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Biomedical subjects

Stephen K Tyring

Publications and source records attributed to Stephen K Tyring.

At least 19 recordsLinked to original sources
PubMed2003

Differentiation-dependent expression of signal transducers and activators of transcription (STATs) might modify responses to growth factors in the cancers of the head and neck.

Overexpression of the epidermal growth factor receptor (EGFR) in the cancers of the head and neck is well demonstrated. In addition, copy numbers of the EGFR mRNA were significantly higher in poorly differentiated tumors than in tumors that had a differentiated phenotype. Studies by others also showed that the constitutively activated signal transducer and activator of transcription-3 (STAT3), but not STAT1, is required for EGFR-mediated cell growth. Our aim was to reveal if STAT expression is differentiation-dependent and thus, might respond to exogenous stimuli in a differentiation-dependent manner. Both reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry revealed that expression of STAT1 was high in well/moderately differentiated tumors in vivo. In contrast, STAT3 was expressed in poorly differentiated tumors. In vitro experiments showed that differentiated primary oral keratinocytes expressed higher levels of STAT1, but lower levels of STAT3 than did their undifferentiated counterparts. Epidermal growth factor treatment of oral keratinocytes with various degrees of differentiation showed the maximal induction of cyclin D1 in undifferentiated cells. Our findings suggest that the level of differentiation might modulate the outcome of EGFR signaling (i.e. cyclin D1 transcription), due to the differentiation-associated intracellular balance of transcriptional regulators (STAT1 versus STAT3).

Biopsy↗
PubMed2003

Expression of glutamate transporter, GABRA6, serine proteinase inhibitor 2 and low levels of glutamate and GABA in the brain of knock-out mouse for Canavan disease.

Canavan disease (CD) is an autosomal recessive leukodystrophy characterized by spongy degeneration of the brain. The clinical features of CD are hypotonia, megalencephaly, and mental retardation leading to early death. While aspartoacylase (ASPA) activity increases with age in the wild type mouse brain, there is no ASPA activity in the CD mouse brain. So far ASPA deficiency and elevated NAA have been ascribed with the CD. Other factors affecting the brain that result from ASPA deficiency may lead pathophysiology of CD. The NMR spectra and amino acid analysis showed lower levels of glutamate and gamma-aminobutyric acid in the CD mouse brain compared to the wild type. Microarray gene expression on CD mouse brain showed glutamate transporter-EAAT4 and gamma-aminobutyric acid-A receptor, subunit alpha6 (GABRA6) were lower 9.7- and 119.1-fold, respectively. Serine proteinase inhibitor 2 (Spi2) was 29.9-fold higher in the CD mouse brain compared to the wild type. The decrease of GABRA6 and high expression of Spi2 in CD mouse brain were also confirmed by real-time RT-PCR. This first report showing abnormal expression of EAAT4, GABRA6, Spi2 combined with lower levels of glutamate and GABA are likely to be associated with the pathophysiology of CD.

Amino Acid Transport System X-AG↗
PubMed2003

A functional interferon regulatory factor-1 (IRF-1)-binding site in the upstream regulatory region (URR) of human papillomavirus type 16.

We recently identified a new enhancer element (HIRE-1, HPV-Interferon Responsive Element-1) in the upstream regulatory region (URR) of human papillomavirus (HPV) type 16. HIRE-1 is located upstream from and in close proximity to the TATA box. HIRE-1 is 1 nt shorter in its 5' sequence in comparison to a consensus IRF-1 binding site (IRF-E). Gel shift analyses clearly demonstrated that HIRE-1 is capable of binding IRF-1 in response to interferon-gamma (IFN-gamma) treatment. In a reporter system, HIRE-1 stimulated transcription in response to IRF-1 or IFN gamma from both a heterologous or the homologous (p97) promoter in a dose-dependent manner. Mutations in the core binding sequence strongly decreased this enhancer activity. Interestingly, HIRE-1 stimulated transcription in the context of the full URR in a cell-type-specific manner, thereby suggesting the role of other cell-type-specific factors that might counteract with its function. Thus, our results may explain the inconsistent clinical and experimental results observed following IFN treatment of cervical lesions or cells. Also, this new enhancer may have an important function during inflammatory responses against HPV type 16.

5' Flanking Region↗
PubMed2003

Polymorphisms for chemical metabolizing genes and risk for cervical neoplasia.

Infection with high-risk human papillomavirus (HPV) plays a major role in the etiology of cervical cancer (CC). However, most infected women do not develop cancer. Therefore, exposure to other carcinogenic agents may be a contributing risk factor for CC. We investigated the hypothesis that environmental exposure to cigarette smoke and inheritance of polymorphic chemical metabolizing genes (CYP2E1, GSTM1, and mEH) significantly increase the risk for neoplasia. We selected 76 cases with high-grade cervical neoplasia or with invasive CC and 75 matched healthy controls. The collected data support the well-established observation that infection with high-risk HPV is the major risk factor for CC (OR = 75; 95% CI = 26-220). In addition, our data show that women who smoked more than 15 "pack-year" had a significant 6.9-fold increase in risk (95% CI = 1.2-40.3) after adjustment for HPV infection. The CYP2E1 variant genotype did not significantly increase the risk for neoplasia. A significant increase in risk for neoplasia was observed for the low-activity mEH 113 His allele after adjustment for smoking (OR = 3.0; 95% CI = 1.4-6.3). The GSTM1 null genotype was associated with a significant 3.3-fold increased risk for neoplasia (95% CI = 1.0-11.8) compared to women who were GSTM1-positive after adjustment for smoking and HPV infection. Our study suggests that genetic differences in the metabolism of cigarette smoke, particularly GSTM1, may confer susceptibility to CC. Further studies using larger populations will be needed to confirm our observations and to validate data for disease prevention.

Adolescent↗
PubMed2003

Effect of epoxide hydrolase polymorphisms on chromosome aberrations and risk for lung cancer.

Microsomal epoxide hydrolase (mEH) gene is polymorphic and its enzyme is involved in the activation and subsequent detoxification of several tobacco carcinogens, for example polycyclic aromatic hydrocarbons. Therefore, we have investigated the association of two polymorphisms at exons 3 and 4 of the mEH gene with the development of lung cancer in 110 patients and 119 matched controls. In addition, we have investigated the relationship between the different mEH alleles and the frequency of chromosome aberrations (CA), as an approach to understand the role of genetic susceptibility on cancer risk. Our results show that only the homozygous exon 4 fast genotype is significantly associated with increased risk for lung cancer (odds ratio [OR]=6.26; 95% confidence interval [CI]=1.02-38.3). When the exons 3 and 4 polymorphisms are considered together, patients carrying the high enzyme activity genotype have a significantly increased risk for lung cancer (OR=2.46; 95% CI=1.06-5.68). More importantly, the increased risk for this group is confirmed by their having the highest frequency of CA compared to any other genotype groups. In addition, genotypes with higher risk had consistently more CA than those with lower risk. Our CA data also indicates that the low activity genotype may exert a protective role in cigarette smokers, as it was associated with a significant decrease in CA compared to the high and intermediate activity genotypes. In conclusion, the CA data provides evidence to support that susceptibility mEH alleles are significantly involved with the development of lung cancer from cigarette smoking.

Case-Control Studies↗
PubMed2003

Evidence for endogenous interleukin-10 during nociception.

Cytokines such as IL-1beta, IL-6 and tumor necrosis factor-alpha (TNF-alpha) have been shown to contribute directly to central and peripheral neuropathic pain. Recently, exogenous interleukin-10 (IL-10) was shown to impede development of dynorphin-induced allodynia presumably by inhibiting IL-1beta. We therefore wanted to determine whether endogenous IL-10 had a role in pain perception. By measuring the latency of the paw licking response, we show in IL-10 knockout mice and in normal mice treated with anti-IL-10 that latency times are increased, suggesting that endogenous IL-10 increases nociception. This does not appear to be directly correlated with IL-10's regulation of DREAM, a transcriptional regulator of prodynorphin synthesis.

Animals↗
PubMed2003

Vaccines for viral diseases with dermatologic manifestations.

Vaccines against infectious diseases have been available since the 1800s, when an immunization strategy against smallpox developed by Jenner gained wide acceptance. Until recently, the only vaccination strategies available involved the use of protein-based, whole killed, and attenuated live virus vaccines. These strategies have led to the development of effective vaccines against a variety of diseases with primary or prominent cutaneous manifestations. Effective and safe vaccines now used worldwide include those directed against measles and rubella (now commonly used together with a mumps vaccine as the trivalent MMR), chickenpox, and hepatitis B. The eradication of naturally occurring smallpox remains one of the greatest successes in the history of modern medicine, but stockpiles of live smallpox exist in the United States and Russia. Renewed interest in the smallpox vaccine reflects concerns about a possible bioterrorist threat using this virus. Yellow fever is a hemorrhagic virus endemic to tropical areas of South America and Africa. An effective vaccine for this virus has existed since 1937, and it is used widely in endemic areas of South America, and to a lesser extent in Africa. This vaccine is recommended once every 10 years for people who are traveling to endemic areas. Advances in immunology have led to a greater understanding of immune system function in viral diseases. Progress in genetics and molecular biology has allowed researchers to design vaccines with novel mechanisms of action (eg, DNA, vector, and VLP vaccines). Vaccines have also been designed to specifically target particular viral components, allowing for stimulation of various arms of the immune system as desired. Ongoing research shows promise in prophylactic and therapeutic vaccination for viral infections with cutaneous manifestations. Further studies are necessary before vaccines for HSV, HPV, and HIV become commercially available.

HIV↗
PubMed2003

Adeno-associated virus-mediated aspartoacylase gene transfer to the brain of knockout mouse for canavan disease.

Canavan disease (CD) is an autosomal recessive leukodystrophy caused by deficiency of aspartoacylase (ASPA). Deficiency of ASPA leads to elevation of N-acetyl-L-aspartic acid (NAA) in the brain and urine. To explore the feasibility of gene transfer to replace ASPA in CD, we generated a knockout mouse and constructed an AAV vector that encodes human ASPA cDNA (hASPA) followed by green fluorescent protein (GFP) after an intraribosomal entry site. We injected CD mice with rAAV-hASPA-GFP in the striatum and thalamus or injected rAAV-GFP identically into control animals. Three to five months after the injection, we determined the presence of ASPA in the CD mouse brain by ASPA activity assay, GFP expression, and Western blot analysis. While rAAV-GFP-injected animals displayed undetectable levels of ASPA, all detection methods revealed significant ASPA levels in rAAV-hASPA-GFP-injected CD mice. We evaluated the functional effects of rAAV-hASPA-GFP-mediated ASPA expression by standard histological methods, magnetic resonance spectroscopy (MRS) for in vivo NAA levels, and magnetic resonance imaging of CD mice. rAAV-hASPA-injected animals displayed a remarkable lack of spongiform degeneration in the thalamus. However, pathology in sites unrelated to the injected areas showed no improvement in histopathology. The improvement in thalamic neuropathology was also detectable via in vivo MRI. MRS revealed that in vivo NAA levels were also reduced. These data indicate that rAAV-mediated ASPA delivery may be an interesting avenue for the treatment of CD.

Amidohydrolases↗
PubMed2003

Rapidly enlarging growth of the proximal nail fold.

BACKGROUND: Squamous cell carcinoma (SCC) of the nail unit is a rare but often underappreciated neoplasm. Treatment can be delayed due to confusion with paronychia and verruca. Infection with human papilloma virus (HPV) has been associated with this malignancy. OBJECTIVE: To describe the development of a superficially invasive SCC of the proximal nail fold in a patient infected with HIV, to report the association of a previously unrecognized HPV genotype, and to review key etiologic, diagnostic, and therapeutic points as related to SCC of the proximal nail fold. RESULTS: This is the first report of HPV 26 coinfection in monogamous sexual partners, both of whom are HIV infected and have demonstrated lesions of malignant degeneration consistent with SCC. CONCLUSION: SCC must be considered in the differential diagnosis of nail fold neoplasm. An immunocompromised condition such as HIV/AIDS may predispose to malignant degeneration of lesions caused by infection with HPV.

Adult↗
PubMed2003

Nonspecific cell-mediated immunity in patients with epidermodysplasia verruciformis.

Epidermodysplasia verruciformis (EV) is a rare disease that usually begins in childhood and is characterized by a generalized infection by human papilloma virus (HPV), frequent associations with cutaneous carcinomas, and abnormalities of cell-mediated immunity (CMI). We studied nonspecific CMI in 13 patients with EV by bacterial skin tests, allergic reactions to dinitrochlorobenzene (DNCB), measurement of responses to phytohemagglutinin (PHA), and quantification of T lymphocytes and T lymphocytes subsets in peripheral blood. Impairment of CMI was manifested by the cutaneous anergy to a variety of common skin antigens and, by the reduction of the lymphocyte transformation to PHA. There were no correlation between the severity of cases and abnormalities of CMI in our patients, however; the impairment of CMI was lower in cases of short duration, suggesting that the impairment of CMI in EV might reflect a long period of disease.

Adolescent↗
PubMed2003

Recurrent genital herpes treatments and their impact on quality of life.

Herpes genitalis is one of the most common viral sexually transmitted diseases in the world, with an estimated seroprevalence in the US of greater than 20%. Two viruses of the same family cause herpes genitalis: herpes simplex virus 1 and 2. After the resolution of primary infection, the virus persists in the nerve roots of the sacral plexus, often causing recurrent (though generally less severe) outbreaks. These outbreaks, as well as the infectious potential to the patient's sexual partners, results in significant psychological stress on the patient, and has a tremendous negative impact on QOL. Current treatment modalities may result in a reduction in the number of outbreaks and viral shedding, but no cure exists. Although studies have clearly demonstrated the negative impact of recurrent genital herpes on QOL, an assessment scale specific to herpes was not developed until recently. Earlier studies indicated that patients did not perceive a significant benefit from episodic treatment with antivirals, but studies using the Recurrent Genital Herpes Quality of Life Questionnaire (RGHQoL) have now demonstrated that suppressive antiviral therapy improves quality of life in patients with frequent recurrences of genital herpes. However, not all patients with recurrent genital herpes need suppressive therapy, and proposed factors to consider include frequency of recurrence, physical and psychological distress caused by recurrences, and the potential for transmission to the patient's sexual partner. Newer therapeutic modalities, including the topical immune response modifier resiquimod and herpes vaccines, may eventually be shown to further decrease the psychological morbidity of recurrent genital herpes.

2-Aminopurine↗
PubMed2003

Seborrheic Keratosis-like lesions in patients with epidermodysplasia verruciformis.

Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by disseminated infection by human papillomavirus (HPV) and malignant transformation of the lesions in about half of the patients. Two phenotypes of EV have been described according to their propensity to develop malignant tumors. The benign form of EV presents a singular type of lesions comprised of flat warts widely disseminated. The malignant form of EV is highly polymorphic and presents as malignant skin tumors, predominantly basal and squamous cell carcinomas, on sun-exposed sites. The seborrheic keratosis-like (SK) lesions in patients of EV have been reported to be associated with the malignant phenotype. In this work, we documented the behavior of SK-like lesions in nine patients with EV, through clinical observations as well as histological and immunohistochemical findings. We suggest that the HPV infection may promote the occurrence of SK-like lesions in EV patients. Despite the fact that we did not observe any malignant transformation of these lesions in our series of patients, this possibility was not completely excluded.

Adolescent↗
PubMed2002

Valacyclovir for herpes simplex virus infection: long-term safety and sustained efficacy after 20 years' experience with acyclovir.

An extensive clinical trial program combined with 5 years' postmarketing experience with valacyclovir provides evidence of favorable safety and efficacy in herpes simplex virus (HSV) management. Valacyclovir enhances acyclovir bioavailability compared with orally administered acyclovir. Long-term use of acyclovir for up to 10 years for HSV suppression is effective and well tolerated. Acyclovir is also approved for use in children, is available in some countries over the counter in cream formulation for herpes labialis, and has been monitored in over 1000 pregnancies. Safety monitoring data from clinical trials of valacyclovir, involving over 3000 immunocompetent and immunocompromised persons receiving long-term therapy for HSV suppression, were analyzed. Safety profiles of valacyclovir (</=1000 mg/day), acyclovir (800 mg/day), and placebo were similar. Extensive sensitivity monitoring of HSV isolates confirmed a very low rate of acyclovir resistance among immunocompetent subjects (<0.5%). The incidence of resistance among immunocompromised patients remains low at about 5%.

Acyclovir↗
PubMed2002

A review of antibiotics in dermatology.

BACKGROUND: Since the early 1930s when antibiotics were first introduced, they have revolutionized the way physicians treat infections. Skin conditions from acne to leprosy, which were once shunned by society, are now easily treated with oral antibiotics. OBJECTIVE: Antibiotics are chemicals derived from bacteria and fungi that uniquely have antibacterial action. The most notable example is penicillin, which is derived from a mold. With hundreds of antibiotics available to the practicing physician, improper use of these drugs has become widespread and expensive and has spawned resistant strains. For the dermatologist, antibiotics are vital weapons in the drug armamentarium for treating various skin conditions. CONCLUSION: This review explores the newest and most common oral, parenteral, and topical antibiotics used in dermatology, their indications, adverse effects, dosage, and spectrum of activity. Furthermore, systemic antibacterial prophylaxis and vaccines pertinent to dermatology are discussed. The penicillins, cephalosporins, tetracyclines, macrolides, fluoroquinolones, sulfonamides, aminoglycosides, lincosamides, folate inhibitors, and a new synthetic class of drugs, the oxazolidinones, are reviewed. These antibiotics are used to treat a variety of organisms.

Anti-Bacterial Agents↗
PubMed2002

Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) in ethnic populations in Texas; a report of a novel MTHFR polymorphic site, G1793A.

The importance of hyperhomocysteinemia, birth defects, and vascular diseases has been the subject of intense investigations. The polymorphic MTHFR mutations (C677T and A1298C) cause mild hyperhomocysteinemia, especially in homozygotes for C677T, but also in compound heterozygotes for C677T/A1298C. The subject of this report is the frequency of the polymorphic mutations in the MTHFR gene C677T, C1298A, and newly discovered mutation G1793A, as well as the association with MTRR polymorphic site A66G in different ethnic groups. Four ethnic groups were studied: African-Americans, Caucasians, Hispanics, and Ashkenazi Jews. There are statistically significant differences in the frequency of these alleles in the different populations studied, which impacts compound heterozygosity for such alleles in these populations. DNA samples obtained from the blood of healthy individuals of African-Americans, Hispanics, and Caucasians from south Texas were analyzed and compared to those obtained from Ashkenazi Jewish individuals. The polymorphic site, the G1793A allele, is least frequent among Ashkenazi individuals, 1.3%, compared to 6.9% among Caucasians (P = 0.001), 5.8% among Hispanics (P = 0.012), and 3.1% among African-Americans. The MTRR polymorphic site shows the lowest allele frequency among Hispanics, 28.6%, compared to 34% among African-Americans, 43.1% among Ashkenazi Jews (P = 0.002), and 54.4% among Caucasians (P < 0.0001). Statistically significant differences in allele frequencies of C677T and C1298A polymorphisms were also observed in these populations. Compound heterozygosity for multiple polymorphic alleles may play a role in birth defects and vascular diseases.

Alleles↗