Prognostic cytogenetic markers in childhood acute lymphoblastic leukemia.
Settin A, Al Haggar M, Al Dosoky T, Al Baz R, Abdelrazik N, Fouda M, Aref S, Al-Tonbary Y.
Genetic Unit, Mansoura University Children's Hospital, Mansoura, Egypt.
Objective. To evaluate children with acute lymphoblastic leukemia (ALL) showing resistance to immediate induction chemotherapy in relation to conventional and advanced cytogenetic analysis.
Methods. This work was conducted on 63 ALL children (40 males and 23 females) with age range 4.5 months - 16 years (mean = 7.76 years). They included 37 cases attained true remission and 26 complicated by failure of remission, early relapse or death. They were subjected to history, clinical examination and investigations including CBC, BM examination, karyotyping, FISH for translocations and flowcytometry for immunophenotyping and minimal residual disease diagnosis.
Results. Cases aged less than 5 years; male sex with organomegaly had better remission although statistically insignificant. Initially low HB less than 8 gm/dl, high WBCs and platelet counts more than 50.000/mm3 also showed better but non-significant remission rates. Most of the present cases were L2 with better remission compared to other immunophenotypes. Forty informative karyotypes were subdivided into 15 hypodiploid, 10 pseudodiploid, 8 normal diploid and 7 hyperdiploid cases; the best remission rates were noticed among the most frequent ploidy patterns. Chromosomes 9, 11 and 22 were the most frequently involved by structural aberrations followed by chromosomes 5, 12 and 17. Resistance was noted with aberrations not encountered among remission group; deletions involving chromosomes 2p, 3q, 10p and 12q; translocations involving chromosome 5; trisomies of chromosomes 16 and 21; monosomies of 5 and X and inversions of 5 and 11.
Conclusion. Some cytogenetic and molecular characterizations of childhood ALL could add prognostic criteria for proper therapy allocation.
How to cite this article:
Settin A, Al Haggar M, Al Dosoky T, Al Baz R, Abdelrazik N, Fouda M, Aref S, Al-Tonbary Y. Prognostic cytogenetic markers in childhood acute lymphoblastic leukemia. Indian J Pediatr 2007;74:255-263
How to cite this URL:
Settin A, Al Haggar M, Al Dosoky T, Al Baz R, Abdelrazik N, Fouda M, Aref S, Al-Tonbary Y. Prognostic cytogenetic markers in childhood acute lymphoblastic leukemia. Indian J Pediatr [serial online] 2007 [cited 2007 Apr 22];74:255-263. Available from: http://www.ijppediatricsindia.org/article.asp?issn=0019-5456;year=2007;volume=74;issue=3;spage=255;epage=263;aulast=Settin
Sunday, April 22, 2007
Friday, April 20, 2007
Acute painful crises of sickle cell disease (SCD) in Egyptian children: predictors of severity for preventive strategy.
Acute painful crises of sickle cell disease (SCD) in Egyptian children: predictors of severity for preventive strategy
Mohammad Al-Haggar † MD, Hala Al-Marsafawy, MD, Nabeel Abdel-Razek, MD Rizk Al-Baz 1 , PhD and Abdel-Hamid Mostafa 2 MD
Paediatrics Department, Faculty of Medicine, Mansoura University, 1 Mansoura University Children’s Hospital (Genetics laboratories), 2 Clinical Pathology Department, Faculty of Medicine, Al-Azhar University, Egypt
This work had been conducted in Mansoura University Children’s Hospital, Dakahlia province, Middle delta, Egypt.
† Correspondence: Mohammad Al-Haggar, MD, Professor of Pediatrics and Genetics, Paediatrics Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt, e-mail: mhajjar2000@yahoo.co.uk
ABSTRACT
Objective; To predict sickle cell infants (SCD) who are prone to develop severe painful crises in future.
Subjects and methods; In mixed hospital-community-based population (76 cases), demographic data, diagnostic parameters of SCD and basal blood counts were correlated to two indices of SCD severity; pain rate (average days of painful episodes per year of follow up) and serious life threatening complications like hyper-hemolytic crises. Data were analyzed blind to these indices; t-test, ANOVA and Pearson correlation were used to determine association to pain rate. Discriminant analysis was the test used for prediction of SCD severity.
Results; Pain rate was significantly high in HB SS patients especially in those with early onset of dactylitis. There were statistically significant negative correlations of pain rate to basal HB level, Hct%, HB F% and arterial oxygen saturation (P < 0.01 for all correlations). The top 3 predictors for SCD severity were genotype, basal HB level and early dactylitis in a descending order.
Conclusion; Severe forms of SCD could be predicted in early infancy with 100% accuracy using the basal diagnostic parameters of the disease; those infants should be closely monitored with special attention to their ventilation status even before the development of dactylitis.
(Keywords; sickle disease, painful crises, prediction)
INTRODUCTION
Acute painful crisis is the most common clinical presentation of children with sickle cell disease (SCD); usually secondary to hypoxia, dehydration and infection. Many studies had been published giving the upper hand to some prognostic parameters over others; some considered early-onset of dactylitis, leucocytosis and low haemoglobin to be of utmost importance [1], others considered the disease genotype and HB F to be more significant [2 - 4]. Nocturnal arterial oxygen desaturation was found in a significant proportion of SCD patients and this explains the night exacerbations in these cases [5 - 8]. Up to our knowledge no available references tried to predict the disease severity from these prognostic parameters in a mathematical fashion.
This work aims to predict infants and young children with SCD who are likely to have severe painful crises using a multivariate analysis. Attempting to define such children will permit accurate prognostication and proper therapy plan in order to minimize the morbidity and mortality associated with SCD.
SUBJECTS AND METHODS
Study Design
This study was conducted on hospital and community based subjects after obtaining a formal written consent from all parents. The hospital-based cases were the newly diagnosed infants and young children with SCD at Paediatric Genetics Unit of Mansoura University Children’s Hospital (MUCH), they constituted 42 cases (23 males and 19 females) with age range 8-34 months (25.4 ± 9.2). The community-based subjects were the old cases with SCD followed at Paediatric Haematology Clinic of MUCH; they were 34 cases (20 males and 14 females) with age range 4-13 years (8.8 ± 3.6).
Data collection
The hospital-based subjects were followed for a period of about 2 years starting at June, 2001 to July, 2003 or until terminal event (start of regular transfusions or analgesic medication or even child death by a relevant cause). We stressed on relevant symptoms like painful crises especially those lasting for > 2 days, increasing pallor, deepening jaundice, number and reasons for hospital admissions. Demographic data, sickling test, HB electrophoresis as well as basal blood counts were the main profile for each child. Enzyme assay was checked whenever possible to rule out the possibility of associated G6PD deficiency. Data of community-based SCD children were retrieved from the files.
Laboratory Diagnosis
Sickling test is a qualitative solubility test for screening HB-S; HB released from lysed RBCs by saponin, is reduced by Dithionate buffer. Reduced HB S is characterized by its very low solubility thus forming nematic liquid crystals (tactoids) causing a turbid system, there is some non-S HBs causing positive sickling [9]. HB electrophoresis depends upon the differential migration of the charged HB variants in an electric field. The migration patterns differ according to pH, temperature, voltage, ionic strength of buffers as well as nature of supporting medium; at alkaline pH (8.6 – 8.8) in a cellulose acetate medium HB SS, Sβ and SA can be differentiated, however to differentiate HB SS from SC, we used acidic buffer (pH 6.2) in agar gel [10]. G6PD is assayed using a semi-quantitative method; enzyme released from lysed RBCs catalyzes conversion of NADP to NADPH which in presence of phenazine methosulphate will reduce the dye colour (dichlorophenol indophenol) to colourless form, the reaction mixture is proportional to RBCs content of G6PD [11].
Patient Categorization
Two dependant variables were concluded from patient’s profile; the 1st one was pain rate (average number of days of hospital stay due to painful episodes or days of extreme relevant illness at home from patient’s own calendar per year of follow up) and the 2nd variable if there was any serious life-threatening complication like protracted haemolysis or hyper-haemolytic crisis in a recently transfused child. Severity was deducted from these 2 variables; cases showing frequent painful episodes (pain rate = > 5 days/year) or any serious events were labelled as severe (15 cases) and those with infrequent hospital attendance (pain rate < 2 days/year) were considered mild (12 cases).
Children presented with frequent nocturnal painful episodes (42 out of 76) were admitted for at least 2 nights; O2 saturation (O2 SAT) was estimated 4 times each night with 2 hours apart, then mean O2 SAT was deducted; cases suggestive of obstructive sleep apnoea were transferred to ENT specialists for further evaluation.
Statistical Analysis
Data of all subjects were merged together regardless to the basis of study to minimize the error of retrospective nature of community-based portion. Data were analyzed blind to the deducted SCD severity using SPSS version 10.0 [12]. Quantitative variables showed preserved normality (Kolmogrov Smirnov test). T-test, one way ANOVA, Pearson’s correlation and Chi square test were done to test for associations to pain rate. At two cut off values of O2 SAT (80% and 90%), pain rate was assessed in the different subgroups. Discriminant analysis was the multivariate test using the different prognostic parameters for prediction of severity in a stepwise approach. Accuracy of prediction was assessed by Wilks’ lambda (X2 for test function was 46.14, with P < 0.001) as well as percentage of correctly classified cases.
RESULTS
Patients with HB SS genotypes (71%) suffered from long painful episodes especially if they had a history of early dactylitis before the age of 2 years (15.7%); the mean pain rate in HB SS patients is the highest with very close and overlapping values of the two other genotypes (table: 1 & figure: 1). Twenty SCD children were presented with dactylitis before age of 2 years (8 of them were SS genotype; X2 for association of early dactylitis to SCD genotype was 9.11 with P = 0.01; not presented in tables).
Pain rate was significantly negative correlated to basal HB, Hct value, HB F%. Also there was a strong negative correlation between pain rate and O2 SAT; note the down slope of the best fit line of scatter diagram with severe cases (solid triangles) being clustered opposite 80% and mild cases (asterisks) being clustered opposite 90% O2 SAT (table: 2 - figure: 2). To determine level of O2 desaturation below which painful episode became severely protracted, patients were categorized according to two cut off values of O2 SAT, mean difference and statistical significance were more evident at 80% O2 SAT (table: 3).
Prediction of SCD severity was determined by discriminant analysis that yielded a predictive equation; formulated from the basal parameters in table 4-a:
Predictive equation = 2.75 X genotype (codes; 1 for HB SS, 2 for HB SC and 3 for HB Sβ) – 0.42 X Early onset of dactylitis (codes; 1 if yes and 0 if no) + 0.74 X Basal HB – 10.95 = Score value.
If score value ≥ 2.88, it will be mild SCD variant, however a score value ≤ - 2.30 will be a severe case. Accuracy of Predictive equation could be assessed by its application to the 27 cases of already known clinical severity (table 4-b). Comparing the original grouping to the predicted grouping, all cases were found correctly classified i.e. no false positive or negative rates, so predictive equation could be considered 100% accurate.
DISCUSSION
Sickle cell disease (SCD) is an inherited autosomal recessive disorder of β-globin chain with high incidence in Middle East due to the high rate of consanguineous marriage. Sickle HB is considered to be the second most common mutation of β globin (after β thalassaemia) accounting for about 12.2% of all mutations of β globin clusters [13 & 14]. Acute painful crisis is the most frequent and intractable problem encountered in this disease [15].
Despite the fact that all subjects with SCD have the same single base pair mutation, the severity of clinical and haematological manifestations is extremely variable from race to race and even within the same race. So, prediction of severity is a hot topic in SCD. Early-onset of dactylitis (defined as pain and tenderness in hands and feet before age of 1 year), leucocytosis (in the absence of infection) and low basal haemoglobin (< 7 gm/dl) were suggested to be the most important prognostic parameters in SCD [1]. Disease genotype and HB F level were considered by other authors to be more important as regards disease severity [2 - 4]; on the other hand some authors lessen the role of HB F level as a predictive parameter of disease severity [16].
In our hospital and community-based study done on Egyptian SCD children, we used multivariate analysis to predict those cases who are liable to develop severe disease in future by analyzing the demographic data of SCD children of known clinical severity. No gender difference in pain severity (P = 0.91) was found in our study opposite to the finding reported on Saudi SCD adults being more severe among males [17]. Analysis of difference between the 3 genotypes of SCD revealed a high statistical significance with the longest pain rate among SS patients (P < 0.001) but with no significant difference between the other 2 genotypes (P 0.09).
In our study, high HB F level was associated with low pain rate irrespective to the disease genotype (r = - 0.29 with P 0.01). Some reports attributed the mild nature of SCD to high HB F; however others found no relation between basal HB F and pain rate [3, 4, 8 & 16]. The mild SCD in most Kuwaitis children was attributed to the elevated HB F although authors described a high incidence of avascular necrosis of femoral head among their population (26.7%) [3]. The high prevalence of Arab-Indian genotype in Iran which is associated with high HB F (30%) accounts for the mild clinical presentation of SCD in Iran [4]. On the other hand, in Lebanese high HB F was not associated with decreased severity of SCD symptoms [16].
In SCD patients having nocturnal painful episodes, O2 SAT was negatively correlated to pain rate denoting that hypoxemia which is possibly due to an underlying upper airway obstruction is a stimulus for bone marrow to correct anaemia. However, in adults there was a paradox of high HB & Hct and low O2 SAT due to the compensated chronic hypoxemia by acclimatization [1].
Prediction of severity was done by discriminant analysis using the relevant parameters as independent variables; the best predictors as determined from their coefficients were genotype, basal HB level and early-onset of dactylitis in a descending order (coefficients were 2.75, 0.737 and -0.420 respectively) with no marked impact for the other parameters. Accuracy of prediction was proved by Wilks Lambda as well as percentage of correctly classified cases (100%). The exclusion of HB F from the top 3 predictors of severity could be explained by the fact that our young cases had a very high HB F level which will be rapidly changing so that statistical analyses would be unlikely to find it as a strong predictor. Further prospective study for these cases should be warranted to check for the importance of HB F at older ages to solve the issue of controversies regarding this parameter [3, 8 & 16].
We can conclude that with the use of this predictive equation, SCD infants beyond age of 6 month could be scored as a high or low risk using the top 3 prognostic parameters incriminated in discriminant analysis. High risk SCD infants should be a target for powerful therapeutic plan that include the availability of newly introduced pain controllers for home use [18] and a community-based educational treatment to increase spiritual well-being and self-efficacy to cope with pain [19]. With the help of these measures altogether SCD morbidity and mortality would be mitigated.
Acknowlegement
We acknowledge all staff members of Genetics unit laboratories, MUCH, Faculty of Medicine, Mansoura University, for blood sampling and laboratory analysis. Particular thanks are due to staff of paediatric haematology unit in MUCH for the efforts in retrieving personal and clinical data of old cases, and recruiting them for further evaluation.
REFERENCES
1. Miller ST, Sleeper LA, Pegelow CH, et al: Prediction of adverse outcomes in children with sickle cell disease. N Engl J Med 2000; 342:83-89.
2. Kaul DK, Fabry ME, Nagel RL: The pathophysiology of vascular obstruction in the sickle syndromes. Blood Rev 1996; 10:29-44.
3. Marouf R, Gupta R, Haider MZ, Al-Wazzan H, Adekile AD: Avascular necrosis of the femoral head in adult Kuwaiti sickle cell disease patients. Acta Hematol 2003; 110(1): 11-15.
4. Rahimi Z, Karimi M, Haghshenass M, Merat A: Beta-globin gene cluster haplotypes in sickle cell patients from southwest Iran. Am J Hematol 2003; 74(3):156-160.
5. Homi J, Levee L, Higgs D, Thomas P, Serjeant G: Pulse oximetry in a cohort study of sickle cell disease. Clin Lab Haematol 1997; 19:17-22.
6. Needleman JP, Franco ME, Varlotta L et al: Mechanisms of nocturnal oxyhemoglobin desaturation in children and adolescents with sickle cell disease. Pediatr Pulmonol 1999; 28:418-422.
7. Wilkey O, Evans JPM, Telfer PT, Kirkham FJ: Predictors of nocturnal hypoxaemia in children with sickle cell disease [abstract]. Arch Dis Child 2002; 86 (suppl 1):A12.
8. Haregrave DR, Wade A, Evans JPM, Hewes DKM, Kirkham, FJ: Nocturnal oxygen saturation and painful sickle cell crises in children. Blood 2003; 101(3): 846-848.
9. Fairbanks VK, Klee GG: In textbook of Clinical Chemistry, Teitz NW (ed) WB Saunders co., Philadelphia, 1986; 1540-1541.
10. Kim HC: Separation of Hemoglobins in Hematology Textbook; 4th edition, Williams WJ and Lecihman MA (eds), McChill, NewYork 1990; 1711-1714.
11. Echier G: Determination of G-6-PD. Am J Med Technol 1983; 49:259.
12. SPSS: Statistical Package for Social Science, standard version 10.0.1; 1999; SPSS Inc., Chicago, IL.
13. Al-Arrayed S, Hafadh N, Amin S, Al-Mukhareq H, Sanad H: Student screening for inherited blood disorders in Bahrain. East Mediterr Health J 2003; 9(3):344-352.
14. Keser I, Sanlioglu AD, Manguoglu E, et al : Molecular analysis of beta-thalassemia and sickle cell anemia in Antalya. Acta Haematol 2004; 111(4):205-210.
15. Platt OS, Thorington BD, Brambilla DJ, et al: Pain in sickle cell disease. Rates and risk factors. N Engl J Med 1991; 325:11-16.
16. Inati A, Taher A, Bou Alawi W, et al: Beta-globin gene cluster haplotypes and HB F levels are not the only modulators of sickle cell disease in Lebanon. Eur J Haematol 2003; 70(2):79-83.
17. Udezue E, Girshab AM: Differences between males and females in adults sickle cell pain crises in eastern Saudi Arabia. Ann Saudi Med 2004; 24(3): 179-182.
18. Graves PA, Kedar A, Koshy M, et al: RheothRx (Poloxamer 188) Injection for the Acute Painful Episode of Sickle Cell Disease: A Pilot Study. Blood 1997; 90(5):2041-2046.
19. Cooper-Effa M, Blount W, Kaslow N, Rothenberg R, Eckman J: Role of spirituality in patients with sickle cell disease. J Am Board Fam Pract 2001; 14(2): 116-122.
Mohammad Al-Haggar † MD, Hala Al-Marsafawy, MD, Nabeel Abdel-Razek, MD Rizk Al-Baz 1 , PhD and Abdel-Hamid Mostafa 2 MD
Paediatrics Department, Faculty of Medicine, Mansoura University, 1 Mansoura University Children’s Hospital (Genetics laboratories), 2 Clinical Pathology Department, Faculty of Medicine, Al-Azhar University, Egypt
This work had been conducted in Mansoura University Children’s Hospital, Dakahlia province, Middle delta, Egypt.
† Correspondence: Mohammad Al-Haggar, MD, Professor of Pediatrics and Genetics, Paediatrics Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt, e-mail: mhajjar2000@yahoo.co.uk
ABSTRACT
Objective; To predict sickle cell infants (SCD) who are prone to develop severe painful crises in future.
Subjects and methods; In mixed hospital-community-based population (76 cases), demographic data, diagnostic parameters of SCD and basal blood counts were correlated to two indices of SCD severity; pain rate (average days of painful episodes per year of follow up) and serious life threatening complications like hyper-hemolytic crises. Data were analyzed blind to these indices; t-test, ANOVA and Pearson correlation were used to determine association to pain rate. Discriminant analysis was the test used for prediction of SCD severity.
Results; Pain rate was significantly high in HB SS patients especially in those with early onset of dactylitis. There were statistically significant negative correlations of pain rate to basal HB level, Hct%, HB F% and arterial oxygen saturation (P < 0.01 for all correlations). The top 3 predictors for SCD severity were genotype, basal HB level and early dactylitis in a descending order.
Conclusion; Severe forms of SCD could be predicted in early infancy with 100% accuracy using the basal diagnostic parameters of the disease; those infants should be closely monitored with special attention to their ventilation status even before the development of dactylitis.
(Keywords; sickle disease, painful crises, prediction)
INTRODUCTION
Acute painful crisis is the most common clinical presentation of children with sickle cell disease (SCD); usually secondary to hypoxia, dehydration and infection. Many studies had been published giving the upper hand to some prognostic parameters over others; some considered early-onset of dactylitis, leucocytosis and low haemoglobin to be of utmost importance [1], others considered the disease genotype and HB F to be more significant [2 - 4]. Nocturnal arterial oxygen desaturation was found in a significant proportion of SCD patients and this explains the night exacerbations in these cases [5 - 8]. Up to our knowledge no available references tried to predict the disease severity from these prognostic parameters in a mathematical fashion.
This work aims to predict infants and young children with SCD who are likely to have severe painful crises using a multivariate analysis. Attempting to define such children will permit accurate prognostication and proper therapy plan in order to minimize the morbidity and mortality associated with SCD.
SUBJECTS AND METHODS
Study Design
This study was conducted on hospital and community based subjects after obtaining a formal written consent from all parents. The hospital-based cases were the newly diagnosed infants and young children with SCD at Paediatric Genetics Unit of Mansoura University Children’s Hospital (MUCH), they constituted 42 cases (23 males and 19 females) with age range 8-34 months (25.4 ± 9.2). The community-based subjects were the old cases with SCD followed at Paediatric Haematology Clinic of MUCH; they were 34 cases (20 males and 14 females) with age range 4-13 years (8.8 ± 3.6).
Data collection
The hospital-based subjects were followed for a period of about 2 years starting at June, 2001 to July, 2003 or until terminal event (start of regular transfusions or analgesic medication or even child death by a relevant cause). We stressed on relevant symptoms like painful crises especially those lasting for > 2 days, increasing pallor, deepening jaundice, number and reasons for hospital admissions. Demographic data, sickling test, HB electrophoresis as well as basal blood counts were the main profile for each child. Enzyme assay was checked whenever possible to rule out the possibility of associated G6PD deficiency. Data of community-based SCD children were retrieved from the files.
Laboratory Diagnosis
Sickling test is a qualitative solubility test for screening HB-S; HB released from lysed RBCs by saponin, is reduced by Dithionate buffer. Reduced HB S is characterized by its very low solubility thus forming nematic liquid crystals (tactoids) causing a turbid system, there is some non-S HBs causing positive sickling [9]. HB electrophoresis depends upon the differential migration of the charged HB variants in an electric field. The migration patterns differ according to pH, temperature, voltage, ionic strength of buffers as well as nature of supporting medium; at alkaline pH (8.6 – 8.8) in a cellulose acetate medium HB SS, Sβ and SA can be differentiated, however to differentiate HB SS from SC, we used acidic buffer (pH 6.2) in agar gel [10]. G6PD is assayed using a semi-quantitative method; enzyme released from lysed RBCs catalyzes conversion of NADP to NADPH which in presence of phenazine methosulphate will reduce the dye colour (dichlorophenol indophenol) to colourless form, the reaction mixture is proportional to RBCs content of G6PD [11].
Patient Categorization
Two dependant variables were concluded from patient’s profile; the 1st one was pain rate (average number of days of hospital stay due to painful episodes or days of extreme relevant illness at home from patient’s own calendar per year of follow up) and the 2nd variable if there was any serious life-threatening complication like protracted haemolysis or hyper-haemolytic crisis in a recently transfused child. Severity was deducted from these 2 variables; cases showing frequent painful episodes (pain rate = > 5 days/year) or any serious events were labelled as severe (15 cases) and those with infrequent hospital attendance (pain rate < 2 days/year) were considered mild (12 cases).
Children presented with frequent nocturnal painful episodes (42 out of 76) were admitted for at least 2 nights; O2 saturation (O2 SAT) was estimated 4 times each night with 2 hours apart, then mean O2 SAT was deducted; cases suggestive of obstructive sleep apnoea were transferred to ENT specialists for further evaluation.
Statistical Analysis
Data of all subjects were merged together regardless to the basis of study to minimize the error of retrospective nature of community-based portion. Data were analyzed blind to the deducted SCD severity using SPSS version 10.0 [12]. Quantitative variables showed preserved normality (Kolmogrov Smirnov test). T-test, one way ANOVA, Pearson’s correlation and Chi square test were done to test for associations to pain rate. At two cut off values of O2 SAT (80% and 90%), pain rate was assessed in the different subgroups. Discriminant analysis was the multivariate test using the different prognostic parameters for prediction of severity in a stepwise approach. Accuracy of prediction was assessed by Wilks’ lambda (X2 for test function was 46.14, with P < 0.001) as well as percentage of correctly classified cases.
RESULTS
Patients with HB SS genotypes (71%) suffered from long painful episodes especially if they had a history of early dactylitis before the age of 2 years (15.7%); the mean pain rate in HB SS patients is the highest with very close and overlapping values of the two other genotypes (table: 1 & figure: 1). Twenty SCD children were presented with dactylitis before age of 2 years (8 of them were SS genotype; X2 for association of early dactylitis to SCD genotype was 9.11 with P = 0.01; not presented in tables).
Pain rate was significantly negative correlated to basal HB, Hct value, HB F%. Also there was a strong negative correlation between pain rate and O2 SAT; note the down slope of the best fit line of scatter diagram with severe cases (solid triangles) being clustered opposite 80% and mild cases (asterisks) being clustered opposite 90% O2 SAT (table: 2 - figure: 2). To determine level of O2 desaturation below which painful episode became severely protracted, patients were categorized according to two cut off values of O2 SAT, mean difference and statistical significance were more evident at 80% O2 SAT (table: 3).
Prediction of SCD severity was determined by discriminant analysis that yielded a predictive equation; formulated from the basal parameters in table 4-a:
Predictive equation = 2.75 X genotype (codes; 1 for HB SS, 2 for HB SC and 3 for HB Sβ) – 0.42 X Early onset of dactylitis (codes; 1 if yes and 0 if no) + 0.74 X Basal HB – 10.95 = Score value.
If score value ≥ 2.88, it will be mild SCD variant, however a score value ≤ - 2.30 will be a severe case. Accuracy of Predictive equation could be assessed by its application to the 27 cases of already known clinical severity (table 4-b). Comparing the original grouping to the predicted grouping, all cases were found correctly classified i.e. no false positive or negative rates, so predictive equation could be considered 100% accurate.
DISCUSSION
Sickle cell disease (SCD) is an inherited autosomal recessive disorder of β-globin chain with high incidence in Middle East due to the high rate of consanguineous marriage. Sickle HB is considered to be the second most common mutation of β globin (after β thalassaemia) accounting for about 12.2% of all mutations of β globin clusters [13 & 14]. Acute painful crisis is the most frequent and intractable problem encountered in this disease [15].
Despite the fact that all subjects with SCD have the same single base pair mutation, the severity of clinical and haematological manifestations is extremely variable from race to race and even within the same race. So, prediction of severity is a hot topic in SCD. Early-onset of dactylitis (defined as pain and tenderness in hands and feet before age of 1 year), leucocytosis (in the absence of infection) and low basal haemoglobin (< 7 gm/dl) were suggested to be the most important prognostic parameters in SCD [1]. Disease genotype and HB F level were considered by other authors to be more important as regards disease severity [2 - 4]; on the other hand some authors lessen the role of HB F level as a predictive parameter of disease severity [16].
In our hospital and community-based study done on Egyptian SCD children, we used multivariate analysis to predict those cases who are liable to develop severe disease in future by analyzing the demographic data of SCD children of known clinical severity. No gender difference in pain severity (P = 0.91) was found in our study opposite to the finding reported on Saudi SCD adults being more severe among males [17]. Analysis of difference between the 3 genotypes of SCD revealed a high statistical significance with the longest pain rate among SS patients (P < 0.001) but with no significant difference between the other 2 genotypes (P 0.09).
In our study, high HB F level was associated with low pain rate irrespective to the disease genotype (r = - 0.29 with P 0.01). Some reports attributed the mild nature of SCD to high HB F; however others found no relation between basal HB F and pain rate [3, 4, 8 & 16]. The mild SCD in most Kuwaitis children was attributed to the elevated HB F although authors described a high incidence of avascular necrosis of femoral head among their population (26.7%) [3]. The high prevalence of Arab-Indian genotype in Iran which is associated with high HB F (30%) accounts for the mild clinical presentation of SCD in Iran [4]. On the other hand, in Lebanese high HB F was not associated with decreased severity of SCD symptoms [16].
In SCD patients having nocturnal painful episodes, O2 SAT was negatively correlated to pain rate denoting that hypoxemia which is possibly due to an underlying upper airway obstruction is a stimulus for bone marrow to correct anaemia. However, in adults there was a paradox of high HB & Hct and low O2 SAT due to the compensated chronic hypoxemia by acclimatization [1].
Prediction of severity was done by discriminant analysis using the relevant parameters as independent variables; the best predictors as determined from their coefficients were genotype, basal HB level and early-onset of dactylitis in a descending order (coefficients were 2.75, 0.737 and -0.420 respectively) with no marked impact for the other parameters. Accuracy of prediction was proved by Wilks Lambda as well as percentage of correctly classified cases (100%). The exclusion of HB F from the top 3 predictors of severity could be explained by the fact that our young cases had a very high HB F level which will be rapidly changing so that statistical analyses would be unlikely to find it as a strong predictor. Further prospective study for these cases should be warranted to check for the importance of HB F at older ages to solve the issue of controversies regarding this parameter [3, 8 & 16].
We can conclude that with the use of this predictive equation, SCD infants beyond age of 6 month could be scored as a high or low risk using the top 3 prognostic parameters incriminated in discriminant analysis. High risk SCD infants should be a target for powerful therapeutic plan that include the availability of newly introduced pain controllers for home use [18] and a community-based educational treatment to increase spiritual well-being and self-efficacy to cope with pain [19]. With the help of these measures altogether SCD morbidity and mortality would be mitigated.
Acknowlegement
We acknowledge all staff members of Genetics unit laboratories, MUCH, Faculty of Medicine, Mansoura University, for blood sampling and laboratory analysis. Particular thanks are due to staff of paediatric haematology unit in MUCH for the efforts in retrieving personal and clinical data of old cases, and recruiting them for further evaluation.
REFERENCES
1. Miller ST, Sleeper LA, Pegelow CH, et al: Prediction of adverse outcomes in children with sickle cell disease. N Engl J Med 2000; 342:83-89.
2. Kaul DK, Fabry ME, Nagel RL: The pathophysiology of vascular obstruction in the sickle syndromes. Blood Rev 1996; 10:29-44.
3. Marouf R, Gupta R, Haider MZ, Al-Wazzan H, Adekile AD: Avascular necrosis of the femoral head in adult Kuwaiti sickle cell disease patients. Acta Hematol 2003; 110(1): 11-15.
4. Rahimi Z, Karimi M, Haghshenass M, Merat A: Beta-globin gene cluster haplotypes in sickle cell patients from southwest Iran. Am J Hematol 2003; 74(3):156-160.
5. Homi J, Levee L, Higgs D, Thomas P, Serjeant G: Pulse oximetry in a cohort study of sickle cell disease. Clin Lab Haematol 1997; 19:17-22.
6. Needleman JP, Franco ME, Varlotta L et al: Mechanisms of nocturnal oxyhemoglobin desaturation in children and adolescents with sickle cell disease. Pediatr Pulmonol 1999; 28:418-422.
7. Wilkey O, Evans JPM, Telfer PT, Kirkham FJ: Predictors of nocturnal hypoxaemia in children with sickle cell disease [abstract]. Arch Dis Child 2002; 86 (suppl 1):A12.
8. Haregrave DR, Wade A, Evans JPM, Hewes DKM, Kirkham, FJ: Nocturnal oxygen saturation and painful sickle cell crises in children. Blood 2003; 101(3): 846-848.
9. Fairbanks VK, Klee GG: In textbook of Clinical Chemistry, Teitz NW (ed) WB Saunders co., Philadelphia, 1986; 1540-1541.
10. Kim HC: Separation of Hemoglobins in Hematology Textbook; 4th edition, Williams WJ and Lecihman MA (eds), McChill, NewYork 1990; 1711-1714.
11. Echier G: Determination of G-6-PD. Am J Med Technol 1983; 49:259.
12. SPSS: Statistical Package for Social Science, standard version 10.0.1; 1999; SPSS Inc., Chicago, IL.
13. Al-Arrayed S, Hafadh N, Amin S, Al-Mukhareq H, Sanad H: Student screening for inherited blood disorders in Bahrain. East Mediterr Health J 2003; 9(3):344-352.
14. Keser I, Sanlioglu AD, Manguoglu E, et al : Molecular analysis of beta-thalassemia and sickle cell anemia in Antalya. Acta Haematol 2004; 111(4):205-210.
15. Platt OS, Thorington BD, Brambilla DJ, et al: Pain in sickle cell disease. Rates and risk factors. N Engl J Med 1991; 325:11-16.
16. Inati A, Taher A, Bou Alawi W, et al: Beta-globin gene cluster haplotypes and HB F levels are not the only modulators of sickle cell disease in Lebanon. Eur J Haematol 2003; 70(2):79-83.
17. Udezue E, Girshab AM: Differences between males and females in adults sickle cell pain crises in eastern Saudi Arabia. Ann Saudi Med 2004; 24(3): 179-182.
18. Graves PA, Kedar A, Koshy M, et al: RheothRx (Poloxamer 188) Injection for the Acute Painful Episode of Sickle Cell Disease: A Pilot Study. Blood 1997; 90(5):2041-2046.
19. Cooper-Effa M, Blount W, Kaslow N, Rothenberg R, Eckman J: Role of spirituality in patients with sickle cell disease. J Am Board Fam Pract 2001; 14(2): 116-122.
Case Report: Early diagnosis of Hodgkin’s disease based On Flow Cytometry parameters
Case Report: Early diagnosis of Hodgkin’s disease based On Flow Cytometry parameters
Mohammad S Al-Haggar (1), Ahmad A Settin (1), Seham A AlMansy (2), Tarek A Atia (3), Rizk A ElBaz (1), Zakaria I AlMorsy (1)
(1) Genetics Unit, Mansoura University Children Hospital
(2) Faculty of Science (Damietta), Mansoura University,
(3) Histology Department, Al-Azhar University, Cairo
Correspondence: Mohammad Al-Haggar, MD, Paediatrics Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt, e-mail: mhajjar2000@yahoo.co.uk
Presentation:
On October 2004, a male patient aged 5.6 years presented to the outpatient clinic of Mansoura University Children’s Hospital, Mansoura, Egypt with cervical lymphadenopathy. Generally, the patient was clinically fit with no local signs other than the above, with no generalized manifestations of any systemic disease or other gland enlargements. Local examination revealed significant lymphadenopathy of 2X3 cm size which is rubbery in consistency and not tender. Laboratory workup included CBC, ESR and serum ferritin; all were found within the normal range. Chest radiograph and abdominal ultrasound were non revealing. Because of the significant size and suspicious consistency we tried to convince the family for the need to do an excision lymph node biopsy but in vain. They only accepted close fine needle aspiration for histological examination and Flow Cytometry (FCM) evaluation of DNA ploidy and apoptosis using FACS caliber flow cytometer (Becton Dickinson, Sunnyvale, CA, USA). The average number of evaluated nuclei per specimen was 20.000; with the rate of nuclei scanning of 120 per second. For the patient, FCM revealed highly suspicious plot diagrams for Lymphoma (figure: 1) although the histological examination was non-informative. The attending oncologist recommended either observational follow up or open biopsy for confirmation followed by chemotherapy. As the case was cold, patient was asked to attend monthly for serial evaluation of the gland size and routine laboratory workup. In March 2005, there was a slight elevation in the sedimentation rate associated with more enlargement of the lymph gland coupled with some tenderness over the gland to the degree the surgeon suspected abscess formation. Excision biopsy was done and a pathological diagnosis of large cell Hodgkin’s was made thus confirming the finding of the Flow Cytometry (figure: 2).
Discussion:
In lymphoma Fine needle aspiration samples sometimes contain few normal cells, a single peak deviation more than 5% from the expected position for diploid cells which is considered as aneuploidy (1). The degree of aneuploidy could be determined by the DNA index (DI), which represents the ratio of fluorescence intensity of aneuploid cells to the diploid cells; DI of a diploid tumor is 1.0, whereas those of aneuploid tumors are progressively higher (2). In Hodgkin’s disease, FCM might miss the diagnosis because of either the intra-tumor DNA heterogeneity or the limited sample size for DNA analysis, thus minimizing the clinical significance of DNA content as a diagnostic parameter in Hodgkin’s disease (3).
Fortunately in our case, DNA content was so informative that it gave a high DI (more than 1.0), low S-phase portion with highly suspicious aneuploidy pattern and apoptotic percentage on FCM evaluation. However, other DNA cycle parameters were not conclusive so that the final conclusion of borderline malignancy was considered. In such cases pathological diagnosis is highly recommended to confirm the possibility of malignancy for early therapeutic intervention.
Reference:
1. Ormerod MG, Tribukait B, Giarretti W: Consensus report of the task force on standardization of DNA flow cytometry in clinical pathology. DNA flow cytometry task force of the European society for analytical cellular pathology. Anal. Cell Pathol (1998); 17:103-110. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10052634&query_hl=3
2. Gِrdon KM, Duckett L, Dual B, Petrie HT: A simple method for detecting up to five immunofluorescent parameters together with DNA staining for cell cycle or viability on a bench top flow cytometry. J Immunol Methods (2003); 275:113-121.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12667675&query_hl=5
3. Kushibe K, Lioka S, Nezu K, Tojo T, Sawabata N, Kitamura S: Flow cytometric analysis of the DNA content of thymoma. Surg Today (1995); 25:334-337. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7633125&query_hl=7
Mohammad S Al-Haggar (1), Ahmad A Settin (1), Seham A AlMansy (2), Tarek A Atia (3), Rizk A ElBaz (1), Zakaria I AlMorsy (1)
(1) Genetics Unit, Mansoura University Children Hospital
(2) Faculty of Science (Damietta), Mansoura University,
(3) Histology Department, Al-Azhar University, Cairo
Correspondence: Mohammad Al-Haggar, MD, Paediatrics Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt, e-mail: mhajjar2000@yahoo.co.uk
Presentation:
On October 2004, a male patient aged 5.6 years presented to the outpatient clinic of Mansoura University Children’s Hospital, Mansoura, Egypt with cervical lymphadenopathy. Generally, the patient was clinically fit with no local signs other than the above, with no generalized manifestations of any systemic disease or other gland enlargements. Local examination revealed significant lymphadenopathy of 2X3 cm size which is rubbery in consistency and not tender. Laboratory workup included CBC, ESR and serum ferritin; all were found within the normal range. Chest radiograph and abdominal ultrasound were non revealing. Because of the significant size and suspicious consistency we tried to convince the family for the need to do an excision lymph node biopsy but in vain. They only accepted close fine needle aspiration for histological examination and Flow Cytometry (FCM) evaluation of DNA ploidy and apoptosis using FACS caliber flow cytometer (Becton Dickinson, Sunnyvale, CA, USA). The average number of evaluated nuclei per specimen was 20.000; with the rate of nuclei scanning of 120 per second. For the patient, FCM revealed highly suspicious plot diagrams for Lymphoma (figure: 1) although the histological examination was non-informative. The attending oncologist recommended either observational follow up or open biopsy for confirmation followed by chemotherapy. As the case was cold, patient was asked to attend monthly for serial evaluation of the gland size and routine laboratory workup. In March 2005, there was a slight elevation in the sedimentation rate associated with more enlargement of the lymph gland coupled with some tenderness over the gland to the degree the surgeon suspected abscess formation. Excision biopsy was done and a pathological diagnosis of large cell Hodgkin’s was made thus confirming the finding of the Flow Cytometry (figure: 2).
Discussion:
In lymphoma Fine needle aspiration samples sometimes contain few normal cells, a single peak deviation more than 5% from the expected position for diploid cells which is considered as aneuploidy (1). The degree of aneuploidy could be determined by the DNA index (DI), which represents the ratio of fluorescence intensity of aneuploid cells to the diploid cells; DI of a diploid tumor is 1.0, whereas those of aneuploid tumors are progressively higher (2). In Hodgkin’s disease, FCM might miss the diagnosis because of either the intra-tumor DNA heterogeneity or the limited sample size for DNA analysis, thus minimizing the clinical significance of DNA content as a diagnostic parameter in Hodgkin’s disease (3).
Fortunately in our case, DNA content was so informative that it gave a high DI (more than 1.0), low S-phase portion with highly suspicious aneuploidy pattern and apoptotic percentage on FCM evaluation. However, other DNA cycle parameters were not conclusive so that the final conclusion of borderline malignancy was considered. In such cases pathological diagnosis is highly recommended to confirm the possibility of malignancy for early therapeutic intervention.
Reference:
1. Ormerod MG, Tribukait B, Giarretti W: Consensus report of the task force on standardization of DNA flow cytometry in clinical pathology. DNA flow cytometry task force of the European society for analytical cellular pathology. Anal. Cell Pathol (1998); 17:103-110. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10052634&query_hl=3
2. Gِrdon KM, Duckett L, Dual B, Petrie HT: A simple method for detecting up to five immunofluorescent parameters together with DNA staining for cell cycle or viability on a bench top flow cytometry. J Immunol Methods (2003); 275:113-121.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12667675&query_hl=5
3. Kushibe K, Lioka S, Nezu K, Tojo T, Sawabata N, Kitamura S: Flow cytometric analysis of the DNA content of thymoma. Surg Today (1995); 25:334-337. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7633125&query_hl=7
Wednesday, April 4, 2007
جــــواهـــر من أقـــوال الســـلف
قال ابن القيم رحمه الله تعالى: سبحان الله؛ في النفس كبر إبليس، وحسد قابيل، وعتو عاد، وطغيان ثمود، وجرأة نمرود، واستطالة فرعون، وبغي قارون، وقحة هامان.
قال بعض السلف: خلق الله الملائكة عقولاً بلا شهوة، وخلق البهائم شهوة بلا عقول، وخلق ابن آدم وركب فيه العقل والشهوة، فمن غلب عقله شهوته التحق بالملائكة، ومن غلبت شهوته عقله التحق بالبهائم.
قال سفيان الثوري: ما عالجت شيئاً أشد عليّ من نفسي، مرة لي ومرة علي.
قال مالك بن دينار - رحمه الله:- رحم الله عبداً قال لنفسه: ألستِ صاحبة كذا ؟ ألستِ صاحبة كذا ؟ ثم ذمها، ثم خطمها ثم ألزمها كتاب الله تعالى فكان لها قائداً.
قال أبو بكر الوراق: استعن على سيرك إلى الله بترك من شغلك عن الله عز وجل، وليس بشاغل يشغلك عن الله عز وجل كنفسك التي هي بين جنبيك.
قال مجاهد: من أعزّ نفسه أذل دينه، ومن أذلّ نفسه أعزّ دينه.
قال سفيان الثوري: الزهد في الدنيا هو الزهد في الناس، وأول ذلك زهدك في نفسك.
قال خالد بن معدان: لا يفقه الرجل كل الفقه حتى يرى الناس في جنب الله أمثال الأباعر، ثم يرجع إلى نفسه فيكون لها أحقر حاقر.
قال الحسن: رحم الله عبداً وقف عند همه، فإن كان لله مضى وإن كان لغيره تأخر.
قال بكر بن عبد الله المزني: لما نظرت إلى أهل عرفات ظننت أنهم قد غُفر لهم، لولا أنني كنت فيهم.
قال يونس بن عبيد: إني لأجد مائة خصلة من خصال الخير، ما أعلم أن في نفسي منها واحدة.
قال الحسن: ما زالت التقوى بالمتقين حتى تركوا كثيراً من الحلال مخافة الحرام.
قال أبو يزيد: ما زلت أقود نفسي إلى الله وهي تبكي، حتى سقتها وهي تضحك.
قال الحسن: من علامة إعراض الله عن العبد أن يجعل شغله فيما لا يعنيه.
قال سهل: من اشتغل بالفضول حُرِم الورع.
قال معروف: كلام العبد فيما لا يعنيه، خذلان من الله عز وجل.
قال يحيى بن معاذ: القلوب كالقدور تغلي بما فيها، وألسنتها مغارفها، فانظر إلى الرجل حين يتكلم، فإن لسانه يغترف لك مما في قلبه، حلو.. حامض.. عذب.. أجاج.. وغير ذلك، ويبين لك طعم قلبه اغتراف لسانه.
قال مالك بن دينار: إن الأبرار لتغلي قلوبهم بأعمال البر، وإن الفجار تغلي قلوبهم بأعمال الفجور، والله يرى همومكم، فانظروا ما همومكم رحمكم الله.
قالت عائشة رضي الله تعالى عنها: أول بدعة حدثت بعد رسول الله صلى الله عليه وسلم؛ الشبع، إن القوم لما شبعت بطونهم، جمحت بهم نفوسهم إلى الدنيا.
قال ابن عباس رضي الله تعالى عنه: لا تجالس أهل الأهواء فإن مجالستهم ممرضة للقلب.
قال أبو الجوزاء: لأن أجالس الخنازير، أحب إلي من أن أجالس رجلاً من أهل الأهواء.
قال ابن القيم رحمه الله تعالى: كل ما كان في القرآن من مدح للعبد فهو من ثمرة العلم، وكل ما كان فيه من ذم فهو من ثمرة الجهل.
قال الشاطبي رحمه الله: آخر الأشياء نزولا من قلوب الصالحين: حب السلطة والتصدر.
قال ابن القيم رحمه الله: ولو لم يكن في العلم إلا القرب من رب العالمين والالتحاق بعالم الملائكة لكفى به شرفاً وفضلاً، فكيف وعزّ الدنيا والآخرة منوط به مشروط بحصوله.
قال ابن الأثير: إن الشهوة الخفية: حب اطلاع الناس على العمل.
قال بشر بن الحارث: ما اتقى الله من أحب الشهرة.
قال علي رضي الله عنه: يهتف العلم بالعمل، فإن أجابه وإلا ارتحل.
قال بشر الحافي: أدوا زكاة الحديث: فاستعملوا من كل مائتي حديث خمسة أحاديث.
قال الحسن: إياك والتسويف، فإنك بيومك ولست بغدك، فإن يكن غداً لك فكن في غد كما كنت في اليوم، وإن لم يكن لك غد لم تندم على ما فرطت في اليوم.
قال محمد بن عبد الباقي: ما أعلم أني ضيعت ساعة من عمري في لهو أو لعب.
قال الذهبي: إن العلم ليس بكثرة الرواية، ولكنه نور يقذفه الله في القلب، وشرطه الاتباع، والفرار من الهوى والابتداع.
قال ابن عباس رضي الله عنهما: العالم الرباني هو الذي يعلم الناس صغار العلم قبل كباره.
قال أحد السلف: إنما العلم مواهب يؤتيه الله من أحب من خلقه، وليس يناله أحد بالحسب، ولو كان لعلة الحسب لكان أولى الناس به أهل بيت النبي صلى الله عليه وسلم.
قيل للشعبي رحمه الله: من أين لك هذا العلم كله ؟ قال: بنفي الاعتماد، والسير في البلاد، وصبر كصبر الجماد، وبكور كبكور الغراب.
قال الذهبي رحمه الله: ما خلا مجتمع من التغاير والحسد، إلا ما كان في جانب الأنبياء والرسل عليهم السلام.
قال الشافعي رحمه الله: والله لو علمت أن الماء البارد يثلم من مروءتي شيئا ما شربت إلا حارا ً.
قيل لأحمد بن حنبل: كيف تعرف الكذابين ؟ قال: بمواعيدهم.
قال هرم بن حيان: ما أقبل عبدٌ بقلبه إلى الله، إلا أقبل الله بقلوب المؤمنين إليه حتى يرزقه ودهم.ونســــــــــألكم الــــــــــــــــــــــدعاء.
قال بعض السلف: خلق الله الملائكة عقولاً بلا شهوة، وخلق البهائم شهوة بلا عقول، وخلق ابن آدم وركب فيه العقل والشهوة، فمن غلب عقله شهوته التحق بالملائكة، ومن غلبت شهوته عقله التحق بالبهائم.
قال سفيان الثوري: ما عالجت شيئاً أشد عليّ من نفسي، مرة لي ومرة علي.
قال مالك بن دينار - رحمه الله:- رحم الله عبداً قال لنفسه: ألستِ صاحبة كذا ؟ ألستِ صاحبة كذا ؟ ثم ذمها، ثم خطمها ثم ألزمها كتاب الله تعالى فكان لها قائداً.
قال أبو بكر الوراق: استعن على سيرك إلى الله بترك من شغلك عن الله عز وجل، وليس بشاغل يشغلك عن الله عز وجل كنفسك التي هي بين جنبيك.
قال مجاهد: من أعزّ نفسه أذل دينه، ومن أذلّ نفسه أعزّ دينه.
قال سفيان الثوري: الزهد في الدنيا هو الزهد في الناس، وأول ذلك زهدك في نفسك.
قال خالد بن معدان: لا يفقه الرجل كل الفقه حتى يرى الناس في جنب الله أمثال الأباعر، ثم يرجع إلى نفسه فيكون لها أحقر حاقر.
قال الحسن: رحم الله عبداً وقف عند همه، فإن كان لله مضى وإن كان لغيره تأخر.
قال بكر بن عبد الله المزني: لما نظرت إلى أهل عرفات ظننت أنهم قد غُفر لهم، لولا أنني كنت فيهم.
قال يونس بن عبيد: إني لأجد مائة خصلة من خصال الخير، ما أعلم أن في نفسي منها واحدة.
قال الحسن: ما زالت التقوى بالمتقين حتى تركوا كثيراً من الحلال مخافة الحرام.
قال أبو يزيد: ما زلت أقود نفسي إلى الله وهي تبكي، حتى سقتها وهي تضحك.
قال الحسن: من علامة إعراض الله عن العبد أن يجعل شغله فيما لا يعنيه.
قال سهل: من اشتغل بالفضول حُرِم الورع.
قال معروف: كلام العبد فيما لا يعنيه، خذلان من الله عز وجل.
قال يحيى بن معاذ: القلوب كالقدور تغلي بما فيها، وألسنتها مغارفها، فانظر إلى الرجل حين يتكلم، فإن لسانه يغترف لك مما في قلبه، حلو.. حامض.. عذب.. أجاج.. وغير ذلك، ويبين لك طعم قلبه اغتراف لسانه.
قال مالك بن دينار: إن الأبرار لتغلي قلوبهم بأعمال البر، وإن الفجار تغلي قلوبهم بأعمال الفجور، والله يرى همومكم، فانظروا ما همومكم رحمكم الله.
قالت عائشة رضي الله تعالى عنها: أول بدعة حدثت بعد رسول الله صلى الله عليه وسلم؛ الشبع، إن القوم لما شبعت بطونهم، جمحت بهم نفوسهم إلى الدنيا.
قال ابن عباس رضي الله تعالى عنه: لا تجالس أهل الأهواء فإن مجالستهم ممرضة للقلب.
قال أبو الجوزاء: لأن أجالس الخنازير، أحب إلي من أن أجالس رجلاً من أهل الأهواء.
قال ابن القيم رحمه الله تعالى: كل ما كان في القرآن من مدح للعبد فهو من ثمرة العلم، وكل ما كان فيه من ذم فهو من ثمرة الجهل.
قال الشاطبي رحمه الله: آخر الأشياء نزولا من قلوب الصالحين: حب السلطة والتصدر.
قال ابن القيم رحمه الله: ولو لم يكن في العلم إلا القرب من رب العالمين والالتحاق بعالم الملائكة لكفى به شرفاً وفضلاً، فكيف وعزّ الدنيا والآخرة منوط به مشروط بحصوله.
قال ابن الأثير: إن الشهوة الخفية: حب اطلاع الناس على العمل.
قال بشر بن الحارث: ما اتقى الله من أحب الشهرة.
قال علي رضي الله عنه: يهتف العلم بالعمل، فإن أجابه وإلا ارتحل.
قال بشر الحافي: أدوا زكاة الحديث: فاستعملوا من كل مائتي حديث خمسة أحاديث.
قال الحسن: إياك والتسويف، فإنك بيومك ولست بغدك، فإن يكن غداً لك فكن في غد كما كنت في اليوم، وإن لم يكن لك غد لم تندم على ما فرطت في اليوم.
قال محمد بن عبد الباقي: ما أعلم أني ضيعت ساعة من عمري في لهو أو لعب.
قال الذهبي: إن العلم ليس بكثرة الرواية، ولكنه نور يقذفه الله في القلب، وشرطه الاتباع، والفرار من الهوى والابتداع.
قال ابن عباس رضي الله عنهما: العالم الرباني هو الذي يعلم الناس صغار العلم قبل كباره.
قال أحد السلف: إنما العلم مواهب يؤتيه الله من أحب من خلقه، وليس يناله أحد بالحسب، ولو كان لعلة الحسب لكان أولى الناس به أهل بيت النبي صلى الله عليه وسلم.
قيل للشعبي رحمه الله: من أين لك هذا العلم كله ؟ قال: بنفي الاعتماد، والسير في البلاد، وصبر كصبر الجماد، وبكور كبكور الغراب.
قال الذهبي رحمه الله: ما خلا مجتمع من التغاير والحسد، إلا ما كان في جانب الأنبياء والرسل عليهم السلام.
قال الشافعي رحمه الله: والله لو علمت أن الماء البارد يثلم من مروءتي شيئا ما شربت إلا حارا ً.
قيل لأحمد بن حنبل: كيف تعرف الكذابين ؟ قال: بمواعيدهم.
قال هرم بن حيان: ما أقبل عبدٌ بقلبه إلى الله، إلا أقبل الله بقلوب المؤمنين إليه حتى يرزقه ودهم.ونســــــــــألكم الــــــــــــــــــــــدعاء.
Tuesday, April 3, 2007
ســـعيد بن عــامر - مثــال الــورع والزهــد والتــقى
أمير المؤمنين وخليفة المسلمين فاروق الأمة عمر بن الخطاب رضي الله عنه يتفقد أحوال المسلمين والرعية في حمص.. وفي جمع حاشد يسأل أهل حمص: ما تقولون في سعيد بن عامر؟؟.. وإذ ببعضهم يقدم شكواه إلى أمير المؤمنين!!..
كيف وهو الذي اختاره من بين الصحابة ليكون أميرا واليا على حمص؟؟..
كيف ولم يعرف عن الصحابي سعيد بن عامر إلا الزهد والورع والتقى؟؟..
كيف وسعيد بن عامر من كبار أصحاب رسول الله وكبار الأنقياء والأتقياء؟؟..
كيف يشكون منه وحين عرض عليه إمارة حمص رفض وقال: لا تَفتني يا أمير المؤمنين.. ليجيبه فاروق الأمة: والله لا أدعك.. أتضعون أمانتكم وخلافتكم في عنقي.. ثم تتركونني؟؟..
كيف يشكون منه وقد أنفق ماله الذي زوده به أمير المؤمنين، ولم يدخر منه سوى القليل؟؟..
إذا لم تشكون منه يا أهل حمص وما نوع شكواكم؟؟..
طلب أمير المؤمنين من أهل حمص أن يعدّدوا شكواهم في هذا العبد الزاهد المتقرب إلى الله.
وإذ بواحد منهم يقول: لا يخرج إلينا حتى يتعالى النهار.. ولا يجيب أحدا بليل.. وله في الشهر يومان لا يخرج فيهما إلينا ولا نراه، وأخرى لا حيلة له فيها ولكنها تضايقنا، وهي أن تأخذه الغشية (أي الإغماء) بين الحين والحين..
أمير المؤمنين وفاروق الأمة عرف أنه لم يولي عليهم إلا الرجل المناسب فدعا الله مبتهلا: اللهم إني أعرفه من خير عبادك.. اللهم لا تخيّب فيه فراستي..
وأحضر بسعيد الصحابي الجليل ليدافع عن نفسه أمام فاروق الأمة وجموع الأمة فقال: أما قولهم: إني لا أخرج إليهم حتى يتعالى النهار.. فوالله لقد كنت أكره ذكر السبب.. إنه ليس لأهلي خادم، فأنا أعجن العجين، ثم أدعه حتى يختمر، ثم أخبز خبزي، ثم أتوضأ للضحى ثم أخرج إليهم..
وأما قولهم: لا أجيب أحدا بليل.. فوالله لقد كنت أكره أن أذكر السبب.. إني جعلت النهار لهم، والليل لربي..
وأما قولهم: إني لي يومين في الشهر لا أخرج فيهما.. فليس لي خادم يغسل ثوبي، وليس لي ثياب أبدلها، فأنا أغسل ثوبي ثم أنتظر حتى يجفّ بعد حين.. وفي آخر النهار أخرج إليهم..
وأما قولهم: إن الغشية تأخذني بين الحين والحين.. فقد شهدت مصرع خبيب الأنصاري بمكة، وقد بضَعت قريش لحمه، وحملوه على جزعة، وهم يقولون أتحب محمدا مكانك وأنت سليم معافى؟؟ فيجيبهم قائلا: والله ما أحبّ أني في أهلي وولدي، معي عافية الدنيا ونعيمها، ويصاب رسول الله بشوكة.. فكلما ذكرت ذلك المشهد الذي رأيته، وأنا يومئذ من المشركين، ثم تذكرت تركي نصرة خبيب يومها، ارتجف خوفا من عذاب الله، ويغشاني الذي يغشاني..
وإذ بأمير المؤمنين يستبشر ويضيء وجهه وهو يرى سعيد ودموعه الورعة الطاهرة البريئة تتساقط على وجنتيه وكأنها لؤلؤة يضيء منها كنز الإيمان ونور الإسلام.
ويعلم فاروق الأمة أنه أحسن حين اختار سعيد واليا على حمص فيقبل جبهة سعيد بن عامر المضيئة بنور الإيمان والهدي والحق ويقول: الحمد لله الذي لم يخيّب فراستي..
هؤلاء والله الرجال العظام الذي يجب علينا نحن أمة القرآن أن نقتدي بهم لنخرج الأمة من كبوتها وغفوتها وسباتها العميق.. سعيد بن عامر الصحابي الجليل يا أمة القرآن تصيبه الغَشية حين يذكر خبيب وهو على خشبة الموت بين أيدي الطغاة المشركين ولم ينصره، مع أنه لم يعلن إسلامه بعد.
نسأل الله أن يردّ الله أمتنا إلى طريق الحق والهدي والاستقامة، وأن يصلح الله نفوسنا من الضغائن والأحقاد، وأن ينصرنا الله على كل من عادى الإسلام والمسلمين إنه سميع مجيب.
كيف وهو الذي اختاره من بين الصحابة ليكون أميرا واليا على حمص؟؟..
كيف ولم يعرف عن الصحابي سعيد بن عامر إلا الزهد والورع والتقى؟؟..
كيف وسعيد بن عامر من كبار أصحاب رسول الله وكبار الأنقياء والأتقياء؟؟..
كيف يشكون منه وحين عرض عليه إمارة حمص رفض وقال: لا تَفتني يا أمير المؤمنين.. ليجيبه فاروق الأمة: والله لا أدعك.. أتضعون أمانتكم وخلافتكم في عنقي.. ثم تتركونني؟؟..
كيف يشكون منه وقد أنفق ماله الذي زوده به أمير المؤمنين، ولم يدخر منه سوى القليل؟؟..
إذا لم تشكون منه يا أهل حمص وما نوع شكواكم؟؟..
طلب أمير المؤمنين من أهل حمص أن يعدّدوا شكواهم في هذا العبد الزاهد المتقرب إلى الله.
وإذ بواحد منهم يقول: لا يخرج إلينا حتى يتعالى النهار.. ولا يجيب أحدا بليل.. وله في الشهر يومان لا يخرج فيهما إلينا ولا نراه، وأخرى لا حيلة له فيها ولكنها تضايقنا، وهي أن تأخذه الغشية (أي الإغماء) بين الحين والحين..
أمير المؤمنين وفاروق الأمة عرف أنه لم يولي عليهم إلا الرجل المناسب فدعا الله مبتهلا: اللهم إني أعرفه من خير عبادك.. اللهم لا تخيّب فيه فراستي..
وأحضر بسعيد الصحابي الجليل ليدافع عن نفسه أمام فاروق الأمة وجموع الأمة فقال: أما قولهم: إني لا أخرج إليهم حتى يتعالى النهار.. فوالله لقد كنت أكره ذكر السبب.. إنه ليس لأهلي خادم، فأنا أعجن العجين، ثم أدعه حتى يختمر، ثم أخبز خبزي، ثم أتوضأ للضحى ثم أخرج إليهم..
وأما قولهم: لا أجيب أحدا بليل.. فوالله لقد كنت أكره أن أذكر السبب.. إني جعلت النهار لهم، والليل لربي..
وأما قولهم: إني لي يومين في الشهر لا أخرج فيهما.. فليس لي خادم يغسل ثوبي، وليس لي ثياب أبدلها، فأنا أغسل ثوبي ثم أنتظر حتى يجفّ بعد حين.. وفي آخر النهار أخرج إليهم..
وأما قولهم: إن الغشية تأخذني بين الحين والحين.. فقد شهدت مصرع خبيب الأنصاري بمكة، وقد بضَعت قريش لحمه، وحملوه على جزعة، وهم يقولون أتحب محمدا مكانك وأنت سليم معافى؟؟ فيجيبهم قائلا: والله ما أحبّ أني في أهلي وولدي، معي عافية الدنيا ونعيمها، ويصاب رسول الله بشوكة.. فكلما ذكرت ذلك المشهد الذي رأيته، وأنا يومئذ من المشركين، ثم تذكرت تركي نصرة خبيب يومها، ارتجف خوفا من عذاب الله، ويغشاني الذي يغشاني..
وإذ بأمير المؤمنين يستبشر ويضيء وجهه وهو يرى سعيد ودموعه الورعة الطاهرة البريئة تتساقط على وجنتيه وكأنها لؤلؤة يضيء منها كنز الإيمان ونور الإسلام.
ويعلم فاروق الأمة أنه أحسن حين اختار سعيد واليا على حمص فيقبل جبهة سعيد بن عامر المضيئة بنور الإيمان والهدي والحق ويقول: الحمد لله الذي لم يخيّب فراستي..
هؤلاء والله الرجال العظام الذي يجب علينا نحن أمة القرآن أن نقتدي بهم لنخرج الأمة من كبوتها وغفوتها وسباتها العميق.. سعيد بن عامر الصحابي الجليل يا أمة القرآن تصيبه الغَشية حين يذكر خبيب وهو على خشبة الموت بين أيدي الطغاة المشركين ولم ينصره، مع أنه لم يعلن إسلامه بعد.
نسأل الله أن يردّ الله أمتنا إلى طريق الحق والهدي والاستقامة، وأن يصلح الله نفوسنا من الضغائن والأحقاد، وأن ينصرنا الله على كل من عادى الإسلام والمسلمين إنه سميع مجيب.
Implementation of a scientific project
Definition:
A scientific project is considered to be successful if it is fulfilling two items:-
1. Evidence was established to confirm the idea.
2. Both evidence and idea are complementary and additive.
Cornerstones:
1. Question or problem:
- define the question or problem in a simple and short phrase.
- why do you want to solve it? Consequently define the aims.
- analyse the parameters of problem, enumerate the closely relevant citations, and select the logic solutions.
- Solutions should be arranged in a descending manner (logistic).
2. Unbiased self evaluation:
- check the format of problem, solutions, citations and all parameters of study in non-biased way as if you are evaluating the work of others.
- repeat this transparent evaluation many times in different moods and situations.
3. Avoid the illusive conclusions: It may be due to:-
- false or irrelevant solution.
- non-expert citations which may be famous OR refusal a citation from an expert non-famous person (because of lack of credibility).
- non-biologic associations.
- rapid and absolute generalizations without any clinical or statistical significance.
- use of hot topics in society that need urgent solutions.
4. Brilliance in mathematics and statistics.
A scientific project is considered to be successful if it is fulfilling two items:-
1. Evidence was established to confirm the idea.
2. Both evidence and idea are complementary and additive.
Cornerstones:
1. Question or problem:
- define the question or problem in a simple and short phrase.
- why do you want to solve it? Consequently define the aims.
- analyse the parameters of problem, enumerate the closely relevant citations, and select the logic solutions.
- Solutions should be arranged in a descending manner (logistic).
2. Unbiased self evaluation:
- check the format of problem, solutions, citations and all parameters of study in non-biased way as if you are evaluating the work of others.
- repeat this transparent evaluation many times in different moods and situations.
3. Avoid the illusive conclusions: It may be due to:-
- false or irrelevant solution.
- non-expert citations which may be famous OR refusal a citation from an expert non-famous person (because of lack of credibility).
- non-biologic associations.
- rapid and absolute generalizations without any clinical or statistical significance.
- use of hot topics in society that need urgent solutions.
4. Brilliance in mathematics and statistics.
Sunday, April 1, 2007
كيـــف يمكنــــك كتـــابة مقـــال محكـــم ؟
لابد أن يتميز المقال بالفرادة والجودة. أما الفرادة فمعناها أن تكون فكرتك جديدة وذات إبداع، وحبذا لو كانت بأسلوب سهل واضح بعيد عن الغموض أو اللبس.. فالفكرة المكتوبة بأسلوب صعب به مفردات غريبة تبعث في القارئ التيه وربما تثير في نفسه قصور الفهم، إن الكتابة على هذا المنوال توحي بعدم اكتمال الفكرة أو عدم نضوج الكاتب، لأنه ليس الغرض من الكتابة ضياع وقت القارئ في الفهم أو اتهامه بالعجز المعرفي
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إن جودة المقال تعتمد بالضرورة على قوة ومناسبة الاستشهاد بالمراجع القوية المعتمدة وذوات الثوابت المتينة. وإذا ذكرت المراجع فلابد من كتابة سندها الصحيح كما هو ثابت في الأعراف، كما يجب توخي دقة المعلومة المنسوبة لهذا المرجع دون إضافة أو حذف، أو تغيير في المعنى المنقول عنه. قد يكون هذا الاستشهاد لتأكيد أو نقض ما ذكر في الأطروحة، وأحيانا لتفسير ملاحظة ملموسة استنتجت في البحث ولم يؤخذ في الاعتبار مسبقا - أثناء الإجراء الجزء العملي – دراسة الكشف عن تفسيرها
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ولكي يرقى المقال إلى درجة علمية عالية لابد أن يكون جيدا وفريدا في آن واحد: أما أن يكون
فريدا وليس جيدا، فمعناه أنه يحتاج لتنقيح وتهذيب من ذوي الخبرة والدراية بكتابة المقالات.
جيدا ولكن ليس فريدا، فهذا في الواقع مقال يغلب عليه الطابع النقلي للمعلومة (أشبه بالتأريخ دون ابتكار أو إبداء للرأي
جيدا ولكن ليس فريدا، فهذا في الواقع مقال يغلب عليه الطابع النقلي للمعلومة (أشبه بالتأريخ دون ابتكار أو إبداء للرأي
غير فريد ولا جيد، فهذا لا يرقي إلى درجة المقال المنشور
How to Write a Perfect Manuscript?
Manuscript must be unique, novel and perfectly-written;
Unique and novel means that the idea is new and creative and written in simple clear words away from any strange and confusing vocabularies. Ideas written in strange words cause confusion to readers and may make readers accusing themselves by lack of understanding!! Manuscripts in this way denote either an immature idea or a young author as the main message of writing an article is to benefit readers, not waste their times and efforts or to accuse their comprehension.
Good articles must be indexed with references which should be suitable, elegantly selected to elaborate a finding in the work, support or even object an observation. The reference must be carefully written for easy access to the original work if needed, with an exact quotation of the text meaning and not to add any personal explanation. Quality of quotation is a very strong index for the perfection of author, errors are not allowed in references or its text.
For an article to be of high scientific rate, it should be unique, novel and perfectly-written in the same time; If it is:-
Unique but not good; it means it need editing by an experienced editor.
Good but not unique; it is like a review article which is sometimes helpful for an issue with available multiple researches by others.
Neither novel nor good; it should be rejected.
Unique and novel means that the idea is new and creative and written in simple clear words away from any strange and confusing vocabularies. Ideas written in strange words cause confusion to readers and may make readers accusing themselves by lack of understanding!! Manuscripts in this way denote either an immature idea or a young author as the main message of writing an article is to benefit readers, not waste their times and efforts or to accuse their comprehension.
Good articles must be indexed with references which should be suitable, elegantly selected to elaborate a finding in the work, support or even object an observation. The reference must be carefully written for easy access to the original work if needed, with an exact quotation of the text meaning and not to add any personal explanation. Quality of quotation is a very strong index for the perfection of author, errors are not allowed in references or its text.
For an article to be of high scientific rate, it should be unique, novel and perfectly-written in the same time; If it is:-
Unique but not good; it means it need editing by an experienced editor.
Good but not unique; it is like a review article which is sometimes helpful for an issue with available multiple researches by others.
Neither novel nor good; it should be rejected.
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