A scoping review of the roles, training, and impact of community health workers in oral health.

OBJECTIVE: To synthesize English or Spanish-language literature on community health workers' (CHWs') roles, training, and impact in oral health. BASIC RESEARCH DESIGN: A scoping review conducted in accordance with the Arksey and O'Malley (2005) methodological framework. METHOD: Electronic literature searches were conducted in Medline (Ovid), Embase (Ovid), DOSS, CINAHL, Web of Science, and Global Health CAB from inception of the databases to April 2020. Three reviewers independently conducted the title and abstract and full-text reviews. This was followed by data charting by three reviewers and data summarizing by two reviewers. RESULTS: Out of the 36 articles that met the inclusion criteria, most took place in the United States (n=15) with most published between 2012 and 2019 (12). CHWs were incorporated in programs that focused on access to dental care (n=10), oral health promotion only (9), early childhood caries (8), oral health promotion and services (5), and oral cancer screening (4). Common roles included providing oral health education and behavior change motivation to community members, facilitating utilization of dental services, and the delivery of diagnostic and dental services to community members. Training and outcomes were not consistently described across studies. CONCLUSION: CHWs have been used in oral health programs and interventions across a wide range of locations and contexts. The implementation and scaling-up of oral health CHW programs requires appropriate provision of training as well as community embedded monitoring and evaluation structures based on rigorous methods with clearly defined outcomes.

Divergent trends in the prevalence of asthma-like symptoms and asthma in a developing country: three repeated surveys between 2002 and 2016.

INTRODUCTION AND OBJECTIVES: There have been differences in temporal trends of asthma prevalence by geographic region and economic prosperity. The aim of this study was to assess temporal trends in asthma prevalence among young adolescents in Skopje, Republic of North Macedonia as a developing country with a low asthma prevalence. SUBJECTS AND METHODS: Data were obtained from three cross-sectional surveys (2002, 2006, and 2016) of adolescents (12-15 years) from randomly selected schools in Skopje. Trends in the prevalence of asthma and asthma-like symptoms were investigated descriptively and using multiple logistic regression to adjust for potential confounding factors. RESULTS: The prevalence of asthma increased, although the changes were not statistically significant (2002: 1.7%; 2006: 2.0%; 2016: 2.8%; p=0.075). Statistically significant (p<0.05) reductions in wheeze prevalence over time (2002, 2006, 2016) were observed for current wheeze (8.8%, 7.2%, 5.5%), exercise-induced wheeze (14.2%, 7.9%, 1.9%), and night dry cough (16.5%, 13.5%, 9.6%). After adjustment for potential confounding factors, there was an increase in asthma likelihood by year compared to 2002 (2006: OR=1.22, 95%CI=0.67-2.22; 2016: OR=2.45, 95%CI=1.24-4.84). In the adjusted analyses, associations between year and the asthma-like symptoms confirmed the descriptive results, except for current wheeze, where statistical significance disappeared. CONCLUSIONS: Divergent trends in prevalence with a decrease in asthma-like symptoms and an increase in physician-diagnosed asthma in Skopje during a period of 14 years were established. Improved asthma labelling and effective preventative treatment of symptoms may explain some of these changes, although changes in environment and lifestyle could not be ruled out.

Eight-year follow-up of a randomized clinical trial comparing ultrasound-guided foam sclerotherapy with surgical stripping of the great saphenous vein.

BACKGROUND: This was an 8-year follow-up of an RCT comparing ultrasound-guided foam sclerotherapy (UGFS) with high ligation and surgical stripping (HL/S) of the great saphenous vein (GSV). METHODS: Patients were randomized to UGFS or HL/S of the GSV. The primary outcome was the recurrence of symptomatic GSV reflux. Secondary outcomes were patterns of reflux according to recurrent varices after surgery, Clinical Etiologic Anatomic Pathophysiologic (CEAP) classification, Venous Clinical Severity Score (VCSS) and EuroQol Five Dimensions (EQ-5D™) quality-of-life scores. RESULTS: Of 430 patients originally randomized (230 UGFS, 200 HL/S), 227 (52·8 per cent; 123 UGFS, 103 HL/S) were available for analysis after 8 years. The proportion of patients free from symptomatic GSV reflux at 8 years was lower after UGFS than HL/S (55·1 versus 72·1 per cent; P = 0·024). The rate of absence of GSV reflux, irrespective of venous symptoms, at 8 years was 33·1 and 49·7 per cent respectively (P = 0·009). More saphenofemoral junction (SFJ) failure (65·8 versus 41·7 per cent; P = 0·001) and recurrent reflux in the above-knee GSV (72·5 versus 20·4 per cent; P = 0·001) was evident in the UGFS group. The VCSS was worse than preoperative scores in both groups after 8 years; CEAP classification and EQ-5D® scores were similar in the two groups. CONCLUSION: Surgical stripping had a technically better outcome in terms of recurrence of GSV and SFJ reflux than UGFS in the long term. Long-term follow-up suggests significant clinical progression of venous disease measured by VCSS in both groups, but less after surgery. Registration number: NCT02304146 (http://www.clinicaltrials.gov).

An international comparison of risk factors between two regions with distinct differences in asthma prevalence.

BACKGROUND AND PURPOSE: Investigation of the geographic variation in asthma prevalence can improve our understanding of asthma etiology and management. The purpose of our investigation was to compare the prevalence of asthma and wheeze among adolescents living in two distinct international regions and to investigate reasons for observed differences. METHODS: A cross-sectional survey of 13-14 year olds was completed in Saskatoon, Canada (n=1200) and Skopje, Republic of Macedonia (n=3026), as part of the International Study of Asthma and Allergies in Childhood (ISAAC) Phase 3 study. Surveys were self-completed by students following the ISAAC protocol. Multiple logistic regression models were used to investigate associations with reports of asthma and current wheeze. A mediation analysis was then completed. RESULTS: Asthma prevalence was much higher in Saskatoon than Skopje (21.3% vs. 1.7%) as was the prevalence of current wheeze (28.2% vs. 8.8%). Higher paracetamol (acetaminophen) use was a consistent risk factor for asthma and wheeze in both locations and showed dose-response relationships. In both countries, paracetamol use and physical activity mediated some of the association for both asthma and wheeze. In Saskatoon, among those with current wheeze, 42.6% reported ever having a diagnosis of asthma compared to 10.2% among Skopje adolescents. CONCLUSIONS: The results suggest that the variation in risk factors between the two locations may explain some of the differences in the prevalence of asthma and wheeze between these two study sites. However, diagnostic labeling patterns should not be ruled out as another potential explanatory factor.

Indoor mold levels and current asthma among school-aged children in Saskatchewan, Canada.

Current knowledge regarding the association between indoor mold exposures and asthma is still limited. The objective of this case-control study was to investigate the relationship between objectively measured indoor mold levels and current asthma among school-aged children. Parents completed a questionnaire survey of health history and home environmental conditions. Asthma cases had a history of doctor-diagnosed asthma or current wheeze without a cold in the past 12 months. Controls were age- and sex-matched to cases. Vacuumed dust samples were collected from the child's indoor play area and mattress. Samples were assessed for mold levels and quantified in colony-forming units (CFU). Sensitization to mold allergens was also determined by skin testing. Being a case was associated with family history of asthma, pet ownership, and mold allergy. Mold levels (CFU/m2 ) in the dust samples of children's mattress and play area floors were moderately correlated (r = 0.56; P < 0.05). High mold levels (≥30 000 CFU/m2 ) in dust samples from play [adjusted odds ratio (aOR) = 2.6; 95% CI: 1.03-6.43] and mattress (aOR) = 3.0; 95% CI: 1.11-8.00) areas were significantly associated with current asthma. In this study high levels of mold are a risk factor for asthma in children.

Urban-rural differences in asthma prevalence among young adolescents: The role of behavioural and environmental factors.

BACKGROUND: Asthma prevalence has been reported to be lower in rural areas compared to urban areas, although this has been inconsistent. This study aims to identify the influence of urban-rural residence on asthma prevalence in adolescents in the Republic of Macedonia and to investigate characteristics that may explain observed associations. METHODS: Following International Study of Asthma and Allergies in Childhood protocol, a national sample of Macedonian urban and rural dwelling adolescents (12-16 years) was recruited in 2006. Self-completed questionnaires were used to collect data on wheeze and asthma as well as personal, environmental and dietary characteristics. Following descriptive and multiple logistic regression analyses, a mediation analysis approach was performed to help explain observed associations. RESULTS: A lower prevalence of current wheeze and ever-diagnosed asthma was observed in rural compared to urban dwelling adolescents (4.9% vs. 7.2% and 1.2% vs. 1.9%, respectively). After adjustment for potential confounders, the associations, although still protective, were not statistically significant (wheeze: OR=0.74, 95%CI=0.46-1.21; asthma: OR=0.97, 95%CI=0.38-2.46). The associations between urban-rural status with current wheeze and asthma were mediated by region of the country (wheeze 9%; asthma 19%) and by diet (>5% change for both wheeze and asthma). Having a dog resulted in a strengthening of the association between urban-rural status and current wheeze by 11.9%. CONCLUSIONS: The prevalence of asthma and wheeze was lower in rural dwelling Macedonian adolescents and the association was mediated by the region of the country with diet likely to be part of the reason for this mediating effect.

Farm Exposures and Allergic Disease Among Children Living in a Rural Setting.

OBJECTIVES: The purpose of this study was to examine the association between farm exposures and asthma and allergic disease in children while also highlighting the experiences of non-farm rural children. METHODS: This was a cross-sectional analysis of data collected from across the province of Saskatchewan, Canada in 2014. Surveys were completed by parents of 2275 rural dwelling children (farm and non-farm) aged 0 to 17 years within 46 rural schools. Questionnaires were distributed through schools for parents to complete. RESULTS: Asthma prevalence was 7.6%, of which 29.5% of cases were allergic. After adjustment for potential confounders, home location (farm vs non-farm) and other farm exposures were not associated with asthma and asthma phenotypes. Those who completed farm safety education were more likely to have asthma (11.7% vs. 6.7%; p = .001) compared to children without asthma. In sub-analyses among 6-12-year-old children, boys were more likely to have asthma (non-allergic) and use short-acting beta-agonists compared to girls. Doing farm work in the summer was associated with an increased risk of asthma [adjusted OR (aOR) = 1.71 (1.02-2.88); p = .041]. Doing routine chores with large animals was associated with an increased risk of asthma [aOR = 1.83 (1.07-3.15); p = .027] and allergic asthma [aOR = 2.37 (95%CI = 1.04-5.40); p = .04]. CONCLUSION: The present study showed that the prevalence of asthma and asthma phenotypes were similar between farm and non-farm rural children. There did not appear to be differential involvement in farming activities between those with and without asthma although those with asthma had more training suggesting possible attempts to mitigate harm from farm exposures.

Effects of celecoxib on major prostaglandins in asthma.

BACKGROUND: Prostaglandin (PG) D(2) is a pro-inflammatory and bronchoconstrictive mediator released from mast cells, and is currently evaluated as a new target for treatment of asthma and rhinitis. It is not known which cyclooxygenase (COX) isoenzyme catalyses its biosynthesis in subjects with asthma. OBJECTIVES: Primarily, to assess whether treatment with the COX-2 selective inhibitor celecoxib inhibited biosynthesis of PGD(2) , monitored as urinary excretion of its major tetranor metabolite (PGDM). Secondarily, to determine the effects of the treatment on biosynthesis of PGE(2) , thromboxane A(2) and PGI(2) , also measured as major urinary metabolites. METHODS: Eighteen subjects with asthma participated in a cross-over study where celecoxib 200mg or placebo were given b.i.d. on 3 consecutive days following 2 untreated baseline days. Six healthy controls received active treatment with the same protocol. Urinary excretion of the eicosanoid metabolites was determined by liquid chromatography/tandem mass spectrometry (LC/MS/MS). Lung function was followed as FEV(1) and airway inflammation as fraction of exhaled nitric oxide (F(E) NO). RESULTS: Celecoxib treatment inhibited urinary excretion of PGEM by 50% or more in subjects with asthma and healthy controls, whereas there was no significant change in the excretion of PGDM. In comparison with the healthy controls, the subjects with asthma had higher baseline levels of urinary PGDM but not of PGEM. The 3-day treatment did not cause significant changes in FEV(1) or F(E) NO. CONCLUSION AND CLINICAL RELEVANCE: Biosynthesis of PGD(2) was increased in subjects with asthma and its formation is catalysed predominantly by COX-1. By contrast, COX-2 contributes substantially to the biosynthesis of PGE(2) . The asymmetric impact of celecoxib on prostanoid formation raises the possibility of long-term adverse consequences of COX-2 inhibition on airway homeostasis by the decreased formation of bronchodilator PGs and maintained production of increased levels of bronchoconstrictor PGs in asthmatics.

Medical treatment after peripheral bypass surgery over the past decade.

OBJECTIVE: The Dutch Bypass and Oral anticoagulants or Aspirin (BOA) Study demonstrated that in patients with peripheral arterial disease after bypass surgery oral anticoagulants were more effective in preventing venous graft occlusions than aspirin, while aspirin was more effective in non-venous grafts. We evaluated if this finding was implemented in the clinical practice of former BOA participants by reconstructing a 10-year overview of their applied various drug treatments including anti-hypertensive and lipid-lowering drugs. METHODS: In 482 patients from six centers that contributed most patients anti-thrombotic, anti-hypertensive, and lipid-lowering drug use was recorded at baseline (n = 478), retrospectively up to two years after BOA (n = 388), and prospectively for patients still alive between 2005 and 2009 (n = 209). RESULTS: At baseline, 54% of patients received anti-thrombotics which increased to 96% at follow-up. At baseline 15% of patients were treated with lipid-lowering drugs and 49% with anti-hypertensives. This increased over time to 65% and 76%, respectively. CONCLUSION: After the BOA Study its recommendations were applied marginally. Despite improvements over time, current lipid-lowering and anti-hypertensive drug use remained suboptimal. Our trend analyses, however, should be interpreted with caution, because drug use and compliance in survivors might be better than average.

Randomised controlled trial comparing sapheno-femoral ligation and stripping of the great saphenous vein with endovenous laser ablation (980 nm) using local tumescent anaesthesia: one year results.

OBJECTIVES: Comparison of sapheno-femoral ligation and stripping (SFL/S) versus endovenous laser ablation (EVLA, 980-nm) in the treatment of great saphenous vein (GSV) insufficiency, using local tumescent anaesthesia. DESIGN: Randomised, single centre trial. MATERIALS AND METHODS: Patients with GSV incompetence and varicose veins were randomised to either SFL/S or EVLA. At days 1, 2, 3, 7, 10, and 14 post-treatment, patients completed questionnaires on pain and quality of life. Recurrent varicose veins were evaluated by Duplex ultrasound (DUS) performed at 1 and 6 weeks, and 6 and 12 months. RESULTS: 130 legs in 121 patients were treated by SFL/S (n=68) or EVLA (n=62). Significantly more post-treatment pain was noted after EVLA at days 7, 10 and 14 (p<0.01; p<0.01; p=0.01), more hindrance in mobility at days 7 (p<0.01) and 10 (p=0.01), and in self care (p=0.03) and daily activities (p=0.01) at day 7 compared to SFL/S. DUS at 1-year follow-up showed 9% recurrences (5/56) after EVLA and 10% (5/49) after SFL/S. CONCLUSION: Both SFL/S and EVLA, using local tumescent anaesthesia, were well tolerated, with no difference in short-term recurrence rate. In the second week after EVLA, patients experienced significantly more pain resulting in restricted mobility, self care and daily activity compared to SFL/S.

What children say and clinicians hear: accounts relating to incisor hypomineralisation of cosmetic concern.

AIM: To explore the range of impacts relating to incisor opacities as described by children, their general dental practitioners and paediatric dentists. METHODS: Participants included 50 children, aged 7-16 years, referred to a UK hospital paediatric dentistry service for management of incisor opacities. All children were subsequently diagnosed with molar incisor hypomineralisation. Following ethical approval, data were recorded as follows: patient demographics, distance travelled, waiting times, nature of any impacts relating to incisor opacities documented in referral letters and/or in subsequent paediatric dentistry assessment records. Additionally, children completed the short form Child Oral Health Impact Profile questionnaire (COHIP-SF19) as a self-report measure of their oral health-related quality of life (OHRQoL). RESULTS: Nearly, half (48%, n = 24) of the referral letters mentioned that the child was experiencing one or more negative social and/or functional impacts. Mean COHIP score was significantly lower (indicating poorer OHRQoL) for children whose referring dentist had identified a negative impact (COHIP = 42.9) compared to those with no documented impact (COHIP = 50.5; p = 0.018, independent t test). At the hospital consultation, negative impacts were elicited by a paediatric dentist in 86% (n = 43) of cases. Again, mean COHIP score was significantly lower for children whose assessment records noted a negative impact (COHIP = 44.5) compared to those with no recorded impact (COHIP = 60.2; p = 0.001). Families travelled a mean distance of 57 km (range 3-218 km) to the hospital service, with an average waiting time of 75 days from referral. CONCLUSION: It is encouraging that dental professionals seem to be aware of the negative psychosocial impacts experienced by some children with enamel opacities, and that children feel able to describe them.

Assessment of endotoxin levels in the home and current asthma and wheeze in school-age children.

UNLABELLED: The relationship between household endotoxin and asthma in children is not clear. To further investigate the relationship between sources of endotoxin and childhood asthma, we conducted a case-control study of children with and without asthma and examined their more frequent household exposures in the home. Children ages 6-13 years with current asthma (n = 70) or wheeze only (n = 19) were sex and age matched (+/-1 year) to 107 controls. Play area and mattress dust were collected for endotoxin analysis. Atopic status was determined by skin prick testing for allergies. A family size of >4 per household was associated with higher endotoxin levels (EU/mg) in the bed dust (P < 0.05). Passive smoking (P < 0.05) and the presence of a cat were associated with higher levels of endotoxin in mattress dust. Endotoxin levels in either the play dust or the bed dust did not differ between cases and controls. Within atopic cases, those with higher endotoxin loads (EU/m2) in bed or play areas were more likely to miss school for chest illness (P < 0.05). In this study, household endotoxin is not a risk factor for current asthma overall but may be associated with increased severity in children with atopic asthma. PRACTICAL IMPLICATIONS: This study did not find that household sources of endotoxin were associated with asthma. However, within atopic asthmatics, asthma severity (as measured by a history of being kept home from school because of a chest illness in the past year) was associated with higher levels of endotoxin in dust from the child's bed. There is a need to further investigate the nature of the relationship between household endotoxin and asthma severity in children which could lead to better management of childhood asthma.

Transcellular activation of platelets and endothelial cells by bioactive lipids in platelet microparticles.

Microparticles are released during platelet activation in vitro and have been detected in vivo in syndromes of platelet activation. They have been reported to express both pro- and anticoagulant activities. Nevertheless, their functional significance has remained unresolved. To address the mechanism(s) of cellular activation by platelet microparticles, we examined their effects on platelets and endothelial cells. Activation of human platelets by diverse stimuli (thrombin, 0.1 U/ml; collagen, 4 microg/ml; and the calcium ionophore A23187, 1 microM) results in shedding of microparticles. Pretreatment of these particles, but not membrane fractions from resting platelets, with (s)PLA2 evokes a dose-dependent increase in platelet aggregation, intracellular [Ca2+] movement, and inositol phosphate formation. These effects localize to the arachidonic acid fraction of the microparticles and are mimicked by arachidonic acid isolated from them. However, platelet activation requires prior metabolism of microparticle arachidonic acid to thromboxane A2. Thus, pretreatment of platelets with the cyclooxygenase (COX) inhibitor, indomethacin (20 microM), the thromboxane antagonist SQ29,548 (1 microM), or the protein kinase C inhibitor GF109203X (5 microM) prevents platelet activation by microparticles. However, platelet microparticles fail to evoke an inositol phosphate response directly, via either of the cloned thromboxane receptor isoforms stably expressed in human embryonic kidney (HEK) 293 cells. Prelabeling platelets with [2H(8)] arachidonate was used to demonstrate platelet metabolism of the microparticle-derived substrate to thromboxane. Platelet microparticles can also induce expression of COX-2 and prostacyclin (PGI2) production, but not expression of COX-1, in human endothelial cells. These effects are prevented by pretreatment with actinomycin D (12 microM) or cycloheximide (5 microg/ml). Expression of COX-2 is again induced by the microparticle arachidonate fraction, which it may then use to synthesize PGI2. Both PGE2 and iloprost, a stable PGI2 analog, evoke human umbilical vein endothelial cell COX-2 expression, albeit with kinetics that differ from the response to platelet microparticles. These studies indicate a novel mechanism of transcellular lipid metabolism whereby platelet activation may be amplified or modulated by concentrated delivery of arachidonic acid to adjacent platelets and endothelial cells.

Effect of regulated expression of human cyclooxygenase isoforms on eicosanoid and isoeicosanoid production in inflammation.

To examine the role of cyclooxygenase (COX) isozymes in prostaglandin formation and oxidant stress in inflammation, we administered to volunteer subjects placebo or bolus injections of lipopolysaccharide (LPS), which caused a dose-dependent increase in temperature, heart rate, and plasma cortisol. LPS caused also dose-dependent elevations in urinary excretion of 2,3-dinor 6-keto PGF(1alpha) (PGI-M) and 11-dehydro thromboxane B(2) (Tx-M). Platelet COX-1 inhibition by chronic administration of low-dose aspirin before LPS did not alter the symptomatic and febrile responses to LPS, but the increment in urinary PGI-M and Tx-M were both partially depressed. Pretreatment with ibuprofen, a nonspecific COX inhibitor, attenuated the febrile and systemic response to LPS and inhibited prostanoid biosynthesis. Both celecoxib, a selective COX-2 inhibitor, and ibuprofen attenuated the pyrexial, but not the chronotropic, response to LPS. Experimental endotoxemia caused differential expression of the COX isozymes in monocytes and polymorphonuclear leucocytes ex vivo. LPS also increased urinary iPF(2alpha)-III, iPF(2alpha)-VI, and 8,12-iso-iPF(2alpha)-VI, isoprostane (iP) indices of lipid peroxidation, and none of the drugs blunted this response. These studies indicate that (a) although COX-2 predominates, both COX isozymes are induced and contribute to the prostaglandin response to LPS in humans; (b) COX activation contributes undetectably to lipid peroxidation induced by LPS; and (c) COX-2, but not COX-1, contributes to the constitutional response to LPS in humans.

Alcohol-induced generation of lipid peroxidation products in humans.

To address the hypothesis that elevated blood alcohol increases systemic oxidant stress, we measured urinary excretion of isoprostanes (iPs), free radical-catalyzed products of arachidonic acid. Ten healthy volunteers received acute doses of alcohol (Everclear-R) or placebo under randomized, controlled, double-blind conditions. Urinary iPF2a-III increased in a time- and dosage-dependent manner after dosing with alcohol, with the peak urinary iPF2a-III excretion correlating with the rise in blood alcohol. To determine whether oxidant stress was associated with alcohol-induced liver disease (ALD), we then studied the excretion of iP in individuals with a documented history of alcohol-induced hepatitis or alcohol-induced chronic liver disease (AC). Both urinary iPF2a-III and urinary iPF2a-VI were markedly increased in patients with acute alcoholic hepatitis. In general, urinary iPF2a-III was significantly elevated in cirrhotic patients, relative to controls, but excretion was more pronounced when cirrhosis was induced by alcohol than by hepatitis C. Excretion of iPF2a-VI, as well as 4-hydroxynonenal and the iPF2a-III metabolite, 2,3-dinor-5, 6-dihydro-iPF2a-III, was also increased in AC. Vitamin C, but not aspirin, reduced urinary iPs in AC. Thus, vasoactive iPs, which serve as indices of oxidant stress, are elevated in the urine in both acute and chronic ALD. Increased generation of iPs by alcohol in healthy volunteers is consistent with the hypothesis that oxidant stress precedes and contributes to the evolution of ALD.

Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man.

To assess the pharmacologic effects of aspirin on endogenous prostacyclin and thromboxane biosynthesis, 2,3-dinor-6-keto PGF1 alpha (PGI-M) and 2,3-dinor-thromboxane B2 (Tx-M) were measured in urine by mass spectrometry during continuing administration of aspirin. To define the relationship of aspirin intake to endogenous prostacyclin biosynthesis, sequential urines were initially collected in individuals prior to, during, and subsequent to administration of aspirin. Despite inter- and intra-individual variations, PGI-M excretion was significantly reduced by aspirin. However, full mass spectral identification confirmed continuing prostacyclin biosynthesis during aspirin therapy. Recovery of prostacyclin biosynthesis was incomplete 5 d after drug administration was discontinued. To relate aspirin intake to indices of thromboxane biosynthesis and platelet function, volunteers received 20 mg aspirin daily followed by 2,600 mg aspirin daily, each dose for 7 d in sequential weeks. Increasing aspirin dosage inhibited Tx-M excretion from 70 to 98% of pretreatment control values; platelet TxB2 formation from 4.9 to 0.5% and further inhibited platelet function. An extended study was performed to relate aspirin intake to both thromboxane and prostacyclin generation over a wide range of doses. Aspirin, in the range of 20 to 325 mg/d, resulted in a dose-dependent decline in both Tx-M and PGI-M excretion. At doses of 325-2,600 mg/d Tx-M excretion ranged from 5 to 3% of control values while PGI-M remained at 37-23% of control. 3 d after the last dose of aspirin (2,600 mg/d) mean Tx-M excretion had returned to 85% of control, whereas mean PGI-M remained at 40% of predosing values. Although the platelet aggregation response (Tmax) to ADP ex vivo was inhibited during administration of the lower doses of aspirin the aggregation response returned to control values during the final two weeks of aspirin administration (1,300 and 2,600 mg aspirin/d) despite continued inhibition of thromboxane biosynthesis. These results suggest that although chronic administration of aspirin results in inhibition of endogenous thromboxane and prostacyclin biosynthesis over a wide dose range, inhibition of thromboxane biosynthesis is more selective at 20 than at 2,600 mg aspirin/d. However, despite this, inhibition of platelet function is not maximal at the lower aspirin dosage. Doses of aspirin in excess of 80 mg/d resulted in substantial inhibition of endogenous prostacyclin biosynthesis. Thus, it is unlikely that any dose of aspirin can maximally inhibit thromboxane generation without also reducing endogenous prostacyclin biosynthesis. These results also indicate that recovery of endogenous prostacyclin biosynthesis is delayed following aspirin administration and that the usual effects of aspirin on platelet function ex vivo may be obscured during chronic aspirin administration in man.

Localization of distinct F2-isoprostanes in human atherosclerotic lesions.

F2-Isoprostanes are prostaglandin (PG) isomers formed in situ in cell membranes by peroxidation of arachidonic acid. 8-epi PGF2alpha and IPF2alpha-I are F2-isoprostanes produced in humans which circulate in plasma and are excreted in urine. Measurement of F2-isoprostanes may offer a sensitive, specific, and noninvasive method for measuring oxidant stress in clinical settings where reactive oxygen species are putatively involved. We determined whether isoprostanes were present in human atherosclerotic lesions, where lipid peroxidation is thought to occur in vivo. 8-epi PGF2alpha ranged from 1.310-3.450 pmol/micromol phospholipid in atherectomy specimens compared with 0.045-0.115 pmol/micromol phospholipid (P < 0.001) in vascular tissue devoid of atherosclerosis. Corresponding values of IPF2alpha-I were 5.6-13.8 vs. 0.16-0.44 pmol/micromol phospholipid (P < 0.001). Levels of the two isoprostanes in vascular tissue were highly correlated (r = 0.80, P < 0.0001). Immunohistochemical studies confirmed that foam cells adjacent to the lipid necrotic core of the plaque were markedly positive for 8-epi PGF2alpha. These cells were also reactive with anti-CD68, an epitope specific for human monocyte/macrophages. 8-epi PGF2alpha immunoreactivity was also detected in cells positive for anti-alpha-smooth muscle actin antibody, which specifically recognizes vascular smooth muscle cells. Our results indicate that 8-epi PGF2alpha and IPF2alpha-I, two distinct F2-isoprostanes and markers of oxidative stress in vivo, are present in human atherosclerotic plaque. Quantitation of these chemically stable products of lipid peroxidation in target tissues, as well as in biological fluids, may aid in the rational development of antioxidant drugs in humans.

[Guideline on 'The treatment of recurrent varicose veins'Supplement to the Dutch Guideline on Venous disease]. / Richtlijn 'Behandeling bij neo-varices'.

The Dutch Guideline on Venous disease was lacking a section on recurrent varicose veins. The newly issued supplement on recurrent varicose veins fills this gap and provides clinicians with solutions concerning the management of patients with recurrent varicose veins following earlier treatment. Because venous disease is nowadays considered to be an ongoing disease, patients with this disorder will often require life-long care and different treatment than patients who have never been treated before.

Identification of lipoxygenase products from arachidonic acid metabolism in stimulated murine eosinophils.

The presence of arachidonic acid lipoxygenase pathways in murine eosinophils was demonstrated by the isolation and identification of several lipoxygenase products from incubations of these cells. The most abundant arachidonate metabolite from murine eosinophils stimulated with ionophore A23187 and exogenous arachidonic acid was 12-S-hydroxyeicosatetraenoic acid (12-S-HETE), and the next most abundant was 15-HETE. Two families of leukotrienes were also recovered from these incubations. One family comprised the hydrolysis products of leukotriene A4, and the other included products derived from the 14,15-oxido analog of leukotriene A4 (14,15-leukotriene A4). Two double oxygenation products of arachidonate were also identified. These compounds were a 5,15-dihydroxyeicosatetraenoic acid (5,15-diHETE) and a 5,12-dihydroxyeicosatetraenoic acid (5,12-diHETE). Eosinophil stimulation promoter is a murine lymphokine which enhances the migration of eosinophils. When murine eosinophils were incubated with eosinophil stimulation promoter in concentrations sufficient to produce a migration response, a 2-3-fold increase in the production of 12-HETE was observed compared to unstimulated cells. Coupled with the recent demonstration that arachidonic acid lipoxygenase inhibitors suppress the migration response to eosinophil stimulation promoter and that 12-HETE induces a migration response, this observation provides further evidence in support of the hypothesis that eosinophil stimulation promoter stimulation of eosinophils results in the generation of lipoxygenase products which modulate the migratory activity of the cells.

Biomarkers of oxidative stress study III. Effects of the nonsteroidal anti-inflammatory agents indomethacin and meclofenamic acid on measurements of oxidative products of lipids in CCl4 poisoning.

Plasma and urinary levels of malondialdehyde-like products (MDA) and isoprostanes were identified as markers of in vivo lipid peroxidation in an animal model of CCl4 poisoning. We sought to determine the extent to which the formation of these oxidation products is influenced by inhibition of the cyclooxygenase enzymes which catalytically generate proinflammatory lipid peroxidation products known as prostaglandins and thromboxane. In the present studies, after induction of oxidant stress in rats with CCl4, lipid peroxidation products measured in plasma and urine demonstrate that isoprostanes and MDA can be partially inhibited by cyclooxygenase inhibitors, albeit to different extents. The lowering of isoprostane and MDA formation, however, may not to due primarily to the diminution of catalytic generation of isoprostanes or MDA by the cyclooxygenases but, rather, may be the result of the suppression of nonenzymatic lipid peroxidation. This is suggested since 8,12-iso-iPF2alpha-VI is also reduced by indomethacin, yet, unlike other isoprostanes and MDA, it is not generated catalytically by the cyclooxygenase. Thus, although the two cyclooxygenase inhibitors we tested have statistically significant effects on the measurements of both isoprostanes and MDA in this study, the results provide evidence that these lipid-degradation products primarily constitute markers of oxidative stress.