fibrosis, including transforming growth factor-β1, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), hyaluronic acid (HA), procollagen type III amino-terminal peptide (PIIINP) and osteopontin (OPN), were measured. The indirect biomarkers aspartate and alanine aminotransferases, albumin and bilirubin were also tested. The results revealed a significant increase in the serum marker levels in HCV-infected children compared with the healthy group, whereas albumin levels exhibited a significant decrease. Significantly higher levels of PIIINP, TIMP-1, OPN and HA were detected in HCV-infected children with moderate to severe fibrosis compared with children with mild fibrosis (p < 0.05). The diagnostic accuracy of these direct biomarkers, represented by sensitivity, specificity and positive predictive value, emphasises the utility of PIIINP, TIMP-1, OPN and HA as indicators of liver fibrosis among HCV-infected children.

Performance of diagnostic biomarkers in predicting liver fibrosis among hepatitis C virus-infected Egyptian children.

The aim of the present study was to identify specific markers that mirror liver fibrosis progression as an alternative to biopsy when biopsy is contraindicated, especially in children. After liver biopsies were performed, serum samples from 30 hepatitis C virus (HCV) paediatric patients (8-14 years) were analysed and compared with samples from 30 healthy subjects. All subjects were tested for the presence of serum anti-HCV antibodies. Direct biomarkers for liver fibrosis, including transforming growth factor-ß1, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), hyaluronic acid (HA), procollagen type III amino-terminal peptide (PIIINP) and osteopontin (OPN), were measured. The indirect biomarkers aspartate and alanine aminotransferases, albumin and bilirubin were also tested. The results revealed a significant increase in the serum marker levels in HCV-infected children compared with the healthy group, whereas albumin levels exhibited a significant decrease. Significantly higher levels of PIIINP, TIMP-1, OPN and HA were detected in HCV-infected children with moderate to severe fibrosis compared with children with mild fibrosis (p < 0.05). The diagnostic accuracy of these direct biomarkers, represented by sensitivity, specificity and positive predictive value, emphasises the utility of PIIINP, TIMP-1, OPN and HA as indicators of liver fibrosis among HCV-infected children.

Teriparatide increases bone mineral density in a man with osteoporosis pseudoglioma.

Osteoporosis Pseudoglioma (OPPG) is characterized by severe juvenile-onset osteoporosis and ocular abnormalities. It is caused by one of several inactivating mutations in LRP5, a gene importantly involved in bone formation. The objective of this study was to evaluate the efficacy of teriparatide in a young man with OPPG. The subject of this case report is a 19-year-old man with congenital blindness and low trauma fractures because of OPPG. A 2-year course of teriparatide, 20 µg/day, was initiated after a 6-year course of intravenous pamidronate infusions, the latter 3 years of which had minimal effects on bone mineral density (BMD). Measurements in serum were made of C-terminal telopeptide of type I collagen (CTX), N-terminal propeptide of type I collagen (P1NP), total and ionized calcium, phosphate, uric acid, complete blood count, and renal and liver function tests. Urinary calcium/creatinine ratio was determined. BMD was measured by DXA yearly. BMD increased by 9.7% in lumbar spine and 10.2% in right femur hip. CTX rose early, peaking in month 3, followed by an increase in P1NP, peaking in month 9. Both indices returned to baseline by month 24. The increase in CTX followed by P1NP is an unusual time course when teriparatide is used to treat osteoporosis but may be typical of low bone turnover states. There were no adverse events. In a patient with OPPG, teriparatide markedly increased BMD in the lumbar spine and femur hip.

The role of serum biomarkers in predicting fibrosis progression in pediatric and adult hepatitis C virus chronic infection.

BACKGROUND/AIMS: Liver biopsy represents the gold standard for damage evaluation, but noninvasive serum markers that mirror liver fibrosis progression are actual goals both in adults and especially in children. The aim was to determine specific serum markers that correlate with liver fibrosis progression during chronic HCV infection. METHODS: Liver biopsies and concomitant serum samples from 22 pediatric and 22 adult HCV patients were analyzed. Histological parameters were evaluated. On serum TGF-ß1, tissue inhibitor of matrix metalloprotein inhibitor-1 (TIMP-1), hyaluronic acid (HA) and aminoterminal peptide of procollagen type III (PIIINP) were tested. RESULTS: Significant fibrosis (F≥2) and advanced fibrosis (F≥3) represented 64% and 20%, respectively in children; while 54% F≥2 and 23% F≥3 in adults. Hyaluronic acid (p = 0.011) and PIIINP (p = 0.016) were related to worse fibrosis stages only in adults, along with TIMP-1 (p = 0.039) just in children; but TGF-ß1 was associated with mild fibrosis (p = 0.022) in adults. The AUROC of TIMP-1 in children to discriminate advanced fibrosis was 0.800 (95%IC 0.598-0.932). In adults, the best AUROCs were that of HA, PIIINP and TGF-ß1 [0.929 (IC95% 0.736-0.994), 0.894 (IC95% 0.689-0.984) and 0.835 (IC95% 0.617-0.957)], respectively. In children, according to the cut off (165.7 ng/mL) value for TIMP-1, biopsies could have been avoided in 72% (18/25). Considering the cut off for HA (109.7 ng/mL), PIIINP (9.1 µg/L), and TGF-ß1 (10,848.3 pg/mL), biopsies could have been avoided in 87% (19/22) of adult patients by using HA and 73% (16/22) using PIIINP or TGF-ß1. CONCLUSIONS: In adults given the diagnostic accuracy of HA, PIIINP, TGF-ß1, their combination may provide a potential useful tool to assess liver fibrosis. This first pediatric study suggests that TIMP-1 is clinically useful for predicting liver fibrosis in HCV patients.

The effects of discontinuing long term alendronate therapy in a clinical practice setting.

OBJECTIVE: To assess bone turnover markers (BTM) and bone mineral density (BMD) after discontinuation of alendronate treatment used for five or more years. SUBJECTS AND METHODS: 40 patients (pt) with post-menopausal osteoporosis treated with alendronate (10 mg/d) for at least five years (Group 1, G1) had their medication discontinued. Group 2 (G2): 25 pt treated with alendronate for at least one year. Group 3 (G3): 23 treatment-naïve osteoporotic pt. BMD was evaluated in G1 and G2 at baseline and after 12 months. Collagen type I cross-linked C-telopeptide (CTX) and procollagen type 1 N-terminal propeptide (P1NP) levels were measured in all pt at baseline, and in G1 and G2 every three months for 12 months. Data were analyzed using ANOVA on ranks and Mann-Whitney tests. RESULTS: Mean BMD values in G1 and G2 did not differ during follow-up. However, 16 pt (45.7%) in G1 and one (5.2%) in G2 lost BMD (P < 0.001). BTM at baseline was not different between G1 and G2, and both were lower than G3. A significant increase in BTM levels was detected in G1 pt after three months, but not in G2. CONCLUSION: Observed BMD loss and BTM rise after alendronate withdrawal imply that bone turnover was not over suppressed, and alendronate discontinuation may not be safe.

The effects of discontinuing long term alendronate therapy in a clinical practice setting / Efeitos da retirada do uso prolongado de alendronato na prática clínica

OBJECTIVE: To assess bone turnover markers (BTM) and bone mineral density (BMD) after discontinuation of alendronate treatment used for five or more years. SUBJECTS AND METHODS: 40 patients (pt) with post-menopausal osteoporosis treated with alendronate (10 mg/d) for at least five years (Group 1, G1) had their medication discontinued. Group 2 (G2): 25 pt treated with alendronate for at least one year. Group 3 (G3): 23 treatment-naïve osteoporotic pt. BMD was evaluated in G1 and G2 at baseline and after 12 months. Collagen type I cross-linked C-telopeptide (CTX) and procollagen type 1 N-terminal propeptide (P1NP) levels were measured in all pt at baseline, and in G1 and G2 every three months for 12 months. Data were analyzed using ANOVA on ranks and Mann-Whitney tests. RESULTS: Mean BMD values in G1 and G2 did not differ during follow-up. However, 16 pt (45.7 percent) in G1 and one (5.2 percent) in G2 lost BMD (P < 0.001). BTM at baseline was not different between G1 and G2, and both were lower than G3. A significant increase in BTM levels was detected in G1 pt after three months, but not in G2. CONCLUSION: Observed BMD loss and BTM rise after alendronate withdrawal imply that bone turnover was not over suppressed, and alendronate discontinuation may not be safe.

OBJETIVO: Avaliar a evolução dos marcadores de metabolismo ósseo (MMO) e da densidade mineral óssea (DMO) após cinco anos de uso de alendronato em mulheres osteoporóticas na pós-menopausa. SUJEITOS E MÉTODOS: 40 pacientes (pct) osteoporóticas, na pós-menopausa, em uso de alendronato (10 mg/dia) por pelo menos 5 anos (Grupo 1 − G1) tiveram o uso do bisfosfonato suspenso. O grupo 2 (G2): 25 mulheres na pós-menopausa, em uso de alendronato (10 mg/dia) há pelo menos 1 ano. Grupo 3 (G3): 23 pct osteoporóticas, controles ainda sem tratamento. G1 e G2 submeteram-se à avaliação da DMO por DXA (basal e após 12 meses de seguimento). Todas as pct colheram amostras basais de CTX e P1NP, e G1 e G2 submeteram-se a coletas trimestrais de CTX e P1NP durante 1 ano. Resultados foram analisados por ANOVA on ranks e Mann-Whitney. RESULTADOS: Níveis médios de DMO não variaram em G1 ou G2 durante o estudo; no entanto, 16 pct (45,7 por cento) no G1 e 1 pct (5,2 por cento) no G2 apresentaram redução clinicamente significativa de DMO (P < 0,001). Níveis basais de CTX e P1NP não diferiram entre G1 e G2, com ambos inferiores aos níveis de G3. Em G1, observou-se elevação significativa de CTX e P1NP após 3 meses. Os níveis de CTX e P1NP em G2 permaneceram estáveis durante todo o seguimento. CONCLUSÃO: Não parece haver supressão excessiva do metabolismo ósseo na prática clínica. A suspensão temporária do alendronato após seu uso prolongado pode não ser segura.

Increased levels of oxidative stress, subclinical inflammation, and myocardial fibrosis markers in primary aldosteronism patients.

BACKGROUND: Patients with primary aldosteronism experience greater left ventricular hypertrophy and a higher frequency of cardiovascular events than do essential hypertensive patients with comparable blood pressure levels. Aldosterone has been correlated with increased oxidative stress, endothelial inflammation, and fibrosis, particularly in patients with heart disease. AIM: To evaluate oxidative stress, subclinical endothelial inflammation, and myocardial fibrosis markers in patients with primary aldosteronism and essential hypertension. DESIGN AND INDIVIDUALS: We studied 30 primary aldosteronism patients and 70 control essential hypertensive patients, matched by age, sex and median blood pressure. For all patients, we measured the serum levels of aldosterone, plasma renin activity, malondialdehyde (MDA), xanthine oxidase, metalloproteinase-9, ultrasensitive C-reactive protein and amino terminal propeptides of type I (PINP), and type III procollagen. We also evaluated the effect of PA treatment in 19 PA individuals. RESULTS: PA patients showed elevated levels of MDA (1.70 ± 0.53 versus 0.94 ± 0.65 µmol/l, P <0.001) and PINP (81.7 ± 50.6 versus 49.7 ± 27 mg/l, P = 0.002) compared with essential hypertensive controls. We found a positive correlation between MDA, PINP, and the serum aldosterone/plasma renin activity ratio in primary aldosteronism patients. Clinically, treating primary aldosteronism patients decreased MDA and PINP levels. CONCLUSION: We detected higher levels of MDA and PINP in primary aldosteronism patients, suggesting increased oxidative stress and myocardial fibrosis in these individuals. Treating primary aldosteronism patients reduced MDA and PINP levels, which may reflect the direct effect of aldosterone greater than endothelial oxidative stress and myocardial fibrosis, possibly mediated by a mineralocorticoid receptor.