Efficacy and safety of deferasirox at low and high iron burdens: results from the EPIC magnetic resonance imaging substudy.

The effect of deferasirox dosing tailored for iron burden and iron loading based on liver iron concentration (LIC) was assessed over 1 year in less versus more heavily iron-overloaded patients in a substudy of the Evaluation of Patients' Iron Chelation with Exjade®. Deferasirox starting dose was 10-30 mg/kg/day, depending on blood transfusion frequency, with recommended dose adjustments every 3 months. Therapeutic goals were LIC maintenance or reduction in patients with baseline LIC <7 or ≥7 mg Fe/g dry weight (dw), respectively. Changes in LIC (R2-magnetic resonance imaging) and serum ferritin after 1 year were assessed. Adverse events (AEs) and laboratory parameters were monitored throughout. Of 374 patients, 71 and 303 had baseline LIC <7 and ≥7 mg Fe/g dw, respectively; mean deferasirox doses were 20.7 and 27.1 mg/kg/day (overall average time to dose increase, 24 weeks). At 1 year, mean LIC and median serum ferritin levels were maintained in the low-iron cohort (-0.02 ± 2.4 mg Fe/g dw, -57 ng/mL; P = not significant) and significantly decreased in the high-iron cohort (-6.1 ± 9.1 mg Fe/g dw, -830 ng/mL; P < 0.0001). Drug-related gastrointestinal AEs, mostly mild to moderate, were more frequently reported in the <7 versus ≥7 mg Fe/g dw cohort (39.4 versus 20.8 %; P = 0.001) and were not confounded by diagnosis, dosing, ethnicity, or hepatitis B and/or C history. Reported serum creatinine increases did not increase in low- versus high-iron cohort patients. Deferasirox doses of 20 mg/kg/day maintained LIC <7 mg Fe/g dw and doses of 30 mg/kg/day were required for net iron reduction in the high-iron cohort, with clinically manageable safety profiles. The higher incidence of gastrointestinal AEs at lower iron burdens requires further investigation.

Renal involvement as a rare complication of Dorfman-Chanarin syndrome: a case report.

Dorfman-Chanarin syndrome is a rare, autosomal recessive inherited lipid storage disease with congenital ichthyotic erythroderma due to an acylglycerol recycling defect. It is characterized by accumulation of neutral lipids in different tissues. Liver, muscle, ear, eye, and central nervous system are generally involved, so we presented a patient with severe ichthyosis, lipid vacuoles in neutrophils, and multiorgan involvement including a very rare complication, renal involvement. A 7-month-old girl was presented with frequent respiratory infection, congenital ichthyotic erithroderma and suspicion for immune deficiency. On her physical examination hepatomegaly, developmental delay, palmar and plantar hyperkeratosis and increased deep tendon reflexes with clonus and high tonus were found. Laboratory investigations revealed elevation at transaminases levels, hypoalbuminemia, hypergammaglobulinemia, presence of autoantibodies and eosinophilia. Vacuolization in leukocytes confirmed Dorfman-Chanarin syndrome, whereas no mutation at RAG1-2 and ARTEMIS genes ruled-out immune deficient status of the patient. At the age of eight months the patient died from severe renal failure. Her necropsies demonstrated microvesicular lipid accumulation not only at the liver but also at the renal species. The variability of involvement of different systems in Dorfman-Chanarin syndrome is well described, however the renal findings has not been reported previously at the literature.

A patient with rubella encephalitis and status epilepticus.

Rubella is an important childhood disease that was historically widespread but is now very infrequent. It is an acute viral infection ordinarily characterized by mild constitutional symptoms. Complications are relatively uncommon in childhood. Encephalitis similar to that seen with measles occurs in about 1 in 6,000 cases. The severity is highly variable, and there is an overall mortality rate of 20%. Symptoms in survivors usually resolve within 1-3 week without neurologic sequelae. An 8.5-year-old boy presented with rubella encephalitis and status epilepticus. Five days before admission the patient had erythematous maculopapular rash on the face, spreading to the trunk and extremities. On the admission day, he had a generalized tonic-clonic seizure with loss of consciousness. Microscopic and cytologic examinations of cerebrospinal fluid showed nonspecific. Electro-encephalography (EEG) showed diffuse slowing. An enzyme linked immunosorbent assay (ELISA) revealed that rubella IgM antibody titer was positive in serum and in cerebrospinal fluid. One day later, the patient became conscious with normal physical condition. As a conclusion, it is possible to prevent the complications of rubella infection, especially the congenital rubella syndrome and encephalitis with a rapid and efficient vaccination program.

Successful desensitization of a case with desferrioxamine hypersensitivity.

Thalassaemia major is a severe chronic hemolytic disease, resulted with iron overload mainly due to regular blood transfusions. Iron overload may lead to serious organ toxicity and even fatal complications, if no iron excretion is achieved by a chelating agent. First introduced in 1976 as s.c. treatment for thalassaemia major, desferrioxamine (DFO) has substantially improved the life expectancy in the disease. While DFO can cause local allergic reactions including redness, itching, pain and lumps, on rare occasion anaphylactic reactions can occur. The mechanism of anaphylaxis like reactions is not well understood. In this case report, we presented a 10 years-old girl with thalassaemia major who had to stop DFO therapy after appearing of systemic allergic reactions with hypotension, tachycardia, pruritus and urticaria against this drug. Serum IgE level was normal, specific IgE and skin prick tests were negative. Intradermal test was resulted with positive reaction to DFO. The patient was hospitalized and desensitization protocol was initiated with rapid s.c. infusions per 15 min. The protocol was stopped at the 17th cycle because of local reaction reappeared. After that, DFO was further diluted and was restarted with lower dosage and longer infusion period. Then, DFO dosage was increased and the dilutions and infusion times were decreased gradually. By this desensitization programme, the patient would continue to use DFO chelation safely for 10 months.

Unusual presentation of brucellosis in a child: acute blindness.

UNLABELLED: In brucellosis, visual impairment due to optic nerve involvement is rare, and acute onset visual loss is an unusual presenting feature. We report a 15-y-old girl who had pancytopenia and who was admitted to our hospital with acute onset of bilateral blindness and fever. There was no light perception, and anterior segment and fundus examination were normal in both eyes. No other abnormal neurological findings were detected. Increased latencies and decreased amplitudes were found in visual evoked potentials. Cranial MR and CT revealed no abnormality. Blood culture was found to be positive for Brucella melitensis. Anti-Brucella treatment and high-dose metil prednisolon were given. Pancytopenia completely resolved 5 d after anti-Brucella treatment, and at the end of the third month her complaints about impaired vision were resolved. CONCLUSION: Brucellosis may present with uncommon symptoms in children. Physicians, particularly in areas where the disease is endemic, must consider this in differential diagnosis of a child with acute blindness and pancytopenia.

The effect of clotting factor concentrates on the immune system in HIV-negative haemophilics.

Immune abnormalities have been reported in patients with haemophilia. Although infections with HIV and hepatitis viruses contribute to these abnormalities, chronic exposure to extraneous proteins in clotting factor concentrates (CFC) may also play a role. A number of studies suggest that the degree of immunological abnormalities correlates with the amount of intermediate purity CFC administered over time. The purpose of this study was to investigate whether there were cellular and humoral immunological abnormalities in haemophilics receiving intensive factor replacement therapy with intermediate purity CFC. For this purpose 48 severe haemophilics and 33 healthy controls were enrolled in this study. T and B lymphocytes, CD4+ and CD8+ cell counts, CD4/CD8 ratio, natural killer cells, active T cells were studied in prophylaxis group, on-demand therapy group and healthy controls. In the percentages and absolute counts of lymphocyte subgroups, no significant difference was found between three groups. We also investigated serum antitetanus IgG levels in these 48 haemophilics and the controls to evaluate the specific antibody response. Antitetanus IgG levels were significantly lower in haemophilics compared to healthy controls (P < 0.001). Additionally we evaluated the response to tuberculin skin test in 45 of 48 haemophilics vaccinated with BCG. The response to PPD test was significantly lower in haemophilics compared to the controls (P = 0.037). There was no response to tuberculin test, which is the best marker of delayed type hypersensitivity (DTH) reactions in 24% of haemophilics. In conclusion, although there was no significant change in the ratio of CD4/CD8 and lymphocyte subgroups, specific antibody responses and DTH tests were partially impaired in haemophilic patients receiving intermediate purity CFC.

Intraleucocyte platelet-activating factor levels in desmopressin-treated patients with haemophilia A and von Willebrand disease.

Despite the intensive clinical use of 1-deamino-8-D-arginine vasopressin (desmopressin; DDAVP) for 20 years, its mechanism of action is still not completely explained. It has been proposed that DDAVP stimulates release of a 'second messenger' which in turn stimulates release of von Willebrand factor (vWF) from endothelial cells. Platelet-activating factor (PAF) and interleukin (IL)-6 were individually proposed to be mediators for haemostatic action. The aim of this study was to investigate cellular-based PAF levels in patients with haemophilia A (HA) and von Willebrand disease (vWD) before and after DDAVP treatment and also to look for any probable relationship between the haemostatic response of DDAVP and cellular PAF activities. In total, 20 patients (11 HA and nine vWD) were enrolled in the study. DDAVP was given subcutaneously as a single dose (0.3 microg kg(-1)). Ten patients responded to DDAVP and were defined as the 'able group' (four mild HA, six type 1 vWD). The remaining 10 patients did not respond to DDAVP and were defined as the 'unable group' (seven severe HA, three type 3 vWD). Released (extracellular) and intracellular (intraleucocyte) PAF levels under the stimulation of specific agents (A23187 and Zymosan) were measured by high-performance liquid chromatography and radioimmunoassay. Extracellular and intracellular PAF activities were not detected without stimulation in healthy children whereas significantly higher PAF levels were found in the patients (extracellular: 37.5 +/- 34.4 ng per 10(7) cells; intracellular: 24.8 +/- 23.5 ng per 10(7) cells; P=0.0001). Intracellular PAF levels obtained from in vitro unstimulated cells were significantly higher in DDAVP-responsive (able) patients in comparison to DDAVP-unresponsive (unable) patients (52.1 +/- 18.5 vs. 28.9 +/- 8.0 ng per 10(7)cells). After in vitro stimulation by A23187, intracellular PAF activities were significantly higher in patients than in controls (209.3 +/- 26.1 vs. 172 +/- 18.1 ng per 10(7) cells). Intracellular PAF levels obtained from in vitro stimulated cells by A23187 were also significantly higher in the 'able' patients in comparison to the 'unable' patients (277 +/- 43.5 vs. 225 +/- 30 ng per 10(7)cells). In conclusion, cellular PAF activities are significantly higher in patients with HA and vWD. We also suggest that PAF, especially intracellular PAF mediates intracellular signalling and may be one of the important mediators for the haemostatic response of DDAVP.

Urinary zinc excretion and zinc status of patients with beta-thalassemia major.

In this study, zinc status and urinary zinc excretion with and without desferrioxamine (DFO) infusion and the relationship between urinary zinc excretion and renal tubular dysfunction in thalassemia major (TM) patients were investigated. Forty TM patients were given four DFO infusions on alternate days over a 1-wk period prior to the transfusion. On each day that DFO was given, a 24-h urine collection initiated. DFO was omitted for 1-wk before the following transfusion and during the period four 24-h urine collections were performed. Twenty healthy children provided 24-h urine collection as controls. Blood samples were taken on each of two consecutive transfusion days of the patients and from the controls. Urinary zinc excretion was measured and plasma and red blood cell (RBC) zinc analysis were performed by inductively coupled plasma-atomic emission spectrophotometry. Urinary N-acetyl-beta-D-glucosaminidase (NAG) activity and creatinine were determined in morning urine specimens. The mean plasma zinc concentration was significantly lower in the patients not given DFO compared to the values of the patients given DFO and the control group. The mean RBC zinc concentration (micromol/g Hb) in the patients (with and without DFO) and the control group were similar. Urinary zinc excretion was significantly higher in the patients receiving DFO compared to the control group, whereas urinary zinc excretion in the patients not given DFO was not different from the controls. Urinary NAG indices (U/g Cr) were significantly higher in the patients compared to controls. Urinary zinc excretion was correlated with the urinary NAG indices.

Sequential use of deferiprone and desferrioxamine in primary school children with thalassaemia major in Turkey.

The effectiveness of the sequential use of deferiprone and desferrioxamine (DFO) in children with thalassaemia major was examined. Seven thalassaemic children in whom urinary iron induced by deferiprone was sufficient to maintain a negative iron balance were enrolled in the long-term trial. Deferiprone at a dose of 75 mg/kd/day in 3 divided doses was given for 4 school days a week. The group was given DFO at a dose of 40-50 mg/kg/day s.c. over 8-12 h with a battery-operated pump for 2 days at the weekend. In addition to the safety variables, they were monitored for serum ferritin levels at 2-month intervals and hepatic iron concentrations in liver tissues were determined at the beginning and the 6th month of therapy. The severity of hepatic damage was graded according to the Knodell hepatic activity index and the fibrosis was quantified. None of the patients suffered adverse effects of the therapy but a transient increase in serum ALT levels was noted. A nonsignificant decline in serum ferritin was observed (p = 0.08), a significant reduction in hepatic iron concentration was also determined (p = 0. 03). The hepatic activity index in liver tissues of the patients at the 6th month of the sequential therapy significantly decreased (p = 0.03) whereas fibrosis scores did not differ significantly (p = 0. 25).

Neuropsychologic sequelae in the long-term survivors of childhood acute lymphoblastic leukemia.

The neurotoxicity of either systemic chemotherapy or central nervous system prophylaxis was studied in 19 children treated for acute lymphoblastic leukemia (ALL). They had completed ALL therapy at least a year before and survived more than 5 years after diagnosis. The duration between age at diagnosis and age at investigation was 8.6 +/- 2.7 years (5-15 years). Neuropsychologic tests, cranial magnetic resonance imaging (MRI), and evoked potentials (EP) were studied. Seventeen healthy siblings were taken as a control group. Emotional evaluation was done using the childhood depression inventory and Beck depression inventory. Cognitive functions were evaluated using Wechsler's Intelligence Scale for Children-Revised (WISC-R) or the Wechsler's Adult Intelligence Scale-Revised (WAIS-R) tests, which were adapted to Turkish children. Performance and total IQ scores (94.0 +/- 16.8 and 92.2 +/- 16.5) were significantly low as compared to the control group (112.1 +/- 18.9 and 105.4 +/- 14.2) (p = .007 and p = .02). Abnormal MRI findings were found in 33.3% (6/18). Three out of 18 patients (16.6%) had abnormal auditory while 5 out of 17 patients (29.5%) displayed abnormal visual EPs. Abnormal findings in MRI, cognitive examination, and electrophysiologic testing were not associated with age at diagnosis, radiotherapy doses, intermediate/high-dose systemic methotrexate administration or central nervous system involvement. But more patients must be studied to demonstrate discrete outcomes of neurotoxicity in long-term survivors of childhood leukemia.

Inhibitor development and substitution therapy in a developing country: Turkey.

Prevalence of inhibitor in developing countries, such as Turkey, where fresh frozen plasma (FFP) is still in use due to high cost of concentrates, is unknown. To determine the frequency of inhibitors in Turkish haemophiliacs exposed to blood products, 53 haemophilia A patients (age range 1-20; median: 11 years) and 12 haemophilia B patients (age range 3-20; median: 10 years), were evaluated; 31 haemophilia A patients (23 severe) received plasma-derived concentrates and 22 patients (10 severe) only FFP. No haemophilia B patients developed inhibitor, compared with seven of 53 (13%) haemophilia A patients, all with a severe defect (7/33; 21%) and treated with concentrates (7/23; 30%), whereas severe patients treated with FFP showed a lower risk to develop inhibitors (0/10, P = 0.07). Inhibitors were detected after 8-125 exposure days (median: 52). Intermediate-purity concentrates and pasteurization seemed to be linked with a higher risk of inhibitor compared to high-purity concentrates and solvent-detergent inactivation for seven patients with inhibitor. In four of seven inhibitor patients low-dose concentrate was administered at 25 IU kg-1 twice weekly and inhibitor disappeared in 1-4 months. This regimen might be recommended for immune tolerance in developing countries for its lower cost.

Prevalence of beta-thalassaemia trait in 1124 students from Aegean region of Turkey.

Although the beta (beta) thalassaemia carrier frequency in Turkey was stated to be 2 per cent, the prevalence rate varies widely in different regions and there is limited data confirming the disorder in Aegean region. This prevalence study was planned to determine frequency of beta thalassaemia trait in the Aegean region among 1124 high school students, between 13 and 18 years old, who were selected as target population. Sensitivity of mean corpuscular volume (MCV) and mean corpuscular haemoglobin (MCH) in prediction of beta thalassaemia trait were evaluated. Venous blood samples were obtained for haemoglobin electrophoresis, HbA2 and HbF, serum iron and total iron binding capacity from students in whom the levels of haemoglobin (Hb), haemotocrite (Hct), MCV, or MCH, were low compared to normal values. The prevalence of beta thalassaemia trait in Aegean region was 3 per cent. Sensitivity of MCV and MCH for determining beta thalassaemia trait were 100 and 96 per cent, respectively.