NMR signal enhancement of >50 000 times in fast dissolution dynamic nuclear polarization.

Herein, we report the synthesis and the study of a novel mixed biradical with BDPA and TEMPO radical units that are covalently bound by an ester group (BDPAesterTEMPO) as a polarizing agent for fast dissolution DNP. The biradical exhibits an extremely high DNP NMR enhancement of >50 000 times, which constitutes one of the largest signal enhancements observed so far, to the best of our knowledge.

A benzyl alcohol derivative of the BDPA radical for fast dissolution dynamic nuclear polarization NMR spectroscopy.

The synthesis, structural characterization and the successful application of a carbon centered radical derived from 1,3-bisdiphenylene-2-phenylallyl (BDPA), its benzyl alcohol derivative (BA-BDPA), as a polarizing agent for Dynamic Nuclear Polarization (DNP) are described. The reported BA-BDPA radical meets all the requirements to become a promising candidate for its use in in vivo DNP-NMR experiments: it is soluble in neat [1-(13)C]pyruvic acid, insoluble in the dissolution transfer solvent and is effective as a polarizing agent in fast dissolution DNP-NMR applications, without the need for using glassing agents. Moreover, it enables a simple but effective in-line radical filtration to obtain hyperpolarized solutions of [1-(13)C]pyruvic acid free of radicals that offers a better polarization performance.

p53 expression in rheumatoid and psoriatic arthritis synovial tissue and association with joint damage.

BACKGROUND: Overexpression and functional mutations of p53 have been found in the synovial tissue (ST) of patients with rheumatoid arthritis (RA), but their clinical significance remains unclear. OBJECTIVE: To analyse p53 expression in the ST of patients with RA and psoriatic arthritis (PsA) and its association with joint damage. METHODS: Synovial biopsy specimens were obtained by arthroscopy in 45 patients (27 RA, 18 PsA). Radiographs of hands, feet, and the joint undergoing arthroscopy were obtained to evaluate the presence of erosive disease. Synovial cell populations were analysed using CD4, CD8, CD138, CD20, and CD68 monoclonal antibodies (mAbs). The p53 protein was determined by immunohistology using DO7 mAb in 34 patients (18 RA, 16 PsA). In 11 patients with early RA, the association between p53 and 1 year progression of radiographic damage was analysed using the Larsen-Scott method. RESULTS: The p53 protein was detected in 16/18 (89%) patients with RA and in 9/16 (56%) patients with PsA, but its expression in RA was significantly higher than in PsA. In RA, p53 expression was significantly associated with erosive disease, and its scores were higher in patients with radiological progression. CD68 expression was also associated with erosions and radiological progression in RA. No association was found between either p53 or CD68 and erosive disease in PsA. CONCLUSIONS: These results suggest that p53 ST overexpression and association with joint damage is characteristic of RA rather than PsA, and that p53 ST expression might be a prognostic marker of joint damage in RA.

Tratamiento multidisciplinar en pacientes con dolor crónico en situación de baja laboral / Multidisciplinary therapy for patients with chronic pain on sick leave

Objetivo: Analizar la eficacia de un programa de tratamiento multidisciplinar en pacientes seleccionados con dolor crónico incapacitante en situación de baja laboral refractario a tratamiento convencional. Material y métodos: Ciento cuatro pacientes con dolor crónico incapacitante recibieron tratamiento multidisciplinar (médico, psicológico, físico y ocupacional) intensivo de cinco horas al día, durante cuatro días a la semana y durante cuatro semanas. Se programaron revisiones al alta y a los 6 y 12 meses de finalizar el tratamiento. Resultados: Al alta del tratamiento se observaron reducciones significativas de la sintomatología dolorosa, depresiva y de ansiedad, así como un incremento significativo de la capacidad funcional (dolor (EVA): 7,4ñ1,6 vs 3,4ñ2) cm (p<0,0001); depresión (BDI): 17ñ9 vs 10ñ8) puntos (p<0,0001); ansiedad (HARS): 19ñ8 vs 14ñ7) puntos (p<0,0001); incapacidad (HAQ): 1,7ñ0,4 vs 0,6ñ0,5 puntos) (p<0,0001). Los tamaños del efecto se distribuyeron entre un valor máximo de 2,5 (EVA dolor) y un valor mínimo de 0,6 (HARS) indicando en todos los casos la obtención de un cambio clínico de amplio a moderado. En ese momento, 75 (78 por ciento) pacientes se reincoporaron a su actividad laboral. Durante el seguimiento se mantuvieron las mejorías significativas en las variables de desenlace evaluadas. De los 62 pacientes que completaron el seguimiento a un año, 47 (63 por ciento) mantienen la situación laboral activa. Conclusiones: Los programas de tratamiento multidisciplinar del dolor crónico no maligno incapacitante son eficaces en la mejoría del dolor y el sufrimiento en pacientes seleccionados en nuestro medio, logrando revertir un elevado porcentaje de la incapacidad laboral (AU)

Long-term biochemical response after bisphosphonate therapy in Paget's disease of bone. Proposed intervals for monitoring treatment.

OBJECTIVES: To monitor the long-term evolution of Paget's disease activity after treatment with tiludronate by using serum total alkaline phosphatase (TAP) and more sensitive markers such as bone alkaline phosphatase (BAP), procollagen type I N propeptide (PINP) and urinary N-terminal cross-linking telopeptide of type I collagen (NTX); to analyse the predictors of long-term response to therapy; and to study the most appropriate intervals of time for monitoring the response to therapy. METHODS: Thirty-two patients with Paget's disease were included in the study. All received 400 mg of oral tiludronate daily for 3 months. A total of 21 patients completed the study. In these patients, serum TAP, BAP and PINP and urinary NTX were measured at baseline and at 1, 6, 12 and 24 months after discontinuation of therapy. Quantitative bone scintigraphy was performed at baseline and at 6 and 24 months after the end of treatment, obtaining a scintigraphic activity index (SAI). Patients were classified into two groups depending on the long-term response to treatment: Group 1, patients who presented a persistent and significant decrease in disease activity at this time, n = 12 (57%) and Group 2, patients who presented a relapse in the activity of the disease at 24 months after treatment, n = 9 (43%). The relapse of disease activity was defined as a significant increase of SAI (>13%) between 6 and 24 months after the end of treatment, whereas the response to therapy was defined as a significant reduction in SAI (>13%) at 6 months after the end of treatment. In addition, these results were compared with the biochemical evolution of bone markers. RESULTS: Biochemical markers and SAI decreased significantly after therapy and the nadir response was observed at 6 months. At this time 100% of patients responded to therapy. The persistent long-term response was associated with lower baseline indices of bone turnover (serum BAP<60 ng/ml or TAP<600 IU/l). The intervals of time for monitoring depended on the marker used: no patient from Group 1 presented a biochemical relapse in serum TAP at 1 and 2 yr after the end of treatment whereas 33 and 45% of these patients showed relapsed serum BAP at these time points. Moreover, all patients from Group 2 presented a biochemical relapse of serum BAP at 2 yr whereas in only 33% of these patients did serum TAP relapse at this time. CONCLUSION: Most of the Pagetic patients treated with tiludronate presented a long-term response, which persisted 2 yr after the end of treatment. The nadir response to treatment was observed 6 months after discontinuation of therapy whereas the relapse of disease activity was already observed 1 yr after the end of therapy and depended on both the baseline disease activity and the bone marker used in the evaluation.

Immunocytochemical evidence on the effects of glucocorticoids on type I collagen synthesis in human osteoblastic cells.

The effects of glucocorticoids on DNA synthesis and cellular function were assessed in cultures of human osteoblastic cells by using indirect immunoperoxidase staining with a type I antiprocollagen antibody and by measuring procollagen type I N and C propeptides (PINP, PICP) in the culture medium by radiometric methods. Likewise, we analyzed the correlation between intracellular immunostaining and procollagen propeptides released into the culture medium, as well as the correlation between PINP and PICP. Human osteoblasts were cultured with and without addition of dexamethasone (DEX) at two supraphysiological concentrations, 10(-6) M and 10(-7) M, for 24 and 48 h. Treatment with DEX at 10(-6) M was associated with a significant decrease in the percentage of cells showing intracellular type I procollagen immunoreactivity at 24 and 48 h ( P < 0.05). Similar effects were observed with 10(-7) M DEX. Dexamethasone 10(-6) M and 10(-7) M also induced significant decreases in PINP and PICP values after 24 and 48 h of treatment ( P < 0.05). The decrease in intracellular procollagen immunoreactivity and propeptide secretion was not associated with a reduction in DNA synthesis. A highly significant correlation was observed between the values of PINP and PICP in the culture medium as well as between the values of intracellular immunostaining and PINP and PICP ( P < 0.001). In conclusion, our results suggest that supraphysiological doses of glucocorticoids produce a direct inhibition on osteoblastic function through their effect on type I procollagen synthesis. Immunoperoxidase detection of type I intracellular procollagen as well as the quantification of PINP and PICP in the culture medium are reliable methods of assessing osteoblast function.

Diagnostic usefulness of synovial vascular morphology in chronic arthritis. A systematic survey of 100 cases.

OBJECTIVES: To assess the diagnostic usefulness of the systematic analysis of synovial vascular morphology in various inflammatory, early, and longstanding arthropathies, and to examine the validity of the vascular patterns in predicting the evolution of a group of patients with undifferentiated arthritis (UA). METHODS: One hundred patients who underwent rheumatologic arthroscopy of a symptomatic joint (85 knees, 11 wrists, 3 elbows, 1 metacarpophalangeal joint) were evaluated. The same observer, blinded to patient diagnosis, analyzed the video recordings of the arthroscopies. Vascular morphology was classified into 3 patterns: straight, tortuous, and mixed. RESULTS: Eighty-one patients had inflammatory arthritis: 35 rheumatoid arthritis (RA), 16 psoriatic arthritis (PsA), 13 spondyloarthropathies (SpA), and 17 UA. Forty-nine percent of patients with RA had a straight pattern, 28% a mixed, and 23% a tortuous one. The sensitivity rate of the straight pattern for RA was 77% and the specificity rate was 70%. Seventy-six percent of RA patients with a straight pattern were rheumatoid factor positive (RF+) against 25% of RA patients with a tortuous pattern. The odds ratio for RA associated to straight compared with tortuous pattern was 57.3 (95% confidence interval, 6.6 to 499.5; P <.001). Patients with PsA and SpA shared the same pattern and were analyzed as 1 group. Ninety-three percent of patients with PsA/SpA had a tortuous pattern, 4% a straight pattern, and 3% a mixed pattern. The sensitivity rate of the tortuous pattern for PsA/SpA was 61% and the specificity rate was 95%. During 2 years of follow-up, 6 of 17 patients with UA were definitely diagnosed: 4 RA (2 RF+ and straight pattern; 2 with a tortuous pattern, 1 with RF+ and HLA-B27+); 1 SpA and 1 PsA, both with a tortuous pattern. No differences in vascular patterns were observed according to disease duration. Our results indicate that vascular patterns are not modified by disease modifying antirheumatic drug (DMARD) treatment. The other 19 patients had osteoarthritis (n = 8) and calcium pyrophosphate dihydrate crystal deposition disease (n = 11) and their predominant vascular pattern was tortuous-like. CONCLUSIONS: Arthroscopic assessment of synovial vascular changes in chronic arthritis may be of diagnostic and pathogenetic interest, although differences between published studies suggest a need for consensus in evaluating vascular patterns. A straight pattern is strongly associated with RF + RA whereas a tortuous pattern is generally associated with PsA or SpA; these associations are independent of disease duration. The vascular pattern likely does not change qualitatively with DMARD therapy. The application of this technique to the diagnosis or prognosis of patients with UA may be a complementary tool for the treatment of these patients, but larger, prospective studies are necessary to confirm this hypothesis.

Prevalence and clinical significance of anti-cyclic citrullinated peptide and antikeratin antibodies in palindromic rheumatism. An abortive form of rheumatoid arthritis?

OBJECTIVE: To analyse the prevalence and clinical significance of anti-cyclic citrullinated peptide antibodies (anti-CCP) and antikeratin antibodies (AKA) in patients with palindromic rheumatism (PR). METHOD: Sixty-three patients with PR were included: 33 were defined as pure or persistent PR at the time of serum test measurement, and 30 as associated PR, defined as patients with past history of PR who had developed persistent arthritis at the time of serum test: [21 with rheumatoid arthritis (RA)]. Sixty patients with early RA, and 80 with seronegative spondyloarthropathy were included as control groups. Anti-CCP were determined by a standardized ELISA test and AKA by indirect immunofluorescence in rat oesophagus. Clinical characteristics of these pure PR patients were compared according to the presence or absence of anti-CCP antibodies. A follow-up study was also performed. RESULTS: Anti-CCP were detected in 18 out of 32 (56.3%) patients with pure PR and 10 out of 30 (33.3%) with associated PR (38.1% in RA-associated PR patients). AKA were detected in 12 patients out of 33, with pure PR (36.4%), and in 9 out of 30 with associated PR (30%) (33.3% in RA-associated PR patients). The prevalence of anti-CCP and AKA in the RA control group was 55% (not significantly different from the pure PR group) and 61.7% (with respect to pure PR patients, P=0.02), respectively. In the spondyloarthropathy group, the prevalence of anti-CCP and AKA was 2.5 and 3.8%, respectively (P<0.001 compared with pure PR patients). No significant clinical differences were observed between pure PR patients with and without CCP antibodies. CONCLUSIONS: Anti-CCP and, to a lesser extent, AKA, were found in a high proportion of patients with PR, suggesting that this syndrome is an abortive form of RA. The predictive value of these antibodies in PR, as markers of progression to an established RA, remains uncertain.

Radiological progression in early rheumatoid arthritis after DMARDS: a one-year follow-up study in a clinical setting.

OBJECTIVE: To analyse the frequency and prognostic factors of radiographic progression in a series of Spanish patients with early rheumatoid arthritis (RA) after 1 yr of treatment with disease-modifying anti-rheumatic drugs (DMARDs). METHODS: Sixty patients (47 females, 13 males) with RA with a disease duration shorter than 2 yr [mean (s.d.) duration 9.5+/-6.6 months] were treated with the same therapeutic protocol using gold salts as the first DMARD and methotrexate as a second option, and were followed up for 1 yr. Radiographic progression in the hands and feet (total radiographic Larsen score and the erosion joint count) was used as the outcome variable. Clinical, laboratory, immunogenetic and radiographic data were obtained at study entry. Disease activity and response to therapy were measured at 6 and 12 months. RESULTS: Erosive disease was found in 21.7% of patients at baseline and in 38.3% after 1 yr. Although a substantial reduction in disease activity was observed during the 1 yr follow-up [disease activity score (DAS28) 5.8+/-0.8 at entry and 3.9+/-1.3 at 12 months, P < 0.001], the Larsen score rose from 1.9+/-3.3 to 5.6+/-9.8 after 1 yr. In 26.6% of patients, a raised erosion joint count was observed after 1 yr. Radiographic progression in the total joint radiographic damage (increase in Larsen score of >or=2) was observed in 36.6%. In the multivariate analysis, baseline pain [visual analogue scale (VAS)] and the presence of two copies of the shared epitope were associated with radiographic progression in the erosion joint count. Disease duration before study entry, VAS pain and Larsen score at baseline were significant predictors of radiographic progression in total damage (Larsen score). Baseline radiographic damage had the highest positive predictive value for progression. CONCLUSIONS: Radiographic progression was observed in up to 36.6% of patients with early RA after 1 yr of DMARD therapy in spite of a significant reduction in disease activity. Baseline factors, such as VAS pain, disease duration until DMARD therapy, damage score at baseline and the presence of two copies of the shared epitope, were associated with radiographic progression.

Serum osteoprotegerin and its ligand in Paget's disease of bone: relationship to disease activity and effect of treatment with bisphosphonates.

OBJECTIVE: To test the following hypotheses: 1) osteoprotegerin (OPG) and receptor activator of nuclear factor kappa B ligand (RANKL) serum levels in patients with Paget's disease are related to disease activity and are different from those in healthy individuals; 2) interleukin-6 (IL-6), a cytokine that has been shown to have higher levels in Paget's disease, modulates these factors; and 3) the antiresorptive effect of bisphosphonates in Paget's disease of bone may be mediated through these local factors. METHODS: The study group comprised 31 patients with Paget's disease who received 400 mg/day of oral tiludronate for 3 months. Serum levels of OPG, RANKL, IL-6, bone alkaline phosphatase (AP), N-terminal type I procollagen propeptide, urinary N-terminal crosslinking telopeptide of type I collagen, and urinary alpha-C-terminal crosslinking telopeptide of type I collagen were measured at baseline and 1 month after the end of therapy. In addition, the RANKL:OPG ratio was calculated, and disease activity was evaluated at baseline by quantitative bone scintigraphy. RESULTS: Mean baseline OPG values were higher in patients with Paget's disease than in healthy control subjects (P < 0.005), but RANKL and IL-6 values and RANKL:OPG ratios in the 2 groups were similar. OPG concentrations decreased significantly after treatment with tiludronate (P < 0.005), whereas no significant changes were observed in serum RANKL values. No correlation was found between either bone markers or quantitative scintigraphic indices and serum levels of OPG, RANKL, IL-6, and RANKL:OPG ratios. Serum OPG decreased significantly only in those patients with baseline OPG values >4.1 pM/liter. CONCLUSION: Serum OPG increases in Paget's disease and decreases after treatment with tiludronate, especially in patients with the highest OPG values. In contrast, RANKL serum levels and RANKL:OPG ratios are unmodified in patients with Paget's disease. Although serum OPG, RANKL, and IL-6 values were unrelated to disease activity, the increase in OPG may reflect a protective mechanism of the skeleton to compensate for increased bone resorption.

Dolor lumbar crónico incapacitante. Tratamiento multidisciplinario / Disabling chronic low back pain: a multidisciplinar treatment

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Pregnancy associated osteoporosis: the familial effect.

OBJECTIVE: The etiology and pathogenesis of pregnancy associated osteoporosis is unclear. Whether pregnancy has simply been an aggravating factor or is a direct etiologic cause responsible for severe bone loss needs to be elucidated. METHODS: In order to evaluate the contribution of familial factors to pregnancy osteoporosis, we analyzed the bone mass of 15 relatives of 5 women with pregnancy osteoporosis. Most of the patients suffered from severe back pain associated with vertebral fractures in their first pregnancy. Extensive clinical, laboratory and radiological investigations were performed to exclude secondary causes of osteoporosis. Bone mineral density measurements were performed on 15 first order family members and the results were compared with those of a control group of 20 healthy members of 5 families. RESULTS: Osteoporosis was present in 53% of the relatives of patients with pregnancy osteoporosis and in 15% of the controls (P < 0.05). CONCLUSION: These results highly suggest that some patients with pregnancy associated osteoporosis have a genetic determination of low peak bone mass, and gestation, due to its association with physiological metabolic disturbances, constitutes a risk factor for the development of skeletal fractures in these patients.

Osteosarcoma en la enfermedad de Paget. Descripción de 6 casos / Osteosarcoma in Paget's disease. Report of six cases

Algunos pacientes con enfermedad ósea de Paget pueden desarrollar un osteosarcoma en la lesión pagética. Aunque se trata de una complicación infrecuente, el diagnóstico precoz de esta entidad es fundamental debido a su elevada mortalidad. Con el fin de analizar las características clínicas de estos pacientes y de valorar la utilidad de las pruebas de laboratorio en la sospecha diagnóstica de este proceso, se han revisado los pacientes con enfermedad ósea de Paget y osteosarcoma atendidos en nuestro centro en los últimos 12 años. Se describen 6 casos que corresponden a 3 varones y 3 mujeres, 5 de ellos con una enfermedad poliostótica, que desarrollaron dolor local intenso, en ocasiones asociado a sintomatología neurológica o a tumefacción de partes blandas. Tres pacientes seguían control por su enfermedad de Paget desde hacía más de 12 años, mientras que en 3 pacientes el diagnóstico del sarcoma óseo coincidió con el de la enfermedad de Paget. En ninguno de los pacientes de los que se disponía de seguimiento previo se observó un cambio significativo en las pruebas básicas de laboratorio (VSG, calcemia), ni en los valores de la fosfatasa alcalina, que alertaran al clínico de la posibilidad de una degeneración sarcomatosa. La sintomatología y las alteraciones radiológicas fueron las principales manifestaciones de este proceso (AU)

Usefulness of biochemical markers of bone turnover in assessing response to the treatment of Paget's disease.

The aim of this study was to investigate the usefulness of biochemical markers of bone turnover for monitoring treatment efficacy of Paget's disease of bone, and also to evaluate the utility of biological variation data in choosing the best markers for assessment of biochemical response to therapy. Thirty-eight patients with Paget's disease were included in a prospective study. All received 400 mg/day of oral tiludronate for 3 months. In 31 patients that completed treatment, biochemical markers were measured at baseline and at 1 and 6 months after treatment ended. In serum we determined the levels of total alkaline phosphatase (tAP), bone alkaline phosphatase (bAP), procollagen type I N-terminal propeptide (PINP), and C-terminal telopeptide of type I collagen (sCTx). Urine samples were analyzed for hydroxyproline (Hyp) and for C- and N-terminal telopeptides of type I collagen (CTx and NTx, respectively). Quantitative bone scintigraphy was performed at baseline and at 6 months after discontinuation of therapy. A ratio for monitoring response to treatment was obtained for each marker. This ratio reflected the size of treatment response of the marker in relation to the value of its critical difference. Thus, ratio values of >1 indicated a significant decrease of the marker after therapy. In addition, response to therapy was evaluated according to disease activity. Mean values of all markers of bone turnover decreased significantly after therapy. Serum bAP and PINP and urinary NTx showed the highest percentage reduction (between 58% and 68%). Furthermore, serum bAP and PINP showed the highest ratios for monitoring changes induced by treatment, followed by serum tAP and urinary NTx. sCTx and urinary CTx as well as Hyp showed mean ratios for monitoring changes of <1, indicating a low sensitivity for monitoring treatment. Patients with polyostotic disease showed a continuous decrease in mean values for all markers at 6 months from the end of therapy, whereas, in monostotic patients, there was a trend toward increased levels at this timepoint. In conclusion, serum bAP and PINP were the most sensitive markers for monitoring treatment efficacy in Paget's disease, although serum tAP and urinary NTx were also sensitive markers for monitoring changes. Data on biological variation are useful for assessing actual changes induced by treatment.

[Efficiency of multidisciplinary treatment of chronic pain with locomotor disability]. / Eficacia del tratamiento multidisciplinario del dolor crónico incapacitante del aparato locomotor.

BACKGROUND AND OBJECTIVE: Disabling chronic pain is especially devastating among working population and, in many cases, it does not respond to conventional therapies. In chronic pain, the importance of psychosocial and occupational factors, in addition to biological ones, has prompted the development of successful multidisciplinary treatment programmes in various countries. We assessed the outcome of a multidisciplinary therapeutic program for work-disabled selected patients with chronic pain refractory to conventional treatment. PATIENTS AND METHOD: The study included 70 patients (58 women, mean age [SD]: 42 [9]years) with chronic pain and sick leave (mean [SD]: 7 [4] months of work disability) diagnosed with fibromyalgia (51%), chronic low back pain (16%), regional myofascial pain (15%), cervicocraneal syndrome (3%), anquilosing spondylitis (3%), and other conditions(12%). All patients had received previous pharmacological treatment,physical therapy and/or other measures (surgery in 12% cases)without improvement. All patients underwent an intensive multidisciplinary treatment of 4 weeks' duration including medical techniques for pain control, cognitive-behavioural therapy, physical therapy,and occupational therapy. Average follow-up was 10 (4) months(1-24 months) post-discharge. RESULTS: Significant improvements were observed with regard to all relevant variables, as reflected in pre and post-discharge measures: pain(Visual-Analogue Scale 1-10 cm): 7.4 (1.5) versus 3.2 (2) (p <0.01); anxiety (HARS), 19 (7) versus 14 (8) (p < 0.01); depression(BDI), 16 (8) versus 10 (8) (p < 0.01); functional ability(HAQ), 1.6 (0.4) versus 0.6 (0.5) (p < 0.001). At discharge,73% of patients returned to work. In addition, 69% of treated patients maintained the acquired improvement and their employment status at the end of follow-up. CONCLUSION: Multidisciplinary treatment of chronic pain with special attention to work return is useful for selected patients with a disabling chronic pain syndrome refractory to conventional treatment.

Bone disease after liver transplantation: a long-term prospective study of bone mass changes, hormonal status and histomorphometric characteristics.

After liver transplantation there is a high incidence of fractures, with important rates of bone loss during the first months. However, the long-term evolution of bone mass and metabolism parameters have been scarcely studied. In order to determine the incidence and risk factors involved in the development of skeletal fractures and to analyze the long-term evolution of bone mass, bone turnover and hormonal status after liver transplantation, a 3-year prospective study was performed in 45 patients following liver transplantation. Serum osteocalcin, parathyroid hormone (PTH), 25-hydroxyvitamin D (25-OH D) and testosterone levels (men), and bone mass at the lumbar spine and femur were measured before and sequentially at different time points during 3 years. Spinal X-rays were obtained during the first year. Histomorphometric analysis of bone biopsies obtained in 24 patients within the first 12 hours after surgery and 6 months after transplantation was performed. Fifteen patients (33%) developed fractures after liver transplantation, and pre-transplant risk factors for fractures were age and low bone mass (odd's ratio for osteoporosis, 95% confidence interval: 5.69, 1.32-24.53). Serum PTH, osteocalcin, 25-OH D, testosterone and creatinine levels increased after transplantation. Moreover, PTH correlated with creatinine and osteocalcin values. Bone mass decreased during the first 6 months and reached baseline values at the lumbar spine the second year, with posterior significant recovery at the femoral neck. Long term evolution of femoral neck BMD correlated with PTH levels. Six months after transplantation bone histomorphometric data showed an increase in bone formation parameters. After liver transplantation there is a high incidence of fractures, specially in elderly patients and those with osteoporosis. Bone mass decreased in the short-term period and improved, initially at the lumbar spine and later at the femur, according to histomorphometric evidences of an increase in bone formation. The increase in creatinine values induces a secondary hyperparathyroidism that influences the changes in femoral bone mass. Treatment of osteoporosis shortly after liver transplantation may be important in the prevention of bone fractures, particularly in patients with low bone mass.

Bone mass and mineral metabolism in liver transplant patients treated with FK506 or cyclosporine A.

The purpose of this study was to compare the effects of Cyclosporine A (CyA) and FK506 on bone mass and mineral metabolism in liver transplantation (LT) patients. A prospective study was performed on 18 male patients who underwent LT treated with CyA, and 7 LT patients who received FK506. Bone mineral density (BMD) of the lumbar spine and proximal femur (DPX-L) was measured before and at 6, 12, and 24 months after transplantation. Moreover, intact parathyroid hormone (PTH) and 25-hydroxyvitamin D (25OHD) levels were determined at the same time. The cumulative dose of glucocorticoids was calculated in all patients. At 6 months, lumbar BMD decreased 5.2 +/- 1.2% (P = 0.0005) and 2.9 +/- 2.1% (p = ns) in CyA and FK506 groups, respectively. Lumbar BMD reached baseline values at 1 year in the FK506 group and 2 years after LT in the CyA group. Moreover, significant intergroup differences in femoral neck BMD changes after 2 years of transplant were observed (CyA: -5.2 +/- 1.97 versus FK506: +1.55 +/- 2.2%; P = 0.039). In the first year posttransplant both groups showed a marked increase in PTH and 25OHD levels. The mean cumulative dose of glucocorticoids was higher in the CyA group (CyA group 11.06 +/- 0.46 g versus FK 506 group 6.71 +/- 0.42 g; P < 0.001), and multiple linear regression analysis showed a negative correlation between BMD changes at the lumbar spine and mean cumulative dose of glucocorticoids (P = 0.022). In conclusion, our data suggest that after liver transplantation treatment with FK506 shows a more favorable long-term effect on bone mass evolution than CyA therapy. These differences seem to be associated with the lower dose of glucocorticoids used in the FK506 group.

The clinical significance of amyloid fat deposits in rheumatoid arthritis: a systematic long-term followup study using abdominal fat aspiration.

OBJECTIVE: To analyze the prevalence of subclinical amyloid fat deposits in patients with rheumatoid arthritis (RA) and to evaluate its clinical significance. METHODS: A cohort of 313 adult RA patients were included in this prospective observational study. Systematic abdominal subcutaneous fat aspiration (ASFA) was performed on all patients at study entry. The prevalence of visceral amyloidosis at study entry and at the end of followup was analyzed for patients with a positive ASFA test result. Followup ranged from 1 to 14 years (mean +/- SD 6.7 +/- 4.1 years). Patients with clinical and subclinical amyloidosis were compared with regard to clinical characteristics and the degree of amyloid deposits in abdominal fat. RESULTS: The first ASFA test found amyloid in the abdominal fat of 51 patients (16.3%), and subsequent ASFA tests found amyloid in the abdominal fat of 10 additional patients. At the time of the ASFA test, amyloidosis was subclinical in 45 of these 61 patients, 41 of whom were followed up. During followup, 11 of these 41 patients developed renal involvement, 5 due to amyloid nephropathy. Thus, amyloidosis remained subclinical in at least 30 of 41 patients (73%) throughout followup. Marked amyloid fat deposits were found more frequently in patients with clinical amyloidosis than in those whose amyloidosis remained subclinical at the end of followup (57% versus 22%; P = 0.04). CONCLUSION: Amyloid fat deposits are not uncommon in adult RA. In the majority of patients, the deposits do not indicate clinically evident organic dysfunction, even after several years of followup. Patients with more extensive fat deposits may have a higher risk of developing clinical amyloidosis.

[Chronic low back pain: multispecialty assessment of 100 patients]. / Dolor lumbar crónico. Valoración multidisciplinaria de 100 pacientes.

OBJECTIVES: Chronic lower-back pain (CLP) is a common pathology and has a high social and economic impact, especially in primary care where its treatment is changing at present. The results of the multi-disciplinary assessment of 100 patients with chronic lower-back pain are given. DESIGN: Cross-sectional, observational and prospective study. SETTING: Out-patient clinics of the rheumatology service of a tertiary-level hospital (referral from base districts where there is no primary care rheumatologist). PATIENTS: 100 consecutive patients seen for back pain lasting for more than 6 months were analysed. INTERVENTIONS: There was no therapeutic intervention. MEASUREMENTS AND MAIN RESULTS: The personal, work, clinical, examination, x-ray, functional and psychological features of 100 patients with CLP were analysed. There were 38 men and 62 women, with average age of 45 +/- 10 years and low social, cultural and job levels. Pain had lasted 82 +/- 7 months and 52% had had time off work. Mean intensity of pain was 6.5 +/- 2.3 (scale of zero to 10). There was vertebral restriction in 16%, and conduct expressing pain on examination in 47%. The x-ray showed disorder in 51%. Functional incapacity was nil or light in 46% and severe in 16%. 74.5% of the patients were depressed; 57% had features of anxiety; and 44% were anxious at the time of the interview. CONCLUSIONS: Patients with CLP are middle-aged, with long-standing pain and frequent time off work. Pain intensity is high, but vertebral restriction, disorders on x-rays and functional incapacity are scant. However, anxiety and depression levels are high. This could suggest a change in how we treat CLP towards a multi-disciplinary approach and psycho-affective, social and labour assessment, both at the time of assessment and in later treatment of patients.