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Non-small cell lung carcinoma (NSCLC) being multifaceted, it acquires genetic and epigenetic variations. These changes tend to control differentiation, proliferation, invasion, and metastasis of tumors. Surgery considered the most effective treatment for NSCLC in the initial stage, about 70 to 80% of patients are not convinced about it essentially because of locoregional tumor extension, extrathoracic spread, or poor physical and functional condition when diagnosed. Cytokines have proved to be successful in cancer treatment, but the impact of certain promising targets on different immune cell populations is still unknown. In the present study, a total of 250 papers including 230 research papers and 20 review papers, extracted from PubMed and Scopus and published from December 31, 1995, to December 31 2021, are reviewed. The most important involved-chemokines in lung cancer including α-chemokine (CC), β-chemokine (CXC), γ-chemokine (C), and δ-chemokine (CX3C). While essential cytokines in lung cancer including TNF-α, IFN- γ, TGF-β and interleukins such as IL-6, IL-1β, IL-8, and IL-18 are introduced. The pathological role of such chemokines and cytokines in cancer signaling pathways are investigated.

The understanding of the Earth through global land monitoring from satellite images paves the way towards many applications including flight simulations, urban management and telecommunications. The twin satellites from the Sentinel-2 mission developed by the European Space Agency (ESA) provide 13 spectral bands with a high observation frequency worldwide. In this paper, we present a novel multi-temporal approach for land-cover classification of Sentinel-2 images whereby a time-series of images is classified using fully convolutional network U-Net models and then coupled by a developed probabilistic algorithm. The proposed pipeline further includes an automatic quality control and correction step whereby an external source can be introduced in order to validate and correct the deep learning classification. The final step consists of adjusting the combined predictions to the cloud-free mosaic built from Sentinel-2 L2A images in order for the classification to more closely match the reference mosaic image.

Automatic footprint extraction from remote sensing images remains a popular yet challenging research topic, driven by numerous applications such as telecommunications and urban management. In this paper, we propose an automatic pipeline for reliable building footprint extraction from high-resolution satellite images. The proposed method takes as the input two images with the corresponding rational polynomial coefficient models, applies deep learning to each image for building segmentation and estimation of contour orientations, then matches extracted building footprints from two images for estimating reliability of each footprint. The pipeline has proven to be efficient for reconstructing accurate building footprints, and estimated reliability scores help to efficiently validate and correct predicted maps.

Automatic city modeling from satellite imagery is a popular yet challenging topic in remote sensing, driven by numerous applications such as telecommunications, defence and urban mamagement. In this paper, we present an automated chain for large-scale 3D reconstruction of urban scenes with a Level of Detail 1 from satellite images. The proposed framework relies on two key ingredient. First, from a stereo pair of images, we estimate a digital terrain model and a digital height model, by using a novel set of feature descriptors based on multiscale morphological analysis. Second, inspired by recent works in machine learning, we extract in an automatic way contour polygons of buildings, by adopting a fully convolutional network U-Net followed by a polygonization of the predicted mask of buildings. We demonstrate the potential of our chain by reconstructing in an automated way different areas of the world.

International audience; Automatic 3D reconstruction of urban scenes from stereo pairs of satellite images remains a popular yet challenging research topic, driven by numerous applications such as telecommunications and defense. The quality of reconstruction results depends particularly on the quality of the available stereo pair. In this paper, we propose an operational pipeline for large-scale 3D reconstruction of buildings from stereo satellite images. The proposed chain uses U-net to extract contour polygons of buildings, and the combination of optimization and computational geometry techniques to reconstruct a digital terrain model and a digital height model, and to correctly estimate the position of building footprints. The pipeline has proven to be efficient for 3D building reconstruction , even if the close-to-nadir image is not available.

Global Earth observation from satellite images is an active research topic, driven by numerous applications, such as telecommunications, defence, natural hazard monitoring and urban management. The recently launched twin Sentinel-2 satellites acquire 13-band optical data with a 2–5 day revisit time, freely available for any use, and thus very valuable for global Earth observation. In this paper, we present a completely automatic operational chain for a global cloud-free mosaic and classification of Sentinel-2 images. The proposed pipeline enables producing the world 10-m cloud-free mosaic, and a 6-class landcover classification map.

Smart devices and Internet-based applications (apps) are largely used in allergic rhinitis and may help to address some unmet needs. However, these new tools need to first of all be tested for privacy rules, acceptability, usability, and cost-effectiveness. Second, they should be evaluated in the frame of the digital transformation of health, their impact on health care delivery, and health outcomes. This review (1) summarizes some existing mobile health apps for allergic rhinitis and reviews those in which testing has been published, (2) discusses apps that include risk factors of allergic rhinitis, (3) examines the impact of mobile health apps in phenotype discovery, (4) provides real-world evidence for care pathways, and finally (5) discusses mobile health tools enabling the digital transformation of health and care, empowering citizens, and building a healthier society. © 2019 American Academy of Allergy, Asthma & Immunology

Lipomatous hypertrophy is an uncommon benign lesion of the atrium, generally asymptomatic, characterized by unencapsulated accumulation of adipose tissue entrapping cardiomyocytes. This pathology generally remains unnoticed and often emerges as an occasional finding. Here, we report two cases from our hospital including a review of the available literature.

Attempts aimed at inducing food tolerance through oral food desensitization (OFD) for the treatment of IgE-mediated food allergies are increasing. In Italy, a number of allergy centres offer this procedure.To collect information on how these centres are organized, how patients are selected, the methods used to administer OFD and how adverse reactions are managed.A questionnaire was e-mailed to all the Italian allergy centres offering OFD.The survey shows a high degree of variability between centres. A correct diagnosis of food allergy is crucial for selecting patients for OFD. In the Italian allergy centres, oral food challenges are mostly open label (84%), but in 16% of cases they are single-blind (8%) or double-blind (8%). A high proportion of allergy centres (83%) offer OFD to children presenting forms of anaphylaxis triggered by traces--or very low doses--of food allergen. The majority of allergy centres (76%) enroll patients over 3 years of age, with 44% enrolling patients above the age of 5. Not-controlled asthma, unreliability of parents in the management of OFD and/or risk of adverse events, are the main reasons for exclusion from the procedure.Although OFD may sometimes be successful and may be considered a valid alternative to an elimination diet, further randomized controlled trials are needed, in order to clarify some controversial points, such as the characteristics of the child undergoing OFD, and the methods of food preparation and administration. Moreover, further studies should further investigate OFD safety, efficacy and costs.

BACKGROUND: Higher vasopressin (AVP) levels have been found in the inferior petrosal sinus ipsilateral to the ACTH-secreting adenoma than in the contralateral one, suggesting a potential pathogenetic role of AVP in Cushing's disease. DESIGN: In order to investigate AVP release, plasma ACTH and AVP concentrations were assayed in the inferior petrosal sinuses and in the peripheral blood before and after CRH stimulation. PATIENTS: Twenty patients with Cushing's disease and 12 with other pituitary diseases were subjected to simultaneous and bilateral inferior petrosal sinus sampling for diagnostic purposes. Ten healthy sex and age-matched subjects served as control for peripheral AVP values. MEASUREMENTS: Plasma ACTH concentrations were measured by RIA using commercial kits. Plasma AVP concentrations were assayed by RIA in acetone extracts of 1-2 ml plasma. RESULTS: Plasma AVP levels in the inferior petrosal sinuses were significantly higher in Cushing's disease than in patients with other pituitary diseases (P < 0.05) and in both groups AVP levels were higher in the inferior petrosal sinuses than in the peripheral blood (P < 0.01). In Cushing's disease, ACTH, but not AVP levels, were higher in the inferior petrosal sinus ipsilateral to the adenoma than in the contralateral one (P < 0.01). Seven patients showed a significant ACTH and AVP increase (greater than 50% of baseline) after CRH stimulation in the inferior petrosal sinus ipsilateral to the adenoma. Conversely, no change was found in AVP levels in the remaining 13 patients. When AVP values were analyzed in relation to surgical cure, higher inferior petrosal sinus levels (P < 0.05) were found in 6 patients with poor outcome: 4 of these patients had significantly decreased plasma AVP concentrations (by 32-43% of baseline) after CRH bolus. Peripheral AVP levels were similar in healthy subjects and patients with Cushing's disease whereas they were significantly reduced in patients with other pituitary diseases (P < 0.002). CONCLUSIONS: The results of this study show that patients with Cushing's disease and poor surgical outcome had the highest AVP levels in our series. CRH administration caused different effects on AVP levels: it increased them in 35% of patients whereas there was no response in the remaining patients. On the basis of these findings, it is hypothesized that AVP might be involved in the persistence of ACTH hypersecretion in a subset of patients poorly responsive to surgery.

Forecasting symptoms of pollen-related allergic rhinoconjunctivitis at the level of individual patients would be useful to improve disease control and plan pharmacological intervention. Information Technology nowadays facilitates a more efficient and easier monitoring of patients with chronic diseases. We aimed this study at testing the efficiency of a model to short-term forecast symptoms of pollen-AR at the "individual" patient level. We analysed the data prospectively acquired from a group of 21 Italian children affected by pollen-related allergic rhinoconjunctivitis and recorded their symptoms and medication "Average Combined Score" (ACS) on a daily basis during April-June 2010-2011 through an informatics platform (Allergymonitor™). The dataset used for prediction included 15 variables in four categories: (A) date, (B) meteo-climatic, (C) atmospheric concentration of 5 pollen taxa, and (D) intensity of the patient's IgE sensitization. A Partial Least Squares Discriminant Analysis approach was used in order to predict ACS values above a fixed threshold value (0.5). The best performing predicting model correctly classified 77.8% ± 10.3% and 75.5% ± 13.2% of the recorded days in the model and test years, respectively. In this model, 9/21 patients showed ≥ 80% correct classification of the recorded days in both years. A better performance was associated with a higher degree of patient's atopic sensitization and a time lag1. Symptom forecasts of seasonal allergic rhinitis are possible in highly polysensitised patients in areas with complex pollen exposure. However, only predictive models tailored to the individual patient's allergic susceptibility are accurate enough. Multicenter studies in large population samples adopting the same acquisition data system on smart phones are now needed to confirm this encouraging outcome.

The mechanism of thermooxidative degradation at 80°C of a narrow distribution linear ethylene-butene copolymer has been described by determining the chemical modifications and molecular weight distribution changes occurring in the polymer chains, and successively fitting the experimental results with a mathematical model which allows scission and crosslinking reactions to occur simultaneously. Degradation takes place with autoacceleration and from the computer simulation a cubic dependence of the degree of crosslinking and degree of scission with exposure time was obtained. It was established that in this system scissions predominate over crosslinking, in accordance with the drop in average molecular weights and the concomitant accumulation of oxidation products. Fil: Chiantore, O.. Università di Torino; Italia Fil: Tripodi, Silvana Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Planta Piloto de Ingeniería Química. Universidad Nacional del Sur. Planta Piloto de Ingeniería Química; Argentina Fil: Sarmoria, Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Planta Piloto de Ingeniería Química. Universidad Nacional del Sur. Planta Piloto de Ingeniería Química; Argentina Fil: Vallés, E.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Planta Piloto de Ingeniería Química. Universidad Nacional del Sur. Planta Piloto de Ingeniería Química; Argentina

BACKGROUND Osteoporosis is common in patients with Cushing's disease and is likely due to an imbalance between bone formation and resorption. Alendronate is an aminobisphosphonate that is able to increase bone mass mainly by inhibiting bone resorption. OBJECTIVE We have evaluated the effect of chronic treatment with alendronate on bone mineral density (BMD) in patients with Cushing's disease. PATIENTS 39 patients with Cushing's disease entered this study. 39 age-, sex- and BMI-matched normals served as controls for baseline evaluation. The 39 patients were divided into four groups: 1) 10 patients with active disease treated with alendronate and ketoconazole; 2) 11 patients with inactive disease treated with alendronate; 3) 8 patients with active disease treated with ketoconazole alone, 4) 10 patients with inactive disease received no treatment. TREATMENT PROTOCOL Alendronate was given for 12 months in a dose of 10 mg orally once daily after fasting at 0800 h in the morning. Ketoconazole was given in a dose of 200–600 mg orally daily, when pituitary surgery was unsuccessful. STUDY DESIGN Lumbar spine (L1–L4) and femoral neck BMD, serum osteocalcin (OC), urinary cross-linked N-telopeptides of type I collagen (Ntx) levels were evaluated at study entry, in patients and controls, and were repeated after 6 and 12 months in the 39 patients. RESULTS BMD values were lower in patients with Cushing's disease than in controls at both L1–L4 (0.72 ± 0.4 vs. 1.01 ± 0.6 g/cm2, P

Background. Oral food challenge (OFC) is the gold standard for the diagnosis of food allergy (FA), but it is risky, expensive and time-consuming. Many studies aimed to avoid OFC by finding a cut off (CO) of skin prick test (SPT) to predict a positive outcome of OFC. Unfortunately the results of these studies are poorly reproducible for various reasons, including the absence of known protein concentration in the extracts. It has also been documented that some doctors mistakenly attributed some symptom/disease, for example recurrent respiratory infections of the upper airways, to the FA, expecially cow milk allergy (CMA). These doctors often performed SPT in their studies to confirm, if the result was positive, their diagnostic suspicion and prescribe an elimination diet without seeking the advice of allergy specialist (AS) and without making an OFC. Objective. To test the diagnostic performances of SPT with fresh cow's milk and commercial extracts of casein, beta-lactoglobulin, alpha-lactoalbumin at known protein concentrations (Milk Prick Four [MP4] test). To look for 2 clusters of SPT CO with positive predictive value (PPV)gt; 95%, one for AS, one for general practitioner (GP). Methods. A prospective study was carried out on 191 children referred by their GP to the allergy center for suspected immediate-type CMA (iCMA). Based on the history, the allergist has divided the children into two groups: a) group A, children with suspected (subgroup A1, 55 children) or known (subgroup A2, 27 children) diagnosis of iCMA; b) group B, 109 children with a clinical history incompatible with iCMA suspicion according to the AS (in this case the GP was wrong to send those patients to the allergy center). SPT with MP4 test was performed on all patients, and OFC was performed on all patients of group A. CO with PPVgt; 95% was calculated separately for the entire population of 191 children (CO for GP) and for the only group A (CO for AS). Results. Fresh cow's milk SPT was the most sensitive single prick test (sensitivity [SE] 94%, negative predictive value [NPV] 98%). The positivity to any of 3 SPT extracts (performed at the same time) had the same SE and NPV of the single fresh cow's milk SPT. Moreover, fresh cow's milk SPT or any of 3 SPT extract had 100% SE and 100% NPV, having excluded 2 children with Food Protein Induced Enterocolitis Syndorme from data analysis. MP4 CO for GP allow a total savings of 4% of OFC, a percentage that rises to 22% in the subgroup A2, and does not give false positives. MP4 CO for AS allow a total saving of 33% of OFC, rising to 67% in the subgroup A2, but they give a 7/82 false positives in group A. SPT CO of alpha-lactoalbumin had the best performance in both settings. Conclusion. MP4 is a safe and cheap test, easy to perform. All doctors may be confident in excluding iCMA if fresh cow's milk SPT is negative. GP could perform SPT to fresh milk at his own clinic, and safely diagnose iCMA by using our CO for GP, although this may happen only in a few cases. MP4 test performed by AS can help save a greater number of OFC, especially among children with known diagnosis of iCMA.

Food-dependent-exercise-induced anaphylaxis (FDEIA) is characterized by anaphylactic symptoms after exercise following ingestion of food. We present a case of FDEIA induced by Rosacee fruits showing some diagnostic problems.A 12 years-old boy with seasonal allergy to olive and cypressus pollens, experienced two distinct episodes of FDEIA, grade 4 and 3 of the Sampson Scale respectively, during intense exercise, about 30 minutes after eating a peach with peel or some cherries. SPT with commercial peach extract and fresh Rosacee fruits scored positive while SPT with a date palm profilin-enriched extract was negative. On in vitro tests total IgE were 44 kU/l and IgE for peach, cherry, Prup 3, Prup 1, Bet v 1, Bet v 2, Bet v 4 were negative. SPT with Prup 3 UniCAP device (cellulose polymer in a plastic reserve highly binding allergen protein) was negative. An oral food challenge, performed at rest using a commercial peach juice, scored negative. An immunoblot analysis performed with peach extract was negative.The main peculiarity of this case of FDEIA is the discrepancy between positive SPT and negative in-vitro findings. The positive SPT with the commercial peach extract suggested hypersensitivity to lipid transfer protein; however, no IgE reactivity to rPrup 3 was found in-vitro. The negative immunoblot analysis, possibly caused by the low levels of specific IgE, did not allow us to investigate the nature of the relevant allergen protein further. It is possible that this patient reacted to a different peach allergen or, alternatively, that he recognized an isoform of LTP that is different fr-om that in Uni-CAP.This case emphasizes once more the diagnostic relevance of SPT with extracts and fresh material to be performed before investigating IgE reactivity to single allergen components in-vitro.

In light of the current evidence, subcutaneous immunotherapy (SCIT) can be suggested for use in pediatric allergic rhinitis and asthma as treatment and preventive management. Sublingual specific immunotherapy (SLIT) can be suggested for use in children with allergic rhino-conjunctivitis, and seasonal asthma, especially if they are mono-sensitive, for a duration of no less than three years. The earlier treatment begins, the better is the outcome. Further randomized, long-term trials in SLIT for the treatment of perennial asthmatic children are still needed. As regards the choice between the methods of administration (the traditional SCIT or the innovative SLIT), it is up to the physician to find the right equilibrium in the single patient.

The effect of corticotropin (ACTH)-releasing hormone (CRH) administration on alpha-melanocyte-stimulating hormone (alpha-MSH), ACTH and beta-endorphin (beta-EPH) was evaluated in the inferior petrosal sinuses and in the periphery of 30 patients affected with Cushing's disease subjected to simultaneous and bilateral inferior petrosal sinus sampling for diagnostic purposes. Baseline PRL levels, sensitivity to dexamethasone and surgery outcome were compared to alpha-MSH response. CRH bolus did not modify alpha-MSH concentrations either in the inferior petrosal sinuses or in the periphery in the 30 patients considered as a whole. In 7 of 30 patients, however, a greater than 50% increase over baseline alpha-MSH levels (from 50 to 115.5%) was recorded in the inferior petrosal sinus ipsilateral to the adenoma (from 42.9 +/- 1.7 to 76.4 +/- 4.6 ng/l; p < 0.001), whereas no change was found in the contralateral inferior petrosal sinus or in the periphery. Conversely, as expected, ACTH and beta-ELI significantly increased in all the patients after CRH both in the inferior petrosal sinuses and in the periphery (particularly in the inferior petrosal sinus ipsilateral to the adenoma). No difference in sensitivity to dexamethasone (urinary cortisol percent decrease: 66.4 +/- 4.9 vs. 67.8 +/- 3.4) and surgery outcome (chi 2 test: p = 0.7) was found between patients with alpha-MSH response to CRH and patients without such a response. By contrast, baseline PRL levels, although being normal in both groups, were significantly higher in patients with alpha-MSH response to CRH (18.1 +/- 1.6 vs. 10.1 +/- 0.7 micrograms/l; p < 0.001). In conclusion, the results of the present study suggest that in a subset of patients with Cushing's disease (23.3% of our series) alpha-MSH may be released after the administration of CRH together with ACTH and beta-EPH by adenomatous corticotrophs. In this subset of patients, PRL levels may be in the upper normal range.

Twenty-six consecutive patients with ACTH-dependent Cushing syndrome were subjected to simultaneous, bilateral inferior petrosal sinus sampling for ACTH assay before and after ACTH-releasing hormone (CRH) stimulation. The baseline ACTH inferior petrosal sinus/periphery (IPS/P) ratio was > or = 2 in 12 of 26 patients (46%), whereas the CRH-stimulated IPS/P ratio was > or = 3 in 19 of 26 patients (73%). A pituitary adenoma, ACTH-secreting at immunostaining, was surgically proved in all of the 19 patients who had an ACTH IPS/P ratio > or = 2 basally or > or = 3 after the CRH test but also in three other patients who did not have such ratios. The value of the basal IPS/P ratio and the complete lack of ACTH increase after CRH led to the diagnosis of an ectopic ACTH syndrome in four patients: a bronchial carcinoid was found in three patients, and the site of the tumor was still unknown in the other. In conclusion, the CRH test improved the diagnostic accuracy of inferior petrosal sinus sampling from 61.5% (12 pituitary, 4 ectopic) to 92.0% (19 pituitary, 4 ectopic). Thus it should be performed during the diagnostic process.

Background. It is assumed that IE is more common in older adults, however no data regarding risk factors for IE are available from large prospective studies. Methods To delineate risk factors for IE in aged individuals we analyzed data from 1779 consecutive IE cases prospectively enrolled in the ICE-PCS. Patients >64 (n=689) were compared with patients 64 p

In 29 consecutive patients with adrenocorticotropin (ACTH)-dependent Cushing's syndrome, we compared the usefulness of multiple baseline ACTH evaluations (10/29), multiple hormone evaluation (29/29) and ACTH-releasing hormone (CRH) stimulation (21/29) during simultaneous and bilateral inferior petrosal sinus sampling. The basal inferior petrosal sinus/periphery ratio for ACTH concentrations was greater than 2 in 18 of the 29 patients and CRH challenge caused the appearance of an inferior petrosal sinus/periphery ratio greater than 3 in 6 other patients. The presence of an ACTH-secreting adenoma was surgically proven in all the 24 patients who had an ACTH inferior petrosal sinus/periphery ratio greater than 2 basally or greater than 3 after the CRH test but also in 1 patient who had an inferior petrosal sinus/periphery ratio lower than 2 basally or 3 after the CRH test. In 4 patients, both the very high peripheral ACTH levels, the inferior petrosal sinus/periphery ratio and the complete lack of ACTH increase after CRH indicated the presence of an ectopic ACTH syndrome: a bronchial carcinoid was found in 2 patients, whereas the site of the tumor is still unknown in the remaining 2. An ACTH intersinus gradient greater than 1.4 was found in 23 patients. Among these 23 patients, the side of the adenoma was correctly predicted in 19 patients and wrongly in 4.(ABSTRACT TRUNCATED AT 250 WORDS)

To investigate the curative effects of thermal water and thermal muds in various cutaneous pathologies.Modifications of phmetry and sebometry using sulphur thermal muds in normal, dry and seborrheic skin have been studied. The three groups of patients have been submitted to a 14 day treatment with thermal muds.The application of thermal mud normalized the value of cutaneous pH and sebometry.These beneficial effects are long-lasting in individuals who have a prolonged treatment with thermal muds.

BACKGROUND: Osteoporosis is common in patients with Cushing's disease and is likely due to an imbalance between bone formation and resorption. Alendronate is an aminobisphosphonate that is able to increase bone mass mainly by inhibiting bone resorption. OBJECTIVE: We have evaluated the effect of chronic treatment with alendronate on bone mineral density (BMD) in patients with Cushing's disease. PATIENTS: 39 patients with Cushing's disease entered this study. 39 age-, sex- and BMI-matched normals served as controls for baseline evaluation. The 39 patients were divided into four groups: 1) 10 patients with active disease treated with alendronate and ketoconazole; 2) 11 patients with inactive disease treated with alendronate; 3) 8 patients with active disease treated with ketoconazole alone, 4) 10 patients with inactive disease received no treatment. TREATMENT PROTOCOL: Alendronate was given for 12 months in a dose of 10 mg orally once daily after fasting at 0800 h in the morning. Ketoconazole was given in a dose of 200-600 mg orally daily, when pituitary surgery was unsuccessful. STUDY DESIGN: Lumbar spine (L1-L4) and femoral neck BMD, serum osteocalcin (OC), urinary cross-linked N-telopeptides of type I collagen (Ntx) levels were evaluated at study entry, in patients and controls, and were repeated after 6 and 12 months in the 39 patients. RESULTS: BMD values were lower in patients with Cushing's disease than in controls at both L1-L4 (0.72 +/- 0.4 vs. 1.01 +/- 0.6 g/cm2, P < 0.05) and femoral neck (0.69 +/- 0.3 vs. 0.96 +/- 0.6 g/cm2, P < 0.05). In the 39 patients with Cushing's disease considered as a whole, serum OC levels were lower (1.1 +/- 0.1 vs 1.5 +/- 0.1 nmol/l, P < 0.01), while Ntx values were higher than in controls (168 +/- 25 vs. 61 +/- 31 nmol BCE/mmol creatinine, P < 0.01). In the alendronate-treated groups, serum OC levels increased, while Ntx levels significantly decreased after 6 and 12 months of treatment without any significant difference between the two groups. BMD values measured at L1-L4 and femoral neck significantly increased after 12 months of therapy. In patients of group 4, a significant increase of serum OC levels and a significant decrease of Ntx levels were observed together with a slight increase of BMD values after 12 months. No significant change in either biochemical markers or BMD values was found in patients of group 3. CONCLUSIONS: Patients with Cushing's disease have osteoporosis which needs to be rapidly reversed to limit the risk of fracture. The results of the present study show that a 12 month treatment period with alendronate induced an improvement in bone mineral density greater than in untreated patients.

The mutagenicity of a new biliary acid, taurohyodeoxycholic acid (THDCA, Io, Praxis, CAS 2958-04-5), was assayed by using 5 different tests. The Ames test (reverse mutation assay on Salmonella typhimurium) and the DNA damage and repair test (in Saccharomyces cerevisiae) allowed to study the genetic THDCA-induced mutations in prokaryotes and eukaryotes (doses of 100, 200 and 400 micrograms/plate or 100, 200 and 400 micrograms/ml, respectively). In vivo and in vitro chromosomal aberrations were studied by using micronucleus test in mice (doses of 100, 220 and 500 mg/kg in oral study and 50, 100 and 200 mg/kg in subcutaneous study) and human lymphocytes cytogenetic test (doses of 50, 100, 220 and 500 micrograms/ml of THDCA). At last the host-mediated assay was performed on THDCA-treated mice (following oral or subcutaneous administration) in order to test the potential mutagenic activity of its metabolites on a S. typhimurium strain. The results obtained in these studies showed that THDCA did not induce any signs of promutagenic, mutagenic or clastogenic direct or metabolite-mediated activity.

Fifty-two-week oral toxicity and 24-week intramuscular toxicity of a new synthetized biliary acid, taurohyodeoxycholic acid (Io, Praxis, CAS 2958-04-5) were investigated in dogs. Taurohyodeoxycholic acid was orally administered at dose levels up to 500 mg/kg/d and i.m. administered at dose levels up to 200 mg/kg/d. No deviations from normality were observed in mortality, physical appearance and general behaviour of the treated animals. Food and water consumption and body weight gain of treated groups did not differ from those of control animals. No treatment-related changes were observed in hematology, serum biochemistry, urinalysis, organ weights and post-mortem macroscopic or histopathological examinations. No dose- or sex-related differences were observed. The no-effect dose level was estimated to be 500 mg/kg/d in the chronic oral toxicity study and 200 mg/kg/d in the intramuscular study.

In this study we investigated the anticholelithogenic and choleretic activities and the general pharmacological action of taurohyodeoxycholic acid (THDCA, Io, Praxis, CAS 2958-04-5), a new biliary acid advocated for use as anticholelithogenic agent. THDCA had no significant activity on the CNS (spontaneous locomotor activity, body temperature, coordinated movement, respiration); it also had no significant anticonvulsant or central anticholinergic actions. With regard to the action on the cardiovascular system, THDCA administration did not give rise to significant changes in blood pressure or ECG. Investigation of its action on the gastrointestinal system revealed no significant changes in the intestinal transport of charcoal after treatment. However, biliary flow and biliary solids content were increased by THDCA intraduodenal doses of 300 mg/kg b.w. In mice fed with lithogenic diet THDCA administration (230 and 450 mg/kg b.w. for 8 weeks) significantly decreased gallstone and steatosis incidence.

Fifty-two-week oral toxicity and 24-week intraperitoneal toxicity of a new synthetized biliary acid, taurohyodeoxycholic acid (Io, Praxis, CAS 2958-04-5), were investigated in rats. Taurohyodeoxycholic acid was orally administered at dose levels up to 500 mg/kg/d and intraperitoneally administered at dose levels up to 200 mg/kg/d. The treated animals showed no deviations from normality in mortality, physical appearance and general behavior. Food and water consumption and body weight gain of the treated groups did not differ from those of the control. No treatment-related changes were observed in hematology, serum biochemistry, urinalysis, organ weights and post-mortem macroscopic or histopathological examinations. No dose- or sex-related differences were observed. The no-effect dose level was estimated to be 500 mg/kg/d in the chronic oral toxicity study and 200 mg/kg/d in the intraperitoneal study.

The reproductive toxicity of taurohyodeoxycholic acid (3 alpha, 6 alpha-dihydroxy-5-beta-cholanoyl-2-amino-ethyl-sulfonic acid, THDCA, Io, Praxis, CAS 2958-04-5), a new synthetized biliary acid patented in Europe, Japan and the United States for prevention and therapy of gallstones and related symptoms, was assayed by performing segment I (fertility and general reproductive performance) and segment II (teratology) studies. In the first study THDCA was administered (100, 220 or 500 mg/kg by oral route) to male and female rats prior to and in the early stage of pregnancy. No adverse effects or dose-related abnormalities were observed in the reproductive performance of either sex; no death or evidence of teratogenicity in fetuses were also observed. In the second study THDCA was administered (100, 220 or 500 mg/kg by oral route) to rats and rabbits during the fetal organogenesis period. No maternal toxicity, teratogenicity or adverse effects on growth of embryos and fetuses and no reduction of the viability index were observed. From these studies the no-effect dose can be estimated at 500 mg/kg.

The pharmacokinetic properties of a new gastroprotective pharmaceutical formulation of diclofenac (CAS 15307-79-6) were investigated in twelve healthy volunteers. In this new form the diclofenac is the nucleus of sequential sucralfate-covered tablets. The experimental design was an open, random, two period balanced cross-over study. All the subjects received a single oral dose of 50 mg diclofenac contained in the new formulation or in the reference enteric-coated tablets. Plasma concentrations of diclofenac were determined at 0.5, 1, 2, 4, 6, and 8 h after drug administration using HPLC method. After administration of a diclofenac-sucralfate association diclofenac was quickly absorbed and the peak plasma concentration (0.773 +/- 0.08 microgram/ml) was achieved in about 1 h. AUC(0-infinity) value was about 1.8 micrograms/ml/h and the mean elimination half-life was 1.20 +/- 0.12 h. The pharmacokinetic profile of diclofenac-sucralfate association is similar to the values reported in previous papers for enteric-coated forms; anyway an early occurrence of the peak plasma concentration was observed for the new formulation. The new diclofenac-sucralfate association shows a different rate of absorption (namely an early and greater peak plasma concentration of diclofenac) and a similar extent of absorption (AUC(0-infinity) being not statistically different) as compared to the reference enteric-coated tablets of 50 mg diclofenac. These results could be related to the delaying and protective effect of sucralfate whose action is different from the one carried by the coat of the enteric-coated tablets.

In a cross-over study performed on 10 patients the intranasal absorption of calcitonin contained in three formulation spray was evaluated. One of them contained biliary acid (sodium taurocholate) as the absorption promoting factor while the other two drugs did not. The dosage of calcitonin in blood was effected by means of radioimmunoassay using salmon calcitonin marked with I126 in competition to the one present in the sample for a limited quantity of specific antibodies for salmon calcitonin. The minimum measurable quantity of calcitonin is 10 pg and the response is linear including values between 20% and 80%. It is observed that the plasmatic concentration of calcitonin dosed in different times after administration of the drug containing sodium taurocholate are always significantly higher (Student "t" test for unpaired data, p less than 0.005) than the measurements after administration of the other two drugs. They are about 8 times higher at the first half an hour, about 6 times after an hour and again double at the second hour. The AUC calculated for sodium taurocholate containing drug (1629 pg/ml/h) results significantly higher in relation to the other two drugs (1133 and 926 pg/ml/h) indicating a better bio-availability of calcitonin contained in that spray. The relative bioavailability between calcitonin spray with sodium taurocholate and the other two drugs in reference resulted to 144% and 176%. The presence of a transmucosal absorption promoting factor at the level of a nasal mucosa, represented in this case by sodium taurocholate, enhances significantly the absorption and the bioavailability of calcitonin present in the formulation spray.

The Authors analyse the functional areas (cortical, paracortical, germinal center, medullary, histiocytosis of the sinuses) of regional lymph nodes in women having uterine carcinoma and previously treated with Thymostimuline, and who were operated on respectively 8 and 14 days after inoculation. They also evaluate the degree of significance when compared with a control group treated locally with a physiological solution. The number of lymph nodes examined is at least 5, and the stereological analysis was carried out with the use of a grid: 200 points, actual area 200 cm2, effective area at the level of the preparation 0.32 mm2 (250 X). The Authors examine the results obtained after 8 days' action by Thymostimuline, and, after 14 days, the difference between the 8-day-after and the 14-day-after administration results, and those between the cervical and the endometrial. 4 women with uterine cancer (Stages I and II) and treated with the same doses of physiological saline solution were used as controls.

A group of 23 patients with dermatophyte or Candida infections of fingernails or toenails were treated with itraconazole 100 mg daily in an open-label study. Treatment was continued for up to 4 months for fingernails and up to 6 months for toenails. At the end of the treatment, 12 patients were cured and eight were not. The response rate for fingernail infection was 54.5% and for toenail infection, 70%. Three patients had slight gastrointestinal side-effects that promptly remitted after stopping the drug.