Role of Estrogen and Estrogen Receptor in GH-Secreting Adenomas

Acromegaly is a rare disease with several systemic complications that may lead to increased overall morbidity and mortality. Despite several available treatments, ranging from transsphenoidal resection of GH-producing adenomas to different medical therapies, complete hormonal control is not achieved in some cases. Some decades ago, estrogens were first used to treat acromegaly, resulting in a significant decrease in IGF1 levels. However, due to the consequent side effects of the high dose utilized, this treatment was later abandoned. The evidence that estrogens are able to blunt GH activity also derives from the evidence that women with GH deficiency taking oral estro-progestins pills need higher doses of GH replacement therapy. In recent years, the role of estrogens and Selective Estrogens Receptor Modulators (SERMs) in acromegaly treatment has been re-evaluated, especially considering poor control of the disease under first- and second-line medical treatment. In this review, we analyze the state of the art concerning the impact of estrogen and SERMs on the GH/IGF1 axis, focusing on molecular pathways and the possible implications for acromegaly treatment

Empirical assessment of the effort needed to attack programs protected with client/server code splitting

Context. Code hardening is meant to fight malicious tampering with sensitive code executed on client hosts. Code splitting is a hardening technique that moves selected chunks of code from client to server. Although widely adopted, the effective benefits of code splitting are not fully understood and thoroughly assessed. Objective. The objective of this work is to compare non protected code vs. code splitting protected code, considering two levels of the chunk size parameter, in order to assess the effectiveness of the protection - in terms of both attack time and success rate - and to understand the attack strategy and process used to overcome the protection. Method. We conducted an experiment with master students performing attack tasks on a small application hardened with different levels of protection. Students carried out their task working at the source code level. Results. We observed a statistically significant effect of code splitting on the attack success rate that, on the average, was reduced from 89% with unprotected clear code to 52% with the most effective protection. The protection variant that moved some small-sized code chunks turned out to be more effective than the alternative moving fewer but larger chunks. Different strategies were identified yielding different success rates. Moreover, we discovered that successful attacks exhibited different process w.r.t. failed ones.Conclusions We found empirical evidence of the effect of code splitting, assessed the relative magnitude, and evaluated the influence of the chunk size parameter. Moreover, we extracted the process used to overcome such obfuscation technique

Remarks on the chemical Fokker-Planck and Langevin equations: Nonphysical currents at equilibrium

The chemical Langevin equation and the associated chemical Fokker-Planck equation are wellknown continuous approximations of the discrete stochastic evolution of reaction networks. In this work, we show that these approximations suffer from a physical inconsistency, namely, the presence of nonphysical probability currents at the thermal equilibrium even for closed and fully detailedbalanced kinetic schemes. An illustration is given for a model case

A Reference Architecture for Software Protection

This paper describes the ASPIRE reference architecture designed to tackle one major problem in this domain: the lack of a clear process and an open software architecture for the composition and deployment of multiple software protections on software applications

Crime at the intersection of rail and retail

This chapter examines shoplifting at rail station shops over a 12 month period in England and Wales. Key findings were: shoplifting is concentrated at particular stations; the top 20 stations account for 85% of shoplifting. Clear temporal patterns were evident; shoplifting was higher on weekdays and during holidays with higher levels of travel; shoplifting is lower when there is a reduced rail service. There was no clear relationship between shoplifting rates outside of a station at shops nearby, and shoplifting within a rail station. It is suggested a correlation may occur for medium and smaller size stations. Large stations may attract offenders in their own right without other shops being nearby. The similarities observed between shoplifting patterns at rail stations and those at non-rail station shops suggest the learning from successful crime prevention measures applied outside of the rail environment could successfully transferred to rail stations

Factors affecting the Faradaic efficiency of Fe(0) electrocoagulation

Electrocoagulation (EC) using Fe(0) electrodes is a low cost water treatment technology that relies on efficient production of Fe(II) from the electrolytic dissolution of Fe(0) electrodes (i.e. a high Faradaic efficiency). However, the (electro)chemical factors that favor Fe(0) oxidation rather than O2 evolution during Fe(0) EC have not been identified. In this study, we combined electrochemical methods, electron microscopy and Fe measurements to systematically examine the interdependent effects of current density (i), anodic interface potential (EA) and solution chemistry on the Faradaic efficiency. We found that Fe(0) oxidation was favored (Faradaic efficiency >0.85) in chloride and bromide solutions at all i, whereas carbonate, phosphate, citrate, and nitrate solutions lead to Faradaic efficiencies <0.1. The anodic reaction (i.e. Fe(0) oxidation or O2 evolution) only depended on i in the sulfate and formate solutions. Experiments in binary-anion solutions revealed that molar ratios of [HCO3−]/[Cl−] near 100 and [NO3−]/[Cl−] near 20 separated the electrochemical domains of Fe(0) oxidation and O2 evolution in the EC system. These molar ratios were supported by experiments in synthetic groundwater solutions. We also found that the EA vs i curves for solutions with poor Faradaic efficiency overlapped but were situated 2–4 V vs Ag/AgCl higher than those of solutions with high Faradaic efficiency. Therefore, the position of the EA vs i curve, rather than the EA alone, can be used to determine unambiguously the reaction occurring on the Fe(0) anode during EC treatment

Complications and mortality of Cushing’s disease: report on data collected over a 20-year period at a referral centre

Context: Cushing’s disease (CD) is rare condition burdened by several systemic complications correlated to higher mortality rates. The primary goal of clinicians is to achieve remission, but it is unclear if treatment can also increase life expectancy. Aim: To assess the prevalence of cortisol-related complications and mortality in a large cohort of CD patients attending a single referral centre. Materials and methods: The clinical charts of CD patients attending a referral hospital between 2001 and 2021 were reviewed. Results: 126 CD patients (median age at diagnosis 39 years) were included. At the last examination, 78/126 (61.9%) of the patients were in remission regardless of previous treatment strategies. Patients in remission showed a significant improvement in all the cardiovascular (CV) comorbidities (p < 0.05). The CV events were more frequent in older patients (p = 0.003), smokers and persistent CD groups (p < 0.05). Most of the thromboembolic (TE) and infective events occurred during active stages of the disease. The CV events were the most frequent cause of death. The standardized mortality ratio (SMR) resulted increased in persistent cases at the last follow-up (SMR 4.99, 95%CI [2.15; 9.83], p < 0.001) whilst it was not higher in those in remission (SMR 1.66, 95%CI [0.34; 4.85], p = 0.543) regardless of the timing or number of treatments carried out. A younger age at diagnosis (p = 0.005), a microadenoma (p = 0.002), and remission status at the last follow-up (p = 0.027) all increased survival. Furthermore, an elevated number of comorbidities, in particular arterial hypertension, increased mortality rates. Conclusions: Patients with active CD presented a poor survival outcome. Remission restored the patients’ life expectancy regardless of the timing or the types of treatments used to achieve it. Persistent CD-related comorbidities remained major risk factors

Corticotropin-releasing hormone test predicts the outcome of unilateral adrenalectomy in primary bilateral macronodular adrenal hyperplasia

Purpose: Primary bilateral adrenal hyperplasia (PBMAH) is associated with hypercortisolism and a heterogeneous clinical expression in terms of cortisol secretion and related comorbidities. Historically, treatment of choice was bilateral adrenalectomy (B-Adx); however, recent data suggest that unilateral adrenalectomy (U-Adx) may be an effective alternative. For the latter, factors predicting the postsurgical outcome (e.g., biochemical control) have not been identified yet. Methods: PBMAH patients undergoing U-Adx for overt Cushing's syndrome (CS) in two tertiary care centers were retrospectively analysed. Remission was defined as a normalization of urinary free cortisol (UFC) without the need for medical treatment. The potential of hCRH test as a predictor of U-Adx outcome was evaluated in a subgroup. Results: 23 patients were evaluated (69% females, mean age 55 years). Remission rate after U-Adx was 74% at last follow up (median 115 months from UAdx). Before U-Adx, a positive ACTH response to hCRH (Δ¬TH increase > 50% from baseline) was associated with higher remission rates. Conclusions: Three of four patients with PBMAH are surgically cured with U-Adx. Pre-operative hCRH testing can be useful to predict long-term remission rates

Paradoxical GH increase after oral glucose load in subjects with and without acromegaly

Objective: A paradoxical GH rise after the glucose load (GH-Par) is described in about one-third of acromegalic patients. Here, we evaluated the GH profile in subjects with and without acromegaly aiming to refine the definition of GH-Par. Design: Observational case–control study. Methods: Our cohort consisted of 60 acromegalic patients, and two groups of subjects presenting suppressed GH (< 0.4 µg/L) and high (non-acro↑IGF−1, n = 116) or normal IGF-1 levels (non-acro, n = 55). The distribution of GH peaks ≥ 120% from baseline, insulin, and glucose levels were evaluated over a 180-min time interval after glucose intake. Results: A similar proportion of subjects in all three groups shows a GH ratio of ≥ 120% starting from 120 min. Re-considering the definition of paradoxical increase of GH within 90 min, we observed that the prevalence of GH peaks ≥ 120% was higher in acromegaly than in non-acro↑IGF−1 and non-acro (respectively 42%, 16%, and 7%, both p < 0.001). In patients without GH-Par, a late GH rebound was observed in the second part of the curve. Higher glucose peak (p = 0.038), slower decline after load, 20% higher glucose exposure (p = 0.015), and a higher prevalence of diabetes (p = 0.003) characterized acromegalic patients with GH-Par (with respect to those without). Conclusions: GH-Par response may be defined as a 20% increase in the first 90 min after glucose challenge. GH-Par, common in acromegaly and associated with an increased prevalence of glucose metabolism abnormalities, is found also in a subset of non-acromegalic subjects with high IGF-1 levels, suggesting its possible involvement in the early phase of the disease