Evaluation of the effect of eltrombopag therapy on the platelet collagen receptor glycoprotein VI (GPVI) expression and soluble GPVI levels in young patients with immune thrombocytopenia.

BACKGROUND: Platelet glycoprotein VI (GPVI) receptor is essential for platelet adhesion and aggregation. Eltrombopag is as an effective treatment for chronic immune thrombocytopenia (ITP); yet, its effect on platelet function is not fully characterized. AIM: This prospective study investigated the effect of eltrombopag therapy on platelet function through assessment of GPVI receptor expression and soluble GPVI levels among pediatric patients with persistent or chronic ITP. METHODS: Thirty-six children and adolescents with persistent or chronic ITP were divided equally into two groups either to receive eltrombopag therapy or the standard of care. All patients were followed-up for 12 months with assessment of bleeding score and complete blood count (CBC). Evaluation of GPVI expression using flow cytometry and measurement of its soluble form by ELISA was done at baseline and at 6 months. RESULTS: ITP patients on eltrombopag had significantly lower bleeding score after 6 months of therapy while the quality of life has significantly improved. Platelet count was significantly increased throughout the study. GPVI expression by flow cytometry and soluble GPVI levels were significantly increased after eltrombopag therapy. After 12 months, ITP patients on eltrombopag were able to maintain a good quality of life and low bleeding score. CONCLUSION: Our data suggest that eltrombopag, through its effect on the GPVI receptor expression and its soluble form, might reduce bleeding manifestations and improve the quality of life of chronic and persistent ITP children independent of its effect on the platelet count.

Endothelin-1 gene polymorphism (G8002A) and endothelial monocyte-activating polypeptide II: Role in vascular dysfunction in pediatric patients with ß-thalassemia major.

BACKGROUND: Endothelin-1 (ET-1), a potent endogenous vasoconstrictor, stimulates production of reactive oxygen species. Endothelial monocyte-activating polypeptide-II (EMAP-II) is a multifunctional polypeptide. AIM: To assess ET-1 gene polymorphism (G8002A) in pediatric patients with ß-thalassemia major (ß-TM) as a potential genetic marker for vascular dysfunction and its possible relation to EMAP II, oxidative stress and vascular complications. METHODS: ß-TM patients (n = 95) without symptomatic cardiac or renal disease were compared with 95 healthy controls. Markers of hemolysis, serum ferritin, urinary albumin-to-creatinine ratio, serum EMAP II, malondialdehyde (MDA) and antioxidant enzymes; superoxide dismutase (SOD), glutathione peroxidase (GPx), reduced glutathione (GSH), glutathione reductase and catalase were measured. ET-1 gene polymorphism (G8002A) was determined using polymerase chain reaction­restriction fragment length polymorphism. RESULTS: ß-TM patients had significantly higher EMAP II than healthy controls. EMAP II was significantly higher among patients with cardiac disease, pulmonary hypertension (PH) risk, nephropathy, poor compliance to therapy and ferritin ≥ 2500 µg/L. There were significant correlations between EMAP II and transfusion index, LDH, ferritin and oxidative stress markers. The AA genotype of ET-1 gene polymorphism (G8002A) was significantly higher among ß-TM patients than controls. The number of patients with cardiac disease, PH risk or nephropathy was significantly higher among AA genotype compared with GG and GA genotypes. Lactate dehydrogenase (LDH), serum ferritin, EMAP II, MDA, SOD and GPx were significantly higher in AA genotype. CONCLUSION: ET-1 gene polymorphism (G8002A) could be a possible genetic marker for prediction of increased susceptibility to cardiopulmonary and renal complications among pediatric patients with ß-TM.

Endothelial specific isoform of type XVIII collagen (COL-18N): A marker of vascular integrity in haemophilic arthropathy.

BACKGROUND: Haemophilic arthropathy (HA) is a major complication in haemophilia. Collagens IV, XV and XVIII are responsible for maintaining the integrity of the vessel wall in the joint. Following joint remodelling and damage, the short isoform of collagen type XVIII (COL-18N) is degraded, releasing measurable fragments. Our goal was to quantify the specific isoform COL-18N in haemophilia A patients and to assess its relation to the clinical and radiological data as well as haemophilia joint health score (HJHS), functional independence score for haemophilia (FISH), and haemophilia quality of life (Haemo-Qol). METHODS: This cross-sectional study included 50 haemophilia A patients recruited from the Paediatric Haematology and Oncology unit, Ain Shams University, Cairo, Egypt. Quantification of COL-18N was done by ELISA. Assessment of joint state clinically using FISH and HJH scores and radiologically by X-rays and ultrasound. RESULTS: Haemophilia A patients had significantly higher median COL-18N levels compared to the control group. Inhibitor positive and negative haemophilia A patients as well as those on non-steroidal anti-inflammatory drug and those not had comparable COL-18N levels. Patients with ≥2 target joints had significantly higher COL-18N level compared to those with one or those without target joints. There were significant positive correlations between COL-18N level and the total HJHS, Haemo-Qol, the HEAD-US score and annual bleeding rate. CONCLUSION: Our results demonstrated a high level of COL-18N in haemophilia A patients and argued its benefit as a potential marker for monitoring the development of haemophilic arthropathy and tailoring the optimal treatment to prevent further joint damage.

Abdominal lymphadenopathy in children with Gaucher disease: Relation to disease severity and glucosylsphingosine.

Few case reports and series reported abdominal lymphadenopathy (ALN) in people with Gaucher disease (GD). However, it's prevalence among Gaucher population, clinical implications and potential biomarkers are unknown. Hence this study aims to assess the prevalence of ALN among children with GD & to correlate it to neutrophil-lymphocytic-ratio (NLR), platelet-lymphocytic-ratio (PLR) and glucosylsphingosine (Lyso-GL1). Fifty children with GD (14 type-1 and 36 type-3) on enzyme-replacement therapy (ERT) were compared to 50 matched healthy controls, focusing on history of pressure manifestations by ALN (diarrhea, constipation, abdominal pain, intestinal obstruction), and history of splenectomy, with calculation of severity scoring index (SSI). NLR, PLR and Lyso-GL1 were measured. Abdominal-ultrasound was done with assessment of liver and spleen volumes and ALN. CT-scan was done for those having significant lymphadenopathy. Twenty-six children with GD had ALN (52%). The most common presentations were abdominal-pain (22%) & constipation (18%), with intestinal-obstruction in 3 children (6%). Children with GD had significantly higher NLR (p < .001) and decreased PLR (p = .024) compared to controls. Interestingly, children with GD having ALN had significantly higher SSI (.012), Lyso-GL1 (p = .002) and NLR (p = .001) than those without ALN. Multivariate-logistic regression showed that ALN was independently related to Lyso-GL1 (p = .027), NLR (p = .023) and SSI (p = .032). Thus, ALN is a prevalent GD morbidity with wide clinical-spectrum ranging from asymptomatic cases to intestinal obstruction. ALN is related to SSI, NLR and Lyso-GL1 in children with GD.HighlightsChildren with GD had significantly higher NLR and lower PLR compared to controls.Children with GD having ALN had significantly higher SSI, Lyso-GL1 and NLR than those without ALN.ALN was independently related to Lyso-GL1, NLR and SSI in children with GD.

A two-dimensional speckle-tracking echocardiography for the diagnosis of early myocardial disease in beta-thalassemia major patients.

Background: Although magnetic resonance imaging T2* is considered the gold standard to assess myocardial iron overload in ß-thalassemia patients, its routine use is limited by the high cost and limited availability. Recent data demonstrated that strain imaging by speckle tracking is a sensitive tool for early assessment of the left ventricular myocardial dysfunction. This study aims to evaluate the clinical utility of two-dimensional (2D) speckle-tracking echocardiography (STE) for the detection of early myocardial disease in beta-thalassemia major (ß-TM) patients. Materials and Methods: 2D STE, magnetic resonance imaging (MRI) heart T2* and MRI liver iron content were done for 30 ß-TM patients with no clinical heart disease, compared to 2D STE in 30 healthy age- and sex-matched controls. Results: There was a significant reduction in the longitudinal systolic strain values by STE among ß-TM patients compared to controls (P = 0.05). A longitudinal peak systolic strain cutoff values of ≤-19 was able to detect ß-TM patients having subclinical cardiac iron overload by MRI T2* (sensitivity = 90%-93.3%, specificity = 83%-100%). Mean serum ferritin in the past 2 years correlated negatively to longitudinal systolic strain values global longitudinal peak systolic strain average (P = 0.05).

Ganglion Cell Complex Thinning in Young Gaucher Patients: Relation to Prodromal Parkinsonian Markers.

BACKGROUND: Patients with Gaucher disease (GD) have an increased risk for parkinsonism. Retinal thinning has been described in parkinsonism as an early nonmotor feature. Scarce reports have addressed retinal thickness changes in GD. OBJECTIVES: The objectives of this study were to compare ganglion cell complex (GCC) thickness in adolescents and young adults (AYAs) with GD with healthy control subjects, and to correlate it with the presence of parkinsonian features (PFs), clinical prodromal markers of parkinsonism, severity score index (SSI), and glucosylsphingosine (Lyso-GL-1). METHODS: This study included 48 AYAs with GD (11-29 years), 11 with manifest PFs (Group 1) and 37 with no PFs (Group 2), and 48 matched healthy control subjects (Group 3). Age of GD onset, disease duration, medication history, history of constipation, SSI, and hematological assessment were done. Neurocognitive evaluation included Parts I, II, and III of the Unified Parkinson's Disease Rating Scale (UPDRS), Wechsler Adult and Intelligence Scale and Wechsler Intelligence Scale for Children, Beck Depression Inventory (BDI), rapid eye movement sleep behavior disorder (RBD) scale, Munich Parasomnia Screening scale, and the olfactory dysfunction scale. Molecular analyses of the acid GBA gene and Lyso-GL-1 were done. Participants underwent full ophthalmological examination and optical coherence tomography with GCC thickness measurement. RESULTS: GCC was significantly thinner in Group 1 than in Groups 2 and 3 (P < 0.001), whereas no significant difference was found between Groups 2 and 3 (P = 0.977). In addition, a significant interocular GCC thickness difference was found among the studied AYAs with GD (P = 0.007). GCC correlated positively with total intelligence quotient (P < 0.001) and negatively with Lyso-GL-1 (P = 0.019), UPDRS (P = 0.004), and BDI (P = 0.029), but not with SSI (P = 0.874), GD type (P = 0.85), or genotype (P = 0.842). A significant negative relationship was found between GCC thickness and PFs (P = 0.001), parasomnia (P = 0.003), constipation (P = 0.031), RBD (P = 0.044), and hyposmia (P = 0.033). CONCLUSIONS: GCC thinning may be a promising biomarker for central nervous system neurodegeneration that has the potential to monitor early PFs among people with GD. © 2020 International Parkinson and Movement Disorder Society.

Cognitive decline and depressive symptoms: early non-motor presentations of parkinsonism among Egyptian Gaucher patients.

Evidence about the link between glucocerebrosidase (GCase) and parkinsonism is growing. Parkinsonism was described in adult type 1 Gaucher disease (GD); few case reports described it in type 3GD. To assess the presence of parkinsonian features in a cohort of Egyptian GD patients and correlate these findings to their genotype, phenotype, severity scoring index (SSI), cognitive function, and the presence of depressive symptoms. Twenty-four GD patients from the Pediatric Hematology Clinic, Ain Shams University, were assessed for medication history, neurological symptoms, depressive symptoms, and family history of parkinsonism. Anthropometric measures, complete neurological assessment, and SSI were examined. Neuropsychiatric evaluation included parts I, II, III, and V of the Unified Parkinson's Disease Rating Scale (UPDRS), Beck Depression Inventory (BDI), and Wechsler Intelligence Scale for Children (WISC-children). Molecular analysis of the acid GBA gene was performed, and SSI was calculated. Sixteen GD patients (66.6%) had parkinsonian features with a male to female ratio of 1:1. Their mean age was 15.69 ± 5.62 (range, 12-26). They were all on enzyme replacement therapy (ERT) with a dose of 60 U/kg/2 weeks. Twelve GD patients were phenotypically type 3 (75%). Thirteen GD patients with parkinsonian features (81.25%) had L483P mutation. GD patients with parkinsonian features had higher SSI (P < 0.001), lower cognitive functions (P = 0.007), and more significant depressive symptoms (P = 0.031). Logistic regression analysis revealed that GD genotype (P = 0.003), GD type (P = 0.006), and cognitive functions (P = 0.03) were the only significant independent factors for the development of parkinsonian features among GD patients. With the increased life span and improved somatic manifestations of type 3GD on ERT, these patients can live to develop parkinsonism. Cognitive decline and depression can be early predictors of parkinsonism among GD population.

Psychiatric manifestations in Egyptian Gaucher patients on enzyme replacement therapy.

OBJECTIVES: Gaucher disease (GD) may include psychiatric symptoms as a part of its wide spectrum of manifestations, with several reports describing its association with mood or psychotic symptoms. We investigated the presence of psychiatric manifestations in an Egyptian sample of Gaucher Disease (GD) patients. METHODS: Our sample consisted of 22 GD patients (diagnosed by low glucocerebrosidase (GBA) activity in leukocytes or fibroblasts and molecular analysis by full (GBA) gene sequencing). 13 patients were classified as GD type 1 and 9 patients as GD type 3. We assessed the presence of psychiatric symptoms using the Mini-international neuropsychiatric interview (M.I.N·I) and the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID) tools. Arabic versions were used. RESULTS: The results showed that 41% of the sample had psychiatric disorders, with the most common being depression. None was receiving any form of psychiatric treatment. We found no statistically significant association between the presence of psychiatric disorders and any of the clinical variables of GD, its phenotype, or genotype. CONCLUSION: The current results suggest that GD patients are susceptible to psychiatric disorders. However, these results need to be replicated on a wider scale. These findings are of ultimate importance, considering the lack of integrated services addressing both the medical and psychological aspects of inborn errors of metabolism in many countries.

Soluble fms-Like Tyrosine Kinase 1 as a Link Between Angiogenesis and Endothelial Dysfunction in Pediatric Patients With ß-Thalassemia Intermedia.

Endothelial damage has been implicated in the pathogenesis of vascular complications in ß-thalassemia intermedia (ß-TI). Soluble fms-like tyrosine kinase 1 (sFLT-1) is a member of the vascular endothelial growth factor receptor (VEGFR) family. Soluble fms-like tyrosine kinase 1 is an antiangiogenic protein that induces endothelial dysfunction by adhering to and inhibiting VEGF and placenta growth factor. The aim of this study was to assess the level of sFLT-1 in 35 children and adolescents with ß-TI, correlating it with markers of hemolysis and iron overload as well as cardiopulmonary complications. Patients were studied focusing on the history of cardiac disease, splenectomy, transfusion, chelation/hydroxyurea therapy, serum ferritin, and sFLT-1 levels. Echocardiography and measurement of carotid intima-media thickness (CIMT) were done for all participants. Soluble fms-like tyrosine kinase 1 was significantly higher in TI patients compared to the control group (median [interquartile range], 110 [80-155] pg/mL versus 70 [60-90] pg/mL; P < .001). Splenectomized patients and those who had pulmonary hypertension risk or heart disease had higher sFLT-1 levels than those without ( P < .001). The sFLT-1 cutoff value that differentiates patients with and without pulmonary hypertension risk or heart disease was determined. Soluble fms-like tyrosine kinase 1 was lower among patients who received chelation therapy and/or hydroxyurea. Significant positive relations were observed between sFLT-1 and lactate dehydrogenase, serum ferritin, liver iron concentration, tricuspid regurgitant jet velocity, and CIMT. We suggest that sFLT-1 represents a link between angiogenesis, endothelial dysfunction, and subclinical atherosclerosis. Measurement of sFLT-1 as a marker of vascular dysfunction in ß-TI may provide utility for early identification of patients at increased risk of cardiopulmonary complications.

Tartrate-Resistant Acid Phosphatase 5b in Young Patients With Sickle Cell Disease and Trait Siblings: Relation to Vasculopathy and Bone Mineral Density.

Bone involvement is a frequent cause of acute morbidity in sickle cell disease (SCD). Tartrate-resistant acid phosphatase 5b (TRACP 5b), a bone resorption marker, is produced specifically by activated osteoclasts. We assessed bone mineral density (BMD) in 30 young patients with SCD and 17 asymptomatic patients with sickle cell trait (SCT) compared with 32 healthy controls and determined TRACP 5b levels in relation to vascular complications. Serum ferritin, alkaline phosphatase (ALP), and TRACP 5b were measured. Echocardiography was performed with assessment of BMD using dual energy X-ray absorptiometry (DXA). The BMD was decreased in patients with SCD compared with SCT and controls (P = .005), with no significant difference between the latter 2 groups. Patients with SCD had higher incidence of bone complications than SCT group and controls (P = .03). The SCD group with abnormal DXA scan had higher ferritin and ALP than normal BMD. Serum TRACP 5b was significantly higher in patients with SCD than SCT and controls (P = .003). The TRACP 5b levels were associated with severe vaso-occlusive crisis (P = .022). Patients treated with hydroxyurea and those on chelation therapy had lower TRACP 5b levels than untreated patients. The TRACP 5b level was positively correlated with lactate dehydrogenase, while there was no relation with ferritin, ALP, or BMD. We suggest that bone complications frequently occur in SCD as reflected by low BMD and high ALP and TRACP 5b. Hemolysis and iron overload may be involved in the occurrence of these complications. The lack of correlation between abnormal DXA scan and high TRACP 5b suggests that bone disease in SCD is multifactorial.

Clinical Predictive Value of Cystatin C in Pediatric Sickle Cell Disease: A Marker of Disease Severity and Subclinical Cardiovascular Dysfunction.

BACKGROUND: Patients with sickle cell disease (SCD) are at high risk of renal dysfunction and cardiovascular morbidity. The association between cystatin C and renal function is well known, however, cystatin C has recently emerged as a strong predictor of cardiovascular events and adverse outcomes in patients with and without kidney disease, mostly related to both inflammation and atherosclerosis. AIM: To determine cystatin C levels in 53 children and adolescents with SCD compared to 40 age- and sex-matched healthy controls and assess its relation to markers of hemolysis, iron overload, sickle vasculopathy, and carotid intima-media thickness (CIMT). METHODS: Patients with SCD in steady state were studied, focusing on hydroxyurea therapy, hematological profile, serum ferritin, high-sensitivity C-reactive protein (hs-CRP), urinary albumin-creatinine ratio (UACR), and serum cystatin C. Echocardiography and CIMT were assessed using high-resolution ultrasound. Heart disease was defined by systolic left ventricle dysfunction (shortening fraction <30% or ejection fraction <55%). RESULTS: Carotid IMT was significantly higher in patients with SCD compared to controls ( P < .001). Patients with SCD having nephropathy, heart disease, or history of frequent sickling crisis (≥3 attacks/y) had significantly higher cystatin C levels than those without ( P < .05). Patients with SCD treated with hydroxyurea had lower cystatin C levels than untreated patients ( P = .039). High-sensitivity C-reactive protein, UACR, ejection fraction, and CIMT were independently related to cystatin C in multiple regression analysis. The cutoff values of cystatin C for detection of renal or cardiovascular complications were determined. CONCLUSION: Cystatin C may be considered a biological marker for vascular dysfunction and subclinical atherosclerosis in SCD.

Growth differentiation factor-15 in children and adolescents with thalassemia intermedia: Relation to subclinical atherosclerosis and pulmonary vasculopathy.

BACKGROUND: Heart disease is the leading cause of mortality and one of the main causes of morbidity in ß-thalassemia. Growth differentiation factor-15 (GDF-15), a member of the transforming growth factor-ß superfamily, is a marker of ineffective erythropoiesis in several anemias. AIM: To determine GDF-15 levels in children and adolescents with TI and the relation to hemolysis, iron overload and cardiovascular complications. METHODS: GDF-15 was measured in 35 TI patients without symptoms for heart disease and correlated to echocardiographic parameters and carotid intima media thickness (CIMT). RESULTS: GDF-15 levels were significantly higher in TI patients compared with controls (p < 0.001). Transfusion dependent patients had higher GDF-15 than non-transfusion dependent patients. TI patients with splenectomy, pulmonary hypertension risk, and heart disease had higher GDF-15 levels than those without. GDF-15 was lower among hydroxyurea-treated patients. Multiple linear regression analysis revealed that transfusion index (p=0.012), serum ferritin (p < 0.001), tricuspid regurgitant jet velocity (p < 0.001), ejection fraction (p=0.01) and CIMT (p=0.007) were independently related to GDF-15. According to ROC curve analysis, the cutoff value of GDF-15 at 1500 pg/mL could differentiate patients with and without heart disease. CONCLUSION: GDF-15 would identify TI patients at increased risk of pulmonary and cardiovascular complications as well as subclinical atherosclerosis.

Budd-Chiari syndrome complicating essential thrombocythemia in an adolescent: favorable outcome of TIPS procedure.

Budd-Chiari syndrome (BCS) is a liver disorder characterized by hepatic venous outflow obstruction, mainly resulting from thrombosis of the terminal part of the hepatic veins or the inferior vena cava. It causes hepatic congestion, ascites, portal hypertension, and collateral circulation between the obstructed and contiguous patent venous territories. BCS is reported complicating myeloproliferative disorders, as well other prothrombotic events. Essential thrombocythemia is one of the most frequent myeloproliferative disorders that cause BCS, and in some cases, it may be the initial presentation. Many treatment options have been proposed for BCS, routine anticoagulation therapy being recommended as the first therapeutic approach.

Endothelial nitric oxide synthase gene intron 4 VNTR polymorphism in sickle cell disease: relation to vasculopathy and disease severity.

BACKGROUND: Impaired NO bioavailability represents the central feature of endothelial dysfunction, and is a common denominator in the pathogenesis of vasculopathy in sickle cell disease (SCD). Evidence indicates the contribution of 4a allele of endothelial NO synthase (eNOS) gene to cardiac and renal diseases. We studied the 27-base pair tandem repeat polymorphism in intron 4 of eNOS gene in 51 patients with SCD compared with 55 healthy controls and evaluated its role in disease severity and hemolysis-associated complications. PROCEDURE: Transfusion history, vaso-occlusive crisis, thrombotic events, urinary albumin excretion, and echocardiography were assessed. Analysis of eNOS intron 4 gene polymorphism was performed by polymerase chain reaction. RESULTS: The distribution of eNOS alleles and genotypes was similar between patients with SCD and controls. Compared with bb genotype, the frequency of eNOS4a allele (aa and ab genotypes) was significantly higher in patients with elevated tricuspid regurgitant velocity (TRV) (P = 0.009), nephropathy (P = 0.006), or history of cerebral stroke (P = 0.029). Logistic regression analysis revealed that eNOS4a allele was an independent risk factor for elevated TRV (P < 0.001). Patients with SCD and eNOS4a allele had higher lactate dehydrogenase, serum ferritin, D-Dimer, and von Willebrand factor antigen (P < 0.05). CONCLUSIONS: We suggest that eNOS intron 4 gene polymorphism is related to endothelial dysfunction and vasculopathy in SCD and could provide utility for prediction of increased susceptibility to vascular complications.

Growth differentiation factor-15 in young sickle cell disease patients: relation to hemolysis, iron overload and vascular complications.

BACKGROUND: High expression of growth differentiation factor-15 (GDF-15) contributes to pathological iron overload in thalassemia. Sickle cell syndromes are characterized by increased levels of erythropoiesis, although the primary defect involves the destruction of mature erythrocytes. AIM: To determine serum GDF-15 in 35 children and adolescents with sickle cell disease (SCD) compared to 35 healthy controls and assess its relation to markers of hemolysis, iron overload and vascular complications. METHODS: GDF-15 was measured and correlated to genotype, frequency of sickling crises, hydroxyurea therapy and serum ferritin. RESULTS: GDF-15 levels were increased in SCD patients whether sickle cell anemia or sickle ß° thalassemia compared with controls (p<0.001) with no significant difference between patients' groups. GDF-15 was significantly higher in patients who had serum ferritin ≥2500 µg/L, previous cerebral stroke, and splenectomy. GDF-15 was not significantly related to frequency of sickling crises, pulmonary hypertension, or hydroxyurea therapy. On regression analysis, transfusion index, lactate dehydrogenase and serum ferritin were independently related to GDF-15. CONCLUSION: Increased GDF-15 in SCD reflects the importance of ineffective erythropoiesis in the pathophysiology and severity of anemia in SCD. GDF-15 levels are related to hemolysis and iron overload and may provide utility for identifying patients at increased risk of thrombotic events.

Evoked potentials and neurocognitive functions in pediatric Egyptian Gaucher patients on enzyme replacement therapy: a single center experience.

BACKGROUND: Effectiveness of enzyme replacement therapy (ERT) in reverting hematologic, skeletal, and visceral symptoms in Gaucher disease (GD) has been demonstrated, although, its efficacy in neurologic involvement is still debated. AIM: We evaluated the extent of neuro-cognitive dysfunction using brain stem evoked potential in GD3 patients, age-matched controls, and GD1 patients without neurological manifestations served as disease control group. METHODS: Study included 56 GD (36 had type 1, 20 had type 3) under ERT. Investigations included complete blood count, beta glucosidase assay in peripheral leucocytes, plasma chitotriosidase and bone marrow examination, electroencephalography, brain stem auditory (AEP), somatosensory (SSEP) and visual evoked potentials (VEP) as well as IQ testing. RESULTS: Both types of GD showed significantly higher mean latency at 75 on left eye, lower PP amplitude ratio, higher latency at 75, 100, 145, lower amplitude, and higher Lat Diff LT-RT ms and Lt-Rt % compared to controls (p < 0.05) with no difference between both groups in other values of VEP. Both groups showed significantly prolonged latency of N 13-19 compared to controls (p < 0.05) with positive correlation between age and duration of therapy with parameters of SSEP (p < 0.01). Both groups of GD had significantly prolonged latency of the mean waves of AEP compared to controls (p < 0.05) with no significant difference between both groups. There was a negative correlation between age and waves II, III, I-III, I-V and threshold values of AEP. IQ level was positively correlated with AEP values. Severity scoring tool was positively correlated with AEP and SSEP values. CONCLUSIONS: Electrophysiological abnormalities were present in both types of GD and have been correlated to cognitive function and disease characteristics.

Pathogenesis and prognosis of neutropenia in infants and children admitted in a university children hospital in Egypt.

This study aimed to assess the prevalence, severity, and etiology of neutropenia in infants and children admitted to a children's hospital in Egypt. A total of 200 patients with neutropenia were recruited from April 1, 2010 to September 30, 2010. Patients with a known hematological or immunological disease were excluded. Patients were followed till recovery or an underlying cause was uncovered. Viral serological analysis was done for patients with moderate/severe neutropenia, including cytomegalovirus (CMV); Epstein-Barr virus (EBV); hepatitis A, B, and C viruses; and HIV. Antineutrophil cytoplasmic antibody (ANCA) tested by enzyme immunoassay and bone marrow aspirate were done for prolonged neutropenia. The results revealed that neutropenia was mild in 90 (45%), moderate in 56 (28%), and severe in 54 (27%). Clinical diagnosis at admission was bronchopneumonia (38%), pyrexia of undetermined etiology (17%), bronchiolitis (13%), urinary tract infection (9%), acute gastroenteritis (8%), hepatitis (6.5%), and septicemia (5%). Patients with mild neutropenia recovered within 1 week. Among 110 patients with moderate/severe neutropenia, 80 (73%) recovered in <3 weeks. Predictors of prolonged neutropenia were age younger than 18 months (P < .01), absolute neutrophils count (ANC) < 500/mm(3) (P < .05), hemoglobin < 10 gm/dL (P < .05), and positive CMV serology (P < .01). CMV and EBV serology were positive in 34.5% and 7.3% of patients, respectively. ANCA was positive in 42.8% of patients with prolonged severe neutropenia. In conclusion, neutropenia is a frequent finding in Egyptian infants and children, usually mild and transient, and mainly associated with infection. CMV and EBV are associated with prolonged neutropenia. Immune neutropenia is a common cause of moderate/severe neutropenia in the first two years of life.

Circulating platelet and erythrocyte microparticles in young children and adolescents with sickle cell disease: Relation to cardiovascular complications.

Sickle cell disease (SCD) is characterized by a complex vasculopathy, consisting of endothelial dysfunction and increased arterial stiffness, with a global effect on cardiovascular function. The hypercoagulable state may result from chronic hemolysis and circulating cell-derived microparticles (MPs) originating mainly from activated platelets and erythrocytes. We measured the levels of platelet and erythrocyte-derived MPs (PMPs and ErMPs) in 50 young SCD patients compared with 40 age- and sex-matched healthy controls and assessed their relation to clinicopathological characteristics and aortic elastic properties. Patients were studied stressing on the occurrence of sickling crisis, transfusion history, hydroxyurea therapy, hematological, and coagulation profile as well as flow cytometric expression of PMPs (CD41b(+)) and ErMPs (glycophorin A(+)). Echocardiography was performed to assess aortic stiffness and distensibility, left ventricular function and pulmonary artery pressure. Both PMPs and ErMPs were significantly elevated in SCD patients compared with control group (p < 0.001). SCD patients had significantly elevated d-dimer and von Willebrand factor antigen (vWF Ag) levels with lower antithrombin III compared with controls (p < 0.001). Aortic stiffness index and pulmonary artery pressure were significantly higher in SCD (p < 0.001), whereas aortic strain and aortic distensibility were significantly lower (p < 0.001) compared with controls. MPs levels were significantly increased in SCD patients with pulmonary hypertension, acute chest syndrome, and stroke as well as those who had history of thrombosis or splenectomy (p < 0.001). Also, patients in sickling crisis during the study had higher PMPs and ErMPs levels than those in steady state (p < 0.001). Patients on hydroxyurea therapy had lower MPs levels than untreated patients (p < 0.001). PMPs and ErMPs were positively correlated with disease duration, transfusion index, white blood cell count, HbS, markers of hemolysis, serum ferritin, D-dimer, and vWF Ag, whereas negatively correlated with hemoglobin and HbF levels (p < 0.05). Both PMPs and ErMPs levels were positively correlated with aortic stiffness, pulmonary artery pressure, and tricuspid regurgitant velocity (p < 0.05) while negatively correlated with aortic distensibility. We suggest that PMPs and ErMPs overproduction may be considered a potential biological marker for vascular dysfunction and disease severity in SCD and may be implicated in the pathogenesis of coagulation abnormalities encountered in those patients. Their levels are closely related to sickling crisis, pulmonary hypertension, markers of hemolysis, fibrinolysis, and iron overload. Therefore, quantification of MPs in SCD may provide utility for identifying patients who are at increased risk of thrombotic events or cardiovascular abnormalities and would help to monitor response to hydroxyurea therapy.

Soluble CD163 in young sickle cell disease patients and their trait siblings: a biomarker for pulmonary hypertension and vaso-occlusive complications.

CD163 is expressed on cells of monocyte-macrophage lineage and is the main hemoglobin-haptoglobin receptor. Inflammation and monocyte activation are predisposing factors to vaso-occlusion and pulmonary hypertension, which are serious complications in sickle cell disease (SCD). Siblings of SCD patients may have the same pathophysiology without displaying symptoms. We assessed soluble CD163 (sCD163) levels in 60 children with SCD and 30 sickle cell trait (SCT) siblings compared with 30 healthy controls as a potential marker for disease severity and treatment response. Patients were studied stressing on the presence of pulmonary hypertension by Dopplar-Echocardiography, sickling crisis, transfusion requirements, hydroxyurea response, hematological profile, high sensitivity C-reactive protein (hs-CRP) and serum sCD163. sCD163 was significantly elevated in SCD patients and SCT siblings compared with controls and the highest levels were in untreated SCD patients (P < 0.001). sCD163 was higher in patients with pulmonary hypertension, acute chest syndrome or stroke as well as in patients who developed sickling crisis during the study period (P < 0.05). Hydroxyurea-treated patients had lower sCD163 compared with untreated patients (P < 0.001). sCD163 was positively correlated to leukocyte count, HbS, hs-CRP, pulmonary artery pressure and tricuspid regurgitant velocity whereas inversely correlated to hemoglobin and HbF levels. The cut-off value of sCD163 at 1400 ng/ml could be considered a predictor for vaso-occlusive crisis in SCD with a sensitivity of 92.3% and specificity of 94.1%. sCD163 can be considered a biomarker for pulmonary hypertension, early crisis prediction and monitoring hydroxyurea response in SCD patients. Elevated sCD163 in trait siblings could reflect increased risk of sickling in challenging situations.

Pulmonary complications in survivors of childhood hematological malignancies: single-center experience.

Children treated for cancer face the risk of complications later in life, including pulmonary dysfunction. The objective of this study was to evaluate frequency and severity of pulmonary complications in survivors of childhood leukemia and lymphoma treated with chemotherapy alone or combined with radiotherapy. Seventy cancer survivors of hematological malignancies were evaluated for pulmonary complications through history taking, chest examination, high-resolution computed tomography (HRCT) chest, and pulmonary function testing (PFTs). Although most survivors were not clinically compromised, the spectrum of impaired PFTs included obstructive pattern (14.3%), restrictive pattern (5.7%), and mixed pattern (20%). Significant pulmonary dysfunction was seen in children older than 10 years of age (P = .003), and in patients treated with combined chemotherapy and radiotherapy (72.7%) compared with those treated with chemotherapy alone (25%) (P = .001). Cumulative dose of bleomycin was significantly associated with abnormal PFTs (P = .04). Multivariate analysis revealed methotrexate therapy as significant predictor of abnormal PFTs (P = .002). Male patients who received combined therapy showed higher frequency of restrictive, obstructive lung disease, abnormal respiratory reactance, and peripheral airway disease (P = .007, P = .04, P = .002, P = .003, P = .05, respectively). Those with abnormal CT findings (n = 14) had lower forced vital capacity (FVC%), forced expiratory volume in 1 second (FEV(1)%), and peak expiratory flow (PEF%) when compared to cases with normal CT (P = .001, P < 0.001, P = .001, respectively). Subclinical pulmonary function abnormalities are found in survivors of childhood hematological malignancies previously treated and off therapy. Pulmonary dysfunction is more evident with combined chemotherapy and radiotherapy, bleomycin, and methotrexate are the most incriminated chemotherapeutic agents, and males are at higher risk than females; therefore a specific and extended follow-up is warranted.