The Contribution of Neuroimaging to the Understanding of Essential Tremor Pathophysiology: a Systematic Review

Essential tremor (ET) is one of the most common movement disorders. Over the last 10 years, magnetic resonance imaging (MRI) has shed light on the structural and functional abnormalities possibly involved in ET pathophysiology. In this systematic review, we aimed to identify the cortical and subcortical structures involved and the role that different brain areas play in the pathophysiology of motor and non-motor ET features. We found that structural (grey and white matter) cerebellar damage and connectivity alterations between the cerebellum and various cortical areas play a role in both motor and non-motor symptoms of ET. In particular, many studies found an association between MRI findings and non-motor symptoms

Targeting the microenvironment in chronic lymphocytic leukemia offers novel therapeutic options

Chronic lymphocytic leukemia (CLL) cells display features consistent with a defect in apoptosis and exhibit prolonged survival in vivo. Survival of these malignant cells is influenced by interactions with non-leukemic cells located in permissive niches in lymphoid organs. Leukemic cells subvert the normal architecture of the lymphoid organs, recruiting stromal cells, dendritic cells and T lymphocytes, all reported as playing active roles in the survival and proliferation of CLL. The same survival-promoting environment also rescues/protects leukemic cells from cytotoxic therapies, giving way to disease relapse. This review summarizes and discusses current knowledge about the intricate network of soluble and cell-bound signals regulating the life and death of CLL cells in different districts. At the same time, it seeks to hone in on which discrete molecular elements are best suited as targets for treating this still incurable disease

Action Selection and Motor Decision Making: Insights from Transcranial Magnetic Stimulation

In everyday life, goal-oriented motor behaviour relies on the estimation of the rewards/costs associated with alternative actions and on the appropriate selection of movements. Motor decision making is defined as the process by which a motor plan is chosen among a set of competing actions based on the expected value. In the present literature review we discuss evidence from transcranial magnetic stimulation (TMS) studies of motor control. We focus primarily on studies of action selection for instructed movements and motor decision making. In the first section, we delve into the usefulness of various TMS paradigms to characterise the contribution of motor areas and distributed brain networks to cued action selection. Then, we address the influence of motivational information (e.g., reward and biomechanical cost) in guiding action choices based on TMS findings. Finally, we conclude that TMS represents a powerful tool for elucidating the neurophysiological mechanisms underlying action choices in humans

CONSERVATION AT THE INDIVIDUAL LEVEL: SUCCESSFUL REHABILITATION AND POST-RELEASE MONITORING OF AN ITALIAN WOLF (Canis lupus italicus) INJURED IN A CAR ACCIDENT.

This case report describes the rescue of an eight-month-old male Italian wolf (Canis lupus italicus), the victim of a car accident that caused it a pulmonary contusion, a fracture of the shaft of right femur, and a metaphyseal fracture of the left stifle. A lateral surgical approach was performed to treat the animal\u2019s multiple contusions and fractures. Afterwards the wolf was transferred to a wild animal recovery center for its rehabilitation, where it fully recovered. After 35 days in captivity the wolf was thus released into the supposed home-range of its original pack, and its movements were monitored by a GPS satellite collar. The collar worked correctly for 479 days. During that period the collar acquired a total of 1202 locations, indicating that the wolf had traveled at least 1590 km, with an average monthly distance (\ub1 SD) of 102 \ub1 40 km, exploring an overall area of about 270 km2. During the first 10 days after its release, the wolf remained in the area of its supposed native pack, whereas at about the age of 10 months the wolf began to make wide extraterritorial movements. The wolf\u2019s last localization was acquired on 13th May 2018, about 17 months after its release, at a linear distance of about 65 km from the release site. This preliminary data showed that the wolf was alive and travelled long distances after its release, and demonstrates how a multidisciplinary management approach can support the recovery and successful release into nature of a rescued wild animal belonging to a flagship species with a notable ecological role, such as the Italian wolf

Očuvanje na individualnoj razini: uspješna rehabilitacija i praćenje talijanskog vuka (Canis lupus italicus) nastradalog na prometnici nakon puštanja na slobodu

This case report describes the rescue of an eight-month-old male Italian wolf (Canis lupus italicus), the victim of a car accident that caused it a pulmonary contusion, a fracture of the shaft of right femur, and a metaphyseal fracture of the left stifle. A lateral surgical approach was performed to treat the animal’s multiple contusions and fractures. Afterwards the wolf was transferred to a wild animal recovery center for its rehabilitation, where it fully recovered. After 35 days in captivity the wolf was thus released into the supposed home-range of its original pack, and its movements were monitored by a GPS satellite collar. The collar worked correctly for 479 days. During that period the collar acquired a total of 1202 locations, indicating that the wolf had traveled at least 1590 km, with an average monthly distance (± SD) of 102 ± 40 km, exploring an overall area of about 270 km2. During the first 10 days after its release, the wolf remained in the area of its supposed native pack, whereas at about the age of 10 months the wolf began to make wide extraterritorial movements. The wolf’s last localization was acquired on 13th May 2018, about 17 months after its release, at a linear distance of about 65 km from the release site. These preliminary data showed that the wolf was alive and travelled long distances after its release, and demonstrates how a multidisciplinary management approach can support the recovery and successful release into nature of a rescued wild animal belonging to a flagship species with a notable ecological role, such as the Italian wolf.Ovaj prikaz slučaja opisuje spašavanje osmomjesečnog mužjaka talijanskog vuka (Canis lupus italicus) koji je bio žrtva naleta vozila s posljedičnim nagnječenjem pluća, prijelomom vrata desne bedrene kosti prijelomom u području metafize lijevoga koljena. Primijenjen je lateralni kirurški pristup kako bi se sanirala višestruka nagnječenja i prijelomi u životinje. Nakon toga je vuk prevezen u centar za oporavak divljih životinja gdje se potpuno oporavio. Nakon 35 dana u zatočeništvu vuk je pušten u okoliš nalik na njegov prirodni te je praćen preko GPS ogrlice. Ogrlica je ispravno radila 479 dana. Za to je vrijeme pokazala 1202 lokacije, upućujući na to da je vuk prešao 1590 km, u prosjeku mjesečno 102 ± 40 km (± SD), istražujući područje od 270 km2. Prvih 10 dana nakon oslobađanja vuk je ostao u području nalik na njegov prirodni okoliš, no u dobi od 10 mjeseci počeo je odlaziti na šire područje. Posljednja je njegova lokacija zabilježena 13. svibnja 2018., oko 17 mjeseci nakon puštanja, na zračnoj udaljenosti od oko 65 km od mjesta ispuštanja. Ovaj preliminarni podatak pokazuje da je vuk bio živ i prelazio velike udaljenosti nakon oslobađanja. Također pokazuje da multidisciplinarni pristup spašavanju može pospješiti oporavak i uspješno vraćanje u prirodu divljih životinja koje pripadaju vodećim vrstama s velikom ekološkom važnošću, kao što je talijanski vuk

Plasma from pre-pubertal obese children impairs insulin stimulated Nitric Oxide (NO) bioavailability in endothelial cells: Role of ER stress.

Childhood obesity is commonly associated with early signs of endothelial dysfunction, characterized by impairment of insulin signaling and vascular Nitric Oxide (NO) availability. However, the underlying mechanisms remain to be established. Hence, we tested the hypothesis that endothelial insulin-stimulated NO production and availability was impaired and related to Endoplasmic Reticulum (ER) in human umbilical vein endothelial cells (HUVECs) cultured with plasma obtained from pre-pubertal obese (OB) children. OB children (N = 28, age: 8.8 ± 2.2; BMI z-score: 2.15 ± 0.39) showed impaired fasting glucose, insulin and HOMA-IR than normal weight children (CTRL; N = 28, age: 8.8 ± 1.7; BMI z-score: 0.17 ± 0.96). The in vitro experiments showed that OB-plasma significantly impaired endothelial insulin-stimulated NO production and bioavailability compared to CTRL-plasma. In parallel, in HUVECs OB-plasma increased GRP78 and activated PERK, eIF2α, IkBα and ATF6 (all ER stress markers). Moreover, OB-plasma increased NF-κB activation and its nuclear translocation. Notably, all these effects proved to be significantly restored by using PBA and TUDCA, known ER stress inhibitors. Our study demonstrate for the first time that plasma from obese children is able to induce in vitro endothelial insulin resistance, which is characterized by reduced insulin-stimulated NO production and bioavailability, endothelial ER stress and increased NF-κB activation

Adenosine signaling mediates hypoxic responses in the chronic lymphocytic leukemia microenvironment

The chronic lymphocytic leukemia (CLL) niche is a closed environment where leukemic cells derive growth and survival signals through their interaction with macrophages and T lymphocytes. Here, we show that the CLL lymph node niche is characterized by overexpression and activation of HIF-1a, which increases adenosine generation and signaling, affecting tumor and host cellular responses. Hypoxia in CLL lymphocytes modifies central metabolic pathways, protects against drug-driven apoptosis, and induces interleukin 10 (IL-10) production. In myeloid cells, it forces monocyte differentiation to macrophages expressing IRF4, IDO, CD163, and CD206, hallmarks of the M2 phenotype, which promotes tumor progression. It also induces IL-6 production and enhances nurturing properties. Low oxygen levels decrease T-cell proliferation, promote glycolysis, and cause the appearance of a population of PD-11 and IL-10–secreting T cells. Blockade of the A2A adenosine receptor counteracts these effects on all cell populations, making leukemic cells more susceptible to pharmacological agents while restoring immune competence and T-cell proliferation. Together, these results indicate that adenosine signaling through the A2A receptor mediates part of the effects of hypoxia. They also suggest that therapeutic strategies to inhibit the adenosinergic axis may be useful adjuncts to chemotherapy or tyrosine kinase inhibitors in the treatment of CLL patients

The Role of Attitudes Toward Medication and Treatment Adherence in the Clinical Response to LAIs: Findings From the STAR Network Depot Study

Background: Long-acting injectable (LAI) antipsychotics are efficacious in managing psychotic symptoms in people affected by severe mental disorders, such as schizophrenia and bipolar disorder. The present study aimed to investigate whether attitude toward treatment and treatment adherence represent predictors of symptoms changes over time. Methods: The STAR Network \u201cDepot Study\u201d was a naturalistic, multicenter, observational, prospective study that enrolled people initiating a LAI without restrictions on diagnosis, clinical severity or setting. Participants from 32 Italian centers were assessed at three time points: baseline, 6-month, and 12-month follow-up. Psychopathological symptoms, attitude toward medication and treatment adherence were measured using the Brief Psychiatric Rating Scale (BPRS), the Drug Attitude Inventory (DAI-10) and the Kemp's 7-point scale, respectively. Linear mixed-effects models were used to evaluate whether attitude toward medication and treatment adherence independently predicted symptoms changes over time. Analyses were conducted on the overall sample and then stratified according to the baseline severity (BPRS < 41 or BPRS 65 41). Results: We included 461 participants of which 276 were males. The majority of participants had received a primary diagnosis of a schizophrenia spectrum disorder (71.80%) and initiated a treatment with a second-generation LAI (69.63%). BPRS, DAI-10, and Kemp's scale scores improved over time. Six linear regressions\u2014conducted considering the outcome and predictors at baseline, 6-month, and 12-month follow-up independently\u2014showed that both DAI-10 and Kemp's scale negatively associated with BPRS scores at the three considered time points. Linear mixed-effects models conducted on the overall sample did not show any significant association between attitude toward medication or treatment adherence and changes in psychiatric symptoms over time. However, after stratification according to baseline severity, we found that both DAI-10 and Kemp's scale negatively predicted changes in BPRS scores at 12-month follow-up regardless of baseline severity. The association at 6-month follow-up was confirmed only in the group with moderate or severe symptoms at baseline. Conclusion: Our findings corroborate the importance of improving the quality of relationship between clinicians and patients. Shared decision making and thorough discussions about benefits and side effects may improve the outcome in patients with severe mental disorders

NAD+-metabolizing ecto-enzymes shape tumor–host interactions: The chronic lymphocytic leukemia model

AbstractNicotinamide adenine dinucleotide (NAD+) is an essential co-enzyme that can be released in the extracellular milieu. Here, it may elicit signals through binding purinergic receptors. Alternatively, NAD+ may be dismantled to adenosine, up-taken by cells and transformed to reconstitute the intracellular nucleotide pool. An articulated ecto-enzyme network is responsible for the nucleotide–nucleoside conversion. CD38 is the main mammalian enzyme that hydrolyzes NAD+, generating Ca2+-active metabolites. Evidence suggests that this extracellular network may be altered or used by tumor cells to (i) nestle in protected areas, and (ii) evade the immune response. We have exploited chronic lymphocytic leukemia as a model to test the role of the ecto-enzyme network, starting by analyzing the individual elements that make up the whole picture