In vivo structural connectome of arousal and motor brainstem nuclei by 7 Tesla and 3 Tesla MRI

Brainstem nuclei are key participants in the generation and maintenance of arousal, which is a basic function that modulates wakefulness/sleep, autonomic responses, affect, attention, and consciousness. Their mechanism is based on diffuse pathways ascending from the brainstem to the thalamus, hypothalamus, basal forebrain and cortex. Several arousal brainstem nuclei also participate in motor functions that allow humans to respond and interact with the surrounding through a multipathway motor network. Yet, little is known about the structural connectivity of arousal and motor brainstem nuclei in living humans. This is due to the lack of appropriate tools able to accurately visualize brainstem nuclei in conventional imaging. Using a recently developed in vivo probabilistic brainstem nuclei atlas and 7 Tesla diffusion-weighted images (DWI), we built the structural connectome of 18 arousal and motor brainstem nuclei in living humans (n = 19). Furthermore, to investigate the translatability of our findings to standard clinical MRI, we acquired 3 Tesla DWI on the same subjects, and measured the association of the connectome across scanners. For both arousal and motor circuits, our results showed high connectivity within brainstem nuclei, and with expected subcortical and cortical structures based on animal studies. The association between 3 Tesla and 7 Tesla connectivity values was good, especially within the brainstem. The resulting structural connectome might be used as a baseline to better understand arousal and motor functions in health and disease in humans

Structural connectivity of autonomic, pain, limbic, and sensory brainstem nuclei in living humans based on 7 Tesla and 3 Tesla MRI

Autonomic, pain, limbic, and sensory processes are mainly governed by the central nervous system, with brainstem nuclei as relay centers for these crucial functions. Yet, the structural connectivity of brainstem nuclei in living humans remains understudied. These tiny structures are difficult to locate using conventional in vivo MRI, and ex vivo brainstem nuclei atlases lack precise and automatic transformability to in vivo images. To fill this gap, we mapped our recently developed probabilistic brainstem nuclei atlas developed in living humans to high-spatial resolution (1.7 mm isotropic) and diffusion weighted imaging (DWI) at 7 Tesla in 20 healthy participants. To demonstrate clinical translatability, we also acquired 3 Tesla DWI with conventional resolution (2.5 mm isotropic) in the same participants. Results showed the structural connectome of 15 autonomic, pain, limbic, and sensory (including vestibular) brainstem nuclei/nuclei complex (superior/inferior colliculi, ventral tegmental area-parabrachial pigmented, microcellular tegmental-parabigeminal, lateral/medial parabrachial, vestibular, superior olivary, superior/inferior medullary reticular formation, viscerosensory motor, raphe magnus/pallidus/obscurus, parvicellular reticular nucleus-alpha part), derived from probabilistic tractography computation. Through graph measure analysis, we identified network hubs and demonstrated high intercommunity communication in these nuclei. We found good (r = .5) translational capability of the 7 Tesla connectome to clinical (i.e., 3 Tesla) datasets. Furthermore, we validated the structural connectome by building diagrams of autonomic/pain/limbic connectivity, vestibular connectivity, and their interactions, and by inspecting the presence of specific links based on human and animal literature. These findings offer a baseline for studies of these brainstem nuclei and their functions in health and disease, including autonomic dysfunction, chronic pain, psychiatric, and vestibular disorders

Trends and safety of bariatric revisional surgery in Italy: multicenter, prospective, observational study

Background: revisional bariatric surgery (RBS) represents a further solution for patients who experience inadequate weight loss (IWL) following primary bariatric surgery (BS) or significant weight regain (WR) following initial satisfactory response. RBS guidelines are lacking; however, an increased trend in further BS offerings has been reported recently. Objective: analyze trend, mortality, complication, readmission, and reoperation rates for any reason at 30 days after RBS in Italy. Setting: ten Italian high-volume BS centers (university hospitals and private centers). Methods: prospective, observational, multicenter study enrolling patients undergoing RBS between October 1, 2021, and March 31, 2022, registering reasons for RBS, technique, mortality, intraoperative and perioperative complications, readmissions, and reinterventions for any reason. Patients undergoing RBS during the same calendar interval in 2016-2020 were considered control patients. Results: a total of 220 patients were enrolled and compared with 560 control-group patients. Mortality was .45% versus .35% (n.s), with an overall mortality of .25%, while open surgery or conversion to open surgery was registered in 1%. No difference was found for mortality, morbidity, complications, readmission (1.3%), and reoperation rates (2.2%). IWL/WR was the most frequent cause, followed by gastroesophageal reflux disease; Roux-en-Y gastric bypass was the most used revisional procedure (56%). Sleeve gastrectomy was the most revised procedure in the study group, while gastric banding was the most revised in the control group. RBS represents up to 9% of the total BS in the Italian participating centers. Conclusions: laparoscopy represents the standard approach for RBS, which appears safe. Current Italian trends show a shift toward sleeve gastrectomy being the most revised procedure and Roux-en-Y gastric bypass being the most frequent revisional procedure

MicroRNAs expression profiling in Paget’s Disease of Bone, Osteoporosis and Hyperparathyroidism

Excluding monogenic bone disorders, it is now well established that in complex multifactorial diseases, with a recognized hereditary component, such as Paget’s disease of bone and osteoporosis, the associated genetic variants have a limited impact on gene expression and explain only a small fraction of the disease risk. Moreover, a larger proportion of variants associated to many human traits or diseases fall in loci which do not encode proteins, suggesting that additional mechanisms other than gene-gene and gene-environment interactions might be involved. In this setting, we focus our attention on Paget’s disease of bone, osteoporosis, and hyperparathyroidism to clarify epigenetic mechanisms involved in their pathogenesis. MicroRNAs (miRNAs) are small (∼22 nt), noncoding single-stranded RNAs that have emerged as important posttranscriptional regulators of gene expression, with an essential role in vertebrate development and several biological processes. They contribute to every step of osteogenesis and bone homeostasis, from embryonic skeletal development to maintenance of adult bone tissue, by regulating the growth, differentiation, and activity of different cell systems inside and outside the skeleton. However, despite the rising number of experimental reports about this issue, our understanding of the exact mechanisms through which miRNAs are involved in the pathogenesis of Paget’s disease of bone, osteoporosis, and hyperparathyroidism remain unclear. For these reasons, we performed a miRNAs expression profiling in peripheric mononuclear cells (PBMCs) and serum of wild type pagetic patients (PDB-WT) and with mutations on the SQSTM1 gene (PDB-MUT) and osteoporotic subjects (OP) compared to healthy controls, using TaqMan Low Density MicroRNA Array Cards. After that, we performed the same analysis in serum of patients with hypercalcemic primary hyperparathyroidism and osteoporosis (H-PHPT) and normocalcemic primary hyperparathyroidism without osteoporosis (N-PHPT), compared to healthy controls. Differentially expressed miRNAs identified in PBMCs of pagetic and osteoporotic patients were then validated in single assay, while the validation of miRNAs identified in the serum of all subjects is ongoing. A bioinformatic analysis (Gene Ontology analysis) was performed to find putative functional pathways and biological processes linked to some differentially expressed miRNAs. These analyses identified numerous genes and pathways involved in regulation of osteoclasts, osteoblasts differentiation and bone metabolism in all the three pathologies considered. These results could be used not only to better understand new molecular mechanisms involved in Paget’s disease, osteoporosis, and hyperparathyroidism pathogenesis, but also as a resource of new biomarkers that could be introduced in the clinical practice as diagnostic tools

MicroRNAs in bone diseases

MicroRNAs are small, noncoding single-stranded RNAs that have emerged as important posttranscriptional regulators of gene expression, with an essential role in vertebrate development and different biological processes. This review highlights the recent advances in the function of miRNAs and their roles in bone remodeling and bone diseases. MicroRNAs (miRNAs) are a class of small (∼22 nt), noncoding single-stranded RNAs that have emerged as important post transcriptional regulators of gene expression. They are essential for vertebrate development and play critical roles in different biological processes related to cell differentiation, activity, metabolism, and apoptosis. A rising number of experimental reports now indicate that miRNAs contribute to every step of osteogenesis and bone homeostasis, from embryonic skeletal development to maintenance of adult bone tissue, by regulating the growth, differentiation, and activity of different cell systems inside and outside the skeleton. Importantly, emerging information from animal studies suggests that targeting miRNAs might become an attractive and new therapeutic approach for osteoporosis or other skeletal diseases, even though there are still major concerns related to potential off target effects and the need of efficient delivery methods in vivo. Moreover, besides their recognized effects at the cellular level, evidence is also gathering that miRNAs are excreted and can circulate in the blood or other body fluids with potential paracrine or endocrine functions. Thus, they could represent suitable candidates for becoming sensitive disease biomarkers in different pathologic conditions, including skeletal disorders. Despite these promising perspectives more work remains to be done until miRNAs can serve as robust therapeutic targets or established diagnostic tools for precision medicine in skeletal disorders

Vescicole extracellulari e metabolismo osseo: ruolo e possibili implicazioni cliniche

Le vescicole extracellulari (EV) sono secrete da vari tipi cellulari e veicolano cargo specifici destinati alle cellule target, mediando così effetti paracrini in meccanismi fisiologici e patologici. Negli ultimi anni lo studio delle EV si è affermato in moltissimi ambiti, compreso il mondo del metabolismo osseo. In questa rassegna riportiamo i più recenti e promettenti studi sul ruolo biologico delle EV nel tessuto osseo e il loro potenziale utilizzo in strategie terapeutiche

The Potential Role of miRNAs as New Biomarkers for Osteoporosis

Osteoporosis is the most common metabolic bone disorder affecting up to 40% of postmenopausal women, characterized by a reduction in bone mass and strength leading to bone fragility and fractures. Despite the available tools for diagnosis and stratification of a fracture risk, bone loss occurs insidiously and osteoporosis is often diagnosed after the first fracture has occurred, with important health-related outcomes. Therefore, the need of markers that could efficiently diagnose bone fragility and osteoporosis is still necessary. Over the past few years, novel studies have focused on miRNAs, small noncoding RNAs that are differentially expressed in many pathological conditions, making them attractive biomarkers. To date, the role of miRNAs in bone disorders remains in great part unclear. In particular, limited and partly conflicting information is available concerning their use as potential biomarkers for osteoporosis, due to differences in patient selection, type of samples, and analytical methods. Despite these limits, concordant information about some specific miRNAs is now arising, making likely their use as additional tools to stratify the risk of osteoporosis and possibly fractures. In this review, we summarize the most relevant studies concerning circulating miRNAs differentially expressed in osteoporotic patients along with their function in bone cells and bone turnover

Treatment needs and current options for postmenopausal osteoporosis

5nononeIntroduction: Osteoporosis is a chronic, skeletal disorder characterized by compromised bone strength and increased risk of fractures, affecting up to 50% of postmenopausal women worldwide. Over the past 2 decades there have been consistent developments in the pharmacotherapy of osteoporosis with the availability of potent inhibitors of bone resorption (bisphosphonates, and denosumab) or stimulators of bone formation (PTH analogs) with substantial improvements over calcitonin or estrogen replacement. Areas covered: In this review we summarize the effects of existing treatment options for postmenopausal osteoporosis along with the unmet clinical needs and we discuss about the potential benefits of new compounds under development. Expert opinion: Despite the recent progresses, there are still limitations and unmeet needs with all the available drugs, mainly concerning treatment adherence, efficacy on the prevention of nonvertebral fractures and the long-term adverse events of antiresorptive regimens. Moreover, PTH analogs are the only available compounds able to stimulate bone formation, but with a restricted anabolic window of no more than 2 years. Of interest, the more recent advances in bone biology identified new targets for the development of drugs with a more potent and selective activity on either osteoclasts or osteoblasts, thus making possible to uncouple bone formation from bone resorption.mixedGennari, Luigi; Rotatori, Stefano; Bianciardi, Simone; Nuti, Ranuccio; Merlotti, DanielaGennari, Luigi; Rotatori, Stefano; Bianciardi, Simone; Nuti, Ranuccio; Merlotti, Daniel

Combustion mechanical noise breakdown : turbocharger noise identification on a V8 engine

The NVH character of an engine is composed of a mixture of various sources. Some of these have been categorized as combustion related noise and others as mechanical noise. The introduction of modern engine technologies, such as turbocharger, direct injection, etc., often results in additional engine vibrations and radiated noise. Therefore being able to extract specific engine noises is of prime interest in the engine development phase and as well as for engine diagnostic purposes. Several methodologies for combustion mechanical breakdown have been developed in the past, namely the multiple regression analysis, the classical Wiener filter and cyclostationary Wiener filter. In the present paper the techniques are applied to micro-phone recordings measured at one meter distance from a Ferrari V8 engine running on a test bench. Strengths and weaknesses of the techniques are evaluated. Moreover the results obtained by the first two aforementioned techniques are compared. Finally a source separation method is combined with microphone array measurements, allowing a localization and quantification of the combustion and mechanical sources of noise on the V8 engine. This is illustrated with an application example for a specific turbocharger noise.status: publishe

Appropriate models for novel osteoporosis drug discovery and future perspectives

6nononeIntroduction: Osteoporosis is a common skeletal disorder characterized by compromised bone strength and increased fracture risk. It is becoming a growing health-economic problem worldwide. Over the past two decades, there has been considerable progress in the availability of compounds with antiresorptive or anabolic activity on bone. However, existing therapeutic strategies still have limitations.Areas covered: In this review, the authors summarize past and current approaches for the development of antiresorptive and anabolic agents for osteoporosis together with their mechanisms of action. They also provide discussion on the application of new technologies for novel osteoporosis drug discovery.Expert opinion: Thanks to the recent advances in molecular biology over the past few years, novel therapeutic targets for antiresorptive or anabolic compounds have been discovered and several promising new drugs are in preclinical and clinical development. Despite these advances, the current understanding of the mechanisms regulating bone remodeling is far from complete, leaving significant drawbacks to the discovery and the clinical development of novel therapeutic agents. Hopefully, improvements in functional genomics and bioinformatics, along with new technological approaches such as RNA silencing, quantitative proteomics, metabolomics, and the use of mesenchymal stem cells, will address these issues and widen our options for treating several disorders of bone metabolism, including osteoporosis.mixedGennari, Luigi; Rotatori, Stefano; Bianciardi, Simone; Gonnelli, Stefano; Nuti, Ranuccio; Merlotti, DanielaGennari, Luigi; Rotatori, Stefano; Bianciardi, Simone; Gonnelli, Stefano; Nuti, Ranuccio; Merlotti, Daniel