Receptor-Receptor Interactions as a Widespread Phenomenon: Novel Targets for Drug Development?

open5The discovery of receptor-receptor interactions (RRI) has expanded our understanding of the role that G protein-coupled receptors (GPCRs) play in intercellular communication. The finding that GPCRs can operate as receptor complexes, and not only as monomers, suggests that several different incoming signals could already be integrated at the plasma membrane level via direct allosteric interactions between the protomers that form the complex. Most research in this field has focused on neuronal populations and has led to the identification of a large number of RRI. However, RRI have been seen to occur not only in neurons but also in astrocytes and, outside the central nervous system, in cells of the cardiovascular and endocrine systems and in cancer cells. Furthermore, RRI involving the formation of macromolecular complexes are not limited to GPCRs, being also observed in other families of receptors. Thus, RRI appear as a widespread phenomenon and oligomerization as a common mechanism for receptor function and regulation. The discovery of these macromolecular assemblies may well have a major impact on pharmacology. Indeed, the formation of receptor complexes significantly broadens the spectrum of mechanisms available to receptors for recognition and signaling, which may be implemented through modulation of the binding sites of the adjacent protomers and of their signal transduction features. In this context, the possible appearance of novel allosteric sites in the receptor complex structure may be of particular relevance. Thus, the existence of RRI offers the possibility of new therapeutic approaches, and novel pharmacological strategies for disease treatment have already been proposed. Several challenges, however, remain. These include the accurate characterization of the role that the receptor complexes identified so far play in pathological conditions and the development of ligands specific to given receptor complexes, in order to efficiently exploit the pharmacological properties of these complexes.openGuidolin, Diego; Marcoli, Manuela; Tortorella, Cinzia; Maura, Guido; Agnati, Luigi FGuidolin, Diego; Marcoli, Manuela; Tortorella, Cinzia; Maura, Guido; Agnati, Luigi

Post mortem computed tomography of heart

Post mortem Computed tomography (CT) has been increasingly used in routine forensic practice and research. While radiological examination is generally considered to be a good complement for conventional autopsy, it was thought to have limited application in cardiovascular pathology. The aim of the present study is to show our experience of radiological analysis of the heart as single organ, as an integrative tool for research and forensic applications. The anatomo-radiologic study for forensic purpose was performed on 10 hearts sampled at autopsy (8M, 2 F, mean age 45 years old). The specimens underwent CT examinations. In 5 out of 10 of cadavers, a myocardial infarction was found at macroscopic and microscopic analysis. In these same cases, the CT examination showed the presence and the localization of calcifications, corresponding to the infarct area. In 90% of cases the presence of calcifications allowed the visualization of the coronary arteries and their branches. Basing on our experience, isolated single-organ CT could be considered a useful integrative tool in addition to traditional autopsy investigation (macroscopic sections and histology) in identifying the cause of death by recognizing the presence and degree of coronary artery pathology

Anatomical iconography in the thirties in Padova: Mario Alfonsi and cardboard, ink and watercolour

The image in Anatomy has a pivotal role, due to the need of the student to learn on images the anatomical structures. This need is unchanged from the past to nowadays. In the last century Mario Alfonsi, a fine illustrator, was the official designer at the Anatomical Institute of Padova, working closely with Professor Tullio Terni. Terni was removed from teaching because of the racial laws and was rejected by the Jewish community and expelled from the Academy of the Lincei. The removal of Terni is the principal reason why the school of anatomical drawing was not founded in Padova. Mario Alfonsi is author of about 300 illustrative plates of Anatomy and the major part of his collection is kept in the archives of the institute of Human Anatomy of Padova. The tables are large (100 x 200 cm), illustrating the systems and organs of the human body, and were used as a teaching tool for lessons to students of Medicine till 1970. They are made of cardboard supported by a rod wood which allowed their exposure in the Falloppio Classroom. The drawings are made with ink and coloured with watercolour or tempera and date back to the thirties. They are signed and report the date expressed in the fascist calendar. They are in good condition, classified and stored in special cabinets. Alfonsi in his career also made drawings for texts of Anatomy and Surgery. In fact, he worked also with surgeons, illustrating step by step innovative surgical procedures

High-quality digital 3D reconstruction of the terminal pathway of a heart stab wound

High-quality digital 3D reconstructions of microscopic findings have been involved in anatomical and histopathological research, but their potentialities in forensic pathology may also be of particular interest. We here present the use of such methods to furtherly analyse a heart stab wound in a suicidal case. External examination revealed multiple incised wounds on the wrists, three stab wounds at the neck and a single stab wound on the chest. At autopsy, injuries to the neck and wrists were superficial whereas the thoracic stab wound penetrated the chest wall and pericardium. Heart examination showed an 8-mm-long stab wound on the anterior surface of the left ventricle. Heart sectioning and inspection of the correspondent internal aspect of the left ventricle did not show a macroscopic injury, but the irregularity of the trabeculae carneae did not permit to exclude a microscopic pathway. Thus, the heart wall including the stab wound was paraffin-embedded and subjected to complete sectioning for microscopic analysis along all the wound extension. Every 10th section was stained with haematoxylin-eosin and was acquired by using a Leica DMR microscope and a high resolution digital camera. The three-dimensional aspect of the lesion was reconstructed with a software system for 3D computer graphics. Microscopic examination and 3D reconstruction demonstrated that the lesion extended to the internal surface of the ventricle wall, although for a very limited extension. 3D reconstruction also showed a certain curvilinear pattern of the lesion in the myocardium, consistent with myocardial contraction at the moment of injury and consequent vitality of the lesion. Moreover, 3D reconstruction permitted to obtain the dimensions of the intra-myocardial injury (corrected for shrinkage and evaluated in the context of muscle contraction), also permitting to furtherly confirm the identification of the knife involved. In conclusion, the present case is indicative of how complete microscopic sectioning and 3D reconstruction may add further information about characteristics of injuries of forensic interest

An anatomo-radiological study of the infrapatellar fat pad

The infrapatellar fat pad (IFP) is an intracapsular, but extrasynovial structure, located between the patellar tendon, femoral condyles and tibial plateau. We have recently described the microscopic orgnisation of the IFP, which consists of white adipose tissue (fibroadipose, lobular type), organised in lobuli delimited by thin connective septa. The aim of the study is to describe the sonoanatomical features of IFP in subjects without knee pathology during flexo-extension movements. Twentyfour volunteers subjects with no history of knee diseases (5M, 19F, mean age: 45yo)were analysed. Examinations was performed using high-resolution grey-scale ultrasound. The mean area of the deepest recognisable adipose chamber in extension were 0,12 and in flexion 0,19 mm2, and the circumference were in extension 1,36 and in flexion 1,19 mm. The area of the closest adipose chamber to the patellar tendon were in extension 0,29 and flexion 0,12 mm2(

The still under-investigated role of cognitive deficits in PML diagnosis

Background: Despite cognitive deficits frequently represent the first clinical manifestations of Progressive Multifocal Leukoencephalopathy (PML) in Natalizumab-treated MS patients, the importance of cognitive deficits in PML diagnosis is still under-investigated. The aim of the current study is to investigate the cognitive deficits at PML diagnosis in a group of Italian patients with PML. Methods: Thirty-four PML patients were included in the study. The demographic and clinical data, the lesion load and localization, and the longitudinal clinical course was compared between patients with (n = 13) and without (n = 15) cognitive deficit upon PML suspicion (the remaining six patients were asymptomatic). Clinical presentation of cognitive symptoms was described in detail. Result: After symptoms detection, the time to diagnosis resulted to be shorter for patients presenting with cognitive than for patients with non cognitive onset (p = 0.03). Within patients with cognitive onset, six patients were presenting with language and/or reading difficulties (46.15%); five patients with memory difficulties (38.4%); three patients with apraxia (23.1%); two patients with disorientation (15.3%); two patients with neglect (15.3%); one patients with object agnosia (7.7%), one patient with perseveration (7.7%) and one patient with dementia (7.7%). Frontal lesions were less frequent (p = 0.03), whereas temporal lesions were slightly more frequent (p = 0.06) in patients with cognitive deficits. The longitudinal PML course seemed to be more severe in cognitive than in non cognitive patients (F = 2.73, p = 0.03), but differences disappeared (F = 1.24, p = 0.29) when balancing for the incidence of immune reconstitution syndrome and for other treatments for PML (steroids, plasma exchange (PLEX) and other therapies (Mefloquine, Mirtazapine, Maraviroc). Conclusion: Cognitive deficits at PML onset manifest with symptoms which are absolutely rare in MS. Their appearance in MS patients should strongly suggest PML. Clinicians should be sensitive to the importance of formal neuropsychological evaluation, with particular focus on executive function, which are not easily detected without a formal assessment

Randomised controlled trial combining vitamin E-functionalised chocolate with physical exercise to reduce the risk of protein-energy malnutrition in predementia aged people: study protocol for Choko-Age

Objective: Protein-energy malnutrition and the subsequent muscle wasting (sarcopenia) are common ageing complications. It is knowing to be also associated with dementia. Our programme will test the cytoprotective functions of vitamin E combined with the cortisol-lowering effect of chocolate polyphenols (PP), in combination with muscle anabolic effect of adequate dietary protein intake and physical exercise to prevent the age-dependent decline of muscle mass and its key underpinning mechanisms including mitochondrial function, and nutrient metabolism in muscle in the elderly. Methods and analysis: In 2020, a 6-month double-blind randomised controlled trial in 75 predementia older people was launched to prevent muscle mass loss, in respond to the 'Joint Programming Initiative A healthy diet for a healthy life'. In the run-in phase, participants will be stabilised on a protein-rich diet (0.9-1.0 g protein/kg ideal body weight/day) and physical exercise programme (high-intensity interval training specifically developed for these subjects). Subsequently, they will be randomised into three groups (1:1:1). The study arms will have a similar isocaloric diet and follow a similar physical exercise programme. Control group (n=25) will maintain the baseline diet; intervention groups will consume either 30 g/day of dark chocolate containing 500 mg total PP (corresponding to 60 mg epicatechin) and 100 mg vitamin E (as RRR-alpha-tocopherol) (n=25); or the high polyphenol chocolate without additional vitamin E (n=25). Muscle mass will be the primary endpoint. Other outcomes are neurocognitive status and previously identified biomolecular indices of frailty in predementia patients. Muscle biopsies will be collected to assess myocyte contraction and mitochondrial metabolism. Blood and plasma samples will be analysed for laboratory endpoints including nutrition metabolism and omics. Ethics and dissemination: All the ethical and regulatory approvals have been obtained by the ethical committees of the Azienda Ospedaliera Universitaria Integrata of Verona with respect to scientific content and compliance with applicable research and human subjects' regulation. Given the broader interest of the society toward undernutrition in the elderly, we identify four main target audiences for our research activity: national and local health systems, both internal and external to the project; targeted population (the elderly); general public; and academia. These activities include scientific workshops, public health awareness campaigns, project dedicated website and publication is scientific peer-review journals. Trial registration number: NCT05343611

Disease-Modifying Therapies and Coronavirus Disease 2019 Severity in Multiple Sclerosis

Objective: This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (PwMS). Methods: We retrospectively collected data of PwMS with suspected or confirmed COVID-19. All the patients had complete follow-up to death or recovery. Severe COVID-19 was defined by a 3-level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID-19 by multivariate and propensity score (PS)-weighted ordinal logistic models. Sensitivity analyses were run to confirm the results. Results: Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID-19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized. After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti-CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18-4.74, p = 0.015) with increased risk of severe COVID-19. Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20-12.53, p = 0.001). Results were confirmed by the PS-weighted analysis and by all the sensitivity analyses. Interpretation: This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, some specific elements of risk emerged. These will need to be considered while the COVID-19 pandemic persists

Optimizing the “Time to pregnancy” in women with multiple sclerosis: the OPTIMUS Delphi survey

BackgroundThe debate on how to manage women affected by multiple sclerosis (MS) during reproductive age is still open, as is the issue of fertility in such patients. Main issue regard the identification of the optimal window for pregnancy and how to deal with medical therapy before and during conception. The aim of this Delphi consensus was to collect the opinions of a multidisciplinary group, involving reproductive medicine specialists and neurologists with experience in the management of multiple sclerosis women with reproductive desire.MethodsFour experts plus scientific coordinators developed a questionnaire distributed online to 10 neurologists and later discussed the responses and amended a list of statements. The statements were then distributed via an online survey to 23 neurologists (comprising the first 10), who voted on their level of agreement/disagreement with each statement. Consensus was achieved if agreement or disagreement with a statement exceeded 66%.ResultsTwenty-one statements reached consensus after two rounds of voting, leading to the following main recommendations: (1) Fertility evaluation should be suggested to wMS, in case of the need to shorten time to pregnancy and before treatment switch in women on DMTs contraindicated in pregnancy, particularly in case of highly active disease and age > 35 years. (2) ART should not be discouraged in wMS, but the use of DMTs until pregnancy confirmation should be suggested; ART may be considered in order to reduce time to pregnancy in MS women with a reduced ovarian reserve and/or age > 35 years, but in case of an expected poor ART prognosis and the need for more than one ART cycle, a switch to a high-efficacy DMD before ART should be offered. (3) Oocyte cryopreservation may be considered in women with reduced ovarian reserve, with unpredictable time to complete diagnostic workup and achieve disease control; a risk/cost–benefit analysis must be performed in women >35 years, considering the diminished ovarian reserve.ConclusionThis consensus will help MS neurologists to support family planning in wMS, respecting MS therapeutic needs while also taking into account the safety and impact of advancing age on fertility