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Effect of deoxynivalenol (vomitoxin) on fertility, pregnancy, and postnatal development of Sprague-Dawley rats.

A diet containing 20 ppm (micrograms/g) of purified deoxynivalenol (DON) was fed to male and female Sprague-Dawley rats for 60 and 15 days, respectively, before breeding. Rats consuming feed amended with DON throughout pregnancy and lactation showed no clinical signs of toxicity, nor did the control or pair-fed control groups. Male rats in the DON treatment group showed no feed refusal but were less efficient than males in control groups in converting feed into body mass. Feed refusal in female rats varied with stage of pregnancy. Before breeding, overall feed consumption was similar in all groups, but in the DON treatment group there was significant feed refusal for the first 2 days. Feed conversion efficiency was reduced in the DON treatment group. Pregnant and lactating rats fed DON-treated feed ate 6% less than did control rats fed solvent-treated feed. Although pair-fed control rats ate 14 to 21% less than rats in the DON treatment group, their body weights were greater than those of the DON group rats throughout most of the feeding trials, indicating that DON has a toxic effect. Only 50% of the matings between DON group rats resulted in pregnancy, compared with 80% in the control groups. There were no differences detected among groups in ratio of male to female pups, survival rate, or average litter number and weight. Pup weight gains in all groups were comparable through postnatal day 14.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

[Effects of specific microbial biocides on N transformation in soil with glucose amendment].

In an incubation test of soil with glucose amendment, two kinds of nitrogenous fertilizer and three kinds of specific microbial biocides were applied, and the contents of soil NH(4+)-N, NO3(-)-N, glucosamine and muramic acid were measured to differentiate the relative contribution and timing characteristics of soil microbes in nitrogen immobilization. The results showed that penicillin and streptomycin decreased the transformation rate of NH(4+)-N markedly, with more significant effects than actidione. The amount ratio of glucosamine to muramic acid after applying penicillin and streptomycin rapidly increased first, and tended to equilibrium then. With the application of actidione, the transformation rate of NO3(-)-N decreased continuously, and the synthesis of glucosamine was inhibited, while penicillin and streptomycin had no significant effects on them. At the early stage of incubation, bacteria could rapidly immobilize both NH(4+)-N and NO3(-)-N, with NH(4+)-N preferred, while at the later stage of incubation, fungi were the dominant contributor to nitrogen transformation, and had much stronger ability of utilizing NO3(-)-N than bacteria.

Anti-Bacterial Agents↗

Environmental tobacco smoke in Finnish restaurants and bars before and after smoking restrictions were introduced.

OBJECTIVES: The Finnish Tobacco Act was amended on 1 March 2000 to include restrictions on smoking in restaurants and bars. To evaluate the effectiveness of the restrictions, environmental tobacco smoke (ETS) concentrations in restaurants and bars were measured prior and after the amended Act entered into force. The Act was enforced in stages so that all stages were effective on 1 July 2003. According to the Act, smoking is prohibited in all Finnish restaurants and bars with certain exceptions. Smoking may be allowed in establishments where the service area is not larger than 50 m(2) if the exposure of employees working there to ETS can be prevented. On premises with larger service area, smoking may be allowed on 50% of the service area, provided tobacco smoke does not spread into the area where smoking is prohibited. At bar counters or gambling tables smoking is not allowed, if the spreading of tobacco smoke cannot be restricted to the employee side of the counter. Therefore, according to the Act all areas where smoking is prohibited are to be smoke-free. METHODS: Establishments with a serving area larger than 100 m(2) were selected for the present study. The evaluation both before and after the enforcement of the Act included the following: The ventilation rate was first measured in each establishment. Then 3-5 area samplers, depending on the layout, were placed in locations that best described the establishment and the working areas of the personnel. The measurements were performed twice at each establishment, during peak hours. The sample collection time was 4 h during which the guests and the cigarettes smoked were counted. The air samples were analysed for nicotine, 3-ethenylpyridine (3-EP) and total volatile organic compounds (TVOC) by thermodesorption-gas chromatography-mass spectrometry. RESULTS: Altogether 20 restaurants and bars situated in three Finnish cities participated in the study out of which 16 participated during all four measurement periods. None of the establishments had introduced a total ban on smoking and they all had reserved only the smallest area allowed by the Finnish Tobacco Act as the smoke-free area. The measured geometric mean (GM) nicotine concentration in all participating establishments was 7.1 microg m(-3) before the amended act was in force and 7.3 microg m(-3) after all stages of the Act had been enforced. The GM concentration of nicotine in food and dining restaurants was 0.7 microg m(-3) before and 0.6 microg m(-3) after the enforcement of the Act, in bars and taverns the concentrations were 10.6 and 12.7 microg m(-3), and in discos and night-clubs 15.2 and 8.1 microg m(-3), respectively. The GM nicotine concentrations measured in the smoke-free sections varied between 2.9 and 3 microg m(-3). 3-EP concentrations measured correlated well with the nicotine concentrations and were approximately one-fifth of the nicotine concentrations. The measurements showed higher TVOC values in the smoking sections than in the smoke-free sections, but because there are many other sources of TVOC compounds in restaurants and bars TVOC cannot be regarded as a marker for ETS. CONCLUSIONS: The overall air nicotine concentration decreased in 10 out of the 18 establishments that participated in the study both before and after all stages of the amended Act had been in force. Structural changes or changes to the ventilation systems had been carried out in nine of these establishments, i.e. the smoke-free sections were actually non-smoking and were mainly separated from other sections by signs and very little was done to keep the smoke from spreading into the smoke-free sections. In four establishments, the highest air nicotine concentration was measured in the smoke-free section. In 10 establishments, the air nicotine concentration at bar counters had dropped after the Act. Exposure of the workers and the public to ETS was, therefore, not reduced as intended by the Finnish legislature. Thus, it seems obvious from the present study that improving ventilation will not be a solution to restricting tobacco smoke from reaching smoke-free areas and physical barriers separating smoking from smoke-free areas are required.

Finland↗

Power toothbrushes: a critical review.

Although the first toothbrush is thought to have been used in about 1000 ad, tooth brushing in America did not gain popularity until after 1945. The introduction of the powered toothbrush in 1960 has led to a large number of studies comparing the safety and efficacy of powered toothbrushes to manual toothbrushes. There is a general agreement that powered toothbrushes are as safe as manual toothbrushes; however, studies show significantly differing conclusions regarding the efficacy of power toothbrushes for the removal of plaque. The recent amendment of the Cochrane report on this subject concluded that the only type of powered toothbrush that removes more plaque than a manual toothbrush is one with rotational oscillation movement. Their conclusion was based on the review of 29 published studies, conducted between 1964 and 2001, with a total of 2547 participants. All these studies used similar research design criteria. The Cochrane conclusion is in agreement with a 1996 study carried out in the Netherlands. Many of the conflicting study conclusions, to date, on powered toothbrushes, are the result of using differing study design criteria. While the dental profession desires evidence-based research, it is clear that dental schools will need to increase the level of attention in their curriculum to address disciplined techniques for research design in order to reconcile the large variances in reported research results.

Dental Plaque↗

Biotransformations of Aroclor 1242 in Hudson River test tube microcosms.

A microcosm system to physically model the fate of Aroclor 1242 in Hudson River sediment was developed. In the dark at 22 to 25 degrees C with no amendments (nutrients, organisms, or mixing) and with overlying water being the only source of oxygen, the microcosms developed visibly distinct aerobic and anaerobic compartments in 2 to 4 weeks. Extensive polychlorinated biphenyl (PCB) biodegradation was observed in 140 days. Autoclaved controls were unchanged throughout the experiments. In the surface sediments of these microcosms, the PCBs were biologically altered by both aerobic biodegrading and reductive dechlorinating microorganisms, decreasing the total concentration from 64.8 to 18.0 micromol/kg of sediment in 1140 days. This is the first laboratory demonstration of meta dechlorination plus aerobic biodegradation in stationary sediments. In contrast, the primary mechanism of microbiological attack on PCBs in aerobic subsurface sediments was reductive dechlorination. The concentration of PCBs remained constant at 64.8 micromol/kg of sediment, but the average number of chlorines per biphenyl decreased from 3.11 to 1.84 in 140 days. The selectivities of microorganisms in these sediments were characterized by meta and para dechlorination. Our results provide persuasive evidence that naturally occurring microorganisms in the Hudson River have the potential to attack the PCBs from Aroclor 1242 releases both aerobically and anaerobically at rapid rates. These unamended microcosms represent a unique method for determining the fate of released PCBs in river sediments.

Aerobiosis↗

[Atresia of the left coronary ostium. Repair in a 2-month-old infant].

A case of atresia of the left coronary ostium revealed by neonatal heart failure is reported. The initial diagnosis was anomalous origin of the left coronary artery from the pulmonary artery. At surgery performed in this 6-week old infant the diagnosis was amended and the malformation was repaired. Soon after the operation the child rapidly developed hypertrophic "myocardiopathy" of the left ventricle. Seven and a half months later, he is asymptomatic and the echocardiographic parameters of left ventricular systolic function are gradually returning to normality. Atresia of the left coronary ostium is an exceptional anomaly which must be considered, together with the other anomalous origins of the left coronary artery, when confronted with a case of severe heart failure caused by coronary ischaemia during the first months of life. The diagnosis rests on opacification of the coronary network during cardiac catheterization. Coronary "revascularization" may be performed either by aortocoronary bypass or by anatomical repair of the malformation.

Angiocardiography↗

[Predictive factors for therapeutic success in depressive syndrome].

In this retrospektive investigation on 659 depressive outpatients, predictors of antidepressant drug response were evaluated. In accordance with the literature, neither demographic variables nor duration of the current episode, severity of depressive symptoms or scores of rating scales showed any clinically relevant relation to outcome. The prognostic value of recovery within the first 2 weeks seems to be the only reliable predictor. In all, 75% of patients without a significant reduction (less than 20%) of the score in the Hamilton Psychiatric Rating Scale for Depression after 2 weeks of treatment will not fulfill response criteria after 6 weeks. For clinical practice these results imply the necessity of reviewing the applied drug regimen early, i.e. about 2 weeks after beginning, to check for compliance with treatment or an individual problem of resorption or metabolism in order to amend the regimen by increasing dosage and/or adding sleep deprivation, lithium, thyroxine or psychotherapy.

Adult↗

Improving REACH.

The European Commission has proposed a new system for chemicals control, the REACH system. The objectives of REACH with respect to risk assessment can be summarized in the form of two overarching goals. First, REACH aims at improved knowledge about the properties and the uses of individual chemical substances. Secondly, REACH is intended to increase the speed and efficiency of the risk assessment process and to make producers and importers of chemicals responsible for this process. The implementation of the REACH proposal will lead to increased availability of toxicological information but not to the extent that would be needed to achieve a sound scientific basis for risk assessment of individual substances. In this paper, we propose certain amendments of the current REACH proposal. The purpose of these proposals is to improve priority-setting and testing strategies and to simplify the risk assessment procedures.

Animals↗

Bacterial chromosomal painting for in situ monitoring of cultured marine bacteria.

We previously described a new method, bacterial chromosomal painting (BCP), for the in situ identification of bacterial cells. Here, we describe the application of this technique to study the ecology and physiology of cultured marine pelagic bacteria from the western Sargasso Sea (WSS). A total of 86 bacteria were isolated from seawater collected from near the surface, at a depth of 250 m and from nutrient-amended seawater incubations. The 10 bacterial isolates that were best represented in environmental genomic DNA from the WSS were selected using reverse genome probing. BCP hybridization cell counts were used to determine the depth-specific distribution of one of the alpha proteobacterial isolates, B5-6, in the WSS during two thermal stratification regimes: stratified and partially mixed. The maximum cell count measured for B5-6 at the summer deep chlorophyll maximum was approximately 4% of the total cell count. This study is the first application of BCP to natural environments.

Alphaproteobacteria↗

Phase I trial of the combination of irinotecan, paclitaxel, and carboplatin in patients with advanced non-small-cell lung cancer.

PURPOSE: To determine the maximum-tolerated dose, toxicities, and dose suitable for phase II/III trials of irinotecan (CPT-11) combined with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage IIIB/IV NSCLC were enrolled to this multicenter, phase I study. The initial regimen was paclitaxel 225 mg/m(2)/3 h, followed by carboplatin area under the curve (AUC) 6 over 30 minutes on day 1, and CPT-11 starting at 40 mg/m(2) over 90 minutes, days 1 and 8, every 3 weeks. Dose-limiting toxicity occurred in three of seven patients. The regimen was amended, with doses reduced to paclitaxel 175 mg/m(2)/3 h, carboplatin AUC 5 and CPT-11 at 40 mg/m(2), all on day 1 every 3 weeks. Dose escalation of CPT-11 proceeded to 80 mg/m(2) then 125 mg/m(2) before dose-limiting toxicities were experienced. Subsequent patients received an intermediate CPT-11 dose of 100 mg/m(2). RESULTS: Thirty-three patients were enrolled; 32 patients were assessable for safety, and 31 were assessable for tumor response. The primary first-cycle dose-limiting toxicities were neutropenia and diarrhea. The most common grade 3/4 toxicity observed during all cycles was neutropenia (16 patients [50%], with six [19%] developing neutropenic fever). Objective tumor response was observed in 39% (12/31, 95% confidence interval, 22% to 58%). The median time to tumor progression was 6.8 months, median survival 11.0 months, and 1-year survival probability 0.46. CONCLUSION: CPT-11 100 mg/m(2), paclitaxel 175 mg/m(2), and carboplatin AUC 5 given every 3 weeks can be safely administered in patients with advanced NSCLC. Neutropenia and diarrhea are the dose-limiting toxicities. The combination shows appreciable activity, and survival data are favorable.

Adult↗

An overview of European Union tobacco control legislation.

The European Union (EU) has been active in tobacco control policy since 1985 when the Milan Council announced its intention to establish a Europe Against Cancer (EAC) Programme, although it had previously adopted several Directives on aspects of tobacco taxation prior to this date. Shortly after the establishment of the EAC first action plan the European Commission presented its first legislative proposals on tobacco control. Three of these proposals on labelling and maximum tar yields became Directives by 1992. The fourth on tobacco advertising finally became law in 1998 and is currently being transposed into national law in the 15 EU Member States. In 1996 the Commission published a Communication on the future of EU tobacco control and in 1999 at the 2nd European Conference on Tobacco or Health the Social Affairs Commissioner announced his intention to bring forward further legislative proposals to amend an consolidate existing EU legislation in this sector. This article is intended to present an overview of EU tobacco control legislation from 1970 until 1998 and to look at future options post year 2000.

Advertising↗

Disability under social security; medical evaluation and decision as to rehabilitation.

Recent amendments to the Social Security Act give privileges to persons who are found to be disabled. In California, the State Bureau of Vocational Rehabilitation has responsibility for determining whether or not an applicant is disabled within the meaning of the Act. Each applicant must submit medical evidence provided by his own physician or by a hospital. The evidence is reviewed by both a physician and a counselor, who determine not only whether disability exists but also whether rehabilitation services might be helpful. In the first 9,000 cases in which determinations were made, 49 per cent of applicants were found to be disabled and 51 per cent not; but in recent months the proportion found disabled has increased. Diseases of the circulatory system and nervous system, including late effects of cerebrovascular accidents, were the largest groups of conditions causing disability. Psychoneurotic conditions and orthopedic and respiratory disorders were next in order. Some 10 to 15 per cent of applicants were referred for rehabilitation services, but of these only about one in six is accepted for rehabilitation, and only half of those accepted actually receive the services. Thus, it appears that only one per cent of workers applying for disability benefits are getting the services made available through state and federal sources to restore them to productive employment. Physicians need to be alert to opportunities provided in programs such as these to utilize all facilities to round out the full cycle of medical care.

California↗

Transduction of Escherichia coli by bacteriophage P1 in soil.

Transduction of Escherichia coli W3110(R702) and J53(RP4) (10(4) to 10(5) CFU/g of soil) by lysates of temperature-sensitive specialized transducing derivatives of bacteriophage P1 (10(4) to 10(5) PFU/g of soil) (P1 Cm cts, containing the resistance gene for chloramphenicol, or P1 Cm cts::Tn501, containing the resistance genes for chloramphenicol and mercury [Hg]) occurred in soil amended with montmorillonite or kaolinite and adjusted to a -33-kPa water tension. In nonsterile soil, survival of introduced E. coli and the numbers of E. coli transductants resistant to chloramphenicol or Hg were independent of the clay amendment. The numbers of added E. coli increased more when bacteria were added in Luria broth amended with Ca and Mg (LCB) than when they were added in saline, and E. coli transductants were approximately 1 order of magnitude higher in LCB; however, the same proportion of E. coli was transduced with both types of inoculum. In sterile soil, total and transduced E. coli and P1 increased by 3 to 4 logs, which was followed by a plateau when they were inoculated in LCB and a gradual decrease when they were inoculated in saline. Transduction appeared to occur primarily in the first few days after addition of P1 to soil. The transfer of Hg or chloramphenicol resistance from lysogenic to nonlysogenic E. coli by phage P1 occurred in both sterile and nonsterile soils. On the basis of heat-induced lysis and phenotype, as well as hybridization with a DNA probe in some studies, the transductants appeared to be the E. coli that was added. Transduction of indigenous soil bacteria was not unequivocally demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)

Bacteriophages↗

Nitrogen mineralisation potential in calcareous soils amended with sewage sludge.

Mineralisation of organic N is an important consideration when determining the annual amount of sewage sludge to be applied to agricultural soils. The mineralisation of sludge organic N was studied in two different textured soils (clayey and sandy soil) treated with aerobic and anaerobic sludge at two different rates (30 and 50 g sludge kg(-1) soil). The mineralisation of sludge organic N was determined during 20 weeks incubation period by analysis of inorganic N produced by a non-leached procedure. Sludge organic N mineralisation was influenced by soil type, organic N mineralisation being greater in the sandy soil (from 30% to 41%) than in the clayey soil (from 13% to 24%). Mineralisation rates decreased rapidly the first two weeks, followed by a slower decrease with time. Although total mineralisation increased with sludge addition rate, net mineralisation decreased with sludge addition rate, probably due to denitrificaton losses. The aerobically treated sludge gave higher mineralisation rates than the anaerobically treated one. The values of N0 and k for treated soils varied depending on the type of sludge and soil.

Aerobiosis↗

Shifts in rhizoplane communities of aquatic plants after cadmium exposure.

In this study we present the comparative molecular analysis of bacterial communities of the aquatic plant Lemna minor from a contaminated site (RCP) and from a laboratory culture (EPA), as well as each of these with the addition of cadmium. Plants were identified as L. minor by analysis of the rpl16 chloroplast region. Comparative bacterial community studies were based on the analyses of 16S rRNA clone libraries, each containing about 100 clones from the root surfaces of plants. Bacterial communities were compared at three phylogenetic levels of resolution. At the level of bacterial divisions, differences in diversity index scores between treatments, with and without cadmium within the same plant type (EPA or RCP), were small, indicating that cadmium had little effect. When we compared genera within the most dominant group, the beta-proteobacteria, differences between unamended and cadmium-amended libraries were much larger. Bacterial diversity increased upon cadmium addition for both EPA and RCP libraries. Analyses of diversity at the phylotype level showed parallel shifts to more even communities upon cadmium addition; that is, percentage changes in diversity indices due to cadmium addition were the same for either plant type, indicating that contamination history might be independent of disturbance-induced diversity shifts. At finer phylogenetic levels of resolution, the effects of cadmium addition on bacterial communities were very noticeable. This study is a first step in understanding the role of aquatic plant-associated microbial communities in phytoremediation of heavy metals.

Araceae↗

The effects of fungicides on the phylloplane yeast populations of creeping bentgrass.

The effects of fungicides on population size and the development of fungicide resistance in the phylloplane yeast flora of bentgrass was investigated. In the spring of 2001, azoxystrobin, chlorothalonil, flutolanil, and propiconazole were applied separately over a 6-week period to creeping bentgrass (Agrostis palustris Huds.). Total and fungicide-resistant yeast populations were assessed by dilution plating onto either potato dextrose agar or potato dextrose agar amended with the test fungicides. Total yeast populations in the fungicide-treated plots were significantly lower than the check plots on three out of four sample dates. In the fall, azoxystrobin or propiconazole were applied twice to the bentgrass over 3 weeks. Significantly larger total yeast populations were observed compared with resistant or highly resistant populations for each treatment on every sample date. Total yeast populations were significantly higher in the check plots compared with either the propiconazole- or azoxystrobin-treated plots on the first three of five sample dates. A collection of yeasts (N = 114) with no prior exposure to fungicides were more sensitive to chlorothalonil, propiconazole, flutolanil, and iprodione than a second group (N = 115) isolated from fungicide-treated turfgrass. These results suggest that fungicide resistance among phylloplane yeasts is widespread and could be an important factor in the development of biological control agents for turfgrass diseases.

Drug Resistance, Microbial↗

Irinotecan (CPT-11) in triplet combinations in patients with advanced non small-cell lung cancer: a review and report of a phase I/II trial.

The objectives of this phase I/II trial were to determine the maximum tolerated dose, toxicities, and the dose suitable for phase II/III trials of irinotecan (CPT-11) combined with paclitaxel and carboplatin in patients with advanced non small-cell lung cancer (NSCLC). Seventy-three patients with stage IIIB/IV NSCLC were enrolled in this multicenter, phase I/II study. The initial regimen was paclitaxel 225 mg/m2 over 3 hours, followed by carboplatin at an area under the curve (AUC) of 6 over 30 minutes on day 1 and CPT-11 starting at 40 mg/m2 over 90 minutes on days 1 and 8, every 3 weeks. Dose-limiting toxicity occurred in three of the original seven patients. The regimen was amended with doses reduced to paclitaxel 175 mg/m2 over 3 hours, carboplatin AUC = 5, and CPT-11 at 40 mg/m2, all on day 1 every 3 weeks. Dose escalation of CPT-11 proceeded to 80 mg/m2 and 125 mg/m2 before dose-limiting toxicities were experienced. Subsequent patients received an intermediate CPT-11 dose of 100 mg/m2. Doses suitable for phase II study were determined to be paclitaxel 175 mg/m2 over 3 hours, carboplatin AUC = 5, and CPT-11 100 mg/m2. The pri-mary first-cycle dose-limiting toxicities were neutropenia and diarrhea. The most common grade 3/4 toxicity observed during all cycles was neutropenia. On the phase I portion of the study, objective tumor response was observed in 39% (12 of 31, 95% confidence interval: 22%-58%). The median time to tumor progression was 6.8 months, median survival was 11.0 months, and 1-year survival probability was 0.46. These data were confirmed in the phase II portion with a 30% objective response rate, median time to progression of 5.6 months, median survival of 12.5 months, and a 1-year survival probability of 0.50. In conclusion, CPT-11 100 mg/m2, paclitaxel 175 mg/m2, and carboplatin AUC = 5 given every 3 weeks can be safely administered in patients with advanced NSCLC. Neutropenia and diarrhea are the dose-limiting toxicities. The combination shows appreciable activity, and survival data are favorable, warranting further study of this regimen. A review of other irinotecan-containing triplet combinations is presented.

Journal Article↗

An expert view on the treatment of acne with systemic antibiotics and/or oral isotretinoin in the light of the new European recommendations.

In 2003 the European Agency for the Evaluation of Medicinal Products amended the summary product characteristics for oral isotretinoin to standardise information provided from the different countries of the European Community. The Committee for Proprietary Medicinal Products recommended that among others, exclusively severe forms of acne (such as nodular or conglobate acne or acne at risk of permanent scarring) resistant to "adequate courses" of standard therapy with systemic antibacterials and local therapy should benefit from oral isotretinoin. However, no indication was provided on what were considered adequate courses or the possibility given to use oral isotretinoin as first line treatment. The aims of the present report were: 1) to provide a specialist view on when it is appropriate to introduce oral isotretinoin as a second line therapy for acne, taking into consideration optimum dosage and duration of systemic antibiotics prior to the start of the oral isotretinoin, and 2) to support the use of oral isotretinoin as first line therapy in specific cases for acne in clinical practice. The recommendations are based on an exhaustive literature review as well as on the personal experience of the members of an European panel of acne specialists. The EEP agreed with the decision made by the CPMP that oral isotretinoin should be administered as 2nd line therapy in those cases of severe acne, which were resistant to or which did not respond successfully to an initial combination regimen with systemic antibiotics and topical treatments (topical retinoids +/- benzoyl peroxide). However, the members emphasized that a number of prognostic factors, as well as psychosocial morbidity should be taken into account when choosing the regimen and that these factors may influence the use of oral isotretinoin as first line therapy.

Acne Vulgaris↗