Background Sarcoidosis is a rare lung disease in children. The aim of the present study was to provide update information on disease presentation and progression, patient management and prognosis factors in a cohort of children with lung sarcoidosis. Methods With the network of the French Reference Centre for Rare Lung Diseases (RespiRare), we collected information on a large cohort of paediatric thoracic sarcoidosis to provide information on disease presentation, management and outcome. Results Forty-one patients were included with a median age at diagnosis of 11.8 years (1.1–15.8), mostly from Afro-Caribbean and Sub-Saharan origin. At diagnosis, 85% presented with a multi-organic disease, and no major differences were found regarding disease severity between the patients diagnosed before or after 10 years old. Corticosteroids were the most used treatment, with more intravenous pulses in the youngest patients. The 18-month outcome showed that patients diagnosed before 10 years old were more likely to recover (50% vs 29%), and presented fewer relapses (29% vs 58%). At 4–5 years of follow-up, relapses were mostly observed for patients diagnosed after 10 years old. Discussion In the included children, mostly of Afro-Caribbean and Sub-Saharan origin, sarcoidosis seems severe, with multi-organic involvement and foreground general symptoms. Common prognosis factors are not suitable in paediatric patients, and a young age at diagnosis does not seem to be associated with a poorer prognosis. The study is ongoing to provide further information on the very-long-term follow-up of paediatric sarcoidosis.,Not all the risk factors for primary pulmonary hypertension (PPH) are known. Appetite suppressants, including fenfluramine derivatives, are strongly suspected aetiological agents. In a 5 year retrospective study fenfluramine use was evaluated among patients referred to a medical centre specialising in the management of PPH. Fifteen (20%) of 73 patients with PPH had used fenfluramine: all of them were women and in 10 (67%) there was a close temporal relation between fenfluramine use and the development of exertional dyspnoea. Initial right heart catheterisation in the 15 women showed severe resting pulmonary hypertension (mean (SD)) with pulmonary artery pressure (PAP) 57 (9) mm Hg, cardiac index 2.1 (0.5) l/min/m2, and pulmonary vascular resistance (PVR) 29 (10) U/m2. Short-term epoprostenol infusion produced a significant vasodilator response in 10 patients (mean fall in PVR 24 (15%) compared with control values). Three fenfluramine users with PPH showed spontaneous clinical and haemodynamic improvement 3, 6 and 12 months after drug withdrawal but there was no significant difference in overall survival (transplant recipients excluded) between fenfluramine users and controls. Histological examination of lung tissue from five women who had used fenfluramine and 22 controls, with PPH showed features typical of advanced plexogenic pulmonary arteriopathy in all. These results do not accord with earlier reports that PPH associated with fenfluramine is less severe and has a better outcome. Fenfluramine may be one aetiological agent that can precipitate or hasten the development of PPH. The results of a European case-control study should give new insights into risk factors for PPH and the cause and effect relation with fenfluramine.
Pulmonary hypertension is often a progressive condition, characterized by a relentless increase in pulmonary vascular resistance that ultimately leads to right-heart failure and death. Although the initiating factors may differ widely in patients with primary and various secondary causes of pulmonary hypertension, there may be common pathways of progression that reflect the limited range of vascular response to injury. Common to many forms of pulmonary hypertension is the proliferation of smooth-muscle cells in the vascular media and frequently the intima, 1 triggered and perpetuated by as yet unknown mechanisms. The resulting intimal and medial thickening may reduce the caliber of resistance . . .
ObjectivesWork-related asthma (WRA) is an important public health problem affecting one quarter of adults with asthma. Although cleaning substances are routinely used in hospitals, few studies have addressed their potential adverse respiratory health effects on healthcare professionals (HCPs). This study attempts to identify relationship between work-related exposure to cleaning-related chemicals and development of WRA among HCPs.MethodsOf 5600 HCPs surveyed, 3650 responded to a validated questionnaire about their occupation, asthma diagnosis, variability of asthma symptoms at and away from work, and exposure to individual cleaning substances. Workplace asthma was defined as a categorical variable with four mutually exclusive categories: work-related asthma symptoms (WRAS), work-exacerbated asthma (WEA), occupational asthma (OA) and none. Multivariable logistic regression analysis was used to evaluate the association between self-reported use of cleaning substances and asthma outcomes among HCPs.ResultsPrevalences of WRAS, WEA and OA were 3.3%, 1.1% and 0.8%, respectively. The prevalence estimates were generally higher among female than male HCPs. The odds of WRAS and WEA increased in a dose-dependent manner for exposure in the longest job to cleaning agents and disinfectants/sterilants, respectively. For exposure in any job, the odds of WRAS were significantly elevated for both factor 1 (bleach, cleaners/abrasives, toilet cleaners, detergents and ammonia) and factor 2 (glutaraldehyde/ortho-phtaldehyde, chloramines and ethylene oxide). Significantly elevated odds of WEA were observed for exposure to bleach, factor 2 and formalin/formaldehyde. Exposure to chloramines was significantly associated with an almost fivefold elevated odds of OA.ConclusionsHCPs are at risk of developing WRA from exposure to cleaning substances.,Background While studies have attributed the favourable birth outcomes of Mexico-born mothers in the USA to a ‘healthy immigrant effect’ that confers protection to immigrants, a comparison of immigrants with the source population in Mexico has been lacking. We compared preterm delivery (PTD) rates of Mexico-born immigrants who delivered in California with Mexico-born women who delivered in Mexico (WIMX) and with a subgroup who delivered in the five top immigrant sending states in Mexico. Methods Using 2009 birth records, we selected all live-born singletons of primiparous WIMX (699 129) and immigrants in California (33 251). We examined the unadjusted and adjusted association between place of delivery and any PTD (<37 weeks gestation), including PTD subcategories (early, moderate, late), using relative risks (RR) and 95% CIs. Multivariate models controlled for demographic and health system characteristics. Results PTD rates were higher among immigrants in California (6.7%) than WIMX (5.8%) and compared to women in the sending states (5.5%). The unadjusted risk of any PTD (RR=1.17 (1.12 to 1.22)), early/moderate PTD (<34 weeks gestation; RR=1.27 (1.18 to 1.38)) and late PTD (34–36 weeks; RR=1.14 (1.08 to 1.19)) was higher for immigrants than for WIMX and remained higher when controlling for age, education and healthcare variables. Birth weight <1500 g was also higher among immigrants (RR=1.27 (1.14 to 1.44)). Similar patterns were observed when comparing women in the sending states. Conclusions We found no evidence of a ‘healthy immigrant effect’. Further research must assess the comparability of gestational-age data in Mexican and Californian birth certificates.,IntroductionMolecular characterisation of tumours is increasing personalisation of cancer therapy, tailored to an individual and their cancer. FOCUS4 is a molecularly stratified clinical trial for patients with advanced colorectal cancer. During an initial 16-week period of standard first-line chemotherapy, tumour tissue will undergo several molecular assays, with the results used for cohort allocation, then randomisation. Laboratories in Leeds and Cardiff will perform the molecular testing. The results of a rigorous pre-trial inter-laboratory analytical validation are presented and discussed.MethodsWales Cancer Bank supplied FFPE tumour blocks from 97 mCRC patients with consent for use in further research. Both laboratories processed each sample according to an agreed definitive FOCUS4 laboratory protocol, reporting results directly to the MRC Trial Management Group for independent cross-referencing.ResultsPyrosequencing analysis of mutation status at KRAS codons12/13/61/146, NRAS codons12/13/61, BRAF codon600 and PIK3CA codons542/545/546/1047, generated highly concordant results. Two samples gave discrepant results; in one a PIK3CA mutation was detected only in Leeds, and in the other, a PIK3CA mutation was only detected in Cardiff. pTEN and mismatch repair (MMR) protein expression was assessed by immunohistochemistry (IHC) resulting in 6/97 discordant results for pTEN and 5/388 for MMR, resolved upon joint review. Tumour heterogeneity was likely responsible for pyrosequencing discrepancies. The presence of signet-ring cells, necrosis, mucin, edge-effects and over-counterstaining influenced IHC discrepancies.ConclusionsPre-trial assay analytical validation is essential to ensure appropriate selection of patients for targeted therapies. This is feasible for both mutation testing and immunohistochemical assays and must be built into the workup of such trials.Trial registration numberISRCTN90061564.,OBJECTIVETo test the dependency of haemolytic and cytocidal manifestations of pathogenicity of Trichomonas vaginalis on direct contact between the target cells and the organism. TEST ORGANISMT vaginalis strain Baltimore 42. DESIGNHaemolysis in the presence of live T vaginalis and of its filter-sterilised metabolic products was compared. The dependence of haemolytic and cytocidal effects on retention of low pH of metabolic products of the organism was demonstrated by parallel titrations of sterile filtrates in normal saline and in phosphate buffered saline (PBS) pH 7.0. RESULTSNear complete lysis was obtained when erythrocytes mixed with T vaginalis were incubated for 1 h at 37 degrees C in saline containing 1% glucose. The same degree of haemolysis was present in filter-sterilised glucose-saline in which the organism was incubated (1 h/37 degrees C) before erythrocytes were added and incubated under the same conditions as in the mixture with the organism. The degree of haemolysis in filtrates was dependent on retention of low pH (below 5.0) of the suspending fluid in which the organism alone was incubated. Dilution of filtrates in PBS, as opposed to normal saline, abolished or diminished the haemolytic effect. Presence of glucose (energy source) in the saline during incubation of the organism had a pronounced enhancing effect. The production of haemolytic metabolites was temperature dependent, whereas the haemolytic process per se was not. The effect was not an exclusive property of T vaginalis since it was also demonstrated with other trichomonads. The same filtrates applied to tissue culture exerted cytocidal effect strikingly similar to that observed in the haemolysis experiments. CONCLUSIONNeither haemolytic nor cytocidal effect of T vaginalis was contact-dependent.
Background Studies on the association between adult asthma and dementia are few. We investigated the risk of dementia in patients diagnosed with adult asthma compared with that of people without asthma who were age and sex matched to the study patients. Methods We used data from the National Health Insurance Research Database. A total of 12 771 patients with newly diagnosed asthma between 2001 and 2003 were evaluated and 51 084 people without asthma were used as the comparison cohort. Cox proportional hazard regression analysis was used to measure the HR of dementia for the asthmatic cohort, compared with that of the non-asthmatic cohort. Results The HR of dementia was 1.27 (95% confidence interval (CI) 1.15 to 1.41) for the asthmatic cohort, compared with the non-asthmatic cohort after adjusting for age, sex, comorbidities, annual outpatient department visits and medicine used. The HR of dementia development increased substantially as frequency of asthma exacerbation and hospitalisation increased. Conclusions This nationwide cohort study suggests that the risk of dementia development is significantly increased in patients with asthma compared with that of the general population. In addition, dementia risk increases substantially with asthma exacerbation and hospitalisation frequency increases.,OBJECTIVEto analyse the prevalence of cervical chlamydia infection and its determinants in an Italian population of women attending outpatients services for contraceptive counselling or routine gynaecological examination. METHODSbetween November 1989 and November 1990 we conducted a cross-sectional study on the prevalence of cervical Chlamydia trachomatis infection among women attending the outpatients service of seven university clinics in Northern (three centres), Central (three centres) and Southern (one centre) Italy. Eligible for the study were subjects with symptomatic low gynaecological tract infection (a total of 2071 women), a history of recurrent abortions (two or more miscarriages and no livebirth (416 subjects)), or sterility (371 subjects), plus a sample of asymptomatic women observed for contraceptive counselling or routine gynaecological examination identified on randomly selected days at the participating centres (1321 subjects). During the gynaecological consultation women were asked about their general characteristics, reproductive history, contraceptive and sexual habits, and history of sexually transmitted diseases (STD) using a standard questionnaire. An endocervical specimen was obtained with a plastic swab. The direct smear immunofluorescent antibody test (IFA test) was used to detect chlamydia antigens. RESULTSout of the 2071 women with genital infection, 104 (5.0%) had cervical chlamydia infection; the corresponding percentages were 4.6 (19/416), 5.4 (20/371) and 3.9 (51/1321) respectively in women with recurrent abortions, sterility and in asymptomatic subjects. The risk of chlamydia infection was higher in women reporting a history of STD: in comparison with those without a history of STD, the relative risk of chlamydia infection was 1.4 (95% confidence interval, CI, 1.0-2.0). Among women reporting current use of a contraceptive method the risk of cervical chlamydia infection was lower in current users of barrier methods; in comparison with oral contraceptive users, the RR was 0.4 (95% CI, 0.2-0.8) in barrier methods users and 0.5 (95% CI, 0.2-1.1) in intrauterine device or other methods users. No consistent relationship emerged with age, reproductive history or number of sexual partners over the last 12 months. CONCLUSIONin this Italian population the frequency of cervical chlamydia infection appeared to be lower than in other selected groups from Northern European and American countries. Users of barrier contraception methods were at reduced risk of infection.,Background Pulmonary hypertension (PH)-targeted therapy in the setting of pulmonary fibrosis (PF) is controversial; the main clinical concern is worsening of systemic hypoxaemia. We sought to determine the effects of gentle initiation and chronic administration of parenteral treprostinil on right heart function in patients with PF associated with an advanced PH phenotype. Methods Open-label, prospective analysis of patients with PF-PH referred for lung transplantation (LT). Advanced PH was defined as mean pulmonary artery pressure (mPAP) ≥35 mm Hg. We compared haemodynamics, Doppler echocardiography (DE), oxygenation, dyspnoea and quality of life indices, and 6 min walk distance (6MWD) before and 12 weeks after parenteral treprostinil. Results 15 patients were recruited in the study. After therapy, there were significant improvements in right heart haemodynamics (right atrial pressure (9.5 ± 3.4 vs 6.0 ± 3.7); mPAP (47 ± 8 vs 38.9 ± 13.4); CI (2.3 ± 0.5 vs 2.7 ± 0.6); pulmonary vascular resistance (698 ± 278 vs 496 ± 229); transpulmonary gradient (34.7 ± 8.7 vs 28.5 ± 10.3); mvO2 (65 ± 7.2 vs 70.9 ± 7.4); and stroke volume index (29.2 ± 6.7 vs 33 ± 7.3)) and DE parameters reflecting right heart function (right ventricular (RV) end diastolic area (36.4 ± 5.2 vs 30.9 ± 8.2 cm2), left ventricular eccentricity index (1.7 ± 0.6 vs 1.3 ± 0.5), tricuspid annular planar systolic excursion (1.6 ± 0.5 vs 1.9 ± 0.2 cm)). These changes occurred without significant alteration in systemic oxygenation, heart rate, or mean systemic arterial pressure. In addition, improvements were seen in 6MWD (171 ± 93 vs 230 ± 114), 36-Item Short Form Health Survey Mental Component Summary aggregate (38 ± 11 vs 44.2 ± 10.7), University of California, San Diego Shortness of Breath Questionnaire (87 ± 17.1 vs 73.1 ± 21), and brain natriuretic peptide (558 ± 859 vs 228 ± 340). Conclusions PH-targeted therapy may improve right heart haemodynamics and echocardiographic function without affecting systemic oxygen saturation in an advanced PH phenotype associated with RV dysfunction in the setting of PF.
The status of small pulmonary arteries may influence diagnosis, surgical selection and postoperative outcome of patients with chronic major vessel thromboembolic pulmonary hypertension (CTEPH). Therefore, in patients with the established diagnosis of CTEPH, lung tissue was obtained by biopsy (15 patients) or at autopsy (16 patients) to assess the histopathologic composition of small pulmonary arteries. Pathologic examination disclosed the full range of pulmonary hypertensive lesions in the small arteries, including plexogenic lesions. The type and extent of hypertensive lesions did not relate to preoperative hemodynamic values, to patient age, or to symptom duration. The findings indicate that primary pulmonary hypertension cannot be differentiated from potentially correctable CTEPH on the basis of histopathologic findings in small pulmonary arteries. Furthermore, none of the histologic findings preclude a positive hemodynamic and clinical result from pulmonary thromboendarterectomy. However, development of these hypertensive changes may explain the deterioration which these patients experience preoperatively over time.
Not all the risk factors for primary pulmonary hypertension (PPH) are known. Appetite suppressants, including fenfluramine derivatives, are strongly suspected aetiological agents. In a 5 year retrospective study fenfluramine use was evaluated among patients referred to a medical centre specialising in the management of PPH. Fifteen (20%) of 73 patients with PPH had used fenfluramine: all of them were women and in 10 (67%) there was a close temporal relation between fenfluramine use and the development of exertional dyspnoea. Initial right heart catheterisation in the 15 women showed severe resting pulmonary hypertension (mean (SD)) with pulmonary artery pressure (PAP) 57 (9) mm Hg, cardiac index 2 1 (0. 5) l/min/m(2), and pulmonary vascular resistance (PVR) 29 (10) U/m(2). Shortterm epoprostenol infusion produced a significant vasodilator response in 10 patients (mean fall in PVR 24 (15%) compared with control values). Three fenfluramine users with PPH showed spontaneous clinical and haemodynamic improvement 3, 6 and 12 months after drug withdrawal but there was no significant difference in overall survival (transplant recipients excluded) between fenfluramine users and controls. Histological examination of lung tissue from five women who had used fenfluramine and 22 controls, with PPH showed features typical of advanced plexogenic pulmonary arteriopathy in all. These results do not accord with earlier reports that PPH associated with fenfluramine is less severe and has a better outcome. Fenfluramine may be one aetiological agent that can precipitate or hasten the development of PPH. The results of a European case-control study should give new insights into risk factors for PPH and the cause with fenfluramine.
OBJECTIVETo develop a valid and reliable outcome measure for patients with varicose veins. DESIGNPostal questionnaire survey of patients with varicose veins. SETTINGSurgical outpatient departments and training general practices in Grampian region. SUBJECTS373 patients, 287 of whom had just been referred to hospital for their varicose veins and 86 who had just consulted a general practitioner for this condition and, for comparison, a random sample of 900 members of the general population. MAIN MEASURESContent validity, internal consistency, and criterion validity. RESULTS281(76%) patients (mean age 45.8; 76% female) and 542(60%) of the general population (mean age 47.9; 54% female) responded. The questionnaire had good internal consistency as measured by item-total correlations. Factor analysis identified four important health factors: pain and dysfunction, cosmetic appearance, extent of varicosity and complications. The validity of the questionnaire was demonstrated by a high correlation with the SF-36 health profile, which is a general measure of patients' health. The perceived health of patients with varicose veins, as measured by the SF-36, was significantly lower than that of the sample of the general population adjusted for age and a lower proportion of women. CONCLUSIONA clinically derived questionnaire can provide a valid and reliable tool to assess the perceived health of patients with varicose veins. IMPLICATIONSThe questionnaire may be used to justify surgical treatment of varicose veins.
We studied the efficacy of low-dose nitric oxide inhalation in nine consecutive patients with severe persistent pulmonary hypertension of the newborn (PPHN) who were candidates for extracorporeal membrane oxygenation (ECMO). All patients had marked hypoxemia despite aggressive ventilator management and echocardiographic evidence of pulmonary hypertension. Associated diagnoses included meconium aspiration syndrome (3 patients), sepsis (3 patients), and congenital diaphragmatic hernia (2 patients). Infants were initially treated with inhaled nitric oxide at 20 ppm for 4 hours and then at 6 ppm for 20 hours. In all infants, oxygenation promptly improved (arterial/alveolar oxygen ratio, 0.077±0.016 at baseline vs 0.193±0.030 at 4 hours; <0.001) without a decrease in systemic blood pressure. Sustained improvement in oxygenation was achieved in eight patients treated with inhaled nitric oxide for 24 hours at 6 ppm (arterial/alveolar oxygen ratio, 0.270±0.053 at 24 hours; <0.001 vs baseline). One patient with overwhelming sepsis had an initial improvement of oxygenation with nitric oxide but required ECMO for multiorgan and cardiac dysfunction. We conclude that low doses of nitric oxide cause sustained clinical improvement in severe PPHN and may reduce the need for ECMO. However, immediate availability of ECMO is important in selected cases of PPHN complicated by severe systemic hemodynamic collapse.
To study the potential role of endothelin-1, a potent endothelium-derived vasoconstrictor peptide, in the pathophysiology of persistent pulmonary hypertension of the newborn (PPHN), we measured arterial concentrations of immunoreactive endothelin-1 (irET-1) in 24 neonates with PPHN. Secondary diagnoses included meconium aspiration syndrome (13 patients), sepsis (2), congenital diaphragmatic hernia (1), asphyxia (1), pulmonary hemorrhage (1), aspiration of blood (1), and respiratory distress syndrome (1). Compared with irET-1 levels in umbilical cord blood in normal infants (15.1±4.1 pg/ml; mean±SEM) and in newborn infants with hyaline membrane disease who were supported by mechanical ventilation (11.8±1.2 pg/ml), infants with PPHN had markedly elevated circulating irET-1 levels (27.6±3.6 pg/ml; <0.01 vs cord blood, hyaline membrane disease). Infants with severe PPHN requiring extracorporeal membrane oxygenation (ECMO) therapy had higher irET-1 levels than infants with milder disease (31.0±4.7 for ECMO-treated infants vs 21.2±2.0 for non-ECMO-treated infants; <0.05). In patients treated without ECMO, irET-1 progressively decreased during the following 3 to 5 days, paralleling clinical improvement. In contrast, irET-1 concentrations remained elevated in infants with severe PPHN during ECMO therapy. We conclude that circulating irET-1 levels are elevated in newborn infants with PPHN, are positively correlated with disease severity, and decline with resolution of disease in patients who do not require ECMO therapy. Whether endothelin-1 contributes directly to the pathophysiology of PPHN or is simply a marker of disease activity remains speculative.