OPG/RANK/RANKL Axis in Egyptian Children With Acute Lymphoblastic Leukemia After Maintenance Therapy: Relationship to Bone Mineral and Vitamin D Status.

Policies to maximize peak bone mass in survivor's children of acute lymphoblastic leukemia (ALL) have been recognized as a priority area for research. The present study aimed to evaluate the relationship between osteoprotegerin (OPG)/receptor activator of nuclear factor kappa-B (RANK)/RANK ligand (RANKL) axis, vitamin D status, and serum magnesium in ALL survivors. Sixty ALL survivors treated with chemotherapy and 60 age and sex-matched controls were included. Vitamin D and parathyroid hormone, RANK, RANKL, and OPG levels were immunoassayed, in addition to serum calcium, phosphorus, magnesium levels, and alkaline phosphatase activity assessment. Furthermore, standard anthropometric measurement, history of fractures since treatment and clinical assessment were recorded. History of bone fractures after the start of therapy was detected in 17 ALL subjects (28.33%). Significantly lower vitamin D, magnesium, calcium, and OPG levels, meanwhile, significantly higher serum parathyroid hormone, RANK, and RANKL levels were detected in survivors compared with the control group. Vitamin D level was significantly positively correlated with magnesium, calcium, and OPG levels. Meanwhile, negatively correlated with RANK and RANKL levels. ALL survivors had a high prevalence of impaired vitamin D status, decreased Mg, and altered OPG/RANK/RANKL axis with impaired bone remodeling. The results herein may open the door for new interventional actions in ALL survivors to protect against bone resorption.

lncRNA GAS5 and RUNX1 Genes in Children With Primary Immune Thrombocytopenia.

We aimed to evaluate the expression levels and the prognostic value of growth arrest specific 5 (GAS5) and runt-related transcription factor 1 (RUNX1) genes in children with ITP. This prospective cohort study included 100 patients with newly diagnosed ITP (patient group) and 100 healthy children of matched age and sex (control group). We evaluated the expression levels of both GAS5 and RUNX1 genes at the time of diagnosis before the introduction of treatment. GAS5 was under-expressed, while RUNX1 was over-expressed among the newly diagnosed ITP children compared with the control group. Patients with GAS5 levels >0.50 had a significantly faster recovery compared with patients with levels≤0.50 while patients with levels of RUNX1≤2.6 had a significantly faster recovery compared with patients with levels >2.6. The best cut-off values of GAS5 and RUNX1 to predict complete recovery of ITP were ˃0.40 and ˂3.18, respectively, yielding a sensitivity of 76.47% and 79.41%, respectively. The best cut-off values of GAS5 and RUNX1 expression that predict chronic ITP were ˂0.17 and ˃4.1, respectively, yielding sensitivity of 88.89% and 77.78%, respectively. GAS5 and RUNX1 could be useful markers in children with primary ITP to predict disease course.

Al-hijamah (the triple S treatment of prophetic medicine) significantly increases CD4/CD8 ratio in thalassemic patients via increasing TAC/MDA ratio: a clinical trial.

Beta thalassemia is associated with decreased immunity possibly due to iron overload. Al-hijamah (Hijamah) is wet cupping therapy (WCT) of prophetic medicine. Prophet Muhammad Peace be upon him said: "The best among your treatments is Al-hijamah". Al-hijamah is a promising excretory treatment to clear blood of causative pathological substances. Al-hijamah is a three-step technique (skin suction, scarification and suction) i.e. triple S technique). Recently, we introduced Al-hijamah as a novel iron excretion therapy (through pressure-dependent filtration then excretion via the skin dermal capillaries) that significantly decreased serum iron overload and related oxidative stress using a physiological excretory mechanism (Taibah mechanism). Iron overload was reported to impair both humoral immunity and cell mediated immunity in patients with beta thalassemia. In this study, twenty patients having ß-thalassemia major (maintained on iron chelation therapy) underwent a single session of Al-hijamah (30-60 minutes) using 4-5 sucking cups only. Another age and sex-matched control group of thalassemic patients received iron chelation therapy only. Al-hijamah enhanced the immunity of thalassemic patients in the form of increased CD4+ T cell count, from 124.10±36.98 to 326.20±57.94 cells/mm3, and an increased CD8+ T cell count from 100.30±36.98 to 272.40±46.37 cells/mm3. CD4/CD8 ratio significantly increased from 1.29 to 1.7 (P<0.001). There was a significant increase of ten times (P<0.001) in serum TAC/MDA ratio (reflects increased antioxidant capacity vs decreased oxidative load and stress) induced by Al-hijamah. After Al-hijamah, both CD4+ and CD8+ T cell counts significantly increased and positively correlated with TAC/MDA ratio (r = 0.246) and (r = 0.190), respectively. Moreover, CD4/CD8 ratio positively correlated with TAC/MDA after Al-hijamah (r = 0.285). In conclusion, Al-hijamah significantly increased CD4/CD8 ratio in thalassemic patients via increasing TAC/MDA ratio. Our study strongly recommends medical practice of Al-hijamah in hospitals for its immune potentiating effects in agreement with the evidence-based Taibah mechanism. Al-hijamah should be generalized for treating other immune-deficiency conditions. Al-hijamah-induced bloody excretion is so minimal and never aggravates the anaemic status.

Cardiac Iron Overload by MRI in Children With B-Thalassemia Major and its Correlation With Cardiac Function by Echocardiography.

BACKGROUND: Serial echocardiography is strongly recommended in asymptomatic B-thalassemia major (TM) patients for early detection of subtle cardiac dysfunction. T2*magnetic resonance imaging (MRI) is a noninvasive measurement of myocardial iron burden. Yet, it is not always available in many centers. Our study aimed to evaluate the myocardial function in TM patients using different echocardiographic modalities and to correlate these findings with cardiac T2*MRI. PATIENTS AND METHODS: This is a cross-sectional study that was carried out on 140 children with a mean age of 10.9±3.7 years. One hundred children with TM and 40 healthy children were matched for age and sex as a control group. Serum ferritin, serum iron, and iron-binding capacity were measured. Cardiac iron overload was assessed by T2*MRI and cardiac function was assessed by echocardiography. The local ethics committee approved the study. RESULTS: Among 100 children with TM, only 32% had cardiac iron overload of 8.525±5.45 detected by cardiac T2*MRI. Iron deposition correlated significantly with age. Markers of iron overload were significantly correlated with cardiac T2*MRI. There were significantly lower values of myocardial performance index, longitudinal strain, circumferential strain, area strain, and radial strain in TM patients compared with the controls (P<0.001). Only the myocardial performance index was correlated with T2*MRI. CONCLUSIONS: This study confirms that some parameters measured by tissue Doppler imaging such as the myocardial performance index could be useful for the early detection of cardiac impairment in asymptomatic TM patients when cardiac MRI is lacking. Further studies on a large scale to identify other parameters with high sensitivity are recommended.

Al-hijamah (the triple S treatment of prophetic medicine) exerts cardioprotective, tissue-protective and immune potentiating effects in thalassemic children: a pilot clinical trial.

Thalassemia is a major health problem in affected children due to iron overload, increased oxidative stress, atherogenic lipid profile and tissue-damage. This study aims at investigating the cardioprotective and tissue-protective benefits of Al-hijamah and their impact on cell-mediated immunity for treating thalassemic children. This study aimed also at investigating the tissue-clearance principle of Taibah mechanism: whenever pathological substances are to be cleared from the human body, Al-hijamah is indicated. Al-hijamah was done to thalassemic children (15 males and 5 females having a mean age of 9.07 ± 4.26 years) using sterile disposable sets in a complete aseptic hospital environment. Prior ethical committee agreement (in addition to written patient's consents) was obtained from Tanta Faculty of Medicine, Egypt. Twenty thalassemic children received iron chelation therapy plus Al-hijamah for one session (30-60 minutes) versus an age and sex-matched thalassemic control group treated with iron chelation therapy only. Al-hijamah is a quite safe outpatient hematological procedure that significantly decreased serum cholesterol (from 129.75 ± 3.67 to 103.5 ± 4.18 mg/dl) and decreased serum triglycerides (from 109.25 ± 8.96 to 91.95 ± 7.22 mg/dl). Interestingly, Al-hijamah exerted significant tissue-protective effects (it decreased serum GPT from 98.65 ± 12.27 to 71.65 ± 32.78 U/L and serum GOT from 96.35 ± 14.33 to 69.35 ± 34.37 U/L). Al-hijamah-induced ferritin excretion caused decreased serum ferritin (high serum ferritin negatively correlated with cell mediated immunity). Al-hijamah exerted cardioprotective and tissue-protective and hypolipidemic effects. Al-hijamah decreased serum cholesterol and is cardioprotective for thalassemic patients as it protects against atherogenesis and atherosclerosis. Medical practice of Al-hijamah is strongly recommended in hospitals. Al-hijamah cleared blood significantly from causative pathological substances e.g. serum ferritin resulting in enhanced cell-mediated immunity (in agreement with the evidence-based Taibah mechanism).

Asymmetric Dimethylarginine Levels and Its Correlation to Cerebral Blood Flow in Children with Sickle Cell Anemia.

Asymmetric dimethylarginine (ADMA) level may play a role in the pathogenesis of cerebrovascular stroke in Children with Sickle Cell Anemia (SCA). To assess the plasma level of ADMA in children with SCA and its correlation to cerebral blood flow. This is a cross sectional study was carried out on 30 children with homozygous SCA under follow up in the Out Patients Clinic, Pediatric Department at Tanta University Hospital and 30 healthy children as a control group. Both groups had undergone the following investigations: Complete blood count, lactate dehydrogenase enzyme, and plasma level of ADMA by a commercial ADMA ELISA Kit. Trans-cranial Doppler were done for both groups. ADMA plasma level was significantly higher in-patient group in comparison to the control group (p < 0.001), with a mean value 1.43 ± 0.20 µmol/l, 0.48 ± 0.16 µmol/l respectively. The time-averaged mean maximum velocities for middle cerebral artery, anterior cerebral artery, inferior cerebral artery and posterior cerebral artery were significantly different between patient and control group, p < 0.05. Trans-cranial Doppler data revealed that, 86.7% of patients have low velocity (< 70 cm/s) and 13.3% having very low velocity (< 10 cm/s) while control group have normal velocity. There was a significant negative correlation between ADMA plasma levels and cerebral blood flow. Elevated ADMA levels may have a role in the pathogenesis of the decreased cerebral blood flow in children with SCA.

Crosstalk between cytokine profile, redox, and iron status in ß-Thalassemia: relation to frequency/duration of blood transfusion.

ß-Thalassemia, a blood disease instigated by mutations in ß-globin genes or their regulatory regions. Infectious complications, immune abnormalities and iron overload related organ damage are the chief causes of morbidity and mortality. The role of inflammatory cytokines in the pathophysiology of ß-thalassemia is still indistinct, so the present study aimed to evaluate immune-inflammatory and redox status in ß-thalassemia and their relation to iron status, frequency/duration of blood transfusion. Seventy ß-Thalassemia patients (35 ß-thalassemia major; 35 ß-thalassemia intermedia) and twenty age and sex-matched healthy controls were included. Interleukin4 (IL4), Interleukin10 (IL10), Interleukin 8 (IL8), and Interleukin 13 (IL13) levels were immunoassayed in addition to iron, hematological and redox status assessment. Significantly increased iron, ferritin, IL8, IL13 levels (p value ˂0.001), meanwhile, decreased IL10 level, total anti-oxidant (TAC) and iron binding capacities were observed in ß-thalassemia major compared with ß-thalassemia intermedia and control groups (p value ˂0.001) . IL4 level was decreased in patients group compared to control. Positive correlation was found between malondialdehyde (MDA), IL8, IL13 and iron load, transfusion frequency/duration, total leucocyte count and lymphocyte (%). Meanwhile, negative correlation was found with IL4, IL10, and TAC. Multiple blood transfusions increased iron stores which may critically impair the immune-regulatory balance with disturbed redox status and cytokine profile.

Thyroid Function in Egyptian Children with Sickle Cell Anemia in Correlation with Iron Load.

BACKGROUND: Sickle Cell Disease (SCD) is characterized by defective hemoglobin synthesis, hemolytic anemia, frequent thrombosis and chronic organ damage including endocrine organs. AIM: To assess thyroid function in children with SCD in correlation and iron load. PATIENTS AND METHOD: This study was conducted on 40 children with SCD with iron overload (serum ferritin more than 1000 ng/ml) including 22 males and 18 females with their ages ranging from 11-14 years and mean age value of 11.63±1.36 years and 40 healthy children of matched age and sex as a control group. For all patients; complete blood count, hemoglobin electrophoresis, serum ferritin, serum iron, iron binding capacity and thyroid function including Free Thyroxine (FT4), Free Triiodothyronine (FT3), Thyroid Stimulating Hormone (TSH), Thyroid Peroxidase Antibody (TPOAb) and Thyroglobulin Antibody (TgAb) were done. RESULTS: Significantly higher serum ferritin and iron and significantly lower Total Iron Binding Capacity (TIBC) were found in patients compared with controls (mean serum ferritin was 1665.2±1387.65ng/ml in patients versus 192.55±107.2ng/ml in controls with p-value of 0. 007, mean serum iron was 164±83.9 ug/dl in patients versus 89.5±4.5ug/dl in controls with p-value of 0.039, mean TIBC was 238±44.5ug/dl in patients versus 308±11ug/dl in controls with p-value of 0.001). Significantly higher serum TSH and significantly lower Free T3 and Free T4 were found in patients compared with controls with no significant correlation between thyroid hormones and serum ferritin (mean serum TSH was 4.61±1.2 µIU/mL in patients versus 2.11 ± 0.54 µIU /mL in controls with p-value of 0. 045, mean serum FT3 was 2.61 ±1.3 pg/mL versus 3.93±0.47pg/mL in controls with p-value of 0.027, mean serum FT4 was 0.91±0.174 ng/dL versus 1.44± 0.164 ng/dLin controls with p-value of 0.047, r = - 0. 008 and p-value was 0. 973 for correlation between free T4 and serum ferritin, r = -0. 028 and p-value was 0. 9 for correlation between TSH and serum ferritin and r= - 0.259 and p-value was 0.27 for correlation betweenT3 and serum ferritin). There were no significant differences between patients and controls regarding thyroid peroxidase antibody and thyroglobulin antibody (mean serum thyroid peroxidase antibody was 22.45± 4.32 in patients versus 22.45 ± 3.21 in controls with p-value of 0.98 while mean serum thyroglobulin antibody was 12.32 ± 2.65 in patients versus 12.99 ± 2.34 in controls with p-value of 0.76. CONCLUSION: Thyroid hormones deficiency may occur in some patients with SCD. RECOMMENDATIONS: Regular assessment of thyroid function in children with SCD may be recommended as they are more vulnerable to develop hypothyroidism and may require replacement therapy.

Al-hijamah (wet cupping therapy of prophetic medicine) significantly and safely reduces iron overload and oxidative stress in thalassemic children: a novel pilot study.

BACKGROUND: Thalassemia is a major health problem due to iron overload, iron deposition and oxidative stress-induced tissue damage. Here, we introduce Al-hijamah (a minor surgical excretory procedure) as a novel percutaneous iron excretion therapy. Al-hijamah is a wet cupping therapy of prophetic medicine, and prophet Muhammad, peace be upon him, strongly recommended Al-hijamah, saying: "The best of your treatment is Al-hijamah". AIM OF THE STUDY: Our study aimed at investigating the safety, iron chelation, pharmacological potentiation and oxidant clearance effects exerted by Al-hijamah to thalassemic children. PATIENTS AND METHODS: Ethical committee's approval and patients' written agreement consents were obtained. We treated 20 thalassemic children (15 males and five females aged 9.07±4.26 years) with iron chelation therapy (ICT) plus Al-hijamah (using sterile disposable sets and in a complete aseptic environment) vs a control group treated with ICT only. This clinical trial was registered in the ClinicalTrial.gov registry under the name "Study of the Therapeutic Benefits of Al-hijamah in Children with Beta Thalassemia Major" (identifier no NCT 02761395) on 30 January 2016. RESULTS: Al-hijamah was quite simple, safe, effective, tolerable (with no side effects) and time-saving procedure (30-60 minutes). A single session of Al-hijamah significantly reduced iron overload (P<0.001) in all thalassemic children. Al-hijamah significantly decreased serum ferritin by 25.22% (from 3,778.350±551.633 ng/mL to 2,825.300±558.94 ng/mL), significantly decreased oxidative stress by 68.69% (P<0.05; serum malondialdehyde dropped from 42.155±12.42 to 13.195±0.68 nmol/L), exerted pharmacological potentiation to ICT and significantly increased total antioxidant capacity (P<0.001) by 260.95% (from 13.195±0.68 nmol/L to 42.86±12.40 nmol/L through excreting reactive oxygen species). Moreover, therapeutic indices for evaluating Al-hijamah were promising. CONCLUSION: Al-hijamah is a novel, safe, effective percutaneous iron excretion therapy through percutaneous iron excretion with minimal blood loss in agreement with the evidence-based Taibah mechanism. Al-hijamah is an effective outpatient hematological procedure that is safer than many pediatric procedures such as catheterization, hemofiltration and dialysis. Increasing the number of cups during Al-hijamah session or the number of sessions reduces iron overload more strongly. Medical practice of Al-hijamah is strongly recommended in hospitals.

Prognostic Value of Transferrin Receptor-1 (CD71) Expression in Acute Lymphoblastic Leukemia.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the commonest childhood cancer. Transferrin receptor 1 (CD71) is a trans-membrane glycoprotein which has important role in iron homeostasis by acting as a gatekeeper regulating iron uptake from transferrin and is an attractive target for anti-cancer agents, particularly those that aim to induce lethal iron deprivation in malignant hematopoietic cells. AIM OF THE WORK: To assess the prognostic value of Transferrin receptor -1 (CD71) in children with newly diagnosed ALL. PATIENTS AND METHODS: This study was carried out on 75 patients with newly diagnosed ALL. Transferrin receptor-1 expression was analyzed on the bone marrow blasts by flow cytometry at time of diagnosis with positive CD71 expression is considered when ≥20% of malignant cells express this marker while negative expression is considered when <20% of malignant cells express this marker. RESULTS: Transferrin receptor-1 positive expression was detected in 45 patients (60%) while negative expression was found in the remaining 30 patients (40%). CD71 expression was significantly higher on T- ALL patients compared with B-ALL patients. Positive CD71 expression at diagnosis was significantly associated with bad clinical and laboratory prognostic factors as lymphadenopathy, higher white blood cell count, higher hemoglobin level, lower platelets count, and higher blast cells in peripheral blood and bone marrow and higher lactate dehydrogenase levels'. There were significant differences in disease free survival (DFS) and overall survival (OS) between positive and negative CD71 expression groups with significantly shorter DFS and OS in positive CD71 expression group compared to negative group. CONCLUSION AND RECOMMENDATIONS: 'Positive Transferrin receptor -1 (CD71) expression in patients with ALL is adverse prognostic factor and should be taken in consideration in designing future therapeutic strategies based on patient- specific risk factors'.

Efficacy of Prophylactic Dexmedetomidine in Preventing Postoperative Junctional Ectopic Tachycardia After Pediatric Cardiac Surgery.

BACKGROUND: Postoperative junctional ectopic tachycardia is one of the most serious arrhythmias that occur after pediatric cardiac surgery, difficult to treat and better to be prevented. Our aim was to assess the efficacy of prophylactic dexmedetomidine in preventing junctional ectopic tachycardia after pediatric cardiac surgery. METHODS AND RESULTS: A prospective controlled study was carried out on 90 children who underwent elective cardiac surgery for congenital heart diseases. Patients were randomized into 2 groups. Group I (dexmedetomidine group): 60 patients received dexmedetomidine; Group II (Placebo group): 30 patients received the same amount of normal saline intravenously. The primary outcome was the incidence of postoperative junctional ectopic tachycardia. Secondary outcomes included bradycardia, hypotension, vasoactive inotropic score, ventilation time, pediatric cardiac care unit stay, length of hospital stay, and perioperative mortality. The incidence of junctional ectopic tachycardia was significantly reduced in the dexmedetomidine group (3.3%) compared with the placebo group (16.7%) with P<0.005. Heart rate while coming off cardiopulmonary bypass was significantly lower in the dexmedetomidine group (130.6±9) than the placebo group (144±7.1) with P<0.001. Mean ventilation time, and mean duration of intensive care unit and hospital stay (days) were significantly shorter in the dexmedetomidine group than the placebo group (P<0.001). However, there was no significant difference between the 2 groups as regards mortality, bradycardia, or hypotension (P>0.005). CONCLUSION: Prophylactic use of dexmedetomidine is associated with significantly decreased incidence of postoperative junctional ectopic tachycardia in children after congenital heart surgery without significant side effects.

Diagnostic and Prognostic Value of Plasma Levels of Cardiac Myosin Binding Protein-C as a Novel Biomarker in Heart Failure.

Heart failure (HF) has high morbidity and mortality in children. This study aimed to investigate the value of cardiac myosin binding protein-C (cMyBP-C) as a diagnostic and prognostic biomarker in children with heart failure. This study was a prospective case-control study that involved 50 children with acute HF and 25 healthy children of matched age and sex as a control group. cMyBP-C plasma levels were measured in patients with HF at the time of admission and 1 month after treatment. Echocardiographic assessment was done for all children. All patients were followed up for a period of 3 months. There was a significant increase in plasma levels of cMyBP-C (ng/ml) in patients with HF at admission (122.44 ± 41.01) as compared to patients after treatment (71.38 ± 49.68) and to control group (24.40 ± 9.83). This increase was associated with increased severity of HF according to pediatric Ross classification of HF. Significant increase in plasma levels of cMyBP-C at admission and its persistent increase after treatment were associated with adverse outcome of mortality and readmission. Plasma levels of cMyBP-C were significantly correlated with echocardiographic and clinical assessment of heart failure. Plasma levels of cMyBP-C were a good biomarker for diagnosis of HF with sensitivity 100% and specificity 96% at cutoff point of 45 ng/ml. Its value in predicting adverse outcome in HF patients was obtained by ROC curve with sensitivity of 90% and specificity 93% at a cutoff point of 152 ng/ml cMyBP-C at admission. cMyBP-C may be a novel useful diagnostic and prognostic biomarker in children with heart failure and determination of severity of HF in these patients.