Prevalence of methicillin-resistant Staphylococcus aureus colonization among healthcare workers and healthy community residents.
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Humans↗
Biomedical subjects
M Mathur
Publications and source records attributed to M Mathur.
Colonisation of methicillin resistant Staphylococcus aureus among health care workers in a tertiary care hospital of Delhi.
Methicillin resistant strains of Staphylococcus aureus have been responsible for many nosocominl epidemics. Colonised employees of hospital such as asymptomatic nasal and hand carriers act as reservoirs for the spread of this organism within hospital. During a period of three months 150 HCW were screened for nasal and hand colonisation by MRSA. 6.6% (10) HCW were colonised by MRSA and 50% of these were carrying MRSA on both hands and anterior nares. 30% (3) of MRSA strains were multidrug resistant and 60% (6) were resistant to ciproflox. Whether the eradication of MRSA carrier state will lead to decreased rate of MRSA infection is yet to be documented.
Disease Reservoirs↗
Expression of RARalpha and RARbeta in human oral potentially malignant and neoplastic lesions.
Retinoids reverse potentially malignant lesions and inhibit the development of second primary cancers in patients with head-and-neck cancer. Many of the effects of retinoids result from modulation of gene expression by 2 distinct classes of nuclear receptor, RARs and RXRs; alterations in their expression can lead to tumorigenesis. To determine whether aberrations in expression of the receptors are related to the development of betel- and tobacco-related oral cancer, we used specific monoclonal antibodies against RARalpha and RARbeta to detect expression of these proteins in 30 histopathologically normal tissues, 45 potentially malignant lesions (leukoplakia) with histological evidence of either hyperplasia (31 cases) or dysplasia (14 cases) and 64 oral squamous-cell carcinomas (SCCs) by immunohistochemistry. Of the 30 normal oral tissues analysed, 8 cases showed detectable levels of RARalpha protein, while 10 cases did not show detectable RARbeta immunoreactivity. Immunostaining for RARalpha protein was observed in 12/31 (39%) hyperplastic lesions, 6/14 (43%) dysplastic lesions and 43/64 (67%) oral SCCs. Expression of RARalpha in oral SCC was significantly associated with the histological differentiation status of tumours (p = 0.016). In contrast, lack of detectable immunoreactivity was observed in 19/31 (61%) hyperplastic lesions, 8/14 (57%) dysplastic lesions and 21/64 (33%) oral SCCs. The hallmark of the study was the significant increase in RARalpha immunopositivity in oral SCCs compared to normal tissue (p = 0.0005) and hyperplastic lesions (p = 0.016). One intriguing feature was the significant decrease in RARbeta immunopositivity in hyperplastic lesions compared with normal oral mucosa (p = 0.05) as well as in oral SCCs compared with normal tissues (p = 0.0008).
Adult↗
Alterations in MDM2 expression in esophageal squamous cell carcinoma: relationship with p53 status.
In view of the significance of MDM2 as a regulator as well as critical target of wild type p53, this study was undertaken to determine the alteration in MDM2 expression in esophageal squamons cell carcinoma (ESCC) and its relationship to clinicopathological parameters as well as p53gene and protein status. Immunohistochemical analysis of MDM2 and p53 proteins on paraffin embedded sections from 64 surgically resected ESCCs and matched histologically normal tissues showed overexpression of MDM2 protein in 23/64 (36%) ESCCs, while the histopathologically normal esophageal tissues did not show detectable level of MDM2 immunoreactivity. Interestingly, MDM2 /p53 + phenotype was observed in 37/64 (58%) cases. None of the cases with p53 mis-sense mutations (12/30, 40%) showed detectable level of MDM2 protein. Missense p53 mutations were significantly associated with discordant p53 + /MDM2 immunophenotype (p= 0.004). The most intriguing feature of the study was accumulation of MDM2 in the absence of detectable p53 in 11% of and overexpression of MDM2 and p53 in 25% of ESCCs, suggesting a p53-independent role for MDM2 in a subset of tumors. These results underscore the involvement of MDM2 in p53-dependent and -independent pathways in the pathogenesis of esophageal cancer in the Indian population.
Adult↗
Alterations in cyclin D1 expression in esophageal squamous cell carcinoma in the Indian population.
PURPOSE: The p16/cyclin D1/pRb pathway plays a critical role in tumourigenesis. We recently reported alterations in expression of tumour suppressor gene products, p16 and pRb in esophageal cancer. Knowledge of alterations in cyclin D1, a vital component of this pathway in esophageal carcinomas from the Indian subcontinent, where the etiology and pathogenesis may be confounded by various unique dietary and environmental factors, is presently scanty. In order to bridge the gap between the accentuating incidence of esophageal cancer and aberrations in the components of this vital pathway, we analysed cyclin D1 expression in esophageal squamous cell carcinoma in the Indian population. METHOD: Immunohistochemical analysis of cyclin D1 expression was carried out in paraffin-embedded sections of surgically resected esophageal squamous cell carcinomas (ESCC) (70 patients) and matched with histopathologically normal esophageal tissues from a distant site. The findings were correlated with clinicopathological parameters. RESULTS: Overexpression of cyclin D1 was observed in the tumour nuclei in 41 out of 70 (59%) patients. We found concomitant alterations in 16 and cyclin D1 (p16-/CycD1+ phenotype) in 16 of the 70 patients (23%), while alterations of pRb and cyclin D1 (pRb-/CycD1+) were observed in 36 of the 70 (51%) patients of ESCCs. Cyclin D1 overexpression was significantly associated with the loss of p16 immunoreactivity (P = 0.005). The pRb- and p16-/pRb-/Cyc D+ phenotypes showed significant association with differentiation of the tumour (P = 0.005, 0.05, respectively). Kaplan-Meier analysis for disease recurrence showed increased disease recurrence in cyclin D1 overexpressed patients. Median time to disease recurrence in the cyclin D1+ group was 15 months as against 18 months observed in the cyclin D1- patients (P = 0.067; log-rank test). CONCLUSION: Alterations in at least one of the components of the p16/cyclin D1/pRb pathway in majority of the 70 patients analysed herein, and concomitant alterations in all the three proteins in 19 patients (35%) underscore the critical role of this pathway in esophageal tumourigenesis. The results of the present study taken together with our previous findings on p16 and pRb alterations in ESCCs suggest that these alterations are not mutually exclusive and may cooperatively provide greater tumour growth advantage. The prognostic significance of alterations in the expression of these components cyclin D1, p16, and pRb remains to be established in a larger cohort.
Adult↗
Esophageal squamous cell carcinomas with DNA replication errors (RER+) are associated with p16/pRb loss and wild-type p53.
PURPOSE: Microsatellite instability (MSI) as a determinant of propensity to esophageal squamous cell carcinoma (ESCC) at seven microsatellite markers at 2p (2p15-16), 3p (3p13, 3p14.1-3, 3p25, and 3p26) and 16q (16q12.1-3) was investigated to analyze their putative role as indicators of predisposition to esophageal malignancies. METHODS: Seven microsatellite loci were amplified by polymerase chain reaction, from surgically resected tumor tissues from 30 ESCC patients from Indian population, to assess the loss of heterozygosity (LOH) and replication error repeats (RER) and to correlate these alterations with aberrations in major cell cycle regulatory proteins and histopathological parameters. RESULTS: LOH and RER analyses at these loci demonstrated moderate microsatellite alterations, suggesting the involvement of MSI in esophageal tumorigenesis in a subset of the Indian population. MSI, defined as RER in at least two or more of the loci studied, was observed in ten of 30 (33%) patients. Twenty-two of 30 patients (73%) showed LOH at one or more loci, while 17 of the 30 patients (60%) showed RER in at least one of the loci studied. RER-positive patients showed a trend towards better prognosis when compared to RER-negative patients. MSI demonstrated a significant association with concomitant loss of p16 and pRb (p16-/pRb- phenotype) (P=0.046). Interestingly, we observed an inverse correlation between MSI and p53 mutations (P=0.03) suggesting that MSI may provide a p53-independent pathway for esophageal tumorigenesis in RER+ patients. MSI showed a trend towards longer survival and absence of distant organ metastasis (P=0.06). CONCLUSIONS: The present study demonstrates the probable role of MSI in esophageal squamous cell carcinoma in the Indian population. Instability associated with the repetitive sequences--the revealing marks of loss of DNA replication fidelity may serve as an indicator of predisposition to esophageal cancer.
Carcinoma, Squamous Cell↗
Anti-tumor promoting activity of Asteracantha longifolia against experimental hepatocarcinogenesis in rats.
Vegetables, natural products of plant origin and numerous non-nutritive dietary constituents have been shown to play a salutary role in cancer chemoprevention. The present study aims to evaluate the chemopreventive efficacy of the methanol fraction of Asteracantha longifolia seed extract against development of 2-acetylaminofluorene (2-AAF)-selected gamma-glutamyl transpeptidase (gamma-GT)-positive foci following diethylnitrosamine (DEN) initiation. Treatment of rats with doses 200 and 400 mg/kg body weight of methanol extract of A. longifolia seeds on alternate days, subsequent to carcinogen treatment, for 6 weeks significantly reduced the incidence and size distribution of gamma-GT-positive foci and tumor formation. Administration of A. longifolia seeds significantly (P<0.001) ameliorated the activities of antioxidant enzymes, glutathione peroxidase (GPx) and catalase (CAT), in a dose-dependent manner. Prophylactic administration of seed extract simultaneous to 2-AAF in the diet, at same doses, significantly suppressed 2-AAF and partial hepatectomy (PH)-induced ornithine decarboxylase (ODC) activity and [(3)H]thymidine incorporation into hepatic DNA, in a dose-dependent manner. Assimilation of the quantitative foci data together with the findings of the modulation of tumor promoting markers give ample evidence to the anti-tumor promoting potential of A. longifolia seeds against chemically-induced hepatocarcinogenesis in Wistar rats.
2-Acetylaminofluorene↗
Correlation between p53 gene mutations and circulating antibodies in betel- and tobacco-consuming North Indian population.
Alterations in p53 tumour suppressor gene and its expression may be implicated in the pathogenesis of betel- and tobacco-related oral cancer. There is wide regional variation in betel- and tobacco-consuming habits in different parts of the Indian subcontinent. The purpose of this study was to determine the correlations between p53 gene mutations, protein accumulation and serum antibodies in oral precancer and cancer. We analysed 30 potentially malignant oral lesions (leukoplakia) and 30 oral squamous cell carcinomas (SCCs) from northern India because the betel quid-consuming habits are different from those prevalent in other regions of India. p53 mutations were analysed by polymerase chain reaction amplification of genomic DNA and direct sequencing, p53 protein accumulation by immunohistochemical analysis and circulating p53 antibodies by ELISA. p53 gene mutations, analysed within exons 5-9, were observed in five out of 30 (17%) potentially malignant oral lesions and seven out of 30 (23%) oral SCCs. All the mutations were base substitution mutations. Three missense and two nonsense mutations were observed in potentially malignant oral lesions, while six missense and one nonsense mutations were identified in oral SCCs. The probable hot spots for the mutations were identified at codons 126, 136 and 174, which have not been observed thus far. A good correlation was observed between p53 missense mutation, p53 antibodies and p53 protein accumulation in matched potentially malignant and malignant oral lesions. All the potentially malignant and cancerous lesions harbouring missense mutations showed accumulation of p53 protein and the majority of these patients showed circulating p53 antibodies suggesting that serological detection of p53 antibodies may serve as a surrogate marker for p53 alterations in oral lesions.
Adolescent↗
Co-expression of colligin and collagen in oral submucous fibrosis: plausible role in pathogenesis.
The high incidence of oral submucous fibrosis (OSF), a potentially malignant condition of the oral cavity, in the Indian subcontinent is causally associated with commonly prevailing habit of chewing areca nut and tobacco. Knowledge of molecular alterations in OSF is meagre. OSF is characterised by progressive accumulation of collagen fibres in lamina propria and oral submucosa. Colligin/HSP47 is a 47KDa stress protein which acts as a chaperone for collagen. We hypothesized that since colligin plays a vital role in folding and assembling collagen it may be involved in the pathogenesis of OSF. The present study was undertaken in tobacco and areca nut chewing Indian OSF patients to investigate the correlation, if any, between the expression of colligin and collagen type I proteins in OSF lesions. Immunohistochemical analysis showed overexpression of colligin and collagen type I proteins in 16/23 (70%) and 15/23 (65%) of OSF cases, respectively. The hallmark of the study was the significant association between the increased expression of type I collagen and its chaperone, colligin, in OSF lesions (P=0.0494). The data suggest that the increased levels of colligin in OSF may contribute to the deposition of collagen and consequent increased fibrosis in the oral submucosa in OSF lesions.
Adolescent↗
PSF is a novel corepressor that mediates its effect through Sin3A and the DNA binding domain of nuclear hormone receptors.
Members of the type II nuclear hormone receptor subfamily (e.g., thyroid hormone receptors [TRs], retinoic acid receptors, retinoid X receptors [RXRs], vitamin D receptor, and the peroxisome proliferator-activated receptors) bind to their response sequences with or without ligand. In the absence of ligand, these DNA-bound receptors mediate different degrees of repression or silencing of gene expression which is thought to result from the association of their ligand binding domains (LBDs) with corepressors. Two related corepressors, N-CoR and SMRT, interact to various degrees with the LBDs of these type II receptors in the absence of their cognate ligands. N-CoR and SMRT have been proposed to act by recruiting class I histone deacetylases (HDAC I) through an association with Sin3, although they have also been shown to recruit class II HDACs through a Sin3-independent mechanism. In this study, we used a biochemical approach to identify novel nuclear factors that interact with unliganded full-length TR and RXR. We found that the DNA binding domains (DBDs) of TR and RXR associate with two proteins which we identified as PSF (polypyrimidine tract-binding protein-associated splicing factor) and NonO/p54(nrb). Our studies indicate that PSF is a novel repressor which interacts with Sin3A and mediates silencing through the recruitment of HDACs to the receptor DBD. In vivo studies with TR showed that although N-CoR fully dissociates in the presence of ligand, the levels of TR-bound PSF and Sin3A appear to remain unchanged, indicating that Sin3A can be recruited to the receptor independent of N-CoR or SMRT. RXR was not detected to bind N-CoR although it bound PSF and Sin3A as effectively as TR, and this association with RXR did not change with ligand. Our studies point to a novel PSF/Sin3-mediated pathway for nuclear hormone receptors, and possibly other transcription factors, which may fine-tune the transcriptional response as well as play an important role in mediating the repressive effects of those type II receptors which only weakly interact with N-CoR and SMRT.
Animals↗
Lactobacillus casei in the control of acute diarrhea--a pilot study.
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Animals↗
14C urea breath test does not predict density of Helicobacter pylori in duodenal ulcer disease.
BACKGROUND & OBJECTIVES: The density of Helicobacter pylori in the gastric mucosa has prognostic significance, higher densities being associated with greater chances of development of duodenal ulcer and chronic atrophic gastritis as well as poor eradication by drug therapy. The aim of this study was to assess if 14C-urea breath test counts reflect bacterial density. METHODS: Sixty patients with endoscopically proven active duodenal ulcer and H. pylori positivity as determined by rapid urease test and gastric histology were studied. Gastric antral and corpus biopsies were graded for chronic gastritis, activity (presence of polymorphonuclear cells) and bacterial density (at surface and in pits) based on the Sydney system on a scale of four grades ranging from 0 to 3 (absent, mild, moderate and severe). 14C urea breath test was performed in all the patients. RESULTS: Chronic gastritis as well as activity was more prevalent as well as severe in the antrum as compared to the corpus. H. pylori density was also significantly more in the antrum as compared to the corpus both at the surface as well as in the pits. H. pylori density correlated with the grade of chronic gastritis and activity both in the antrum and in the corpus. Urea breath test counts ranged from 331.3 cpm (counts per minute) to 8770.5 cpm and these did not correlate with histological H. pylori density at any of the sites. INTERPRETATION & CONCLUSIONS: 14C urea breath test does not reflect H. pylori density on histology in patients of duodenal ulcer disease.
Adolescent↗
Prognostic impact of Ets-1 overexpression in betel and tobacco related oral cancer.
In oral squamous cell carcinoma (SCC), the presence of lymph node metastasis is one of the most important prognostic factors, correlating locoregional spread, recurrence, distant metastasis and survival. However, the biological factors implicated and the mechanisms underlying these events are not completely elucidated. We reported Ets-1 expression in oral SCC and proposed that it may serve as a plausible marker of invasive potential and lymph node metastasis. Herein, we investigate the prognostic significance of Ets-1 expression in oral cancer. One hundred oral SCCs assessed for Ets-1 expression showed significant association with tumor stage (P = .027), lymph node involvement (P < 10(-6)) and distant organ metastasis (P = .007). The transcription factor Ets-1 regulates the expression of several genes involved in extracellular matrix remodeling that may account for its association with lymph node and distant organ metastasis. Kaplan-Meier survival analysis entailed significant association of Ets-1 expression in oral SCCs with reduced disease free survival (P = .0041), suggesting its utility as a prognosticator for oral cancer. In conclusion, these findings underscore the role of Ets-1 in oral tumor invasion and metastasis and may thus account for its association with diminished disease free survival.
Areca↗
Detection of tubercle bacilli in sputum: application of sodium hypochlorite concentration method.
Tuberculosis has emerged as the leading cause of death due to single infectious agent. Sputum microscopy forms mainstay of diagnosis as it is most reliable, specific and objective method available especially in developing countries. However, this method is hampered by lack of sensitivity. Liquefaction and concentration of sputum before Ziehl Neelsen staining improves yield and also makes examination of smears rapid and convenient. A total of 304 sputum samples were studied by direct staining and after sodium hypochlorite treatment and centrifugation. Direct smears stained with Auramine-Phenol were also examined. Use of sodium hypochlorite method increased the number of positive samples from 52 to 96. No false positives were detected by either method. The method is simple as the only extra reagent required is sodium hypochlorite that is easily available. Additional advantage is that sodium hypochlorite, being a potent disinfectant, reduces the risk of laboratory acquired infections.
Humans↗
Circulating p53 antibodies, p53 gene mutational profile and product accumulation in esophageal squamous-cell carcinoma in India.
Esophageal cancer (EC) in the Indian population presents in advanced stages with poor prognosis and warrants the identification of a non-invasive marker for early detection and better prognostic assessment. We have previously reported high prevalence of p53 protein accumulation in esophageal squamous-cell carcinomas (ESCCs). The present study was designed to determine (i) if esophageal cancer patients elicit a humoral immune response to intra-tumoral p53 protein accumulation and (ii) their relationship with p53 gene mutations. The goal was to compare the cellular events, p53 protein accumulation and gene mutations with the presence of serum anti-p53 antibodies (p53-Abs) and to assess the utility of serological p53-Ab analysis as a surrogate marker for p53 alterations in esophageal cancer. A high prevalence of circulating p53-Abs was observed in 36 of 60 (60%) ESCC patients. In a subset of 44 ESCCs, exons 5-9 of the p53 gene were examined for mutations by PCR and direct sequencing of PCR products. Mutational data have been correlated with p53-Abs and p53 protein accumulation in ESCCs. Circulating p53-Abs in ESCC patients were significantly associated with intra-tumoral p53 protein accumulation (p=0.0005). A strong correlation observed between humoral immune response against p53 protein, missense gene mutations and protein accumulation warrants the application of serological p53-Abs as a non-invasive surrogate marker in screening high-risk populations for early detection of malignancy.
Adult↗
Novel polymorphism in p21(waf1/cip1) cyclin dependent kinase inhibitor gene: association with human esophageal cancer.
p21(waf1/cip1), an important regulator of the cell cycle, binds to PCNA and acts as a mediator of the growth suppressing and apoptosis promoting functions of p53. We report a hitherto unobserved polymorphism in the carboxy terminal domain (codon 149) of p21(waf1/cip1) gene, the domain encoding the PCNA binding motif. The codon 149 polymorphism (GAT-->GGT) was observed in 42 of 50 (84%) esophageal squamous cell carcinomas (ESCCs) and eight of 50 (16%) normal individuals. The resultant amino acid substitution from aspartate to glycine may have vital implication in PCNA mediated cell cycle regulation by p21(waf1/cip1). The second polymorphism at codon 31, involving a C-->A transversion at nucleotide 168 (AGC-->AGA) changing the amino acid from serine to arginine, was observed in 2/50 (4%) ESCCs at a relatively lower frequency in the Indian population than that reported in the West. No significant association was observed between p21(wap1/cip1) polymorphism at codon 149 and p21(wap1/cip1) protein expression in ESCC in this cohort of patients. Interestingly, the frequency of p21(wap1/cip1) variants (codon 149) in ESCCs (18 of 19 cases) with wild-type p53 was significantly higher than in tumors with p53 mutations, suggesting that this polymorphism affects the p53 pathway and may play an important role in esophageal tumorigenesis. Analysis of p21(waf1/cip1) expression in relation to p53 gene and protein status revealed its induction by p53-dependent as well as independent pathways in esophageal tumorigenesis.
Carcinoma, Squamous Cell↗
Frequent alterations in the expression of tumor suppressor genes p16INK4A and pRb in esophageal squamous cell carcinoma in the Indian population.
PURPOSE: Alterations in the cell cycle regulatory p16INK4a/Cyclin D1/pRb pathway play a pivotal role in tumorigenesis. Knowledge of alterations in the tumor suppressor protein pRb and its negative regulator, p16CDKN2/MTS1/INK4a in esophageal squamous cell carcinoma (ESCC) from the Indian subcontinent is meager. To gain insight into the mechanisms underlying tumorigenesis and to search for diagnostic molecular markers for ESCC, we analyzed the expression of p16INK4a and pRb in ESCCs in the Indian population. METHODS: Immunohistochemical analysis of pRb and p16INK4a proteins was carried out in paraffin-embedded sections from 61 surgically resected ESCCs and matched normal tissues, and the results correlated with clinicopathological parameters using chi square and Fisher's exact tests. Dual immunohistochemical analysis has been carried out to demonstrate the concomitant loss of expression of p16INK4a and pRb. RESULTS: Fifty-nine of 61 (97%) cases showed aberration(s) in either or both of these proteins confirming their critical role in esophageal tumorigenesis. Loss of pRb was observed in 51 of the 61 (84%) and loss of p16INK4a was observed in 35 of 61 (57%) cases. Loss of pRb showed significant association with dedifferentiation of the tumor (P = 0.004). p16-/pRb-, and p16+/pRb- phenotypes were significantly associated with nodal metastasis (P = 0.017 and 0.027, respectively), while p16-/pRb+ phenotype was associated with dedifferentiation of the tumor (P = 0.012). CONCLUSION: pRb/p16INK4a pathway plays a critical role in esophageal tumorigenesis in the Indian population. The dual hits (concomitant loss) of pRb and p16INK4a expression suggest that these two components are not mutually exclusive, and can both be altered in a significant proportion of primary ESCCs serving as putative diagnostic markers for esophageal cancer. However, the impact of dual hit on tumor behavior and disease prognosis remains to be determined.
Adult↗
A histopathological study of esophageal atresia and tracheoesophageal fistula.
BACKGROUND/PURPOSE: Histopathologic examination of the esophagus has not been reported often in esophageal atresia (EA) and tracheoesophageal fistula (TEF). Abnormal esophageal motility has been reported after successful repair of EA and TEF, although the exact etiology of this motility disorder remains unclear. Histological evaluation of the fistulous portion of the esophagus has been performed to document any abnormality that may be responsible for the abnormal motility. METHODS: Histopathological study of fistulous segment of esophageal atresia and distal TEF was conducted on 65 patients, which included autopsy material from 3 patients in whom the entire esophagus was examined by serial section. Special stains were administered to each specimen to look for tracheobronchial remnants and the arrangement of muscle fibers. Clinical evaluation was performed in 27 patients who were available for review 6 months to 9 years after successful surgical treatment. These patients were categorized into 3 groups according to their clinical status. RESULTS: These findings showed that the majority of these patients have tracheobronchial remnants in the esophagus in the form of abnormal mucous glands and ducts, abnormal mucin secretion, presence of cartilage, and a disorganized muscle coat. CONCLUSIONS: The presence of abnormal mucous glands and abnormal mucin secretion has not been highlighted before. Although tracheobronchial remnants and a disorganized muscle coat are common findings in the fistulous portion of the esophagus, these may not reflect the structure of the remaining esophagus.
Biopsy↗