Biomedical subjects

S K Tyring

Publications and source records attributed to S K Tyring.

At least 73 records · Page 4Linked to original sources

PubMed1998

Detection of human herpesvirus-8 DNA in Kaposi's sarcomas from iatrogenically immunosuppressed patients.

BACKGROUND: Kaposi's sarcoma (KS) accounts for more than 5% of malignancies in immunosuppressed organ transplant patients (OKS). A new herpesvirus (HHV-8) was identified with high prevalence in biopsy specimens of AIDS-KS, endemic KS, and classic KS and in OKS. KS has also been associated with other underlying diseases in patients treated with corticosteroids, but this subset of KS has been reported to contain HHV-8 in only a few case reports. OBJECTIVE: In this larger study, we determined the prevalence of HHV-8 in seven patients of Jewish origin in whom KS developed during immunosuppressive therapy for different primary diseases (ISKS). METHODS: The study included HHV-8 DNA detection by polymerase chain reaction (PCR) coupled with Southern blot and sequence analysis as well as by in situ hybridization. RESULTS: HHV-8 sequences were detected by PCR with confirmation by Southern blot and sequence analysis in 100% of the ISKS samples. Direct sequencing revealed several previously unknown base changes within the 208 bp region from open reading frame 26 (ORF26[208]) of HHV-8 in ISKS. CONCLUSION: Ours is the largest known study describing the presence of HHV-8 in iatrogenic KS from immunosuppressed nontransplant patients and provides data of previously unknown sequence variations within the ORF26 of HHV-8 DNA.

Aged↗

PubMed1998

Isoforms of cathepsin D and human epidermal differentiation.

Cathepsin D is an ubiquitously expressed lysosomal aspartic proteinase, with well-determined structural and chemical properties but a less clearly defined biological role. In stratified epithelia, the chronology of cathepsin D activation and degradation can be connected with stages of cellular differentiation. We partially purified cathepsin D from human epidermis and from separated stratum corneum by standard biochemical procedures, monitored by SDS-PAGE and Western blotting, and verified its identity as to molecular mass, pH optimum, N-terminal sequencing, reactivity with the specific antibody, inhibition by pepstatin A, and specific enzyme activity. It had hemoglobin-degrading activity over the acid range, with maximum at pH 3. It also degraded bovine serum albumin, human keratins, and stratum corneum extracts at pH 4. We discerned all three isoforms of human cathepsin D (the 52 kDa proenzyme and the active forms at 48 kDa and 33 kDa) in the epidermis; both active forms were also seen in the stratum corneum, but the proenzyme was not. Gene expression of cathepsin D in epidermal keratinocytes resembled that of suprabasal structural proteins (involucrin, keratin K10, transglutaminase) in its response to the calcium switch. An antibody to the 33 kda isoform immunolocalized to the granular layer and the stratum corneum (whereas antibodies to the 48 kDa isoform have been reported to stain mainly the upper spinous and granular layers). A plausible hypothesis to harmonize these results is that cathepsin D is first expressed as the proenzyme in the upper spinous layer, is activated in the lysosomes in the granular layer to the 48 kDa form, and is degraded to the 33 kDa form in the transition zone between the granular layer and the stratum corneum. As the stratum corneum is an acid environment, with an ambient pH of approximately 4.5, cathepsin D is available and suited to contribute to desquamation.

Amino Acid Sequence↗

PubMed1998

Advances in antiviral therapy in dermatology.

For years, investigators have sought to control viral transmission and to find appropriate treatment for people who have viral infections. Exposure control (e.g. vaccines, sanitation, vector control, blood testing, condoms/abstinence, and education) has been extremely important in management of viral spread. Several antiviral agents have received approval from the United States Food and Drug Administration over the past few years. There continues to be extensive research on new antiviral agents as well as new vaccines to control viral disease and spread. Most viral diseases continue to be treated symptomatically; however, the discovery of new and improved antiviral agents has added great power to our ability to treat certain hard-to-control viruses that plague patients.

Antiviral Agents↗

PubMed1998

Herpes. Atypical clinical manifestations.

Herpes simplex viruses (HSV) 1 and 2 are responsible for genital herpes which is usually recognized as vesicles that ulcerate and eventually heal but recur periodically. Atypical genital herpes is often described in immunocompromised patients and can present as large, chronic, hyperkeratotic ulcers. Acyclovir-resistant HSV is occasionally isolated from such ulcers. Most cases of HSV infection reproduce subtle signs and symptoms, or more commonly, asymptomatic viral shedding. Such subclinical presentations may be responsible for most of the 30% increase in the prevalence of genital herpes in the United States during the past two decades.

AIDS-Related Opportunistic Infections↗

PubMed1998

Antiviral treatment of diseases in pediatric dermatology.

Pediatric dermatologic disease that have specific therapies and/or specific prophylactic measures are reviewed. Herpes simplex virus and varicella-zoster virus infections, human papillomavirus infections, and molluscum contagiosum infections are discussed with special emphasis on recent advances of therapy and prophylaxis.

Chickenpox↗

PubMed1998

New antiviral agents for dermatologic disease.

The topic of antiviral agents for dermatologic disease is an area that is rapidly changing and expanding as our knowledge of herpes viruses, HIV, and human papilloma viruses continues to expand. New drugs are continuing to make therapy for these viruses more efficacious day by day. This review will discuss the recent advances in antiviral therapy, new therapies currently being developed or studied, and the future of antiviral vaccines.

Anti-HIV Agents↗

PubMed1998

Serologic and molecular evidence of human herpesvirus 8 activation in renal transplant recipients.

This study was designed to determine whether there is serologic or molecular evidence of human herpesvirus 8 (HHV-8) activation in renal transplant patients, an immunocompromised population at risk for development of Kaposi's sarcoma. Indirect immunofluorescence for detection of HHV-8 serum antibody and Southern blot polymerase chain reaction (PCR) for detection of viral DNA in whole blood were used. Seroprevalence and geometric mean titer (GMT) were significantly increased in the transplant group compared with healthy adults and were comparable to those in human immunodeficiency virus (HIV)-positive adults (transplant patients, 50% [GMT 1:210]; healthy adults, 7% [GMT 1:44]; HIV-positive patients, 73% [GMT 1:172]). Viral DNA was present in the blood of some renal transplant patients (3/33 PCR-positive) but in none of 20 healthy adults. Thus, there is both serologic and molecular evidence of HHV-8 activation in the renal transplant population compared with healthy adults (P<.01). The serologic results approximate those obtained for HIV-positive adults.

Adult↗

PubMed1998

A randomized, controlled, molecular study of condylomata acuminata clearance during treatment with imiquimod.

Imiquimod, an immune response modifier, has been demonstrated to be safe and effective in the treatment of external genital and perianal warts caused by human papillomavirus (HPV). To identify the molecular mechanism(s) by which condylomata acuminata clear during topical treatment with imiquimod, wart skin biopsies were taken from patients before treatment, at treatment week 6, and at the end of treatment. Tissues were analyzed for HPV DNA and for mRNA of several cytokines and HPV gene products. Wart clearance was associated with evidence of tissue production of interferon-alpha, -beta, and -gamma and tumor necrosis factor-alpha. Regression of warts was strongly associated with a decrease in HPV DNA and in mRNA expression for both early and late viral proteins. Thus, topical imiquimod treatment of anogenital warts led to significant increases in local production of multiple interferon mRNAs and a significant reduction in virus load as measured by decreases in HPV DNA and mRNA for early HPV proteins.

Administration, Topical↗

PubMed1998

Combined Epstein-Barr virus and human papillomavirus infection in nasopharyngeal carcinoma.

Epstein-Barr virus (EBV) has been shown to be a likely etiologic agent in nasopharyngeal carcinogenesis. Human papillomaviruses (HPVs) have previously been identified in numerous upper aerodigestive tract carcinomas. This pilot study was undertaken to investigate the prevalence of combined EBV and HPV infection in 17 patients with nasopharyngeal carcinoma (NPCA) using polymerase chain reaction (PCR). The primary goal was to determine if the presence of HPV could be correlated with molecular, histologic, or clinical parameters. There were seven patients with undifferentiated NPCA (World Health Organization [WHO] type III) and 10 patients with squamous cell carcinoma (WHO type I). All 17 patients had stage IV disease at presentation. EBV was identified in 15 patients (88.2%), and HPV subtypes were identified in samples from nine patients (52.9%). All HPV-positive cases were also EBV positive. Western blot analysis of six samples showed a high level of expression of c-myc and cdc2 kinase and a low level of p53 protein in NPCAs that contained both HPV and EBV (n = 3). Increased expression of c-myc and cdc2 kinase was seen in the cases that contained EBV only, but to a lesser extent (n = 2). These findings indicate an effect of the virus on cellular proliferation and differentiation. Similarly, an elevated level of Rb protein was found only in the HPV-containing NPCAs. Moderate differentiation (keratinization) occurred in four of eight HPV-negative and none of the nine HPV-positive NPCAs. (All HPV-positive cases were poorly differentiated or undifferentiated.) This difference is statistically significant for this sample size (P < 0.03). There was a trend for the group that was HPV positive to have WHO III histology and for the HPV-negative group to have WHO I. The presence of HPV could not be correlated with any clinical parameters in this small group of patients with advanced disease; however, these data suggest that coexistence of EBV and HPV infection may be a factor in the pathogenesis of NPCA and may have an effect on regulation of cellular proliferation and differentiation.

Adolescent↗

PubMed1998

Malignant transformation of recurrent respiratory papillomatosis associated with integrated human papillomavirus type 11 DNA and mutation of p53.

Recurrent respiratory papillomatosis (RRP), usually confined to the nasopharynx, trachea, and larynx, occasionally can progress to extensive bronchopulmonary disease. Most cases of bronchopulmonary and laryngeal papillomatosis are cytologically benign and do not undergo malignant transformation; however, squamous cell carcinoma (SCC) can arise in RRP in the absence of known risk factors such as radiation and smoking. In this study, the authors investigated molecular genetic alterations occurring in a case of metastasizing SCC that arose in long-standing bronchopulmonary papillomatosis. Genomic DNA from tracheal papillomata, tracheobronchial papillomata, SCC of the lung, and a lymph node metastasis was extracted. The physical state of the human papillomavirus type 11 (HPV-11) DNA was investigated by two-dimensional gel electrophoresis. Molecular genetic alterations of the host genome were studied by direct sequencing of polymerase chain reaction-amplified gene fragments and restriction fragment length polymorphism (RFLP) analysis. Episomal and integrated forms of HPV-11 sequences were detected in histologically benign tumors, but only the integrated form of the viral DNA could be found in malignant tissue samples. Molecular genetic studies revealed that an allelic loss of the interferon-beta gene (IFNbeta-1) and an endogenous type of mutation of the p53 antioncogene were found only in the malignant lesions. Mutations were not observed in the ras, neu, or multiple tumor suppressor (MTS1/p16) genes in any specimens. The authors' data indicated that the p53 genetic mutation was associated with integration of HPV-11 in histologically malignant lesions. This association may promote a progressive genetic instability that can lead to the development and clonal expansion of malignant lesions in RRP.

Adult↗

PubMed1998

Differentiation and cathepsin D expression in human oral tumors.

OBJECTIVES/HYPOTHESIS: This study aimed to ascertain whether cathepsin D expression could be related to the stage of differentiation of oral tumors. STUDY DESIGN: Human oral biopsies of 10 squamous cell carcinomas and of the corresponding perilesional normal tissues were used. The tumors had all been clinically graded as advanced stage but nonmetastatic; five were classified histopathologically as poorly differentiated. METHODS: The gene expression of cathepsin D and keratin K13 in the biopsies was measured by reverse transcription polymerase chain reaction. Ratios of tumor-to-control readings helped compensate for sample variability. RESULTS: Keratin K13, as a suprabasal cell marker, tended to confirm the histological grading of the tumors (but was not otherwise useful in distinguishing tumors from normal tissue). Substantial overexpression of cathepsin D was found in the poorly differentiated tumors. CONCLUSIONS: Cathepsin D overexpression is considered a prognostic indicator of metastasis. In this sample, it was also associated with dedifferentiation. Cathepsin D might serve as a valuable gauge in clinical exploration of the connection between dedifferentiation and metastasis.

Adult↗

PubMed1998

A randomized phase II study comparing four different interferon therapies in patients with recalcitrant condylomata acuminata.

BACKGROUND: Interferon (IFN) alpha and IFN gamma have synergistic in vitro and in vivo effects and have each been used in the treatment of anogenital condylomata acuminata. STUDY GOALS: To compare the efficacy and safety of regional 3 x 10(6) U IFN alpha (Group A), 3 x 10(6) U IFN gamma (Group B), 1.5 x 10(6) U IFN alpha plus 1.5 x 10(6) U IFN gamma (Group C), and 3 x 10(6) U IFN alpha plus 1.5 x 10(6) U IFN gamma (Group D) in the treatment of recalcitrant anogenital condylomata acuminata. STUDY DESIGN: Six-week courses of regional IFNs were administered in a randomized, double-blind, multicenter study. Response was assessed as change in the total area affected by condylomata. RESULTS: The treatments of Groups A, B, and C were similarly effective (complete response in 13.6%, 18.5%, and 16.0%, respectively). Group D had the lowest rate of complete response (3.8%), but this combination was the most effective when partial and complete responses were combined (73.0%). CONCLUSION: Regional IFN is a moderately effective and safe treatment in patients with recalcitrant anogenital condylomata acuminata. Combinations of IFNs alpha and gamma were not superior to IFN monotherapy.

Condylomata Acuminata↗

PubMed1998

Imiquimod, a patient-applied immune-response modifier for treatment of external genital warts.

Genital human papillomavirus infection is one of the most common sexually transmitted diseases. Imiquimod is a new agent, an immune-response modifier, that has been demonstrated to have potent in vivo antiviral and antitumor effects in animal models. The present prospective, multicenter, double-blind, randomized, vehicle-controlled trial evaluated the efficacy and safety of daily patient-applied imiquimod for up to 16 weeks for the treatment of external genital warts. Wart recurrence was investigated during a 12-week treatment-free follow-up period. In the intent-to-treat analysis, baseline warts cleared from 49 of 94 (52%) patients treated with 5% imiquimod cream, 13 of 90 (14%) patients treated with 1% imiquimod cream, and 3 of 95 (4%) vehicle-treated patients; the differences between the groups treated with vehicle and imiquimod were significant (P < 0.0001). For subjects who completed the follow-up period, recurrence rates after a complete response were 19% (9 of 48 patients) in the 5% imiquimod cream group, 17% (2 of 12) in the 1% imiquimod cream group, and 0% (0 of 3) in the vehicle-treated group. There were no systemic reactions, although local skin reactions (generally of mild or moderate severity) were common, particularly in the 5% imiquimod cream group. Local reactions caused two patients to discontinue treatment. The most frequently reported local skin reactions were erythema, excoriation or flaking, and erosion. Patient-applied 5% imiquimod cream is effective for the treatment of external genital warts and has a favorable safety profile.

Administration, Topical↗

PubMed1998

Sorivudine versus acyclovir for treatment of dermatomal herpes zoster in human immunodeficiency virus-infected patients: results from a randomized, controlled clinical trial. Collaborative Antiviral Study Group/AIDS Clinical Trials Group, Herpes Zoster Study Group.

The present randomized, double-blind, placebo-controlled, multicenter clinical trial was designed to compare the efficacy and tolerability of sorivudine [1-beta-D-arabinofuranosyl-E-(2-bromovinyl)uracil] and acyclovir for the treatment of dermatomal herpes zoster in human immunodeficiency virus (HIV)-seropositive patients. A total of 170 HIV-seropositive adults presenting with herpes zoster (confirmed by direct fluorescent-antigen testing and/or viral culture) were enrolled and randomized to receive a 10-day course of orally administered sorivudine (40 mg once daily plus acyclovir placebos) or acyclovir (800 mg five times daily plus sorivudine placebo). Patients were monitored daily to document the events of cutaneous healing, pain, zoster-related complications, and drug-related adverse events. Patients were reassessed on days 21 and 28 and then once monthly for 1 year. The primary efficacy endpoint was time to the cessation of new vesicle formation. Secondary efficacy endpoints included times to other events of cutaneous healing, resolution of pain, and frequency of dissemination and zoster recurrence. In a multivariate analysis, sorivudine was superior to acyclovir for reducing the times to the cessation of new vesicle formation (relative risk [RR] = 1.54, 95% confidence interval [CI] = 1.00 to 2.36; P = 0.049) and total lesion crusting (RR = 1.48, 95% CI = 1.07 to 2.04; P = 0.017). In a univariate analysis, there was a trend favoring sorivudine for the cessation of new vesicle formation (median of 3 versus 4 days; P = 0.07) and a significant advantage for time to total lesion crusting (median of 7 versus 8 days; P = 0.02). The time to the resolution of zoster-associated pain, the frequency of dissemination, and the frequency of zoster recurrence were not different between the two treatment groups. Both drugs were well tolerated. Sorivudine is an effective drug for the treatment of herpes zoster in HIV-infected patients and results in accelerated cutaneous healing when compared with acyclovir therapy.

AIDS-Related Opportunistic Infections↗

PubMed1998

Tissue specific HPV expression and downregulation of local immune responses in condylomas from HIV seropositive individuals.

OBJECTIVE: To study the effect of tissue specific human papillomavirus (HPV) expression and its effect on local immunity in condylomas from HIV positive individuals. METHODS: Biopsy specimens of eight penile and eight perianal condylomas from HIV seropositive individuals were analysed. Expression of viral genes (HIV-tat and HPV E7 and L1) was determined by RT-PCR. The status of local immunity also was determined by RT-PCR by measuring CD4, CD8, CD16, CD1a, HLA-DR, and HLA-B7 mRNA levels in the tissues. Differentiation was determined by measuring involucrin, keratinocyte transglutaminase, as well as cytokeratins 10, 16, and 17. Proliferation markers such as PCNA and c-myc were also determined. RESULTS: The transcription pattern of HPV in perianal condylomas, which preferentially expressed the early (E7) gene, was different from that of penile condylomas, which primarily expressed the late (L1) gene. This transcription pattern is in good correlation with the keratinisation and differentiation patterns of the two epithelia: perianal biopsies preferentially expressed K16 and K17 while penile warts mainly expressed K10, markers of parakeratotic and orthokeratotic epithelia, respectively. Perianal biopsies also showed a higher degree of proliferation (PCNA and c-myc). Interestingly, transcription of HIV-tat was also higher in perianal than in penile biopsies. A high degree of local immunodeficiency was observed in perianal biopsies--that is, levels of CD4, CD16, and CD1a mRNAs were significantly lower. A negative correlation between CD1a (Langerhans cells) levels and HPV E7 levels was established. HPV E7 levels positively correlated with HIV-tat levels. Perianal tissues demonstrated more CD1a depression and tat associated HPV upregulation. CONCLUSION: HIV influences the expression of HPV genes resulting in local immunosuppression that might lead to an inappropriate immune surveillance of viral infection. Also, tissue type is an important factor in controlling viral transcription in a differentiation dependent manner. These findings may explain the higher rate of dysplasia and neoplasia in the perianal area.

Antibody Formation↗

PubMed1998

Status of cytokine and antigen presentation genes in Merkel cell carcinoma of the skin.

BACKGROUND: Merkel carcinoma (MCC) of the skin is an aggressive form of skin cancer, morphologically demonstrating both epithelial and neuroendocrine properties. However, little is known about its molecular characteristics. OBJECTIVE: The aims of the study were to explore growth characteristics and immune responses of MCCs at the molecular level. METHODS: A reverse transcription-polymerase chain reaction (RT-PCR) technique was employed to study those parameters in biopsies of MCCs and their adjacent areas. RESULTS: Analyzing mRNA levels of various epithelial genes (c-myc, cdc2 kinase, E2F, PCNA, p53, and RB, cytokeratins 5 and 10) we concluded that MCCs express markers of epithelial hyperproliferation together with markers of neuroendocrine differentiation (NSE). On the other hand, there is a lack of cytokines (IL-2, IFN-g) typical for a specific, T cell-mediated immune response in MCCs. However, several cytokines (e. g., IL-12) are produced that are required for the initial steps of that type of immune response. CONCLUSION: The epithelial hyperproliferation and impaired local immune responses might contribute to the aggressive behaviour of the tumour.

Antigen Presentation↗

PubMed1998

Systemic immunosuppression by HIV infection influences HPV transcription and thus local immune responses in condyloma acuminatum.

Human immunodeficiency virus (HIV) infection is considered to influence the pathogenesis of human papillomavirus (HPV)-associated diseases. It is not clear whether this occurs directly through molecular interactions between viral genes and/or indirectly through effects on the immune functions. In the present study we compared molecular characteristics of penile condylomas from immunocompetent and HIV-positive individuals. Using polymerase chain reaction (PCR) and reverse transcriptase (RT)-PCR techniques we determined some characteristics of local immune responses and transcriptional activity of both viruses. Our findings revealed that HIV-seropositivity was accompanied by multiple HPV infection and a CD4-count-dependent appearance of oncogenic HPV-types. HIV infection also changed the patterns of HPV transcription favouring transcription of early genes such as E7. Apparently, HIV infection influences local immunity by altering HPV transcription and by systemic immunodeficiency.

Condylomata Acuminata↗

PubMed1998

High-grade dysplasia in genital warts from two patients infected with the human immunodeficiency virus.

Cancer-associated human papillomavirus (HPV) types are detected in genital warts removed from immunosuppressed individuals more commonly than from those occurring in otherwise healthy individuals. The prognosis of genital warts containing cancer-associated HPV types is not known. Because it is assumed that genital warts are benign lesions, they are usually treated by destructive therapies without prior knowledge of histopathology. The aim of the present study was to determine whether genital warts from individuals with or without human immunodeficiency virus (HIV) contain high-risk HPV types or areas of dysplasia. The study design was a nonrandomized analysis of genital warts removed by excision biopsy from 15 HIV-infected patients and 15 HIV-negative patients. The tissue was analyzed for HPV DNA by hybrid capture, and microscopic sections of each biopsy were examined for areas of dysplasia. Genital warts from HIV-infected patients contained cancer-associated ("high risk") HPV types in 9 of 15 cases, including 1 that contained only a high-risk type. High-grade dysplastic abnormalities were present in 2 of the 15 lesions from this group, both of which contained high-risk HPV types. Four genital warts removed from HIV-negative patients contained high-risk HPV types, but none contained dysplastic abnormalities. It is concluded that genital warts from HIV-infected patients often contain high-risk HPV types. Such lesions may exhibit dysplastic changes. The frequency of dysplastic changes in genital warts from HIV-infected patients is not known. Biopsy of genital warts may be indicated prior to additional therapy in HIV-infected patients, and surgical removal should be considered as a preferred treatment option in these patients.

Anus Diseases↗