Endocrine and metabolic assessment in adults with Langerhans cell histiocytosis.

CONTEXT: Diabetes insipidus (DI) is one of most common complications of Langerhans cell histiocytosis (LCH) but prevalence of anterior pituitary deficiencies and metabolic alterations have not been clearly defined yet. OBJECTIVES: Evaluate prevalence of endocrine and metabolic manifestations in a cohort of patients affected by Pulmonary LCH. METHODS: Observational cross-sectional study on 18 adults (7 M/11 F, 42±12years) studied for complete basal and dynamic endocrine lab tests and glucose metabolism. RESULTS: Hypothalamic-pituitary endocrine alterations were found in 9 patients: 9 had DI, 5 Growth Hormone Deficiency (GHD), 5 central hypogonadism, 3 central hypothyroidism and 1 central hypoadrenalism. Hyperprolactinemia and hypothalamic syndrome were found in 2 patients each. All these central endocrine alterations were always associated to DI. Five of the 10 MRI performed showed abnormalities. Prevalence of obesity and glucose alterations (either DM or IFG/IGT) were respectively 39% and 33%, higher than expected basing on epidemiological data on general Italian population. Multi-system-LCH without risk-organ involvement (LCH MS-RO-) seems to have slightly higher prevalence of insulin resistance, glucose alterations and metabolic syndrome than LCH with isolated lung involvement (LCH SS lung+). A papillary BRAFV600E positive thyroid carcinoma was diagnosed in one patient. CONCLUSIONS: The presence of anterior pituitary deficiencies should be systematically sought in all LCH patients with DI both at diagnosis and during the follow-up by basal and dynamic hormonal assessment. Patients with pulmonary LCH, particularly those with MS disease, have a worse metabolic profile than general population. Occurrence of papillary thyroid carcinoma has been reported.

Efficacy of pirfenidone for idiopathic pulmonary fibrosis: An Italian real life study.

BACKGROUND: In this retrospective Italian study, which involved all major national interstitial lung diseases centers, we evaluated the effect of pirfenidone on disease progression in patients with IPF. METHODS: We retrospectively studied 128 patients diagnosed with mild, moderate or severe IPF, and the decline in lung function monitored during the one-year treatment with pirfenidone was compared with the decline measured during the one-year pre-treatment period. RESULTS: At baseline (first pirfenidone prescription), the mean percentage forced vital capacity (FVC) was 75% (35-143%) of predicted, and the mean percentage diffuse lung capacity (DLCO) was 47% (17-120%) of predicted. Forty-eight patients (37.5%) had mild disease (GAP index stage I), 64 patients (50%) had moderate IPF (stage II), and 8 patients (6.3%) had severe disease (stage III). In the whole population, pirfenidone attenuated the decline in FVC (p = 0.065), but did not influence the decline in DLCO (p = 0.355) in comparison to the pre-treatment period. Stratification of patients into mild and severe disease groups based on %FVC level at baseline (>75% and ≤75%) revealed that attenuation of decline in FVC (p = 0.002) was more pronounced in second group of patients. Stratification of patients according to GAP index at baseline (stage I vs. II/III) also revealed that attenuation of decline in lung function was more pronounced in patients with more severe disease. CONCLUSIONS: In this national experience, pirfenidone reduced the rate of annual FVC decline (p = 0.065). Since pirfenidone provided significant treatment benefit for patients with moderate-severe disease, our results suggest that the drug may also be effective in patients with more advanced disease.

A randomized clinical trial of photodynamic therapy with methyl aminolaevulinate vs. diclofenac 3% plus hyaluronic acid gel for the treatment of multiple actinic keratoses of the face and scalp.

BACKGROUND: A gel containing diclofenac and hyaluronic acid (DHA) and photodynamic therapy with methyl aminolaevulinate (MAL-PDT) are widely used treatments for actinic keratoses (AKs). OBJECTIVES: The aim of this single-centre, open-label, prospective, nonsponsored, randomized controlled clinical trial was to compare the treatment results and cost-effectiveness of MAL-PDT and DHA. METHODS: Patients with multiple AKs of the face and scalp were randomized to receive MAL-PDT or DHA. After 90 days, the overall complete remission (CR) rate of patients and the CR rate of lesions according to thickness score were assessed, and patients and an investigator scored the cosmetic outcome. In addition, patients scored their overall satisfaction with the treatment. Patients with CR of all lesions were followed up for 12 months. RESULTS: Two hundred patients with a total of 1674 AKs were enrolled. The lesion CR rates at 3 months were 85·9% with MAL-PDT and 51·8% with DHA (P < 0·0001). AKs of all thicknesses were significantly more responsive to MAL-PDT. The patient CR rates at 3 months were 68% with MAL-PDT and 27% with DHA. At the 12-month examination, the number of patients with CR reduced to 37 with MAL-PDT and seven with DHA. Rating of cosmetic outcome was very good or excellent in the vast majority of patients with both treatments. The analysis of cost-effectiveness showed that the costs per patient with CR at 3 months and at 12 months are €566·7 and €1026·2, respectively, with MAL-PDT and €595·2 and €2295·6, respectively, with DHA. CONCLUSIONS: Efficacy, cosmetic outcome and patients' overall satisfaction with MAL-PDT are superior in comparison with DHA. MAL-PDT is more expensive but it is more cost-effective.

Cryotherapy is preferable to ablative CO2 laser for the treatment of isolated actinic keratoses of the face and scalp: a randomized clinical trial.

BACKGROUND: Actinic keratosis (AK) may progress to squamous cell carcinoma. In the case of normal or mildly photodamaged skin, lesion-directed treatments are considered valuable options despite poor published evidence of their therapeutic activity. OBJECTIVES: The aim of this single-centre, open-label, prospective, nonsponsored, randomized, controlled clinical trial was to compare CO2 laser ablation with cryotherapy in the treatment of isolated AKs of the face and scalp. PATIENTS AND METHODS: Patients with isolated (≤ 4) AKs of the face and scalp were randomized to receive CO2 laser ablation or cryotherapy. After 90 days, the overall complete remission (CR) rates of patients and lesions were assessed and correlated with thickness grade. RESULTS: Two hundred patients with a total number of 543 AKs were enrolled. The CR rates of lesions after 3 months were 78·2% with cryotherapy and 72·4% with CO2 laser ablation. Thicker lesions were significantly more responsive to cryotherapy (P = 0·034). Seventy-three patients (71·6%) had CR of all lesions 3 months after cryotherapy and 64 (65·3%) after laser ablation. At 12 months after treatment the number of patients with CR was reduced to 53 with cryotherapy and 14 with laser ablation. CONCLUSIONS: The rate of patients and lesions with CR is similar after 3 months, but more patients remain in stable remission for 12 months after cryotherapy. Cryotherapy is more effective for thick lesions. The cosmetic outcome was good or excellent in almost all patients.

Factors that influence the employment status of people with multiple sclerosis: a multi-national study.

Paid employment is valuable for society and for the individual. A diagnosis of a chronic illness such as multiple sclerosis (MS) can influence a person's employment status. Previous studies have reported that demographic and disease-related aspects can predict whether a person with MS will leave their job. The aim of the study was to assess the factors that people with MS believe to contribute to their employment status and to determine whether any of these differentiate people with MS who are employed from those who are not employed. A multinational questionnaire assessed aspects related to employment that facilitate or hinder job maintenance. Data was collected in 18 European countries. A total of 1,141 questionnaires were completed. Of those responding, 694 (61%) subjects were employed and 477 (39%) were unemployed. The items that significantly differentiated the groups were related to MS symptoms, workplace environment and financial considerations. While MS influences employment status for many people who face difficult symptoms, aspects like a flexible work schedule and financial security are important and perhaps key to promoting job maintenance among people with MS.

Methylaminolaevulinate-based photodynamic therapy of Bowen's disease and squamous cell carcinoma.

BACKGROUND: Photodynamic therapy (PDT) with methylaminolaevulinate (MAL) is an approved noninvasive treatment option for actinic keratosis and Bowen's disease (BD), two precursors of invasive squamous cell carcinoma (SCC). OBJECTIVES: To assess efficacy, prognostic features, tolerability and cosmetic outcome of MAL-PDT for the treatment of BD and SCC. METHODS: In total, 112 biopsy-proven lesions of BD and SCC in 55 subjects were treated in an outpatient setting. MAL cream (160 mg g(-1)) was applied for 3 h prior to illumination with a light-emitting diode source (wavelength range 635 +/- 18 nm; light dose 37 J cm(-2)). A second MAL-PDT session was given 7 days later. Complete response rate at 3 months after the last treatment, recurrence rate at the 24-month follow-up, and cosmetic outcome were recorded. RESULTS: The overall complete response rates were 73.2% at 3 months and 53.6% at 2 years. Clinical thickness, atypia and lesion depth were significant predictors of the response at 3 months when using a univariate analysis (P < 0.001). A multivariate logistic regression model, with robust variance estimation, showed that cell atypia was the only statistically significant independent predictor of the treatment outcome at 3 months. CONCLUSIONS: MAL-PDT may represent a valuable, effective and well tolerated treatment option with good cosmetic outcome for superficial, well-differentiated (Broders' scores I and II) BD and microinvasive SCC. In contrast, its use for superficial SCCs with a microinvasive histological pattern and for nodular, invasive lesions, particularly if poorly differentiated keratinocytes are present (Broders' scores III and IV), should be avoided.

Quality of life and patients' satisfaction in chronic urticaria and respiratory allergy.

BACKGROUND: Few articles are available about chronic urticaria (CU) impact on patients' quality of life (QoL). The aim of our study was to evaluate QoL in CU patients both focusing on health status and subjective satisfaction. We adopted two generic tools: SF-36 (an health status questionnaire) and SAT-P (a satisfaction profile). METHODS: Twenty-one untreated patients (five males, 16 females; aged 46.3 +/- 12.4) affected by CU, were enrolled. SF-36 and SAT-P scores of CU patients were compared with scores of a group of 27 patients with respiratory allergy. Published reference values of 608 and 241 Italian healthy subjects were used as controls, respectively, for SF-36 and SAT-P. RESULTS: Patients with CU compared with allergic patients referred significantly lower scores in physical functioning (P = 0.046), role physical (P = 0.01), bodily pain (P = 0.0001), general health (P = 0.0043) and role emotional (P = 0.04), and compared with reference sample reported lower scores in all SF-36 domains (P < 0.0001). SAT-P scores of CU patients compared with patients with respiratory allergy and with reference sample were significantly lower in many aspects of daily life. CONCLUSIONS: These results show a significant impact on health status and on subjective satisfaction in patients with CU: the symptoms affect everyday life, limiting and impairing physical and emotional functioning, and acts as an indirect burden on life satisfaction.

Rhinasthma: a new specific QoL questionnaire for patients with rhinitis and asthma.

INTRODUCTION: To date we have available specific instruments assessing health-related quality of life (HRQL) in rhinoconjunctivitis or in asthma, but not instruments evaluating rhinitis and asthma together, although they often coexist. The aim of our study was to develop and validate a specific quality of life (QoL) questionnaire for adult patients with rhinoconjunctivitis, asthma or both. MATERIALS AND METHODS: A pool of 42 items covering the main symptoms and problems related to respiratory allergy, was generated based on literature review and clinical experience. The items were randomly listed and presented to 148 consecutive outpatients 46 suffering from asthma (age 32.9 +/- 14.3 years), 53 suffering from rhinoconjunctivitis (age 32.6 +/- 11.5 years) and 49 from asthma and rhinoconjunctivitis (age 35.6 +/- 12.2 years). The patients were asked to indicate which item they had directly experienced and for each of them, its importance on a four-point scale (1 = not important; 4 = very important). Twelve items were cancelled from the list, because of low importance or redundance. In the instrument validation phase, 104 patients (42 with rhinoconjunctivitis alone and 62 with asthma and rhinoconjunctivitis) were evaluated with the generic instrument SF-36 and the new questionnaire (RHINASTHMA). RESULTS: RHINASTHMA was able to differentiate patients with rhinitis from those with both rhinitis and asthma. In stable condition, RHINASTHMA showed good reliability. The factor analysis extracted three factors with a good reliability (0.93, 0.87, 0.76). DISCUSSION: RHINASTHMA is the first tool aimed at evaluating HRQL impairment in patients with rhinitis and/or asthma. It provides a short and simple assessment, and has overall psychometric properties. This is of relevance because of the frequent asthma-rhinitis comorbidity.

Variance component linkage analysis indicates a QTL for femoral neck bone mineral density on chromosome 1p36.

Osteoporosis is a common condition characterized by reduced skeletal strength and increased susceptibility to fracture. Eight million Americans over the age of 50 have osteoporosis of the femoral neck. The most important risk factor for osteoporosis is low bone mineral density (BMD), and several epidemiological studies have shown the importance of genetic factors in determining variability of BMD. An initial genome screen in seven large pedigrees suggested that a candidate region conferring susceptibility to low BMD of the femoral neck was located on chromosome 1p36. We have now confirmed and extended this finding by analyzing nine microsatellite markers spanning a 40 cM interval across the candidate region in an expanded sample of 42 families. Heritability of femoral neck BMD was estimated as 0.51 +/- 0.13 in these families, after accounting for the effects of age, sex, body mass index, height and weight. Variance component linkage analysis yielded a maximum multipoint LOD score of 3.53 for linkage of femoral neck BMD to a quantitative trait locus (QTL) located near marker D1S214. The associated empirical P-value by simulation analysis was equal to 0.0001. The results strongly support the hypothesis that a major QTL controlling femoral neck BMD is located on chromosome 1p36.2-p36.3, and further analysis of candidate genes in this region is warranted.

Novel X-linked mental retardation syndrome with short stature maps to Xq24.

We describe a large family from Sardinia, Italy, in which a novel X- linked mental retardation (XLMR) syndrome segregates. The phenotype observed in the 8 affected males includes severe mental retardation (MR), lack of speech, coarse face, distinctive skeletal features with short stature, brachydactyly of fingers and toes, small downslanting palpebral fissures, large bulbous nose, hypoplastic ear lobe and macrostomia. Carrier females are not mentally retarded, although some of them have mild dysmorphic features such as minor ear lobe abnormalities, as well as language and learning problems. Linkage analysis for X-chromosome markers resulted in a maximum lod score of 3.61 with marker DXS1001 in Xq24. Recombination observed with flanking markers identified a region of 16 cM for further study. None of the other XLMR syndromes known to map in the same region shows the same composite phenotype. This evidence strongly suggests that the genetic disease in this family is unique.

Evidence-based diagnosis of familial non-X-linked dilated cardiomyopathy. Prevalence, inheritance and characteristics.

AIMS: To assess the prevalence of familial non-X-linked dilated cardiomyopathy, to diagnose early asymptomatic cases evaluate inheritance and characterize clinical phenotypes. METHODS AND RESULTS: We screened 472 relatives of 104 consecutive patients diagnosed with dilated cardiomyopathy; males with X-linked dilated cardiomyopathy were excluded based on systematic immunohistochemical and molecular analysis. Relatives underwent clinical examination, electrocardiography, echocardiography and serum creatine-phosphokinase determination. Twenty-six index patients (25%) had familial disease: four youths (< or = 20 years) had rapidly progressive outcome and underwent emergency transplantation. In a sib-pair, the onset was with atrioventricular block. Inheritance was autosomal dominant in 15, undetermined in seven (four sib-pairs); mitochondrial DNA pathological mutations were found in four. The screening identified 23 newly diagnosed relatives in the familial group. Transplantation (P = 0.04) and atrial fibrillation (P = 0.04) were more frequent, and left bundle branch block (P = 0.04) less frequent in index patients with familial than in those with non-familial disease. Several non-affected relatives had instrumental abnormalities potentially useful as pre-clinical markers: their prevalence was similar in both groups. CONCLUSIONS: The prevalence of familial, non X-linked dilated cardiomyopathy was 25%. The immediate benefits of screening family members of index patients was early diagnosis in unaware symptomless affected relatives.

Comparison of sib pair-based approaches for identifying quantitative trait loci underlying asthma in the Busselton families.

The goal of this study is to determine the linkage relationship between IgE levels and the 269 microsatellite markers using the Genetic Analysis Workshop 12 Busselton data set. Analyses were carried out using both traditional and new Haseman-Elston methods, the maximum likelihood quantitative trait locus estimation (MLE QTL) method and the nonparametric (NP QTL) method. Our analyses confirmed some of the signals reported by Daniels et al. [Nature 383:247-50, 1996]. We also observed that several significant signals reported in the original report became insignificant (D6S76 and D11S96) and several new signals showed up after the data were reanalyzed using the new Haseman-Elston method, the MLE QTL method, and the NP QTL method. Based on the original and the current analyses, we recommend that follow-up studies of three regions including D7S2250, FCER1B, D11S901, and six markers on chromosome 16 be given higher priority.

Interpretation and diagnostic implications of an immunoblotting (INNOLIA) test for HCV serology.

The association analysis of antibodies versus HCV, carried out with INNOLIA test, prevented a clear determination of the existence of specific serological patterns. In this respect, it may be of interest to monitor the immune response to the non-structural genomic regions (NS3, NS4, NS5). The INNOLIA kit is reliable, but susceptible to improvement in terms of specificity, sensitivity and biological standardization.

Coinheritance of Gilbert syndrome increases the risk for developing gallstones in patients with hereditary spherocytosis.

The precocious formation of bilirubinate gallstones is the most common complication of hereditary spherocytosis (HS), and the prevention of this problem represents a major impetus for splenectomy in many patients with compensated hemolysis. Because Gilbert syndrome has been considered a risk factor for gallstone formation, there are reasons for postulating that the association of this common inherited disorder of hepatic bilirubin metabolism with HS could increase cholelithiasis. To test this hypothesis, 103 children with mild to moderate HS who, from age 1, have undergone a liver and biliary tree ultrasonography every year, were retrospectively examined. The 2-bp (TA) insertion within the promoter of the uridine diphosphate-glucuronosyltransferase gene (UGT1A1), associated with Gilbert syndrome, was screened. The risk of developing gallstones was statistically different among the 3 groups of patients: homozygotes for the normal UGT1A1 allele, heterozygotes, and homozygotes for the allele with the TA insertion. Fitting a Cox regression model, in fact, a statistically significant hazard ratio of 2.19 (95% confidence interval: 1.31 to 3.66) was estimated from one to the next of these genetic classes. The individual proneness to form gallstones from TA insertion in the TATA-box of the UGT1A1 promoter should be considered during the follow-up of patients with HS. Although patients with HS were the only ones studied, extrapolating these data to patients who have different forms of inherited (eg, thalassemia, intraerythrocytic enzymatic deficiency) or acquired (eg, autoimmune hemolytic anemia, hemolysis from mechanical heart valve replacement) chronic hemolysis can be warranted.