Biomedical subjects
Publications and source records attributed to R Weller.
Nitric oxide has varied effects on the skin. In this review the role of nitric oxide in cutaneous wound healing, apoptosis, carcinogenesis and psoriasis is discussed.
Psoriasis is a chronic inflammatory dermatosis characterized by hyperproliferative keratinocytes (KC). The skin lesions are infiltrated by T cells, which secrete gamma interferon (gamma-IFN) and are believed to be necessary to maintain the psoriatic phenotype. In normal KC, gamma-IFN is a potent inhibitor of proliferation, but proliferation of KC persists in psoriatic plaques despite the presence of gamma-IFN. Immunostaining of interferon regulatory factor-1 (IRF-1) revealed that IRF-1 was localized to the basal cells of the epidermis in normal and in nonlesional psoriatic skin, but was suprabasal or completely absent in lesional psoriatic skin. This finding led to the hypothesis that abnormal signaling in the gamma-IFN pathway may occur in psoriatic KC. To test this hypothesis, we measured activation of IRF-1 and signal transducer and activator of transcription (STAT)-1alpha transcription factors in KC after stimulation with gamma-IFN. Primary cultures of KC from normal and nonlesional psoriatic skin were stimulated with gamma-IFN and subsequent transcription factor activation was measured by electrophoretic mobility shift assay. Psoriatic KC showed a reduced induction of IRF-1 and STAT-1alpha activation after stimulation with gamma-IFN, compared with normal KC. Reduced activation of IRF-1 and STAT-1alpha in response to gamma-IFN indicates a fundamental defect in the growth and differentiation control of psoriatic KC in the absence of the influence of other cell types.
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BACKGROUND: Nitric oxide is continually released from normal skin and has antimicrobial effects. An acidified nitrite cream releases supraphysiologic concentrations of nitric oxide and is fungicidal in vitro. OBJECTIVE: The purpose of this study was to assess the efficacy of an acidified nitrite cream as treatment for tinea pedis. METHODS: Sixty patients were recruited with both a clinical diagnosis of tinea pedis and hyphae identified on direct microscopy; they were randomly placed into an active group treated with twice-daily application of a mixture of 3% salicylic acid in aqueous cream and 3% nitrite in aqueous cream for 4 weeks and a control group treated with 3% salicylic acid in aqueous cream and aqueous cream alone. Nineteen patients completed the trial in the active group and 16 patients in the control group. Mycologic cure (negative results on microscopy and culture) and clinical improvement were measured at 0, 2, and 4 weeks and after a 2-week interval with no treatment. RESULTS: At the end of the treatment period, 18 of the 19 patients in the active group were mycologically cured as were 11 of 16 in the control group (p = 0.042). Two weeks after the cessation of treatment, 13 of 19 patients in the active group were mycologically cured and 5 of 16 in the control group (p = 0.028). The initial clinical scores in the active and control groups were 8.1 and 8.19 (two-tailed p = 0.95). At 4 weeks they were 1.66 and 6.0 (two-tailed p = 0.002) and after 2 weeks with no treatment 1.45 and 7.4 (two-tailed p < 0.0002). CONCLUSION: Acidified nitrite is effective therapy for tinea pedis.
Although the relationship between streptococcal tonsillitis and acute guttate psoriasis is well recognized, its relationship to chronic forms of psoriasis is less established. In order to explore this further, the authors questioned 35 patients with severe psoriasis and 35 age-matched eczema controls about their history of significant sore throats (i.e. requiring a GP visit) and any resultant worsening of the skin condition. A third of the psoriasis patients reported recurrent sore throats which worsened their skin condition. This was true of only one (3%) of the 35 eczema controls. The authors discuss these findings in the context of recent laboratory work on the association between streptococcal infection and psoriasis.
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BACKGROUND: Studies of antipsoriatic therapy often rely on subjective scoring. Objective measures have been developed but have not previously been compared with subjective scoring. OBJECTIVE: Our purpose was to compare subjective and objective measures of reduction of psoriasis with topical therapy. METHODS: A 2-week, double-blind, left-to-right comparative trial of betamethasone valerate against white soft paraffin was performed in 12 patients. The subjective scores were erythema, elevation, scale, and a composite total. Objective measures were nitric oxide production measured by chemiluminescence; erythema reflectance; ultrasound scan for thickness, scale, and echo-poor zone; and computerized image analysis of video images. RESULTS: Subjective and objective measures had similar power to detect therapeutic effect. The subjective measures showed greater variation and relatively overestimated improvement. There was correlation between measures and estimates for area, redness, and thickness. Nitric oxide production was the most powerful objective measure. CONCLUSION: Thickness determined by ultrasound scan and nitric oxide production are useful measures of reduction of psoriasis, which lend themselves to more powerful statistical tests than subjective interval data.
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Community composition, succession, and performance were compared in three fluidized bed reactors (FBR) operated to test preemptive colonization and the influence of toluene compared with a mixture of benzene, toluene, and p-xylene (BTX) as feeds. One reactor was inoculated with toluene-degrading strains Pseudomonas putida PaW1, Burkholderia cepacia G4, and B. pickettii PKO1. PaW1 outcompeted the other two strains. When groundwater strains were allowed to challenge the steady-state biofilm developed by inoculated strains, they readily displaced the inoculated strains and further reduced the toluene effluent concentration from 0.140 to 0.063 mg/liter for 98% removal. Amplified ribosomal DNA restriction analysis (ARDRA) of reactor community DNA showed a succession of populations to a pattern that was stable for at least 4 months of operation. Parallel reactors fed toluene and BTX but inoculated directly from groundwater had the same treatment performance and the same ARDRA profiles as each other and as the seeded reactor once the groundwater community took over. Convergence and stability of populations were confirmed by genotype analysis of 120 isolates taken from all reactors and at several times. Ninety percent of the isolates were of 4 of the 12 genotypes found, and their ARDRA patterns accounted for most of the community ARDRA patterns. Estimates of the maximum specific growth rates (mu max), half-saturation constants (K(m)), and maximum substrate utilization rates (Vmax) of the 12 genotypes isolated revealed a rather high diversity of toluene use kinetics even though the toluene in the feed was constant. The climax populations, however, generally showed kinetic parameters indicative of greater competitiveness than the inocula. rRNA sequence analysis of three codominant strains showed them to be members of the alpha, beta, and gamma subdivisions of the Proteobacteria. Two were similar to Comamonas and Pseudomonas putida, but the member of the alpha group was somewhat distant from any organism in the rRNA database. The convergence of communities to the same composition from three different starting conditions and their constancy over several months suggests that a rather stable community was selected.
Nitric oxide (NO) is synthesized by many cells in the body. Low concentrations of NO have homeostatic roles in the circulation and nervous system, whereas high concentrations are biocidal, cytocidal and have immunomodulatory roles. The place of NO in the skin has recently become the focus of much attention, and this review highlights studies on the part played by NO in health and disease.
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Urinary incontinence imposes a considerable workload on urological and gynecological practice. Many treatments exist, but recurrent stress incontinence remains a significant problem and the reasons remain unclear. Pathological and electrophysiological studies have shown that significant pelvic nerve damage and consequent denervation and reinnervation are associated with stress incontinence, and furthermore there are collagenous changes in the pelvic floor which are related to childbirth, endogenous hormone changes and the effects of increasing age. These changes include increased nerve fiber density and pudendal nerve terminal motor latency, hypertrophy of fiber types 1 and 2, type 1 fiber predominance and fiber type grouping. Connective tissue changes involve a reduction in hydroxyproline excretion, increased cross-linking and increased muscle collagen. It is only through a better understanding of the anatomy and pathophysiology of the pelvic floor that we will be able to improve outcome in women with stress incontinence and identify patients that may not be appropriate for surgical therapy. This paper reviews recent advances in the understanding of the etiology of stress incontinence.
Nitric oxide (NO) is known to be synthesized by mammalian cells from L-arginine by a group of NO synthase enzymes. We now show that NO is generated from human skin and propose a different mechanism of production. Whereas enzymatic NO synthesis is inhibited by monomethyl L-arginine, this arginine analog, when infused into the brachial artery at concentrations sufficient to inhibit endothelial NO synthase activity, has little effect on hand skin NO production. Hand skin NO production is increased by topical acidification of the skin surface and greatly increased by the addition of nitrite solutions. We propose that NO generation from skin derives from sweat nitrite (the concentration of which was found to average 3.4 microM in six subjects) due to chemical reduction consequent to the acidic nature of sweat. Sweat contains nitrate in appreciable amounts, and skin commensal bacteria can synthesize nitrate reductase enzyme. Patients on long-term tetracycline antibiotics showed significantly reduced skin NO synthesis, although topical antiseptic and antibiotics had little effect on NO generation in the short-term. We propose that NO generation from skin is dependent on bacterial nitrate reduction to nitrite and subsequent reduction by acidification. We speculate that this has a physiologic role in the inhibition of infection by pathogenic fungi and other susceptible microorganisms and may affect cutaneous T-cell function, keratinocyte differentiation, and skin blood flow.
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