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Biomedical subjects

K Visvanathan

Publications and source records attributed to K Visvanathan.

At least 19 recordsLinked to original sources
PubMed2006

Breast cancer risk is not associated with polymorphic forms of xeroderma pigmentosum genes in a cohort of women from Washington County, Maryland.

BACKGROUND: The genes mutated in the cancer-prone syndrome, xeroderma pigmentosum (XP genes), have been well studied both biochemically and mechanistically. These genes are important components of the DNA nucleotide excision repair (NER) pathway, which protects against environmentally-induced cancers. XP genes are also downstream of the hereditary breast cancer syndrome gene, BRCA1, suggesting that XP genes may be important to hereditary forms of breast cancer as well. Although mutated XP genes are rare, polymorphic forms with potential functional deficiencies are common, and could pose a significant cancer risk in the general population. HYPOTHESIS: This study tested the hypothesis that common polymorphic variants of XP genes were associated with the risk of breast cancer among a population of women in Washington County, Maryland. METHODS: Five single nucleotide polymorphisms (SNPs) among four XP genes (XPC, XPD, XPF and XPG) were genotyped from DNA samples collected at baseline, and then analyzed by conditional logistic regression for association with the incidence of breast cancer. 321 cases were individually matched to 321 controls, by age and menopausal status. RESULTS: No significant associations were found between breast cancer risk and any of the XP genotypes. Odds ratios for all genotypes ranged from 0.61 to 1.14, and none were statistically significant. Adjustment and stratification for family history of breast cancer did not alter the findings. CONCLUSION: These results suggest that polymorphisms of XP genes are not likely to be significant risk factors for women within the general population. This study did not address, however, risks for subpopulations of women with high exposures to DNA damaging agents.

Breast Neoplasms↗
PubMed2006

Toll-like receptor expression in chronic hepatitis C: correlation with pro-inflammatory cytokine levels and liver injury.

BACKGROUND/AIMS: Toll-like receptors (TLR's) are critical receptors that promote innate immune responses to pathogen-associated molecular patterns. Activation of TLR's leads to production of pro-inflammatory cytokines such as tumour necrosis factor (TNF)-alpha. This study investigates whether peripheral blood monocyte expression of TLR's is disturbed in patients with chronic hepatitis C and whether levels of expression of these molecules are significantly correlated with hepatitis C virus (HCV) genotype, viral load, hepatic necroinflammatory activity, histological stage and circulating TNF-alpha concentrations. METHODS: In 18 non-cirrhotic patients with biopsy-proven, virologically-confirmed chronic hepatitis C and 32 controls, we measured expression of TLR2 and TLR4 on peripheral blood monocytes. HCV genotype, viral load, serum alanine aminotransferase (ALT) levels, histological stage of disease and circulating TNF-alpha and endotoxin levels were also determined. RESULTS: Peripheral blood monocyte expression of TLR2 and TLR4 were significantly increased in patients with chronic hepatitis C compared to controls, irrespective of HCV genotype or histological stage of disease. Circulating levels of TNF-alpha were also significantly increased in patients with chronic hepatitis C. In both the overall study cohort and patients with chronic hepatitis C, monocyte expression of TLR2, but not of TLR4, correlated significantly with serum TNF-alpha levels. In patients with chronic hepatitis C, monocyte expression of TLR2, but not of TLR4, also correlated significantly with serum ALT levels. Expression of TLR's was not significantly correlated with viral load. CONCLUSIONS: Up-regulation of peripheral blood monocyte expression of TLR2 and TLR4 occurs in patients with chronic hepatitis C. Increased monocyte expression of TLR2, but not of TLR4, correlates significantly with both increased circulating TNF-alpha levels and hepatic necroinflammatory activity in this disorder.

Adolescent↗
PubMed2006

The microbiology and outcome of sepsis in Victoria, Australia.

We analysed data from 33741 patients with ICD-10-AM-defined sepsis from an Australian hospital morbidity dataset to investigate the relationships between specific types of organisms, potential risk factors for infection, organ dysfunction, ICU utilization and hospital mortality. A total of 24% of patients received some of their care in an intensive care unit, and the overall hospital mortality rate was 18%. Gram-positive bacteria were isolated in 27% of cases and Gram-negative bacteria in 20%. Sepsis due to Staphylococcus aureus was associated with vascular and joint devices whereas Pseudomonas aeruginosa and Gram-negative rods were more common with genitourinary devices and lymphoproliferative disease. Sepsis-associated organ dysfunction most commonly involved the respiratory system, followed by the renal and circulatory systems. These patterns may provide useful clues to the pathogenesis and therapy of this often fatal syndrome which is a major ongoing problem for hospitalized patients.

Adolescent↗
PubMed2005

Screening for unilateral intracranial abnormalities using near infrared spectroscopy: a preliminary report.

Near infrared spectroscopy (NIRS) is being increasingly used for medical applications, including neurosurgical care. This preliminary report describes the use of a low cost, indigenous, non-invasive system where NIRS is used to identify superficial unilateral intracranial abnormalities. The optical density (OD) over each hemisphere was initially studied in 50 normal volunteers. The specificity, sensitivity, reliability and reproducibility of the NIRS generated from the developed equipment in detecting OD were thus confirmed. The OD over each hemisphere was then measured in 71 other individuals, immediately after a computed tomography (CT) scan of the brain was performed. Data was statistically analysed to find the average OD difference (compared to the opposite side) of the various intracranial compartments. Differences in OD suggested a unilateral intracranial abnormality. All those in whom OD differences were detected with the NIRS system had unilateral abnormalities on the CT scan. None of the 53 patients who had a normal CT scan had significant differences in OD.

Adolescent↗
PubMed2005

Regulation of Toll-like receptor (TLR)2 and TLR4 on CD14dimCD16+ monocytes in response to sepsis-related antigens.

Rapid overproduction of proinflammatory cytokines are characteristic of sepsis. CD14(dim)CD16(+) monocytes are thought to be major producers of cytokine and have been shown to be elevated in septic patients. Toll-like receptors (TLR) are pattern recognition receptors important in mediating the innate immune response and their activation can lead to production of cytokines. Using whole blood culture and flow cytometry we have investigated TLR2 and TLR4 regulation after stimulation with sepsis-relevant antigens [lipopolysaccharide (LPS), Staphylococcal enterotoxin B (SEB) and peptidoglycan (PGN)]. The percentage of CD14(dim)CD16(+) monocyte population expanded at 20 h post-stimulation, after a rise in tumour necrosis factor (TNF)-alpha and interleukin (IL)-6 at 2 h. A strong positive correlation between the percentage of CD14(dim)CD16(+) monocytes and secreted TNF-alpha was demonstrated (r = 0.72). Furthermore, we were able to induce expansion of the CD14(dim)CD16(+) population to approximately 35% of all monocytes with the addition of recombinant TNF-alpha to the whole blood culture. TLR4 was found to be expressed 2.5 times higher on CD14(dim)CD16(+) compared to CD14(+) CD16(-) monocytes, while TLR2 expression was similar in both subpopulations. The CD14(dim)CD16(+) and CD14(+) CD16(-) monocyte populations were different in their response to various antigens. LPS down-regulated TLR4 by 4.9 times in CD16(+) monocytes compared to only 2.3 times in CD16(-) monocytes at 2 h. LPS was able to up-regulate TLR2 by 6.2 times after 2 h, with no difference between the subpopulations. LPS further up-regulated TLR2 by 18.4 times after 20 h only in the CD14(+) CD16(-) population. PGN and SEB induced no significant changes in TLR2 or TLR4 expression. We hypothesize that following exposure to bacterial antigens, subsequent TNF-alpha drives a differentiation of monocytes into a CD14(dim)CD16(+) subpopulation.

Adult↗
PubMed2004

Differences in ornithine decarboxylase and androgen receptor allele frequencies among ethnic groups.

Recent evidence suggests that the A allele of the ornithine decarboxylase (ODC) gene is a genetic risk factor for prostate cancer. ODC is a target gene of the highly polymorphic androgen receptor (AR) gene, short alleles of which have been associated in some studies with increased prostate cancer risk. We determined ODC allele frequencies and distribution of AR alleles in American Caucasians, African-Americans, Hispanics, Europeans, and Africans. The frequency of the ODC A allele varied from 0.183 (Hispanics, Europeans) to 0.415 (Africans) with American Caucasian and African-Americans having intermediate values. The mean number of CAG repeats in the AR gene varied from 19.8 (African-Americans) to 25.1 (Hispanics). It is possible that ethnic differences in risk alleles for ODC and AR may account for some of the ethnic variation in prostate cancer risk.

Black or African American↗
PubMed2004

Effect of foot sole hardness, thickness and footwear on foot pressure distribution parameters in diabetic neuropathy.

This paper presents details of the study undertaken to find the effects of foot sole hardness, thickness and footwear on walking-foot pressure distribution parameters (power ratio (PR)) in diabetic neuropathy. The foot sole hardness is characterized by Shore level. PR represents the ratio of high-frequency power to the total power in the power spectrum of the walking-foot pressure image distribution obtained from the optical pedobarograph. Spatial frequency distributions in the walking-foot pressure images were analysed to calculate the PR in each of the foot sole areas at different levels of foot sole sensation loss and mechanical and geometrical properties. The results show that the increase in PR in the upper foot sole Shore ranges (30-40) is 1.2-2.5 times the corresponding increase in lower Shore ranges (20-30) for some foot sole areas, implying a higher possibility of development of plantar ulcers when combined with deterioration of foot sole sensation. Plantar ulcers are found in feet with foot sole Shore values of 30, a sensation level of 45 mN and PR of 35; for Shore values of 40, sensation levels of 100 mN, with PR 52; and for Shore values above 40, sensation level > 100 mN with PR 58. Providing microcellular rubber insole footwear based on optimum hardness and thickness was found to be helpful in healing plantar ulcers in three to four weeks. Wearing preventive footwear for six months reduced hardness of the foot sole and PR values to near-normal values.

Adult↗
PubMed2002

Automated fragment analysis method for determining androgen receptor CAG repeat length.

Several studies have associated polymorphisms in the androgen receptor gene with the risk of developing hormone-dependent cancers. A highly polymorphic (CAG)n repeat in exon 1 encodes a polyglutamine tract of varying length. The determination of the number of CAG repeats in the androgen receptor has typically been performed on denaturing polyacrylamide gels with autoradiographic orfluorescent detection of differently sized alleles. Samples run on a capillary electrophoresis-based ABI Prism 310 Genetic Analyzer gave anomalous results when internal standards supplied by the manufacturer were used Here we report a modified procedure for androgen receptor allele size determination that can be used on an automated capillary electrophoresis-based DNA sequencer equipped with the appropriate software. The assay is very precise, comparable to DNA sequencing, and is compatible with the latest generation of automated DNA sequencers.

Electrophoresis, Capillary↗
PubMed2001

Inhibition of bacterial superantigens by peptides and antibodies.

The pyrogenic exotoxins of group A streptococci and staphylococcal enterotoxins are a family of structurally related superantigens with similar biological activity. Two distinct areas have been identified which have a highly conserved amino acid homology in all of the toxin families. A number of peptides were constructed from these regions, some of which were concatenated and polymerized to enhance their immunogenicity in animals. Antibodies prepared against these polymerized peptides were used to serologically identify the majority of the superantigen toxins, block the biological activities of the superantigens, and protect an experimental animal model against shock. In addition certain peptides were able per se to block up to 90% of the proliferative responses induced by the toxins. The peptide also proved protective in a septic shock model in mice. Binding experiments indicate that the peptide binds tightly to the major histocompatibility complex class II molecule, thus preventing binding and hence activation of the superantigen. The selective and rapid binding of the peptide to the major histocompatibility complex class II molecule may lead to a novel therapeutic modality in treatment of superantigen-mediated diseases.

Amino Acid Sequence↗
PubMed2000

What are the microbial components implicated in the pathogenesis of sepsis? Report on a symposium.

Despite considerable efforts in the past quarter century to improve therapy for sepsis, mortality rates remain unacceptably high. Microbe-derived constituents can induce the host to produce many mediators that can contribute to immune dysregulation, tissue damage, and death. Although endotoxin-mediated events are clearly important in gram-negative infections, gram-positive bacteria can also play a dominant role. Understanding the interplay of microbial constituents and host immune or inflammatory responses prompted a meeting at Rockefeller University in May 1998. Participants discussed the relative merits of a "2-hit" hypothesis to explain the course of lethal septic shock and a "multihit" synergistic threshold hypothesis. Recommendations include the following: (1) developing animal models that closely mimic human sepsis; (2) further investigating antibiotic effects on bacteria; (3) assessing the relationships between endotoxin, prokaryotic DNA, and peptidoglycan (i.e., independent, additive, or synergistic) in inducing host responses; and (4) developing new strategies to improve outcomes. Studies are needed to better define which and how different microbial constituents lead to sepsis and to provide critical leads for therapeutic intervention.

Amino Acid Sequence↗
PubMed2000

Immunogenic and Genetic Factors in Rheumatic Fever.

Although rheumatic fever has virtually disappeared in many developed countries, it remains the number one acquired heart disease among children in developing countries. Many hypotheses advanced to explain the pathogenic mechanisms of this disease include the concept of an abnormal humoral and cellular response within the host to streptococcal antigens cross-reacting with mammalian tissues. This report examines the most recent evidence supporting this concept. It emphasizes the importance of the cellular arm of the immune response in cardiac damage, as wall as possible genetic disposition to the disease.

Journal Article↗
PubMed2000

Autoimmune mechanisms in movement disorders.

A number of disorders, including childhood-onset obsessive compulsive disorder (OCD) and Gilles de la Tourette's syndrome (TS), are known to be neurobiological in nature. Both TS and OCD are neuropsychiatric diagnoses that involve congitive and perceptual dysfunction in addition to motor and psychiatric manifestations. The association of the B-cell marker with both Sydenham's chorea and a group of neuropsychiatric disorders, such as OCD, tics, and TS, has been useful as a marker in these diseases. This evidence, coupled with the recent finding of anti-brain antibodies in the sera of these patients, raises a number of interesting questions concerning the pathological mechanisms involved in these diseases. Thus, further molecular characterization of the brain and streptococcal antigens will be crucial to our understanding of the neurophysiological processes involved in these disorders.

Antibodies, Monoclonal↗
PubMed1999

Rheumatic Fever.

There have been numerous reports stating that treatment of acute rheumatic fever with either aspirin or corticosteroids does not alter the long-term outcome of rheumatic heart disease. Yet, it should be emphasized that most of these studies were carried out with the first generic corticosteroids before the advent of the more active and more potent corticosteroid agents. In spite of this caveat, there is no question that all the clinical and laboratory parameters of inflammation (erythrocyte sedimentation rate, C-reactive protein) return to normal much more rapidly with corticosteroids than with aspirin alone. It is therefore our belief that steroids should be used when clinical and laboratory evidence of carditis exists, and aspirin should be reserved for cases of acute rheumatic arthritis with no evidence of carditis. The incidence of long-term valvular disease in active carditis may be decreased with steroid therapy. For example, the number of valve replacements differs markedly in centers that do use steroids and in those that do not. In Capetown, South Africa, where steroids are routinely used for carditis, valve replacement is quite rare. In contrast, in Johannesburg, where steroids are rarely used, the rate of valve replacement is quite high. The racial backgrounds of both groups of patients are similar, thus eliminating the question of racial differences. Concerning secondary prophylaxis, there is also controversy concerning the best second-line therapy. It is now well known that monthly intramuscular injections of benzathine penicillin are really effective for only 20 days. Thus, there is a window in which penicillin coverage is not adequate. To circumvent this problem, some investigators give benzathine penicillin every 3 weeks. These injections are quite painful, however, and it has been our "rule" that compliance with this treatment is inversely proportional to the ratio of the size of the child to the mother. In our own experience over 30 years with the follow-up of more than 300 patients with acute rheumatic fever, careful discussion of the consequences of missing oral doses has been adequate to insure proper compliance. An analysis of our patients on oral penicillin prophylaxis compared with other groups using benzathine penicillin revealed that there was very little difference in recurrence rate.

Journal Article↗
PubMed1999

Structure and function of streptococcal and staphylococcal superantigens in septic shock.

The pyrogenic exotoxins of Group A Streptococci and enterotoxins of Staphylococcus aureus constitute a family of related toxins that acts as "superantigens" because of their ability to stimulate large numbers of T-cell subsets. These toxins have been implicated in gastrointestinal food poisoning, toxic shock syndromes, Gram-positive sepsis, and, possibly, septic shock. There is increasing evidence that Gram-positive infections frequently coexist in septic shock and that bacterial superantigens play a major role.

Gram-Negative Bacterial Infections↗
PubMed1998

A flow cytometric assay for D8/17 B cell marker in patients with Tourette's syndrome and obsessive compulsive disorder.

D8/17 is proving to be an important diagnostic and treatment tool in patients with Tourette's syndrome (TS) and obsessive compulsive disorder (OCD). The present study represents a direct comparison of immunofluorescence microscopy and flow cytometry in terms of their relative efficiency in the detection of the DB/17 B cell marker. Analysis of 41 patients with OCD or TS and 31 control subjects by immunofluorescence microscopy and flow cytometer demonstrated an average of 6.5% of D8/17-positive B cells in controls with an average of 19.6% in OCD patients. Using the flow cytometer, values of 6.2% for controls and 22.4% for OCD patients were obtained. The flow cytometer test was able to count many more cells, induce less operator error and offer faster analysis while correlating strongly with the microscopic technique. Overall in our sample, the FACS assay test has a sensitivity of 77% and a specificity of 87%. The ease of use and close correlation to disease activity makes this an ideal test for clinical laboratories.

Adult↗
PubMed1998

Epidemiology, prevention, and early detection of breast cancer.

The evidence that alcohol consumption increases a woman's chances of getting breast cancer is now more persuasive. Higher blood concentrations of organochlorine compounds were not associated with increased risk of breast cancer in recent studies. The relationship of exogenous estrogen use to breast cancer risk is now clarified: current users of both oral contraceptives and hormone replacement therapy experience a slightly elevated risk that dissipates after cessation of use. Alcohol consumption and hormone replacement therapy are both associated with slightly increased breast cancer risk, but the overall health benefits of hormone replacement therapy and low levels of alcohol consumption appear to outweigh the risks in the general population. These circumstances underscore the complex decisions facing women and the need to consider individual risk factor profiles. For the genes BRCA1 and BRCA2, more data are needed to understand the risks associated with specific mutations, optimal implementation of genetic testing, and prevention and early detection strategies for women who have positive test results. Interesting leads in identifying women at increased risk for breast cancer have been generated via the study of genetic polymorphisms. The results of tamoxifen in the Breast Cancer Prevention Trial have made the possibility of chemoprevention for breast cancer a reality. Raloxifene, another antiestrogen, has emerged as a potential chemopreventive agent. Its efficacy in reducing breast cancer risk will be compared with that of tamoxifen in a randomized trial.

BRCA2 Protein↗
PubMed1997

Expression of TNF-alpha by human plasma cells in chronic inflammation.

Tumor necrosis factor-alpha (TNF-alpha) is a potent pro-inflammatory cytokine and mediator of the inflammatory response. It has been implicated in the pathogenesis of many inflammatory disorders, including rheumatoid arthritis (RA), septic shock, and Crohn's disease. Using a specific anti-human TNF-alpha antibody we detected immunoreactivity for this cytokine in the cytoplasm of inflammatory cells in several chronic inflammatory disorders, including RA, scleritis, and polyarteritis nodosa. These cells were identified predominantly as IgG-expressing plasma cells. Lymph nodes from patients with Hodgkin's lymphoma and breast cancer, but not from control subjects, were also found to contain TNF-alpha-positive plasma cells. Cultured EBV-B lymphocytes and a human plasma cell line (ARH-77) when stimulated with phorbol myristate acetate demonstrated cytoplasmic TNF-alpha immunoreactivity. Western blot analysis of cell membranes and conditioned media from both cell types revealed the presence of the 26-kDa membrane-bound from and the 17-kDa soluble from of TNF-alpha, respectively. TNF-alpha was quantitated by enzyme-linked immunosorbent assay and found to be biologically active as determined by the L929 cytotoxicity assay. This is the first demonstration that plasma cells may be capable of modulating immune and inflammatory responses, not only by antibody production, but also by their secretion of a key inflammatory mediator, TNF-alpha.

Animals↗