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Biomedical subjects

A Narayan

Publications and source records attributed to A Narayan.

15 recordsLinked to original sources
PubMed2000

Hypersensitivity to radiation-induced non-apoptotic and apoptotic death in cell lines from patients with the ICF chromosome instability syndrome.

Immunodeficiency, centromeric region instability, and facial anomalies (ICF), a rare recessive chromosome instability syndrome, involves the loss of DNA methyltransferase 3B activity and the consequent hypomethylation of a small portion of the genome. We demonstrate for the first time that ICF cells are strongly hypersensitive to a genotoxic agent, namely, ionizing radiation. However, unlike cell lines from patients with ataxia telangiectasia or Nijmegen breakage syndrome, chromosome instability syndromes also associated with unusual sensitivity to ionizing radiation, ICF cells did not show any deficiencies in their cell cycle checkpoints. ICF lymphoblastoid cell lines demonstrated increased apoptosis, long-term cell cycle arrest, and loss of viability in clonogenicity assays after irradiation compared to analogous normal cell lines. Also, the ICF cell lines were subject to high frequencies of rapid non-apoptotic cell death upon irradiation but not to abnormally high levels of radiation-induced, cytogenetically detectable chromosome abnormalities. ICF-associated undermethylation of some regulatory gene(s) might lead to an exaggerated response to radiation-induced breaks in DNA yielding increased rates of cell death and irreversible cell cycle arrest. As a defense against their frequent spontaneous breaks in chromosomes 1 and 16, ICF patients may be abnormally prone to chromosome break-induced apoptosis, non-apoptotic cell death, and permanent cell cycle arrest so as to minimize the number of cycling cells with spontaneous rearrangements. A similarly increased cell death and cycle-arrest response to chromosome breaks due to cancer-linked DNA hypomethylation might occur during carcinogenesis.

Apoptosis↗
PubMed2000

Whole-genome methylation scan in ICF syndrome: hypomethylation of non-satellite DNA repeats D4Z4 and NBL2.

The ICF (immunodeficiency, centromeric instability and facial abnormalities) syndrome is a rare recessive disease characterized by immunodeficiency, extraordinary instability of certain heterochromatin regions and mutations in the gene encoding DNA methyltransferase 3B. In this syndrome, chromosomes 1 and 16 are demethylated in their centromere-adjacent (juxtacentromeric) heterochromatin, the same regions that are highly unstable in mitogen-treated ICF lymphocytes and B cell lines. We investigated the methylation abnormalities in CpG islands of B cell lines from four ICF patients and their unaffected parents. Genomic DNA digested with a CpG methylation-sensitive restriction enzyme was subjected to two-dimensional gel electrophoresis. Most of the restriction fragments were identical in the digests from the patients and controls, indicating that the methylation abnormality in ICF is restricted to a small portion of the genome. However, ICF DNA digests prominently displayed multicopy fragments absent in controls. We cloned and sequenced several of the affected DNA fragments and found that the non-satellite repeats D4Z4 and NBL2 were strongly hypomethylated in all four patients, as compared with their unaffected parents. The high degree of methylation of D4Z4 that we observed in normal cells may be related to the postulated role of this DNA repeat in position effect variegation in facio- scapulohumeral muscular dystrophy and might also pertain to abnormal gene expression in ICF. In addition, our finding of consistent hypomethylation and overexpression of NBL2 repeats in ICF samples suggests derangement of methylation-regulated expression of this sequence in the ICF syndrome.

B-Lymphocytes↗
PubMed2000

DNA hypomethylation and unusual chromosome instability in cell lines from ICF syndrome patients.

The ICF syndrome (immunodeficiency, centromeric region instability, facial anomalies) is a unique DNA methylation deficiency disease diagnosed by an extraordinary collection of chromosomal anomalies specifically in the vicinity of the centromeres of chromosomes 1 and 16 (Chr1 and Chr16) in mitogen-stimulated lymphocytes. These aberrations include decondensation of centromere-adjacent (qh) heterochromatin, multiradial chromosomes with up to 12 arms, and whole-arm deletions. We demonstrate that lymphoblastoid cell lines from two ICF patients exhibit these Chr1 and Chr16 anomalies in 61% of the cells and continuously generate 1qh or 16qh breaks. No other consistent chromosomal abnormality was seen except for various telomeric associations, which had not been previously noted in ICF cells. Surprisingly, multiradials composed of arms of both Chr1 and Chr16 were favored over homologous associations and cells containing multiradials with 3 or >4 arms almost always displayed losses or gains of Chr1 or Chr16 arms from the metaphase. Our results suggest that decondensation of 1qh and 16qh often leads to unresolved Holliday junctions, chromosome breakage, arm missegregation, and the formation of multiradials that may yield more stable chromosomal abnormalities, such as translocations. These cell lines maintained the abnormal hypomethylation in 1qh and 16qh seen in ICF tissues. The ICF-specific hypomethylation occurs in only a small percentage of the genome, e.g., ICF brain DNA had 7% less 5-methylcytosine than normal brain DNA. The ICF lymphoblastoid cell lines, therefore, retain not only the ICF-specific pattern of chromosome rearrangements, but also of targeted DNA hypomethylation. This hypomethylation of heterochromatic DNA sequences is seen in many cancers and may predispose to chromosome rearrangements in cancer as well as in ICF.

5-Methylcytosine↗
PubMed1999

Satellite DNA hypomethylation vs. overall genomic hypomethylation in ovarian epithelial tumors of different malignant potential.

Rearrangements in heterochromatin in the vicinity of the centromeres of chromosomes 1 and 16 are frequent in many types of cancer, including ovarian epithelial carcinomas. Satellite 2 DNA is the main sequence in the unusually long heterochromatin region adjacent to the centromere of each of these chromosomes. Rearrangements in these regions and hypomethylation of satellite 2 DNA are a characteristic feature of patients with a rare recessive genetic disease, ICF (immunodeficiency, centromeric region instability, and facial anomalies). In all normal tissues of postnatal somatic origin, satellite 2 DNA is highly methylated. We examined satellite 2 DNA methylation in ovarian tumors of different malignant potential, namely, ovarian cystadenomas, low malignant potential (LMP) tumors, and epithelial carcinomas. Most of the carcinomas and LMP tumors exhibited hypomethylation in satellite 2 DNA of both chromosomes 1 and 16. A comparison of methylation of these sequences in the three types of ovarian neoplasms demonstrated that there was a statistically significant correlation between the extent of this satellite DNA hypomethylation and the degree of malignancy (P<0.01). Also, there was a statistically significant association (P<0.005) between genome-wide hypomethylation and undermethylation of satellite 2 DNA among these 17 tumors. In addition, we found abnormal hypomethylation of satellite alpha DNA in the centromere of chromosome 1 in many of these tumors. Our findings are consistent with the hypothesis that one of the ways that genome-wide hypomethylation facilitates tumor development is that it often includes satellite hypomethylation which might predispose cells to structural and numerical chromosomal aberrations. Several of the proteins that bind to pericentromeric heterochromatin are known to be sensitive to the methylation status of their target sequences and so could be among the sensors for detecting abnormal demethylation and mediating effects on chromosome structure and stability.

5-Methylcytosine↗
PubMed1999

Frequent hypomethylation in Wilms tumors of pericentromeric DNA in chromosomes 1 and 16.

Rearrangements in the pericentromeric heterochromatin of chromosome 1 or 16 are often found in many types of cancers, including Wilms tumors, and have been suggested to contribute to oncogenesis or tumor progression. The oncogenic potential of these rearrangements has been ascribed to the resulting chromosome arm imbalances affecting the dosage of tumor suppressor genes or protooncogenes. Because DNA hypomethylation has been linked to rearrangements in the pericentromeric regions of chromosome 1 and 16 in two types of non-cancer cell populations, we examined methylation of normally highly methylated satellite DNA sequences in these regions in Wilms tumors. Hypomethylation was found to be frequent in juxtacentromeric (satellite 2) sequences and, especially, in centromeric (satellite alpha) sequences of chromosome 1. Hypomethylation of satellite 2 DNA of chromosome 16 showed a high degree of concordance with that of satellite 2 DNA of chromosome 1. We discuss the relationship of this satellite DNA hypomethylation in Wilms tumors to chromosome aberrations, as determined by assays for loss of heterozygosity.

Centromere↗
PubMed1998

Hypomethylation of pericentromeric DNA in breast adenocarcinomas.

Drug-induced DNA demethylation in normal human cells and inherited localized hypomethylation in mitogen-stimulated lymphocytes from patients with a rare recessive disease (ICF: immunodeficiency, centromeric region instability, facial anomalies) are associated with karyotypic instability. This chromosomal recombination is targeted to heterochromatin in the vicinity of the centromere (pericentromeric region) of human chromosome 1. Pericentromeric rearrangements in this chromosome as well as overall genomic hypomethylation are frequently observed in many kinds of cancer, including breast adenocarcinoma. We found that almost half of 25 examined breast adenocarcinomas exhibited hypomethylation in satellite 2 DNA, which is located in the long region of heterochromatin adjacent to the centromere of chromosome 1 and is normally highly methylated. One of the 19 examined non-malignant breast tissues displaying fibrocystic changes was similarly hypomethylated in this satellite DNA. We also looked at an opposing type of methylation alteration in these cancers, namely, hypermethylation in a tumor-suppressor gene region that is frequently hypermethylated in breast cancers. We found that increased methylation in the E-cadherin promoter region and decreased methylation in satellite 2 DNA were often present in the same breast cancers. While hypermethylation in certain tumor-suppressor gene regions may favor tumorigenesis by repressing transcription, demethylation of other DNA sequences may predispose to cancer-promoting chromosomal re-arrangements.

Adenocarcinoma↗
PubMed1993

Early discharge after operation.

To assess the feasibility and advantages of short-stay surgery in India, a policy of early discharge was adopted for 386 patients undergoing various major and minor operations. The mean postoperative and total hospital stays of patients admitted for minor surgery were 1.9 and 3.7 days respectively; the corresponding figures for age- and sex-matched historical controls were 7.4 and 11.3 days. The mean postoperative and total stays of patients who had undergone major surgery were 4.1 and 8.0 days respectively; the corresponding control values were 8.9 and 12.5 days. The use of absorbable subcuticular skin sutures helped to shorten postoperative hospital stay and avoided an extra follow-up visit. The overall complication rate in the study group was 9.6 per cent and in historical controls 13.4 per cent (P > 0.05). A total of 2357 hospital bed-days were saved during the study and 95.6 per cent of patients approved of short-stay surgery.

Adolescent↗
PubMed1987

Soluble antigen fluorescent antibody (SAFA) test is not useful in childhood tuberculosis.

The diagnostic value of the soluble antigen fluorescent antibody (SAFA) test in childhood tuberculosis was studied in 117 children in the age group 0-12 years; 79 cases belonged to the study group, 23 children were non-tuberculous controls and 15 were tuberculin-negative healthy controls. The SAFA test was positive in 35 of 44 children with only pulmonary tuberculous lesions (80%) and in 21 of 35 children with other types of tuberculosis (60%). In the 23 non-tuberculous and 15 healthy controls it was positive in 11 cases (48%) and 7 cases (47%), respectively. The sensitivity, specificity and predictivity of the test were found to be 71%, 53% and 72%, respectively. The diagnostic value of the SAFA test was thus found to be low in childhood tuberculosis, especially in disseminated disease and tuberculous meningitis.

Child↗
PubMed1985

Prediction of digoxin treatment failure in infants with supraventricular tachycardia: role of transesophageal pacing.

Transesophageal atrial pacing was used to initiate and terminate tachycardia in 24 infants (seven female and 17 male, aged 1 to 34 days) with ECG documentation of supraventricular tachycardia. Six infants received no chronic treatment, and chronic oral digoxin prophylaxis was administered to 18 infants in an effort to prevent recurrences of tachycardia. In these 18 infants, the effectiveness of digoxin therapy in preventing the initiation of tachycardia by transesophageal pacing was compared with its ability to prevent spontaneous recurrences of supraventricular tachycardia. While receiving chronic oral digoxin therapy, tachycardia could be reinitiated in 15/18 (83%) infants. In these infants, the cycle length of tachycardia and the atrioventricular interval were the same before and during chronic digoxin treatment. Three infants in whom tachycardia could not be initiated during chronic digoxin therapy had no spontaneous recurrences during 6 months of follow-up, whereas 10/15 (67%) infants in whom tachycardia could be reinitiated had clinically significant recurrences in spite of chronic digoxin therapy. Six infants who received no chronic drug treatment had no documented recurrences during 6 months of follow-up. This study demonstrates that digoxin was effective in preventing significant spontaneous recurrences of supraventricular tachycardia in only 8/18 (44%) infants treated with digoxin. The ability to initiate supraventricular tachycardia with transesophageal pacing may be useful in determining which digoxin-treated infants are at risk for recurrence. Finally, not all infants with supraventricular tachycardia require chronic prophylaxis; six of the untreated infants had no documented recurrences.

Atrioventricular Node↗