The ocular albinism type 1 protein, an intracellular G protein-coupled receptor, regulates melanosome transport in pigment cells

The protein product of the ocular albinism type 1 gene, named OA1, is a pigment cell-specific G protein-coupled receptor exclusively localized to intracellular organelles, namely lysosomes and melanosomes. Loss of OA1 function leads to the formation of macromelanosomes, suggesting that this receptor is implicated in organelle biogenesis, however the mechanism involved in the pathogenesis of the disease remains obscure. We report here the identification of an unexpected abnormality in melanosome distribution both in retinal pigment epithelium (RPE) and skin melanocytes of Oa1-knock-out (KO) mice, consisting in a displacement of the organelles from the central cytoplasm towards the cell periphery. Despite their depletion from the microtubule (MT)-enriched perinuclear region, Oa1-KO melanosomes were able to aggregate at the centrosome upon disruption of the actin cytoskeleton or expression of a dominant-negative construct of myosin Va. Consistently, quantification of organelle transport in living cells revealed that Oa1-KO melanosomes displayed a severe reduction in MT-based motility; however, this defect was rescued to normal following inhibition of actin-dependent capture at the cell periphery. Together, these data point to a defective regulation of organelle transport in the absence of OA1 and imply that the cytoskeleton might represent a downstream effector of this receptor. Furthermore, our results enlighten a novel function for OA1 in pigment cells and suggest that ocular albinism type 1 might result from a different pathogenetic mechanism than previously thought, based on an organelle-autonomous signalling pathway implicated in the regulation of both membrane traffic and transport

Beta-Blocker Use in Older Hospitalized Patients Affected by Heart Failure and Chronic Obstructive Pulmonary Disease: An Italian Survey From the REPOSI Register

Beta (β)-blockers (BB) are useful in reducing morbidity and mortality in patients with heart failure (HF) and concomitant chronic obstructive pulmonary disease (COPD). Nevertheless, the use of BBs could induce bronchoconstriction due to β2-blockade. For this reason, both the ESC and GOLD guidelines strongly suggest the use of selective β1-BB in patients with HF and COPD. However, low adherence to guidelines was observed in multiple clinical settings. The aim of the study was to investigate the BBs use in older patients affected by HF and COPD, recorded in the REPOSI register. Of 942 patients affected by HF, 47.1% were treated with BBs. The use of BBs was significantly lower in patients with HF and COPD than in patients affected by HF alone, both at admission and at discharge (admission, 36.9% vs. 51.3%; discharge, 38.0% vs. 51.7%). In addition, no further BB users were found at discharge. The probability to being treated with a BB was significantly lower in patients with HF also affected by COPD (adj. OR, 95% CI: 0.50, 0.37-0.67), while the diagnosis of COPD was not associated with the choice of selective β1-BB (adj. OR, 95% CI: 1.33, 0.76-2.34). Despite clear recommendations by clinical guidelines, a significant underuse of BBs was also observed after hospital discharge. In COPD affected patients, physicians unreasonably reject BBs use, rather than choosing a β1-BB. The expected improvement of the BB prescriptions after hospitalization was not observed. A multidisciplinary approach among hospital physicians, general practitioners, and pharmacologists should be carried out for better drug management and adherence to guideline recommendations

Antidiabetic Drug Prescription Pattern in Hospitalized Older Patients with Diabetes

Objective: To describe the prescription pattern of antidiabetic and cardiovascular drugs in a cohort of hospitalized older patients with diabetes. Methods: Patients with diabetes aged 65 years or older hospitalized in internal medicine and/or geriatric wards throughout Italy and enrolled in the REPOSI (REgistro POliterapuie SIMI—Società Italiana di Medicina Interna) registry from 2010 to 2019 and discharged alive were included. Results: Among 1703 patients with diabetes, 1433 (84.2%) were on treatment with at least one antidiabetic drug at hospital admission, mainly prescribed as monotherapy with insulin (28.3%) or metformin (19.2%). The proportion of treated patients decreased at discharge (N = 1309, 76.9%), with a significant reduction over time. Among those prescribed, the proportion of those with insulin alone increased over time (p = 0.0066), while the proportion of those prescribed sulfonylureas decreased (p < 0.0001). Among patients receiving antidiabetic therapy at discharge, 1063 (81.2%) were also prescribed cardiovascular drugs, mainly with an antihypertensive drug alone or in combination (N = 777, 73.1%). Conclusion: The management of older patients with diabetes in a hospital setting is often sub-optimal, as shown by the increasing trend in insulin at discharge, even if an overall improvement has been highlighted by the prevalent decrease in sulfonylureas prescription

The “Diabetes Comorbidome”: A Different Way for Health Professionals to Approach the Comorbidity Burden of Diabetes

(1) Background: The disease burden related to diabetes is increasing greatly, particularly in older subjects. A more comprehensive approach towards the assessment and management of diabetes’ comorbidities is necessary. The aim of this study was to implement our previous data identifying and representing the prevalence of the comorbidities, their association with mortality, and the strength of their relationship in hospitalized elderly patients with diabetes, developing, at the same time, a new graphic representation model of the comorbidome called “Diabetes Comorbidome”. (2) Methods: Data were collected from the RePoSi register. Comorbidities, socio-demographic data, severity and comorbidity indexes (Cumulative Illness rating Scale CIRS-SI and CIRS-CI), and functional status (Barthel Index), were recorded. Mortality rates were assessed in hospital and 3 and 12 months after discharge. (3) Results: Of the 4714 hospitalized elderly patients, 1378 had diabetes. The comorbidities distribution showed that arterial hypertension (57.1%), ischemic heart disease (31.4%), chronic renal failure (28.8%), atrial fibrillation (25.6%), and COPD (22.7%), were the more frequent in subjects with diabetes. The graphic comorbidome showed that the strongest predictors of death at in hospital and at the 3-month follow-up were dementia and cancer. At the 1-year follow-up, cancer was the first comorbidity independently associated with mortality. (4) Conclusions: The “Diabetes Comorbidome” represents the perfect instrument for determining the prevalence of comorbidities and the strength of their relationship with risk of death, as well as the need for an effective treatment for improving clinical outcomes

Clinical features and outcomes of elderly hospitalised patients with chronic obstructive pulmonary disease, heart failure or both

Background and objective: Chronic obstructive pulmonary disease (COPD) and heart failure (HF) mutually increase the risk of being present in the same patient, especially if older. Whether or not this coexistence may be associated with a worse prognosis is debated. Therefore, employing data derived from the REPOSI register, we evaluated the clinical features and outcomes in a population of elderly patients admitted to internal medicine wards and having COPD, HF or COPD + HF. Methods: We measured socio-demographic and anthropometric characteristics, severity and prevalence of comorbidities, clinical and laboratory features during hospitalization, mood disorders, functional independence, drug prescriptions and discharge destination. The primary study outcome was the risk of death. Results: We considered 2,343 elderly hospitalized patients (median age 81 years), of whom 1,154 (49%) had COPD, 813 (35%) HF, and 376 (16%) COPD + HF. Patients with COPD + HF had different characteristics than those with COPD or HF, such as a higher prevalence of previous hospitalizations, comorbidities (especially chronic kidney disease), higher respiratory rate at admission and number of prescribed drugs. Patients with COPD + HF (hazard ratio HR 1.74, 95% confidence intervals CI 1.16-2.61) and patients with dementia (HR 1.75, 95% CI 1.06-2.90) had a higher risk of death at one year. The Kaplan-Meier curves showed a higher mortality risk in the group of patients with COPD + HF for all causes (p = 0.010), respiratory causes (p = 0.006), cardiovascular causes (p = 0.046) and respiratory plus cardiovascular causes (p = 0.009). Conclusion: In this real-life cohort of hospitalized elderly patients, the coexistence of COPD and HF significantly worsened prognosis at one year. This finding may help to better define the care needs of this population

Clinical features and outcomes of elderly hospitalised patients with chronic obstructive pulmonary disease, heart failure or both

Background and objective: Chronic obstructive pulmonary disease (COPD) and heart failure (HF) mutually increase the risk of being present in the same patient, especially if older. Whether or not this coexistence may be associated with a worse prognosis is debated. Therefore, employing data derived from the REPOSI register, we evaluated the clinical features and outcomes in a population of elderly patients admitted to internal medicine wards and having COPD, HF or COPD + HF. Methods: We measured socio-demographic and anthropometric characteristics, severity and prevalence of comorbidities, clinical and laboratory features during hospitalization, mood disorders, functional independence, drug prescriptions and discharge destination. The primary study outcome was the risk of death. Results: We considered 2,343 elderly hospitalized patients (median age 81 years), of whom 1,154 (49%) had COPD, 813 (35%) HF, and 376 (16%) COPD + HF. Patients with COPD + HF had different characteristics than those with COPD or HF, such as a higher prevalence of previous hospitalizations, comorbidities (especially chronic kidney disease), higher respiratory rate at admission and number of prescribed drugs. Patients with COPD + HF (hazard ratio HR 1.74, 95% confidence intervals CI 1.16-2.61) and patients with dementia (HR 1.75, 95% CI 1.06-2.90) had a higher risk of death at one year. The Kaplan-Meier curves showed a higher mortality risk in the group of patients with COPD + HF for all causes (p = 0.010), respiratory causes (p = 0.006), cardiovascular causes (p = 0.046) and respiratory plus cardiovascular causes (p = 0.009). Conclusion: In this real-life cohort of hospitalized elderly patients, the coexistence of COPD and HF significantly worsened prognosis at one year. This finding may help to better define the care needs of this population

Amélioration du diagnostic in vivo de la qualité osseuse dans le contexte de l'ostéoporose

Cette étude visait à améliorer le diagnostic in vivo de l'ostéoporose par IRM. Dans la clinique un outil de diagnostic précis de l'ostéoporose fait toujours défaut et les caractéristiques de la micro architecture osseuse ne sont pas prises en compte bien qu'elles jouent un rôle important dans la résistance structurelle des os. D'abord a été évalué la capacité de l'IRM à estimer la morphologie osseuse et à suivre l'administration de la thérapie sur des patients in vivo. Ensuite, en comparant l'IRM et le µCT sur des fémurs proximaux cadavériques, il a été évalué la taille de pixel minimale pour évaluer les travées osseuses. En comparant les paramètres morphologiques des os obtenus par IRM avec différentes intensités de champ (3T vs 7T) et séquences d'impulsions (GRE vs TSE), une approche optimisée a été présentée et validée. L'enquête à grande échelle basée sur la DMO clinique et la morphologie osseuse utilisant le test de fracture comme référence a montré que la morphologie osseuse fournissait des informations supplémentaires sur l'état de santé des os. Les changements dus à l'ostéoporose et aux échelles d'investigation inférieures (micro-, nano- et moléculaire) ont été interrogés en utilisant une approche multimodale. Les résultats ont montré que le col fémoral entraînait la sous-région proximale du fémur plus touchée par l'ostéoporose et donc, à risque plus élevé de fracture de fragilité. Aucun changement stoechiométrique dans la composition chimique de l'hydroxyapatite (HA) ne puisse être associé à la maturation minérale, au site anatomique ou à l'ostéoporose, des différences dans le cristal de HA pourraient être associées à l'ordre local et à la micro architectureThis study aimed to improve the in vivo diagnosis of osteoporosis using MRI. Despite the largely recognized burden of osteoporosis, an accurate diagnostic tool is still lacking, bone microarchitecture features are not taking into consideration although playing an important role in bone structural resistance.In this study, it has been first evaluated the MRI ability to assess bone morphology and follow up the therapy delivery on in vivo patients. Then comparing MRI and µCT on cadaveric proximal femurs it has been evaluated the minimum pixel size to assess the bone trabeculae. Moreover, by comparing the bone morphological parameters obtained from MRI with different field strengths (3T vs. 7T) and pulse sequences (GRE vs. TSE) an optimized approach has been presented and validated. The macroscale investigation based on clinical BMD and bone morphology using fracture test as reference have showed that bone morphology provided additional information to the bone health state and fracture risk assessment showing that osteoporosis deteriorates the trabecular architecture. The changes due to osteoporosis and lower investigative scales (micro-, nano- and molecular) have been questioned using a multimodal approach. The results showed that the femoral neck resulted the proximal femur subregion more affected by osteoporosis and hence at in general higher risk fragility fracture compared to both femoral head and great trochanter. Moreover, while no stoichiometric changes in the hydroxyapatite (HA) chemical composition can be associated to mineral maturation, anatomical site or osteoporosis, differences in the HA crystal could be associated to the local order and microarchitectur

Development of a new approach for the assessment of complex blood flow patterns in the left atrium from 4D flow MRI imaging

Mitral valve regurgitation is a common disorder affecting 2-3% of the general population. The morphological and functional remodelling of the left atrium caused by this disease could favour blood stagnation and consequently stroke risk. Several clinical studies suggest that stroke risk stratification may be improved by using hemodynamic information on the left atrium. The goal of this study was therefore to develop a new approach for the assessment of complex blood flow patterns in the left atrium which could quantify the hemodynamic implications of the mitral valve regurgitation on sick patients compared to healthy volunteers. This analysis may enable optimized patient risk stratification and therapy. 4D Flow MRI imaging on the subjects provides information of the anatomy and the velocity field in the three directions in space and time for all the acquisitions. We selected three time frames: the S, E and A wave corresponding to the reservoir, conduit and boosting pump function of the atrium, respectively. We derived the patient- specific anatomical model of the left atrium, by applying a Chan-Vese segmentation, furthermore, we derived the modulus of the velocities and calculated the vorticity performing the curl of the velocities field. We individuated and implemented four different criteria for the identification of vortex cores inside the left atrium, ω, Δ, Q and λ_2 criterion. We evaluated the N_k number defined as the quality of rotation of a vortex core and we proposed a scale to quantitatively quantify them. We also calculated other different features as kinetic energy, pressure gradient and Fourier transformation. In this preliminary testing, the interface and the method proposed, returned a good segmentation and velocities in the expected range. All the features and methods proposed seem to indicate that a reduced blood washout in the left atrium occurs in sick patients, which might facilitate clot formation and increase of the thromboembolic risk