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Biomedical subjects

S K Tyring

Publications and source records attributed to S K Tyring.

At least 127 records · Page 7Linked to original sources
PubMed1996

Monitoring populations for DNA repair deficiency and for cancer susceptibility.

The induction of a mutator phenotype has been hypothesized to cause the accumulation of multiple mutations in the development of cancer. Recent evidence suggests that the mutator phenotype is associated with DNA repair deficiencies. We have been using a challenge assay to study exposed populations to test our hypothesis that exposure to environmental toxicants induce DNA repair deficiency in somatic cells. In this assay, lymphocytes were irradiated in vitro to challenge cells to repair the radiation-induction DNA strand breaks. An increase of chromosome aberrations in the challenged cells from toxicant-exposed populations compared to nonexposed populations is used to indicate abnormal DNA repair response. From studies of cigarette smokers, butadiene-exposed workers, and uranium-exposed residents, the assay showed that these exposed populations had mutagen-induced abnormal DNA repair response. The phenomenon was also demonstrated using experimental animals. Mice were exposed in vivo to two different doses of N-methyl-N'-nitro-N-nitroso-guanidine (MNNG) and their lymphocytes were challenged with one dose of a radiomimetic chemical, bleomycin, in vitro. These challenged lymphocytes showed an MNNG dose-dependent increase of abnormal DNA repair response. In a population that was potentially exposed to teratogens--mothers having children with neural tube defects--lymphocytes from these mothers did not have the abnormal response in our assay. In studies with patients, we reported that lymphocytes from Down's syndrome patients have the abnormal DNA repair response. Lymphocytes from skin cancer-prone patients (epidermodysplasia verruciformis) have normal response to gamma-ray challenge but abnormal response to UV-light challenge. These patient studies also indicate that the challenge assay is useful in documenting the radiosensitivity of Down's syndrome and the UV sensitivity in EV patients. In most cases, the challenge assay is more sensitive in detecting biological effects than the standard chromosome aberration assay. Our series of studies indicates that the challenge assay can be used to document biological effects from exposure to mutagens and that the effect is an abnormal DNA repair response. This abnormality can increase the risk for development of cancer. The repair deficiency is currently being validated using a plasmid transfection (host-reactivation) assay. The need to integrate chromosome aberration and the challenge assays with other relevant assays for better documentation of biological effects and for more precise prediction of health risk will be presented. Our experience in using genetic polymorphism and host-reactivation assays will be discussed.

Animals↗
PubMed1996

Antiviral therapy of acute herpes zoster in older patients.

Although herpes zoster (shingles) can occur in anyone with a history of chickenpox, it is more prevalent and usually more severe in older patients (i.e. persons over 50 years of age). While the cutaneous manifestations of shingles usually resolve in approximately 4 weeks, the pain can persist for several months, or even years in the untreated patient. This pain following healing of the skin, termed post-herpetic neuralgia (PHN), can be very severe. Three well tolerated and effective antiviral drugs are available for the therapy of acute herpes zoster. The nucleoside analogues, aciclovir, famciclovir and valaciclovir, appear to shorten the duration of PHN to a similar degree, but none affects the incidence of PHN. Aciclovir is taken 5 times daily for 7 days, while famciclovir is taken 3 times daily for 7 days. Valaciclovir, the L-valyl ester of aciclovir, when taken orally, produces plasma levels of aciclovir equivalent to those seen following intravenous administration of aciclovir. Valaciclovir has not only been proved to be more efficient than aciclovir (i.e. 3 times daily administration) but also more effective than aciclovir in shortening the duration of PHN. Current studies are determining the relative efficacy of valaciclovir versus famciclovir. Presently, a fourth drug, sorivudine, is being compared with aciclovir for the therapy of acute herpes zoster in older patients, but data from these trials are not yet available. Corticosteroids have been used to treat herpes zoster for much longer than the antiviral drugs, but the effect of corticosteroids on PHN does not appear to be consistent. Corticosteroids plus aciclovir did not provide an added benefit over aciclovir alone in one study but this combination did appear to improve the quality of life of older patients in another investigation. The recent availability of the varicella zoster vaccine may cause shingles to be an uncommon and/or mild disease by the mid twenty-first century. Meanwhile, the search continues for more effective and efficient therapies for acute herpes zoster with the primary goal in older patients to affect the most important sequela of zoster in this population, PHN.

Aged↗
PubMed1996

Efficacy of famciclovir in the treatment of herpes zoster.

Although vidarabine was the first systemic antiviral drug for the treatment of acute herpes zoster, the agent now used most frequently is acyclovir, a far safer drug that became available a decade ago. However, even with widespread use of acyclovir, postherpetic neuralgia (PHN) remains a principal cause of postinfectious morbidity. Newer antiviral agents, such as famciclovir and valacyclovir, have recently been introduced for the treatment of uncomplicated herpes zoster. In a double-blind, randomized study, 500 mg of famciclovir three times daily for 7 days was compared with placebo; in a second study, 500 mg of famciclovir three times daily for 7 days was compared with 800 mg of acyclovir five times daily for 7 days. Famciclovir significantly reduced duration of viral shedding (P = 0.0001) and accelerated lesion resolution compared with placebo. Famciclovir was comparable to acyclovir for these acute parameters. Most importantly, famciclovir recipients lost PHN two times faster than those receiving placebo (P = 0.02 all patients; P = 0.004 patients > or = 50 years) resulting in a reduction in the median duration of PHN (56 days all patients; 100 days patients > or = 50 years). This reduction translated to a 3.5-month reduction in the median duration of PHN for patients 50 years or older, those at greatest risk for developing the most common complication of herpes zoster. Famciclovir 500 mg administered three times a day for 7 days is an effective and well-tolerated treatment for acute herpes zoster, and is the only oral antiviral agent proven to reduce the duration of PHN when administered during acute zoster infection.

2-Aminopurine↗
PubMed1995

Herpesvirus-like DNA sequences in non-Kaposi's sarcoma skin lesions of transplant patients.

Herpesvirus-like DNA sequences (KSHV) have been reported to be associated with various forms of Kaposi's sarcoma (KS). To determine if KSHV was associated with other proliferative skin lesions from non-AIDS immunocompromised patients, 33 skin lesions (basal cell carcinomas, squamous cell carcinomas, actinic keratoses, verruca vulgaris, atypical squamous proliferations, and seborrhoeic keratosis) from 4 organ-transplant patients receiving immunosuppressive therapy were tested for KSHV by PCR. KSHV sequences were detected in 82% of these skin lesions. Our results suggest that KSHV is associated with lesions other than KS in non-AIDS immunocompromised patients, and may also be involved in the pathogenesis of the various forms of proliferative skin lesions from organ-transplant patients.

Base Sequence↗
PubMed1995

Herpesvirus-like DNA sequences in classic Kaposi's sarcomas.

Kaposi's sarcoma (KS) accounts for more than 15% of AIDS-related malignancies. The etiology of KS is unresolved but is postulated to be multifactorial, involving viruses and overexpression of cellular growth factors and/or oncogenes. Recently, herpesvirus-like sequences (KSHV) were identified with high prevalence in AIDS-KS (AKS), endemic KS, and in classic KS biopsies (CKS). To confirm the presence and the prevalence of the KSHV sequences, 18 CKS and 13 AKS samples were tested using polymerase chain reaction (PCR) analysis. To our knowledge this is the highest number of CKS samples that has ever been included in a single study, and it is also important that the biopsies were obtained from different institutions and geographical locations. KSHV sequences were detected in 100% of the AKS samples and 72% of the CKS biopsies using PCR analysis. The presence of the unique KSHV sequences was confirmed by direct sequencing of representative PCR products obtained from AKS and CKS samples. Reverse transcriptase (RT)-PCR experiments showed that the KSHV sequences were transcribed to mRNA in both AKS and CKS samples. Our results confirm that the putative new herpesvirus-like agent is associated with both AKS and CKS and may have an etiological role in the pathogenesis of this malignancy.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Production of interferon gamma messenger RNA by cells of non-immune origin.

There is general agreement that IFN-gamma is produced only by cells of immune origin (T-cells, NK cells, and recently macrophages). However, indirect evidence has suggested that undetectable, low levels of IFN-gamma produced by cells of non-immune lineage, such as the murine line L-929, enhanced the antiviral activity of IFNs-alpha and/or beta following induction by agents such as the double stranded RNA poly ICLC. Since L-929 cells were one of the prototypic cell lines for studying murine IFN induction and action, we felt that it would be important to validate this observation by detection of the mRNA for IFN-gamma. If confirmed, it might indicate a role for IFN-gamma in non-immune cells. The present investigations revealed that mouse L-929 fibroblasts produce IFN-gamma message following exposure to conventional IFN-alpha/beta inducers such as poly ICLC or Newcastle disease virus. In addition, we found that IFN-gamma itself will induce its own message. We further show that this is not a phenomenon isolated to transformed cells since we found that normal mouse embryo fibroblasts also produced the message, however in a constitutive fashion.

Animals↗
PubMed1995

Human herpesvirus-8: detection of novel herpesvirus-like DNA sequences in Kaposi's sarcoma and other lesions.

Kaposi's sarcoma (KS) is a malignancy suspected of having an infectious etiology. Unique viral DNA sequences were recognized in KS lesions, using a novel technique that identifies small differences between two complex genomes. The virus had homology with the herpesvirus family, especially Epstein Barr virus (EBV), yet it was distinct from the known herpesviridae, and was appropriately named human herpesvirus 8 (HHV-8) or Kaposi's sarcoma-associated herpesvirus (KSHV). HHV-8 DNA sequences were present in AIDS-associated KS, classic KS, African endemic KS, Mediterranean KS, iatrogenic KS, and KS in homosexual men without HIV infection. HHV-8 DNA sequences were also present in peripheral blood mononuclear cells (PBMC) of KS+ patients; body-cavity-based lymphomas in HIV positive patients without KS; and in tissue from a number of malignant and non-malignant lesions in patients without HIV infection. The role of HHV-8 in KS and other malignancies is not known. Viruses are notoriously trophic for lesional tissue. Therefore, in order to determine the role of HHV-8 in KS pathogenesis, HHV-8 needs to be isolated and shown to induce immortalization in a suitable system. Regardless of its role in KS, another human herpesvirus has been discovered, and the extent of its pathogenicity needs to be uncovered.

DNA, Viral↗
PubMed1995

Presence of interleukin-10 transcripts in human pituitary and hypothalamus.

1. Recent data have shown that interleukin-10 (IL-10) is expressed and acts in mouse pituitary tumor cells and freshly isolated mouse pituitaries. 2. In this study, we show that poly(A+) RNA derived from normal human pituitary and hypothalamus expresses IL-10 message. 3. The majority of transcripts was likely from the pituitary and hypothalamus, and not from lymphocytes in the pituitary and hypothalamic vasculature, since both IL-10 and interferon-gamma mRNA levels, compared to equivalent amounts of RNA from peripheral blood lymphocytes, were much lower. 4. These results indicate that IL-10 may function in human neuroendocrine process as it does in the murine system, thus serving as an important signal molecule for bidirectional communication between the neuroendocrine and the immune systems.

Adolescent↗
PubMed1995

Interleukin-10 messenger ribonucleic acid in human placenta: implications of a role for interleukin-10 in fetal allograft protection.

OBJECTIVE: Our purpose was to determine whether interleukin-10 is expressed in human placental tissue, which might imply a role for it in fetal allograft protection. STUDY DESIGN: Detection of interleukin-10 messenger ribonucleic acid in human placental tissue and in human placental JAR cells by reverse transcription-coupled polymerase chain reaction was studied. RESULTS: Interleukin-10 messenger ribonucleic acid was detected in human placental tissue from term mothers and in human placental JAR cells. Sequence analysis of the expected interleukin-10 complementary deoxyribonucleic acid fragment revealed 100% homology to authentic interleukin-10 complementary deoxyribonucleic acid. CONCLUSION: Our results indicated that human placental tissue from term mothers expressed high levels of interleukin-10 messenger ribonucleic acid, suggesting that cells that produce interleukin-10 and that are associated with the placenta may play a role in preventing rejection of the fetal allograft by the mother.

Base Sequence↗
PubMed1995

Gene expression of markers associated with proliferation and differentiation in human keratinocytes cultured from epidermis and from buccal mucosa.

Normal keratinocytes from epidermis and from buccal mucosa underwent dissimilar stages of differentiation in the same culture medium and responded differently to changes in the composition of the medium. Manifestations of these variations were examined in terms of the expression at the mRNA level (as measured by reverse transcriptase-polymerase chain reaction) of three regulatory genes (cdc2, c-myc, and p53) and five that encode structural proteins (keratins K5, K10 and K13, involucrin, and filaggrin), in three growth-medium formulations. The culture conditions enhanced or retarded maturation; the observed alterations in gene expression correlated with these changes. Except for the proliferation genes, the non-keratinizing buccal mucosa generally responded more weakly than the orthokeratotic epidermis to culture-medium supplementation favouring differentiation. Gene expression in cultured keratinocytes reflected their ability to differentiate in vivo; genes were expressed even when the corresponding protein was not seen in vitro. Although keratin K10 is not prevalent in the buccal mucosa nor keratin K13 in the epidermis, the genes for both were found to be expressed in both tissues.

Calcium↗
PubMed1995

Interferons alpha, beta and gamma therapy of anogenital human papillomavirus infections.

Anogenital condyloma acuminatum (genital warts) is the most commonly diagnosed sexually transmitted viral disease in the United States. At least 14 of the more than 60 types of human papillomaviruses (HPVs) are responsible for condyloma acuminatum. Anogenital condyloma acuminatum has a broad spectrum of manifestations in men and women, including subclinical latent infection, clinically apparent warts, abnormal genital cytology and squamous carcinoma. Traditional therapeutic modalities include cytolytic chemical agents and ablative techniques. These anti-wart methods are used in an attempt to eliminate clinically apparent disease. However, they are associated with high rates of recurrence because they do not eradicate the subclinical or latent reservoir of HPV remaining in adjacent epithelial cells and mucous membranes. Immunologic therapy with interferons (IFNs) represents a promising new antiviral modality that can be directed against all sites of infection, including clinical, subclinical and latent disease. IFN-alpha, IFN-beta and IFN-gamma are the three major groups of IFNs. These three groups of IFNs have been used successfully as monotherapy or in combination with traditional modalities to treat anogenital condyloma acuminatum. This review focuses on IFN-alpha, IFN-beta and IFN-gamma therapy of anogenital HPV infections.

Animals↗
PubMed1995

Chromosomal radiosensitivity of lymphocytes from skin cancer-prone patients.

Frequencies of spontaneous and radiation-induced chromosome aberrations were documented in lymphocytes from patients with basal cell nevus syndrome (BCNS) and from those with epidermodysplasia verruciformis (EV). Cells were irradiated with single or double doses of gamma-rays or UV light. For the double dose irradiation protocol, the two doses were separated from each other by 60 min. After irradiation of cells with 4 or 2 + 2 J/m2 UV light, lymphocytes from seven BCNS patients had a similar number of aberrant cells compared with normal controls, while cells from three EV patients showed a significantly increased number of cells containing aberrations, particularly chromatid-type aberrations, compared to controls (p < 0.03, Student's t-test). Similar results were observed whether the cells were irradiated with single or double doses of UV light. In addition, lymphocytes from EV patients had significantly lower mitotic indices than controls whether the cultures were irradiated with UV light or unirradiated (p < 0.05; Student's t-test). After irradiation with 100, 100 + 100 or 50 + 50 cGy gamma-rays, the mean chromosome aberration frequencies from nine BCNS patients and two EV patients were not significantly different from the controls. The spontaneous chromosome aberration frequencies were similar for the patients and the controls. Our data indicate that BCNS and EV lymphocytes irradiated with gamma-rays have a normal DNA repair response. However, cells from EV patients have an abnormal repair response to UV light induced DNA damage. This abnormality is probably caused by deficiency in DNA repair and it is consistent with the patients' sensitivity to UV light induced cutaneous squamous cell carcinomas.

Adolescent↗
PubMed1995

Type-specific primer-mediated direct sequencing of consensus primer-generated PCR amplicons of human papilloma viruses: a new approach for the simultaneous detection of multiple viral type infections.

Consensus degenerate primers specific for the L1 and E1 regions were used to amplify anogenital HPV-DNA fragments. The mixture of the viral fragments was then directly sequenced with HPV-6, -11, -16, -18 and -33 type-specific computer-designed oligonucleotides as sequencing primers. The linking of a consensus primer-generated PCR amplification with type-specific primer-mediated direct sequencing and computer data bank analysis provided precise, more objective viral detection in the simultaneous presence of different HPV types. The method was successfully adapted for viral typing in clinical lesions which simultaneously contained different anogenital HPV sequences.

Anus Neoplasms↗
PubMed1995

Induction of apoptotic nuclei by interferon-gamma and by predesquamin in cultured keratinocytes.

Predesquamin is a glycoprotein found in the transition layer and the lower stratum corneum of human epidermis. Interferon-gamma (IFN-gamma) induces the synthesis of predesquamin by keratinocytes in culture. We now show ultrastructurally that exogenous addition of either predesquamin or IFN-gamma to cultured keratinocytes induces apoptotic nuclei with condensed chromatin. Degradation of cellular DNA is also evident as a ladder pattern in an agarose gel. After incubation with both predesquamin and IFN-gamma (but not either alone), the mobility of plasmid DNA in a gel shows retardation specific for guanine residues. This binding to the DNA may impart to it a conformational change that facilitates access by endogenous cellular nucleases. In epidermal cells cultured with IFN-gamma supplementation, we also show by RT-PCR that there is an upregulation of the genes c-myc, p53, gadd45, dsRNA-activated protein kinase, and 2'-5'-oligo(A)-dependent RNase, which have all been implicated in apoptosis in other cell types. These results are pertinent to the mechanism of occurrence of apoptosis in the epidermis in vivo, where predesquamin and IFN-gamma are endogenous. Programmed cell death is an inherent step in the terminal differentiation and desquamation of the epidermis.

Apoptosis↗
PubMed1995

Effect of interferon therapy on human papillomavirus copy number in patients with Condyloma acuminatum.

Interferons exert antiviral, antiproliferative, and immunomodulatory effects on target cells. The effectiveness of interferon treatment can be followed by measuring parameters involved in interferon action. The clinical effectiveness of interferons has been proved in the human papillomavirus (HPV)-associated disease condyloma acuminatum. Because one of the most important goals in the treatment of this condition is the elimination of recurrences, it was asked whether clinically effective interferon therapy was associated with elimination of HPV DNA. The authors used a polymerase chain reaction-based method to detect the HPV from minute amounts of clinical biopsies. Human papillomavirus-transformed cell lines or cloned HPV genomes served as different copy number controls. The intensity ratio of L1 HPV and the human beta-globin (which served as an internal control) fragments was determined and used for estimation of HPV copy number in different biopsies. A direct effect of interferon treatment on HPV viral genome copies was observed in a group of responder patients, but not in the clinically resistant group. With these data, a correlation was found between virologic data and clinical findings. This method also can be used in other lesions to determine the HPV copy number and HPV type and may have value in determining the antiviral activities of other agents used in the treatment of HPV-related lesions.

Cell Line↗