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Biomedical subjects

Stephen K Tyring

Publications and source records attributed to Stephen K Tyring.

At least 91 records · Page 5Linked to original sources

Tropical dermatology: viral tropical diseases.

Viruses are important pathogens in tropical areas; most of them, especially the tropical hemorrhagic fevers, produce mucocutaneous manifestations. More than any other kind of pathogen, viruses have the possibility for being widespread, since they have a greater probability of mutation than do bacteria, can cross species barriers easily, and infect both human beings and animals in habitats with a great biodiversity. Tropical habitats also have been subject to major ecologic changes in the last few decades, exposing humans to direct contact with these viruses and allowing hemorrhagic fevers due to new emergent viruses such as flaviviruses, filoviruses, arenaviruses, and hantaviruses to become major threats to public health. The collapse of eradication programs in many countries, as well as population increases and ecologic modifications, have led to the spread of dengue and yellow fever to large portions of the world owing to the dissemination of vectors, especially mosquitoes, with broad ecologic ranges. Viruses previously restricted to some geographic areas, such as Rift Valley fever, Crimean-Congo hemorrhagic fever, West Nile fever, and monkeypox are now affecting new countries and populations. Other viruses such as herpes B infection often affect travelers and animal handlers in most parts of the world. Dermatologic lesions occur in all these diseases and can facilitate a rapid diagnosis, leading to control of the virus and helping prevent possible outbreaks.

Animals↗

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↗

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↗

High levels of orexin A in the brain of the mouse model for phenylketonuria: possible role of orexin A in hyperactivity seen in children with PKU.

Phenylketonuria (PKU) is a metabolic disorder caused by phenylalanine hydroxylase deficiency leading to increased levels of phenylalanine in the brain. Hyperactivity is reportedly induced by a high level of orexin A, and therefore orexin A content was studied in the PKU mice. Hypothalamus and brain stem had higher levels of orexin A compared to cerebrum and cerebellum both in wild type and PKU mice brains as observed by radioimmunoassay method. Interestingly, all these regions of the brain in PKU mouse showed a higher level of orexin A compared to the wild type. Heart and plasma also had higher levels of orexin A in PKU compared to the wild type. Immunohistochemical analysis revealed an increased number of orexin A-stained cells in the brain and heart of PKU mouse compared to the wild type. This is the first report of increased level of orexin in the PKU mouse brain. Hyperactivity is commonly observed in children with PKU; thus these findings suggest that orexin A is a contributing factor for the hyperactivity.

Animals↗

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↗

Vulvar squamous cell carcinoma: guidelines for early diagnosis and treatment.

The incidence of vulvar squamous cell carcinoma (SCC), the most common vulvar cancer in women, is increasing worldwide. Furthermore, despite the increasing prevalence, this disease is commonly misdiagnosed by physicians. Unfortunately, late-stage vulvar SCC has a poorer prognosis compared with early vulvar neoplasia and requires aggressive therapy such as radical surgical intervention. Therefore, early diagnosis by physicians is critical to reduce both the mortality and morbidity rates of vulvar SCC. This review discusses the etiology, clinical characteristics, and diagnostic staging of vulvar SCC. Treatment options are reviewed, including novel topical immunotherapies such as imiquimod.

Adult↗

Molluscum contagiosum: the importance of early diagnosis and treatment.

Molluscum contagiosum is a viral infection that is becoming an increasing problem in sexually active individuals and in patients with human immunodeficiency virus. Although molluscum contagiosum lesions are generally self-limiting, it may take 6 months to 5 years for lesions to disappear. Furthermore, patients with weakened immune systems have increased difficulty in clearing lesions; therefore lesions typically persist for prolonged periods. Although there has been continued debate about whether molluscum contagiosum lesions should be treated or allowed to resolve spontaneously, many clinicians recommend treatment of genital molluscum contagiosum lesions to reduce the risk of sexual transmission, prevent autoinoculation, and increase patient quality of life. Treatment options for molluscum contagiosum include physician-administered and patient-administered therapies. Novel patient-administered treatment options allow administration in the privacy of a patient's home, providing added convenience and reducing patient embarrassment or stress. With the novel treatment opportunities currently available or in development, physicians are able to improve patient quality of life while providing patients with a convenient, well-tolerated, easily administered treatment regimen. This review summarizes the clinical diagnosis of molluscum contagiosum and provides a critical assessment of several current and emerging treatment options.

AIDS-Related Opportunistic Infections↗

Polymorphisms of the interleukin 10 gene promoter in patients from Brazil with epidermodysplasia verruciformis.

BACKGROUND: Epidermodysplasia verruciformis (EV) is a rare genetic disorder characterized by development of lesions associated with human papillomavirus in early childhood and malignant transformation in approximately half of individuals during adulthood. The persistence of human papillomavirus infection in EV is thought to be a result of an immunogenetic defect, which determines the generation of several cytokines capable of down-regulating cell-mediated immunity. OBJECTIVE: We sought to study the prevalence of interleukin 10 (IL-10) promoter polymorphisms in skin biopsy specimens of patients with EV compared with DNA samples from healthy individuals. Patients and methods DNA samples extracted from normal skin of 22 patients from Brazil with EV and blood samples from 27 healthy Brazilian individuals were studied for IL-10 promoter polymorphisms using restriction fragment length polymorphism analysis. RESULTS: The patients with EV showed an increased rate of low-production genotypes of IL-10 compared with control subjects (P =.003). Patients with EV and skin cancer were more likely to have low-production IL-10 genotypes than patients with benign forms of EV. CONCLUSION: IL-10 genotypes associated with low levels of IL-10 production may have an important role in the pathogenesis of EV, including the susceptibility for development of skin cancer in patients with EV.

Brazil↗

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↗

Molecular basis of Canavan's disease: from human to mouse.

Canavan's disease is an autosomal recessive disorder caused by aspartoacylase deficiency. The deficiency of aspartoacylase leads to increased concentration of N-acetylaspartic acid in brain and body fluids. The failure to hydrolyze N-acetylaspartic acid causes disruption of myelin, resulting in spongy degeneration of the white matter of the brain. The clinical features of the disease are hypotonia in early life, which changes to spasticity, macrocephaly, head lag, and progressive severe mental retardation. Although Canavan's disease is panethnic, it is most prevalent in the Ashkenazi Jewish population. Research at the molecular level led to the cloning of the gene for aspartoacylase and development of a knockout mouse for Canavan's disease. These developments have afforded new tools for research in the attempts to understand the pathophysiology of Canavan's disease, design new therapies, and explore methods for gene transfer to the central nervous system.

Amidohydrolases↗

Metabolic changes in the knockout mouse for Canavan's disease: implications for patients with Canavan's disease.

Canavan's disease is an autosomal recessive disorder caused by aspartoacylase deficiency, which leads to accumulation of N-acetylaspartic acid in the brain and blood and an elevated level of N-acetylaspartic acid in the urine. The brain of patients with Canavan's disease shows spongy degeneration. How the enzyme deficiency and elevated N-acetylaspartic acid cause the pathophysiology observed in Canavan's disease is not obvious. The creation of a knockout mouse for Canavan's disease is being used as a tool to investigate metabolic pathways in the mouse and correlate them with the patients with Canavan's disease. The level of glutamate is lower in the knockout mouse brain than in the wild-type mouse brain, similar to what we have found in children with Canavan's disease, and so are the levels of gamma-aminobutyric acid (GABA). The level of aspartate is higher in the Canavan's disease mouse brain. The activity of aspartate aminotransferase, an enzyme involved in the malate-aspartate shuttle, is lower in the Canavan's disease mouse brain. The lower weight of the Canavan's disease mouse was in direct proportion to low total-body fat and bone mineral density. These changes might be similar to what is seen in patients with Canavan's disease and could have therapeutic implications.

Animals↗

Mild elevation of N-acetylaspartic acid and macrocephaly: diagnostic problem.

Patients with slightly increased excretion of N-acetylaspartic acid in urine, together with macrocephaly, present a dignostic dilemma for Canavan's disease. We describe a 13-year-old male patient with macrocephaly, mild developmental delay, increased signal intensity in the basal ganglia bilaterally, partial cortical blindness, and retinitis pigmentosa. Although the clinical course and magnetic resonance imaging findings did not resemble typical Canavan's disease, N-acetylaspartic acid excretion in the patient's urine was slightly elevated, 99.90 +/- 4.00 microg/mg creatinine, whereas the normal control range was < 83 microg/mg creatinine. Cultured skin fibroblasts from the patient showed no aspartoacylase activity. Cloning of genomic DNA isolated from the patient's fibroblasts showed an intronic mutation, specifically deletion of -2A and -3C at the acceptor site of exon 3 and disrupting the normal splicing of the gene. A second mutation was found in exon 6, 863 A-->G in aspartoacylase complementary DNA, causing a tyrosine-to-cysteine (Y288C) amino acid substitution. Expression of the mutation on exon 6 showed normal aspartoacylase activity. These data suggest that expression of the mutation may help to understand the enzyme defect in a patient with slightly increased N-acetylaspartic acid excretion.

Adolescent↗

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↗

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↗

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↗