Biomedical subjects

Stephen K Tyring

Publications and source records attributed to Stephen K Tyring.

At least 55 records · Page 3Linked to original sources

PubMed2005

Biological and clinical basis for molecular studies of interferons.

The cytokine family of interferons (IFNs) has multiple functions, including antiviral, anti-tumor, and immunomodulatory effects and regulation of cell differentiation. The multiple functions of the IFN system are thought to be an innate defense against microbes and foreign substances. The IFN system consists first of cells that produce IFNs in response to viral infection or other foreign stimuli and second of cells that establish the antiviral state in response to IFNs. This process of innate immunity involves multiple signaling mechanisms and activation of various host genes. Viruses have evolved to develop mechanisms that circumvent this system. IFNs have also been used clinically in the treatment of viral diseases. Improved treatments will be possible with better understanding of the IFN system and its interactions with viral factors. In addition, IFNs have direct and indirect effects on tumor cell proliferation, effector leukocytes and on apoptosis and have been used in the treatment of some cancers. Improved knowledge of how IFNs affect tumors and the mechanism that lead to a lack of response to IFNs would help the development of better IFN treatments for malignancies.

Animals↗

PubMed2004

Nested PCR with the PGMY09/11 and GP5(+)/6(+) primer sets improves detection of HPV DNA in cervical samples.

Based on epidemiological and research evidence, HPV has a causal role in cervical carcinogenesis. Several HPV detection methods exist to date; the most commonly used method for detection of genital HPVs consists of nested PCR using the MY09/11 and GP5(+)/6(+) primer sets (MY/GP(+)). Recently, the PGMY09/11 primer set, a modified version of the MY09/11 primer set, was introduced for single PCR and was found to detect a wider range of HPV types. The next logical step was taken and the efficacy of nested PCR using the PGMY09/11 and GP5(+)/6(+) primer sets (PGMY/GP(+)) to detect HPV in cervical samples was evaluated. In this comparative study, nested PCR using the novel PGMY/GP(+) primer set combination was found to be more type sensitive than the nested PCR with the MY/GP(+) primer sets, detecting a wider range of HPV types, low copy HPVs, and better characterizing samples infected with multiple strains of HPV. Standardization and use of the PGMY/GP(+) PCR system could aid physicians in providing more efficient HPV screening and better treatment for patients.

Cervix Uteri↗

PubMed2004

Mouse neural progenitor cells differentiate into oligodendrocytes in the brain of a knockout mouse model of Canavan disease.

Canavan disease (CD) is an autosomal recessive disorder that leads to spongy degeneration in the white matter of the brain. Aspartoacylase (ASPA) synthesizing cells, oligodendrocytes, are lost in CD. Transplantation of neural progenitor cells (NPCs) offers an interesting therapeutic approach for treating neurodegenerative diseases by replacing the lost cells. Therefore, the NPCs transplantation to the brain of the CD mouse was studied. Injection of mouse NPCs to the striatum and cerebellum of juvenile CD mouse showed numerous BrdU positive cells at 1 month after injection. The same result was also observed in the adult CD mouse brain after 5 weeks of post-transplantation period. The implanted cells differentiated into oligodendrocytes and fibrous astrocytes, as observed using glial cell marker. This is the first report to describe the survival, distribution and differentiation of NPCs within the brain of CD mouse and a first step toward the potential clinical use of cell therapy to treat CD.

Amidohydrolases↗

PubMed2004

Inhibition of smoothened signaling prevents ultraviolet B-induced basal cell carcinomas through regulation of Fas expression and apoptosis.

Abnormal activation of the hedgehog-signaling pathway is the pivotal abnormality driving the growth of basal cell carcinomas (BCCs), the most common type of human cancer. Antagonists of this pathway such as cyclopamine may therefore be useful for treatment of basal cell carcinomas and other hedgehog-driven tumors. We report here that chronic oral administration of cyclopamine dramatically reduces ( approximately 66%) UVB induced basal cell carcinoma formation in Ptch1(+/-) mice. Fas expression is low in human and murine basal cell carcinomas but is up-regulated in the presence of the smoothened (SMO) antagonist, cyclopamine, both in vitro in the mouse basal cell carcinoma cell line ASZ001 and in vivo after acute treatment of mice with basal cell carcinomas. This parallels an elevated rate of apoptosis. Conversely, expression of activated SMO in C3H10T1/2 cells inhibits Fas expression. Fas/Fas ligand interactions are necessary for cyclopamine-mediated apoptosis in these cells, a process involving caspase-8 activation. Our data provide strong evidence that cyclopamine and perhaps other SMO antagonists are potent in vivo inhibitors of UVB-induced basal cell carcinomas in Ptch1(+/-) mice and likely in humans because the majority of human basal cell carcinomas manifest mutations in PTCH1 and that a major mechanism of their inhibitory effect is through up-regulation of Fas, which augments apoptosis.

Animals↗

PubMed2004

Aspartoacylase deficiency does not affect N-acetylaspartylglutamate level or glutamate carboxypeptidase II activity in the knockout mouse brain.

Aspartoacylase (ASPA)-deficient patients [Canavan disease (CD)] reportedly have increased urinary excretion of N-acetylaspartylglutamate (NAAG), a neuropeptide abundant in the brain. Whether elevated excretion of urinary NAAG is due to ASPA deficiency, resulting in an abnormal level of brain NAAG, is examined using ASPA-deficient mouse brain. The level of NAAG in the knockout mouse brain was similar to that in the wild type. The NAAG hydrolyzing enzyme, glutamate carboxypeptidase II (GCP II), activity was normal in the knockout mouse brain. These data suggest that ASPA deficiency does not affect the NAAG or GCP II level in the knockout mouse brain, if documented also in patients with CD.

Amidohydrolases↗

PubMed2004

HPV typing in Brazilian patients with epidermodysplasia verruciformis: high prevalence of EV-HPV 25.

BACKGROUND: Epidermodysplasia verruciformis is a rare genetic disorder characterized by development of lesions associated with HPV#5 or HPV#8 in early childhood; malignant transformation occurs in approximately half of individuals during adulthood. OBJECTIVE: Our goal was to study the presence and spectrum of EV-HPV types in Brazilian EV patients, a population that had never been studied in this regard. PATIENTS AND METHODS: Forty-one biopsies from different lesions (benign and skin tumors) and one biopsy from clinically normal skin from each of 20 Brazilian patients with EV were studied for HPV typing using nested PCR. RESULTS: EV-HPV DNA was detected in all 41 skin lesions of the patients and was also identified in specimens considered as normal skin from 8 patients (40%). In this study HPV-EV 25 was the most prevalent (70%), and HPV 14d (67%) was highly associated with malignant lesions. CONCLUSION: EV-HPV 25 was the most prevalent in our study. The noteworthy association of EV-HPV type 14d with skin cancers suggests its possible oncogenic role in malignant transformation in this population.

Adolescent↗

PubMed2004

High level of orexin A observed in the phenylketonuria mouse brain is due to the abnormal expression of prepro-orexin.

Orexins/hypocretins are recently discovered neuropeptides, synthesized mainly in the lateral hypothalamus of the brain. Orexins regulate various functions including sleep and apetite. We recently reported increased amount of orexin A in the phenylketonuria (PKU) mouse brain. Whether this is caused by overexpression of the precursor for orexins, prepro-orexin was studied in the PKU mouse brain. Microarray expression analysis revealed overexpression of orexin gene in the brain of PKU mouse. Quantitative real-time RT-PCR showed increased level of prepro-orexin mRNA in the PKU mouse brain. In addition, expression of genes associated with cell signal and growth regulation was also affected in the PKU mouse brain, as observed by microarray analysis. These data suggest that up-regulation of orexin mRNA expression is the possible factor for inducing high orexin A in the brain of PKU mouse. The metabolic environment in the brain of PKU mouse affects normal expression of other genes possibly to result in pathophysiology seen in the PKU mouse, if documented also in patients with PKU.

Animals↗

PubMed2004

Species identification of all eight human herpesviruses with a single nested PCR assay.

There are eight currently known human herpesviruses, all of which are capable of latent persistence and reactivation following primary infection. Herpesvirus induced disease is common, widespread, and associated with significant morbidity, particularly in the immunocompromised human host. Current methods of herpesvirus detection include viral culture and polymerase chain reaction (PCR). A robust PCR method based upon amplification of the highly conserved herpesvirus DNA polymerase gene that is capable of detection of all eight human herpesviruses, including EBV and HHV-6 subtypes, from clinical material is described. Species identification of PCR products is accomplished by either of two methods, chemiluminescent dot blot hybridization and heteroduplex mobility shift assay, both of which allow for simultaneous detection of multiple herpesviruses. This method should prove useful for rapid and accurate species identification of all eight human herpesviruses from clinical material.

Cytomegalovirus↗

PubMed2004

Once-daily valacyclovir to reduce the risk of transmission of genital herpes.

BACKGROUND: Nucleoside analogues against herpes simplex virus (HSV) have been shown to suppress shedding of HSV type 2 (HSV-2) on genital mucosal surfaces and may prevent sexual transmission of HSV. METHODS: We followed 1484 immunocompetent, heterosexual, monogamous couples: one with clinically symptomatic genital HSV-2 and one susceptible to HSV-2. The partners with HSV-2 infection were randomly assigned to receive either 500 mg of valacyclovir once daily or placebo for eight months. The susceptible partner was evaluated monthly for clinical signs and symptoms of genital herpes. Source partners were followed for recurrences of genital herpes; 89 were enrolled in a substudy of HSV-2 mucosal shedding. Both partners were counseled on safer sex and were offered condoms at each visit. The predefined primary end point was the reduction in transmission of symptomatic genital herpes. RESULTS: Clinically symptomatic HSV-2 infection developed in 4 of 743 susceptible partners who were given valacyclovir, as compared with 16 of 741 who were given placebo (hazard ratio, 0.25; 95 percent confidence interval, 0.08 to 0.75; P=0.008). Overall, acquisition of HSV-2 was observed in 14 of the susceptible partners who received valacyclovir (1.9 percent), as compared with 27 (3.6 percent) who received placebo (hazard ratio, 0.52; 95 percent confidence interval, 0.27 to 0.99; P=0.04). HSV DNA was detected in samples of genital secretions on 2.9 percent of the days among the HSV-2-infected (source) partners who received valacyclovir, as compared with 10.8 percent of the days among those who received placebo (P<0.001). The mean rates of recurrence were 0.11 per month and 0.40 per month, respectively (P<0.001). CONCLUSIONS: Once-daily suppressive therapy with valacyclovir significantly reduces the risk of transmission of genital herpes among heterosexual, HSV-2-discordant couples.

Acyclovir↗

PubMed2004

Resiquimod: a new immune response modifier with potential as a vaccine adjuvant for Th1 immune responses.

Genital herpes is one of the most common sexually transmitted diseases worldwide. Currently, there are three FDA-approved nucleoside analogs and other therapies such as foscarnet and cidofovir used to treat genital herpes. Resiquimod, the latest immune response modifier (IRM), has shown in vivo evidence of efficacy against herpes simplex virus (HSV) type 2. The first clinical trial involving resiquimod demonstrated that it reduced the recurrence rate of genital herpes, but phase III trials were suspended due to lack of efficacy. Resiquimod shows promise for other viral infections and as a vaccine adjuvant.

Adjuvants, Immunologic↗

PubMed2004

Vaccines and immunotherapies for the prevention of infectious diseases having cutaneous manifestations.

Although the development of antimicrobial drugs has advanced rapidly in the past several years, such agents act against only certain groups of microbes and are associated with increasing rates of resistance. These limitations of treatment force physicians to continue to rely on prevention, which is more effective and cost-effective than therapy. From the use of the smallpox vaccine by Jenner in the 1700s to the current concerns about biologic warfare, the technology for vaccine development has seen numerous advances. The currently available vaccines for viral illnesses include Dryvax for smallpox; the combination measles, mumps, and rubella vaccine; inactivated vaccine for hepatitis A; plasma-derived vaccine for hepatitis B; and the live attenuated Oka strain vaccine for varicella zoster. Vaccines available against bacterial illnesses include those for anthrax, Haemophilus influenzae, and Neisseria meningitidis. Currently in development for both prophylactic and therapeutic purposes are vaccines for HIV, herpes simplex virus, and human papillomavirus. Other vaccines being investigated for prevention are those for cytomegalovirus, respiratory syncytial virus, parainfluenza virus, hepatitis C, and dengue fever, among many others. Fungal and protozoan diseases are also subjects of vaccine research. Among immunoglobulins approved for prophylactic and therapeutic use are those against cytomegalovirus, hepatitis A and B, measles, rabies, and tetanus. With this progress, it is hoped that effective vaccines soon will be developed for many more infectious diseases with cutaneous manifestations.

Bacterial Infections↗

PubMed2004

A review of licensed viral vaccines, some of their safety concerns, and the advances in the development of investigational viral vaccines.

Viral vaccines could be considered among the most important medical achievements of the 20th century. They have prevented much suffering and saved many lives. Although some curative antiviral drugs exist, we desperately depend on efforts by academic, governmental and industrial scientists in the advancement of viral vaccines in the prevention and control of infectious diseases. In the next decade, we hope to see advancement in the development of current and investigational viral vaccines against childhood and adult infections. In this article, we will review the licensed viral vaccines, some of their safety concerns, and the advances in the development of investigational viral vaccines.

Adolescent↗

PubMed2004

Trends in enzyme therapy for phenylketonuria.

Phenylketonuria (PKU) is an inborn error of amino acid metabolism caused by phenylalanine hydroxylase (PAH) deficiency. Dietary treatment has been the cornerstone for controlling systemic phenylalanine (Phe) levels in PKU for the past 4 decades. Over the years, it has become clear that blood Phe concentration needs to be controlled for the life of the patient, a difficult task taking into consideration that the diet becomes very difficult to maintain. Therefore alternative models of therapy are being pursued. This review describes the progress made in enzyme replacement therapy for PKU. Two modalities are discussed, PAH and phenylalanine ammonia-lyase PAH. Developing stable and functional forms of both enzymes has proven difficult, but recent success in producing polyethylene glycol-modified forms of active and stable PAH shows promise.

Biopterins↗

PubMed2004

Once, twice, or three times daily famciclovir compared with aciclovir for the oral treatment of herpes zoster in immunocompetent adults: a randomized, multicenter, double-blind clinical trial.

BACKGROUND: Famciclovir, the well absorbed oral pro-drug of penciclovir, is effective in the treatment of herpes zoster when given three times daily. Because the intracellular half-life of penciclovir triphosphate in varicella-zoster virus (VZV)-infected cells (7h) is considerably longer than that of aciclovir triphosphate (1h), it may be possible to administer famciclovir less frequently than three times daily for herpes zoster: aciclovir is administered five times daily. METHODS: 559 immunocompetent adults presenting with herpes zoster whose skin lesions were present for less than 72 h were randomized to receive famciclovir 750 mg once daily (od), 500 mg twice daily (bid), or 250 mg three times daily (tid), or aciclovir 800 mg five times daily. All treatments were given for 7 days. Participants were evaluated until complete healing or for 4 weeks, whichever occurred first. RESULTS: There were no significant differences between the four treatment groups with respect to times to full crusting; loss of vesicles, ulcers and crusts; cessation of new lesion formation; a 50% reduction in the area of affected skin; and the loss of acute pain. CONCLUSIONS: Famciclovir 750 mg once daily, 500 mg twice daily and 250 mg daily, and aciclovir 800 mg five times daily are three times comparable in efficacy with respect to the cutaneous healing of herpes zoster. The current study was not designed to assess the effects of the treatments on postherpetic neuralgia (PHN).

2-Aminopurine↗

PubMed2004

Comprehensive analysis of genetic polymorphisms in the interleukin-10 promoter: implications for immune regulation in specific ethnic populations.

The association of interleukin-10 (IL-10) promoter single-nucleotide polymorphisms (SNPs) as risk factors for certain inflammatory diseases, viral infections, cancers, and transplant rejection have been the subject of recent studies. The SNPs -1082 G --> A, -819 C --> T, and -592 C --> A, which have been associated with differential IL-10 production, are strongly linked with ethnicity. In this study, we determined the ethnic distribution of IL-10 promoter SNPs and their haplotype rates among Hispanics, African Americans, and Caucasians from Texas and Ashkenazi Jews from New York. Significant differences in prevalence rates of IL-10 SNPs (and their haplotype distribution) were found. African Americans and Hispanics have a lower rate of putative high-producer SNPs and a higher rate of low IL-10 producers when compared to Caucasians or Ashkenazi Jews. No statistically significant differences in allelic frequencies and haplotype rates were observed between Caucasians and Ashkenazi Jews. This study provides critical new information on the ethnic distribution of IL-10 promoter SNPs in a regional U. S. population and is the first to analyze the rate of SNPs in an unstudied ethnic population, Ashkenazi Jews. Knowledge of IL-10 promoter polymorphisms may prove useful in prediction of immunization responses, disease severity, and in the intelligent design of customized immunotherapy.

Black or African American↗

PubMed2004

Association of p53 arginine polymorphism with skin cancer.

BACKGROUND: The presence of arginine at codon 72 in p53 protein is proposed to be a genetic risk factor in human papillomavirus (HPV)-related carcinogenesis. OBJECTIVE: To study the prevalence of p53 polymorphism at codon 72 in skin biopsies of epidermodysplasia verruciformis (EV) patients compared to DNA samples from healthy individuals. PATIENTS AND METHODS: DNA samples extracted from normal skin and tumor biopsies of 22 Brazilian patients with EV and blood samples from 27 healthy Brazilian individuals were studied for p53 codon 72 polymorphisms using restriction fragment length polymorphism (RFLP) analysis. RESULTS: All EV patients with the malignant form of EV were homozygous for arginine (Arg/Arg) at codon 72 of the p53 gene, in contrast to none with the benign form (P < 0.0001). CONCLUSIONS: p53 arginine polymorphism is likely to be associated with the development of skin malignancies in EV patients from Brazil.

Arginine↗

PubMed2004

Therapy of cutaneous human Papillomavirus infections.

Human Papillomaviruses (HPV) are double-stranded DNA viruses, which result in a variety of clinical manifestations according to type. The most common cutaneous lesions include warts located on the skin and genitalia. Because there is currently no cure for HPV infection, treatment focuses on the alleviation of signs and symptoms. Unfortunately, therapy has not been proved to affect transmissibility. Traditional treatment modalities have focused on the destruction of infected tissue through a variety of techniques. These include podophyllin resin, podophyllotoxin, salicylic acid, trichloroacetic acid, bichloroacetic acid, cryotherapy, laser, and surgical techniques. None of these modalities have been proved to be superior. More recently, immunomodulatory compounds with antiviral properties have demonstrated superior efficacy with clearance rates up to 77% and low recurrence rates. Most importantly, clinical trials of vaccines to prevent acquisition of oncogenic HPV are demonstrating marked safety and efficacy.

Humans↗

PubMed2004

Therapy of HIV infection.

HIV is a devastating disease caused by the human immunodeficiency virus. Symptoms of illness can manifest in every organ system, including the skin. Although there is no definitive cure, the creation of antiretroviral drugs and aggressive treatment regimens have dramatically altered disease morbidity and mortality. However, the precise drug selection is often difficult and intimidating given the sheer abundance of drug therapies available. In this article, the HIV disease course is reviewed and different classes of antiretroviral medications are presented with emphasis on initial drug regimens, potential adverse effects, particularly those of dermatologic nature, possible drug interactions, patient compliance, and the emergence of drug resistance.

Anti-HIV Agents↗