Osteoprotegerin/RANKL system imbalance in active polyarticularonset juvenile idiopathic arthritis: a bone damage biomarker?

Objective: To evaluate the importance of receptor activator of nuclear factor kappa B (RANK)/receptor activator of nuclear factor kappa B ligand (RANKL)/osteoprotegerin (OPG) modulation in active polyarticular juvenile idiopathic arthritis (pJIA) patients with and without bone erosions. Methods: Thirty female patients (mean age 11.07 +/- 3.77 years, range 4-17 years) with active pJIA and 30 healthy gender-and age-matched controls were consecutively selected for this study. All involved articulations were assessed by X-ray and examined for the presence of bone erosions. The serum levels of RANKL and OPG were measured using an enzyme-linked immunosorbent assay (ELISA). Results: Patients with active pJIA had higher levels of serum RANKL than controls [2.90 (0.1-37.4) vs. 0.25 (0.1-5.7) pg/mL, p=0.007] and a lower OPG/RANKL ratio [21.25 (1.8-897.6) vs. 347.5 (9-947.8), p=0.005]. However, levels of OPG were comparable in both groups [55.24 (28.34-89.76) vs. 64.42 (30.68-111.28) pg/mL, p=0.255]. Higher levels of serum RANKL and a lower OPG/RANKL ratio were also observed in active pJIA patients with bone erosions compared to controls [3.49 (0.1-37.4) vs. 0.25 (0.1-5.7) pg/mL, p=0.0115 and 14.3 (1.8-897.6) vs. 347.5 (9-947.8), p=0.016]. However, RANKL levels and OPG/RANKL ratio were similar in pJIA patients without bone erosion and controls [1.75 (0.1-10.9) vs. 0.25 (0.1-5.7) pg/mL, p=0.055 and 29.2 (3.3-756.8) vs. 347.5 (9-947.8), p=0.281]. Conclusion: These data suggest that active pJIA with bone erosions is associated with high serum levels of RANKL and a low OPG/RANKL ratio, indicating that these alterations may reflect bone damage in this disease.

Clues for Previously Undiagnosed Connective Tissue Disease in Patients With Trigeminal Neuralgia

Background: Connective tissue diseases (CTD) may be associated with idiopathic trigeminal neuralgia (TN). The prevalence and diagnostic implications of this association are, however, not well established. Objectives: The objective of this study was to evaluate, in TN patients, if rheumatologic clinical and laboratory findings could contribute to the early diagnosis of rheumatic diseases. Methods: Forty-six consecutive TN patients, 67% female, mean disease duration 8.78 +/- 7.25 years, and 47 controls were initially interviewed using a standard questionnaire based on common signs/symptoms of systemic lupus erythematosus, Sjogren syndrome, mixed CTD, and systemic sclerosis. Autoantibodies were detected by standard techniques. Those with rheumatologic complaints or positive autoantibodies were referred to the Rheumatology Outpatient Clinic for a more detailed evaluation. Secondary causes of TN were excluded. Results: The frequency of Raynaud phenomenon (P = 0.026) and ANA reactivity (P = 0.04) were significantly higher in TN patients compared with controls. Fourteen TN patients were ANA positive. Seven of them reported concomitant rheumatic complaints, and interestingly, diffuse CTD was diagnosed in 4 (57%) of these patients: 1 systemic lupus erythematosus; 2 Sjogren syndrome; and 1 undifferentiated disease with scleritis and positive parotid scintigraphy. In all cases, TN preceded by at least 10 months the rheumatologic signs/symptoms. Moreover, these 4 TN patients with CTD had a higher frequency of sicca symptoms (P = 0.001) and higher titers of ANA (>= 1:320) (P = 0.006) than the remaining 42 TN patients without CTD diagnoses. Sixteen patients had isolated laboratory or clinical abnormalities, and none of them had CTD diagnoses. Conclusions: The concomitant presence of sicca symptoms and high titer ANA are clues for the early investigation of rheumatic diseases in TN patients.

Survival in Patients With Idiopathic, Familial, and Anorexigen-Associated Pulmonary Arterial Hypertension in the Modern Management Era

Background-Novel therapies have recently become available for pulmonary arterial hypertension. We conducted a study to characterize mortality in a multicenter prospective cohort of patients diagnosed with idiopathic, familial, or anorexigen-associated pulmonary arterial hypertension in the modern management era. Methods and Results-Between October 2002 and October 2003, 354 consecutive adult patients with idiopathic, familial, or anorexigen-associated pulmonary arterial hypertension (56 incident and 298 prevalent cases) were prospectively enrolled. Patients were followed up for 3 years, and survival rates were analyzed. For incident cases, estimated survival (95% confidence intervals [CIs]) at 1, 2, and 3 years was 85.7% (95% CI, 76.5 to 94.9), 69.6% (95% CI, 57.6 to 81.6), and 54.9% (95% CI, 41.8 to 68.0), respectively. In a combined analysis population (incident patients and prevalent patients diagnosed within 3 years before study entry; n = 190), 1-, 2-, and 3-year survival estimates were 82.9% (95% CI, 72.4 to 95.0), 67.1% (95% CI, 57.1 to 78.8), and 58.2% (95% CI, 49.0 to 69.3), respectively. Individual survival analysis identified the following as significantly and positively associated with survival: female gender, New York Heart Association functional class I/II, greater 6-minute walk distance, lower right atrial pressure, and higher cardiac output. Multivariable analysis showed that being female, having a greater 6-minute walk distance, and exhibiting higher cardiac output were jointly significantly associated with improved survival. Conclusions-In the modern management era, idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension remains a progressive, fatal disease. Mortality is most closely associated with male gender, right ventricular hemodynamic function, and exercise limitation. (Circulation. 2010; 122: 156-163.)

Muscle sympathetic nerve activity in patients with Chagas` disease

Background: The progression of heart failure in Chagas` disease has been explained by remodeling, leading to neurohumoral activation, or by the direct parasite damage to parasympathetic neurons during acute phase, leading to early sympathetic activation and progressive heart failure. To help distinguish between these hypotheses we studied muscle sympathetic nerve activity (MSNA) at rest and during handgrip exercise (30% of maximal voluntary contraction) in patients with Chagas` disease and normal ejection fraction vs. patients with heart failure. Methods: A consecutive study of 72 eligible out-patients/subjects was conducted between July 1998 and November 2004. The participants were classified in three advanced heart failure groups (New York Heart Association Functional Classes II-III): Chagas` disease (n-15), ischemic (n=15) and idiopathic cardiomyopathy (n-15). Twelve Chagas` disease patients without heart failure and normal ejection fraction, and 15 normal controls were also studied. MSNA was recorded directly from the peroneal nerve by microneurography technique. Results: MSNA was greater in heart failure patients when compared with Chagas` disease patients without heart failure (51 +/- 3 vs. 20 +/- 2 bursts/min P=0.0001). MSNA in Chagas` patients with normal ejection fraction and normal controls was not different. During exercise, MSNA was similar in all 3 heart failure groups. And, was lower in the Chagas` patients with normal ejection fraction than in patients with Chagas` disease and heart failure (28 +/- 1 vs. 63 +/- 5 bursts/min, respectively). Conclusion: MSNA is not elevated in patients with Chagas` disease with normal ejection fraction. These findings support the concept of remodeling and neurohumoral activation as a common pathway following significant cardiac injury. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

Effects of proportional assisted ventilation on exercise performance in idiopathic pulmonary fibrosis patients

Background: Patients with idiopathic pulmonary fibrosis (IPF) present an important ventilatory (imitation reducing their exercise capacity. Non-invasive ventilatory support has been shown to improve exercise capacity in patients with obstructive diseases; however, its effect on IPF patients remains unknown. Objective: The present study assessed the effect of ventilatory support using proportional, assist ventilation (PAV) on exercise capacity in patients with IPF. Methods: Ten patients (61.2 +/- 9.2 year-old) were submitted to a cardiopulmonary exercise testing, plethysmography and three submaximal. exercise tests (60% of maximum load): without ventilatory support, with continuous positive airway pressure (CPAP) and PAV. Submaximal tests were performed randomly and exercise capacity, cardiovascular and ventilatory response as well as breathlessness subjective perception were evaluated. Lactate plasmatic levels were obtained before and after submaximal. exercise. Results: Our data show that patients presented a limited exercise capacity (9.7 +/- 3.8 mL O(2)/kg/min). Submaximal. test was increased in patients with PAV compared with CPAP and without ventilatory support (respectively, 11.1 +/- 8.8 min, 5.6 +/- 4.7 and 4.5 +/- 3.8 min; p < 0.05). An improved arterial oxygenation and lower subjective perception to effort was also observed in patients with IPF when exercise was performed with PAV (p < 0.05). IPF patients performing submaximal exercise with PAV also presented a lower heart rate during exercise, although systolic and diastolic pressures were not different among submaximal tests. Our results suggest that PAV can increase exercise tolerance and decrease dyspnoea and cardiac effort in patients with idiopathic pulmonary fibrosis. (C) 2009 Elsevier Ltd. All rights reserved.

Increased circulating pro-inflammatory cytokines and imbalanced regulatory T-cell cytokines production in chronic idiopathic urticaria

The immunologic characterization of chronic idiopathic urticaria (CIU), mainly regarding cytokine profile needs more investigation. We examined circulating inflammatory cytokine levels, T-cell induced secretion, and cytokine mRNA expression in patients with CIU subjected to the intradermal autologous serum skin test (ASST). Increased levels of circulating pro-inflammatory cytokines, such as TNF-alpha, IL-1 beta, IL-12p70, and IL-6 have been observed in most of patients with CIU, together with an enhancement of IL-2 secretion following T-cell stimulation. Highlighting the inflammatory profile in CIU found in ASST positive, is the enhanced B-cell proliferative responsiveness and increased IL-17 secretion levels. ASST-positive patients also exhibited impaired IL-4 secretion associated with increased IL-10 production. Altered cytokine expression in patients with ASST-negative, was the down-modulation of spontaneous IL-10 mRNA expression levels in peripheral blood mononuclear cells. Our findings support the concept of immunologic dysregulation in CIU, revealing a systemic inflammatory profile associated with disturbed cytokine production by T cells, mainly related to IL-17 and IL-10 production. (c) 2008 Elsevier B.V. All rights reserved.

Immunophenotyping and remodeling process in small airways of idiopathic interstitial pneumonias: functional and prognostic significance

Background and Aims: To test whether different degrees of immunologic and fibrotic airway remodeling processes occur in idiopathic interstitial pneumonias (IIPs), with impact on functional tests and survival, we studied the collagen/elastic system and immune cell density in the bronchiolar interstitium of lungs with the major types of IIPs. Materials and Methods: Histochemistry, immunohistochemistry and morphometric analysis were used to evaluate collagen/elastic fibers and immune cells in the bronchiolar interstitium of open lung biopsies of patients with cryptogenic organizing pneumonia [COP/organizing pneumonia (OP) = 10], acute interstitial pneumonia [AIP/diffuse alveolar damage (DAD) = 20], nonspecific interstitial pneumonia (NSIP/NSIP = 20) and idiopathic pulmonary fibrosis/usual interstitial pneumonia (UIP) = 20. Results: OP lungs presented a significant increase in collagenous/elastic fibers and in the total density of immune cells in the bronchiolar interstitium compared to controls, DAD, NSIP and UIP. We observed a significant increase in CD4, CD8 and CD20 lymphocytes, as well as in neutrophils, macrophages and plasma cells in OP. The increased amount of elastic fibers in the bronchiolar interstitium from OP lungs has a direct association with forced vital capacity (FVC) (r(s) = 0.99, P = 0.03). The most important survival predictor was CD20+ lymphocytes in the bronchiolar interstitium. In decreasing order, patients with UIP [Odds Ratio (OR) = 35.01], high forced expiratory volume in 1 s (FEV1)/FVC FVC (OR = 7.01), increased CD20+ lymphocytes (OR = 4.44) and collagenous/elastic fiber densities (OR = 2.03 and OR = 1.49, respectively) in the bronchiolar interstitium were those who had the greatest risk of death, followed by those with AIP, NSIP and COP. Conclusion: Different degrees of immunologic and fibroelastotic airway remodeling processes occur in the major types of IIPs with impact on physiological tests and survival.

Arterial and interstitial remodelling processes in non-specific interstitial pneumonia: systemic sclerosis versus idiopathic

Aims: To compare septal and vascular matrix remodelling, vascular occlusion, Pulmonary function tests and survival between two groups: one with idiopathic non-specific interstitial pneumonia (NSIP) and one with NSIP associated with systemic sclerosis (SSc). Methods and results: Pulmonary biopsy specimens were examined from 40 patients, 22 with NSIP and 18 with NSIP associated with SSc. The content of septal collagen and elastic fibres, as well as the elastic fibres in the vascular interstitium, were higher in the SSc group (P = 0.01, P = 0.001 and P < 0.0001, respectively). Among pulmonary function tests. the diffusing capacity for carbon monoxide/alveolar volume was affected to a greater extent in the SSc group (59%) of the predicted value in SSc and 97% in the idiopathic group). There were no differences in collagen content of the vascular interstitium, arterial occlusion, or survival between the two groups. Conclusions: Although the fibrotic process is more intense in the SSc group. it, does not affect the prognosis of these patients. Because the elastotic process is higher in the SSc group, this might suggest that autoimmune inflammatory mechanisms affecting the elastic fibre system play a greater role in the pathogenesis and pulmonary remodelling process of SSc NSIP than in idiopathic NSIP.

Small Airway Remodeling in Idiopathic Interstitial Pneumonias: A Pathological Study

Background: Few studies have addressed small airway (SA) histopathological changes and their possible role in the remodeling process in idiopathic interstitial pneumonias. Objectives: To study morphological, morphometrical and immunohistochemical features of SA in idiopathic pulmonary fibrosis (usual interstitial pneumonia, UIP) and nonspecific interstitial pneumonia (NSIP). Methods: We analyzed SA pathology in lung biopsies from 29 patients with UIP and 8 with NSIP. Biopsies were compared with lung tissue from 13 patients with constrictive bronchiolitis (CB) as positive controls and 10 normal autopsied control lungs. We semi-quantitatively analyzed SA structure, inflammation, architectural features and the bronchiolar epithelial immunohistochemical expression of TGF-beta, MMP-2, 7, 9, and their tissue inhibitors (TIMP-1, 2). Results: Compared to controls, patients with UIP, NSIP and CB presented increased bronchiolar inflammation, peribronchiolar inflammation and fibrosis and decreased luminal areas. UIP patients had thicker walls due to an increase in most airway compartments. NSIP patients presented increased epithelial areas, whereas patients with CB had larger inner wall areas. All of the groups studied presented increased bronchiolar expression of MMP-7 and MMP-9, compared to the controls. Conclusion: We conclude that SAs are pathologically altered and may take part in the lung-remodeling process in idiopathic interstitial pneumonias. Copyright (C) 2009 S. Karger AG, Basel

Decreased recent thymus emigrant number in rheumatoid factor-negative polyarticular juvenile idiopathic arthritis

Objectives To determine TCR excision circle (TREC) levels, a marker of recent thymic emigrants, in the peripheral lymphocyte pool of rheumatoid factor-negative (RF circle divide) polyarticular juvenile idiopathic arthritis (JIA) children. Materials and methods We studied TREC levels in peripheral blood mononuclear cells (PBMC) in 30 RF circle divide polyarticular JIA children with active disease and in 30 age- and gender-matched healthy controls. Signal-joint TREC concentration was determined by real-time quantitative-PCR as the number of TREC copies/mu g PBMC DNA gauged by a standard curve with known number of TREC-containing plasmids. Results TREC levels in PBMC were significantly lower in JIA (4.90 +/- 3.86 x 10(4) TRECs/mu g DNA) as compared to controls (10.45 +/- 8.45 x 10(4) TRECs/mu g DNA, p=0.001). There was an inverse correlation between age and TREC levels in healthy children (r=-0.438, p=0.016) but not in JIA. No clinical association was observed between TREC levels and disease activity and use of oral steroids and methotrexate. Conclusions The finding of decreased PBMC TREC levels in RF circle divide polyarticular JIA children is consistent with a low proportion of recent thymus emigrants. This may interfere with the equilibrium between populations of polyclonal and naive T cells versus oligoclonal memory auto-reactive T cells and, therefore, may hinder the maintenance of immune tolerance in this disease.

Severe Psychosocial Compromise in Idiopathic Trigeminal Neuralgia: Case Report

Objective. This article describes a 60-year-old man with 17 years of idiopathic trigeminal neuralgia (ITN) which affected tooth brushing for 6 years, causing severe dental complications and psychosocial problems. Methods. Case report. Results. Following ITN diagnosis, this patient underwent neurosurgery (microcompression of the trigeminal ganglion with a balloon) with immediate relief, but after three months, pain recurred and was accompanied by dysesthesia and periodontal disease. After dental treatment, he had complete alleviation of pain and no further need of medication over the following 3 years. The intense suffering of this patient represents the importance of a multidisciplinary evaluation for pain-caused secondary complications. Conclusion. ITN is a simple diagnosis but may have complex course. Appropriately trained health professionals are necessary to evaluate and treat these patients.

Diffuse plane idiopathic normolipemic xanthoma with hiperesplenism

Diffuse plane normolipemic xanthoma is a rare disease, of a group of clinical syndromes called histiocytoses, characterized by the presence of yellowish or yellow-orange plaques, distributed symmetrically on the cutaneous surface and usually accompanied by xanthelasma. It affects mainly adults and it may cause discrete changes in serum lipids. The case of an 85-year-old female patient who has been showing extensive asymptomatic yellow-orange plaques in the trunk and abdomen for a year is reported. Laboratory tests did not show an increase in serum lipids or the occurrence of reticuloendothelial disorders.

Final height of adults with childhood-onset steroid-responsive idiopathic nephrotic syndrome

The aim of this study was to evaluate the final stature of adults with childhood-onset steroid-responsive idiopathic nephrotic syndrome (INS) and the influence of disease-related issues on the achievement of their target heights. We analyzed 60 (41 male) patients and/or their records, with a minimum age of 19 years or at a Tanner`s pubertal stage 4 for boys or status postmenarche for girls, and normal glomerular filtration rate. Mean age at first and last consultation was 5.3 +/- 2.4 years and 20.5 +/- 3.1 years, respectively. Mean follow-up period was 15.10 years. Mean cumulative dose of prednisone was 1254 +/- 831.40 mg/kg. Mean initial and final height Z scores (HtZ) were, respectively, -0.60 +/- 1.0 and -0.64 +/- 0.92 (p = 0.72). The final HtZ showed a significant correlation only with the initial HtZ and the target HtZ (THZ). Six patients achieved a final HtZ below -2, which in male patients correlated strongly to the initial HtZ and THZ. A strong correlation was demonstrated between final HtZ, initial HtZ, and THZ. INS-related issues did not prevent the final stature to reach the predicted target height.

Impaired IFN-alpha secretion by plasmacytoid dendritic cells induced by TLR9 activation in chronic idiopathic urticaria

P>Background The evolution and therapeutic outcome of American tegumentary leishmaniasis (ATL) depend upon many factors, including the balance between Th1 and Th2 cytokines to control parasite multiplication and lesion extension. Other cytokines known for their role in inflammatory processes such as interleukin IL-17 or IL-18 as well as factors controlling keratinocyte differentiation and the inflammatory process in the skin, like the Notch system, could also be involved in the disease outcome. Notch receptors are a group of transmembrane proteins that regulate cell fate decisions during development and adulthood in many tissues, including keratinocyte differentiation and T-cell lineage commitment, depending on their activation by specific groups of ligands (Delta-like or Jagged). Objectives To compare the in situ expression of Notch system proteins (receptors, ligands and transcriptional factors) and cytokines possibly involved in the disease outcome (IL-17, IL-18, IL-23 and transforming growth factor-beta) in ATL cutaneous and mucosal lesions, according to the response to therapy with N-methyl glucamine. Methods Cutaneous and mucosal biopsies obtained from patients prior to therapy with N-methyl glucamine were analysed by immunohistochemistry and real-time polymerase chain reaction. Results Notch receptors and Delta-like ligands were found increased in patients with ATL, particularly those with poor response to therapy or with mucosal lesions. Conclusions The increase of Notch receptors and Delta-like ligands in patients with a poor response to treatment suggests that these patients would require a more aggressive therapeutic approach or at least a more thorough and rigorous follow-up.

Oral and pharyngeal transit of a paste bolus in Chagas` disease

We measured the oral and pharyngeal transit of a paste bolus in 20 patients with Chagas` disease and 21 controls. Each subject swallowed of a 10-ml paste bolus prepared with 50 ml of water and 4.5 g of instant food thickener labeled with 55.5 MBq of 99(m) technetium phytate. After the scintigraphic recording of the transit, we delineated regions of interest (ROI) corresponding to mouth, pharynx, and proximal esophagus. Time-activity curves were generated for each ROI. There was no difference between patients with Chagas` disease and controls with respect to the duration of oral and pharyngeal transit, amount of pharyngeal residue, or flux of bolus entry into the proximal esophagus. The amount of oral residue was higher in patients with Chagas` disease (median = 0.71 ml) than in controls (median = 0.45 ml). The pharyngeal clearance duration was longer in patients with Chagas` disease (median = 0.85 s) than in controls (median = 0.60 s). The oral transit duration of the patients with Chagas` disease and dysphagia (median = 0.55 s, n = 14) was shorter than the oral transit duration of chagasic patients without dysphagia (median = 0.80 s, n = 6). We conclude that when swallowing a paste bolus, patients with Chagas` disease may have an increased amount of oral residue and a longer pharyngeal clearance duration than asymptomatic volunteers.