AA-amyloidosis caused by visceral leishmaniasis in a human immunodeficiency virus-infected patient.

AA-amyloidosis in the setting of chronic visceral leishmaniasis (VL) has been reported in animal models but documentation in humans is unavailable. Here, we report on a Portuguese man who in 1996 was diagnosed with both human immunodeficiency virus (HIV)-infection and VL. Antiretroviral treatment led to sustained suppression of HIV viremia but CD4+ lymphocytes rose from 8 to only 160 cells/mL. Several courses of antimony treatment did not prevent VL relapses. Renal failure developed in 2006 and renal biopsy revealed AA-amyloidosis. The patient had cryoglobulinemia and serum immune complexes containing antibodies directed against seven leishmanial antigens. Antimony plus amphotericin B, followed by oral miltefosine resulted in a sustained VL treatment response with elimination of circulating Leishmania infantum DNA and CD4+ recovery. The concomitant reduction of serum AA levels and disappearance of circulating leishmanial immune complexes suggests that prolonged VL may lead to AA-amyloidosis in immunocompromised humans.

Association of mutations in the NALP3/CIAS1/PYPAF1 gene with a broad phenotype including recurrent fever, cold sensitivity, sensorineural deafness, and AA amyloidosis.

OBJECTIVE: Familial cold urticaria (FCU) and Muckle-Wells syndrome (MWS) are dominantly inherited autoinflammatory disorders that cause rashes, fever, arthralgia, and in some subjects, AA amyloidosis, and have been mapped to chromosome 1q44. Sensorineural deafness in MWS, and provocation of symptoms by cold in FCU, are distinctive features. This study was undertaken to characterize the genetic basis of FCU, MWS, and an overlapping disorder in French Canadian, British, and Indian families, respectively. METHODS: Mutations in the candidate gene NALP3, which has also been named CIAS1 and PYPAF1, were sought in the study families, in a British/Spanish patient with apparent sporadic MWS, and in matched population controls. Identified variants were sought in 50 European subjects with uncharacterized, apparently sporadic periodic fever syndromes, 48 subjects with rheumatoid arthritis (RA), and 19 subjects with juvenile idiopathic arthritis (JIA). RESULTS: Point mutations, encoding putative protein variants R262W and L307P, were present in all affected members of the Indian and French Canadian families, respectively, but not in controls. The R262W variant was also present in the subject with sporadic MWS. The V200M variant was present in all affected members of the British family with MWS, in 2 of the 50 subjects with uncharacterized periodic fevers, and in 1 of 130 Caucasian and 2 of 48 Indian healthy controls. No mutations were identified among the subjects with RA or JIA. CONCLUSION: These findings confirm that mutations in the NALP3/CIAS1/PYPAF1 gene are associated with FCU and MWS, and that disease severity and clinical features may differ substantially within and between families. Analysis of this gene will improve classification of patients with inherited or apparently sporadic periodic fever syndromes.

AA amyloidosis treated with tocilizumab: case series and updated literature review.

BACKGROUND: In published case reports, tocilizumab (TCZ) has shown good efficacy for AA amyloidosis in almost all patients. We investigated the efficacy and safety of TCZ in AA amyloidosis in a multicentre study of unselected cases. METHODS: We e-mailed rheumatology and internal medicine departments in France, Switzerland and North Africa by using the Club Rhumatismes Inflammation (CRI) network and the French TCZ registry, Registry RoAcTEmra (REGATE), to gather data on consecutive patients with histologically proven AA amyloidosis who had received at least one TCZ infusion. Efficacy was defined as a sustained decrease in proteinuria level and/or stable or improved glomerular filtration rate (GFR) and by TCZ maintenance. RESULTS: We collected 12 cases of AA amyloidosis treated with TCZ as monotherapy (mean age of patients 63 ± 16.2 years, amyloidosis duration 20.6 ± 31.3 months): eight patients had rheumatoid arthritis (RA), six with previous failure of anti-tumor necrosis factor α (anti-TNF-α) therapy. In total, 11 patients had renal involvement, with two already on hemodialysis (not included in the renal efficacy assessment). For the nine other patients, baseline GFR and proteinuria level were 53.6 ± 32.8 mL/min and 5 ± 3.3 g/24 h, respectively. The mean follow-up was 13.1 ± 11 months. TCZ was effective for six of the eight RA patients (87.5%) according to European League Against Rheumatism response criteria (four good and two moderate responders). As expected, C-reactive protein (CRP) level decreased with treatment for 11 patients. Renal amyloidosis (n = 9) progressed in three patients and was stabilized in three. Overall, three patients showed improvement, with sustained decrease in proteinuria level (42%, 82% and 96%). Baseline CRP level was higher in subsequent responders to TCZ than other patients (p = 0.02). Among the six RA patients with previous anti-TNF-α therapy, amyloidosis was ameliorated in one and stabilized in three. Three serious adverse events occurred (two diverticulitis and one major calciphylaxia due to renal failure). Finally, 7 of 12 (58%) patients continued TCZ. CONCLUSIONS: The efficacy of TCZ for AA amyloidosis varies depending on the inflammatory status at treatment onset. Discrepancies between our study of unselected consecutive patients and reported cases may be due to publication bias. These results support further prospective trials of TCZ for AA amyloidosis.

Secondary amyloidosis: a severe complication of ankylosing spondylitis. Two case-reports.

STUDY OBJECTIVE: To report two cases of amyloidosis secondary to ankylosing spondylitis. PATIENTS AND RESULTS: Of the 47 ankylosing spondylitis patients who have received follow-up at our department over the last few years, two have developed AA amyloidosis. Both have extremely severe, long-standing joint disease, with virtually complete spinal ankylosis and destructive peripheral arthritis of the hips and wrists; one also has tarsal joint destruction. Renal dysfunction was the first manifestation of amyloidosis in both cases. One patient required chronic hemodialysis and developed peritonitis due to colonic perforation, probably at a site of amyloid deposition. CONCLUSIONS: Secondary amyloidosis is a rare complication of ankylosing spondylitis that can cause severe renal and gastrointestinal complications. No treatment capable of clearing established amyloid deposits is available to date.

Evidence-based recommendations for genetic diagnosis of familial Mediterranean fever.

Familial Mediterranean fever (FMF) is a disease of early onset which can lead to significant morbidity. In 2012, Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) was launched with the aim of optimising and disseminating diagnostic and management regimens for children and young adults with rheumatic diseases. The objective was to establish recommendations for FMF focusing on provision of diagnostic tools for inexperienced clinicians particularly regarding interpretation of MEFV mutations. Evidence-based recommendations were developed using the European League against Rheumatism standard operating procedure. An expert committee of paediatric rheumatologists defined search terms for the systematic literature review. Two independent experts scored articles for validity and level of evidence. Recommendations derived from the literature were evaluated by an online survey and statements with less than 80% agreement were reformulated. Subsequently, all recommendations were discussed at a consensus meeting using the nominal group technique and were accepted if more than 80% agreement was reached. The literature search yielded 3386 articles, of which 25 were considered relevant and scored for validity and level of evidence. In total, 17 articles were scored valid and used to formulate the recommendations. Eight recommendations were accepted with 100% agreement after the consensus meeting. Topics covered were clinical versus genetic diagnosis of FMF, genotype-phenotype correlation, genotype-age at onset correlation, silent carriers and risk of amyloid A (AA) amyloidosis, and role of the specialist in FMF diagnosis. The SHARE initiative provides recommendations for diagnosing FMF aimed at facilitating improved and uniform care throughout Europe.

Hereditary Autoinflammatory Syndromes: A Brazilian Multicenter Study

To evaluate the prevalence of genetic defects in clinically suspected autoinflammatory syndromes (AIS) in a Brazilian multicenter study. The study included 102 patients with a clinical diagnosis of Cryopyrin Associated Periodic Syndromes (CAPS), TNF Receptor Associated Periodic Syndrome (TRAPS), Familial Mediterranean Fever (FMF), Mevalonate Kinase Deficiency (MKD) and Pediatric Granulomatous Arthritis (PGA). One of the five AIS-related genes (NLRP3, TNFRSF1A, MEFV, MVK and NOD2) was evaluated in each patient by direct DNA sequencing, based on the most probable clinical suspect. Clinical diagnoses of the 102 patients were: CAPS (n = 28), TRAPS (n = 31), FMF (n = 17), MKD (n = 17) and PGA (n = 9). Of them, 27/102 (26 %) had a confirmed genetic diagnosis: 6/28 (21 %) CAPS patients, 7/31 (23 %) TRAPS, 3/17 (18 %) FMF, 3/17 (18 %) MKD and 8/9 (89 %) PGA. We have found that approximately one third of the Brazilian patients with a clinical suspicion of AIS have a confirmed genetic diagnosis.

Amyloïdose rénale [Renal amyloidosis].

Amyloidosis is defined as the extracellular deposition of proteins that have the capacity to form beta-pleated sheets and become insoluble. More than 17 types of amyloidosis have been described. Systemic light chain amyloid (AL) and AA amyloid (secondary to chronic inflammatory process) are by far the most frequent forms of amyloidosis. In these systemic forms, organs involved are the kidneys, the heart and the gastrointestinal tract in AL amyloidosis. The diagnostic can be established only by tissue biopsy. Treatment of primary amyloidosis (AL) aims at suppressing the responsible clone whereas treatment of secondary amyloidosis relies on controlling the underlying inflammatory process. Prognosis is globally poor and depends on the extend of organs involvement particularly cardiac and renal. The prognosis is even worse in patients requiring dialysis.

Atraumatic splenic rupture in amyloidosis

BACKGROUND: Splenic involvement in amyloidosis is rather frequent (5-10%). An atraumatic rupture of the affected spleen is however an extremely rare event. We report on a patient with undiagnosed amyloidosis who underwent emergency splenectomy for atraumatic splenic rupture. METHODS: Review of the literature and identification of 31 patients, including our own case report, with atraumatic splenic rupture in amyloidosis. Analysis of the clinical presentation, the surgical management, the nomenclature and definition of predisposing factors of splenic rupture. RESULTS: We identified 15 women and 16 men (mean age 53.3 +/- 12.4 years; median 52, range: 27-82 years) with an atraumatic splenic rupture. Easy skin bruisability and factor X deficiency were detected in four (13%) and five patients (16%), respectively. The diagnosis of splenic rupture was made either by computed tomography (n = 12), ultrasound (n = 5), exploratory laparotomy (n = 9) or autopsy (n = 4). All patients underwent surgery (n = 27) or autopsy (n = 4). Amyloidosis was previously diagnosed in nine patients (29%). In the remaining 22 patients (71%), the atraumatic splenic rupture represented the initial manifestation of amyloidosis. Twenty-five patients (81%) suffered from primary (AL) and four patients (13%) from secondary amyloidosis (AA). In two patients, the type of amyloidosis was not specified. A moderate splenomegaly was a common feature (68%) and the characteristic intraoperative finding was an extended subcapsular hematoma with a limited parenchymal laceration (65%). In five patients with known amyloidosis, the atraumatic splenic rupture was closely associated with autologous stem-cell transplantation (ASCT) (16%). Three patients were suffering from multiple myeloma (10%). A biopsy-proven amyloidotic liver involvement was present in 14 patients (45%), which lead to atraumatic liver rupture in two patients. The splenic rupture related 30-day mortality was 26% (8/31). CONCLUSIONS: Atraumatic splenic rupture in amyloidosis is associated with a high 30-day mortality. It occurs predominantly in patients with previously undiagnosed amyloidosis. A moderate splenomegaly, coagulation abnormalities (easy skin bruisability, factor X deficiency) and treatment of amyloidosis with ASCT are considered predisposing factors for an atraumatic splenic rupture.

Characterization of serum amyloid A protein mRNA expression and secondary amyloidosis in the domestic duck

Secondary amyloidosis is a common disease of water fowl and is characterized by the deposition of extracellular fibrils of amyloid A (AA) protein in the liver and certain other organs. Neither the normal role of serum amyloid A (SAA), a major acute phase response protein, nor the causes of secondary amyloidosis are well understood. To investigate a possible genetic contribution to disease susceptibility, we cloned and sequenced SAA cDNA derived from livers of domestic ducks. This revealed that the three C-terminal amino acids of SAA are removed during conversion to insoluble AA fibrils. Analysis of SAA cDNA sequences from several animals identified a distinct genetic dimorphism that may be relevant to susceptibility to secondary amyloid disease. The duck genome contained a single copy of the SAA gene that was expressed in liver and lung tissue of ducklings, even in the absence of induction of acute phase response. Genetic analysis of heterozygotes indicated that only one SAA allele is expressed in livers of adult birds. Immunofluorescence staining of livers from adult ducks displaying early symptoms of amyloidosis revealed what appear to be amyloid deposits within hepatocytes that are expressing unusually high amounts of SAA protein. This observation suggests that intracellular deposition of AA may represent an early event during development of secondary amyloidosis in older birds.

Investigation of the corrosion behaviour of AA 2024-T3 in low concentrated chloride media

Aluminium alloy (AA) 2024-T3 is an important engineering material due to its widespread use in the aerospace industry. However, it is very prone to localized corrosion attack in chloride containing media, which has been mainly associated to the presence of coarse intermetallics (IMs) in its microstructure. In this work the corrosion behaviour of AA 2024-T3 in low concentrated chloride media was investigated using microscopy and electrochemical methods. TEM/EDS observations on non-corroded samples evidenced the heterogeneous composition within the IMs. In addition, SEM observations showed that intermetallics with the same nominal composition present different reactivity, and that both types of coarse IMs normally found in the alloy microstructure are prone to corrosion. Moreover, EDS analyses showed important compositional changes in corroded IMs, evidencing a selective dissolution of their more active constituents, and the onset of an intense oxygen peak, irrespective to the IM nature, indicating the formation of corrosion products. On the other hand, the results of the electrochemical investigations, in accordance with the SEM/EDS observations, evidenced that IMs corrosion dominates the electrochemical response of the alloy during the first hours of immersion in the test electrolyte. (c) 2008 Elsevier Ltd. All rights reserved.

Superior oblique muscle amyloidosis mimicking myositis

A 47-year-old man presented with complaints of progressive diplopia in downgaze and a painful firm mass on the left medial superior canthus. On examination, there was marked hyperemia of the superior bulbar conjunctiva of the left eye. Systemic examination revealed erythematous papules on his trunk and pulmonary infiltrates. CT of the orbits revealed a fusiform enlargement of the left superior oblique muscle and diffuse infiltration of the left temporal region. Biopsy of the left superior oblique muscle and temporal muscle disclosed Congo red deposits that show apple-green birefringence under polarized light. A comprehensive systemic investigation failed to show any disease that could explain the amyloid deposits. The patient was then diagnosed as having primary systemic amyloidosis. We think that this case highlights the necessity of a biopsy in any atypical extraocular muscle enlargement before a diagnosis of myositis.

Iogurte simbiótico de açaí (Euterpe edulis Mart.): caracterização físico-química e viabilidade de bactérias láticas e probióticas

Os iogurtes simbióticos, que combinam microrganismos probióticos e substâncias prebióticas, adicionados de polpa de frutas são uma tendência crescente no mercado. O fruto açaí (Euterpe edulis) se destaca pela presença de compostos bioativos, como as antocianinas. Neste contexto, o presente trabalho teve como objetivo caracterizar e avaliar os parâmetros físico-químicos e a viabilidade microbiológica de iogurte simbiótico de açaí enriquecido com inulina e adicionado de cultura probiótica de Bifidobacterium animallis subsp. lactis BB-12. As formulações de iogurte atenderam aos requisitos físico-químicos exigidos pela IN no 46/2007 do MAPA apresentando teor de cinzas de 0,86 % ± 0,10, extrato seco total de 23,18 % ± 2,59, teor de gordura de 4,16 % ± 0,31, acidez de 0,70 % ± 0,05 e pH de 4,45 ± 0,10. Entre as formulações o conteúdo fenólico total variou de 18,17 a 117,84 mg de AGE/100 g, teor de antocianinas de 1,92 a 47,88 mg/100 g e atividade antioxidante de 0,71 a 6,95 μmol Trolox/g, observando-se um aumento de acordo com o aumento do teor de polpa de açaí adicionada. Ao final de 28 dias de armazenamento a 5 °C, observou-se uma redução no teor de antocianinas e da atividade antioxidante. Verificou-se a contribuição positiva da polpa de açaí na viabilidade das bactérias láticas totais, cujas contagens variaram de 4,56 a 7,04 log UFC.g-1 e de B. lactis BB-12 que variou de 3,17 a 6,34 log UFC.g-1, favorecendo a multiplicação dessas bactérias nos iogurtes. Nas formulações com 20 e 25 % de polpa de açaí as contagens das bactérias láticas totais e probiótica mantiveram-se viáveis de acordo com a IN no 46/2007 do MAPA e a Lista de Alegação de Propriedade Funcional (Anvisa), durante os 28 dias de armazenamento a 5 oC. Concluiu-se que a adição de polpa de açaí E. edulis, inulina e B. lactis BB-12 foi tecnologicamente viável na elaboração de iogurte simbiótico de açaí, sendo uma excelente alternativa de diversificação do produto no mercado.

A dinâmica do mercado de açaí fruto no Estado do Pará: de 1994 a 2009

O objetivo deste trabalho foi analisar a dinâmica do mercado de açaí fruto no Estado do Pará, no período de 1994 a 2009, mediante a estimação simultânea da demanda e da oferta, pelo Método de Momentos Generalizados (MMG). Os resultados mostraram que a demanda e a oferta são inelásticas a preço. A elasticidade cruzada indicou que as outras frutas comercializadas no mercado paraense são substitutas do açaí. A elasticidade renda, com valor igual a 2,36, revelou que o açaí está enquadrado na categoria de bens de luxo. A elasticidade custo mostrou que o salário rural é fator de forte influência na redução da oferta do açaí, porque o sistema de produção é fortemente dependente de mão de obra. Por fim, a elasticidade de ajustamento mostrou que a produção de açaí de um ano exerce significativa influência no ajuste da oferta da safra do ano seguinte.