Deposition In Various Organs Research Articles

AL Amyloid Imaging and Therapy with a Monoclonal Antibody to a Cryptic Epitope on Amyloid Fibrils

The monoclonal antibody 2A4 binds an epitope derived from a cleavage site of serum amyloid protein A (sAA) containing a -Glu-Asp- amino acid pairing. In addition to its reactivity with sAA amyloid deposits, the antibody was also found to bind amyloid fibrils composed of immunoglobulin light chains. The antibody binds to synthetic fibrils and human light chain (AL) amyloid extracts with high affinity even in the presence of soluble light chain proteins. Immunohistochemistry with biotinylated 2A4 demonstrated positive reaction with ALκ and ALλ human amyloid deposits in various organs. Surface plasmon resonance analyses using synthetic AL fibrils as a substrate revealed that 2A4 bound with a KD of ∼10 nM. Binding was inhibited in the presence of the –Glu-Asp- containing immunogen peptide. Radiolabeled 2A4 specifically localized with human AL amyloid extracts implanted in mice (amyloidomas) as evidenced by single photon emission (SPECT) imaging. Furthermore, co-localization of the radiolabeled mAb with amyloid was shown in biodistribution and micro-autoradiography studies. Treatment with 2A4 expedited regression of ALκ amyloidomas in mice, likely mediated by the action of macrophages and neutrophils, relative to animals that received a control antibody. These data indicate that the 2A4 mAb might be of interest for potential imaging and immunotherapy in patients with AL amyloidosis.

Oral findings associated with primary hyperoxaluria type I

In the present paper we report the oral findings of a patient who was diagnosed with hyperoxaluria.Hyperoxalurias can basically be classified as primary and secondary, with the first being inborn errors of metabolism and the second a result of excessive oxalate intake.Primary hyperoxalurias form a rare group of metabolic diseases that are inherited in the autosomal recessive fashion. The affected genes code for specific hepatic enzymes that are involved in glyoxylate metabolism and their deficiency results in overproduction of oxalate.Two different types are described: Primary hyperoxaluria type I results from a deficiency of peroxisomal enzyme alanine–glyoxylate aminotransferase and the more rare type II from a deficiency of cytosolic enzyme d-glycerate dehydrogenase.Since oxalate is primarily excreted through the kidneys, abnormally high concentration of oxalate in the urine occurs. This can in turn result in recurrent kidney stones and parenchymal renal damage and end-stage renal disease (ESRD). Inability to further excrete oxalate through the kidneys leads to its deposition in various organs (oxalosis).Several oral findings have been described in patients with oxalosis, most important of whose are bone resorption in the jaws, external root resorption and rapidly progressive dental mobility, as well as dental pain associated with deposition of oxalate in the dentine and the pulp.

Case report: A case of light chain deposition disease involving liver and stomach with chronic hepatitis C virus infection and hepatocellular carcinoma

Light chain deposition disease (LCDD) is a rare, plasma cell proliferative disorder characterized by mainly abnormal light chain deposition in various organs. Hepatitis C virus (HCV) is a hepatotrophic and lymphotrophic virus and significantly related to B-cell proliferation. This is a case report of systemic LCDD involving liver, stomach, bone marrow, and probably kidney, in a patient with HCV-related hepatocellular carcinoma (HCC). A 62-year-old man with chronic HCV infection who presented with a small HCC in segment 8 of the liver and nephrotic syndrome showed kappa typed immunoglobulin light chain depositions in biopsy specimens of bone marrow, stomach, and non-tumorous liver parenchyma. After treatment of the HCC with transarterial chemoembolization, antiviral therapy for chronic hepatitis C was started. The patient showed early virologic response at 12 weeks of treatment; however, antiviral therapy was discontinued due to adverse effects and he was lost to follow-up. This is the first case of LCDD involving the liver and stomach in a patient with chronic HCV infection and HCC, which may represent LCDD as a rare HCV-associated B cell proliferative disease.

Son Dönem Böbrek Hastalığı Olan Bir Süt Çocuğunda Eritropoietine Dirençli Anemi

renal disease (ESRD) in infancy. Bartter syndrome and the primary hyperoxalurias (PH) are the main causes of severe nephrocalcinosis with ESRD in infancy period. Bartter syndrome was ruled out because of the absence of hyponatremic hypokalemic metabolic alkalosis and recurrent dehydration attacks in our patient. Urinary chloride level was normal. Furthermore, SLC12A1 and CLCNKB gene analyses showed no mutation. Therefore, the most likely etiology in this infant with ESRD was the primary hyperoxalurias. The primary hyperoxalurias are autosomal recessive and rare metabolic disorders resulting from deficiencies of the hepatic peroxisomal enzyme alanine-glyoxlate aminotransferase (PH-1) and the enzyme glyoxylate reductase/hydroxypyruvate reductase (PH-2) which cause excessive oxalate formation and calcium oxalate deposition in various organs.1,2 The most common type of primary hyperoxaluria is type 1. Diagnosis relies on detection of increased levels of oxalate in urine (N: < 0.5 mmol/l/1.73m2 per day) and either assay enzyme activity from liver biopsy or molecular genetic testing of associated gene. Liver biopsy is still considered as the gold standard, but it is an invasive process and bears some risks. Genetic analysis provides some additional non-diagnostic information.1,2 However, the diagnosis of PH-1 was mainly established on the basis of clinical and radiologic findings in our case. Urine oxalate level could not be measured on admission due to financial problems of the family, and then urine output abruptly decreased.

T-type calcium channel as a portal of iron uptake into cardiomyocytes of beta-thalassemic mice

Iron-overload condition can be found in β-thalassemic patients with regular blood transfusion, leading to iron deposition in various organs including the heart. Elevated cardiac iron causes iron-overload cardiomyopathy, a condition that provokes mortality because of heart failure in patients with thalassemia. Previous studies demonstrated that myocardial iron uptake may occur via L-type calcium channels (LTCCs). However, direct evidence regarding the claimed pathway in thalassemic cardiomyocytes has never been investigated. Hearts from genetic-altered β-thalassemic mice and adult wild-type mice were used for cultured ventricular cardiomyocytes. Blockers for LTCC, T-type calcium channel (TTCC), transferrin receptor1 (TfR1), and divalent metal transporter1 (DMT1) were used, and quantification of cellular iron uptake under various iron loading conditions was performed by Calcein-AM fluorescence assay. Microarray analysis was performed to investigate gene expressions in the hearts of these mice. This study demonstrated that iron uptake under iron-overload conditions in the cultured ventricular myocytes of thalassemic mice was greater than that of wild-type cells (P <0.01). TTCC blocker, efonidipine, and an iron chelator, deferoxamine, could prevent iron uptake into cultured cardiomyocytes, whereas blockers of TfR1, DMT1, and LTCC could not. Microarray analysis from thalassemic hearts demonstrated highly up-regulated genes of TTCC, zinc transporter, and transferrin receptor2. Our findings indicated that iron uptake mechanisms in cultured thalassemic cardiomyocytes are mainly mediated by TTCC, suggesting that TTCC is the important pathway for iron uptake in this cultured thalassemic cardiomyocyte model.

Cortical nephrocalcinosis in an infant caused by primary hyperoxaluria type 1

An 8-month-old boy was referred for an upper gastrointestinal study for vomiting. Scout abdominal radiograph shows bilateral cortical nephrocalcinosis (Fig. 1, arrows). US shows hyperechoic cortical rim with acoustic shadowing confirming cortical nephrocalcinosis (Fig. 2, arrows). Laboratory and genetic testing confirmed primary hyperoxaluria type 1 (PH-1). PH-1 is a rare autosomal-recessive disorder resulting from deficiency of the hepatic peroxisomal enzyme alanineglyoxylate aminotransferase, which causes excessive oxalate formation and calcium oxalate deposition in various organs. Kidneys show cortical or medullary nephrocalcinosis and recurrent urolithiasis causing progressive renal failure [1]. Skeletal manifestations of PH-1 sometimes result from oxalate deposition but more commonly result from chronic renal failure, leading to secondary hyperparathyroidism and renal osteodystrophy [2]. Findings include metaphyseal sclerotic lines and bands, lucent bands, cystic changes, permeative lucencies and vertebral diffuse or endplate osteosclerosis (rugger jersey appearance). Flat pelvic bones, carpal and tarsal bones, and patella might show a radiolucent rim.

Increased interleukin-23 receptor+T cells in peripheral blood mononuclear cells of patients with systemic lupus erythematosus

IntroductionSystemic lupus erythematosus (SLE) is an autoimmune disorder characterized by production of autoantibodies and immune complex deposition in various organs. Aberrations in the T lymphocyte compartment and dysregulated cytokine production are key features of SLE pathogenesis and disease progression. Recently, the role of the interleukin (IL)-17/IL-23 axis in the pathogenesis of SLE has been reported. IL-23 and IL-23R are essential for expansion of pathogenic IL-17-producing T lymphocytes and have been shown to be important in the pathogenesis of lupus in animal models.MethodsIn this study, the expression of IL-23R and IL-17 in CD4+ and CD8+ T lymphocytes in peripheral blood mononuclear cells (PBMCs) of SLE patients and control subjects were examined by flow cytometry. Twenty-nine SLE patients and 10 control subjects were recruited in this study. Patients were divided into active and inactive groups based on the SLE disease activity index (SLEDAI). As another disease control population, five psoriatic patients were recruited in this study.ResultsPercentages of both IL23R+ CD4+ and IL-23R+ CD8+ T cell subsets were significantly higher in freshly isolated PBMCs from both groups of SLE patients compared to control subjects (P = 0.0021 and P = 0.0006, respectively). In addition, this difference was maintained after ex vivo stimulation with plate-bound anti-CD3/CD28 antibodies (P = 0.007 and P = 0.0019, respectively). When the fold increase in IL-17+ T cells after ex vivo stimulation for three days was compared between patients and controls, SLE patients exhibited significantly higher increases in CD4+ IL-17+ and CD8+ IL-17+ T cells, suggesting that PBMCs from SLE patients promoted the expansion of IL-17-producing T cells upon stimulation more vigorously than control PBMCs. These trends were not observed in psoriasis patients. The correlations between IL-23R+ T cells and IL-17+ T cells and IL-23R+ CD8+ T cells and SLEDAI scores in patients were also found to be statistically significant.ConclusionsThe results of our study confirmed the relevance of the IL-23/IL-17 axis in the pathogenesis of SLE and further highlighted the importance of IL-23R+ T cell subsets in this autoimmune disease.

Systemic Amyloidosis Presenting as Chronic Diarrhea in a Patient With Ankylosing Spondylitis

Secondary (AA) amyloidosis is a disease that is caused by systemic deposition of amyloid fibrils. Circulating serum amyloid A protein is an acute phase reactant and levels are therefore high during inflammatory states. Chronic elevation of serum amyloid A levels results in accumulation and deposition in various organs, leading to organ dysfunction. Unless the inciting inflammatory state can be controlled, the subsequent development of amyloidosis diminishes patient survival. We report a case of systemic amyloidosis that presented primarily as chronic diarrhea in a patient with ankylosing spondylitis. Unfortunately for the patient, the diagnosis of amyloidosis was delayed for years despite encounters with multiple physicians. Early medical intervention to control chronic inflammation is imperative and could prevent morbidity and mortality related to the development of secondary amyloidosis. Consideration of amyloidosis as a diagnosis in patients who have chronic uncontrolled inflammatory conditions is also important in preventing poor outcomes related to this disease.

Efficacy of the Combination of Bortezomib and Dexamethasone in Systemic AL Amyloidosis.

Abstract 2871Poster Board II-847 Introduction:AL amyloidosis is characterized by misfolding of structurally unstable light chains that form deposits in various organs thereby causing impaired organ function. Treatment of AL amyloidosis remains challenging and is primarily directed towards the underlying abnormal plasma cell clone. Novel agents with proven efficacy in multiple myeloma like the proteasome inhibitor bortezomib have also shown initial promising results in patients with AL amyloidosis, but its value needs to be further established. In this retrospective analysis, we have collected data regarding efficacy and tolerability of treatment with bortezomib plus dexamethasone in patients with AL amyloidosis. Patients and Methods:25 patients with histologically proven systemic AL amyloidosis were included in this analysis. All patients received bortezomib at a standard dose of 1.3mg/m2 (days 1, 4, 8, 11 of a 3-week cycle) in combination with dexamethasone (8mg to 20mg administered on the day of bortezomib and the day after). Routine clinical and laboratory parameters including evaluation were obtained on a monthly basis. Results:Patients (male n=13, female n=12) were at a median age of 57 years (range 42-83), and 17 patients (68%) received bortezomib/dexamethasone as their first line treatment. The majority of patients had an ECOG performance status of < 2. Twelve patients (48%) had only one organ involved, whereas > 2 organs were involved in 6 patients (24%). Organs most frequently involved were kidneys (100%), heart (28%), liver (12%) and the gastrointestinal tract (12%). At the time of analysis, a median of 3 cycles of bortezomib/dexamethasone (range, 1 to 8) have been administered. A hematologic response was observed in 14 patients (56%) including 5 patients (20%) qualifying for a complete response (CR). All CR patients received bortezomib/dexamethasone as their first line treatment, and parameters of organ function also improved in these patients. Median overall survival has not yet been reached after a median follow-up of 12 months. Grade 3 and 4 toxicities were rare and consisted predominantly of transient thrombocytopenia. Grade 2 neurotoxicity was observed in 24% of patients. Other grade 1/2 toxicities observed at higher frequencies included hypotension (16%), edema (16%), and fatigue (12%). Conclusion:Our results confirm the activity of bortezomib/dexamethasone in patients with AL amyloidosis (hematologic response rate 56% including a 20% CR rate). Disclosures:Ludwig:Celgene: Honoraria; Mundipharma: Honoraria; AMGEN: Honoraria; Ortho-Biotech : Honoraria; Janssen-Cilag: Research Funding; Roche: Honoraria.

Immunophenotype of neoplastic plasma cells in AL amyloidosis

Aim:AL amyloidosis (ALA) is a form of plasma cell (PC) dyscrasia characterised by deposition of insoluble fibrillar deposits in various organs causing organ damage. This is believed to be the...

舌および顎下部の腫脹を契機に発見された全身性アミロイドーシスの1例

Amyloidosis is caused by amyloid substance deposition in various organs and tissues of the body. A case of systemic amyloidosis with swelling in the tongue and submandibular region as an initial symptom is reported. A 63-year-old man presented with swelling of the tongue and submandibular region. Detailed clinical examinations and biopsy were performed. There were no signs suggesting a malignant tumor. Subsequently, purpura of the lips and induration of the lower lip and buccal mucosa appeared. Chest radiographic examination revealed cardiac hypertrophy and pleural fluid. Systemic amyloidosis was suspected. A biopsy specimen taken from the buccal mucosa revealed deposition of amyloid. Congo-red stain for amyloid was positive. Systemic amyloidosis was diagnosed. The patient was followed up in the department of internal medicine. After 14 months, the patient died of cardiac failure due to amyloid deposition.

Severity of Baseline Proteinuria Predicts Renal Response in Immunoglobulin Light Chain–Associated Amyloidosis after Autologous Stem Cell Transplantation

Ig light chain-associated amyloidosis is a fatal plasma cell proliferative disorder that is characterized by fibril deposition in various organs. High-dose melphalan followed by autologous stem cell transplantation has been shown to improve organ dysfunction and survival. This study was undertaken to investigate factors that influence renal response. Patients who had AL amyloidosis with > or =1 g/d proteinuria and a minimum follow-up of 12 mo were recruited. Renal response was defined by >50% reduction in proteinuria with <25% decline in renal function. Hematologic response was defined as a 50% reduction in serum monoclonal protein or free light chains. Baseline characteristics were examined for relationship to renal response. Thirteen of the 135 patients were excluded for various reasons. Median follow-up was 45.4 mo. Hematologic and renal response was noted in 73 and 43.4% of the patients, respectively. Median response time for the kidney was 10 mo (1 to 40 mo). In univariate analysis, low cardiac troponin T (cTnT), higher albumin, lower proteinuria, and hematologic response were associated with renal response. In multivariate analysis, cTnT and proteinuria were predictive of renal response. Renal response was associated with a longer survival than hematologic response alone. This study showed that severe proteinuria and high cTnT negatively affected renal response after autologous stem cell transplantation. Achievement of renal response was associated with improved survival. These results suggest that early intervention with aggressive therapy is not only justified but recommended to achieve optimal response.

Where do we go from HEIRS?

Where do we go from HEIRS?

Carcinoid tumour of the small intestine with secondary deposits in various organs

Journal Article Carcinoid tumour of the small intestine with secondary deposits in various organs Get access Philip Wrightson Philip Wrightson Darlington Search for other works by this author on: Oxford Academic Google Scholar British Journal of Surgery, Volume 36, Issue 142, October 1948, Pages 215–217, https://doi.org/10.1002/bjs.18003614222 Published: 05 December 2005

Introduction

Introduction

Serum transthyretin monomer in patients with familial amyloid polyneuropathy

Although dissociation of the transthyretin (TTR) tetramer is suspected of being the first step in amyloid fibril formation in hereditary TTR amyloidosis, including familial amyloid polyneuropathy (FAP), the TTR monomer has never been examined in vivo. Therefore, we analyzed the TTR monomer in the serum of FAP patients and normal individuals. Free TTR monomer was detected in both groups using gel filtration chromatography and immunoblotting. Both the mean concentration of free TTR monomer and the total serum TTR were significantly lower in FAP patients than in normal individuals. Moreover, in FAP patients, mass spectrometry showed that the variant TTR monomer was markedly decreased compared with the wild-type TTR monomer. These findings suggest that the free variant TTR monomer is unstable in serum, and that it aggregates in deposits in various organs or is adsorbed by preexisting amyloid fibrils before it is degraded.

Hemochromatosis as a Risk Factor for Fulminant Staphylococcus aureus Pneumonia*

Hemochromatosis as a Risk Factor for Fulminant Staphylococcus aureus Pneumonia*

The severity and distribution of amyloid deposition in the late-onset familial amyloidotic polyneuropathy (FAP) — a clinicopathological analysis of three autopsy cases

In our previous studies of 17 autopsy cases of FAP, we confirmed marked amyloid deposition in the peripheral nerve tissues, autonomic nervous system, choroid plexus, cardiovascular system, kidneys, anterior and posterior roots of the spinal cord, spinal ganglia, thyroid and gastrointestinal tract. Most of the cases had initially developed peripheral nervous distrubances, autonomic dysfuncUon, cardiac conduction disturbances, or orthostatic hypotension between the age of 16 and 43. In the present study, the severity of amyloid depostion in three autopsy cases of the late-onset FAP was investigated pathologically, histochemically, and compared with that in the ordinary type. As initial signs and symptoms, two of the three late-onset cases showed sensory disturbances in bilateral lower extremeties at age 56 and 73, respectively, while the other manifested cardiac failure at age 54. The duration of clinical course to death in the three cases was 6 to 7 years, shorter than in the ordinary FAP cases (10.1 years on average). Histochemical and immunohistochemical approaches were utilized to detect amyloid deposition in various organs and tissues obtained from the cases at autopsy. In all cases, amyloid deposits in the peripheral nerve tissues, autonomic nervous system, and posterior and anterior roots of the spinal cord were slight or nearly absent. In two of the three cases, amyloid involvement was marked in the kidneys and thyroid, but slight in the cardiovascular system. In the other case, ~unyloid deposition was prominent in the cardiac wall, causing marked cardiac hypertrophy (690g). In all three cases, the severity of amyloid deposition in the other organs and tissues was generally slight, compared to the ordinary FAP cases. These data provide evidence that the severity and distribution of amyloid deposition correlate with the clinical manifestations and duration of late-onset FAP, although the mechanisms causing the delay of amyloid deposition are unknown.

舌に腫りゅうの形成を認めた原発性アミロイドーシスの１症例

Amyloidosis is a lesion in which an amyloid substance deposits in various organs and tissues of the body.Recently, we experienced a case of primary amyloidosis forming multiple nodules in the tongue. The patient was a 74-year-old male.Multiple nodules, 5-10mm in diameter, were observed in the tongue and the lingual frenulum. Histopatliologically, the excised nodules were diagnosed as amyloidosis. The amyloid protein was identified as protein AL by potassium permanganate treatment.

The genetic origin of murine lupus-associated autoantibodies.

Systemic lupus erythematosus and rheumatoid arthritis in human and murine systems are characterized by circulating autoantibodies and immune complex deposition in various organs causing tissue damage and disease. To define the molecular and clonotypic origin of these anti-self responses, and to determine whether abnormalities in Ig genes or somatic mechanisms generating autoantibody diversity may contribute to lupus etiology, we performed molecular analyses of the Ig germline gene organization and the Ig gene segments expressed in monoclonal autoantibodies from autoimmune mice. Comparative restriction fragment length polymorphism analysis of a large number of Ig gene loci from autoimmune and normal mice indicated that (a) lupus can develop in different Ig heavy and kappa light chain variable region gene haplotypes, and (b) the Ig germline genes in lupus mice might be normal. To determine whether autoantibodies are encoded by unique Ig gene segments present in the normal germline repertoire, but not expressed in exogenous responses, we compared nucleic acid sequences encoding lupus autoantibodies and antibodies against foreign antigens. Similar, and in some instances even identical, gene segments were expressed in both types of antibodies, indicating that anti-self and anti-foreign responses use the same, or at least an overlapping, germline gene repertoire. A large variety of Ig variable, diversity, and joining gene segments encoded these autoantibodies with different specificities. Hence, the overall murine lupus-associated anti-self response may be essentially unrestricted. Furthermore, limited evidence has been obtained that both germline genes and somatically mutated genes encode autospecificity, making gross abnormalities in mechanisms for somatic mutation of Ig variable genes unlikely.(ABSTRACT TRUNCATED AT 250 WORDS)