Clinical characteristics and SAP scintigraphic findings in 10 patients with AGel amyloidosis.

The clinical features of hereditary gelsolin (AGel) amyloidosis include corneal lattice dystrophy, distal sensorimotor, cranial neuropathy and cutis laxa. To date, four mutations of the gelsolin (GSN) gene encoding the following variants have been identified as the cause of this malady; p.D214N, p.

AA amyloidosis complicating the hereditary periodic fever syndromes.

Objective: AA amyloidosis is a life-threatening complication of the hereditary periodic fever syndromes (HPFS), which are otherwise often compatible with normal life expectancy. This study was undertaken to determine the characteristics, presentation, natural history, and response to treatment in 46 patients who had been referred for evaluation at the UK National Amyloidosis Centre.

Methods: Disease activity was monitored by serial measurement of serum amyloid A.

Phenotype, genotype, and sustained response to anakinra in 22 patients with autoinflammatory disease associated with CIAS-1/NALP3 mutations.

Objective: To characterize the multisystem chronic inflammatory phenotype, dermatopathologic features, and response to therapy with interleukin 1 receptor antagonist (anakinra) in patients with mutations in the CIAS-1/NALP3 gene.

Design: Retrospective review of medical records and evaluation of histologic findings.

Setting: The National Amyloidosis Centre, London, and a tertiary referral clinic for urticaria.

Organ transplantation in hereditary apolipoprotein AI amyloidosis.

Patients with hereditary apolipoprotein AI (apoAI) amyloidosis often have extensive visceral amyloid deposits, and many develop end-stage renal failure as young adults. Solid organ transplantation to replace failing organ function in systemic amyloidosis is controversial due to the multisystem and progressive nature of the disease and the risk of recurrence of amyloid in the graft. We report the outcome of solid organ transplantation, including dual transplants in 4 cases, among 10 patients with apoAI amyloidosis who were followed for a median (range) of 16 (4-28) and 9 (0.

AA amyloidosis complicating hyperimmunoglobulinemia D with periodic fever syndrome: a report of two cases.

AA amyloidosis is the most serious potential complication of the inherited autoinflammatory syndromes and frequently results in end-stage renal failure. Although this complication is well recognized in familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, and Muckle-Wells syndrome, there is only 1 previous published report of its occurrence in hyperimmunoglobulinemia D with periodic fever syndrome (HIDS). We report 2 further cases of patients with AA amyloidosis in HIDS, both of whom developed dialysis-dependent renal failure, and we describe the outcome of the first renal transplant in this setting.

Hearing improvement in a patient with variant Muckle-Wells syndrome in response to interleukin 1 receptor antagonism.

Background: Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome, and neonatal onset multisystem inflammatory disease, also called chronic, infantile, neurological, cutaneous, and articular syndrome, are three hereditary autoinflammatory syndromes caused by mutations affecting the CIAS1/NALP3 gene on chromosome 1q44. The proinflammatory cytokine, interleukin 1beta, is believed to have a fundamental role in their pathogenesis.

Case Report: The case is described of a 59 year old white woman who presented with increasingly severe MWS-type features over a 15 year period.

Clinical and subclinical inflammation in patients with familial Mediterranean fever and in heterozygous carriers of MEFV mutations.

Objective: To prospectively monitor inflammatory activity over a prolonged period in a cohort of Turkish patients with FMF, their healthy relatives and healthy controls and to relate this to their MEFV genotypes.

Methods: 43 patients with FMF and 75 of their asymptomatic relatives underwent fortnightly assessments and venesection for measurement of CRP and SAA over 5 months. 50 unrelated healthy population matched controls were also studied.

Hereditary amyloidosis in early childhood associated with a novel insertion-deletion (indel) in the fibrinogen Aalpha chain gene.

Background: Systemic amyloidosis occurring in early childhood is extremely rare, and is usually of AA type complicating chronic inflammatory diseases. We report the molecular basis of amyloidosis in a Korean girl who presented at 7 years of age with asymptomatic proteinuria and developed amyloid hepatomegaly and end-stage renal failure within 2 years.

Methods: Renal biopsy showed enlarged glomeruli virtually replaced by amyloid, but without interstitial or vascular involvement.

Aiming at "de feet" and diabetes: a rural model to increase annual foot examinations.

Something is afoot in south central Idaho. After 2 years of work, the percentage of people with diabetes receiving recommended annual foot examinations has increased by 13.8%, exceeding the state average.

Familial amyloidotic polyneuropathy with severe renal involvement in association with transthyretin Gly47Glu in Dutch, British and American-Finnish families.

Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant disorder associated with more than 80 different transthyretin (TTR) mutations. The clinical features of FAP are broad and variable, but knowledge of the pattern and natural history of disease associated with particular mutations nevertheless offers the best guidance for management of individual patients, including the role and timming of treatment by orthotopic liver transplantation. FAP in association with TTR Gly47Glu has been described previously in an Italian kindred, and we report here its phenotype in 7 additional patients from Dutch, British, and American (Finnish) families.

Autoimmunity and glomerulonephritis in mice with targeted deletion of the serum amyloid P component gene: SAP deficiency or strain combination?

Human serum amyloid P component (SAP) binds avidly to DNA, chromatin and apoptotic cells in vitro and in vivo. 129/Sv x C57BL/6 mice with targeted deletion of the SAP gene spontaneously develop antinuclear autoantibodies and immune complex glomerulonephritis. SAP-deficient animals, created by backcrossing the 129/Sv SAP gene deletion into pure line C57BL/6 mice and studied here for the first time, also spontaneously developed broad spectrum antinuclear autoimmunity and proliferative immune complex glomerulonephritis but without proteinuria, renal failure, or increased morbidity or mortality.

Allelic variants in genes associated with hereditary periodic fever syndromes as susceptibility factors for reactive systemic AA amyloidosis.

We investigated the hypothesis that low-penetrance mutations in genes (TNFRSF1A, MEFV and NALP3/CIAS1) associated with hereditary periodic fever syndromes (HPFs) might be risk factors for AA amyloidosis among patients with chronic inflammatory disorders, including rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), Crohn's disease, undiagnosed recurrent fevers and HPFs themselves. Four of 67 patients with RA plus amyloidosis had MEFV variants compared with none of 34 RA patients without amyloid (P value=0.03).

Heterogeneity among patients with tumor necrosis factor receptor-associated periodic syndrome phenotypes.

Objective: To investigate the prevalence of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) among outpatients presenting with recurrent fevers and clinical features consistent with TRAPS.

Methods: Mutational screening was performed in affected members of 18 families in which multiple members had symptoms compatible with TRAPS and in 176 consecutive subjects with sporadic (nonfamilial) "TRAPS-like" symptoms. Plasma concentrations of soluble tumor necrosis factor receptor superfamily 1A (sTNFRSF1A) were measured, and fluorescence-activated cell sorter analysis was used to measure TNFRSF1A shedding from monocytes.

MHC typing in variant Creutzfeldt-Jakob disease.

Identification of factors that cause susceptibility to, and clinical expression of, variant Creutzfeldt-Jakob disease (vCJD) is essential for future management of the disease. We established MHC genotypes of 76 individuals with vCJD and 131 controls, and analysed MHC phenotypes in relation to age of onset of vCJD and its duration from presentation to death. There were no significant differences between vCJD and control populations in frequencies of any MHC types, nor were there associations between MHC type and age of onset or duration of vCJD disease.

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.

Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis.

Background: Hereditary, autosomal dominant amyloidosis, caused by mutations in the genes encoding transthyretin, fibrinogen A alpha-chain, lysozyme, or apolipoprotein A-I, is thought to be extremely rare and is not routinely included in the differential diagnosis of systemic amyloidosis unless there is a family history.

Methods: We studied 350 patients with systemic amyloidosis, in whom a diagnosis of the light-chain (AL) type of the disorder had been suggested by clinical and laboratory findings and by the absence of a family history, to assess whether they had amyloidogenic mutations.

Results: Amyloidogenic mutations were present in 34 of the 350 patients (9.

The genetic basis of autosomal dominant familial Mediterranean fever.

Familial Mediterranean fever (FMF) is classically an autosomal recessive periodic inflammatory disease occurring in Mediterranean and Middle Eastern populations. It is caused by mutations affecting both alleles of MEFV, a gene that encodes pyrin (marenostrin), an uncharacterized neutrophil protein. Occasional reports of autosomal dominant FMF have often been discounted, on the basis that asymptomatic FMF carriers are common in certain populations, and give rise to pseudo-dominant inheritance.

Phenotypic and molecular analysis of six human cell lines derived from patients with plasma cell dyscrasia.

Cell lines RPMI 8226, JJN3, U266 B1, NCI-H929 (all EBV-) and ARH77 and HS-Sultan (both EBV+) have been extensively characterized in this study. EBV- lines expressed the phenotype (CD138-, CD19+, CD20+) whereas EBV+ were (CD138+, CD19-, CD20-). CD56 expression was restricted to EBV- cell lines, with the exception of U266 B1, whereas PCA-1 was strongly expressed on five of the six cell lines.

Serum amyloid P component controls chromatin degradation and prevents antinuclear autoimmunity.

Serum amyloid P component (SAP), a highly conserved plasma protein named for its universal presence in amyloid deposits, is the single normal circulating protein that shows specific calcium-dependent binding to DNA and chromatin in physiological conditions. The avid binding of SAP displaces H1-type histones and thereby solubilizes native long chromatin, which is otherwise profoundly insoluble at the physiological ionic strength of extracellular fluids. Furthermore, SAP binds in vivo both to apoptotic cells, the surface blebs of which bear chromatin fragments, and to nuclear debris released by necrosis.

CD34+-selected peripheral blood progenitor cell transplantation in patients with multiple myeloma: tumour cell contamination and outcome.

Thirty-six patients with multiple myeloma (23 PR1, nine PR2, four stable disease) were entered into a pilot study evaluating the use of CD34+-selected peripheral blood progenitor cell transplantation (PBPCT) following high-dose melphalan alone or high-dose melphalan and total body irradiation. Peripheral blood progenitor cells (PBPCs) were mobilized with cyclophosphamide and granulocyte colony stimulating factor (G-CSF). CD34+ selection using the Cellpro Ceprate-SC system was performed in 22 cases with an adequate yield in 20.

Molecular and functional characterisation of E2F-5, a new member of the E2F family.

The transcription factor DRTF1/E2F is implicated in the control of cellular proliferation due to its interaction with key regulators of cell cycle progression, such as the retinoblastoma tumour suppressor gene product and related pocket proteins, cyclins and cyclin-dependent kinases. DRTF1/E2F DNA binding activity arises when a member of two distinct families of proteins, DP and E2F, interact as DP/E2F heterodimers. Here, we report the isolation and characterisation of a new member of the E2F family of proteins, called E2F-5.

Proto-oncogenic properties of the DP family of proteins.

The cellular transcription factor DRTF1/E2F is implicated in the control of cellular proliferation due to its interaction with key regulators of cell cycle progression, such as the retinoblastoma tumour suppressor gene product, cyclins and cyclin-dependent kinases. DRTF1/E2F is a heterodimeric DNA binding activity which arises when a member of two distinct families of proteins, DP and E2F, interact as DP/E2F heterodimers, for example, DP-1 and E2F-1. In DRTF1/E2F the activity of DP-1 is under cell cycle control, possibly by phosphorylation, and in many types of cells it is a frequent, if not general DNA binding component of DRTF1/E2F.