Rising testicular cancer incidence in Spain despite declining mortality: an age-period-cohort analysis.

BACKGROUND: Testicular cancer, primarily affecting young men, has seen an alarming rise globally. This study delves into incidence and mortality trends in Spain from 1990 to 2019 using the Global Burden of Disease (GBD) database and the Age-Period-Cohort (A-P-C) model. METHODS: We analyzed GBD data on testicular cancer cases and deaths in Spain, calculating age-standardized rates (ASIR and ASMR) and employing Joinpoint regression to identify significant shifts. The A-P-C model further dissected the effects of age, period, and birth cohort on these trends. RESULTS: A striking doubling in testicular cancer incidence was observed, from 3.09 to 5.40 per 100,000 men (1.9% annual increase), while mortality rates remained stable and even decreased in younger age groups (0.34 to 0.26 per 100,000, 0.8% annual decrease). Joinpoint analysis revealed four distinct periods of increasing incidence, with a recent slowdown. The A-P-C model highlighted a consistent rise in incidence risk with each successive generation born after 1935, contrasting with a progressive decline in mortality risk across cohorts, particularly marked for those born since the 1960s. CONCLUSION: While mortality rates are encouraging, Spain reflects the global trend of escalating testicular cancer incidence. The A-P-C analysis suggests a generational influence, but the underlying causes remain elusive. Further research is crucial to understand these trends and implement effective prevention strategies to combat this growing health concern.

Disease risk estimates in V30M variant transthyretin amyloidosis (A-ATTRv) from Mallorca.

BACKGROUND: Variant transthyretin amyloidosis (A-ATTRv) is an autosomal dominant disease caused by a range of TTR gene variants which entail great phenotypical heterogeneity and penetrance. In Majorca, the A-ATTRv caused by the V30M gene variant (A-ATTRV30M) is the most common. Since asymptomatic carriers are at risk of developing the disease, estimating age of onset is vital for proper management and follow-up. Thus, the aim of this study was to estimate age-related penetrance in ATTRV30M variant carriers from Majorca. METHODS: The disease risk among carriers from ATTRV30M families from Majorca was estimated by Non-parametric survival estimation. Factors potentially involved in the disease expression, namely gender and parent of origin were also analysed. RESULTS: A total of 48 heterozygous ATTRV30M families (147 affected patients and 123 were asymptomatic carriers) were included in the analysis. Penetrance progressively increased from 6% at 30 years to 75% at 90 years of age. In contrast to other European populations, we observe a similar risk for both males and females, and no difference of risk according to the parent of origin. CONCLUSIONS: In this first study assessing the age-related penetrance of ATTRV30M variant in Majorcan families, no effect of gender or parent of origin was observed. These findings will be helpful for improving management and follow-up of TTR variant carrier individuals.

Mortality rates for Parkinson's disease are increasing in Spain. An age-period-cohort and joinpoint analysis of mortality rates from 1981 to 2020.

BACKGROUND: Mortality in Parkinson's disease is increasing worldwide, but Spanish data need further study. OBJECTIVE: To analyse the mortality trends of Parkinson's disease in Spain between 1981 and 2020. METHODS: This observational retrospective study assessed the Parkinson's disease mortality data from 1981 to 2020 collected from the National Statistics Institute of Spain. Age-standardised mortality rates were analysed by age and sex groups, detecting significant mortality trends through a joinpoint analysis. Age-period-cohort effect and potential years of life lost analyses were conducted. The European standard population of 2013 was considered for the analyses. RESULTS: A total of 88 034 deaths were assessed. The overall age-standardised mortality rate rose throughout the period from 3.67 to 8.57 per 100 000 inhabitants. Mortality rates in men were higher than in women, 11.63 versus 6.57 deaths per 100 000 inhabitants. The sex ratio showed an increase in premature mortality in men during 2020. The overall joinpoint analysis recorded a rise in mortality, primarily since the 20th century, mainly in male and older groups, that matched with a period effect. The age effect was detected, confirming higher mortality at an older age. The analysis of potential years of life lost detected a growth in this rate, changing from 0.66 in 1981 to 1.06 in 2020. CONCLUSIONS: Mortality data for Parkinson's disease in Spain rose significantly in forty years. Mortality rate was higher in the male and age group above 75 years of age. The sex ratio showed premature mortality in men in 2020, which will need further study.

Efficacy and safety of oral sirolimus for high-flow vascular malformations in real clinical practice.

BACKGROUND: Vascular malformations are a complex pathology with few treatment options. In previously published studies, oral sirolimus (rapamycin) has shown promising results in the treatment of low-flow vascular malformations, but its usefulness in high-flow vascular malformations is controversial. AIM: To evaluate the efficacy and safety of sirolimus for the treatment of high-flow vascular malformations in real-life practice. METHODS: In a unit specializing in vascular anomalies, patients treated with oral sirolimus for high-flow vascular malformations were located by consulting the drug dispensations. Reviewing the electronic medical records, data on patient demographics, vascular malformation characteristics, treatments, toxicity and clinical course were collected and statistically analysed. RESULTS: Nine patients with vascular malformations were included: eight had arteriovenous malformation and one had arteriovenous fistula. Six of these malformations were isolated while three were part of a syndrome. Sirolimus was initiated at a dosage of 1-4 mg/day to be taken as a single dose. Partial response was observed in eight of the nine patients (88.9%) with high-flow vascular malformation, while worsening was observed in the remaining patient. The treatment was well tolerated and at the most recent follow-up, five patients remained on treatment with oral sirolimus. CONCLUSION: Our results show that oral sirolimus is a well-tolerated therapeutic option, with an excellent safety profile, which can be useful in the long-term stabilization of patients with high-flow vascular malformations. Single-daily dosage may improve long-term adherence to treatment without worsening its effectiveness.

Low serum osteocalcin levels are associated with diabetes mellitus in glucocorticoid treated patients.

Bone turnover markers are decreased in GC-treated subjects with DM. Decreased OC levels in GC-treated patients were associated with an increased risk of DM. These results suggest the involvement of OC in glucose homeostasis regulation in DM. INTRODUCTION: Osteocalcin (OC) is involved in the regulation of glucose homeostasis. Glucocorticoid (GC) treatment is associated with impaired osteoblast function, decreased OC levels, and the development and/or worsening of pre-existing diabetes mellitus (DM). Whether decreased OC levels in GC-treated subjects contribute to DM is not well known. The aim of this study was to analyse whether OC levels in GC-treated patients are associated with the presence of DM. METHODS: One hundred twenty-seven patients (aged 61.5 ± 17.9 years) on GC treatment were included. GC dose, treatment duration, presence of DM and bone formation (OC, bone ALP, PINP) and resorption markers (urinary NTX, serum CTX) were analysed. The cut-offs of each bone turnover marker (BTM) for the presence of DM were evaluated and optimised with the Youden index and included in the logistic regression analysis. RESULTS: Among the patients, 17.3% presented DM. No differences were observed in GC dose or duration or the presence of fractures. Diabetics showed lower levels of OC (7.57 ± 1.01 vs. 11.56 ± 1; p < 0.001), PINP (21.48 ± 1.01 vs. 28.39 ± 1; p = 0.0048), NTX (24.91 ± 1.01 vs. 31.7 ± 1; p = 0.036) and CTX (0.2 ± 1.01 vs. 0.3 ± 1; p = 0.0016). The discriminating BTM cut-offs for DM presence were < 9.25 ng/mL for OC, < 24 ng/mL for PINP, < 27.5 nMol/mM for NTX and < 0.25 ng/mL for CTX. In a multivariate logistic regression model adjusted for GC dose, BMI, age and the above four BTMs, only OC remained independently associated with DM presence. Thus, in a model adjusted for GC dose, BMI and age, OC was significantly associated with DM (OR: 6.1; 95%CI 1.87-19.89; p = 0.001). CONCLUSION: Decreased OC levels in GC-treated patients are associated with increased odds of DM, and only OC was independently associated with DM in a model including four BTMs.

Estudio descriptivo sobre el perfil de los pacientes derivados a la Unidad de Tratamiento del Dolor Crónico del Hospital Universitario de Gran Canaria Dr. Negrín (utdc-hugcdn) como base para la reorganización de esta / Descriptive study on the profile of patients sent to the Chronic Pain Treatment Unit of the University Hospital of Gran Canaria Dr. Negrín (utdc-hugcdn) as a basis for the reorganization of this

Objetivo: Conocer las necesidades y fortalezas de nuestra Unidad derivadas del conocimiento del perfil de paciente que es remitido para la atención en la misma. Pacientes y métodos: Estudio descriptivo transversal sobre 5000 pacientes derivados a nuestra Unidad entre 2017 y 2020. Se recogieron de forma anónima los siguientes datos: número de pacientes remitidos por mes, edad, sexo, servicio remisor, localización del dolor, pacientes/interconsultas preferentes, rechazados y atendidos previamente. De los 1000 primeros pacientes también se registraron los antecedentes quirúrgicos, existencia o no de obesidad y consumo de fármacos psicoactivos. Resultados: Son derivados para valoración unos 1560 pacientes de media anuales (130 al mes), con una edad media de 59,8 años (± 14,3) de los cuales el 62,6 % son mujeres. Un 62,08 % se encontraba en edad laboral. Los servicios asistenciales que remitieron más pacientes fueron: Traumatología, Neurocirugía, Unidad de Raquis y Rehabilitación. El 6,6 % de las derivaciones fueron calificadas como preferentes. Fueron rechazadas el 9,98 % de las interconsultas. Los tipos de dolores según su localización más frecuentes fueron: lumbalgia, cervicalgia y dolores generalizados. Se constató la toma habitual de ansiolíticos y/o antidepresivos en un 34,9 %, el 10,8 % eran obesos y el 10,3 % sufrían dolor crónico postquirúrgico. Conclusiones: El perfil del paciente predominante derivado a nuestra unidad suele ser el de un adulto mayor, en edad laboral, de género femenino, derivado desde el servicio de Traumatología y con dolor en la región lumbar, perfil muy similar al descrito en otras unidades del dolor del mundo occidental desarrollado. Más de 1 de cada 3 pacientes puede sufrir ansiedad y/o depresión, siendo también muy frecuente el dolor postquirúrgico y la obesidad.(AU)

Objective: Determine the shortcomings and strengths of our pain clinic derived from the knowledge of the profile of the patients who are referred for care in the clinic. Patients and methods: Cross-sectional descriptive study on 5000 patients referred to our pain clinic between 2017 y 2020. The following data were collected: number of patients referred per month, age, sex, referring service, location of pain, patients referred preferentially, rejected patients, and previously attended consultations. Data on surgical history, obesity, and use of psychoactive drugs were also recorded for the first 1000 patients. Results: An average of 1560 patients were referred for evaluation per year (130 per month), with a mean age of 59.8 years (± 14.3) of which 62.6 % are women and 62.08 % were of working age. The healthcare services that referred the most patients were Orthopedic Surgery, Neurosurgery, Spine Unit and Rehabilitation. 6.6 % of the requests were derived preferentially. Of the referrals, 9.98 % were rejected. The most frequent pain locations were low back pain, neck pain and generalized pain. In the The usual taking of anxiolytics and / or antidepressants was found in 34.9 %, 10.8 % were diagnosed as obese and 10.3 % were referred for chronic postoperative pain. Conclusions: The profile of the predominant patient referred to our pain clinic is an older adult, of working age, female, referred from the orthopedics department and with pain in the lumbar region. This described profile is very similar to other pain units in the developed western world. Almost one in 3 patients may suffer from anxiety and / or depression, and post-surgical pain and obesity are also very common.(AU)

[Paraneoplastic and disimmune sensory neuronopathies or ganglionopathies. Importance of an early detection]. / Ganglionopatías o neuronopatías sensoriales paraneoplásicas y disinmunes. Importancia de una detección temprana.

INTRODUCTION: Sensory ganglionopathies or sensory neuronopathies are subacute acquired diseases of the dorsal root ganglion, frequently associated with disinmune, paraneoplastic and toxic agents. Patients present sensory alteration of asymmetric distribution and early ataxia. Early identification is essential, as they may announce an underlying neoplasia or autoimmune disease. AIM: To study asymmetries of the sensory nervous action potential (SNAP) of nerve pairs and the relationship amplitude of ulnar sensory/ulnar motor potential (USMAR) with serial electroneurophysiological studies for the early diagnosis of sensory ganglionopathies. PATIENTS AND METHODS: Six patients with sensory ganglionopathies were retrospectively studied with electroneurophysiological studies: four paraneoplastic cases with positivity for onconeuronal antibodies, one associated with Sjogren's syndrome and two idiopathic. RESULTS: Electroneurophysiological studies showed axonal sensory involvement in all cases, with asymmetry > 50% in SNAP amplitude in two pairs of nerves in four cases and normal motor with USMAR < 0.71 in five cases. Serial electroneurophysiological studies were essential in the diagnosis of two cases in the beginning of the disease with mild sensory symptoms. CONCLUSIONS: This work evidences the importance of the study of asymmetries in the amplitude of the SNAP of nerve pairs, the USMAR and the serial electroneurophysiological studies in the early diagnosis of sensory ganglionopathies, to further identification of the disinmune and onconeuronal associated antibodies with the nervous system affection to search for hidden neoplasia.

TITLE: Ganglionopatías o neuronopatías sensoriales paraneoplásicas y disinmunes. Importancia de una detección temprana.Introducción. Las ganglionopatías o neuronopatías sensoriales son enfermedades subagudas adquiridas del ganglio raquídeo dorsal, frecuentemente asociadas con trastornos disinmunes y paraneoplásicos, y agentes tóxicos. Los pacientes presentan alteración sensorial de distribución asimétrica y ataxia temprana. La identificación temprana es esencial, ya que pueden anunciar una neoplasia subyacente o una enfermedad autoinmune. Objetivo. Estudiar las asimetrías del potencial de acción nervioso sensitivo (SNAP) de pares de nervios y la relación de amplitud del potencial de acción sensitivomotor del nervio cubital (USMAR) con estudios electroneurofisiológicos seriados para el diagnóstico precoz de las ganglionopatías sensoriales. Pacientes y métodos. Se estudió retrospectivamente a siete pacientes con ganglionopatías sensoriales con estudios electroneurofisiológicos: cuatro casos paraneoplásicos con positividad para anticuerpos onconeuronales, uno asociado al síndrome de Sjögren y dos idiopáticos. Resultados. Los estudios electroneurofisiológicos mostraron afectación sensorial axonal en todos los casos, con asimetría mayor del 50% en la amplitud de SNAP en dos pares de nervios en cuatro casos y motor normal con USMAR menos de 0,71 en cinco casos. Los estudios electroneurofisiológicos seriados fueron esenciales en el diagnóstico de dos casos en el inicio de la enfermedad con síntomas sensoriales leves. Conclusiones. Este trabajo evidencia la importancia del estudio de asimetrías en la amplitud del SNAP de pares de nervios, la USMAR y los estudios electroneurofisiológicos seriados en el diagnóstico temprano de ganglionopatías sensoriales, para la consiguiente identificación de los anticuerpos disinmunes y onconeuronales con afectación del sistema nervioso periférico y la búsqueda de neoplasia oculta.

Renal tubular acidosis type IV as a complication of lupus nephritis.

Renal tubular acidosis (RTA) is a rare complication of renal involvement of systemic lupus erythematosus (SLE). We describe a 24-year-old male with type IV lupus nephropathy as a presenting manifestation of SLE. He presented with improvement of renal function following induction therapy with three pulses of methylprednisolone and 500 mg biweekly pulses of cyclophosphamide. However, a week after the first pulse of cyclophosphamide, the patient presented with a significant increase in legs edema and severe hyperkalemia. Type IV RTA associated with hyporeninemic hypoaldosteronism was suspected in the presence of metabolic acidosis with a normal anion gap, severe hyperkalemia without worsening renal function, and urinary pH of 5. RTA was confirmed with a transtubular potassium concentration gradient of 2 and low levels of plasma aldosterone, renin, angiotensin II, and cortisol. Intravenous bicarbonate, high-dose furosemide, and fludrocortisone were administered with normalization of potassium levels and renal function.

Small-vessel vasculitis with prominent IgG4 positive plasma cell infiltrates as potential part of the spectrum of IgG4-related disease: a case report.

IgG4-related disease (IgG4-RD) is a systemic entity characterised by multiorgan inflammatory lesions with abundant IgG4+ plasma cells, obliterative phlebitis, and storiform fibrosis. Involvement of several organs such as the pancreas, gastrointestinal tract, salivary glands, periorbital tissue and lymph nodes has been described. Up to now, vascular involvement by IgG4-RD has been thought to be essentially confined to large vessels. We present a patient with small-vessel systemic vasculitis involving muscle, peripheral nerve and kidney (glomerulonephritis) in the context of IgG4-RD diagnosed on the basis of elevated serum IgG4+ concentrations and histologically consistent signs in all biopsied tissues. Thoracic and abdominal aortic aneurysms in addition to aortitis, suggestive of large-vessel involvement, were also present. This observation expands the spectrum of vascular involvement in the context of IgG4-RD and supports the inclusion of IgG4-RD in the category of vasculitis associated with systemic disorder.

Review of Theoretical Prediction Models for Organic Extract Metabolites, Effect of Drying Temperature on Smooth Muscle Relaxing Activity Induced by Organic Extracts Specially Cecropia Obtusifolia Portal and Web Server Predictors of Drug-Protein Interaction.

Cecropia obtusifolia bertol is medicinal specie used in the treatment of diabetes mellitus and hypertension and it has scientific studies that support the traditional use. However, it is required to understand the influence of drying temperature on the yield and pharmacological activity. Drying rate, extraction efficiency, changes in the UV-Vis spectrum and estimating chlorophylls were stimulated with the increasing temperature. Finally, relaxant activity of vascular smooth muscle is increased by 70ºC and reducing ability by the method of CARF increases with temperature. Analytical studies are required to identify changes in the metabolic content and those that ensure the safety and efficacy for human consumption. In this sense, bioinformatic studies may be helpful. Studies such as QSAR can help us to study these metabolites derived from natural products. MIND-BETS model and NL MIND-BETS model to predict DPIs was introduced using MARCH-INSIDE (MI) software to calculate structural parameters for drugs and enzymes respectively. We firstly revised the state-of-art on the design with review of previous works with hypertension activity based on theoretical studies. A study, evaluating the effect of drying temperature of leaves of C. obtusifolia on the relaxing of vascular smooth muscle, antioxidant activity and the presence of chlorophylls, with a focus on Cecropia metabolites. Last, we carried out QSAR studies using MIND-BEST and NL MIND-BEST web servers in order to understand the essential metabolites structural requirement for binding with receptors for FDA proteins.

Epidemiological study of primary systemic vasculitides among adults in southern Spain and review of the main epidemiological studies.

OBJECTIVES: To study the incidence and prevalence of primary systemic vasculitides (PSV) in the Costa del Sol region (southern Spain) and to compare the major epidemiological studies in PSV with the results obtained in our area. METHODS: Retrospective study including permanent residents ≥14 years (or older) diagnosed with PSV at the Hospital Costa del Sol (Marbella, Spain) between 1994 and 2010. Epidemiological data were collected and the annual incidence rate during the study period and the prevalence in 2010 were calculated per million population, except for GCA, which was estimated per 100,000 population >50 years. RESULTS: Seventy-four adult patients were diagnosed with PSV, representing an annual incidence of 15.8 (95%CI 12.2-19.4) patients/million population. These diagnoses included 29 (39.1%) giant cell arteritis (GCA), 5 (6.7%) Takayasu's arteritis (TKA), 3 (4%) poly-arteritis nodosa (PAN), 29 (39.1%) antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) [10 (13.5%) granulomatosis with polyangiitis (GPA) (Wegener), 16 (21.6%) microscopic polyangiitis (MPA) and 3 (4%) eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss)], 7 (9.4%) IgA vasculitis (Henoch-Schönlein) (IgAV) and one (1.3%) cryobulinaemic vasculitis (CV). The annual incidence and 2010 prevalence for each of the PSV, respectively, were: GCA: 2.2/12.2; TKA: 1.1/10.5; PAN: 0.6/2.6; AAV: 6.2/44.8 (GPA: 2.1/15.8; MPA: 3.4/23.8; EGPA: 0.6/5.3); IgAV: 1.5/7.9; and CV: 0.2/0. CONCLUSIONS: The first epidemiological study of PSV in southern Spain corroborates their infrequency, with GCA and AAV as the PSV most often diagnosed. In southern Spain, the incidence and prevalence of PSV are lower than in northern Spain and in countries in the Northern Hemisphere.

Influence of the IL17A locus in giant cell arteritis susceptibility.

OBJECTIVE: Different lines of evidence have highlighted the role of IL-17A in the inflammatory process occurring in giant cell arteritis (GCA). The aim of the present study was to assess whether the IL17A locus influences GCA susceptibility and its clinical subphenotypes. METHODS: We carried out a large meta-analysis including a total of 1266 biopsy-proven GCA patients and 3779 healthy controls from four European populations (Spain, Italy, Germany and Norway). Five IL17A polymorphisms (rs4711998, rs8193036, rs3819024, rs2275913 and rs7747909) were selected by tagging and genotyped using TaqMan assays. Allelic combination and dependency tests were also performed. RESULTS: In the pooled analysis, two of the five analysed polymorphisms showed evidence of association with GCA (rs2275913: PMH=1.85E-03, OR=1.17 (1.06-1.29); rs7747909: PMH=8.49E-03, OR=1.15 (1.04-1.27)). A clear trend of association was also found for the rs4711998 variant (PMH=0.059, OR=1.11 (1.00-1.23)). An independent effect of rs2275913 and rs4711998 was evident by conditional regression analysis. In addition, the haplotype harbouring the risk alleles better explained the observed association than the polymorphisms independently (likelihood p value <10(-05)). CONCLUSIONS: Polymorphisms within the IL17A locus show a novel association with GCA. This finding supports the relevant role of the Th17 cells in this vasculitis pathophysiology.

Identification of the PTPN22 functional variant R620W as susceptibility genetic factor for giant cell arteritis.

OBJECTIVE: To analyse the role of the PTPN22 and CSK genes, previously associated with autoimmunity, in the predisposition and clinical phenotypes of giant cell arteritis (GCA). METHODS: Our study population was composed of 911 patients diagnosed with biopsy-proven GCA and 8136 unaffected controls from a Spanish discovery cohort and three additional independent replication cohorts from Germany, Norway and the UK. Two functional PTPN22 polymorphisms (rs2476601/R620W and rs33996649/R263Q) and two variants of the CSK gene (rs1378942 and rs34933034) were genotyped using predesigned TaqMan assays. RESULTS: The analysis of the discovery cohort provided evidence of association of PTPN22 rs2476601/R620W with GCA (PFDR=1.06E-04, OR=1.62, CI 95% 1.29 to 2.04). The association did not appear to follow a specific GCA subphenotype. No statistically significant differences between allele frequencies for the other PTPN22 and CSK genetic variants were evident either in the case/control or in stratified case analysis. To confirm the detected PTPN22 association, three replication cohorts were genotyped, and a consistent association between the PTPN22 rs2476601/R620W variant and GCA was evident in the overall meta-analysis (PMH=2.00E-06, OR=1.51, CI 95% 1.28 to 1.79). CONCLUSIONS: Our results suggest that the PTPN22 polymorphism rs2476601/R620W plays an important role in the genetic risk to GCA.

A case-control study suggests that the CCR6 locus is not involved in the susceptibility to giant cell arteritis.

OBJECTIVES: Polymorphisms of the CC chemokine receptor 6 (CCR6) gene have been recently reported to be associated with a number of autoimmune diseases. We aimed to investigate the possible influence of CCR6 rs3093024 gene variant in the susceptibility to and clinical expression of GCA. METHODS: The CCR6 polymorphism rs3093024 was genotyped in a total of 463 Spanish patients diagnosed with biopsy-proven GCA and 920 healthy controls using a TaqMan® allelic discrimination assay. PLINK software was used for the statistical analyses. RESULTS: No significant association between this CCR6 variant and GCA was observed (p=0.42, OR=0.94, CI95% 0.79-1.10). Similarly, when patients were stratified according to the specific clinical features of GCA such as polymyalgia rheumatica, visual ischaemic manifestations or irreversible occlusive disease, no statistical significant difference was detected either between the case subgroups and the control set or between GCA patients with and without the specific features of the disease. CONCLUSIONS: Our results suggest that the CCR6 rs3093024 polymorphism may not play a relevant role in the GCA pathophysiology.

Increased expression of the endothelin system in arterial lesions from patients with giant-cell arteritis: association between elevated plasma endothelin levels and the development of ischaemic events.

OBJECTIVE: Approximately 15-20% of patients with giant-cell arteritis (GCA) develop ischaemic complications often preceded by transient ischaemia. The expression of the endothelin (ET) system in GCA lesions was investigated to assess its relationship with the development of ischaemic complications. METHODS: Plasma ET-1 was quantified by immunoassay in 61 patients with biopsy-confirmed GCA and 16 healthy donors. ET-1, endothelin-converting enzyme (ECE-1) and endothelin receptor (ET(A)R and ET(B)R) messenger RNA were measured by real-time quantitative reverse transcriptase-PCR in temporal arteries from 35 of these patients and 19 control arteries. Proteins were measured by immunoassay and Western blot. RESULTS: ET-1 concentration was increased at the protein level in temporal artery samples from GCA patients compared with controls (0.98 (SEM 0.32) vs 0.28 (SEM 0.098) fmol/mg, p = 0.028). ECE-1, ET(A)R and ET(B)R/actin ratios (Western blot) were also significantly higher in GCA patients. Intriguingly, mRNA expression of ET-1, ECE-1 and both receptors was significantly reduced in GCA lesions compared with control arteries. When investigating mechanisms underlying these results, platelet-derived growth factor and IL-1beta, present in GCA lesions, were found to downregulate ET-1 mRNA in cultured human temporal artery-derived smooth muscle cells. Glucocorticoid treatment for 8 days did not result in significantly decreased endothelin tissue concentration (0.87 (SEM 0.2) vs 0.52 (SEM 0.08); p = 0.6). Plasma endothelin concentrations were higher in patients with ischaemic complications (1.049 (SEM 0.48) vs 1.205 (SEM 0.63) pg/ml, p = 0.032). CONCLUSIONS: The endothelin system is increased at the protein level in GCA lesions creating a microenvironment prone to the development of ischaemic complications. Recovery induced by glucocorticoids is delayed, indicating persistent exposure to endothelin during initial treatment.

Arteriovenous malformation of the brain mimicking primary central nervous system vasculitis.

In the diagnosis of primary central nervous system (CNS) vasculitis, it is crucial to rule out clinical, angiographic, and pathological mimics. We report a case of arteriovenous malformation (AVM) mimicking primary CNS vasculitis. A young male presented with intracerebral haemorrhage and no other clinical, laboratory, or angiographic features suggesting vasculitis. Cerebral biopsy showed perivascular inflammation and slight infiltration of the muscular layer of cerebral vessels by chronic inflammatory cells close to the haemorrhagic areas. These findings led to a diagnosis of CNS vasculitis. The patient was initially treated with corticosteroids, but 10 months after the discovery and surgical repair of the AVM, the patient is not receiving any immunosuppressant and has not developed any features of cerebral or systemic vasculitis.

Imatinib mesylate inhibits in vitro and ex vivo biological responses related to vascular occlusion in giant cell arteritis.

OBJECTIVES: Ischaemic complications occur in 15-20% of patients with giant cell arteritis (GCA). The aim of our study was to explore the effect of mesenchymal growth factors expressed in GCA lesions on myointimal cell responses related to the development of intimal hyperplasia and vessel occlusion. METHODS: We developed a method to obtain primary human temporal artery derived myointimal cells (HTAMCs) based on the culture of temporal artery sections on Matrigel. RESULTS: Among the factors tested (platelet-derived growth factor (PDGF)-AB, fibroblast growth factor (FGF)-2, vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), transforming growth factor (TGF)beta, chemokine (C-C motif) ligand (CCL)2, interleukin (IL)6 and IL1beta), PDGF exhibited the strongest activity in inducing HTAMC proliferation and migration. As assessed by protein array, immunoassay and quantitative real-time reverse transcriptase (RT)-PCR, PDGF stimulated matrix proteins (collagen I, collagen III and fibronectin) as well as CCL2 and angiogenin production by HTAMCs. Imatinib mesylate inhibited PDGF-mediated activation of signalling pathways (Src, extracellular signal-regulated kinase (ERK) and Akt phosphorylation) related to cell motility and survival, efficiently resulting in inhibition of PDGF-induced HTAMC responses. Myointimal cell outgrowth from cultured temporal artery sections from patients with GCA, where multiple interactions take place, was also efficiently reduced by imatinib. CONCLUSION: Among several mediators produced in GCA, PDGF has the highest vaso-occlusive potential. PDGF may also contribute to disease perpetuation by stimulating the production of angiogenic factors (angiogenin) and chemoattractants (CCL2). Imatinib mesylate strongly inhibits PDGF-mediated responses, suggesting a therapeutic potential to limit vascular occlusion and ischaemic complications in large vessel vasculitis.