The Effect of Lipofilling and Platelet-Rich Plasma on Patients with Moderate-Severe Vulvar Lichen Sclerosus who were Non-Responders to Topical Clobetasol Propionate: A Randomized Pilot Study.

BACKGROUND: The first-line treatment for vulvar lichen sclerosus (VLS) is 3 months of topical corticosteroid therapy. However, limited evidence is available concerning the use of fat grafting and platelet-rich plasma as a second-line treatment for patients who do not respond to first-line treatment. METHODS: This prospective single-center randomized pilot trial included 20 patients with a clinical and histological diagnosis of moderate to severe VLS. The patients in the treatment group (TG) received two infiltrations (at 3-month intervals) of nanofat mixed with platelet-rich plasma (PRP) into the vulvar area, while the control group (CG) received standard topical corticosteroid therapy. Fat was aspirated from the medial thigh or lower abdomen regions. Microfat was obtained after centrifugation and was emulsified to obtain a nanofat suspension. Treatment efficacy was determined by measuring changes in the vulvar skin elasticity, histopathology, and clinical signs, symptoms, and patient quality of life at after 1 year. RESULTS: A total of 19 patients were finally assessed (9 TG and 10 CG). At the end of the study (1 year), there had been no significant improvement in vulvar skin elasticity. However, patients in the TG showed a significant improvement in their symptoms (itching, pain, burning, and dyspareunia) and clinical signs (cervical erosions, fissures, stenosis, and leukoderma). Analysis of skin biopsies revealed a significant decrease in all inflammatory cell types in the TG. No adverse events related to the autologous treatment were recorded. CONCLUSIONS: Compared with topical corticosteroids, two infiltrations delivered 3 months apart decreased the inflammation of the vulva and improved most of the clinical signs and symptoms associated with VLS. Nonetheless, no improvement in vulvar skin elasticity was derived from the autologous treatment. LEVEL OF EVIDENCE I: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Haemophilic arthropathy: basic protocols for clinical examination and imaging.

In haemophilia, screening protocols in the prevention and treatment of common lesions still require unification of criteria. Patients with haemophilia seek medical consultation exclusively for two reasons: because they have requested an appointment for a routine check-up (1-2 times a year in case of severe haemophilia) or because they have developed acute bleeding that requires treatment. The purpose of this paper is to emphasize the importance of an early differential diagnosis of joint damage and to review the techniques that allow an effective evaluation. The World Federation of Haemophilia recommends the 'Primary Prophylaxis' treatment modality, and today, severe haemophilia patients adhering to that factor VIII/IX therapy have significantly reduced common injuries: haematomas, haemarthrosis, synovitis, and haemophilic arthropathy. The basic protocols and minimum data for the control of musculoskeletal health are described. In summary, the primary goal of the haematologist-led multidisciplinary care team treating patients with haemophilia is likely to restore and/or preserve joint and musculoskeletal health, which is essential to promoting quality of life. Appropriate factor replacement regimens are required to prevent bleeding, these should be combined with physical activity and a physiotherapy program, in accordance with the recommendations of the World Health Organization for the general population.

Respiratory health and endotoxin: associations and modification by CD14/-260 genotype.

Exposure to endotoxin has been associated with increased respiratory symptoms and decrements in lung function in occupational settings but little is known about the health effects of domestic exposure in adults. Here, we describe the association of respiratory disease, immunoglobulin (Ig)E sensitisation, bronchial reactivity and lung function with mattress endotoxin levels in adults, and determine whether these associations are modified by polymorphisms in CD14. Endotoxin levels in mattress dust from a population-based sample of 972 adults were measured. Associations were examined using generalised linear mixed models, adjusting for individual and household confounders. Effect modification of these associations by CD14/-260 (rs2569190) was assessed. Mattress endotoxin levels varied from 0.1 to 402.6 EU · mg(-1). Although there was no overall association of lung function with endotoxin exposure, there was evidence that the association of forced expiratory volume in 1 s and forced vital capacity with endotoxin was modified by CD14/-260 genotype (p-value for interaction 0.005 and 0.013, respectively). There was no evidence that symptoms, IgE sensitisation or bronchial reactivity were associated with mattress endotoxin levels. In this large epidemiological study of adults, there was no evidence that mattress endotoxin level was associated with respiratory symptoms or IgE sensitisation but the association of lung function with endotoxin levels may be modified by CD14 genotype.

Inner southern magnetosphere observation of Mercury via SERENA ion sensors in BepiColombo mission.

Mercury's southern inner magnetosphere is an unexplored region as it was not observed by earlier space missions. In October 2021, BepiColombo mission has passed through this region during its first Mercury flyby. Here, we describe the observations of SERENA ion sensors nearby and inside Mercury's magnetosphere. An intermittent high-energy signal, possibly due to an interplanetary magnetic flux rope, has been observed downstream Mercury, together with low energy solar wind. Low energy ions, possibly due to satellite outgassing, were detected outside the magnetosphere. The dayside magnetopause and bow-shock crossing were much closer to the planet than expected, signature of a highly eroded magnetosphere. Different ion populations have been observed inside the magnetosphere, like low latitude boundary layer at magnetopause inbound and partial ring current at dawn close to the planet. These observations are important for understanding the weak magnetosphere behavior so close to the Sun, revealing details never reached before.

ADRB2 Gly16Arg polymorphism, asthma control and lung function decline.

Arg/Arg homozygotes for the Gly16Arg polymorphism in the ß2-adrenoreceptor gene (ADRB2) have a reduced response to short-acting ß2-agonists but no effect has been associated with long-acting ß2-agonists (LABAs). We selected 604 subjects with current asthma from the European Community Respiratory Health Study to evaluate whether asthma control and lung function decline were associated with Gly16Arg polymorphism, and to test whether LABA or inhaled corticosteroid (ICS) use modified these effects. There was an increased risk of noncontrolled asthma (OR 1.33, 95% CI 1.01-1.75; p = 0.046) for each Arg allele. Among nonusers of ICS, the odds ratio of noncontrolled asthma among Arg/Arg versus Gly/Gly subjects was 2.73 (95% CI 1.28-5.82; p = 0.009). No increased risk of noncontrolled asthma associated with the Arg allele was observed among ICS and/or LABA users. For each Arg allele, a mean ± se decrease in decline in forced expiratory volume in 1 s of 7.7 ± 2.5 mL·yr⁻¹ was found (p-value for trend 0.003), irrespective of ICS or LABA use. Arg/Arg subjects had an increased risk of bronchial hyperresponsiveness (BHR) versus Gly/Gly subjects, with an odds ratio of 2.51 (95% CI 1.12-5.63; p = 0.025) if they did not use ICS. The Arg allele was associated with poorer asthma control, a steeper lung function decline and BHR. Absence of genotypic effects on asthma control among ICS users may be due to reversed ß2-adrenoreceptor desensitisation.

SERENA: Particle Instrument Suite for Determining the Sun-Mercury Interaction from BepiColombo.

The ESA-JAXA BepiColombo mission to Mercury will provide simultaneous measurements from two spacecraft, offering an unprecedented opportunity to investigate magnetospheric and exospheric particle dynamics at Mercury as well as their interactions with solar wind, solar radiation, and interplanetary dust. The particle instrument suite SERENA (Search for Exospheric Refilling and Emitted Natural Abundances) is flying in space on-board the BepiColombo Mercury Planetary Orbiter (MPO) and is the only instrument for ion and neutral particle detection aboard the MPO. It comprises four independent sensors: ELENA for neutral particle flow detection, Strofio for neutral gas detection, PICAM for planetary ions observations, and MIPA, mostly for solar wind ion measurements. SERENA is managed by a System Control Unit located inside the ELENA box. In the present paper the scientific goals of this suite are described, and then the four units are detailed, as well as their major features and calibration results. Finally, the SERENA operational activities are shown during the orbital path around Mercury, with also some reference to the activities planned during the long cruise phase.

Positionally cloned genes and age-specific effects in asthma and atopy: an international population-based cohort study (ECRHS).

BACKGROUND: Several genes identified by positional cloning have been associated with asthma and atopy, but few findings have been replicated. Age at onset of asthma has been associated with different phenotypic characteristics, and with variants at chromosome 17q21 identified through genome-wide association. This study examined the associations and age-specific effects on asthma, atopy and bronchial hyper-responsiveness (BHR) of five candidate genes previously identified by positional cloning (ADAM33, PHF11, NPSR1, DPP10, SPINK5). METHODS: 51 polymorphisms from 2474 participants from 13 countries who took part in the European Community Respiratory Health Survey (1990-2000) were studied. Asthma and age at onset of asthma were assessed by questionnaire data, BHR by methacholine challenge and atopy by specific immunoglobulin E to four common allergens. RESULTS: Significant associations with asthma, atopy and particularly for asthma with atopy were observed for a large region of 47 kb in the NPSR1 gene, even after Bonferroni correction for multiple comparisons (p<0.001). The associations with NPSR1 were stronger in those reporting a first attack of asthma before the age of 15, with statistically significant interactions with age of onset found for three SNPs. The evidence for ADAM33 and BHR and for an age-specific effect of two SNPs in DPP10 and asthma was weaker. CONCLUSION: This study provides further evidence for an effect of NPSR1 on asthma, atopy and atopic asthma. In addition, this analysis suggests a role for NPSR1 in early-onset asthma driven by the strong effect of this gene on atopic asthma.

Joint effect of obesity and TNFA variability on asthma: two international cohort studies.

Obesity is a risk factor for asthma. Adipose tissue expresses pro-inflammatory molecules including tumour necrosis factor (TNF), and levels of TNF are also related to polymorphisms in the TNF-alpha (TNFA) gene. The current authors examined the joint effect of obesity and TNFA variability on asthma in adults by combining two population-based studies. The European Community Respiratory Health Survey and the Swiss Cohort Study on Air Pollution and Lung and Heart Disease in Adults used comparable protocols, questionnaires and measures of lung function and atopy. DNA samples from 9,167 participants were genotyped for TNFA -308 and lymphotoxin-alpha (LTA) +252 gene variants. Obesity and TNFA were associated with asthma when mutually adjusting for their independent effects (odds ratio (OR) for obesity 2.4, 95% confidence interval (CI) 1.7-3.2; OR for TNFA -308 polymorphism 1.3, 95% CI 1.1-1.6). The association of obesity with asthma was stronger for subjects carrying the G/A and A/A TNFA -308 genotypes compared with the more common G/G genotype, particularly among nonatopics (OR for G/A and A/A genotypes 6.1, 95% CI 2.5-14.4; OR for G/G genotype 1.7, 95% CI 0.8-3.3). The present findings provide, for the first time, evidence for a complex pattern of interaction between obesity, a pro-inflammatory genetic factor and asthma.

Air pollution, oxidative stress and dietary supplementation: a review.

The aim of the present review was to provide an up-to-date overview of the biological and epidemiological evidence of the role of oxidative stress as a major underlying feature of the toxic effect of air pollutants, and the potential role of dietary supplementation in enhancing antioxidant defences. A bibliographic search was conducted through PubMed. The keywords used in the search were "air pollutant", "oxidative stress", "inflammation", "antioxidant polyunsaturated fatty acids" and "genetics". In addition, the authors also searched for biomarkers of oxidative stress and nutrients. The review presents the most recent data on: the biological and epidemiological evidence of the oxidative stress response to air pollutants; the role of dietary supplementation as a modulator of these effects; and factors of inter-individual variation in human response. The methodology for further epidemiological studies will be discussed in order to improve the current understanding on how nutritional factors may act. There is substantial evidence that air pollution exposure results in increased oxidative stress and that dietary supplementation may play a modulating role on the acute effect of air pollutants. Further epidemiological studies should address the impact of supplementation strategies in the prevention of air-pollution-related long-term effects in areas where people are destined to be exposed for the distant future.

TNFA -308G>A in two international population-based cohorts and risk of asthma.

Genetic association studies have related the tumour necrosis factor-alpha gene (TNFA) guanine to adenine substitution of nucleotide -308 (-308G>A) polymorphism to increased risk of asthma, but results are inconsistent. The aim of the present study was to test whether two single-nucleotide polymorphisms, of TNFA and of the lymphotoxin-alpha gene (LTA), are associated with asthma, bronchial hyperresponsiveness and atopy in adults, by combining the results of two large population-based multicentric studies and conducting a meta-analysis of previously published studies. The European Community Respiratory Health Survey (ECRHS) and Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) used comparable protocols, including questionnaires for respiratory symptoms and measures of lung function and atopy. DNA samples from 11,136 participants were genotyped at TNFA -308 and LTA 252. Logistic regression employing fixed and random effects models and nonparametric techniques were used. The prevalence of asthma was 6%. The TNFA -308G>A polymorphism was associated with increased asthma prevalence and with bronchial hyperresponsiveness. No consistent association was found for atopy. The LTA 252A>G polymorphism was not associated with any of the outcomes. A meta-analysis of 17 studies showed an increased asthma risk for the TNFA -308 adenine allele. The tumour necrosis factor-alpha gene nucleotide -308 polymorphism is associated with a moderately increased risk of asthma and bronchial hyperresponsiveness, but not with atopy. These results are supported by a meta-analysis of previously published studies.

Translational study identifies XPF and MUS81 as predictive biomarkers for oxaliplatin-based peri-operative chemotherapy in patients with esophageal adenocarcinoma.

Oxaliplatin-based chemotherapy is used to treat patients with esophageal adenocarcinoma (EAC), but no biomarkers are currently available for patient selection. We performed a prospective, clinical trial to identify potential biomarkers associated with clinical outcomes. Tumor tissue was obtained from 38 patients with resectable EAC before and after 2 cycles of oxaliplatin-fluorouracil chemotherapy. Pre-treatment mRNA expression of 280 DNA repair (DNAR) genes was tested for association with histopathological regression at surgery, disease-free survival (DFS) and overall survival (OS). High expression of 13 DNA damage repair genes was associated with DFS less than one year (P < 0.05); expression of 11 DNAR genes were associated with worse OS (P < 0.05). From clinical associations with outcomes, two genes, ERCC1 and EME1, were identified as candidate biomarkers. In cell lines in vitro, we showed the mechanism of action related to repair of oxaliplatin-induced DNA damage by depletion and knockout of protein binding partners of the candidate biomarkers, XPF and MUS81 respectively. In clinical samples from the clinical trial, pre-treatment XPF protein levels were associated with pathological response, and MUS81 protein was associated with 1-year DFS. XPF and MUS81 merit further validation in prospective clinical trials as biomarkers that may predict clinical response of EAC to oxaliplatin-based chemotherapy.

Patterns of opiate use in a heroin maintenance programme.

RATIONALE: Little is known about patterns of opiate use by heroin addicts. OBJECTIVES: To describe opiate use over time among heroin addicts who had access to legally prescribed intravenous heroin and oral opiates. METHODS: Analysis of daily drug administration records of 37 patients enrolled in the Geneva heroin maintenance programme for 4-29 months (total 23,136 patient-days). RESULTS: The average dose of intravenous heroin was 466 mg/day; the total opiate dose, after conversion of oral opiates to heroin-equivalents, was 543 mg/day. Patients received intravenous heroin only on 39% of days, oral opiates only on 7% of days, and mixed regimens on 49% of days; the remaining 4% of days were spent outside the programme, usually on oral opiates. The daily dose of heroin-equivalents increased during the first trimester in the programme, by 30 mg/day per month (95% confidence interval 12-46 mg/day per month), but decreased gradually thereafter, by 12 mg/day per month (95% confidence interval, 8-17 mg/day per month). In patients who alternated between heroin and methadone, 1 mg methadone typically replaced 4.1 mg heroin. During follow-up, five patients switched to methadone maintenance, five underwent detoxification, and three were discharged for noncompliance with regulations. CONCLUSIONS: Heroin users who have facilitated access to legally prescribed drugs consume about 0.5 g heroin per day. Consumption patterns vary, but the daily amount of opiates remains stable or decreases over time. A substantial minority of patients elect for alternative treatments after several months of heroin maintenance.

Inpatient opiate detoxification in Geneva: follow-up at 1 and 6 months.

The aim of this study was to identify predictors of treatment success and of relapse, 1 and 6 months after inpatient opiate detoxification in an 8-bed unit in Geneva. Of all 73 patients admitted between June 1994 and June 1995, a majority (73%) successfully finished opiate detoxification. Detoxification was performed mainly with methadone tapering; the average duration of hospitalisation was 15 days. Factors associated with treatment failure were: cocaine abuse, presence of legal problems, and short duration of hospital stay. After 1 month, 65% of the patients were using drugs (half of them were dependent again, half of them had used occasionally) and 35% were completely abstinent (21% when excluding those in residential treatment). Predictors of rapid relapse were cocaine abuse and little concern with own psychological situation at baseline. After 6 months, 50% were physically dependent again, 13% had lapsed occasionally, 37% were abstinent (28% when excluding those in residential treatment). Only high benzodiazepine use at baseline was associated with medium term abstinence. Addiction severity index composite scores had considerably improved between baseline and 6 months. Prevention of relapse to opiate use after inpatient detoxification, especially for those with a concurrent cocaine abuse, should be improved.

New constituents of the leaf and stem exudate of Ozothamnus hookeri (Asteraceae).

The exudate of Ozothamnus hookeri has been investigated for its non-flavonoid constituents. A new natural C6-C3 ester of a long chain fatty acid and seven structurally related kaurane-diterpenoids were isolated. Three of the latter are new natural products, too. A rare 8-methoxy flavonol was also identified.

A new oxyprenyl coumarin and highly methylated flavones from the exudate of Ozothamnus lycopodioides (Asteraceae).

A new oxyprenyl coumarin was isolated from the lipophilic exudate of Ozothamnus lycopodioides. Its structure was established as 7-(3,3'-dimethylallyloxy)-5-hydroxy-6-methoxycoumarin from its UV, MS and NMR spectral data, especially two dimensional experiments. In addition to six earlier reported flavonols, we found four highly substituted flavones, including two rare methylenedioxyflavones.