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Biomedical subjects

C A Johnson

Publications and source records attributed to C A Johnson.

At least 109 records · Page 6Linked to original sources
PubMed1999

Comparison of central and peripheral visual field properties in the optic neuritis treatment trial.

PURPOSE: To compare the results of peripheral kinetic visual field testing and central static perimetry for patients enrolled in the Optic Neuritis Treatment Trial to determine (1) whether loss and recovery of visual field sensitivity in the far periphery was different from that observed in the central visual field and (2) whether the far peripheral visual field provided additional useful information that was not available in the central visual field results. METHODS: Both affected and fellow eyes of 448 patients with optic neuritis in the Optic Neuritis Treatment Trial were evaluated according to the trial protocol during the patients' first 3 years in the study. Central static visual field tests were performed with program 30-2 on the Humphrey Field Analyzer, and peripheral kinetic testing consisted of plotting the I3e and II4e isopters on the Goldmann perimeter. Both test procedures were conducted according to the trial protocols, and quality control assessments and clinical evaluations were performed on all the visual fields. RESULTS: For both affected and fellow eyes at all 11 visits, there was a greater number of abnormal visual fields in the central static perimetry results than in the peripheral kinetic data. Only 2.9% of affected eyes had an abnormal peripheral visual field with a normal Humphrey mean deviation during year 1. At baseline, 97.1% of affected eyes had an abnormal Humphrey mean deviation on central static testing, whereas only 69.9% had abnormal peripheral kinetic visual fields. Approximately 80% of the I3e and II4e isopters for affected eyes that were abnormal at baseline were within normal limits at 30 days, but it took until week 19 for even 70% of the Humphrey mean deviations to return to normal. In addition, the II4e isopters (more peripheral than the I3e isopters) that were abnormal at baseline showed a somewhat greater percentage of improvement from baseline through day 30 than the abnormal I3e isopters. Although this difference is statistically significant, it is probably not clinically significant. For visits after week 19, approximately 25% to 30% of affected eyes had an abnormal Humphrey mean deviation, whereas only 10% to 15% of peripheral kinetic fields were abnormal. CONCLUSIONS: For the affected eye in optic neuritis, the central visual field shows greater abnormalities than the far peripheral visual field. When the results obtained through Humphrey automated central static visual fields and Goldmann peripheral kinetic isopters are compared, the far periphery appears to recover more rapidly and more completely than the central field, at least in more severe cases of optic neuritis. In most cases, recovery in optic neuritis can probably be monitored effectively with automated perimetry of the central visual field alone. However, in cases of severe loss of the central visual field, a peripheral kinetic visual field obtained with a Goldmann perimeter may provide additional information about the patient's vision in the far periphery.

Adolescent↗
PubMed1999

The natural history of early recurrent carotid artery stenosis.

BACKGROUND: Early recurrent carotid stenosis, defined as greater than 50% stenosis within 2 years of a carotid endarterectomy (CEA), occurs in 4% to 19% of patients. These lesions are secondary to myointimal hyperplasia (MH). The natural history of these lesions has been examined prospectively, but the appropriate management of these lesions has not been clearly defined. The vascular surgery service at Madigan Army Medical Center (MAMC) has prospectively collected a cohort of patients with recurrent high-grade carotid stenoses following CEA to determine their natural history and define the ideal therapeutic approach for those lesions. METHODS: Patients undergoing CEA between January 1, 1993, and January 1, 1997, at a single tertiary care institution were followed prospectively with postoperative carotid duplexes at 3-month intervals for the first year and then every 6 months for a year and then annually thereafter. Data were collected regarding patient demographics, type of carotid closure, neurologic morbidity, and death. These results were compared with accepted rates in the literature. Discrete variables were tested for significance by chi-square analysis and Fisher's exact test. A P value less than or equal to 0.05 was considered significant. RESULTS: One hundred and seventy-four (174) patients with 181 operative sites were evaluated. Fourteen patients with 17 sites (9%) had recurrent stenosis. Twelve patients with 14 sites (7%) had stenoses of 50% to 79%. All were asymptomatic. Two patients with 3 sites (2%) had stenoses greater than 80%. Two sites were managed operatively because of neurologic symptoms or preocclusive nature and one remains asymptomatic and stable on serial duplex imaging. All lesions were present at 6 months and those in the 50% to 79% category did not progress in follow-up. Recurrent carotid stenosis occurred to a significantly higher degree in women (women 11 of 60 18.3% versus men 6 of 114 5.3%; P = 0.25), primary closure versus patch angioplasty (primary 6 of 22 27.3% versus patch 11 of 159 6.9%; P = 0.01), and dacron versus polytetrafluoroethylene (PTFE) patch angioplasty (dacron 7 of 36 19.4% versus PTFE 2 of 100 2.0%; P = 0.02). CONCLUSION: Early recurrent stenosis (50% to 79%) is a benign lesion. Patch angioplasty is preferred over primary closure. Dacron patches had a significantly higher rate of recurrent stenosis when compared with PTFE patches. Women undergoing CEA are more prone to recurrent stenosis. Postoperative duplex at 3 and 6 months will identify recurrent carotid stenosis (given a normal duplex prior to discharge following CEA). Moderate high-grade (50% to 79%) stenoses are benign. High-grade (80% to 99%) stenoses require individual management.

Angioplasty↗
PubMed1999

Estimating effectiveness in an observational study: a case study of dornase alfa in cystic fibrosis. The Investigators and Coordinators of the Epidemiologic Study of Cystic Fibrosis.

Patients with cystic fibrosis (CF) receiving dornase-alfa had improved pulmonary function relative to a control group in a large randomized phase III controlled study. We reviewed data from a large observational phase IV study to estimate the observed drug effect in patients receiving dornase alfa as part of their routine care. Patients 6 years or older and with a baseline forced expiratory volume in 1 second (FEV1) of at least 40% predicted who had been enrolled for at least 18 months were included (n = 283). The control group consisted of 2382 patients who had never received dornase alfa. Patients in the study had a baseline spirometry and a second spirometry recorded 12 months later; a baseline observation period of 6 months preceded the initial spirometry, and dornase alfa had to have been started after the baseline spirometry (within 3 months) and to have continued through the 12-month follow-up spirometry. Patients treated with dornase alfa had lower pulmonary functions, more bacterial colonization, and more exacerbations at baseline (FEV1 : 76.0% vs 87.6%, Pseudomonas aeruginosa : 64.1% vs 46.7%, pulmonary exacerbations during the previous 6 months: 56.4% vs 22. 2%). Mean values of FEV1 for patients treated with dornase alfa improved by 3.9% of predicted compared with a decline of 1.6% in the untreated cohort. Covariate adjustment provided an estimated benefit of dornase alfa of 4.3% predicted FEV1 (SE = 0.9, P <.0001). This analysis provides evidence for the effectiveness of dornase alfa therapy in clinical practice.

Child↗
PubMed1999

Pharmacokinetics of intraperitoneal epoetin alfa in patients on peritoneal dialysis using an 8-hour "dry dwell" dosing technique.

Pharmacokinetic studies of intraperitoneal (IP) epoetin alfa administered to continuous ambulatory peritoneal dialysis (CAPD) patients have shown low bioavailability, primarily attributable to the dilutional effect of coadministered dialysate. However, bioavailability is improved by instilling the dose into a dry peritoneum. The current study was designed to determine whether absorption after administration into a dry peritoneum is improved by extending the dry dosing period from 4 to 8 hours. The pharmacokinetics of a single 100-unit/kg IP epoetin alfa dose were studied in 8 noninfected CAPD patients. The dose was instilled into a dry peritoneum via the peritoneal catheter and allowed to dwell for 8 hours. CAPD was then resumed. Blood samples were collected for 96 hours after the dose. A 14-hour effluent dialysate sample was collected to determine epoetin alfa recovery. Enzyme immunoassay was used for epoetin alfa analysis of serum and effluent. Standard pharmacokinetic methods were employed for analysis of the serum concentration time data. The extent of epoetin alfa absorption was significantly greater than previously reported for a 4-hour dry dwell. The mean (+/-SD) dose-normalized area-under-the-curve (nlAUC(0-infinity)) using the 8-hour dry dwell dosing technique was 6,331 +/- 2,536 mIU. h/mL. This is significantly greater than the value of 2,589 +/- 1,450 mIU. h/mL (two-sided P value = 0.002) from a previous study in which patients received the same 100-unit/kg dose using a 4-hour dry dwell. The absorption of epoetin alfa administered by the intraperitoneal route is improved by extending the time the dose resides in a dry peritoneum.

Adolescent↗
PubMed1999

Smoking patterns of Asian-American youth in California and their relationship with acculturation.

PURPOSE: To examine patterns of smoking behavior among subgroups of Asian-American youth in California and their relationship with acculturation status. METHODS: Data were from the 1990-1996 California Tobacco Survey and the California Youth Tobacco Survey, which assessed smoking-related attitudes and behaviors among California youth in grades 7-12. Among the 20,482 respondents, 1,810 were Asian-Americans. Variables assessed included lifetime smoking prevalence, 30-day smoking prevalence, and age of smoking onset. Acculturation status was assessed with measures of English usage, language spoken at home, and age at immigration to the United States. RESULTS: Of the 1,810 Asian-Americans (52% male), 19% were Chinese, 33% Filipino, 8% Japanese, 13% Korean, and 26% other Asian-Americans. Lifetime smoking prevalence was 16.1% for Asians and 26.1% for non-Asians. The 30-day smoking rate was 6.9% for Asians and 14.2% for non-Asians. Subgroup-specific analyses revealed differences in lifetime smoking prevalence (18.9% for Filipinos, 17.3% for Japanese, 16.3 % for Koreans, 11.0% for Chinese, and 13.7% for other Asian-Americans) and 30-day smoking rate (8.6% for Filipinos, 8.3% for Koreans, 7.4% for Japanese, 2.8% for Chinese, and 7.2% for other Asian-Americans). Gender differences in lifetime smoking prevalence varied by Asian subgroup; smoking prevalence was higher among males than among females for Chinese and Koreans, but smoking prevalence was higher among females than among males for Japanese and other Asians. The average age of smoking onset was 12.9 years for Asians and 12.8 years for non-Asians. Age of smoking onset differed among Asian-American subgroups but did not differ by gender. In addition, smoking behaviors of the Asian respondents were significantly associated with their acculturation status. CONCLUSIONS: Asian-American youth have relatively lower smoking rates and later age of smoking onset than non-Asian youth in California. In addition, subgroups of Asian-American youth vary widely in their smoking behavior. High levels of acculturation among Asian-American youth are associated with higher smoking prevalence rates and earlier age of smoking onset.

Acculturation↗
PubMed1999

MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex.

Mammalian DNA is methylated at many CpG dinucleotides. The biological consequences of methylation are mediated by a family of methyl-CpG binding proteins. The best characterized family member is MeCP2, a transcriptional repressor that recruits histone deacetylases. Our report concerns MBD2, which can bind methylated DNA in vivo and in vitro and has been reported to actively demethylate DNA (ref. 8). As DNA methylation causes gene silencing, the MBD2 demethylase is a candidate transcriptional activator. Using specific antibodies, however, we find here that MBD2 in HeLa cells is associated with histone deacetylase (HDAC) in the MeCP1 repressor complex. An affinity-purified HDAC1 corepressor complex also contains MBD2, suggesting that MeCP1 corresponds to a fraction of this complex. Exogenous MBD2 represses transcription in a transient assay, and repression can be relieved by the deacetylase inhibitor trichostatin A (TSA; ref. 12). In our hands, MBD2 does not demethylate DNA. Our data suggest that HeLa cells, which lack the known methylation-dependent repressor MeCP2, use an alternative pathway involving MBD2 to silence methylated genes.

Amino Acid Sequence↗
PubMed1999

Attitudes toward anti-tobacco policy among California youth: associations with smoking status, psychosocial variables and advocacy actions.

To prevent smoking and exposure to environmental tobacco smoke, California has implemented anti-tobacco policies, including laws restricting youth access to tobacco, and smoking bans in workplaces, schools, restaurants and bars. Although studies have examined adults' attitudes toward anti-tobacco policies, little is known about adolescents' awareness of and support for these policies. This study examined attitudes toward anti-tobacco policies in a sample of 6887 10th grade California adolescents. Awareness of anti-tobacco policies was highest among current smokers and lowest among susceptible never-smokers. Support for anti-tobacco policies was highest among non-susceptible never-smokers and lowest among current smokers. Policy awareness and support were significantly associated with psychosocial tobacco-related variables (e.g. perceived consequences of smoking, friends' smoking, perceived access to cigarettes, prevalence estimates of smoking among peers, cigarette offers and cigarette refusal self-efficacy). Policy awareness and support were associated with the probability of performing advocacy actions against tobacco use. Although these results cannot prove a causal association, they suggest that adolescents' attitudes toward anti-tobacco policies may play a role in their decisions about smoking. Tobacco control and education programs should include information about existing anti-tobacco policies, and should educate youth about the importance and benefits of anti-tobacco policies.

Adolescent↗
PubMed1999

Frequency doubling technology perimetry using a 24--2 stimulus presentation pattern.

PURPOSE: To assess whether smaller targets and a 24-2 stimulus presentation pattern would improve the ability of frequency doubling technology (FDT) perimetry to detect and characterize early glaucomatous visual field loss. METHODS: One hundred normal subjects between the ages of 20 and 85 participated in this study. In addition, 53 patients who either had early glaucomatous visual field loss (n = 23) or were high-risk glaucoma suspects with normal conventional visual fields (n = 30) were evaluated with the commercial version of FDT perimetry (full threshold test) with 17 stimuli (four 10 degrees diameter square targets per quadrant and a central 5 degrees circular target) and a custom version of FDT perimetry using 54 stimuli (4 degrees targets with 6 degrees grid spacing) arranged in a 24-2 stimulus presentation pattern. RESULTS: The custom FDT test using a 24-2 stimulus presentation pattern had a similar dynamic range, and demonstrated normal aging characteristics and test-retest reliability that were similar to the commercial version of FDT perimetry using 17 larger stimuli. Both FDT tests showed an age-related sensitivity reduction of approximately 0.6 dB per decade, and exhibited an average test-retest reliability of 1 to 1.5 dB. The custom 24-2 FDT perimetry test had a greater variation of sensitivity with eccentricity than the commercial version of FDT perimetry that was probably related to the difference in stimulus size. The custom 24-2 FDT perimetry test had a greater percentage of abnormal test locations than the commercial FDT test for both early glaucomas and high-risk glaucoma suspects. CONCLUSIONS: FDT perimetry can be performed with smaller targets using a presentation pattern that is similar to conventional automated perimetry. In comparison to the commercially available 17 target display, the 24-2 stimulus pattern appears to have modestly higher sensitivity for detection of early glaucomatous loss and provides better characterization of the pattern of visual field loss, but the test takes approximately twice as long.

Adult↗
PubMed1999

Normal aging effects for frequency doubling technology perimetry.

PURPOSE: To determine the influence of normal aging on contrast sensitivity for frequency doubling technology (FDT) perimetry. METHODS: Contrast sensitivity measures were obtained for frequency-doubled stimuli (0.25 cycles per degree sinusoidal gratings undergoing 25 Hz counterphase flicker) at 17 target locations (4 per quadrant plus the central 5 degrees ) using a prototype of the Welch Allyn (Skaneateles, NY)/Humphrey Systems FDT perimeter (Humphrey Systems, Dublin, CA). A total of 407 normal subjects (761 eyes) between the ages of 15 and 85 years were tested. RESULTS: Between the ages of 15 and 60 years there was an approximately linear decrease in contrast sensitivity of 0.6 dB per decade. After the age of 70, there was a slightly greater sensitivity loss with age. There were no meaningful differences in sensitivity loss as a function of age for different visual field locations. A small but consistent reduction in contrast sensitivity (approximately 0.7 dB) was found at all visual field locations for the second eye tested that may be due to a central adaptation process. CONCLUSIONS: Normal aging effects for FDT perimetry are similar to those obtained for conventional automated perimetry, except that the FDT perimetry aging effects do not appear to be eccentricity dependent. These normative data provide a basis for establishing a statistical analysis procedure and probability plots for FDT perimetry.

Adolescent↗
PubMed1999

The detection of circulating melanoma cells correlates with tumour thickness and ulceration but is not predictive of metastasis for patients with primary melanoma.

We analysed peripheral blood samples from 143 patients with primary melanoma (PM) for the presence of tyrosinase mRNA by reverse transcription-polymerase chain reaction (PCR) to determine whether the early detection of circulating melanoma cells (CMCs) is of clinical value in monitoring melanoma progression. Ten of the patients (7%) with PM had detectable CMCs. The percentage of PCR-positive patients was higher for stage II patients (9.0%) than for stage I (5.3%), but the difference was not significant. A significantly higher percentage (P<0.05) of PCR-positive patients were found to have tumours greater than 1.5 mm in thickness or had ulcerated tumours. This suggests that tumour thickness and ulceration are the two most significant prognostic factors. The detection rate of 9% for patients with stage II disease is much lower than would be expected, since 23.9% (16 out of 67) of the stage II patients subsequently developed metastases. Of these 16 patients, only one was PCR-positive, 1 week before the metastases became clinically evident. Thus, the current technique fails to predict the likelihood of developing metastatic disease (P=0.3485). The other nine PCR-positive patients had not developed metastases after a median follow-up period of 4 years. It is concluded that this technique for the detection of CMCs is of limited clinical value in predicting the likelihood of metastasis in patients with PM. It is suggested that the detection of micrometastases in other anatomical compartments, such as sentinel lymph nodes, should be explored for the identification of patients at risk for developing metastases.

Disease Progression↗
PubMed1999

Pharmacokinetics of quinupristin-dalfopristin in continuous ambulatory peritoneal dialysis patients.

Quinupristin-dalfopristin may be useful for treatment of organisms causing peritoneal dialysis-related peritonitis, including methicillin-resistant coagulase-negative staphylococci, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant enterococci. The pharmacokinetic profiles of single intravenous doses of this combination streptogramin antibiotic of 7.5 mg/kg of body weight were characterized for eight noninfected patients receiving continuous ambulatory peritoneal dialysis. Comparison was made to pharmacokinetic profiles determined for eight healthy volunteers matched by age, sex, and race. Drug was measured in dialysate up to 6 h following the dose. Plasma and dialysate were assayed for parent compounds and metabolites. Mean pharmacokinetic parameters were compared between groups. No statistically significant differences were observed between groups for maximal concentrations in plasma, times to maximal concentration, areas under the curve, distribution volumes, rates of total body clearance, or half-lives in plasma for quinupristin and dalfopristin. No statistically significant differences were observed in maximal concentrations in plasma, times to maximal concentration, areas under the curve, or half-lives for cysteine, the glutathione conjugates of quinupristin, or the pristinamycin IIA metabolite of dalfopristin. The measurements in dialysate of the parent and most metabolites were below the expected MICs. Dialysis clearance was insignificant. Quinupristin-dalfopristin was well tolerated in both groups, causing only mild adverse events that resolved prior to discharge from the study. The disposition of quinupristin, dalfopristin, or their primary metabolites following a single dose was unaltered in patients receiving peritoneal dialysis. Intravenous dosing of this antibiotic combination is unlikely to be adequate for the treatment of peritonitis associated with peritoneal dialysis.

Adolescent↗
PubMed1999

Is acculturation a risk factor for early smoking initiation among Chinese American minors? A comparative perspective.

OBJECTIVE: To determine the extent to which Chinese American and white minors differ in age of smoking initiation, and to determine the effect of acculturation on smoking initiation. DESIGN: Cross-sectional telephone surveys. SETTING: Stratified random samples of the state of California, United States. SUBJECTS: 347 Chinese American and 10 129 white adolescents aged 12 through 17 years, from the California Tobacco Survey (1990-93) and the California Youth Tobacco Survey (1994-96). OUTCOME MEASURES: Hazards (risk) of smoking initiation by age, smoking initiation rate, cumulative smoking rate, mean age of smoking initiation, and acculturation status. STATISTICAL METHODS: Life table methods, proportional hazards models, and chi(2) tests. RESULTS: The risk of smoking initiation by age among Chinese American minors was about a third of that among white minors. The risk for Chinese Americans continued to rise even in later adolescence, in contrast to that for whites, which slowed after 15 years of age. Acculturation was associated significantly with smoking onset among Chinese Americans. Acculturation, smoking among social network members, attitudes toward smoking, and perceived benefits of smoking were associated with the difference in hazards of smoking onset between Chinese American minors and their white counterparts. CONCLUSIONS: Chinese American adolescents had a lower level and a different pattern of smoking onset than white adolescents. Levels of acculturation and other known risk factors were associated with the hazards of smoking initiation among Chinese American minors and with the difference in smoking initiation between the Chinese and white adolescents. Tobacco prevention policies, strategies, and programmes for ethnically diverse populations should take acculturation factors into account.

Acculturation↗
PubMed1999

Test-retest variability of frequency-doubling perimetry and conventional perimetry in glaucoma patients and normal subjects.

PURPOSE: To compare the test-retest variability characteristics of frequency-doubling perimetry, a new perimetric test, with those of conventional perimetry in glaucoma patients and normal control subjects. METHODS: The study sample contained 64 patients and 47 normal subjects aged 66.16+/-11.86 and 64.26+/-7.99 years (mean +/- SD), respectively. All subjects underwent frequency-doubling perimetry (using the threshold mode) and conventional perimetry (using program 30-2 of the Humphrey Field Analyzer; Humphrey Instruments, San Leandro, CA) in one randomly selected eye. Each test was repeated at 1-week intervals for five tests with each technique over 4 weeks. Empirical 5th and 95th percentiles of the distribution of threshold deviations at retest were determined for all combinations of single tests and mean of two tests, stratified by threshold deviation. The influence of visual field eccentricity and overall visual field loss on variability also were examined. RESULTS: Mean test time with frequency-doubling perimetry in patients and normal control subjects was 5.90 and 5.25 minutes, respectively, and with conventional perimetry was 17.20 and 14.01 minutes, respectively. In patients, there was a significant correlation between the results of the two techniques, in the full field and in quadrants, whereas in normal subjects there was no such correlation. In patients, the retest variability of conventional perimetry in locations with 20-dB loss was 120% (single tests) and 127% (mean tests) higher compared with that in locations with 0-dB loss. Comparative figures for frequency-doubling perimetry were 40% and 47%, respectively. Variability also increased more with threshold deviation in normal subjects tested with conventional perimetry. In both patients and normal subjects, variability increased with visual field eccentricity in conventional perimetry, but not in frequency-doubling perimetry. Both techniques showed an increase in variability with overall visual field damage. CONCLUSIONS: Frequency-doubling perimetry has different test-retest variability characteristics than conventional perimetry and may have potential for monitoring glaucomatous field damage.

Aged↗
PubMed1999

Intravenous iron products.

Intravenous iron has been used extensively and successfully as part of the treatment of anemia in dialysis patients. Iron dextran can be used safely, however, there is a slight risk of severe, anaphylactoid reactions. Iron gluconate and iron sucrose are less likely to cause hypersensitivity reactions. These products should be safe and effective alternatives to iron dextran.

Anemia, Iron-Deficiency↗
PubMed1998

Molecular cloning of Drosophila melanogaster cDNAs that encode a novel histone deacetylase dHDAC3.

The steady-state level of histone acetylation in eukaryotes is established and maintained by multiple histone acetyltransferases (HATs) and histone deacetylases (HDACs) and affects both the structure and the function of chromatin. Histone deacetylases play a key role in the regulation of transcription, and form a highly conserved protein family in many eukaryotic species. Here we describe the cloning, sequencing and genetic mapping of two histone deacetylase genes in Drosophila melanogaster: dHDAC1 is essentially identical to the previously cloned D. melanogaster d-Rpd3 gene and dHDAC3, a novel gene, is orthologous to the human and the chicken (Gallus gallus) HDAC3 genes. The predicted amino acid sequence (438 aa) of dHDAC3 shows 58.1% identity with dHDAC1/d-Rpd3, the only previously known member of the HDAC family in this organism. The map positions on polytene chromosomes for dHDAC1 and dHDAC3 were determined as 64C1-6 and 83A3-4 respectively. A search for other dHDAC3-like genes failed to find other potential paralogues in D. melanogaster, but identified significant homologies with bacterial and fungal genes encoding enzymes that metabolise acetyl groups, and with genes for other hydrolyases such as carboxypeptidase. In addition, histone deacetylase activity in D. melanogaster nuclear extracts can be inhibited by high concentrations of zinc and activated by low concentrations, which is identical to the properties of bovine carboxypeptidase A. On the basis of sequence and functional similarities, we suggest that histone deacetylases are metal-substituted enzymes.

Amino Acid Sequence↗
PubMed1998

Activation of the epidermal platelet-activating factor receptor results in cytokine and cyclooxygenase-2 biosynthesis.

Recent studies suggest that the lipid mediator platelet-activating factor (PAF) is involved in keratinocyte function and skin inflammation. Indeed, PAF is found in association with inflammatory skin diseases, intradermal injections of PAF induce inflammation, and keratinocytes express functional PAF receptors (PAF-R). One mechanism by which the keratinocyte PAF-R could contribute to epidermal functions and inflammatory states would be through the synthesis of inflammatory regulators, such as PAF, PGs, and cytokines. The ability of the epidermal PAF-R to induce the synthesis of these immunomodulators was tested using a model system created by transduction of the PAF-R-negative human epidermal cell line KB with the PAF-R. Activation of this epidermal PAF-R resulted in arachidonic acid release, and the biosynthesis of PAF and PGE2. In addition, the KB PAF-R triggered increased levels of mRNA and protein for the inducible isozyme of cyclooxygenase (COX-2) as well as IL-6 and IL-8, both of which have been implicated in skin inflammatory processes. Studies with the human keratinocyte-derived epidermal cell line HaCaT revealed that activation of the endogenous PAF-R led to the increased accumulation of COX-2, IL-6, and IL-8 mRNA similar to that seen with the KB PAF-R model system. Finally, treatment of HaCaT keratinocytes with IL-8 resulted in PAF biosynthesis, indicating the existence of a positive feedback loop between IL-8 and PAF in epidermal cells. These studies suggest involvement of PAF and the PAF-R in the epidermal cytokine network.

Arachidonic Acid↗
PubMed1998

Expression of the platelet-activating factor receptor results in enhanced ultraviolet B radiation-induced apoptosis in a human epidermal cell line.

Recent studies have demonstrated that ultraviolet B radiation (UVB) damages human keratinocytes in part by inducing oxidative stress and cytokine production. Severe UVB damage to the keratinocyte can also result in apoptosis or programmed cell death. Although the lipid mediator platelet-activating factor (PAF) is synthesized in response to epidermal cell damage and epidermal cells express PAF receptors, it is not known whether PAF is involved in UVB-induced epidermal cell apoptosis. These studies examined the role of the PAF system in UVB-induced epidermal cell apoptosis using a novel model system created by retroviral-mediated transduction of the PAF receptor-negative human epidermal cell line KB with the human PAF receptor (PAF-R). Expression of the PAF-R in KB cells did not affect base-line growth or apoptosis, yet resulted in a decrease in the lag time between treatment of the cells and the induction of apoptosis following irradiation with 400 J/m2 UVB. This effect was inhibited by pretreatment with the PAF-R antagonists WEB 2086 and A-85783, confirming involvement of the PAF-R in this process. At lower doses (100-200 J/m2) of UVB, only KB cells that expressed the PAF-R became apoptotic. Treatment of PAF-R-expressing KB clones with the metabolically stable PAF-R agonist 1-hexadexyl-2-N-methylcarbamoyl-3-glycerophosphocholine (CPAF) alone did not induce apoptosis but augmented the degree of apoptosis observed if CPAF was used in combination with lower doses (200 J/m2) of UVB irradiation. Interestingly, UVB irradiation was found to stimulate PAF synthesis only in PAF-R-expressing KB cell clones. The antioxidants N-acetyl cysteine, 1,1,3,3-tetramethyl-2-thiourea, and vitamin E inhibited both UVB-induced PAF biosynthesis as well as the augmentation of UVB-induced apoptosis in PAF-R-expressing KB clones, suggesting the possibility that UVB stimulates the production of oxidized lipid species with PAF-R agonistic activity in this model system. Thus, these studies indicate that a component of UVB-induced epidermal cell cytotoxicity can be modulated by PAF-R activation through the production of PAF and PAF-like species.

Apoptosis↗