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Central hypogonadotropic hypogonadism (CHH) is an emerging pathological condition frequently associated with overweight, metabolic syndrome, diabetes, and midline defects. The genetic mechanisms involve mutations in at least twenty-four genes regulating GnRH neuronal migration, secretion, and activity. So far, the mechanisms underlying CHH, both in prepubertal and in adulthood onset forms, remain unknown in most of the cases. Indeed, all detected gene variants may explain a small proportion of the affected patients (43%), indicating that other genes or epigenetic mechanisms are involved in the onset of CHH. The aim of this review is to summarize the current knowledge on genetic background of CHH, organizing the large amount of data present in the literature in a clear and concise manner, to produce a useful guide available for researchers and clinicians.

Inherited retinal degeneration (RD) is a devastating and currently untreatable neurodegenerative condition that leads to loss of photoreceptor cells and blindness. The vast genetic heterogeneity of RD, the lack of “druggable” targets, and the access-limiting blood–retinal barrier (BRB) present major hurdles toward effective therapy development. Here, we address these challenges (i) by targeting cGMP (cyclic guanosine- 3′,5′-monophosphate) signaling, a disease driver common to different types of RD, and (ii) by combining inhibitory cGMP analogs with a nanosized liposomal drug delivery system designed to facilitate transport across the BRB. Based on a screen of several cGMP analogs we identified an inhibitory cGMP analog that interferes with activation of photoreceptor cell death pathways. Moreover, we found liposomal encapsulation of the analog to achieve efficient drug targeting to the neuroretina. This pharmacological treatment markedly preserved in vivo retinal function and counteracted photoreceptor degeneration in three different in vivo RD models. Taken together, we show that a defined class of compounds for RD treatment in combination with an innovative drug delivery method may enable a single type of treatment to address genetically divergent RD-type diseases.

Poly(lactic- co -glycolic acid) particles in the 200–400-nm size range were formulated through nanoprecipitation and solvent evaporation methods. Different concentrations of the polymer and stabilizer (Pluronic® F 68) were tested in order to identify the best conditions for making poly(lactic- co -glycolic acid) particles of suitable size, stable in time, and to be used as carriers for brain-targeting drugs. The particles with the best characteristics for delivery system design were those formulated by nanoprecipitation with an organic/water phase ratio of 2:30, a polymer concentration of 25 mg/mL, and a surfactant concentration of 0.83 mg/mL; their surface charge was reasonably negative (approximately -27 mV) and the average size of the almost monodisperse population was roughly 250 nm. Particle characterization was obtained through ζ -potential measurements, scanning electron microscope observations, and particle size distribution determinations; the latter achieved by both photon-correlation spectroscopy and sedimentation field flow fractionation. Sedimentation field flow fractionation, which is considered more reliable than photon-correlation spectroscopy in describing the possible particle size distribution modifications, was used to investigate the effects of 3 months of storage at 4 °C had on the lyophilized particles. Figure Particle size ditribution from the SdFFF and the PCS techniques

Poly(lactic-co-glycolic acid) particles in the 200400-nm size range were formulated through nanoprecipitation and solvent evaporation methods. Different concentrations of the polymer and stabilizer (Pluronic® F 68) were tested in order to identify the best conditions for making poly(lactic-co-glycolic acid) particles of suitable size, stable in time, and to be used as carriers for brain-targeting drugs. The particles with the best characteristics for delivery system design were those formulated by nanoprecipitation with an organic/water phase ratio of 2:30, a polymer concentration of 25 mg/mL, and a surfactant concentration of 0.83 mg/mL; their surface charge was reasonably negative (approximately -27 mV) and the average size of the almost monodisperse population was roughly 250 nm. Particle characterization was obtained through θ-potential measurements, scanning electron microscope observations, and particle size distribution determinations; the latter achieved by both photon-correlation spectroscopy and sedimentation field flow fractionation. Sedimentation field flow fractionation, which is considered more reliable than photoncorrelation spectroscopy in describing the possible particle size distribution modifications, was used to investigate the effects of 3 months of storage at 4 °C had on the lyophilized particles.

Adverse drug event (ADEs) are a significant cause of emergency department (ED) visits and consequent hospitalization. Preventing ADEs and their related ED visits in outpatients remains a public health safety challenge. In this context, the aims of the present study were to describe the frequency, seriousness and preventability of outpatients' ADE-related ED visits and hospitalizations in the Italian general population, and to identify the presence of potential predictors of ADE-related hospitalization. We performed a nationwide, multicentre, observational, retrospective study based on reports of suspected ADEs collected between January 1, 2007 and December 31, 2018 in 94 EDs involved in the MEREAFaPS project. Patients' demographic characteristics, their clinical status, suspected and concomitant drugs, ADE description, and its degree of seriousness, were collected. Causality and preventability were assessed using validated algorithms, and logistic regression analyses were used to estimate the reporting odds ratios (RORs) with 95% confidence intervals (CIs) of ADE-related hospitalization, considering the following covariates: age, sex, ethnicity, number of implicated medications, parenteral administration, presence of interaction, therapeutic error, and/or complementary and alternative medicines (CAM). Within 12 years, 61,855 reports of suspected ADE were collected, of which 18,918 (30.6%) resulted in hospitalization (ADE defined as serious). Patients were mostly female (56.6%) and Caucasians (87.7%), with a mean age of 57.5 ± 25.0 years. 58% of patients were treated with more than two drugs, and 47% of ADEs leading to hospitalization were preventable. Anticoagulants, antibiotics, and nonsteroidal anti-inflammatory drugs (NSAIDs) were the most frequently implicated agents for ED visits and/or hospitalization, which included clinically significant ADEs, such as haemorrhage for anticoagulants, moderate to severe allergic reactions for antibiotics, and dermatologic reactions and gastrointestinal disturbances for NSAIDs. Older age (1.54 [1.48-1.60]), higher number of concomitantly taken drugs (2.22 [2.14-2.31]), the presence of drug-drug interactions (1.52 [1.28-1.81]), and therapeutic error (1.54 [1.34-1.78]), were significantly associated with an increased risk of hospitalization. Our long-term active pharmacovigilance study in ED provided a valid estimation of ADE-related hospitalization in a representative sample of the Italian general population and can suggest further focus on medication safety in outpatients, in order to early recognise and prevent ADEs.

Fatal Adverse Events (FADEs) are a major public health problem, and some FADEs could be preventable. The aim of the present study is to describe the frequency, the drugs involved and the preventability in the FADEs collected through the MEREAFaPS Study between 2012 and 2018. All cases including the outcome “death” have been examined. We excluded cases with vaccine-related ADEs, overdose or suicide, and ADEs occurred during the hospitalisation. Two trained assessors evaluated all cases fulfilling the inclusion criteria. ADEs’ preventability was evaluated applying the Schumock and Thornton algorithm. During the study period, we observed 429 cases of death, 92 of which were excluded. The remaining 337 cases involved 187 women and 150 men, with a mean age of 79 and of 77 years, respectively. For each report, the suspected drugs and concomitant ones were 1.26 and 4.20, respectively. Anticoagulants and antiplatelet agents account for more than 40% of FADE cases and the most frequent reactions are haemorrhages (37.5%). The 25% of the FADEs were preventable. This study confirms that FADEs are still a relevant clinical occurrence, and are often caused by widely used old drugs associated with adverse events. The death of one in four patients was preventable. Further efforts should be done to improve the appropriateness of the therapy, especially in older patients who are treated with anticoagulants.