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Authors are the souls of any journal, and deserve much respect. To publish a journal manuscripts are needed from authors. Authors have a great responsibility for producing facts of their work in terms of number and results truthfully and an individual honesty is expected from authors in this regards. Both ways its true "No authors-No manuscripts-No journals" and "No journals–No manuscripts–No authors". Reviewing a manuscript is also a very responsible and important task of any peer-reviewed journal and to be taken seriously. It needs knowledge on the subject, sincerity, honesty and determination. Although the process of reviewing a manuscript is a time consuming task butit is expected to give one's best remarks within the time frame of the journal.
Salient features of the JCDR: It is a biomedical, multidisciplinary (including all medical and dental specialities), e-journal, with wide scope and extensive author support. At the same time, a free text of manuscript is available in HTML and PDF format. There is fast growing authorship and readership with JCDR as this can be judged by the number of articles published in it i e; in Feb 2007 of its first issue, it contained 5 articles only, and now in its recent volume published in April 2011, it contained 67 manuscripts. This e-journal is fulfilling the commitments and objectives sincerely, (as stated by Editor-in-chief in his preface to first edition) i e; to encourage physicians through the internet, especially from the developing countries who witness a spectrum of disease and acquire a wealth of knowledge to publish their experiences to benefit the medical community in patients care. I also feel that many of us have work of substance, newer ideas, adequate clinical materials but poor in medical writing and hesitation to submit the work and need help. JCDR provides authors help in this regards.
Timely publication of journal: Publication of manuscripts and bringing out the issue in time is one of the positive aspects of JCDR and is possible with strong support team in terms of peer reviewers, proof reading, language check, computer operators, etc. This is one of the great reasons for authors to submit their work with JCDR. Another best part of JCDR is "Online first Publications" facilities available for the authors. This facility not only provides the prompt publications of the manuscripts but at the same time also early availability of the manuscripts for the readers.
Indexation and online availability: Indexation transforms the journal in some sense from its local ownership to the worldwide professional community and to the public.JCDR is indexed with Embase & EMbiology, Google Scholar, Index Copernicus, Chemical Abstracts Service, Journal seek Database, Indian Science Abstracts, to name few of them. Manuscriptspublished in JCDR are available on major search engines ie; google, yahoo, msn.
In the era of fast growing newer technologies, and in computer and internet friendly environment the manuscripts preparation, submission, review, revision, etc and all can be done and checked with a click from all corer of the world, at any time. Of course there is always a scope for improvement in every field and none is perfect. To progress, one needs to identify the areas of one's weakness and to strengthen them.
It is well said that "happy beginning is half done" and it fits perfectly with JCDR. It has grown considerably and I feel it has already grown up from its infancy to adolescence, achieving the status of standard online e-journal form Indian continent since its inception in Feb 2007. This had been made possible due to the efforts and the hard work put in it. The way the JCDR is improving with every new volume, with good quality original manuscripts, makes it a quality journal for readers. I must thank and congratulate Dr Hemant Jain, Editor-in-Chief JCDR and his team for their sincere efforts, dedication, and determination for making JCDR a fast growing journal.
Every one of us: authors, reviewers, editors, and publisher are responsible for enhancing the stature of the journal. I wish for a great success for JCDR."
Thanking you
With sincere regards
Dr. Rajendra Kumar Ghritlaharey, M.S., M. Ch., FAIS
Associate Professor,
Department of Paediatric Surgery, Gandhi Medical College & Associated
Kamla Nehru & Hamidia Hospitals Bhopal, Madhya Pradesh 462 001 (India)
E-mail: drrajendrak1@rediffmail.com
On May 11,2011
Dr. Shankar P.R.
"On looking back through my Gmail archives after being requested by the journal to write a short editorial about my experiences of publishing with the Journal of Clinical and Diagnostic Research (JCDR), I came across an e-mail from Dr. Hemant Jain, Editor, in March 2007, which introduced the new electronic journal. The main features of the journal which were outlined in the e-mail were extensive author support, cash rewards, the peer review process, and other salient features of the journal.
Over a span of over four years, we (I and my colleagues) have published around 25 articles in the journal. In this editorial, I plan to briefly discuss my experiences of publishing with JCDR and the strengths of the journal and to finally address the areas for improvement.
My experiences of publishing with JCDR: Overall, my experiences of publishing withJCDR have been positive. The best point about the journal is that it responds to queries from the author. This may seem to be simple and not too much to ask for, but unfortunately, many journals in the subcontinent and from many developing countries do not respond or they respond with a long delay to the queries from the authors 1. The reasons could be many, including lack of optimal secretarial and other support. Another problem with many journals is the slowness of the review process. Editorial processing and peer review can take anywhere between a year to two years with some journals. Also, some journals do not keep the contributors informed about the progress of the review process. Due to the long review process, the articles can lose their relevance and topicality. A major benefit with JCDR is the timeliness and promptness of its response. In Dr Jain's e-mail which was sent to me in 2007, before the introduction of the Pre-publishing system, he had stated that he had received my submission and that he would get back to me within seven days and he did!
Most of the manuscripts are published within 3 to 4 months of their submission if they are found to be suitable after the review process. JCDR is published bimonthly and the accepted articles were usually published in the next issue. Recently, due to the increased volume of the submissions, the review process has become slower and it ?? Section can take from 4 to 6 months for the articles to be reviewed. The journal has an extensive author support system and it has recently introduced a paid expedited review process. The journal also mentions the average time for processing the manuscript under different submission systems - regular submission and expedited review.
Strengths of the journal: The journal has an online first facility in which the accepted manuscripts may be published on the website before being included in a regular issue of the journal. This cuts down the time between their acceptance and the publication. The journal is indexed in many databases, though not in PubMed. The editorial board should now take steps to index the journal in PubMed. The journal has a system of notifying readers through e-mail when a new issue is released. Also, the articles are available in both the HTML and the PDF formats. I especially like the new and colorful page format of the journal. Also, the access statistics of the articles are available. The prepublication and the manuscript tracking system are also helpful for the authors.
Areas for improvement: In certain cases, I felt that the peer review process of the manuscripts was not up to international standards and that it should be strengthened. Also, the number of manuscripts in an issue is high and it may be difficult for readers to go through all of them. The journal can consider tightening of the peer review process and increasing the quality standards for the acceptance of the manuscripts. I faced occasional problems with the online manuscript submission (Pre-publishing) system, which have to be addressed.
Overall, the publishing process with JCDR has been smooth, quick and relatively hassle free and I can recommend other authors to consider the journal as an outlet for their work."
Dr. P. Ravi Shankar
KIST Medical College, P.O. Box 14142, Kathmandu, Nepal.
E-mail: ravi.dr.shankar@gmail.com
On April 2011 Anuradha
Dear team JCDR, I would like to thank you for the very professional and polite service provided by everyone at JCDR. While i have been in the field of writing and editing for sometime, this has been my first attempt in publishing a scientific paper.Thank you for hand-holding me through the process.
Dr. Anuradha
E-mail: anuradha2nittur@gmail.com
On Jan 2020
Original article / research
Full Version
Relation Between the Uridine Diphosphate Glucuronosyltransferase 1A1 Polymorphism and the Bilirubin Levels in Sickle Cell Disease
Correspondence Address :
Dr. Renu Saxena,
Professor and Head
Department of Haematology,
I.R.C.H. Building (1st floor),
All India Institute of Medical Sciences,
Ansari Nagar, New Delhi – 110 029,India.
Phone: 91-011-26594670.
Telefax: 91-011-26588663.
E-mail: renusax@hotmail.com
Background: Genetic variations in the promoter of uridine diphosphate (UDP)–glucuronosyltransferase 1A1 (UGT1A1) may be associated with hyperbilirubinaemia and it appears to be a risk factor for gallstone formation.
Aims: Our aim was to detect the correlation between the UGT 1A1 (TA)n repeats and hyperbilirubinaemia and gall stone formation in Indian sickle cell patients.
Settings and Design:This was a cross-sectional study; which was carried in an autonomous tertiary care hospital.
Materials and Methods: The study subjects were 50 sickle cell anaemia and 70 sickle cell β-thalassaemia patients who were diagnosed by HPLC. The haemogram of the patients was measured by using an automated cell analyzer, while the serum bilrubin measurement was done by using a Beckman- CX-9 auto analyzer. The presence of gall stones was detected by ultra sound examination.
Statistical Analysis: ANOVA and the T-test were applied to compare the means of the groups. The allele frequencies were calculated according to the Hardy-Weinberg equilibrium.
Results: The allele, 7/7 TA of the UGT1A1 genotype was more frequent in the sickle cell patients and it was associated with hyperbilirubinaemia and gall stone formation.
Conclusions: The allele, 7/7 TA of the UGT1A1 polymorphism affects the bilirubin levels and the development of gallbladder stone in the Indian sickle cell patients.
Haemoglobinopathies, Sickle cell anaemia, UDP-Glucuronosyltransferase1A1
Introduction
UGT is encoded by the UGT1A1(uridine diphosphate glucuronosyltransferase 1A1) gene at chromosome 2q37.1, whose genotypes with a reduced enzyme activity, are known to lead to the Crigler-Najjar syndrome type 1 and type 2 and the Gilbert’s syndrome (1). Bilirubin UDP-glucuronosyltransferase 1A1 (UGT1A1) is the hepatic enzyme that catalyzes the glucuronidation of bilirubin into a water-soluble conjugated form to facilitate its efficient excretion (2). The variation in a (TA) tandem repeat sequence within the promoter region affects the UGT1A1 gene expression. The wild type UGT1A1 promoter region contains a (TA)nTAA sequence with 6 (TA) tandem repeats, although variant alleles with 5, 7, and 8 (TA) repeats have been identified. Persons with the homozygous 7/7 UGT1A1 genotype have the Gilbert syndrome with a phenotype of mild unconjugated hyperbilirubinaemia from the decreased UGT1A1 enzyme activity (2),(3),(4). Children with sickle cell anaemia have a variability in the clinical disease expression, which include a wide range in the steady-state laboratory parameters. Almost every child with homozygous HbSS has an elevated serum bilirubin concentration (5). Associations among the UGT1A1 promoter variation, high indirect bilirubin levels, and gallstone formation have also been reported in β-thalassaemia, haemoglobin E/β-thalassaemia, and hereditary spherocytosis (6),(7),(8). Bilirubin monoglucuronide triggers bilirubin gallstone initiation, as has been demonstrated in patients with many forms of haemolytic anaemia (8),(9),(10). Many children with HbSS and hyperbilirubinaemia develop gallstones with a cumulative incidence of 50%, by adulthood (11),(12).The laboratory and clinical variability in hyperbilirubinaemia and gallstone formation may reflect environmental factors (13).There is a paucity of data in terms of the UGT1A1 variation and the gall stone formation with hyperbilirubinaemia in Indian sicklers. Thus, our aim was to detect the UGT1A1 (TA)n repeats with hyperbilirubinaemia and gall stone formation in Indian sickle cell patients.
The subjects were sickle cell patients who attended the out patients department; All India Institute of Medical Sciences (AIIMS), New Delhi, India. This study was done in the Department of Haematology and it was approved by the institutional ethical committee. The gallbladder examinations were done by ultrasound. About 5 ml blood sample was collected from the patients after taken their informed consent. The complete blood count and the red cell indices were measured by an automated cell analyzer (SYSMEX K-4500, Kobe Japan). The quantitative assessment of Hb F, Hb A, Hb A2 and Hb S and the diagnosis of the sickle homozygous and the sickle beta thalassaemia patients was done by high performance liquid chromatography (HPLC-Bio-Rad-VariantTMBio Rad, CA, USA). DNA extraction was performed by the phenol-chloroform method. The UGT1A1 (TA)n promoter length variability was genotyped according to the method of Eden et al., (14) (2005). The measurement of serum bilrubin was done by a Beckman- CX-9 auto analyzer by using the Randox diagnostic kit. The allele frequency was calculated according to the Hardy-Weinberg equilibrium. The ANOVA test were applied to compare the means between the three groups, while the T- test was applied to compare the means of two groups on the GraphPad (version 3.06) software. A p-value of <0.05 was considered as statistically significant.
The study subjects were 50 sickle cell anaemia (32 males and 18 females with a mean age of 11.2±5.4 years) and seventy sickle cell β-thalassaemia patients (46 males and 24 females with a mean age of 11.8±5.5 years). The total bilirubin was 3.2±1.3 mg% in the sickle cell homozygous patients and it was 2.5±1.4 mg% in the sickle beta thalassaemia patients. The total bilirubun value was higher in the sickle cell anaemia patients than in the sickle beta thalassaemia patients and it was statistically significant (p-value 0.006), while the unconjugated bilrubin concentration was 2.1±0.45 mg% in the sickle homozygous patients and it was 1.9±0.38 mg% in the sickle beta thalassaemia patients (p-value 0.009). The TA repeats, 6/6, 6/7 and 7/7 of the UGT1A1 genotype promoter polymorphism were identified in our cases. The allele 7/7( TA) repeats were more frequent in sickle beta thalassaemia (54.28%) as well as in sickle homozygous (52%) patients, while the 6/6 TA repeats were 18% in the sickle homozygous patients and they were 15.71% in the sickle beta thalassaemia patients. The 6/7 TA repeats were 30% in the sickle homozygous as well as in the sickle beta thalassaemia patients. The allele frequencies of the 6/6, 6/7 and the 7/7 (TA)n repeats in the sickle homozygous patients was 0.104, 0.436 and 0.456 respectively, while they were 0.094, 0.424 and 0.478 respectively in the sickle β-thalassemia patients . The bilirubin levels were higher in the 7/7 (TA) genotype in the sickle cell anaemia patients as well as in the sickle beta thalasseamia patients and all the values were statistically significant (p-value <0.05). All the details of the bilirubin levels with the (TA)n genotypes in the sickle homozygous and in the sickle β-thalassaemia patients are given in (Table/Fig 1) and (Table/Fig 2) respectively. The bilirubin levels in the sickle homozygous and in the sickle β-thalassaemia patients with and without the presence of gall stones had a great variability with significant differences (p-value <0.05). Details are given in (Table/Fig 3). A higher frequency of the gall stones was present in male patients than in the female patients, while the patients of the 12-17 years age group presented a higher frequency of gall stone formation. Details of the age and sex wise presentation of the gall stones in the sickle homozygous and the sickle β-thalassaemia patients are given in (Table/Fig 4).
The UGT1A1 promoter polymorphism exerts a powerful influence on the bilirubin levels and the development of gallbladder disease in sickle cell anaemia (15),(16),(17),(18),(19). Few studies have stated that the UGT1A1 gene promoter polymorphism and the age-at-onset of cholelithiasis were strongly correlated (17),(20). A study also proved that the (TA)7/(TA)(7) genotype may be a risk factor for the symptomatic gallstones in older people with sickle cell disease (14). A study with hydroxyurea in relation to the UGT1A1 gene promoter polymorphism in Indian patients with different haemoglobinopathies concluded that higher bilirubin levels were associated with the (TA)(7)/(TA)(7) (21). The serum bilirubin levels are elevated in individuals who have a TA repeat polymorphism in the promoter region or a Gly71Arg polymorphism in the first exon of the gene [3,20-24]. Individuals with seven TA (7-TA) repeats in the UGT1A1 promoter have elevated serum bilirubin levels that cause a mild hyperbilirubinaemia (Gilbert’s syndrome), but individuals with the more common six TA (6-TA) repeats do not have this condition (3),(4). In some cases, the (7)-TA polymorphism as well as other mutations have also been associated with severe (Crigler-Najjar type II disease) hyperbilirubinaemia (22),(24),(25),(26). In our cases, the (TA)7 alleles were more frequent in the sickle homozygous as well as in the sickle β-thalassemia patients. The (TA)7 alleles of the UGT1A1 genotype were significantly associated with hyperbilirubinaemia in both the groups of patients (p-value <0.05). Gall stones were more frequent with the 7/7 alleles with hyperbilirubinaemia in the sickle cell anaemia and the sickle β-thalassaemia patients. Over the past several years, two new UGT1A1 TA repeat promoter polymorphisms,5-TA and 8-TA, have been identified primarily in individuals of African descent. A recent experimental work demonstrated that the four different promoters, (5-TA, 6-TA, 7-TA, 8-TA) had a transient transcriptional activity that was inversely related to the number of the TA repeats. In contrast, the concentrations of unconjugated serum bilirubin which were found in the circulation have been found to be increase directly with the number of the TA repeat elements (27),(31). Hence, the UGT1A1 repeat polymorphisms were predictive of the serum bilirubin concentration and subsequently, the UGT1A1 genotypes could be indicative of the susceptibility to or of the protection against the oxidative damage which was mediated through the modulation of the bilirubin levels. Gallstone formation was thought to develop from the increased bilirubin monoglucuronide in comparison to the usually more predominant diglucuronide form (9). The primary bilirubin catabolizing hepatic enzyme, uridine diphosphate (UDP) glucuronosyltransferase 1A1 (UGT1A1) mediates the conjugation of bilirubin into a water-soluble form that is excreted in bile (32). A simple dinucleotide repeat polymorphism, (TA)5-8, in the TATA box of the UGT1A1 gene is associated with a reduced expression of the hepatic enzyme and this results in the chronic unconjugated hyperbilirubinaemia that occurs in Gilbert’s syndrome (3),(4),(22),(33),(34). The coinheritance of the Gilbert’s syndrome with disorders that increase the turnover of the red blood cells or their precursors, has been reported to elevate the bilirubin levels in β-thalassaemia (35),(36). The G6PD deficiency and the hydroxyurea therapy response in sickle cell (SS) disease (37),(38),(39),(40),(41). The variant (TA)7 UGT1A1 allele was reported to influence the serum bilirubin levels in patients with chronic haemolytic anaemia, such as a β-thalassaemia trait or the G6PD deficiency and it was found to be associated with gallstone formation in hereditary spherocytosis or homozygous β-thalassaemia (6),(8), (42). Among our cases, adolescents and male patients were found to be more susceptible to gall stone formation. (TA)6 was less frequent while (TA)7 more frequent in the sickle homozygous as well as in the sickle β-thalassaemia patients. Total bilirubin and unconjugated bilirubin with the frequency of the gall stone were significantly higher in patients with the (TA)7/(TA)7 genotypes than in those with other genotypes. These observations of our study concluded that the 7/7 TA alleles of the UGT1A1 genotype promoter polymorphism influenced the bilirubin production and the development of gallbladder stones in Indian sickle cell patients. This study provided us the clinical phenotype and the genotype information and it helped us in producing good preliminary results to explore the clinical trends and the genetic associations of the UGT1A1 polymorphism in sickle cell patients. Further studies with a large sample size are required to elucidate the role of the UGT1A1 polymorphism in gallstone formation and in the symptom manifestations in sickle cell patients.
Financial Support
This study supported by ICMR & Hematology Department AIIMS, New Delhi India.
Acknowledgements
Sincere thanks to technical staff of department of hematology AIIMS, for expert assistance.
Date of Submission: Nov 03, 2011
Date of Peer Review: Jan 07, 2012
Date of Acceptance: Apr 25, 2012
Date of Publishing: Jun 22, 2012
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