Search

Although repeatedly reported in the literature, the extracranial involvement by giant-cell arteritis has been considered anecdotal until recent years. The emergence of new or improved imaging techniques along with a closer follow-up of these patients and their increase in life expectancy are beginning to underline that the clinical impact of extracranial involvement by GCA may be more relevant than previously thought. This review focuses on the extent of vascular involvement in GCA as reported by pathology and imaging studies as well as the clinical consequences of imperfect vascular remodelling in various vascular territories.

Objective: We report our experience using rapamycin in patients with Wegener's granulomatosis (WG) who failed to achieve remission with conventional treatment., Methods: Eight patients received rapamycin for severe, refractory WG. Clinical outcomes were reviewed retrospectively., Results: Four patients treated with rapamycin sustained remissions of at least 6 months' duration while receiving prednisone

Barrel formation is delayed in nutritionally restricted rats. The underlying cause of such delay is yet unclear. Because barrels appear upon the arrival of somatosensory thalamo-cortical afferents and the reorientation of the dendritic arborizations of cortical spiny stellate neurons, it is likely that at least one of these processes is altered by nutritional restriction. Also, the serotoninergic afferent system has been implicated in regulating barrel segregation and growth during early postnatal life. We then evaluated the pattern of immunostaining of the serotonin transporter (SERT) and of the serotonin receptor 1B (5-HT(1B)), as well as the growth and arrival time of somatosensory thalamo-cortical afferents, to infer the contribution of these elements in the delayed formation of barrels observed in nutritionally restricted rats. It was found that the rates of development and the segregation of thalamo-cortical fibers were normal in nutritionally restricted rats. SERT, but not 5-HT(1B) immunoreactivity, was decreased in the primary somatosensory cortex during barrel specification. The availability of both proteins in nutritionally restricted rats was lower than that observed in their well fed counterparts at later developmental times. It is concluded that the delayed formation of barrels observed in nutritionally restricted rats is due to a retarded reorientation of dendritic arbors of cortical neurons. This might happen as a secondary effect of decreasing the availability of SERT and/or increasing the availability of 5-HT(1B) receptor early in postnatal life.

Objective: Giant cell arteritis (GCA) may involve the aorta. Retrospective studies have demonstrated a higher prevalence of aortic aneurysm among patients with GCA compared with the general population. We investigated the prevalence of aortic aneurysm in a cohort of patients with biopsy-proven GCA using a defined protocol and assessed whether persisting low-grade disease activity is associated with higher risk of developing aortic aneurysm., Methods: Fifty-four patients with GCA (14 men and 40 women) were cross-sectionally evaluated after a median followup of 5.4 years (range 4.0-10.5 years). The screening protocol included a chest radiograph, abdominal ultrasonography scan, and computed tomography scan when aortic aneurysm was suspected or changes with respect to the baseline chest radiograph were observed. Clinical and laboratory data, corticosteroid requirements, and relapses were prospectively recorded., Results: Twelve patients (22.2%) had significant aortic structural damage (aneurysm/dilatation), 5 of them candidates for surgical repair. Aortic aneurysm/dilatation was more frequent among men (50%) than women (12.5%; relative risk 3.5, 95% confidence interval 1.53-8.01, P = 0.007). At the time of screening, patients with aneurysm/dilatation had lower serum acute-phase reactants, lower relapse rate, and needed shorter periods to withdraw prednisone than patients without aortic structural damage., Conclusion: There is a substantial risk of developing aortic aneurysm/dilatation among patients with GCA. Our data do not support that aneurysm formation mainly results from persistent detectable disease activity. Additional factors including characteristics of the initial injury or the target tissue may also determine susceptibility to aortic aneurysm/dilatation.

Purpose of Review: To provide a critical analysis of a rare disorder, single-organ vasculitis, emphasizing those organs in which the excision of the vasculitic lesion can be curative. To recommend a rational approach to diagnosis, longitudinal follow-up and treatment., Recent Findings: Patients with focal single-organ vasculitis affecting abdominal and genitourinary organs, breast and aorta have been reported as individual cases and small series. Single-organ vasculitis differs from systemic forms of vasculitis in disease expression and prognosis. Occasionally, what appears to be a localized process evolves into a systemic disease. Depending on the organ affected, some clinical, serological and histopathologic features may be helpful in predicting the extent of the vasculitic process. With the exception of severe ischemic or hemorrhagic complications affecting the abdominal organs and dissection or rupture of the aortic arch, the prognosis of focal single-organ vasculitis tends to be excellent. Resection of the inflammatory lesion may be curative., Summary: The diagnosis of focal single-organ vasculitis is always presumptive and requires exclusion of systemic illness at the time of diagnosis as well as throughout the period of continued care. Clues from clinical symptoms, laboratory tests and histopathologic features at the time of diagnosis may assist in devising surveillance strategies.

Objectives: Gelatinases (MMP2 and MMP9) are expressed in giant-cell arteritis (GCA) and are thought to play a role in vessel disruption. However, their activation status and enzymatic activity have not been evaluated. Our aim was to investigate the distribution and proteolytic activity of gelatinases in GCA lesions at different stages., Methods: Expression of MMP2, MMP9, MMP2-activator MMP14 and their natural inhibitors TIMP1 and TIMP2 was determined by real-time PCR and immunohistochemistry in temporal artery sections from 46 patients and 12 controls. MMP activation status and enzymatic activity were assessed by gelatin and film in situ zymography., Results: Vascular smooth muscle cells from normal specimens constitutively expressed pro-MMP2 and its inhibitor TIMP2 with no resulting proteolytic activity. In GCA MMP2, MMP9 and MMP14 were strongly expressed in their active form by infiltrating leucocytes. Inflamed arteries also expressed TIMP1 and TIMP2. However, the MMP9/TIMP1 and MMP2/TIMP2 ratios were higher in patients compared with controls, indicating an increased proteolytic balance in GCA which was confirmed by in situ zymography. Maximal gelatinase expression and activity occurred at the granulomatous areas surrounding the internal elastic lamina (IEL). Myointimal cells also expressed MMPs and exhibited proteolytic activity, suggesting a role for gelatinases in vascular remodelling and repair., Conclusions: GCA lesions show intense expression of gelatinases. Activators and inhibitors are regulated to yield enhanced gelatinase activation and proteolytic activity. Distribution of expression and proteolytic activity suggests that gelatinases have a major role not only in the progression of inflammatory infiltrates and vessel destruction but also in vessel repair.

Clinicians who treat patients with giant cell arteritis (GCA) face many unresolved challenges. Visual loss still occurs in 15% to 20% of patients despite the availability of therapy for the disease that is generally effective. Aneurysm formation and large vessel stenosis are increasingly recognized complications. Substantial iatrogenic morbidity stems from glucocorticoid therapy, and recent trials have failed to identify an efficient steroid sparing agent. In this review, the authors address five major clinical conundrums in the management of GCA.

Background and Objective: The PROCES (Programa de Reanimació Cardiopulmonar Orientat a Centres d'Ensenyament Secundari) program is aimed at teaching basic cardiopulmonary resuscitation (b-CPR) to teenagers within high school. Our aim was to analyze the results obtained from the pilot program., Subjects and Method: PROCES was splitted in 7 sessions: 5 of them (5 hours) were taught by teachers at high school and 2 of them (4 hours, including how to perform b-CPR) were taught by emergency physicians. To assess the degree of students' learning, they were administered a 20-question test before and after the program. Epidemiological characteristics and students' opinions (all them were requested to rate the program from 0 to 10) were also collected., Results: Students were 14 years-old in 38%, 15 in 38% and 16 or more in 24%. Before PROCES, the mean mark (over 20 points) was 8.5 (2.4). After PROCES, marks improved up to 13.5 (3.2) (p < 0.001). Participants who had previously taken a first-aid course or were in the 4th course obtained significantly better marks than the rest. These differences disappeared after PROCES completion. Students rated the theoretical part as 7.9 (1.1), the skill part as 8.2 (1.2), and the emergency physicians classes as 8.4 (1.1)., Conclusions: PROCES is an useful tool for teaching and improving teenagers' knowledge and skills in b-CPR, with no exceptions associated with teenagers' characteristics.

Vascular inflammation in giant cell arteritis is generally described as a process involving dendritic cells, T-lymphocytes, and effector tissue macrophages. Less is known about the contribution of phagocytes that are recruited early, such as monocytes and neutrophils. These cells express and secrete pro-inflammatory S100 proteins which directly activate endothelial cells. In this study the expression of S100A8/S100A9 and S100A12, pro-inflammatory proteins specific for early recruited phagocytes, was studied in biopsies from 36 patients with giant cell arteritis. In addition, serum concentrations of these proteins were analysed in serum samples from 42 patients and 35 healthy controls. The S100A8/S100A9 complex was found to be abundant in the adventitia and media in affected arteries. Besides neutrophils, cells expressing these proteins belonged to a pro-inflammatory subtype of CD68-positive monocytes. In contrast, S100A12 expression was restricted to neutrophils that were found around the vasa vasorum within the adventitial layer. Both S100A8/S100A9 and S100A12 serum concentrations were significantly higher in patients with giant cell arteritis than in healthy controls. In conclusion, recently recruited phagocytes expressing pro-inflammatory S100 proteins take part in the vascular inflammation of giant cell arteritis. They may play important roles at the vasa vasorum of affected vessels, which represent sites of entry for recruited inflammatory cells. These data indicate that phagocytes within the adventitia and media contribute to the process of inflammation via release of the pro-inflammatory S100 proteins S100A8, S100A9, and S100A12., (Copyright (c) 2004 Pathological Society of Great Britain and Ireland.)

Endothelial cells play a pivotal role in the pathogenesis of systemic vasculitis. Endothelial cells have significant proinflammatory activities, amplifying and perpetuating the inflammatory process and contributing to vessel regeneration and repair. Significant contributions have improved the understanding of additional ways through which antineutrophil cytoplasmic antibodies (ANCA) may potentiate neutrophil- and monocyte-mediated endothelial cell activation and damage. Signaling pathways mediating ANCA effects have been delineated, and new animal models have demonstrated the pathogenic role of ANCA in the development of systemic vasculitis. Significant efforts have identified anti-endothelial cell antibody specificities and elucidated mechanisms through which these antibodies may promote endothelial cell activation and injury. New ways to assess in vivo endothelial cell damage and dysfunction also have been developed. In addition, besides being a relevant compensatory mechanism for ischemia, angiogenesis may have important proinflammatory functions in vasculitis. The potential relevance of bone-marrow-derived endothelial cell precursors in neovascularization has begun to be appreciated.

Background and Objective: Emergency department (ED) overcrowding has been increasing over the last years. The aims are to define ED overcrowding, and to determine and quantify which factors explain it., Patients and Method: For 3 consecutive weeks throughout 3 years (2000-2002), we recorded every 3-hour period, the arrivals, the occupancy rate (OR) of patients in ED, in first aid area (FAA), and in observation area (OA) according to the reason for their stay. The data was subjected to multiple logistic regression analysis including as a dependent variable non overcrowding/overcrowding for each area (ED, FAA, and OA). Overcrowding was defined as an OR >= 100%. Models from the three areas were calculated according to goodness of fit and were discriminated by ROC methodology. Models were set up after randomizing data in two groups: selection set (88% of data) and validation set (12% of data)., Results: Variables associated with overcrowding in the ED model were OR of patients waiting for test results, for a bed going to be left, to find a bed, for test performed out of ED, and for outcome. In the FAA model, they were OR of patients being seen, and waiting for test results. Finally, in the OA model they were OR of patients waiting for a bed going to be left, to find a bed, for test performed out of ED, and for outcome. For all models sensitivity and specificity were greater than 85%, with a ROC area greater than 0.97. We did not find any relationship between number of arrivals and overcrowding for none model. Results were corroborated on the validation data set., Conclusions: Patients remaining in the ED due to factors related to both hospital (waiting for a bed going to be left, or to find a bed), and ED itself (waiting for outcome) are the main reason for ED overcrowding.

Background: Vascular inflammatory lesions from patients with giant-cell arteritis show a remarkable amount of neovascularization, but its clinical implications have never been investigated., Methods and Results: To assess the clinical relevance of neovascularization in giant-cell arteritis, angiogenesis was measured in temporal artery sections from 31 patients with biopsy-proven giant-cell arteritis by staining endothelial cells with Ulex europaeus lectin. Angiogenesis was highly variable among these patients. Patients without ischemic complications had higher tissue angiogenesis scores than patients with ischemic events (5.69+/-0.6 versus 2.91+/-0.6, P=0.003). Angiogenesis was also more prominent in patients with a strong acute phase response (score: 5.31+/-0.6) compared with those with a weak systemic inflammatory reaction (2.30+/-0.44; P=0.0007). Serum angiogenic activity was studied in an additional series of 38 biopsy-proven patients. Sera from patients without ischemic events tended to be more active in stimulating human umbilical vein endothelial cell growth (optical density x1000, 270+/-15 versus 192+/-14, P=0.065) and differentiation into capillary-like structures (107+/-5 versus 84+/-8 relative units, P=0.0058) than patients with ischemic complications. Sera from patients without ischemic events had more in vivo full angiogenic activity tested in the chick chorioallantoic membrane than sera from patients with ischemic complications., Conclusion: Inflammation-induced angiogenic activity may play a compensatory role for ischemia in patients with giant-cell arteritis.

Objective: To assess whether the intensity of the initial systemic inflammatory response is able to predict response to therapy in patients with giant cell arteritis (GCA)., Methods: Retrospective review of 75 patients (49 women and 26 men) with biopsy-proven GCA who had regular followup and were treated according to uniform criteria. Four parameters were used to evaluate the baseline inflammatory response at diagnosis: fever, weight loss, erythrocyte sedimentation rate > or = 85 mm/hour, and hemoglobin < 110 gm/liter. Patients were considered to have a weak inflammatory response if they had 2 or fewer inflammatory parameters (group 1) and a strong inflammatory response if 3 or 4 parameters were present (group 2). Time required to achieve a maintenance dose of less than 10 mg prednisone/day was recorded and analyzed by the Kaplan-Meier survival analysis method. Tumor necrosis factor alpha (TNFalpha) and interleukin 6 (IL-6) serum levels were also determined in 62 patients and 15 controls., Results: Forty patients had a weak (group 1) and 35 had a strong (group 2) initial inflammatory response. Patients in group 2 had significantly higher levels of circulating TNFalpha (31.9 +/- 16.8 versus 22.3 +/- 9 pg/ml; P = 0.01) and IL-6 (28.2 +/- 17.4 versus 16.6 +/- 13 pg/ml; P = 0.004) than patients in group 1. In group 1, 50% of patients required a median of 40 weeks (95% CI 37-43) to reach a maintenance dose of <10 mg, whereas in group 2 a median of 62 weeks (95% CI 42-82) was necessary (P = 0.0062). Patients in group 2 experienced more flares than patients in group 1 (P = 0.01) and received higher cumulative steroid doses (8.974 +/- 3.939 gm versus 6.893 +/- 3.075 gm; P = 0.01)., Conclusion: GCA patients with a strong initial systemic inflammatory reaction have more elevated circulating levels of IL-6 and TNFalpha, have higher and more prolonged corticosteroid requirements, and experience more disease flares during corticosteroid therapy than patients with a weak systemic acute phase response.

Objective: Occasionally, a temporal artery biopsy reveals small-vessel vasculitis (SVV) surrounding a spared temporal artery, the significance of which is unclear. We analyzed the final diagnosis in a series of patients with this condition and tried to identify histopathologic features with potential usefulness in predicting the ultimate diagnosis., Methods: We performed a clinical and histopathologic review of 28 patients in whom SVV surrounding a spared temporal artery was the first histologic finding that led to the diagnosis of vasculitis. For comparison purposes, we analyzed the pattern of small vessel involvement in 30 patients with biopsy-proven giant cell arteritis (GCA)., Results: GCA was considered the most likely diagnosis in 12 patients, based on the absence of clinical evidence of additional organ involvement and normal findings on muscle biopsy and electrophysiologic study. Three patients had systemic necrotizing vasculitis (SNV), based on the demonstration of typical lesions on subsequent muscle, nerve, or kidney biopsy. After extensive evaluation, 4 patients remained unclassifiable. Nine patients were incompletely studied. Fibrinoid necrosis was significantly more frequent in patients with SNV (P = 0.0022), whereas involvement of vasa vasorum was more frequent in patients classified as having GCA (P = 0.022). No differences in the pattern of small vessel involvement were found in patients with SVV surrounding a spared temporal artery who were classified as having GCA compared with patients with biopsy-proven GCA. Granulocytes were observed at similar frequency in all conditions., Conclusion: SVV may be the only abnormal feature in a temporal artery biopsy and the only histologic evidence of vasculitis. The diagnosis of GCA can be reasonably established in most of these patients when there is no apparent evidence of additional organ involvement. However, when fibrinoid necrosis is observed or the temporal artery vasa vasorum are not involved, SNV must be extensively excluded.

Objective: To investigate the expression pattern of adhesion molecules involved in leukocyte-endothelial cell interactions in giant cell arteritis (GCA)., Methods: Immunohistochemical analysis was performed on frozen temporal artery sections from 32 patients with biopsy-proven GCA and from 12 control patients with other diseases. Adhesion molecules identified were intercellular adhesion molecule 1 (ICAM-1), ICAM-2, ICAM-3, vascular cell adhesion molecule 1 (VCAM-1), platelet endothelial cell adhesion molecule 1 (PECAM-1), E-selectin, P-selectin, L-selectin, lymphocyte function-associated antigen 1 (LFA-1), very late activation antigen 4 (VLA-4), Mac-1 (CD18/CD11b), and gp 150,95 (CD18/CD11c). Clinical and biochemical parameters of inflammation in the patients, as well as the duration of previous corticosteroid treatment, were prospectively recorded., Results: Constitutive (PECAM-1, ICAM-1, ICAM-2, and P-selectin) and inducible (E-selectin and VCAM-1) endothelial adhesion molecules for leukocytes were mainly expressed by adventitial microvessels and neovessels within inflammatory infiltrates. Concurrent analysis of leukocyte receptors indicated a preferential use of VLA-4/VCAM-1 and LFA-1/ICAM-1 at the adventitia and Mac-1/ICAM-1 at the intima-media junction. The intensity of inducible endothelial adhesion molecule expression (E-selectin and VCAM-1) correlated with the intensity of the systemic inflammatory response. Previous corticosteroid treatment reduced, but did not completely abrogate, the expression of the inducible endothelial adhesion molecules E-selectin and VCAM-1., Conclusion: Inflammation-induced angiogenesis is the main site of leukocyte-endothelial cell interactions leading to the development of inflammatory infiltrates in GCA. The distribution of leukocyte-endothelial cell ligand pairs suggests a heterogeneity in leukocyte-endothelial cell interactions used by different functional cell subsets at distinct areas of the temporal artery.

The purpose of the present study was the characterization of the receptors participating in the regulatory mechanism of glial Na+/K+-ATPase by serotonin (5-HT) in rat brain. The activity of the Na+ pump was measured in four brain regions after incubation with various concentrations of serotoninergic agonists or antagonists. A concentration-dependent increase in enzyme activity was observed with the 5-HT1A agonist R (+)-2-dipropylamino-8-hydroxy-1,2,3, 4-tetrahydronaphthalene hydrobromide (8-OH-DPAT) in homogenates or in glial membrane enriched fractions from cerebral cortex and in hippocampus. Spiperone, a 5-HT1A antagonist, completely inhibited the response to 8-OH-DPAT but had no effect on Na+/K+-ATPase activity in cerebellum where LSD, a 5-HT6 agonist, elicited a dose-dependent response similar to that of 5-HT. In brainstem, a lack of response to 5-HT and other agonists was confirmed. Altogether, these results show that serotonin modulates glial Na+/K+-ATPase activity in the brain, apparently not through only one type of 5-HT receptor. It seems that the receptor system involved is different according to the brain region. In cerebral cortex, the response seems to be mediated by 5-HT1A as well as in hippocampus but not in cerebellum where 5-HT6 appears as the receptor system involved.

The discovery of the strong association between hepatitis C virus (HCV) infection and the development of mixed cryoglobulinemia has motivated active testing of antiviral-directed alternative therapies. Several trials have demonstrated that classic cryoglobulinemia-associated manifestations improve with interferon-alpha (IFNalpha) treatment. Herein we report on 3 HCV-infected patients with severe cryoglobulinemia-related ischemic manifestations who were closely followed up during IFNalpha therapy. Clinical evaluations with special attention to ischemic lesions, liver function tests, and cryocrit determinations were serially performed. In addition to prednisone and immunosuppressive agents, the patients received IFNalpha at 3 x 10(6) units, 3 times per week for 2 months, 3 months, and 4 months, respectively. In all 3 patients, systemic features improved, liver function results returned to normal, and cryocrit values decreased. However, ischemic lesions became less vascularized and ischemia progressed, leading to transmetatarsal and subcondylar amputation, respectively, in 2 of the patients and fingertip necrosis and ulcer enlargement in the third. Skin biopsies performed before IFNalpha therapy and after 2 months of IFNalpha therapy in the third patient showed a significant decrease in subepidermal microvessels. When IFNalpha was discontinued, the lesions finally healed. Cryoglobulinemia-related ischemic lesions may worsen during IFNalpha treatment, presumably through a decrease in inflammation-induced angiogenesis. The anti-angiogenic activity of IFNalpha may delay the appropriate healing of ischemic lesions.

Currently serotonin (5-HT) is recognized as one of the classic neurotransmitters in the adult brain. Results from our laboratory have suggested a trophic role of 5-HT in the fetal brain. Stimulation of 5-HT synthesis during gestation with its precursor, L-tryptophan, has shown the existence of biosynthetic machinery for this amine in the fetal brain. Attempts to demonstrate directly a molecular recognizing system for 5-Ht in the fetal brain have not been conclusive until now. We have profited of a special preparation of axonal growth cones (AGC) derived from neuroblasts of the rat fetal brain. In this neuronal structures actively differentiating we were able to demonstrate a high-affinity and saturable uptake system for 5-HT and the possibility of a regulated release of the amine. In postnatal AGC the 5-Ht uptake has similar kinetics to the adult, whereas fetal AGC have a transitional uptake kinetics with a higher Vmax for the amine. Also in these structures we demonstrated, directly, for the first time, a specific binding system for (3H) 5-HT, saturable, reversible and of high affinity. Altogether, these results strongly support the hypothesis of an important trophic role of 5-HT during neurogenesis.

Previous results in from our laboratory have shown that early malnutrition causes an increase in brain serotonin (5-HT) synthesis. In the present work, male rats were submitted to proteinic-caloric malnutrition during gestation, lactation or both. A significant increase in 5-HT concentration was confirmed in the cerebral cortex and in the hypothalamus. In the macronutrients selection behavior test an important reduction in carbohydrates consumption was noted. Acute experiments in which an increase of the brain neurotransmitter was also induced, support the chronic ones, with a significant decrease in the carbohydrates intake. Altogether, these results suggest that the increase of the brain neurotransmitter during development has a functional role because there is a positive correlation with the modification of feeding behavior.

The effect of prenatal L-tryptophan supplementation on the serotonin (5-HT) synthesis and the activity of Na+,K+-ATPase in the cerebral cortex was studied during postnatal development, from birth up to day 30. A parallel and significant elevation of the serotonin content and the activity of tryptophan-5-hydroxylase was observed in the brain of infant rats born to mothers treated with L-tryptophan, as related to non-treated controls. The activity of Na+,K+-ATPase was also significantly elevated at the different ages studied throughout the developmental period, as related to controls. These results suggest an important role of L-tryptophan in the early regulation of the serotonin-synthesizing machinery, which lasts postnatally. Elevation of ATPase activity seems to be associated to the elevation in the activity of the 5-HT system.