Deposition In Various Organs Research Articles

Low incidence of focal lesions in the thyroid glands of patients with hereditary haemochromatosis — a single-centre study from Poland

Hereditary hemochromatosis (HH) is a disease characterized by the excessive absorption of iron and its deposition in various organs. Late complications of this disease include cirrhosis, hepatocellular carcinoma and endocrine disorders. Data from literature on thyroid disorders in patients with HH are inconsistent and ambiguous and no research has been done to determine the relationship between excessive accumulation of iron and the thyroid volume. Therefore, the aim of this study was to characterize thyroid function and ultrasound image in patients with clinically overt hereditary hemochromatosis. We studied 40 patients who were diagnosed with hereditary hemochromatosis with one of the mutation of HFE gene and iron deposites in liver in specimen from liver biopsy (graded G2 to G4) or in MRI. To assess the thyroid function, the ultrasound examination of the thyroid gland was performed and serum TSH concentrations were measured. We showed in our study that patients with HH have diagnosed with nodular goiters statistically less frequent than in control group. We did not reveal any statistically significant differences in TSH concentrations between patients with HH and the general population. However patients with more severe iron deposits in liver showed lower TSH. Our results indicate that iron overload syndromes and iron deposition could have prevent from formation of focal lesions in thyroid gland. Excess iron may act as a "protective" factor against the formation of nodular lesions in the thyroid gland through the production of peripheral thyroid hormones, i.e. thyroxine (T4) and triiodothyronine (T3), and the reduction of TSH concentration.

Nanocapillary-Based Sensors for Detection of Copper Ions in Biological Systems

Copper performs a various biological function in living organisms. Dysregulation of copper ions can lead to unwanted redox reactions (Haber - Weiss reaction) caused by an increase in the free copper concentration or to its deposition in various organs (brain, kidney, eye cornea). Wilson’s, Menkes’s and Alzheimer’s disease are the most frequently mentioned diseases which associated with dysregulation of copper ions. These diseases are currently treatable only in the early stages. However, monitoring of the free copper concentration is extremely necessary.

Study of pulmonary function tests in multitransfused children with beta thalassemia major: an observational study

Background: Thalassemia is a hemoglobinopathy requiring multiple blood transfusions leading to iron deposition in various organs. Abnormalities in pulmonary function in thalassemia major patients have been found in various studies. Our aim was to study pulmonary function tests (PFT) in multitransfused children with beta thalassemia major.Methods: PFT was done in forty beta thalassemia major (TM) patients and forty normal healthy age and sex matched individuals and the results were analyzed.Results: Out of 40 thalassemia major patients, 20 (50%) had normal PFT and the rest 20 (50%) had an abnormal PFT out of which 18 (90%) had restrictive PFT and 2 (10%) had obstructive PFT. Out of 40 controls, all 40 (100%) had normal PFT.Conclusions: Alteration of pulmonary function can be seen even in well-chelated TM patients. The respiratory system should be evaluated annually by PFTs even in asymptomatic patients to prevent pulmonary sequelae.

WHEN LIGHTNING STRIKES TWICE: A CROSSOVER SYNDROME WITH LIGHT CHAIN DEPOSITION AND LYMPHOID INTERSTITIAL PNEUMONIA

SESSION TITLE: Medical Student/Resident Diffuse Lung Disease SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Light chain deposition disease (LCDD) is a rare cystic lung disease, involving monoclonal proliferation and deposition of light chains. Lymphoid Interstitial Pneumonia (LIP) is an uncommon interstitial lung disease (ILD) usually seen with connective tissue disorders (CTD). We present a challenging case involving the co-existence of LCDD and LIP. CASE PRESENTATION: We present the 25-year long clinical course of a 47-year-old male who was initially diagnosed with a mucosa-associated lymphoid tissue (MALT) lymphoma of the parotid gland, treated with excision. Over the subsequent 5-10 years, he was diagnosed with rheumatoid arthritis and Sjogren’s syndrome. Treatment with methotrexate was complicated by the development of human anti-murine antibodies. He also developed progressive cough and dyspnea. Computed Tomography (CT) imaging of the chest revealed bilateral nodules and interstitial infiltrate, suggestive of LIP. Right lower lobe wedge resection was performed; histopathology demonstrated lymphoplasmacytic infiltrate and eosinophilic proteinaceous deposits which were negative on Congo red staining. Immunohistochemistry revealed predominantly kappa light chains within the eosinophilic material. Serial follow-up imaging was notable for the development of diffuse cystic lung disease. He was diagnosed with LCDD and was treated with bortezomib, but developed Steven-Johnson syndrome. This was followed by treatment with lenalidomide and then cyclophosphamide. A follow up positron emission tomography (PET) CT scan showed no change in the size of pulmonary nodules. The patient was also trialed on bendamustine and ofatumumab, an anti-CD20 monoclonal antibody, with no significant improvement. A recent chest CT, obtained 15 years following the onset of lung disease, demonstrated wide-spread thin walled cysts and nodular disease (Fig 1,2). His symptoms have stabilized with oxygen supplementation and treatment of exacerbations with steroids and antibiotics, and he is currently on surveillance. DISCUSSION: LCDD, an entity caused by plasma cell proliferation and monoclonal light chain deposits in various organs often found in association with lymphoproliferative conditions, can manifest as diffuse cystic lung disease. (1) It has a poor prognosis. Treatment options include immunomodulators and chemotherapeutic agents, including bortezomib, daratumumab, and bendamustine. LIP, an ILD, is usually seen in patients with CTD and HIV. (2) Therapeutic options include immunosuppressants such as rituximab and cyclophosphamide. Our case was challenging, given the confluence of two syndromes- LIP with underlying rheumatic conditions, and LCDD due to a lymphoproliferative disorder. Multiple avenues of treatment were attempted but failed to produce an objective improvement in disease course. CONCLUSIONS: LIP and LCDD can occur in tandem; enrollment in study trials should be considered for these patients given poor prognosis. Reference #1: Arrossi AV, Merzianu M, Farver C, et al. Nodular pulmonary light chain deposition disease: an entity associated with Sjögren syndrome or marginal zone lymphoma. J Clin Pathol. 2016 Jun;69(6):490-6. Reference #2: Swigris JJ, Berry GJ, Raffin TA, et al. Lymphoid interstitial pneumonia: a narrative review. Chest. 2002 Dec;122(6):2150-64. DISCLOSURES: No relevant relationships by Pius Ochieng, source=Web Response No relevant relationships by NISHANT SHARMA, source=Web Response No relevant relationships by Pandi Todhe, source=Web Response

CARDIAC AA AMYLOIDOSIS SECONDARY TO FAMILIAL MEDITERRANEAN FEVER PRESENTING AS INTERMITENT COMPLETE HEART BLOCK: A RARE CASE WITH LITERATURE REVIEW

SESSION TITLE: Medical Student/Resident Cardiovascular Disease Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Cardiac amyloidosis is rare but relatively more frequently seen with ATTR and AL types of amyloidosis. AA amyloidosis related cardiomyopathy or conduction abnormalities are rare owing to less frequent involvement of the myocardium in AA amyloidosis. We present a case of complete heart block in the setting of AA amyloidosis secondary to familial mediterranean fever. CASE PRESENTATION: A 50-year-old female with history of familial mediterranean fever (FMF) presented with syncopal episode. On presentation patient's vitals were stable, labs including TSH were within normal limits. Orthostatic vitals were positive. High-sensitivity troponins were negative with a normal EKG on presentation. Laterally displaced apical beat was noticed on examination. During hospitalization patient was noticed to have complete heart block that was not responsive to atropine and transcutaneous pacing however a response was noticed with epinephrine drip. TTE revealed heart failure with reduced ejection fraction of 41% with severe concentric left ventricular thickening typical for amyloid cardiomyopathy with a well-preserved E/A-wave, which is not usually seen in as thickened ventricle as patients. CRP and SAA were elevated. Patient had endomyocardial biopsy that confirmed amyloid deposition staining positive for amyloid AA and negative for TTR, kappa and lambda and a technetium pyrophosphate scan was also negative. A biventricular pacemaker was placed for complete heart block without adequate escape rhythm, which resulted in resolution of episodes of dizziness associated with bradycardia. Patient's FMF was managed with colchicine and anakinra with the help of rheumatology. Patient was started on diuresis during hospitalization and continued on discharge. Patient followed up with amyloidosis clinic after discharge. DISCUSSION: Systemic amyloidosis is rare and results from deposition of amyloid deposits in various organs and hence a wide range of effects. Prognosis may be vary with the type and extent of amyloidosis. More than 95% of cardiac amyloidosis is secondary to light chain/AL amyloidosis or transthyretin amyloidosis (ATTR), both genetic/hereditary and wild type.[1] Cardiac involvement from AA amyloidosis is very rare. Cardiac amyloidosis usually manifests with syncope or postural hypotension, which may be related with bradyarrhythmias.[2] Like the involvement of cardiovascular system, developments of arrhythmias are also common with ATTR type of amyloidosis as compared to other types and may require pacemaker placement. AA cardiac amyloidosis is rare and bradyarrhythmias or conduction system involvement has also been rarely reported. We report a rare case of complete heart block secondary to AA amyloidosis from familial Mediterranean fever requiring pacemaker placement. CONCLUSIONS: We present cardiac AA amyloidosis as a rare cause of syncope and orthostatic hypotension. Reference #1: Sipe, J.D., et al., Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines. Amyloid, 2016. 23(4): p. 209-213. Reference #2: Chamarthi, B., et al., Features and prognosis of exertional syncope in light-chain associated AL cardiac amyloidosis. Am J Cardiol, 1997. 80(9): p. 1242-5 DISCLOSURES: No relevant relationships by Usama Talib, source=Web Response

Polymer materials as promoters/inhibitors of amyloid fibril formation

Polymers are omnipresent materials that are widely used in medicine, e.g., as construction materials for medical devices or as polymer nanoparticle drug delivery systems. Therefore, their possible effects on biomolecules, such as lipids, proteins, and other molecules, present in the human body must be examined. This review addresses the effects of polymer materials (such as dendrimers, polysaccharides) on the process of amyloid fibril formation. Amyloidoses are very serious diseases that are characterized by amyloid deposition in various organs and tissues, causing their dysfunction. The treatment of amyloidoses, such as Alzheimer’s disease (AD), using polymer materials is a challenge. Studies aiming to elucidate the effects of polymers on the process of amyloid fibril formation are therefore also of key importance for understanding the process of amyloid fibril formation and amyloidoses in general.

The dual FXa/thrombin inhibitor SATI prevents fibrin and platelet deposition in hypercoagulant rats

IntroductionSystemic hypercoagulation is often a severe complication of infective and inflammatory diseases, which overcome the hemostatic balance and lead to multiple thrombotic occlusions in the microvasculature and organ damage and is related to high mortality rates. SATI is a potent dual inhibitor of FXa and thrombin with antithrombotic efficacy in venous and arterial thrombosis models. In this study, the antithrombotic efficacy of SATI was investigated in a microthrombosis model in rats with an induced hypercoagulant state. Materials and methodsThe hypercoagulant state was generated by infusion of TF in sixty rats (12 groups, consisting of 5 rats each). SATI was administered in two different doses by constant infusion and its antithrombotic efficacy was investigated using two different approaches: 1) measuring 125I-fibrin deposition in various organs and 2) continuous whole-body imaging of 111In-platelet biodistribution in anesthetized animals. ResultsAfter start of the TF infusion in rats with radioactively-labeled fibrinogen, the radioactivity was accumulated in liver, spleen, kidney, and mostly in the lung as a consequence of fibrin generation. SATI efficiently reduced the pulmonary deposition of fibrin in a dose- and time-dependent manner. In the SATI groups the splenic and renal radioactivity was enhanced at later time points probably as consequence of the clearance of 125I-fibrin(ogen). Imaging of rats that received 111In-platelets prior to systemic TF administration showed retention of the radioactivity mainly in the lungs in the control group. SATI efficiently blocked the platelet accumulation in the lungs and increased platelet recruitment by the spleen. ConclusionsSATI is a promising candidate for prevention of microcirculatory disturbances by inhibiting fibrin deposition and platelet accumulation in the lungs and thereby conferring organ protection. Both methods used in this study are suitable for investigating the antithrombotic efficacy of new drugs in microthrombosis. Continuous imaging of 111In-platelets allowed for follow-up of thrombus formation in living animals without the need for tissue harvesting.

Thymic B Cells Promote Germinal Center-Like Structures and the Expansion of Follicular Helper T Cells in Lupus-Prone Mice.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the activation of autoreactive T and B cells, autoantibody production, and immune complex deposition in various organs. Previous evidence showed abnormal accumulation of B cells in the thymus of lupus-prone mice, but the role of this population in the progression of the disease remains mostly undefined. Here we analyzed the spatial distribution, function, and properties of this thymic B cell population in the BWF1 murine model of SLE. We found that in diseased animals, thymic B cells proliferate, and cluster in structures that resemble ectopic germinal centers. Moreover, we detected antibody-secreting cells in the thymus of diseased-BWF1 mice that produce anti-dsDNA IgG autoantibodies. We also found that thymic B cells from diseased-BWF1 mice induced the differentiation of thymocytes to follicular helper T cells (TFH). These data suggest that the accumulation of B cells in the thymus of BWF1 mice results in the formation of germinal center-like structures and the expansion of a TFH population, which may, in turn, activate and differentiate B cells into autoreactive plasma cells. Therefore, the thymus emerges as an important niche that supports the maintenance of the pathogenic humoral response in the development of murine SLE.

Influence of short peptides with aromatic amino acid residues on aggregation properties of serum amyloid A and its fragments

Serum amyloid A variant 1.1 (SAA1.1) is an acute phase protein. In response to injury, inflammation or infection its production increases highly, which may lead to aggregation of the protein and accumulation of its deposits in various organs. Due to the cellular toxicity of the aggregates, as well as the fact that accumulated deposits are a burden that obstructs proper functioning of the affected tissues, it is vital to find a way to suppress the process of pathological aggregates formation. To make this possible, it is necessary to investigate thoroughly the oligomerization process and recognize factors that may influence its course. Some previous studies showed that aromatic interactions are important to the potential of an inhibitor to suppress the aggregation process. In our research we had proved that a five-residue peptide RSFFS (saa1-5) is an efficient inhibitor of aggregation of the most amyloidogenic fragment of SAA1.1, SAA1-12. In the present work the oligomerization and aggregation propensity of SAA1-12 was compared to that of SAA1-27, in order to determine the contribution of the sequence which extends beyond the most amyloidogenic region but encompasses residues reportedly involved in the stabilization of the SAA native conformation. Thioflavin T fluorescence assay, quantitative chromatographic analysis of the insoluble fraction and transmission electron microscopy allowed for a deeper insight into the SAA aggregation process and the morphology of aggregates. Substitutions of Phe3 and/or Phe4 residues in saa1-5 sequence with tryptophan, tyrosine, homophenylalanine, naphthylalanine and β,β-diphenylalanine allowed to study the influence of different aromatic systems on the aggregation of SAA1-12 and SAA1-27, and evaluate these results in relation to hSAA1.1 protein. Our results indicate that compounds with aromatic moieties can affect the course of the aggregation process and change the ratio between the soluble and insoluble aggregates.

Asymmetrical Ocular Manifestations of Nephropathic Cystinosis; A Case Report

Patient: Female, 22Final Diagnosis: Nephrogenic cystinosisSymptoms: Bilateral eye painMedication: —Clinical Procedure: —Specialty: OphthalmologyObjective:Rare co-existance of disease or pathologyBackground:Infantile nephropathic cystinosis is the most common and severe variant of cystinosis, which is a rare autosomal recessive condition related to a defect in the transportation of the protein cystine resulting in its deposition in various organs. Due to the rarity of this condition, only 1 case with extensive ocular involvement has been found in the English-language literature. Here, we report a second such case to highlight the significance of early diagnosis in avoiding devastating but preventable vision loss.Case Report:We describe the extensive asymmetrical ocular involvement in a 22-year-old woman who had nephropathic cystinosis since childhood. Despite frequent follow up and systemic and topical cysteamine therapy, she developed ocular complications, including increased intraocular pressure, uveitis, and retinal changes with complete loss of vision in her left eye. In addition, her general condition requires a renal transplant in the near future.Conclusions:Ophthalmologists should be aware of cystinosis and the sequalae of ocular involvement in this disease, despite its rarity. Identification of the earliest corneal deposits should not be overlooked, especially in the context of other systemic manifestations that are indicative of the nephropathic variant of cystinosis.

Primary gastrointestinal amyloidosis with gastrointestinal hemorrhage and intestinal pseudo-obstruction: a report of a rare case

Amyloidosis is a syndrome involving amyloid protein deposition in various organs, resulting in organ dysfunction. Symptoms of gastrointestinal amyloidosis are usually nonspecific, such as diarrhea and body weight loss. We, here, report a patient who presented to the hospital with simultaneous hematemesis, melena, and intestinal pseudo-obstruction, leading to a diagnosis of primary gastrointestinal amyloidosis based on computed tomography (CT) and endoscopic findings. CT showed diffuse wall thickening from the duodenum to the jejunum, jejunal dilation, and fluid accumulation throughout the gastrointestinal tract. Upper gastrointestinal endoscopy revealed duodenal mucosal edema, jejunal dilation, and small hemorrhages from jejunal mucosal erosion. The definite diagnosis was done based on biopsy results. This report describes the early diagnosis of gastrointestinal amyloidosis based on CT and endoscopy findings.

The occurrence of pulmonary hypertension in patients with thalassemia major

Background The life of patients with thalassemia major dependson blood transfusions, while repeated blood transfusions may causeadverse effects such as iron deposition in various organs, includ-ing heart and lungs, which eventually increases the pulmonaryarterial pressure.Objective This study was proposed to know the occurrence ofpulmonary hypertension in patients with thalassemia major, mea-sured by echocardiography in the Thalassemia Clinic, Departmentof Child Health, Medical School, Padjadjaran University/HasanSadikin Hospital, Bandung.Methods A descriptive cross-sectional study was carried outon 30 patients with thalassemia major, aged 10-14 year-old whoreceived repeated blood transfusions. The study was conductedfrom April to May 2002. Subjects were examined right after ablood transfusion completed and the pulmonary arterial pres-sure was assessed using Doppler–echocardiography and 2-Dechocardiography.Results Twenty two out of 30 subjects showed pulmonary hyper-tension, with pulmonary arterial pressure ranged between 32.3 to46.2 mmHg. According to the age group, pulmonary hypertensionwas found in 12 out of 17 subjects aged 10-12 years old and 10out of 13 subjects aged 13-14 years old.Conclusion The occurrence of pulmonary hypertension in patientswith thalassemia major at Hasan Sadikin Hospital was 22/30 andseemed to increase with the age of the patients

Wilsons disease -A Rare Entity: Case Report and Review of Literature

Wilson’s disease is described by kinnier Wilson in 1912. It is a rare condition where there is increase in copper levels in the body. There is also copper deposition in various organs of the body. Copper forms an integral part of various enzymes. It also helps in functioning of central nervous system, synthesis of melanin and plays key role in the metabolism of iron. The excess copper accumulation in the body gives rise to various symptoms such as K-F Rings in eyes. In acute stages, there is copper accumulation in the liver. Liver plays an important role in metabolism of drugs and synthesis of coagulation factors. Bleeding tendency is common in patients with liver disease. Here we present a rare case of Wilson’s disease and dental considerations involving it

Gastrointestinal Primary Light Chain Amyloidosis (AL): Safety and Utility of Endoscopic Evaluation and Management of GI Bleeding

Introduction: Multiple reports have cited the potential for GIB in patients with AL. We report 2 cases demonstrating the utility and risks of endoscopy in this setting. Case 1: A 50yo F with multiple myeloma (MM) presented with recurrent hematemesis. Multiple gastric mucosal ulcers and submucosal hematomas (SMH) were found during initial EGD [1a]; biopsies confirmed AL. Repeat exam was performed prior to consideration of stem cell transplant (SCT) one year later. On scope insertion, patchy areas of scar with mottled mucosal discoloration were noted [1b]. On scope withdrawal, spontaneous development of multiple enlarging SMHs and mucosal tears were found in the gastric body related to scope +/- barotrauma not amenable to endotherapy [1c]. Clotting parameters were normal. Although no intervention was required, the patient was deemed not to be a candidate for SCT given high bleeding risk and was continued on lenalidomide. Case 2: A 69yo M with MM s/p SCT on therapy for relapse presented with recurrent hematochezia. During colonoscopy, multiple SMHs and ulcers were found with normal intervening mucosa [2]. Although negative on 3 prior occasions, repeat biopsies confirmed AL. Selective APC and endoclips had been tried without success. Bleeding continued and ultimately total colectomy was performed; unfortunately he passed soon after with complications from systemic amyloidosis. Discussion: AL results in abnormal extracellular protein deposition in various organs including the GI tract and is commonly associated with MM (>15%). Overt GIB may occur in ˜40%. Amyloid infiltration of submucosal vessels induces ischemic change and increases vascular fragility as well as rigidity of the intestinal wall, which can lead to tearing with hemorrhage. Common endoscopic findings include diffuse mucosal erosions, ulcerations, and SMHs, which can be massive. SMHs are highly suggestive of AL in the proper clinical setting, although biopsy is still required to confirm diagnosis, which can be challenging. In most reported cases, SMHs were identified on endoscope insertion and were not thought to have resulted from scope-induced trauma or shear forces associated with scope manipulation. However our experience shows that endoscopy can be traumatic and should be considered high risk. Treatment is often difficult and of limited utility. Conclusion: Guidelines for endoscopy in the setting of GI amyloidosis and GIB are lacking and these patients should be approached with caution.Figure 1Figure 2

Recombinant soluble thrombomodulin: coagulation takes another chance to reduce sepsis mortality

The striking coagulopathy in patients with severe sepsis and the increasing insight into the intricate link between inflammation and coagulation has been an inspiration for many researchers and pharmaceutical companies to explore potential therapeutic interventions for severe sepsis [1]. Indeed, in view of the high incidence of severe sepsis and sepsis mortality ranging from 20 to 50%, there is a urgent need for better treatment options [2]. As dysfunctional physiological anticoagulant regulators, such as antithrombin, activated protein C, and tissue factor pathway inhibitor, were shown to be key players in the sepsis-associated activation of coagulation, and animal studies supported the hypothesis that restoration of these pathways resulted in attenuation of coagulopathy and organ dysfunction and reduced mortality, large clinical studies were performed to establish the beneficial effect of these interventions in patients with severe sepsis [2-5]. Although some of these studies demonstrated some advantage in subgroups of patients with most extreme coagulopathies an overall reduction in mortality was not confirmed. This article is protected by copyright. All rights reserved

Primary Hyperoxaluria Diagnosed Based on Bone Marrow Biopsy in Pancytopenic Adult with End Stage Renal Disease.

Inborn errors of metabolism cause increase of metabolites in serum and their deposition in various organs including bone marrow. Primary hyperoxaluria (PH) is a rare inborn error in the pathway of glyoxylate metabolism which causes excessive oxalate production. The disease is characterized by widespread deposition of calcium oxalate (oxalosis) in multiple organs. Urinary tract including renal parenchyma is the initial site of deposition followed by extrarenal organs such as bone marrow. This case report introduces a 54-year-old woman with end stage renal disease presenting with debilitating fatigue and pancytopenia. The remarkable point in her past medical history was recurrent episodes of nephrolithiasis, urolithiasis, and urinary tract infection since the age of 5 years and resultant end stage renal disease in adulthood in the absence of appropriate medical evaluation and treatment. She had an unsuccessful renal transplantation with transplant failure. The patient underwent bone marrow biopsy for evaluation of pancytopenia. Microscopic study of bone marrow biopsy led to the diagnosis of primary hyperoxaluria.

Obstructive uropathy induced visceral gout in crested serpent eagle (Spilornischeela)

A case of mortality in two captive Crested Serpent Eagles (Spilornischeela) from Aizawl zoo was investigated for cause of death. Postmortem findings of chalky white deposits on visceral organs was indicative of visceral gout. Presence of urate deposits in various organs was confirmed by De-galantha's method. Urate tophi were also evident in sections stained with H&E. The lesions observed in both the birds were common. The kidney tubules revealed severe pathological changes and urate deposits. Similarly liver sections also revealed tophi and degenerative changes. However there was no inflammatory reaction in both the organs except around tophi. Obstructive uropathy was diagnosed as the cause of visceral gout.

AB0992 Indirect Assessment of Amyloid A Deposits in Various Organs – A New Approach of Histological Diagnosis Based on A Postmortem Clinicopathologic Study of 161 Rheumatoid Arthritis Patients

BackgroundAmyloidosis is a progressive cumulative process, in its early stage only a few structures in some organs are affected, and in later stages of the disease increasingly more may be...

Characterization of Novel PI3Kδ Inhibitors as Potential Therapeutics for SLE and Lupus Nephritis in Pre-Clinical Studies.

SLE is a complex autoimmune inflammatory disease characterized by pathogenic autoantibody production as a consequence of uncontrolled T–B cell activity and immune-complex deposition in various organs, including kidney, leading to tissue damage and function loss. There is a high unmet need for better treatment options other than corticosteroids and immunosuppressants. Phosphoinositol-3 kinase δ (PI3Kδ) is a promising target in this respect as it is essential in mediating B- and T-cell function in mouse and human. We report the identification of selective PI3Kδ inhibitors that blocked B-, T-, and plasmacytoid dendritic cell activities in human peripheral blood and in primary cell co-cultures (BioMAP®) without detecting signs of undesired toxicity. In an IFNα-accelerated mouse SLE model, our PI3Kδ inhibitors blocked nephritis development, whether administered at the onset of autoantibody appearance or the onset of proteinuria. Disease amelioration correlated with normalized immune cell numbers in the spleen, reduced immune-complex deposition as well as reduced inflammation, fibrosis, and tissue damage in the kidney. Improvements were similar to those achieved with a frequently prescribed drug for lupus nephritis, the potent immunosuppressant mycophenolate mofetil. Finally, we established a pharmacodynamics/pharmacokinetic/efficacy model that revealed that a sustained PI3Kδ inhibition of 50% is sufficient to achieve full efficacy in our disease model. These data demonstrate the therapeutic potential of PI3Kδ inhibitors in SLE and lupus nephritis.

Diagnosis and treatment of hereditary hemochromatosis: an update

Hereditary hemochromatosis is an inherited iron overload disorder caused by inappropriately low hepcidin secretion leading to increased duodenal absorption of dietary iron, most commonly in C282Y homozygous individuals. This can result in elevated serum ferritin, iron deposition in various organs and ultimately end-organ damage, although there is incomplete biochemical and clinical penetrance and variable phenotypic expression of the HFE mutation in hereditary hemochromatosis. An elevated SF <1000 µg/l is associated with an increased risk of cirrhosis and mortality in C282Y homozygotes. Conversely, a SF <1000 µg/l is associated with a very low likelihood of cirrhosis, making liver biopsy unnecessary among C282Y homozygotes in the absence of concomitant risk factors for liver disease. Phlebotomy remains the mainstay of treatment and new treatments being studied include erythrocytapheresis and ‘mini-hepcidins’. Iron overload is being recognized to play a carcinogenic role in hepatocellular carcinoma and other cancers, possibly supporting iron depletion in these patients.