Showing papers by "Maria Domenica Cappellini published in 2013"

A hepcidin lowering agent mobilizes iron for incorporation into red blood cells in an adenine-induced kidney disease model of anemia in rats

Abstract: Background. Anemia is a common complication of chronic kidney disease (CKD) that negatively impacts the quality of life and is associated with numerous adverse outcomes. Excess levels of the iron regulatory hormone hepcidin are thought to contribute to anemia in CKD patients by decreasing iron availability from the diet and from body stores. Adenine treatment in rats has been proposed as an animal model of anemia of CKD with high hepcidin levels that mirrors the condition in human patients. Methods. We developed a modified adenine-induced kidney disease model with a higher survival rate than previously reported models, while maintaining persistent kidney disease and anemia. We then tested whether the small molecule bone morphogenetic protein (BMP) inhibitor LDN-193189, which was previously shown to lower hepcidin levels in rodents, mobilized iron into the plasma and improved iron-restricted erythropoiesis in this model. Results. Adenine-treated rats exhibited increased hepatic hepcidin mRNA, decreased serum iron, increased spleen iron content, low hemoglobin (Hb) and inappropriately low erythropoietin (EPO) levels relative to the degree of anemia. LDN-193189 administration to adenine-treated rats lowered hepatic hepcidin mRNA, mobilized stored iron into plasma and increased Hb content of reticulocytes. Conclusions. Our data suggest that hepcidin lowering agents may provide a new therapeutic strategy to improve iron availability for erythropoiesis in CKD.

Evaluation of the 5mg/g liver iron concentration threshold and its association with morbidity in patients with β-thalassemia intermedia.

Abstract: Iron overload may still occur in transfusion-independent patients with β-thalassemia intermedia due to increased intestinal iron absorption. In this study, we evaluated the association between iron overload, using a liver iron concentration threshold of therapeutic significance (≥5mg/g), and morbidity in 168 chelation naive patients with β-thalassemia intermedia. We demonstrated that patients with a liver iron concentration ≥5mg/g have a significantly higher prevalence of several serious vascular and endocrine/bone morbidities than do patients with <5mg/g, and we established absolute morbidity risk values differentiating both groups. We also demonstrated that the association between iron overload and morbidity in such patients is independent of the effects of advancing age and disease severity. These findings suggest that treating iron burden in β-thalassemia intermedia may be associated with reduction in serious morbidity risk.

Hepatocellular carcinoma in hepatitis-negative patients with thalassemia intermedia: A closer look at the role of siderosis

Abstract: Borgna-Pignatti C, 2004, BRIT J HAEMATOL, V124, P114, DOI 10.1046-j.1365-2141.2003.04732.x; BRADBEAR RA, 1985, J NATL CANCER I, V75, P81; Bruix J, 2011, HEPATOLOGY, V53, P1020, DOI 10.1002-hep.24199; Chung HY, 2003, HEPATOL RES, V26, P254, DOI 10.1016-S1386-6346(03)00109-8; Fleming RE, 2002, ANNU REV PHYSIOL, V64, P663, DOI 10.1146-annurev.physiol.64.081501.155838; HERRINTON LJ, 1995, AM J EPIDEMIOL, V142, P692; Ioannou GN, 2003, CLIN GASTROENTEROL H, V1, P246, DOI 10.1016-S1542-3565(03)00126-5; Kowdley KV, 2004, GASTROENTEROLOGY, V127, pS79, DOI 10.1016-j.gastro.2004.09.019; Mancuso A, 2006, HEMOGLOBIN, V30, P119, DOI 10.1080-03630260500455565; Mancuso A, 2005, AM J HEMATOL, V78, P158, DOI 10.1002-ajh.20289; Mancuso A, 2010, WORLD J HEPATOL, P171; Moyo VM, 1998, EUR J HAEMATOL, V60, P28; Musallam KM, 2011, HAEMATOL-HEMATOL J, V96, P1605, DOI 10.3324-haematol.2011.047852; Origa R, 2007, HAEMATOL-HEMATOL J, V92, P583, DOI 10.3324-haematol.10842; Pietrangelo A, 2007, HEPATOLOGY, V46, P1291, DOI 10.1002-hep.21886; Restivo Pantalone G, 2010, BRIT J HAEMATOL, P245; STEVENS RG, 1988, NEW ENGL J MED, V319, P1047, DOI 10.1056-NEJM198810203191603; Taher A, 2008, HAEMATOL-HEMATOL J, V93, P1584, DOI 10.3324-haematol.13098; Taher A, 2009, BRIT J HAEMATOL, V146, P569, DOI 10.1111-j.1365-2141.2009.07810.x; Taher A, 2009, BRIT J HAEMATOL, V147, P634, DOI 10.1111-j.1365-2141.2009.07848.x; Taher AT, 2011, BRIT J HAEMATOL, V152, P512, DOI 10.1111-j.1365-2141.2010.08486.x; TURLIN B, 1995, HEPATOLOGY, V22, P446, DOI 10.1016-0270-9139(95)90564-2

Iron overload in β-thalassemia intermedia: an emerging concern.

Abstract: Casanovas G, 2013, HAEMATOLOGICA, V98, P444, DOI 10.3324-haematol.2012.069807; Gardenghi S, 2010, J CLIN INVEST, V120, P4466, DOI 10.1172-JCI41717; Ginzburg Y, 2011, BLOOD, V118, P4321, DOI 10.1182-blood-2011-03-283614; Karimi M, 2011, EUR J INTERN MED, V22, P607, DOI 10.1016-j.ejim.2011.05.013; Li HH, 2010, NAT MED, V16, P177, DOI 10.1038-nm.2073; Maakaron JE, 2013, ANN HEPATOL, V12, P142; Musallam KM, 2012, ANN HEMATOL, V91, P235, DOI 10.1007-s00277-011-1291-3; Musallam KM, 2011, HEMOGLOBIN, V35, P503, DOI 10.3109-03630269.2011.605499; Musallam KM, 2012, BLOOD CELL MOL DIS, V49, P136, DOI 10.1016-j.bcmd.2012.06.001; Musallam KM, 2011, HAEMATOL-HEMATOL J, V96, P1605, DOI 10.3324-haematol.2011.047852; Musallam KM, 2012, CSH PERSPECT MED, V2, DOI 10.1101-cshperspect.a013482; Musallam KM, 2012, BLOOD, V120; Musallam KM, 2012, BLOOD, V120; Musallam KM, 2012, BLOOD REV, V26, pS16, DOI 10.1016-S0268-960X(12)70006-1; Musallam KM, 2011, EUR J HAEMATOL, V87, P539, DOI 10.1111-j.1600-0609.2011.01706.x; Musallam KM, 2012, THROMB RES, V130, P695, DOI 10.1016-j.thromres.2012.07.013; Nai A, 2012, BLOOD, V119, P5021, DOI 10.1182-blood-2012-01-401885; Origa R, 2007, HAEMATOL-HEMATOL J, V92, P583, DOI 10.3324-haematol.10842; Pakbaz Z, 2007, PEDIATR BLOOD CANCER, V49, P329, DOI 10.1002-pbc.21275; Parrow NL, 2012, BLOOD, V119, P3187, DOI 10.1182-blood-2012-01-405563; Rivella S, 2012, BLOOD REV, V26, pS12, DOI 10.1016-S0268-960X(12)70005-X; Taher A, 2008, HAEMATOL-HEMATOL J, V93, P1584, DOI 10.3324-haematol.13098; Taher A, 2009, BRIT J HAEMATOL, V146, P569, DOI 10.1111-j.1365-2141.2009.07810.x; Taher A, 2012, HAEMATOLOGICA, V96, P0924; Taher A., 2012, HAEMATOLOGICA, V96; Taher AT, 2010, AM J HEMATOL, V85, P288, DOI 10.1002-ajh.21626; Taher AT, 2010, BRIT J HAEMATOL, V150, P486, DOI 10.1111-j.1365-2141.2010.08220.x; Taher AT, 2012, BLOOD, V120, P970, DOI 10.1182-blood-2012-02-412692; Taher AT, 2011, BRIT J HAEMATOL, V152, P512, DOI 10.1111-j.1365-2141.2010.08486.x; Taher AT, 2012, BLOOD, V120, P3258; Taher AT, 2010, BLOOD, V115, P1886, DOI 10.1182-blood-2009-09-243154; Wood John C, 2011, Hematology Am Soc Hematol Educ Program, V2011, P443, DOI 10.1182-asheducation-2011.1.443; Ziyadeh FN, 2012, NEPHRON CLIN PRACT, V121, pC136, DOI 10.1159-000339787

Assessment and management of iron overload in β-thalassaemia major patients during the 21st century: a real-life experience from the Italian Webthal project

Abstract: Summary We conducted a cross-sectional study on 924 β-thalassaemia major patients (mean age 30·1 years) treated at nine Italian centres using the webthal software, to evaluate real-life application of iron overload assessment and management standards. Serum ferritin 2 years. Patients who never had a cardiac MRI (CMR) T2* measurement were 2 years. Deferoxamine (22·8%) was more commonly used in patients with Hepatitis C Virus or high serum creatinine. Deferiprone (20·6%) was less commonly prescribed in patients with elevated alanine aminotransferase; while a deferoxamine + deferiprone combination (17·9%) was more commonly used in patients with serum ferritin >2500 ng/ml or CMR T2* <20 ms. Deferasirox (38·3%) was more commonly prescribed in patients <18 years, but less commonly used in those with heart disease or high iron intake. These observations largely echoed guidelines at the time, although some practices are expected to change in light of evolving evidence.

Epidemiology of Clostridium difficile-associated disease in internal medicine wards in northern Italy

Abstract: Clostridium difficile-associated disease (CDAD) is a growing health care problem. Elderly patients with multiple comorbidities and repeated hospitalization are at high risk for developing the disease. Few data are available on epidemiology of CDAD in Italy and no studies have focused on CDAD burden in internal medicine wards. We retrospectively analysed all CDAD cases in four internal medicine wards of a city hospital in northern Italy and reviewed the medical records of patients who developed CDAD during hospitalization. We identified 146 newly acquired cases, yielding a cumulative incidence of 2.56 per 100 hospitalizations and an incidence rate of 23.3 per 10,000 patient-days. Main risk factors were advanced age and length of hospitalization. A high proportion of CDAD patients had several comorbidities and had been treated with more than one antibiotic. The incidence is among the highest previously reported, this may be due to the characteristics of patients admitted to internal medicine wards and to the wards per se. We conclude that efforts are needed to reduce CDAD’s burden in this setting, paying attention to logistics, patients care and antibiotic use.

Geographical variations in current clinical practice on transfusions and iron chelation therapy across various transfusion-dependent anaemias

Abstract: Abetz L, 2006, HEALTH QUAL LIFE OUT, V4, DOI 10.1186-1477-7525-4-73; Adams RJ, 1998, NEW ENGL J MED, V339, P5, DOI 10.1056-NEJM199807023390102; Adams RJ, 2005, NEW ENGL J MED, V353, P2769; Angelucci E, 2008, HAEMATOL-HEMATOL J, V93, P741, DOI 10.3324-haematol.12413; Arrizabalaga B, 2008, HAEMATOLOGICA S1, V93, P3; Bennett JM, 2008, AM J HEMATOL, V83, P858, DOI 10.1002-ajh.21269; BRITTENHAM GM, 1994, NEW ENGL J MED, V331, P567, DOI 10.1056-NEJM199409013310902; Cabantchik ZI, 2005, BEST PRACT RES CL HA, V18, P277, DOI 10.1016-j.beha.2004.10.003; Cappellini MD, 2010, HAEMATOL-HEMATOL J, V95, P557, DOI 10.3324-haematol.2009.014696; Cappellini MD, 2006, BLOOD, V107, P3455, DOI 10.1182-blood-2005-08-3430; Daar S, 2009, EUR J HAEMATOL, V82, P454, DOI 10.1111-j.1600-0609.2008.01204.x; Esposito BP, 2003, BLOOD, V102, P2670, DOI 10.1182-blood-2003-03-0807; Fung EB, 2007, AM J HEMATOL, V82, P255, DOI 10.1002-ajh.20809; Gattermann N, 2005, HEMATOL ONCOL CLI S1, V19, P18; Hellstrom-Lindberg E, 2005, SEMIN HEMATOL, V42, pS10, DOI 10.1053-j.seminhematol.2005.01.002; Lee JW, 2008, INT J HEMATOL, V88, P16, DOI 10.1007-s12185-008-0117-0; Lee JW, 2010, BLOOD, V116, P2448, DOI 10.1182-blood-2010-01-261289; Marsh JCW, 2009, BRIT J HAEMATOL, V147, P43, DOI 10.1111-j.1365-2141.2009.07842.x; National Comprehensive Cancer Network, 2010, NCCN CLIN PRACT GUID; National Institutes of Health NHLBI, 2002, NIH PUBL; OLIVIERI NF, 1994, NEW ENGL J MED, V331, P574, DOI 10.1056-NEJM199409013310903; Riewpaiboon Arthorn, 2010, BMC Res Notes, V3, P29, DOI 10.1186-1756-0500-3-29; Sickle Cell Society, 2008, STAND CLIN CAR AD SI; Storb R, 1997, J Intraven Nurs, V20, P317; St Pierre TG, 2004, NMR BIOMED, V17, P446, DOI 10.1002-nbm.905; Suzuki T, 2008, INT J HEMATOL, V88, P30, DOI 10.1007-s12185-008-0119-y; Taher A, 2009, EUR J HAEMATOL, V82, P458, DOI 10.1111-j.1600-0609.2009.01228.x; Telfer PT, 2000, BRIT J HAEMATOL, V110, P971, DOI 10.1046-j.1365-2141.2000.02298.x; Thalassaemia International Federation, 2008, GUID CLIN MAN THAL; Vichinsky E, 2008, STANDARDS CARE GUIDE; Viprakasit V, 2009, INT J HEMATOL, V90, P435, DOI 10.1007-s12185-009-0432-0

An update on thalassemia intermedia

Abstract: Thalassemia intermedia is a genetically diverse group of diseases that is the result of an imbalance in the production of the alpha and beta chains with ensuing chronic hemolysis, ineffective erythropoiesis, and iron overload. Resulting complications include bone changes, hypercoagulability, and end-organ damage due to iron overload. This decade has witnessed major breakthroughs in the management of thalassemia. In this article, we examine these novelties in therapy including iron chelation therapy, stem cell transplant, and gene therapy. Iron chelation therapy has been revolutionized with the advent of deferasirox, a once-daily oral iron chelator, that has been shown to be safe and efficacious. Gene therapy was also at the core of this revolution with the discovery of novel gene elements and viral vectors allowing for better control and improved outcomes.

Mosaic segmental uniparental isodisomy and progressive clonal selection: a common mechanism of late onset β-thalassemia major.

Abstract: Genomic DNA of 3 patients, born as healthy carriers and developing a late-onset severe transfusion-dependent beta-thalassemia major was studied by high-density genome wide SNP array analysis. A mosaic loss of heterozygosity for almost the entire 11p was found, not attributable to deletions but involving mosaicism for segmental paternal isodisomy of 11p. Mitotic recombination leading to mosaic segmental uniparental isodisomy on chromosome 11p in multiple tissues has been described as a molecular disease mechanism for a subset of sporadic Beckwith-Wiedemann syndrome cases. A similar mechanism also seems to be involved in causing late-onset disease in carriers of recessive mutations in other genes located in 11p, such as late-onset beta-thalassemia major and sickle cell disease. We suggest that the loss of maternally imprinted IGF-2 and H19 genes may account for the selective advantage of hematopoietic cells containing this segmental paternal isodisomy of 11p carrying the β-thalassemia mutation.

Altered iron homeostasis in an animal model of hypertensive nephropathy: stroke-prone rats.

Abstract: BACKGROUND AND AIM Iron is the most abundant metal in mammalian cells, and plays a pivotal role in many metabolic processes. Dysregulated iron homeostasis is involved in the cause of a number of pathological processes including renal diseases. METHODS AND RESULTS Longitudinal MRI scans of salt-loaded spontaneously hypertensive stroke-prone rats (SHRSP), an animal model that spontaneously develops hypertensive nephropathy, showed a decrease in renal and hepatic T2 SI (a sign of iron accumulation) of, respectively, 42.3 ± 2.5% (P < 0.01) and 60.4 ± 15.1% (P < 0.01) in comparison with SHRSP fed a standard diet. This was accompanied by the development of renal inflammation and oxidative stress (as evaluated by immunohistochemical and proteomic analyses), mitochondrial dysfunction, massive proteinuria and sustained intravascular hemolysis with the subsequent depletion of plasma haptoglobin, which was responsible for the renal uptake of hemoglobin and iron accumulation. In order to investigate the role of iron in these pathological processes, we subcutaneously treated the salt-loaded rats with the iron chelator deferoxamine (200 mg/kg per day). The pharmacological treatment prevented iron tissue accumulation, as indicated by the increase in renal and hepatic T2 SI of, respectively, 120.0 ± 10.1% (P < 0.01) and 73.9 ± 4.4% (P < 0.01) in comparison with salt-loaded rats treated with vehicle alone. Deferoxamine also preserved renal morphology and function, the renal infiltration of ED-1-positive macrophages/monocytes, and the expression of MCP-1 and TGF-β mRNA, reduced the level of reactive oxygen species, and improved the activity of mitochondrial cytochrome c oxidase. CONCLUSION These findings suggest that iron dysmetabolism is involved in the development of hypertensive nephropathy in SHRSP.

Very high frequency of TMPRSS6 gene variations in iron deficiency anaemia of patients with polyendocrine autoimmune syndromes: more than a casual association?

Abstract: Sophie Gandrille R egis Peffault de Latour Emeline Levionnois Paula Rodriguez-Otero Isabelle Galy–Fauroux Laurence Zemori Sarah Abbes Anna D. Petropoulou G erard Soci e Anne-Marie Fischer Dominique Helley INSERM U765, Paris, France, Univ Paris Descartes, Sorbonne Paris Cit e, Paris, France, AP-HP, Biological Haematology, Georges Pompidou European Hospital, Paris, France, AP-HP, Haematology Bone Marrow Transplantation, Hospital Saint-Louis, Paris, France, Univ Paris Diderot, Sorbonne Paris Cit e, Paris, France, and INSERM U728 Paris, France E-mail: dominique.helley@egp.aphp.fr

Prolonged PT and aPTT in a patient with severe proteinuria.

Abstract: Dr. Motta and Dr. Migone: A 70-year-old woman was admitted to our medical unit because of severe leg and pedal edema and peripheral paresthesias gradually developed during the prior 3 months; she was suffering from cramps during the previous week. The patient had a history of hypertension and type 2 diabetes (glycated hemoglobin 6.4 %) well-controlled by oral hypoglycemic drugs for the last 6 years. Ten months prior to admission, blood and urinalysis were normal, ophthalmologic examination and US Doppler of legs arteries did not show pathological signs. Six months before admission, the patient underwent surgery for a carpal tunnel syndrome. She also underwent hysterectomy 20 years prior and cholecystectomy 40 years prior; both surgeries were uncomplicated. The home treatment during the prior 3 months was candesartan/hydrochlorothiazide, allopurinol, nebivolol, amlodipine, gliclazide, cardioaspirin. At admission, the patient was alert and cooperative. Blood pressure was 130/70 mmHg, pulse 98 beats/min and saturation was 96 % on room air. BMI was 34. On examination, she was pale and had severe bilateral legs edema from the knees. Peripheral pulses were good distally. The chest was clear and a 2/6 systolic murmur was heard. The abdomen was obese, soft, non tender, non distended, no hepatosplenomegaly was appreciated; bowel sounds were active. On neurologic examination she complained paresthesias of the extremities, no focal deficits were present. Blood tests revealed a mild renal insufficiency (serum creatinine 1.38 mg/dl, MDRD GFR 40 ml/min/1.73 mq, BUN 91 mg/dl) that rapidly worsened, with severe hyperkalemia and hypoalbuminemia. A nephrotic proteinuria associated with a mild microscopic hematuria was detected (Table 1).

Challenges in dealing with a cirrhotic patient

Abstract: Dr. Spinelli We report a case of a 75-year-old woman with Child-Pugh Class 7 B HCV cirrhosis, admitted to our hospital for high fever (38.5 C), chills and fatigue. These symptoms started approximately 1 month prior, and progressively worsened. At home, she was treated with levofloxacin without benefit. She reported anorexia and loss of weight of 4 kg. A recent upper-digestive endoscopy (EGDS) showed fine caliber esophageal varices; the ultrasonography of the abdomen revealed signs of chronic liver disease and splenomegaly. The patient was alert and oriented, even if a bit slackened. On physical examination, she had no sign of meningismus and no jaundice. Vital signs: body temperature 37.5 C, heart rate 72 beats/min, blood pressure of 100/60 mmHg. Oxygen saturation by pulse oximetry was 95 % on room air. Body mass index (BMI): 19.9. Cranial nerve examination was normal. She had minimal ascites and hepatomegaly. There was edema of grade-2 in the lower extremity bilaterally. The rest of the general body examination was normal. Blood laboratory tests revealed a sever iron deficiency anaemia (haemoglobin 7.6 g/dl), increased transaminases, low pseudocholinesterase and hypoalbuminemia. Inflammation indices were negative. She was transfused with several red blood cells (RBC) units, and was initially treated with ceftriaxone without benefit. She was initially supported with a balanced hypoproteinemic low-sodium oral diet. Because of worsening deterioration of the general condition, she was also treated with parenteral nutrition (aminoacid solution, vitamins, glucose, electrolytes, lipids) for a total caloric contribution of 1,320 kcal/daily.