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Toluene diisocyanate (TDI)-induced asthma is a common cause of occupational asthma and it affects 5–15% of the exposed population suggesting an underlying genetic susceptibility. To investigate the role of genetic factors in the development of TDI-induced asthma, we analyzed the distribution of human leukocyte antigen (HLA) class I genes and of tumor necrosis factor (TNF)- α A-308G polymorphism in 142 patients with TDI-induced asthma and in 50 asymptomatic exposed subjects. Neither the distribution of HLA class I antigens nor the distribution of TNF- α A-308G polymorphism was different between patients with TDI-induced asthma and asymptomatic exposed subjects. These results suggest that HLA class I antigens and TNF- α A-308G are not associated with susceptibility or resistance to the development of TDI-induced asthma. [ABSTRACT FROM AUTHOR] more...

Objective: The PACIFIC trial established standard therapy for patients with unresectable stage III NSCLC who did not progress after platinum-based concurrent chemoradiation therapy. However, real-world data, particularly from Latin America, remain limited. The LACOG 0120 study aimed to evaluate the efficacy and safety of consolidation therapy with durvalumab in a real-world setting in Brazil., Methods: Patients with unresectable stage III NSCLC who received chemoradiotherapy followed by durvalumab consolidation therapy through an expanded access program were evaluated. The primary objective was to assess progression-free survival (PFS). Secondary endpoints included overall survival (OS), treatment compliance, and safety, with a focus on the incidence and severity of immune-mediated adverse events (NCT04948411)., Results: Thirty-one patients from seven centers were evaluated. Median follow-up was 50.3 months (95% CI: 48.6-54.4). Median PFS was 9.9 months (95% CI: 7.3-52.4), with a 36 month-PFS of 34.5% (95% CI: 17.7-52.1). Median OS was 34.9 months (95% CI: 26.0-NR), and the 36 month-OS was 46.3% (95% CI: 25.7-64.6). Durvalumab was administered for a median of 17 cycles (10 to 24), with 45.2% of patients completing the planned therapy. The main reason for discontinuation was disease progression. Treatment-related adverse events of any grade occurred in 12 patients (38.7%), with grade 3 events reported in two (6.5%). Pneumonitis was observed in 4 patients (12.9%) - grade 3 in 1 patient., Conclusions: PFS was lower in this analysis compared to the PACIFIC trial; however, OS was similar, indicating comparable efficacy in a real-world setting among Brazilian patients with unresectable stage III NSCLC. No new safety concerns were identified. more...

Background: Night shift work can disrupt circadian rhythm and cause chronic sleep deprivation, which might increase the risk of lymphoma through immunosuppression and oxidative stress., Material and Methods: We investigated the association between night shift work and risk of lymphoma subtypes in 867 incident cases and 774 controls, who participated in a multicentre Italian study between 2011 and 2017. Based on questionnaire information, occupational experts assessed the lifetime probability of night shift work, the total number of night shifts and years of night shift work among study participants. OR and 95% CI for lymphoma and its major subtypes associated with night shift work was calculated with logistic regression, adjusting by age, gender, education, study area, marital status and family history of haemolymphatic cancer., Results: Ever working night shifts was associated with an increase in the risk of chronic lymphocytic leukaemia (CLL) (OR 1.9, 95% CI 1.14 to 3.32), which was highest after a 15-34 years latency. However, there was not a linear increase in risk by probability of exposure, years of night shift work, nor lifetime number of night shifts whether under rotating or permanent work schedules. Risk of lymphoma overall, B cell lymphoma (BCL), its major subtypes other than CLL, and other less prevalent BCL subtypes combined did not show an association., Conclusions: We found conflicting evidence of an association between night shift work and the risk of CLL. We did not observe an association with other lymphoma subtypes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.) more...

Background: The International Agency for Research on Cancer (IARC) recently classified glyphosate, the most used herbicide worldwide, as a probable human carcinogen. We inquired into the association between occupational exposure to glyphosate and risk of lymphoma subtypes in a multicenter case-control study conducted in Italy., Methods: The Italian Gene-Environment Interactions in Lymphoma Etiology (ItGxE) study took place in 2011-17 in six Italian centres. Overall, 867 incident lymphoma cases and 774 controls participated in the study. Based on detailed questionnaire information, occupational experts classified duration, confidence, frequency, and intensity of exposure to glyphosate for each study subject. Using unconditional regression analysis, we modelled risk of major lymphoma subtypes associated with exposure to glyphosate adjusted by age, gender, education, and study centre., Results: Very few study subjects (2.2%) were classified as ever exposed to glyphosate. Risk of follicular lymphoma (FL) was elevated 7-fold in subjects classified as ever exposed to glyphosate with medium-high confidence, 4.5-fold in association with medium-high cumulative exposure level, 12-fold with medium-high exposure intensity, and 6-fold with exposure for 10 days or more per year. Significant upward trends were detected with all the exposure metrics, but duration. The overall p-value for an upward trend with four independent metrics was 1.88 × 10 - 4 . There was no association with risk of lymphoma (any subtype), Non Hodgkin Lymphoma, B-cell lymphoma, or the major lymphoma subtypes other than FL., Conclusions: Our findings provide limited support to the IARC decision to classify glyphosate as Group 2A human carcinogen. more...

Although the evidence is not consistent, epidemiologic studies have suggested that taller adult height may be associated with an increased risk of some non-Hodgkin lymphoma (NHL) subtypes. Height is largely determined by genetic factors, but how these genetic factors may contribute to NHL risk is unknown. We investigated the relationship between genetic determinants of height and NHL risk using data from eight genome-wide association studies (GWAS) comprising 10,629 NHL cases, including 3,857 diffuse large B-cell lymphoma (DLBCL), 2,847 follicular lymphoma (FL), 3,100 chronic lymphocytic leukemia (CLL), and 825 marginal zone lymphoma (MZL) cases, and 9,505 controls of European ancestry. We evaluated genetically predicted height by constructing polygenic risk scores using 833 height-associated SNPs. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for association between genetically determined height and the risk of four NHL subtypes in each GWAS and then used fixed-effect meta-analysis to combine subtype results across studies. We found suggestive evidence between taller genetically determined height and increased CLL risk (OR = 1.08, 95% CI = 1.00-1.17, p = 0.049), which was slightly stronger among women (OR = 1.15, 95% CI: 1.01-1.31, p = 0.036). No significant associations were observed with DLBCL, FL, or MZL. Our findings suggest that there may be some shared genetic factors between CLL and height, but other endogenous or environmental factors may underlie reported epidemiologic height associations with other subtypes., (Copyright © 2020 Moore, Kane, Wang, Panagiotou, Teras, Monnereau, Wong Doo, Machiela, Skibola, Slager, Salles, Camp, Bracci, Nieters, Vermeulen, Vijai, Smedby, Zhang, Vajdic, Cozen, Spinelli, Hjalgrim, Giles, Link, Clavel, Arslan, Purdue, Tinker, Albanes, Ferri, Habermann, Adami, Becker, Benavente, Bisanzi, Boffetta, Brennan, Brooks-Wilson, Canzian, Conde, Cox, Curtin, Foretova, Gapstur, Ghesquières, Glenn, Glimelius, Jackson, Lan, Liebow, Maynadie, McKay, Melbye, Miligi, Milne, Molina, Morton, North, Offit, Padoan, Patel, Piro, Ravichandran, Riboli, de Sanjose, Severson, Southey, Staines, Stewart, Travis, Weiderpass, Weinstein, Zheng, Chanock, Chatterjee, Rothman, Birmann, Cerhan and Berndt.) more...

Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease characterized by the clonal expansion of malignant B cells. To predict the clinical course of the disease, the identification of diagnostic biomarkers is urgently needed. Aberrant methylation patterns may predict CLL development and its course, being very early changes during carcinogenesis. Our aim was to identify CLL specific methylation patterns and to evaluate whether methylation aberrations in selected genes are associated with changes in gene expression. Here, by performing a genome-wide methylation analysis, we identified several CLL-specific methylation alterations. We focused on the most altered one, at a CpG island located in the body of SHANK1 gene, in our CLL cases compared to healthy controls. This methylation alteration was successfully validated in a larger cohort including 139 CLL and 20 control in silico samples. We also found a positive correlation between SHANK1 methylation level and absolute lymphocyte count, in particular CD19+ B cells, in CLL patients. Moreover, we were able to detect gains of methylation at SHANK1 in blood samples collected years prior to diagnosis. Overall, our results suggest methylation alteration at this SHANK1 CpG island as a biomarker for risk and diagnosis of CLL, and also in the personalized quantification of tumor aggressiveness., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflict of interest. more...

Purpose: Middle-income countries like Brazil often have a dichotomous health care system in which patients may be treated in either public or private institutions that differ substantially in terms of level of access to diagnostic and therapeutic procedures., Patients and Methods: This was a prospective, observational study to assess real-world data in 1,230 female patients with breast cancer who were treated in a private health care institution between 2012 and 2016 in Brazil., Results: Breast cancer in these patients mostly was diagnosed at early (79.0% stages I or II) or locally advanced (16.1% stage III) stages. The primary tumor was resected in 89.0% of cases, most often through breast-conserving surgery (55.1%). Patients with locally advanced disease received more aggressive therapy (eg, higher rates of mastectomy, axillary dissection and chemotherapy use) than patients with early-stage disease. The estimated 2-year overall survival (OS) was 95.3%. Survival was significantly longer among patients with stage I or II disease (2-year OS, 97.9% and 97.5%, respectively) than those with stage III or IV disease (89.4% and 69.5%, respectively; P < .01). Tumor grade was also correlated with OS in the overall cohort ( P = .05); triple-negative status was only prognostic for patients with stage III disease ( P < .01)., Conclusion: The data provided aid understanding of the current scenario of breast cancer presentation and treatment in the Brazilian private health care system and may serve as a foundation to guide resource allocation. Our results reinforce the need to pursue adequate access to cancer care in low- and middle-income countries to optimize patient outcome. more...

The aryl hydrocarbon receptor (AhR) is a transcription factor implicated in several pathways known to be relevant in lymphomagenesis. Aim of our study was to explore the link between AhR activation and risk of lymphoma subtypes. We used a Dual-Luciferase Assay ® and a luminometer to detect the activation of the luciferase gene, in HepG2 cells transfected with a specific reporter systems, by a 50 ml serum aliquot of cases of diffuse large B cell lymphoma (N = 108), follicular lymphoma (N = 85), chronic lymphocytic leukemia (N = 72), multiple myeloma (N = 80), and Hodgkin lymphoma (N = 94) and 357 controls who participated in the multicentre Italian study on gene-environment interactions in lymphoma etiology (ItGxE). Risk of each lymphoma subtype associated with AhR activation was calculated with polytomous logistic regression adjusting by age, gender, and study centre. The overall prevalence of AhR activation ranged 13.9-23.6% by subtype, and it varied by study area (8-39%). Risk associated with AhR activation was moderately elevated for follicular lymphoma (OR = 1.56, 95% CI 0.86, 2.80) and chronic lymphocytic leukemia (OR = 1.56, 95% CI 0.83, 2.96). Despite our inconclusive findings about the association with risk of lymphoma subtypes, we showed that the Dual-Luciferase Assay can be reliably and easily applied in population-based studies to detect AhR activation., Competing Interests: None. more...

Background: Breast cancer is the most common cancer and the leading cause of cancer death in women. Early detection is essential to reduce cancer mortality. Studying participation in an organised breast cancer screening program is important in order to evaluate the program effectiveness. Breast screening both enables minimally invasive breast surgery and reduces cause-specific mortality., Methods: The main objective of this study was to evaluate, through the use of a questionnaire, the influence of socio-economic characteristics (age, education, occupational status, participation in other screening programs etc.) on participation in a mammography screening program organized by the local health units (LHU) of Novara and Verbano-Cusio-Ossola, located in the Italian region of Piedmont. A sample of 500 women was identified. Eligible participants included women aged 50-69 years, resident in the area of the LHUs of Novara and Verbano-Cusio-Ossola who had been invited to participate in the screening program 2006-2007. Twenty six women were excluded, leaving 474 women in the final analysis: 23 women were unable to be contacted due to incorrect contact details and 3 women were unable to complete the questionnaire due to neurodegenerative diseases. A postal questionnaire was sent by post during 2008-2009. Two postal reminders were sent to non-responders, followed by a phone call. One group of women received an additional copy of the questionnaire with the first postal reminder and another group received only the reminder letter. The socio-personal profiles and their influence in women's participation in the screening program were evaluated., Results: Among the responders, 93% of the women (348/374) received a mammogram at least once following LHU invitation for check-up. 74.1% of women got a mammogram at least once using the organized screening program, an additional 17.8% got a mammogram in a private clinic, and the type of prevention was unknown for 8.1% of the women. 25.3% began having mammogram for prevention before the age of 45., Conclusions: A screening program is a sanitary intervention of secondary prevention and the identification of the attitude towards this kind of prevention is quite complex. Some causes of non-participation in this screening program were the belief that mammogram is not necessary, fear of pain, and presence of family problems. This study obtained a higher response than expected and the data also allowed an assessment of the degree of participation of women in the prevention services, identifying that most of them carried out a mammogram using an organized screening program. more...

Asbestos exposure is the main risk factor for malignant pleural mesothelioma (MPM), a rare aggressive tumor. Nevertheless, only 5-17% of those exposed to asbestos develop MPM, suggesting the involvement of other environmental and genetic risk factors. To identify the genetic risk factors that may contribute to the development of MPM, we conducted a genome-wide association study (GWAS; 370,000 genotyped SNPs, 5 million imputed SNPs) in Italy, among 407 MPM cases and 389 controls with a complete history of asbestos exposure. A replication study was also undertaken and included 428 MPM cases and 1269 controls from Australia. Although no single marker reached the genome-wide significance threshold, several associations were supported by haplotype-, chromosomal region-, gene- and gene-ontology process-based analyses. Most of these SNPs were located in regions reported to harbor aberrant alterations in mesothelioma (SLC7A14, THRB, CEBP350, ADAMTS2, ETV1, PVT1 and MMP14 genes), causing at most a 2-3-fold increase in MPM risk. The Australian replication study showed significant associations in five of these chromosomal regions (3q26.2, 4q32.1, 7p22.2, 14q11.2, 15q14). Multivariate analysis suggested an independent contribution of 10 genetic variants, with an Area Under the ROC Curve (AUC) of 0.76 when only exposure and covariates were included in the model, and of 0.86 when the genetic component was also included, with a substantial increase of asbestos exposure risk estimation (odds ratio, OR: 45.28, 95% confidence interval, CI: 21.52-95.28). These results showed that genetic risk factors may play an additional role in the development of MPM, and that these should be taken into account to better estimate individual MPM risk in individuals who have been exposed to asbestos. more...

Dyspnea is a common symptom in patients admitted to the Emergency Department (ED), and discriminating between cardiogenic and non-cardiogenic dyspnea is often a clinical dilemma. The initial diagnostic work-up may be inaccurate in defining the etiology and the underlying pathophysiology. The aim of this study was to evaluate the diagnostic accuracy and reproducibility of pleural and lung ultrasound (PLUS), performed by emergency physicians at the time of a patient's initial evaluation in the ED, in identifying cardiac causes of acute dyspnea. Between February and July 2007, 56 patients presenting to the ED with acute dyspnea were prospectively enrolled in this study. In all patients, PLUS was performed by emergency physicians with the purpose of identifying the presence of diffuse alveolar-interstitial syndrome (AIS) or pleural effusion. All scans were later reviewed by two other emergency physicians, expert in PLUS and blinded to clinical parameters, who were the ultimate judges of positivity for diffuse AIS and pleural effusion. A random set of 80 recorded scannings were also reviewed by two inexperienced observers to assess inter-observer variability. The entire medical record was independently reviewed by two expert physicians (an emergency medicine physician and a cardiologist) blinded to the ultrasound (US) results, in order to determine whether, for each patient, dyspnea was due to heart failure, or not. Sensitivity, specificity, and positive/negative predictive values were obtained; likelihood ratio (LR) test was used. Cohen's kappa was used to assess inter-observer agreement. The presence of diffuse AIS was highly predictive for cardiogenic dyspnea (sensitivity 93.6%, specificity 84%, positive predictive value 87.9%, negative predictive value 91.3%). On the contrary, US detection of pleural effusion was not helpful in the differential diagnosis (sensitivity 83.9%, specificity 52%, positive predictive value 68.4%, negative predictive value 72.2%). Finally, the coexistence of diffuse AIS and pleural effusion is less accurate than diffuse AIS alone for cardiogenic dyspnea (sensitivity 81.5%, specificity 82.8%, positive predictive value 81.5%, negative predictive value 82.8%). The positive LR was 5.8 for AIS [95% confidence interval (CI) 4.8-7.1] and 1.7 (95% CI 1.2-2.6) for pleural effusion, negative LR resulted 0.1 (95% CI 0.0-0.4) for AIS and 0.3 (95% CI 0.1-0.8) for pleural effusion. Agreement between experienced and inexperienced operators was 92.2% (p < 0.01) and 95% (p < 0.01) for diagnosis of AIS and pleural effusion, respectively. In early evaluation of patients presenting to the ED with dyspnea, PLUS, performed with the purpose of identifying diffuse AIS, may represent an accurate and reproducible bedside tool in discriminating between cardiogenic and non-cardiogenic dyspnea. On the contrary, US detection of pleural effusions does not allow reliable discrimination between different causes of acute dyspnea in unselected ED patients. more...

Malignant mesothelioma (MM) is a rare and aggressive tumor of the pleura. The most important causal factor for the development of MM is occupational exposure to asbestos. Different lines of evidence suggest a role of genetic background in MM development, as for other cancers. Two published studies observed an association between MM and N-acetyl-transferase 2 (NAT2) polymorphisms. First, a Finnish study observed that the NAT2 slow acetylator phenotype was associated with an increased risk of MM. Conversely, MM risk was higher in Italian subjects carrying the NAT2 fast acetylator genotypes. The conflicting results obtained in Finland and Italy could be ascribed to random chance, considering the small panel of patients and controls in the two studies, but also ethnic or other differences may have been important. To ascertain the role of NAT2 genotype, we performed a study on 252 MM patients and 262 controls recruited in two Northern Italy areas that were characterized by high asbestos exposure, due to intense industrial activities (an asbestos cement factory in Casale Monferrato, mainly shipyards and refineries in Liguria). Unconditional multivariate logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). NAT2 fast acetylator genotypes showed an increased OR, although not statistically significant, both in asbestos-exposed subjects (OR=1.47; 95% CI=0.96-2.26) and in the entire population (OR=1.38; 95% CI=0.93-2.04). These results suggest that NAT2 polymorphisms do not exert a strong effect on individual susceptibility to MM. more...

Eighty-seven cases of occupational asthma induced by toluene diisocyanate (TDI) were diagnosed by an inhalation challenge with TDI and methacholine. After an average follow-up interval of 11 yrs, all subjects were re-examined. Of the 87 subjects examined, 13 (15%) had remained in the same job, 44 (50.5%) had been removed from exposure for <10 yrs and 30 (34.5%) had been removed for >10 yrs. The proportion of subjects who experienced symptoms of asthma and those who were hyperresponsive to methacholine was significantly lower. Of the patients, 59% used short-acting bronchodilators, 8% long-acting bronchodilators and 18% were on regular inhaled glucocorticoids. Thus, multiple regression analysis showed a positive correlation between forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) at follow-up and FVC and FEV1 at diagnosis, and a negative correlation with smoking and with therapy with bronchodilators. Stepwise logistic regression showed that the follow-up provocative dose causing a 20% fall in the FEV1 (PD20) could be predicted from baseline PD20. These results indicate that respiratory symptoms and airway hyperresponsiveness to methacholine persist in subjects removed from exposure to TDI for >10 yrs. A more favourable prognosis was associated with a better lung function and a lower degree of airway hyperresponsiveness to methacholine at diagnosis. more...

Background: Polymorphism at the pi class glutathione-S-transferase locus (GSTP1) is associated with allergen-induced asthma and related phenotypes., Objective: We sought to determine whether GSTP1 polymorphism influences susceptibility to asthma induced by toluene diisocyanate (TDI)., Methods: The role of GSTP1 was assessed in 131 workers exposed to TDI, 92 with TDI-induced asthma and 39 asymptomatic subjects. The phenotype of the disease was characterized by using detailed clinical history, lung volumes, airway responsiveness to methacholine, and airway responsiveness to TDI. GST genotypes were determined by using PCR-based assays., Results: In patients exposed to TDI for 10 or more years, the frequency of the GSTP1 Val/Val genotype was lower in subjects who had asthma (odds ratio, 0.23; 95% confidence interval, 0.05-1.13; P =.074). Similarly, the frequency of this genotype was significantly lower in subjects with evidence of moderate-to-severe airway hyperresponsiveness to methacholine compared with the frequency in subjects with normal or mild hyperresponsiveness (P =.033)., Conclusion: These data suggest that homozygosity for the GSTP1*Val allele confers protection against TDI-induced asthma and airway hyperresponsiveness. This view is supported by the finding that the protective effect increases in proportion to the duration of exposure to TDI. more...

ADP-ribosyl cyclase/CD38 is a bifunctional enzyme that catalyzes at its ectocellular domain the synthesis from NAD(+) (cyclase) and the hydrolysis (hydrolase) of the calcium-mobilizing second messenger cyclic ADP ribose (cADPR). Furthermore, CD38 mediates cADPR influx inside a number of cells, thereby inducing Ca(2+) mobilization. Intracellularly, cADPR releases Ca(2+) from ryanodine-sensitive pools, thus activating several Ca(2+)-dependent functions. Among these, the inhibition of osteoclastic-mediated bone resorption has been demonstrated. We found that HOBIT human osteoblastic cells display ADP-ribosyl cyclase activity and we examined the effects of CD38 stimulation on osteoblasts function. Extracellular NAD(+) induced elevation of cytosolic calcium due to both Ca(2+) influx from the extracellular medium and Ca(2+) release from ryanodine-sensitive intracellular stores. Culturing these cells in the presence of NAD(+) caused a complete growth arrest with a time-dependent decrease of cell number and the appearance of apoptotic nuclei. The first changes could be observed after 24 h of treatment and became fully evident after 72-96 h. We propose a role of extracellular NAD(+) in bone homeostatic control., (Copyright 2001 Academic Press.) more...

The outcome of kidney transplantation was evaluated in 246 nondiabetic, CsA-treated recipients of primary cadaver transplant, divided into 4 groups according to length of time on dialysis: group <; or = 2, 0-24 months; group 2-5, 25-60 months; group 5-15, 61-180 months; group > 15, over 180 months. The 4 groups did not differ in graft survival, proteinuria (g/die), or estimated GFR values at 1, 2, 3, 4, and 5 years after grafting. They did not differ in the frequency of cataract, hip osteonecrosis, tumors, or posttransplant diabetes mellitus at 3 years after grafting. Ocular hypertone (p < 0.02), tendon ruptures (p < 0.001), arterial occlusive disease of lower limbs (p < 0.01), cholelithiasis (p < 0.05), and chronic hepatitis--which occurred only in anti-HCV and/or HBs Ag-positive patients--(p < 0.001), were more frequent in group > 15, and in all these cases but ocular hypertone a linear trend of increasing frequencies with increasing dialytic age was statistically significant. Group 5-15 had the lowest patient survival (p < 0.02). Moreover, a progressive decline of patient survival with increasing dialytic age was noted in groups < or = 2, 2-5, and 5-15. Unexpectedly, group > 15 had remarkably good survival, and this finding denies the hypothesis of a purely linear decline of patient survival after transplantation with increasing dialytic age. more...

Plasma cortisol, progesterone, testosterone and aldosterone levels were measured on serial blood samples drawn in 10 healthy adult human males up to 6h after single administration at about 07 of increasing amounts of the short-chain analogue ACTH-agonist alsactide (Synchrodyn 1-17). The following doses were employed: 2, 4, 8, 10 and 20 micrograms subcutaneously (s.c.), as well as 2, 4 and 8 micrograms intravenously (i.v.). Data were compared with those obtained by placebo (isotonic saline) injections. The s.c. injections of 2 and 4 micrograms resulted to be ineffective in changing the hormonal pattern. A significant rise of cortisol and progesterone, but not of aldosterone and testosterone, followed the s.c. injections of 8 and 10 micrograms. The differential pattern of the glucocorticoid vs. the mineralocorticoid response was also apparent after the s.c. injection of 20 micrograms alsactide; when compared with placebo, this dose was able to elicit a significant increase of all examined hormones except testosterone. All i.v. injections of 2, 4 and 8 micrograms alsactide were effective; the highest dose did cause a sustained rise of plasma cortisol, progesterone and aldosterone, but also the other doses were able to change significantly the mineralocorticoid levels. These results provide evidence that circadian-stage-specified s.c. or i.v. administration of the analogue can be employed in the clinical practice for enhancing selectively and transiently the morning glucocorticoid secretion. more...