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1.
Ann Hematol ; 98(7): 1583-1592, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31041514

RESUMO

Despite the advances in the management of hemoglobinopathies, further insight into disease pathophysiology is necessary to improve our therapeutic approach. Activin-A has emerged as a regulator of erythropoiesis and bone turnover in malignant disorders; however, clinical data in hemoglobinopathies are currently scarce. Thus, we aimed to investigate the role of activin-A among hemoglobinopathy patients and evaluate the rationale of its targeting. Circulating levels of activin-A were measured in patients (n = 227) with beta-thalassemia major (TM) (n = 58), beta-thalassemia intermedia (TI) (n = 43), double heterozygous sickle cell/beta-thalassemia (HbS/beta-thal) (n = 109), or homozygous sickle cell disease (n = 17), and we explored possible correlations with clinical and laboratory data. Seventeen age- and gender-matched, healthy individuals served as controls. Bone marrow density (BMD) was determined using dual-energy X-ray absorptiometry. TM and HbS/beta-thal patients had elevated activin-A compared to controls (p = 0.041 and p = 0.038, respectively). In TM patients, high circulating activin-A showed strong correlations with hemolysis markers, namely reticulocyte count (p = 0.011) and high lactate dehydrogenase (LDH; p = 0.024). Similarly, in HbS/beta-thal patients, activin-A showed positive correlations with indirect bilirubin (p < 0.001), ferritin (p = 0.005), and LDH (p = 0.044). High activin-A correlated with low Z-score of both lumbar spine BMD in TI patients (p < 0.01) and femoral neck BMD in TM patients (p < 0.01). Serum activin-A is elevated in patients with TM and HbS/beta-thal and correlates with markers of hemolysis and low BMD. These data support a role of activin-A in the biology of these disorders and provide further rationale for the broader clinical development of activin-A inhibitors in this setting.


Assuntos
Ativinas/sangue , Anemia Falciforme , Densidade Óssea , Hemólise , Heterozigoto , Talassemia beta , Ativinas/genética , Adulto , Idoso , Anemia Falciforme/sangue , Anemia Falciforme/genética , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Contagem de Reticulócitos , Talassemia beta/sangue , Talassemia beta/genética
2.
Ann Hematol ; 98(6): 1457-1466, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30895351

RESUMO

The exact role of regulatory T cells (Tregs) in multiple myeloma (MM) has not been yet determined. Data regarding alterations of Tregs during therapy with novel agents (NA), i.e., bortezomib and lenalidomide are conflicted and limited. We evaluated prospectively alterations of Tregs and searched for correlations with disease characteristics, response, and outcome in 29 patients with active MM treated with either bortezomib-dexamethasone (BD; 11 patients) or lenalidomide-dexamethasone (LenDex, 18 patients). Additionally, we recorded changes of lymphocytes subsets and cytokines related to Tregs function and MM biology, i.e., interleukin (IL) 6, 2, 17, and TGF-ß. Compared with controls, patients had significantly higher median levels of Tregs%, IL-6, and IL-17 (p < 0.001). Median CD4 T and B cells frequencies were significantly lower, whereas CD8 T and natural killers were increased compared to controls. In BD group, no significant alterations of Tregs% were observed. Patients treated with LenDex, displayed a significant reduction of Tregs% (p < 0.001) especially those who achieved at least very good partial response (≥vgPR) (p = 0.04). Lymphocyte subsets or cytokines did not significantly change during therapy. In summary, Tregs% are higher in patients with active MM compared with controls, and they significantly decrease after treatment with LenDex but not with BD; After therapy with LenDex, Tregs reduction between baseline and major response correlated with achievement of ≥vgPR suggesting a possible predictive role, that may contribute to therapeutic strategy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Bortezomib/administração & dosagem , Bortezomib/farmacologia , Citocinas/sangue , Dexametasona/administração & dosagem , Dexametasona/farmacologia , Feminino , Humanos , Lenalidomida/administração & dosagem , Lenalidomida/farmacologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/tratamento farmacológico , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo , Fator de Crescimento Transformador beta/análise , Resultado do Tratamento
3.
Hematology ; 24(1): 318-324, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30665323

RESUMO

INTRODUCTION: Noggin is an antagonist of bone morphogenetic proteins (BMPs) and has a strong effect on osteogenesis. Osteoporosis is a common complication of transfusion dependent beta-thalassemia (TDT) and denosumab has been recently emerged as a promising therapeutic option. This was a post hoc investigation of serum noggin levels among TDT patients with osteoporosis who participated in a randomized, placebo-control, phase 2b study. METHODS: Patients received either 60 mg denosumab (n = 32) or placebo (n = 31) every 6 months for 12 months. Noggin was measured, for the first time in thalassemia patients, at baseline and at 12 months, using a recently developed high sensitivity fluorescent immunoassay. RESULTS: Both groups showed a significant increase in noggin serum levels (denosumab p < 0.001; placebo p < 0.0001). Interestingly, the increase was higher in the placebo group. Furthermore, we observed a strong correlation between noggin and wrist bone mineral density (r = -0.641, p = 0.002) only in the denosumab group. CONCLUSION: In conclusion, higher noggin levels reflected more BMP inhibition, since our assay detects free bioactive noggin, which in turn impaired bone formation in placebo group. Therefore, denosumab possibly regulates noggin and favours bone turnover in TDT patients with osteoporosis through a novel mechanism of action.


Assuntos
Proteínas de Transporte/sangue , Denosumab/administração & dosagem , Osteoporose/sangue , Osteoporose/tratamento farmacológico , Talassemia/sangue , Talassemia/tratamento farmacológico , Adulto , Idoso , Remodelação Óssea/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
4.
Am J Hematol ; 94(4): 400-407, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30592079

RESUMO

Optimizing consolidation treatment in transplant-eligible newly diagnosed multiple myeloma patients in order to improve efficacy and bone-related outcomes is intriguing. We conducted an open-label, prospective study evaluating the efficacy and safety of bortezomib and lenalidomide (VR) consolidation after ASCT, in the absence of dexamethasone and bisphosphonates. Fifty-nine patients, who received bortezomib-based induction, were given 4 cycles of VR starting on day 100 post-ASCT. After ASCT, 58% of patients improved their response status, while following VR consolidation 39% further deepened their response; stringent complete response rates increased to 51% after VR from 24% post-ASCT. VR consolidation resulted in a significant reduction of soluble receptor activator of nuclear factor-κB ligand/osteoprotegerin ratio and sclerostin circulating levels, which was more pronounced among patients achieving very good partial response or better. After a median follow-up of 62 months, no skeletal-related events (SREs) were observed, despite the lack of bisphosphonates administration. The median TTP after ASCT was 37 months, while median overall survival (OS) has not been reached yet; the probability of 4- and 5-year OS was 81% and 64%, respectively. In conclusion, VR consolidation is an effective, dexamethasone- and bisphosphonate-free approach, which offers long OS with improvements on bone metabolism and no SREs.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Doenças Ósseas , Quimioterapia de Consolidação , Mieloma Múltiplo , Transplante de Células-Tronco , Adulto , Idoso , Autoenxertos , Doenças Ósseas/metabolismo , Doenças Ósseas/mortalidade , Doenças Ósseas/patologia , Doenças Ósseas/terapia , Bortezomib/administração & dosagem , Bortezomib/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Difosfonatos/administração & dosagem , Difosfonatos/efeitos adversos , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Estudos Prospectivos , Taxa de Sobrevida
5.
Blood Adv ; 2(21): 2837-2847, 2018 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-30381400

RESUMO

Denosumab (DNM) is a fully human monoclonal antibody against the receptor activator of nuclear factor kappa-B ligand (RANKL) that has been licensed for the treatment of different types of osteoporosis. However, the prospective data for the evaluation of DNM efficacy on transfusion-dependent thalassemia (TDT)-induced osteoporosis are rather limited. Thus, we conducted a randomized, placebo-controlled, double-blind, phase 2b clinical trial to evaluate DNM in TDT osteoporosis. Patients were assigned to receive either 60 mg DNM (n = 32) or placebo (n = 31) subcutaneously on day 0 and 180 during a total of 12 months of follow-up. The percentage increase of L1-L4 bone mineral density was higher in the DNM group than the placebo group (5.92% ± 5.25% vs 2.92% ± 5.56%, respectively; P = .043), whereas the advantage of DNM regarding wrist bone mineral density was much higher compared with placebo (-0.26% ± 5.31% vs -3.92% ± 8.71%, respectively; P = .035). No grade 3 or 4 toxicity was observed. DNM reduced pain scores that remained unaltered in the placebo group. DNM showed a significant reduction of soluble RANKL (sRANKL), sRANKL/osteoprotegerin ratio, C-telopeptide of collagen type I, tartrate-resistant acid phosphatase isoform-5b, and bone-specific alkaline phosphatase between baseline and the 12th month (P < .01 for all comparisons) without changes in dickkopf-1, sclerostin, and osteocalcin. On the contrary, placebo patients showed an increase in sRANKL, osteoprotegerin, dickkopf-1, sclerostin, C-telopeptide of collagen type I, tartrate-resistant acid phosphatase isoform-5b, and bone-specific alkaline phosphatase during the study period (P < .01 for all comparisons). In conclusion, DNM increased lumbar spine and wrist bone mineral density and reduced pain and bone remodeling markers, and thus it is another valuable option for the management of TDT-induced osteoporosis. This trial was registered at www.clinicaltrials.gov as #NCT02559648.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Denosumab/uso terapêutico , Osteoporose/tratamento farmacológico , Talassemia/complicações , Adulto , Idoso , Densidade Óssea , Conservadores da Densidade Óssea/efeitos adversos , Remodelação Óssea , Colágeno Tipo I/metabolismo , Denosumab/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Feminino , Cefaleia/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/etiologia , Osteoprotegerina/metabolismo , Peptídeos/metabolismo , Efeito Placebo , Ligante RANK/metabolismo , Resultado do Tratamento
6.
Clin Lymphoma Myeloma Leuk ; 18(6): 431-437, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29685422

RESUMO

BACKGROUND: Serum receptor activator of nuclear factor κB ligand (sRANKL) and chemokine (C-C) motif ligand 3 (CCL-3) have been reported to be elevated in Waldenström macroglobulinemia (WM) patients. However, there are no published data regarding the prognostic value of these molecules in WM regarding progression-free and overall survival. METHODS: To evaluate the effect of these markers of bone remodeling on survival parameters, we prospectively evaluated serum cytokines and biological markers in 55 patients with symptomatic WM before they received any kind of treatment. Serum levels of CCL-3 and bone remodeling markers were also evaluated in asymptomatic WM and IgM monoclonal gammopathy of undetermined significance. Furthermore, we assessed bone marrow biopsy samples from newly diagnosed WM patients for CCL-3 and RANKL expression. RESULTS: High circulating sRANKL values predicted shorter median overall survival (46 months vs. not reached, P = .025). High serum levels of CCL-3 predicted shorter median progression-free survival (27 months vs. not reached, P = .048). At bone marrow biopsy evaluation, the whole number of the neoplastic cells revealed strong cytoplasmic positivity for CCL-3, while the neoplastic clone did not express RANKL. CONCLUSION: We conclude that WM cells produce CCL-3 and possibly enhance the production of RANKL in the bone microenvironment. The correlation of sRANKL and CCL-3 with survival reveals the importance of these cytokines in disease biology and highlights the significance of the interactions between WM and stromal cells for the development of WM. Finally, these findings provide the rationale for the use of anti-RANKL and anti-CCL-3 drugs in animal models of WM before their clinical evaluation.


Assuntos
Biomarcadores Tumorais/sangue , Quimiocina CCL3/sangue , Ligante RANK/sangue , Macroglobulinemia de Waldenstrom/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Assintomáticas , Biomarcadores Tumorais/metabolismo , Biópsia , Medula Óssea/patologia , Quimiocina CCL3/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gamopatia Monoclonal de Significância Indeterminada/sangue , Prognóstico , Intervalo Livre de Progressão , Estudos Prospectivos , Ligante RANK/metabolismo , Análise de Sobrevida , Macroglobulinemia de Waldenstrom/sangue , Macroglobulinemia de Waldenstrom/patologia
7.
Eur J Haematol ; 100(2): 131-139, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29105864

RESUMO

OBJECTIVES: As the interaction between hematopoietic stem cells (HSCs) and endosteal and endothelial niches in HSCs homing is essential, we aimed to study bone turnover and angiogenesis in 29 patients with lymphoma/multiple myeloma undergoing hematopoietic stem cell transplantation (HSCT). METHODS: Serum samples were collected before high-dose chemotherapy (HDT), at the end of HDT, after HSC infusion, at the nadir of myelotoxicity, and at engraftment. Bone metabolism (CTX, TRACP-5b, bALP, OC, DKK1, RANKL, OPG), and angiogenesis (Ang1, Ang2) markers were measured. These markers were also measured in 21 control patients before and after conventional chemotherapy. RESULTS AND CONCLUSIONS: Bone resorption declined during HSCT (decrease in TRACP-5b [P < .001] and CTX [P = .006]). Bone formation declined as well (decrease in bALP and OC [P < .001 for both]). RANKL/OPG ratio, an indicator of osteoclastic activation, did not change significantly (P = .5). Ang1/Ang2 ratio, a vessel equilibrium marker, decreased significantly (P < .001) suggesting endothelial destabilization. The changes observed in the control group were similar except of bALP and RANKL/OPG ratio. Moreover, Ang1/Ang2 ratio on the day after HSC infusion strongly correlated with time to neutrophil and platelet engraftment (P < .001 for both). Conclusively, bone turnover and vessel destabilization represent important events during HSCT probably reflecting the effect of chemotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Remodelação Óssea , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Transplante de Células-Tronco Hematopoéticas , Neovascularização Patológica , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Feminino , Sobrevivência de Enxerto , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Células-Tronco Hematopoéticas/metabolismo , Humanos , Linfoma/complicações , Linfoma/patologia , Linfoma/terapia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Osteogênese , Transplante Autólogo , Adulto Jovem
8.
J Bone Miner Metab ; 36(4): 399-409, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28660376

RESUMO

Hematopoietic stem cell (HSC) mobilization involves cleavage of ligands between HSC and niche components. However, there are scarce data regarding the role of bone cells in human HSC mobilization. We studied biochemical markers of bone metabolism and angiogenic cytokines during HSC mobilization in 46 patients' sera with lymphoma and multiple myeloma, by ELISA. Significant changes between pre-mobilization and collection samples were found: (1) Bone alkaline phosphatase (BALP) increased, indicating augmentation of bone formation; (2) Receptor activator of Nf-κB ligand/osteoprotegerin ratio (RANKL/OPG) increased, showing osteoclastic differentiation and survival; however, there was no evidence of increased osteoclastic activity; and (3) Angiopoietin-1/Angiopoietin-2 ratio (ANGP-1/ANGP-2) decreased, consistent with vessel destabilization. Poor mobilizers had significantly higher carboxy-terminal telopeptide of collagen type I (CTX) and lower ANGP-1 at pre-mobilization samples, compared to good ones. CTX, amino-terminal telopeptide of collagen type I (NTX) and ANGP-1 pre-mobilization levels correlated significantly with circulating CD34+ peak cell counts. Our results indicate that bone formation and vessel destabilization are the two major events during human HSC mobilization. Osteoblasts seem to be the orchestrating cells, while osteoclasts are stimulated but not fully active. Moreover, ANGP-1, CTX and NTX may serve as predictors of poor mobilization.


Assuntos
Biomarcadores/metabolismo , Osso e Ossos/metabolismo , Citocinas/metabolismo , Mobilização de Células-Tronco Hematopoéticas , Neovascularização Fisiológica , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Citocinas/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteoprotegerina/metabolismo , Ligante RANK/metabolismo , Fatores de Tempo , Adulto Jovem
9.
Clin Cases Miner Bone Metab ; 14(2): 269-271, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29263750

RESUMO

Juvenile Paget's disease (JPD) is a rare, autosomal recessive disorder featuring markedly increased serum alkaline phosphatase activity, indicative of greatly accelerated bone turnover throughout the skeleton. The main aim of this study was to evaluate circulating periostin and sclerostin levels in two adult patients with mild JPD (due to "Balkan" mutation). We measured periostin and sclerostin levels in a previously described woman and a newly diagnosed man with JPD, and 10 apparently healthy individuals, matched (1:5) to JPD patients for gender, age and body mass index. Sclerostin levels were similar between JPD patients and controls. Periostin levels were about 2.5 times higher in JPD patients. Periostin and sclerostin levels were negatively correlated (rs= -0.63; p=0.03). In conclusion, a trend towards higher periostin levels was observed in JPD patients, whereas sclerostin levels were similar to controls.

10.
J BUON ; 22(4): 1022-1031, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28952223

RESUMO

PURPOSE: The role of Protein Z (PZ) in conditions, such as thrombosis, inflammation or cancer, is under investigation. Plasminogen Activator Inhibitor-1 (PAI-1) is an acute phase reactant that promotes thrombosis and tumorigenesis. Subject of this work was to study PZ and PAI-1 in patients with Hodgkin Lymphoma (HL), a malignancy with inflammatory background and relatively low incidence of thrombosis. METHODS: Newly diagnosed patients were enrolled in the study. Healthy individuals were used as controls. RESULTS: PZ levels were higher in patients compared to controls (not significantly), while PAI-1 levels were significantly higher in patients. Both PZ and PAI-1 concentrations did not correlate with most of patients' characteristics. Lower PZ levels at diagnosis were associated with presence of B symptoms and positive final positron emission tomography (PET) and higher baseline PAI-1 levels with positive final PET, too. PZ had a declining trend, but PAI-1 increased initially and decreased thereafter, during the treatment period. CONCLUSIONS: Conclusively, PAI-1, but not PZ, seems to be an acute phase protein in HL. Lower PZ and higher PAI-1 levels at diagnosis may be indicative of aggressive disease. These results need further verification.


Assuntos
Proteínas Sanguíneas/metabolismo , Doença de Hodgkin/sangue , Doença de Hodgkin/metabolismo , Inibidor 1 de Ativador de Plasminogênio/sangue , Proteínas da Fase Aguda/metabolismo , Adulto , Idoso , Feminino , Humanos , Inflamação/sangue , Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Trombose/sangue , Trombose/metabolismo , Adulto Jovem
12.
Metabolism ; 71: 198-201, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28521873

RESUMO

PURPOSE: Langerhans cell histiocytosis (LCH) is a rare proliferative disease of cells of the CD1a+/CD207+ myeloid dendritic cell lineage that may infiltrate one or more organs or systems at all ages. We aimed to evaluate periostin and sclerostin serum levels in adult patients with LCH. PROCEDURES: This was a cross-sectional study comparing 38 adult patients with LCH with 38 age- and sex-matched healthy controls. Serum periostin and sclerostin levels were measured to compare between LCH patients and controls as well as between patients with active and non-active disease. RESULTS: Serum periostin levels were significantly lower in LCH patients than controls (457±72ng/ml vs. 721±79ng/ml, p=0.014) but this was not the case for sclerostin levels which did not differ between patients and controls, respectively (29.0±1.8pmol/L vs. 39.5±3.8pmol/L, p=0.12). Patients with active disease had significantly lower periostin levels than those with inactive disease (240±78ng/ml vs. 558±94ng/ml, p=0.008). No effect of specific site involvement, extend of disease, or treatment administered was found on any of the above parameters measured. CONCLUSIONS: Lower serum periostin levels were observed in adult LCH patients with active disease. The finding warrants further investigation to define whether periostin could serve as a serum biomarker for LCH activity.


Assuntos
Moléculas de Adesão Celular/sangue , Moléculas de Adesão Celular/deficiência , Histiocitose de Células de Langerhans/sangue , Histiocitose de Células de Langerhans/fisiopatologia , Adulto , Antígenos CD1 , Biomarcadores/sangue , Índice de Massa Corporal , Proteínas Morfogenéticas Ósseas/sangue , Estudos Transversais , Feminino , Marcadores Genéticos , Humanos , Masculino , Adulto Jovem
13.
Clin Rheumatol ; 36(8): 1865-1872, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28451870

RESUMO

Primary knee osteoarthritis (OA) contributes to disability among middle-aged and elderly people. Dickkopf-1 (Dkk-1) and sclerostin are inhibitors of Wnt/ß-catenin signaling pathway implicated in regulation of cartilage homeostasis and bone formation, respectively. We aim to investigate the association between the serum(s) and synovial fluid (SF) Dkk-1 and sclerostin levels and disease severity in patients with primary knee OA. Forty patients aged 56-87 years with primary knee OA and 20 healthy individuals were recruited. Weight-bearing anteroposterior radiographs of the affected knee were used to determine the disease severity according to Kellgren and Lawrence criteria. Dkk-1 and sclerostin levels in serum and SF were measured by ELISA. SF Dkk-1 levels were significantly higher in the OA, compared to control group (180 ± 182 vs 128 ± 330 pg/ml, p < 0.001). However, OA patients did not differ significantly regarding the sDkk-1 concentrations compared to healthy controls (1289.8 pg/ml vs 1214.1, respectively, p = 0.630). SF Dkk-1 levels in Kellgren and Lawrence (KL) grade 4 were significantly elevated compared to those of KL grades 2 and 3 (1.97 vs 2.23 pg/ml, p = 0.017, log transformed because data were not normally distributed), whereas sDkk-1 levels between those groups demonstrated marginally statistically significant difference (1111.8 vs 1415.9 pg/ml, p = 0.057). SFSclerostin and sSclerostin levels did not have any significant difference between the OA and control groups. SF Dkk-1 levels are positively related to the severity of joint damage in knee OA. Sclerostin levels failed to substantiate an association to knee OA progression. Dkk-1 could play a potential role in the degenerative process of OA. Thus, DKK-1 may emerge as a promising future therapeutic manipulation of OA.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Articulação do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/metabolismo , Líquido Sinovial/metabolismo , Idoso , Idoso de 80 Anos ou mais , Proteínas Morfogenéticas Ósseas/sangue , Proteínas Morfogenéticas Ósseas/metabolismo , Progressão da Doença , Feminino , Marcadores Genéticos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/sangue , Radiografia , Índice de Gravidade de Doença , Transdução de Sinais/fisiologia
16.
Artigo em Inglês | MEDLINE | ID: mdl-27274845

RESUMO

UNLABELLED: Pituitary abscess is a rare life-threating entity that is usually misdiagnosed as a pituitary tumor with a definite diagnosis only made postoperatively. Over the last several decades, advances in healthcare have led to a significant decrease in morbidity and mortality due to pituitary abscess. We report a case of a 34-year-old woman who was admitted to our department for investigation of a pituitary mass and with symptoms of pituitary dysfunction, headaches and impaired vision. During her admission, she developed meningitis-like symptoms and was treated with antibiotics. She eventually underwent transsphenoidal surgery for excision of the pituitary mass. A significant amount of pus was evident intraoperatively; however, no pathogen was isolated. Six months later, the patient was well and had full recovery of the anterior pituitary function. Her menses returned, and she was only on treatment with desmopressin for diabetes insipidus that developed postoperatively. LEARNING POINTS: Pituitary abscess is a rare disease and the reported clinical features vary mimicking other pituitary lesions.The diagnosis of pituitary abscess is often very difficult to make and rarely included in the differential.The histological findings of acute inflammatory infiltration confirm the diagnosis of pituitary abscess.Medical and surgical treatment is usually recommended upon diagnosis of a pituitary abscess.

17.
J Bone Miner Metab ; 34(4): 447-56, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26056025

RESUMO

There is increasing evidence for bone-liver interplay. The main aim of this study was to determine serum sclerostin and Dickkopf (DKK)-1 levels in patients with nonalcoholic fatty liver disease (NAFLD) and their association with the disease severity. Patients with biopsy-proven NAFLD, 13 with nonalcoholic simple steatosis (SS) and 14 with steatohepatitis (NASH), and 20 gender-, age-, body mass index- and waist circumference-matched controls were enrolled. Serum sclerostin, DKK-1, bone turnover markers, vitamin D, insulin and standard biochemical and hematologic parameters were measured; lumbar spinal dual-energy X-ray absorptiometry was performed. We observed that there was a progressive decline in serum sclerostin levels from the controls (76.1 ± 6.8) to SS (53.5 ± 6.4) and NASH (46.0 ± 8.1 pmol/l) patients (p = 0.009); in adjusted pairwise comparisons, sclerostin was significantly higher in the controls than in NASH patients (p = 0.012). Although serum DKK-1 did not differ between groups (p = 0.135), there was a trend toward U-shaped distribution (controls 35.8 ± 2.8; SS 27.3 ± 2.9; NASH 36.8 ± 4.4 pmol/l). Higher DKK-1 levels were independently associated with NASH. Regarding specific histological lesions, DKK-1 levels were marginally lower in NAFLD patients with lower (≤33 %) than higher (>33 %) steatosis grade (27.7 ± 3.1 and 38.8 ± 4.7 pmol/l, respectively; p = 0.049). No other significant difference was observed within histological lesions. In conclusion, serum sclerostin levels were lower in NASH patients than in controls. DKK-1 levels were independently associated with NASH in NAFLD patients. The potential importance of these findings indicates a possible bone-liver interaction and warrants further investigation.


Assuntos
Proteínas Morfogenéticas Ósseas/sangue , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Hepatopatia Gordurosa não Alcoólica/sangue , Absorciometria de Fóton , Estudos Transversais , Feminino , Marcadores Genéticos , Humanos , Região Lombossacral/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Índice de Gravidade de Doença , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/metabolismo
18.
Metabolism ; 64(10): 1291-7, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26198440

RESUMO

PURPOSE: To compare denosumab-induced changes in lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD), bone markers and free soluble receptor activator of nuclear factor kappaB ligand (sRANKL) between treatment naïve postmenopausal women with low bone mass (naïve group) and those who were previously treated with a single zoledronic acid infusion (post-Zol group). PROCEDURES: Procollagen type 1N-terminal propeptide (P1NP), C-terminal cross-linking telopeptide of type 1 collagen (CTx) and sRANKL levels were measured in serum samples obtained at baseline and 3, 6 and 12months after denosumab initiation. LS and FN BMD were measured at baseline and 12months. RESULTS: LS and FN BMD increased significantly in both naïve and post-Zol group (p<0.001 and p=0.025 vs. p<0.001 and p=0.017, respectively). Despite the higher P1NP and CTx levels in naïve patients at baseline (both p<0.001), denosumab caused comparable decreases in both groups at month 3, which returned to post-Zol group baseline levels at month 6 and 12 in all patients. Similarly, sRANKL levels decreased significantly at month 3 in both groups and returned to baseline levels at months 6 and 12. CONCLUSIONS: In patients previously treated with zoledronic acid, sequential denosumab treatment is effective in terms of BMD increases and bone turnover suppression. Despite the lower baseline levels in patients pre-treated with zoledronic acid, bone markers are similarly decreased in both groups following denosumab administration and maintain their reversibility. Denosumab reversibly suppresses endogenous free sRANKL levels in both naïve and zoledronic acid pre-treated patients.


Assuntos
Conservadores da Densidade Óssea/administração & dosagem , Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Denosumab/administração & dosagem , Difosfonatos/uso terapêutico , Imidazóis/uso terapêutico , Osteoporose Pós-Menopausa/tratamento farmacológico , Biomarcadores/sangue , Colágeno Tipo I/sangue , Difosfonatos/administração & dosagem , Esquema de Medicação , Feminino , Seguimentos , Humanos , Imidazóis/administração & dosagem , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/sangue , Fragmentos de Peptídeos/sangue , Peptídeos/sangue , Pós-Menopausa/efeitos dos fármacos , Pró-Colágeno/sangue , Ligante RANK/sangue , Ácido Zoledrônico
19.
Eur J Haematol ; 95(4): 342-51, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25645321

RESUMO

OBJECTIVE: The aim of this study was to evaluate bone involvement in patients with Gaucher disease (GD) and to propose a novel semi-quantitative magnetic resonance imaging (MRI) staging. METHODS: MRI of the lumbar spine, femur, and tibia was performed in 24 patients with GD and 24 healthy controls. We also measured circulating levels of C-C motif ligand-3 (CCL-3) chemokine, C-telopeptide of collagen type-1 (CTX), and tartrate-resistant acid phosphatase isoform type-b (TRACP-5b). RESULTS: We used the following staging based on MRI data: stage I: region of interest (ROI) 1/2 of normal values and bone infiltration up to 30%; stage II: ROI 1/3 of normal values and bone infiltration from 30 to 60%; stage III: ROI 1/4 of normal values and bone infiltration from 60% to 80%; and stage IV: detection of epiphyseal infiltration, osteonecrosis and deformity regardless of the ROI's values. All but two patients had abnormal MRI findings: 9 (37.5%), 6 (25%), 3 (12.5%), and 4 (16.7%) had stages I-IV, respectively. Patients with GD had elevated chitotriosidase, serum TRACP-5b, and CCL-3 levels (P < 0.001). CONCLUSIONS: We propose an easily reproducible semi-quantitative scoring system and confirm that patients with GD have abnormal MRI bone findings and enhanced osteoclast activity possibly due to elevated CCL-3.


Assuntos
Doenças Ósseas/diagnóstico , Doenças Ósseas/etiologia , Doença de Gaucher/complicações , Imagem por Ressonância Magnética , Adolescente , Adulto , Idoso , Biomarcadores , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Feminino , Doença de Gaucher/diagnóstico , Doença de Gaucher/genética , Doença de Gaucher/terapia , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Adulto Jovem
20.
Hormones (Athens) ; 14(2): 245-50, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25402376

RESUMO

OBJECTIVE: We aimed to determine the prevalence of 25(OH)D (D2 and D3 independently) inadequacy in healthy young/middle-aged men and to investigate its relationship with BMD, bone markers, demographic and lifestyle parameters such as age, BMI, smoking, alcohol consumption and dietary calcium intake. DESIGN: We determined 25(OH)D levels using LC-MS/MS, a robust method for measurement of both 25(OH)D3 and 25(OH)D2, iPTH, osteocalcin, beta C terminal cross-linked telopeptides of type I collagen (b-CTXs), procollagen type 1 amino-terminal propeptide (PINP), BMD at L2-L4 and proximal femur, smoking habits, daily dietary calcium intake and alcohol consumption in 181 randomly selected healthy men aged 20-50y. RESULTS: The prevalence of vitamin D deficiency (25(OH)D < 20 ng/ml) was 50.3%. Only 8.8% of the participants had vitamin D sufficiency (25(OH)D ≥ 30 ng/ml). We found a strong correlation between 25(OH)D and smoking in the totality of participants (p<0.001). 25(OH)D level was lower by approximately 4.3 ng/dl (p<0.001) in a smoker compared to a non-smoker among the totality of participants, while this value increased to 9.2 ng/ml in the 40-50y subgroup (p=0.003). A multinomial logistic regression model demonstrated that a young smoker (20-29y) had 58% increased likelihood of having vitamin D deficiency compared to a non-smoker of the same age group (p=0.041). CONCLUSIONS: A high prevalence of vitamin D deficiency was identified in a young and middle-aged male population. Smoking is a significant determinant of serum 25(OH)D, while it increases significantly the likelihood of having vitamin D deficiency. In our hands, vitamin D levels are not a determinant of bone turnover and BMD in this population.


Assuntos
25-Hidroxivitamina D 2/sangue , Calcifediol/sangue , Fumar/epidemiologia , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/epidemiologia , Adulto , Densidade Óssea/fisiologia , Remodelação Óssea/fisiologia , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Prevalência , Fumar/sangue , Fumar/fisiopatologia , Deficiência de Vitamina D/fisiopatologia , Adulto Jovem
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