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1.
J Clin Transl Sci ; 1(3): 176-183, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29082031

RESUMO

OBJECTIVE: Clinical research involving humans is critically important, but it is a lengthy and expensive process. Most studies require institutional review board (IRB) approval. Our objective is to identify predictors of delays or accelerations in the IRB review process and apply this knowledge to inform process change in an effort to improve IRB efficiency, transparency, consistency and communication. METHODS: We analyzed timelines of protocol submissions to determine protocol or IRB characteristics associated with different processing times. Our evaluation included single variable analysis to identify significant predictors of IRB processing time and machine learning methods to predict processing times through the IRB review system. Based on initial identified predictors, changes to IRB workflow and staffing procedures were instituted and we repeated our analysis. RESULTS: Our analysis identified several predictors of delays in the IRB review process including type of IRB review to be conducted, whether a protocol falls under Veteran's Administration purview and specific staff in charge of a protocol's review. CONCLUSIONS: We have identified several predictors of delays in IRB protocol review processing times using statistical and machine learning methods. Application of this knowledge to process improvement efforts in two IRBs has led to increased efficiency in protocol review. The workflow and system enhancements that are being made support our four-part goal of improving IRB efficiency, consistency, transparency, and communication.

2.
3.
Clin Trials ; 12(5): 449-56, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26374678

RESUMO

The oversight of research involving human participants is a complex process that requires institutional review board review as well as multiple non-institutional review board institutional reviews. This multifaceted process is particularly challenging for multisite research when each site independently completes all required local reviews. The lack of inter-institutional standardization can result in different review outcomes for the same protocol, which can delay study operations from start-up to study completion. Hence, there have been strong calls to harmonize and thus streamline the research oversight process. Although the institutional review board is only one of the required reviews, it is often identified as the target for harmonization and streamlining. Data regarding variability in decision-making and interpretation of the regulations across institutional review boards have led to a perception that variability among institutional review boards is a primary contributor to the problems with review of multisite research. In response, many researchers and policymakers have proposed the use of a single institutional review board of record, also called a central institutional review board, as an important remedy. While this proposal has merit, the use of a central institutional review board for multisite research does not address the larger problem of completing non-institutional review board institutional review in addition to institutional review board review­and coordinating the interdependence of these reviews. In this article, we describe the overall research oversight process, distinguish between institutional review board and institutional responsibilities, and identify challenges and opportunities for harmonization and streamlining. We focus on procedural and organizational issues and presume that the protection of human subjects remains the paramount concern. Suggested modifications of institutional review board processes that focus on time, efficiency, and consistency of review must also address what effect such changes have on the quality of review. We acknowledge that assessment of quality is difficult in that quality metrics for institutional review board review remain elusive. At best, we may be able to assess the time it takes to review protocols and the consistency across institutions.


Assuntos
Pesquisa Biomédica/ética , Pesquisa Biomédica/normas , Ensaios Clínicos como Assunto/ética , Ensaios Clínicos como Assunto/normas , Tomada de Decisões/ética , Comitês de Ética em Pesquisa/ética , Projetos de Pesquisa/normas , Humanos , Estados Unidos
5.
Bone ; 54(2): 213-21, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23403405

RESUMO

Although recent studies have established that osteocytes function as secretory cells that regulate phosphate metabolism, the biomolecular mechanism(s) underlying these effects remain incompletely defined. However, investigations focusing on the pathogenesis of X-linked hypophosphatemia (XLH), autosomal dominant hypophosphatemic rickets (ADHR), and autosomal recessive hypophosphatemic rickets (ARHR), heritable disorders characterized by abnormal renal phosphate wasting and bone mineralization, have clearly implicated FGF23 as a central factor in osteocytes underlying renal phosphate wasting, documented new molecular pathways regulating FGF23 production, and revealed complementary abnormalities in osteocytes that regulate bone mineralization. The seminal observations leading to these discoveries were the following: 1) mutations in FGF23 cause ADHR by limiting cleavage of the bioactive intact molecule, at a subtilisin-like protein convertase (SPC) site, resulting in increased circulating FGF23 levels and hypophosphatemia; 2) mutations in DMP1 cause ARHR, not only by increasing serum FGF23, albeit by enhanced production and not limited cleavage, but also by limiting production of the active DMP1 component, the C-terminal fragment, resulting in dysregulated production of DKK1 and ß-catenin, which contributes to impaired bone mineralization; and 3) mutations in PHEX cause XLH both by altering FGF23 proteolysis and production and causing dysregulated production of DKK1 and ß-catenin, similar to abnormalities in ADHR and ARHR, but secondary to different central pathophysiological events. These discoveries indicate that ADHR, XLH, and ARHR represent three related heritable hypophosphatemic diseases that arise from mutations in, or dysregulation of, a single common gene product, FGF23 and, in ARHR and XLH, complimentary DMP1 and PHEX directed events that contribute to abnormal bone mineralization.


Assuntos
Calcificação Fisiológica , Homeostase , Osteócitos/metabolismo , Osteomalacia/metabolismo , Osteomalacia/fisiopatologia , Fosfatos/metabolismo , Raquitismo/fisiopatologia , Animais , Fator de Crescimento de Fibroblastos 23 , Humanos , Osteomalacia/genética , Raquitismo/genética , Raquitismo/metabolismo
6.
J Bone Miner Res ; 28(1): 56-72, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22886699

RESUMO

Inactivating mutations of the "phosphate regulating gene with homologies to endopeptidases on the X chromosome" (PHEX/Phex) underlie disease in patients with X-linked hypophosphatemia (XLH) and the hyp-mouse, a murine homologue of the human disorder. Although increased serum fibroblast growth factor 23 (FGF-23) underlies the HYP phenotype, the mechanism(s) by which PHEX mutations inhibit FGF-23 degradation and/or enhance production remains unknown. Here we show that treatment of wild-type mice with the proprotein convertase (PC) inhibitor, decanoyl-Arg-Val-Lys-Arg-chloromethyl ketone (Dec), increases serum FGF-23 and produces the HYP phenotype. Because PC2 is uniquely colocalized with PHEX in osteoblasts/bone, we examined if PC2 regulates PHEX-dependent FGF-23 cleavage and production. Transfection of murine osteoblasts with PC2 and its chaperone protein 7B2 cleaved FGF-23, whereas Signe1 (7B2) RNA interference (RNAi) transfection, which limited 7B2 protein production, decreased FGF-23 degradation and increased Fgf-23 mRNA and protein. The mechanism by which decreased 7B2•PC2 activity influences Fgf-23 mRNA was linked to reduced conversion of the precursor to bone morphogenetic protein 1 (proBMP1) to active BMP1, which resulted in limited cleavage of dentin matrix acidic phosphoprotein 1 (DMP1), and consequent increased Fgf-23 mRNA. The significance of decreased 7B2•PC2 activity in XLH was confirmed by studies of hyp-mouse bone, which revealed significantly decreased Sgne1 (7B2) mRNA and 7B2 protein, and limited cleavage of proPC2 to active PC2. The expected downstream effects of these changes included decreased FGF-23 cleavage and increased FGF-23 synthesis, secondary to decreased BMP1-mediated degradation of DMP1. Subsequent Hexa-D-Arginine treatment of hyp-mice enhanced bone 7B2•PC2 activity, normalized FGF-23 degradation and production, and rescued the HYP phenotype. These data suggest that decreased PHEX-dependent 7B2•PC2 activity is central to the pathogenesis of XLH.


Assuntos
Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Raquitismo Hipofosfatêmico Familiar/patologia , Doenças Genéticas Ligadas ao Cromossomo X , Proteína Secretora Neuroendócrina 7B2/metabolismo , Oligopeptídeos/uso terapêutico , Osteoblastos/patologia , Pró-Proteína Convertase 2/metabolismo , Animais , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Proteínas da Matriz Extracelular/metabolismo , Raquitismo Hipofosfatêmico Familiar/diagnóstico por imagem , Raquitismo Hipofosfatêmico Familiar/metabolismo , Feminino , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Proteína Secretora Neuroendócrina 7B2/genética , Oligopeptídeos/farmacologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/enzimologia , Fenótipo , Pró-Proteína Convertase 2/antagonistas & inibidores , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Radiografia
9.
J Bone Miner Res ; 26(11): 2565-78, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21915901

RESUMO

With the aging of the population, the scope of the problem of age-related bone loss and osteoporosis will continue to increase. As such, it is critical to obtain a better understanding of the factors determining the acquisition and loss of bone mass from childhood to senescence. While there have been significant advances in recent years in our understanding of both the basic biology of aging and a clinical definition of age-related frailty, few of these concepts in aging research have been evaluated adequately for their relevance and application to skeletal aging or fracture prevention. The March 2011 Forum on Aging and Skeletal Health, sponsored by the NIH and ASBMR, sought to bring together leaders in aging and bone research to enhance communications among diverse fields of study so as to accelerate the pace of scientific advances needed to reduce the burden of osteoporotic fractures. This report summarizes the major concepts presented at that meeting and in each area identifies key questions to help set the agenda for future research in skeletal aging.


Assuntos
Envelhecimento/fisiologia , Pesquisa Biomédica , Osso e Ossos/fisiologia , Saúde , Minerais/metabolismo , Sociedades Científicas , Reabsorção Óssea/genética , Reabsorção Óssea/patologia , Osso e Ossos/patologia , Senescência Celular , Fraturas Ósseas/genética , Fraturas Ósseas/patologia , Predisposição Genética para Doença , Humanos , Atividade Motora
10.
J Bone Miner Res ; 26(5): 1047-56, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21542006

RESUMO

The mechanisms by which inorganic phosphate (P(i)) homeostasis controls bone biology are poorly understood. Here we used Dmp1 null mice, a hypophosphatemic rickets/osteomalacia model, combined with a metatarsal organ culture and an application of neutralizing fibroblast growth factor 23 (FGF-23) antibodies to gain insight into the roles of P(i) in bone biology. We showed (1) that abnormal bone remodeling in Dmp1 null mice is due to reduced osteoclast number, which is secondary to a reduced ratio of RANKL/OPG expressed by osteoclast supporting cells and (2) that osteoblast extracellular matrix mineralization, growth plate maturation, secondary ossification center formation, and osteoblast differentiation are phosphate-dependent. Finally, a working hypothesis is proposed to explain how phosphate and DMP1 control osteocyte maturation.


Assuntos
Diferenciação Celular , Osteócitos/patologia , Osteogênese/fisiologia , Fósforo/metabolismo , Animais , Anticorpos/administração & dosagem , Anticorpos/farmacologia , Biomarcadores/metabolismo , Remodelação Óssea/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proteínas da Matriz Extracelular/deficiência , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/imunologia , Homeostase/efeitos dos fármacos , Camundongos , Camundongos Knockout , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteoblastos/patologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteoclastos/patologia , Osteócitos/efeitos dos fármacos , Osteócitos/metabolismo , Osteogênese/efeitos dos fármacos , Fosfatos/metabolismo
11.
J Bone Miner Res ; 26(2): 331-40, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20734454

RESUMO

Dentin matrix protein 1 (DMP-1) is a key molecule in controlling osteocyte formation and phosphate homeostasis. Based on observations that full-length DMP-1 is not found in bone, but only cleaved fragments of 37 and 57 kDa are present, and in view of the finding that mutations in the 57-kDa fragment result in disease, we hypothesized that the 57-kDa C-terminal fragment is the functional domain of DMP-1. To test this hypothesis, a 3.6-kb type I collagen promoter was used to express this 57-kDa C-terminal fragment for comparison with full-length DMP-1 in Dmp1 null osteoblasts/osteocytes. Not only did expression of the full-length DMP-1 in bone cells fully rescue the skeletal abnormalities of Dmp1 null mice, but the 57-kDa fragment also had similar results. This included rescue of growth plate defects, osteomalacia, abnormal osteocyte maturation, and the abnormal osteocyte lacunocanalicular system. In addition, the abnormal fibroblast growth factor 23 (FGF-23) expression in osteocytes, elevated circulating FGF-23 levels, and hypophosphatemia were rescued. These results show that the 57-kDa C-terminal fragment is the functional domain of DMP-1 that controls osteocyte maturation and phosphate metabolism.


Assuntos
Proteínas da Matriz Extracelular/metabolismo , Osteócitos/citologia , Animais , Osso e Ossos/metabolismo , Condrócitos/citologia , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/química , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Eletrônica de Varredura/métodos , Microscopia Eletrônica de Transmissão/métodos , Osteoblastos/citologia , Estrutura Terciária de Proteína , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Microtomografia por Raio-X/métodos
13.
Am J Physiol Renal Physiol ; 300(3): F783-91, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21177780

RESUMO

Increased acidic serine aspartate-rich MEPE-associated motif (ASARM) peptides cause mineralization defects in X-linked hypophosphatemic rickets mice (HYP) and "directly" inhibit renal phosphate uptake in vitro. However, ASARM peptides also bind to phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) and are a physiological substrate for this bone-expressed, phosphate-regulating enzyme. We therefore tested the hypothesis that circulating ASARM peptides also "indirectly" contribute to a bone-renal PHEX-dependent hypophosphatemia in normal mice. Male mice (n = 5; 12 wk) were fed for 8 wk with a normal phosphorus and vitamin D(3) diet (1% P(i) diet) or a reduced phosphorus and vitamin D(3) diet (0.1% P(i) diet). For the final 4 wk, transplantation of mini-osmotic pumps supplied a continuous infusion of either ASARM peptide (5 mg·day(-1)·kg(-1)) or vehicle. HYP, autosomal recessive hypophosphatemic rickets (ARHR), and normal mice (no pumps or ASARM infusion; 0.4% P(i) diet) were used in a separate experiment designed to measure and compare circulating ASARM peptides in disease and health. ASARM treatment decreased serum phosphate concentration and renal phosphate cotransporter (NPT2A) mRNA with the 1% P(i) diet. This was accompanied by a twofold increase in serum ASARM and 1,25-dihydroxy vitamin D(3) [1,25 (OH)(2)D(3)] levels without changes in parathyroid hormone. For both diets, ASARM-treated mice showed significant increases in serum fibroblast growth factor 23 (FGF23; +50%) and reduced serum osteocalcin (-30%) and osteopontin (-25%). Circulating ASARM peptides showed a significant inverse correlation with serum P(i) and a significant positive correlation with fractional excretion of phosphate. We conclude that constitutive overexpression of ASARM peptides plays a "component" PHEX-independent part in the HYP and ARHR hypophosphatemia. In contrast, with wild-type mice, ASARM peptides likely play a bone PHEX-dependent role in renal phosphate regulation and FGF23 expression. They may also coordinate FGF23 expression by competitively modulating PHEX/DMP1 interactions and thus bone-renal mineral regulation.


Assuntos
Ácido Aspártico , Proteínas da Matriz Extracelular/fisiologia , Glicoproteínas/fisiologia , Rim/metabolismo , Endopeptidase Neutra Reguladora de Fosfato PHEX/fisiologia , Peptídeos/fisiologia , Fosfatos/sangue , Fosfoproteínas/fisiologia , Serina , Sequência de Aminoácidos , Animais , Proteínas da Matriz Extracelular/metabolismo , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/metabolismo , Hipofosfatemia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Dados de Sequência Molecular , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIa/metabolismo
14.
J Clin Invest ; 118(2): 722-34, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18172553

RESUMO

Patients with X-linked hypophosphatemia (XLH) and the hyp-mouse, a model of XLH characterized by a deletion in the Phex gene, manifest hypophosphatemia, renal phosphate wasting, and rickets/osteomalacia. Cloning of the PHEX/Phex gene and mutations in affected patients and hyp-mice established that alterations in PHEX/Phex expression underlie XLH. Although PHEX/Phex expression occurs primarily in osteoblast lineage cells, transgenic Phex expression in hyp-mouse osteoblasts fails to rescue the phenotype, suggesting that Phex expression at other sites underlies XLH. To establish whether abnormal Phex in osteoblasts and/or osteocytes alone generates the HYP phenotype, we created mice with a global Phex knockout (Cre-PhexDeltaflox/y mice) and conditional osteocalcin-promoted (OC-promoted) Phex inactivation in osteoblasts and osteocytes (OC-Cre-PhexDeltaflox/y). Serum phosphorus levels in Cre-PhexDeltaflox/y, OC-Cre-PhexDeltaflox/y, and hyp-mice were lower than those in normal mice. Kidney cell membrane phosphate transport in Cre-PhexDeltaflox/y, OC-Cre-PhexDeltaflox/y, and hyp-mice was likewise reduced compared with that in normal mice. Abnormal renal phosphate transport in Cre-PhexDeltaflox/y and OC-Cre-PhexDeltaflox/y mice was associated with increased bone production and serum FGF-23 levels and decreased kidney membrane type IIa sodium phosphate cotransporter protein, as was the case in hyp-mice. In addition, Cre-PhexDeltaflox/y, OC-Cre-PhexDeltaflox/y, and hyp-mice manifested comparable osteomalacia. These data provide evidence that aberrant Phex function in osteoblasts and/or osteocytes alone is sufficient to underlie the hyp-mouse phenotype.


Assuntos
Osso e Ossos/patologia , Raquitismo Hipofosfatêmico Familiar/enzimologia , Doenças Genéticas Ligadas ao Cromossomo X , Osteoblastos/enzimologia , Osteócitos/enzimologia , Endopeptidase Neutra Reguladora de Fosfato PHEX/fisiologia , Vitamina D/metabolismo , Animais , Transporte Biológico , Osso e Ossos/anormalidades , Osso e Ossos/diagnóstico por imagem , Modelos Animais de Doenças , Fêmur/anormalidades , Fêmur/diagnóstico por imagem , Fêmur/patologia , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/sangue , Fatores de Crescimento de Fibroblastos/metabolismo , Rim/metabolismo , Camundongos , Camundongos Knockout , Endopeptidase Neutra Reguladora de Fosfato PHEX/genética , Fósforo/sangue , Fósforo/metabolismo , Radiografia
15.
WMJ ; 106(8): 466-72, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18237070

RESUMO

As a result of low dietary intake and sun avoidance, low vitamin D status is endemic in Wisconsin. In a convenience sample of postmenopausal Wisconsin residents, 59% had suboptimal D status. Only recently, the medical community has begun to appreciate that low vitamin D status underlies multiple deleterious health consequences including skeletal fragility, muscle weakness, and a potential multitude of non-skeletal morbidities. At present, a routine recommendation indicates that at least 1000 IU of vitamin D3 (cholecalciferol) daily is indicated, although the true requirement may be greater. This review details vitamin D physiology and the prevalence of low vitamin D status in Wisconsin and elsewhere, and provides approaches to optimizing vitamin D status.


Assuntos
Deficiência de Vitamina D/epidemiologia , Deficiência de Vitamina D/prevenção & controle , Vitamina D/uso terapêutico , Idoso , Densidade Óssea , Feminino , Humanos , Masculino , Prevalência , Luz Solar , Wisconsin/epidemiologia
17.
Nat Genet ; 38(11): 1310-5, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17033621

RESUMO

The osteocyte, a terminally differentiated cell comprising 90%-95% of all bone cells, may have multiple functions, including acting as a mechanosensor in bone (re)modeling. Dentin matrix protein 1 (encoded by DMP1) is highly expressed in osteocytes and, when deleted in mice, results in a hypomineralized bone phenotype. We investigated the potential for this gene not only to direct skeletal mineralization but also to regulate phosphate (P(i)) homeostasis. Both Dmp1-null mice and individuals with a newly identified disorder, autosomal recessive hypophosphatemic rickets, manifest rickets and osteomalacia with isolated renal phosphate-wasting associated with elevated fibroblast growth factor 23 (FGF23) levels and normocalciuria. Mutational analyses showed that autosomal recessive hypophosphatemic rickets family carried a mutation affecting the DMP1 start codon, and a second family carried a 7-bp deletion disrupting the highly conserved DMP1 C terminus. Mechanistic studies using Dmp1-null mice demonstrated that absence of DMP1 results in defective osteocyte maturation and increased FGF23 expression, leading to pathological changes in bone mineralization. Our findings suggest a bone-renal axis that is central to guiding proper mineral metabolism.


Assuntos
Proteínas da Matriz Extracelular/genética , Minerais/metabolismo , Osteócitos/fisiologia , Osteomalacia/genética , Fosfoproteínas/genética , Raquitismo/genética , Adulto , Animais , Osso e Ossos/patologia , Calcificação Fisiológica/genética , Calcificação Fisiológica/fisiologia , Células Cultivadas , Análise Mutacional de DNA , Feminino , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Rim/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteócitos/patologia , Osteomalacia/sangue , Osteomalacia/patologia , Fosfatos/metabolismo , Raquitismo/sangue , Raquitismo/patologia
18.
Endocr Pract ; 12(4): 406-10, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16901796

RESUMO

OBJECTIVE: To report a case of calciphylaxis in the absence of renal failure in a patient with secondary hyperparathyroidism and low calcium/phosphorus product, in whom total parathyroidectomy resulted in relief of pain and healing of ulcerations. METHODS: We present the clinical, laboratory, and pathologic findings in a 62-year-old woman with calciphylaxis in the absence of end-stage renal disease. RESULTS: A 62-year-old woman presented with painful nonhealing bilateral calf ulcerations. Pathology examination of tissue specimens from surgical débridement revealed intravascular calcification, consistent with calciphylaxis. Laboratory investigation revealed normal renal function; however, hypocalcemia and hypophosphatemia were present--a corrected serum calcium level of 7.5 mg/dL (normal, 8.5 to 10.2) and a serum phosphorus value of 1.0 mg/dL (normal, 2.5 to 4.5). These abnormalities were likely due to vitamin D deficiency, evidenced by a 25-hydroxyvitamin D level of 14 ng/mL, which provoked an elevation of the serum parathyroid hormone (PTH) concentration, documented by an intact PTH of 213 pg/mL (normal, 15 to 65) and a whole PTH (1-84 PTH) of 70.6 pg/mL (normal, 7 to 36). Her quality of life was severely impaired, not only by the ulcerations but also by intractable pain that necessitated epidural analgesia during the hospitalization. The patient underwent total parathyroidectomy and transcervical thymectomy, with cryopreservation of parathyroid tissue. One year after the parathyroidectomy, the patient had no recurrence of calciphylaxis. CONCLUSION: This case suggests that despite the potential complex pathophysiologic aspects of calciphylaxis, even in the absence of both renal failure and an elevated calcium/phosphorus product, early parathyroidectomy in patients with appreciably increased PTH levels may improve wound healing and diminish pain.


Assuntos
Calciofilaxia/diagnóstico , Calciofilaxia/etiologia , Hiperparatireoidismo Secundário/complicações , Dermatopatias Metabólicas/etiologia , Calciofilaxia/patologia , Feminino , Humanos , Hiperparatireoidismo Secundário/diagnóstico , Hiperparatireoidismo Secundário/cirurgia , Falência Renal Crônica/diagnóstico , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Paratireoidectomia , Dermatopatias Metabólicas/diagnóstico , Dermatopatias Metabólicas/patologia , Cicatrização
19.
Arthritis Rheum ; 54(6): 1838-46, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16729277

RESUMO

OBJECTIVE: Although oral bisphosphonates are effective treatments for postmenopausal women with osteoporosis, oral dosing may be unsuitable for some patients. An efficacious intravenously administered bisphosphonate could be beneficial for such patients. Ibandronate, a potent nitrogen-containing bisphosphonate, can be administered using extended dosing intervals, either orally or by rapid intravenous injection. The aim of this study was to identify the optimal intravenous dosing regimen for ibandronate in postmenopausal women with osteoporosis. METHODS: In a randomized, double-blind, double-dummy, phase III, noninferiority study, we compared 2 regimens of intermittent intravenous injections of ibandronate (2 mg every 2 months and 3 mg every 3 months) with a regimen of 2.5 mg of oral ibandronate daily, the latter of which has proven antifracture efficacy. The study group comprised 1,395 women (ages 55-80 years) who were at least 5 years postmenopausal. All patients had osteoporosis (lumbar spine [L2-L4] bone mineral density [BMD] T score less than -2.5). Participants also received daily calcium (500 mg) and vitamin D (400 IU). The primary end point was change from baseline in lumbar spine BMD at 1 year. Changes in hip BMD and in the level of serum C-telopeptide of type I collagen (CTX) were also measured, as were safety and tolerability. RESULTS: At 1 year, mean lumbar spine BMD increases were as follows: 5.1% among 353 patients receiving 2 mg of ibandronate every 2 months, 4.8% among 365 patients receiving 3 mg of ibandronate every 3 months, and 3.8% among 377 patients receiving 2.5 mg of oral ibandronate daily. Both of the intravenous regimens not only were noninferior, but also were superior (P < 0.001) to the oral regimen. Hip BMD increases (at all sites) were also greater in the groups receiving medication intravenously than in the group receiving ibandronate orally. Robust decreases in the serum CTX level were observed in all arms of the study. Both of the intravenous regimens were well tolerated and did not compromise renal function. CONCLUSION: As assessed by BMD, intravenous injections of ibandronate (2 mg every 2 months or 3 mg every 3 months) are at least as effective as the regimen of 2.5 mg orally daily, which has proven antifracture efficacy, and are well tolerated.


Assuntos
Conservadores da Densidade Óssea/administração & dosagem , Difosfonatos/administração & dosagem , Osteoporose Pós-Menopausa/tratamento farmacológico , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Densidade Óssea , Cálcio/administração & dosagem , Colágeno Tipo I/sangue , Método Duplo-Cego , Feminino , Humanos , Ácido Ibandrônico , Injeções Intravenosas , Pessoa de Meia-Idade , Peptídeos/sangue , Vitamina D/administração & dosagem
20.
Clin Chem ; 52(6): 1120-6, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16574756

RESUMO

BACKGROUND: The concentration of 25-hydroxyvitamin D [25(OH)D] in serum has been designated the functional indicator of vitamin D (VitD) nutritional status. Unfortunately, variability among 25(OH)D assays limits clinician ability to monitor VitD status, supplementation, and toxicity. METHODS: We developed an HPLC method that selectively measures 25-hydroxyvitamin D2 [25(OH)D2] and D3 [25(OH)D3] and compared this assay with a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, a competitive protein-binding assay (CPBA) on the Nichols Advantage platform, and an RIA from Diasorin. RESULTS: For the new HPLC assay, between-run CVs were 2.6%-4.9% for 25(OH)D3 and 3.2%-13% for 25(OH)D2; recoveries were 95%-102%; and the assay was linear from 5 microg/L to at least 200 microg/L. Comparison data were as follows: for HPLC vs LC-MS/MS, y = 1.01x - 4.82 microg/L (Sy/x = 4.93 microg/L; r = 0.996) for 25(OH)D3, and y = 0.902x - 0.566 microg/L (Sy/x = 2.56 microg/L; r = 0.9965 for 25(OH)D2; for HPLC vs Diasorin RIA, y = 0.709x - 5.86 microg/L (Sy/x = 7.35 microg/L; r = 0.7509); and for HPLC vs Nichols Advantage CPBA, y = 1.00x - 3.60 microg/L (Sy/x = 32.7 microg/L; r = 0.6823). CONCLUSIONS: The new HPLC method is reliable, robust, and has advantages compared with the Nichols Advantage CPBA and the Diasorin RIA. The Nichols Advantage CPBA overestimated or underestimated 25(OH)D concentrations predicated on the prevailing metabolite present in patients' sera.


Assuntos
25-Hidroxivitamina D 2/sangue , Calcifediol/sangue , Cromatografia Líquida de Alta Pressão , Humanos , Espectrometria de Massas , Radioimunoensaio
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