Autoimmune polyendocrine syndrome type 1: an Italian survey on 158 patients.

BACKGROUND: Autoimmune Polyglandular Syndrome type 1 (APS-1) is a rare recessive inherited disease, caused by AutoImmune Regulator (AIRE) gene mutations and characterized by three major manifestations: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism (CH) and Addison's disease (AD). METHODS: Autoimmune conditions and associated autoantibodies (Abs) were analyzed in 158 Italian patients (103 females and 55 males; F/M 1.9/1) at the onset and during a follow-up of 23.7 ± 15.1 years. AIRE mutations were determined. RESULTS: The prevalence of APS-1 was 2.6 cases/million (range 0.5-17 in different regions). At the onset 93% of patients presented with one or more components of the classical triad and 7% with other components. At the end of follow-up, 86.1% had CH, 77.2% AD, 74.7% CMC, 49.5% premature menopause, 29.7% autoimmune intestinal dysfunction, 27.8% autoimmune thyroid diseases, 25.9% autoimmune gastritis/pernicious anemia, 25.3% ectodermal dystrophy, 24% alopecia, 21.5% autoimmune hepatitis, 17% vitiligo, 13.3% cholelithiasis, 5.7% connective diseases, 4.4% asplenia, 2.5% celiac disease and 13.9% cancer. Overall, 991 diseases (6.3 diseases/patient) were found. Interferon-ω Abs (IFNωAbs) were positive in 91.1% of patients. Overall mortality was 14.6%. The AIRE mutation R139X was found in 21.3% of tested alleles, R257X in 11.8%, W78R in 11.4%, C322fsX372 in 8.8%, T16M in 6.2%, R203X in 4%, and A21V in 2.9%. Less frequent mutations were present in 12.9%, very rare in 9.6% while no mutations in 11% of the cases. CONCLUSIONS: In Italy, APS-1 is a rare disorder presenting with the three major manifestations and associated with different AIRE gene mutations. IFNωAbs are markers of APS-1 and other organ-specific autoantibodies are markers of clinical, subclinical or potential autoimmune conditions.

Gonadal function in males with autoimmune Addison's disease and autoantibodies to steroidogenic enzymes.

Steroidogenic enzyme autoantibodies (SEAbs) are frequently present and are markers of autoimmune premature ovarian failure (POF) in females with autoimmune Addison's disease (AAD). The prevalence and significance of SEAbs in males with AAD have not yet been defined. We studied the prevalence of SEAbs in a large cohort of males with AAD and assessed the relationship between SEAbs positivity and testicular function. A total of 154 males with AAD (mean age 34 years) were studied. SEAbs included autoantibodies to steroid-producing cells (StCA), detected by immunofluorescence, and steroid 17α-hydroxylase (17α-OHAbs) and side chain cleavage enzyme (SCCAbs) measured by immunoprecipitation assays. Gonadal function was evaluated by measuring follicle-stimulating hormone (FSH), luteinizing hormone (LH), total testosterone (TT), sex hormone-binding globulin (SHGB), anti-müllerian hormone (AMH) and inhibin-B (I-B). Twenty-six males, 10 SEAbs((+)) and 16 SEAbs((-)), were followed-up for a mean period of 7·6 years to assess the behaviour of SEAbs and testicular function. SEAbs were found in 24·7% of males with AAD, with the highest frequency in patients with autoimmune polyendocrine syndrome type 1 (APS-1). The levels of reproductive hormones in 30 SEAbs((+)) males were in the normal range according to age and were not significantly different compared to 55 SEAbs((-)) males (P > 0·05). During follow-up, both SEAbs((+)) and SEAbs((-)) patients maintained normal testicular function. SEAbs were found with high frequency in males with AAD; however, they were not associated with testicular failure. This study suggests that the diagnostic value of SEAbs in males with AAD differs compared to females, and this may be related to the immunoprivileged status of the testis.

The impact of psychological distress on weight regain in post-bariatric patients during the COVID-19 pandemic: A latent profile analysis.

OBJECTIVE: The COVID-19 pandemic has caused a global health crisis disrupting healthcare delivery for people with severe obesity who have undergone bariatric surgery. This study examined the role of psychological distress during the first Italian COVID-19 lockdown in predicting post-operative outcomes in post-bariatric patients reaching the end of the 12-18 months follow-up during the lockdown. By using a person-centered approach, groups of patients with different psychological distress profiles were identified. We hypothesized that compared to post-bariatric patients with low psychological distress, post-bariatric patients with high psychological distress will be more at risk of weight regain. METHODS: A total of 67 patients (71.6% female, Mage = 45.9) participated in this observational retrospective cohort study. Patients' anthropometric data were gathered from medical records while the weight at the end of the lockdown through phone interviews. Psychological distress, operationalized with anxiety symptoms, depressive symptoms, and sleep disturbances, was assessed by an online self-report questionnaire. RESULTS: Significant differences were highlighted in the high and low psychological distressed group in weight changes, F(1,58) = 5.2, p < 0.001, η2 = 0.3. Specifically, compared to post-bariatric patients in the low psychological distress group, those in the high psychological distressed group reported weight regained (95% CI = 1.0, 2.6). CONCLUSION: Results highlight the need to target post-bariatric patients with high psychological distress who are at risk for weight regain during the COVID-19 pandemic. Interventions mitigating psychological distress and obesogenic behaviors during future pandemics or in post-COVID times are needed in vulnerable post-bariatric patients reporting high psychological distress.

Autoimmune-polyendocrinopathy-candidiasis-ectodermal-dystrophy in Calabria: clinical, immunological and genetic patterns.

UNLABELLED: Autoimmune polyendocrinopathy-candidiasis-ectodermal- dystrophy (APECED), also known as autoimmune polyendocrine syndrome type 1 (APS-1), is a very rare disease. Diagnosis requires the presence of at least two of three major clinical features: chronic mucocutaneous candidiasis, chronic hypoparathyroidism, and Addison's disease. DESIGN: In this study, we analyzed Autoimmune Regulator (AIRE) gene mutations and genotype-phenotype correlation in APECED patients originating from Calabria, a region in the south of Italy. PATIENTS AND METHODS: Four patients and their first-degree relatives were evaluated for clinical manifestations, autoantibody presence and AIRE gene mutations. RESULTS: Three patients carried a homozygous W78R mutation on exon 2, typical of patients with APECED from Apulia; the fourth patient had a homozygous R203X mutation on exon 5, typical of APECED patients from Sicily. Clinical disease expression showed wide variability. Analysis of relatives allowed the identification of 6 heterozygotes, none of whom showed major findings of APECED. CONCLUSIONS: No AIRE gene mutations specific to Calabria were found in patients with APS-1, but mutations similar to those in patients from Apulia and Sicily. Heterozygosity for AIRE gene mutation is not associated with major findings of APECED.

Autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED) in Sicily: confirmation that R203X is the peculiar AIRE gene mutation.

BACKGROUND: Autoimmune polyendocrinopathycandidiasis-ectodermal-dystrophy (APECED), also known as autoimmune polyendocrine syndrome type 1 (APS-1) (OMIM 240300), is a very rare disease. Accepted criteria for diagnosis require the presence of at least 2 of 3 major clinical features: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism (CH), and Addison's disease (AD). AIM: We analyzed AIRE gene mutations and genotype-phenotype correlation in APECED patients originating from Sicily and in their relatives. SUBJECTS AND METHODS: In 4 patients, clinical evaluations, genetic analysis of AIRE, and APECED-related autoantibodies were performed. RESULTS: Two patients carried the mutation R203X in homozygosis on exon 5. One had the mutation R203X combined with R139X. The fourth had the R203X mutation in heterozygosis with R257X. Expression of the disease showed wide variability of clinical manifestations. Analysis of relatives allowed the identification of 10 heterozygotes for AIRE gene mutations. None of these subjects presented major findings of APECED. Three of the 4 patients were positive for autoantibodies to interferon-ω. CONCLUSIONS: In Sicily, R203X is confirmed to be the typical recessive and prevalent AIRE gene mutation on exon 5. Genotype-phenotype correlation failed to reveal a relationship between detected mutations and clinical expression. Mutations in heterozygosity in AIRE gene are not associated with major findings of APECED.

Response to high-energy photons of PTW31014 PinPoint ion chamber with a central aluminum electrode.

Since its introduction the PinPoint (PTW-Freiburg) micro-ionization chamber has been proposed for relative dosimetry (output factors, depth dose curves, and beam profiles) as well as for determination of absolute dose of small high-energy photon beams. This paper investigates the dosimetric performance of a new design (type 31014) of the PinPoint ion chamber with a central aluminum electrode. The study included characterization of inherent and radiation-induced leakage, ion collection efficiency and polarity effect, relative response of the chamber, measurement of beam profiles, and depth dose curves. The 6 and 15 MV photon beams of a Varian 2100 C/D were considered. At the nominal operating voltage of 400 V the PinPoint type 31014 chamber was found to present a strong field size dependence of the polarity correction factor and an excess of the collected charge, which can lead to an underestimation of the collection efficiency if determined with the conventional "two-voltage" method. In comparison to the original PinPoint design (type 31006) the authors found for type 31014 chamber no overresponse to large-area fields if polarity correction is applied. If no correction is taken into consideration, the authors found the chamber's output to be inaccurate for large-area fields (0.5% accuracy limited up to the 12 x 12 and 20 x 20 cm2 field for the 6 and 15 MV beams, respectively), which is a direct consequence of the stem and polarity effects due to the chamber's very small sensitive volume (0.015 cc) and cable irradiation. Beam profiles and depth dose curves measured with type 31014 PinPoint chamber for small and medium size fields were compared to data measured with a 0.125 cc ion chamber and with high-resolution Kodak EDR2 films. Analysis of the penumbra (80%-20% distance) showed that the spatial resolution of type 31014 PinPoint ion chamber approaches (penumbra broadening < or = 0.6 mm) EDR2 film results.

Dosimetric analysis of Tomotherapy-based intracranial stereotactic radiosurgery of brain metastasis.

PURPOSE: This paper analyzes Tomotherapy-based intracranial stereotactic radiosurgery (HTSRS) of brain metastasis targeting two end-points: 1) evaluation of dose homogeneity, conformity and gradient scores for single and multiple lesions and 2) assay of dosimetric criticality of completion of HTSRS procedures. METHODS: 42 treatment plans of 33 patients (53 brain lesions) treated with HTSRS were analyzed. Dose to healthy brain, homogeneity, conformity and gradient indexes were evaluated for each lesion. Influence of Field Length and multiple lesions cross-talk effect were assessed. Treatment interruption and completion was investigated using radiochromic films in order to examine the delivered dose and its robustness to patient intrafraction movement. RESULTS: The average dose homogeneity index was 1.04 ±â€¯0.02 (SD). Average dose conformity and gradient score indexes were 1.4 ±â€¯0.2 and 50 ±â€¯14 respectively. We found a strong correlation of the dose to healthy brain and conformity and gradient indexes with target(s) volume for which analytical functions were obtained. Field Length and cross-talk effect were significantly correlated with poor gradient scores, but were found not to affect dose conformity. CONCLUSIONS: Homogeneity and conformity of HTSRS plans achieved excellent scores, while dose falloff and dose to healthy brain were slightly larger when compared with non-coplanar SRS techniques. Care should be given if treating large (>3 cc) or multiple near in-plane lesions in order to reduce dose to healthy brain. Analysis of interrupted treatments suggests splitting HTSRS treatments in two consecutive fractions in order to prevent target miss and overdosage due to patient intrafraction movement.

Chagas disease knocks on our door: a cross-sectional study among Latin American immigrants in Milan, Italy.

OBJECTIVES: We aimed to assess the prevalence and risk factors for Chagas disease (CD) in Latin American immigrants and to evaluate the accuracy of diagnostic tests. Moreover, we offered to all positive subjects a complete free-of-charge clinical/instrumental evaluation as well as benznidazole treatment in order to stage the disease and verify drug tolerability. METHODS: A cross-sectional survey of CD among Latin Americans living in Milan and its metropolitan area was conducted between July 2013 and July 2014. Blood samples were tested for serologic evidence of CD together with a questionnaire covering demographic and clinical-epidemiological information. RESULTS: Forty-eight (9.6%) of the 501 tested subjects were conclusively diagnosed as having CD. The highest prevalence of CD was among those from Bolivia (43/169, 25.4%) and El Salvador (4/68, 5.9%). Older age (adjusted odds ratio (aOR)] 1.05, p =0.004), a Bolivian origin (aOR 8.80; p =0.003), being born in the department of Santa Cruz (aOR 3.72, p =0.047), having lived in mud houses (aOR 2.68; p =0.019), and having an affected relative (aOR 12.77, p =0.001) were independently associated with CD. The ARCHITECT Chagas test showed the highest sensitivity (100%) and specificity (99.8%). Twenty-nine of the subjects with CD (60.4%) underwent disease staging, 10 of whom (35.7%) showed cardiac and/or digestive involvement. Benznidazole treatment was associated with high frequency of adverse reactions (19/27, 70.4%) and permanent discontinuation (8/27, 29.6%). CONCLUSIONS: CD is highly prevalent among Bolivians and Salvadorans living in Milan. Regions with a large Latin American immigrant population should implement programmes of active detection and treatment.

Helical Tomotherapy of the breast: can thermoplastic immobilization improve the reproducibility of the treatment setup and the accuracy of the delivered dose?

PURPOSE: To evaluate the impact of thermoplastic mask immobilization in the setup reproducibility and delivered dose for Helical Tomotherapy (HT) of the breast/chest wall. METHODS: 16 patients treated with Accuray Hi-Art HT for breast-cancer were considered. Patients were positioned supine with arms extended above the head using Civco Wing Board (WB) system. In 50% of patients an Orfit thermoplastic mask was added in order to improve immobilization. Before each treatment fraction a megavoltage CT (MVCT) scan was taken and registered to the planning CT by experienced medical staff. The impact of thermoplastic mask was investigated analysing MVCT shift-roll data and MVCT dose distribution using Planned Adaptive software. RESULTS: In the analysed cases, the addition of thermoplastic mask had minor impact on the lateral, longitudinal and roll data distribution. Variance of vertical shifts was significantly reduced in the WB + Orfit group. Van Herk's margins were not affected by addition of thermoplastic immobilization. In both groups, target coverage (V95) and maximum dose (D1) were almost identical to planned values. D1 of organs at risk were not significantly different in the two groups. CONCLUSIONS: Analysis of shift-roll data shows no improvement in the group of patients immobilized with the addition of thermoplastic mask. Van Herk's margin is quite large (7-10 mm) in both groups evidencing the need to perform daily setup correction. The adapted dose distribution complies well with the planned one, showing that if MVCT is used before each treatment fraction, a 3 mm margin (setup component) for CTVs expansion could be adequate.

The determination of dose characteristics of ruthenium ophthalmic applicators using radiochromic film.

Ruthenium ophthalmic applicators are energetic beta ray sources, supplied in several shapes and dimensions, and used in intraocular tumor therapy. Because of their small dimensions, the determination of dosimetric characteristics represents a technical challenge. We developed a semiautomatic method to define surface dose, dose distribution, and percentage depth dose of such applicators using radiochromic dosimetric media. These detectors consist of a thin (7 microns) radiation sensitive layer on polyester base (100 microns total thickness) changing color as a function of radiation exposure. Transmission images of exposed films were then grabbed with a TV-digitizer system to obtain a gray-level image from which dosimetric characteristics such as isodose distribution, dose values, and homogeneity of nuclide distribution were derived. Good agreement between experimental results and Monte Carlo simulation performed using the GEANT 3 code, appear to be a confirmation of the validity of the method. Moreover while manufacturer specifications of absolute and relative dose rates present a standard deviation error of +/- 30% on dose rate and +/- 6% on accuracy of relative dose values, the proposed method reduces the errors to +/- 10% and +/- 4%, respectively.

Neutrophil function during cyclic chemotherapy for cancer disease.

A study of some aspects of granulocyte function was carried out before, during, and after cyclic chemotherapy in 9 patients surgically treated for carcinoma and in 6 patients with very advanced and inoperable cancer. In most patients, total leukocyte mobilization, Candida-stimulated nitroblue tetrazolium dye reduction, and phagocytosis increased after chemotherapy. Furthermore, delayed hypersensitivity skin reactions to PPD and above all to Varidase increased in the same cases. A significant correlation between accumulation of polymorphonuclear leukocytes into skin chambers and skin tests was found in both groups of patients (p less than 0.001). In some instances, fluctuations in the levels of circulating immune complexes without a distinct correlation between these complexes and granulocyte function were found. The data support the hypothesis that depressed granulocyte function may contribute to an increased susceptibility to infections and may be considered an additional factor that favors tumor dissemination. Chemotherapy seems to restore polymorphonuclear function and delayed hypersensitivity skin reactions.

Defective function of granulocytes in patients with cancer.

Mobilization of granulocytes into a serum-filled chamber, histochemical nitroblue tetrazolium (NBT) reduction tests, and phagocytosis were performed in 11 patients with solid tumors treated with surgical excision and chemotherapy and in 22 untreated or surgically treated patients. The results revealed a decreased mobilization (p less than 0.001) and an impaired capability of neutrophils to reduce NBT after stimulation (p less than 0.05) in both groups of patients. The decrease in the values in the stimulated reduction of NBT was more pronounced in untreated patients than in treated ones. At the same time the phagocytic activity of neutrophils on Candida albicans, which was decreased (p less than 0.01) in untreated patients, was normal in those who had been treated with chemotherapy. There were no distinctive correlations between circulating immune complexes and granulocyte function. We propose that this newly demonstrated defect in neutrophil mobilization and low median C. albicans-stimulated NBT reduction contributes more in the evolution of the tumor than in the pathogenesis of infections and that chemotherapy seems to restore a better granulocyte function.

Patients with high titers of circulating immune complexes are most likely to benefit from plasmapheresis treatment.

Intermittent flow centrifugation system was utilized in the management of 17 patients with IC diseases. 14 out of 14 patients that had high levels of ICs prior to plasmapheresis showed both clinical and immunochemical evidence of improvement with plasmapheresis. 3 patients had no evidence of circulating ICs prior to plasmapheresis: in these cases no apparent result was achieved after the apheretic therapy. Although the striking correlation between IC removal and clinical result is not a formal proof of responsibility of CIC in the pathogenesis of the disease, it is suggested that quantitative determination of CICs (utilizing several different recognition units) may be a useful parameter in the decision to apply plasmapheresis in the therapy of selected autoimmune diseases.

[Plasma exchange treatment in a patient with severe Schoenlein-Henoch purpura]. / Il trattamento mediante plasma-exchange di una paziente con grave porpora di Schoenlein-Henoch.

A patient with severe Henoch-Schoenlein purpura was successfully treated by combined plasmapheresis and cyclophosphamide therapy. PE proved to be effective in the symptomatic treatment of the disease. Its possible role in the prevention and treatment of HS nephritis is suggested.

Plasma exchange in neurological diseases. A critical approach.

The rationale for and results of plasma exchange (PE) in the therapy of different immune-mediated neurological diseases such as myasthenia gravis, multiple sclerosis, acute and chronic-relapsing Guillain-Barré syndromes, polymyositis, dermatomyositis and amyotrophic lateral sclerosis are reviewed. Dialysis dementia and Refsum's disease, subacute sclerosing panencephalitis and schizophrenia are mentioned, too. If we exclude the treatment of acute Guillain-Barré syndrome, where PE alone appears to be sufficient to produce recovery or improvement, the combined use of immunosuppressive drugs and/or lymphocytapheresis is probably needed in the treatment of the other diseases. PE allows the disease to be controlled rapidly while long-term pharmacological control is established. An underlying theme in this review is the need of adequately controlled studies or at least of large case lists with exhaustive reports concerning both positive and negative results since a new perspective is needed for this topic. Nonetheless, a number of uncontrolled observations suggest that probably PE effectiveness in most immune-mediated neurological diseases could be proven if the requisite trials were performed.

An evaluation of N-ethyl-maleimide-induced lipid peroxidation in platelet concentrates stored at 4 or 22 degrees C.

A method for the quality control of platelet viability, based on N-ethyl-maleimide (NEM)-induced lipid peroxidation, is reported. Duplicate platelet concentrates from individual donors were stored at 22 and 4 degrees C, respectively. At time 0 and at 24-hour intervals, pH, O2 and CO2 tensions, ADP-induced aggregation, glass adhesivity, hypotonic shock response (HSR) and NEM-induced lipid peroxidation were measured. A highly significant correlation between NEM-induced lipid peroxidation and HSR was established, which suggests that the former method can be used for the in vitro prediction of posttransfusion survival of preserved platelets.

[The post-transfusional toxoplasmosis (author's transl)]. / Note sulla toxoplasmosi post-trasfusionale.

The sera of 85 patients suffering from Cooley anemia, 100 normal children of the same group of age, and 550 blood donors have been tested for the presence of anti-toxoplasma antibodies by indirect immunofluorescence test. The sera of 10 thalassemic patients gave positive reactions at a dilution reaging from 1/64 to 1/2048; in 2 sera a positive reaction was obtained with specific anti-IgM antibodies, indicating an active infection. In the control group, only 2 positive sera have been found. In donors group, instead, 5 sera were positive, and in 2 cases IgM antibodies were detectable. The analysis of data confirms, although indirectly, that heavily transfused patients are at a particular risk to acquire the infection from Toxoplasma Gondii.

Fibronectin and cryoprecipitation.

Fourteen patients with essential mixed cryoglobulinemia were studied. The relevance of fibronectin (FN) in cryoprecipitation seems to be of relative importance since only two thirds of the cryoprecipitates have a higher cryocrit level when FN is present. On the other hand, the other samples show a lower precipitating activity after plasma heating at 60 degrees C. This reduction may reflect either a structural FN modification by heating or the denaturation of other cryoprecipitating molecules. It is possible, even if not necessary, that at least in vitro FN plays a role in the cryoprecipitate formation.