Dopamine: The Neuromodulator of Long-Term Synaptic Plasticity, Reward and Movement Control

Dopamine (DA) is a key neurotransmitter involved in multiple physiological functions including motor control, modulation of affective and emotional states, reward mechanisms, reinforcement of behavior, and selected higher cognitive functions. Dysfunction in dopaminergic transmission is recognized as a core alteration in several devastating neurological and psychiatric disorders, including Parkinson's disease (PD), schizophrenia, bipolar disorder, attention deficit hyperactivity disorder (ADHD) and addiction. Here we will discuss the current insights on the role of DA in motor control and reward learning mechanisms and its involvement in the modulation of synaptic dynamics through different pathways. In particular, we will consider the role of DA as neuromodulator of two forms of synaptic plasticity, known as long-term potentiation (LTP) and long-term depression (LTD) in several cortical and subcortical areas. Finally, we will delineate how the effect of DA on dendritic spines places this molecule at the interface between the motor and the cognitive systems. Specifically, we will be focusing on PD, vascular dementia, and schizophrenia

Phantom model and scoring system to assess ability in ultrasound-guided chest drain positioning

Background: Chest tube positioning is an invasive procedure associated with potentially serious injuries. In the last few years, we have been running a project directed at developing a practical simulator of a surgical procedure taught on our medical training program. The phantom model reconstructs the pleural anatomy, visible by lung ultrasound, used for the assessed performance of the Seldinger technique. The aim of the present study was to investigate the validity of this simulation technology for assessing residents in anesthesia and intensive care medicine; specifically, their skill in positioning a US-guided chest tube drain was tested using the simulator device. The second aim of the paper was to evaluate the learning curve of our residents over their 5-year study course and validate the phantom scoring system. Methods: This was a prospective, single-blinded observational study. Participants were recruited from residents in anesthesia and intensive care medicine and divided into two groups: \u2018Novice\u2019 and \u2018Expert,\u2019 based on the course year attended (years 1, 2, and 3 vs. years 4 and 5, respectively). We asked them to position a chest tube drain in a phantom model, guided by ultrasound, to drain a simulated pleural effusion. Each subject performed two tests that simulated pleural effusions of 4 and 2\ua0cm, respectively. Every step of the maneuver was constantly monitored and the performance scored by the investigators. We then performed a Spearman correlation analysis to evaluate the effect of experience level on the performance of the two groups of residents. Results: Thirty-one residents were included in this study: 20 in the Novice group and 11 in the Expert group. The mean performance rating score was 0.75\ua0\ub1\ua04.38 for the Novice Group and 5.91\ua0\ub1\ua03.75 for the Expert group (p\ua0=\ua00.0026). The Spearman correlation analysis examining the relationship between year of residency and performance rating score confirmed a positive correlation (r\ua0=\ua00.58, p\ua0=\ua00.0006). Post-test trend analysis revealed a statistically significant linear trend for skill growth across time, i.e., course year (p\ua0=\ua00.0022). Conclusions: Our simulated procedure using a phantom model of lung anatomy can accurately and reliably be used to assess the skill levels of operators in their ability to drain pleural effusion

Could the use of bedside lung ultrasound reduce the number of chest x-rays in the intensive care unit?

Background: Lung ultrasound can be used as an alternative to chest radiography (CXR) for the diagnosis and follow-up of various lung diseases in the intensive care unit (ICU). Our aim was to evaluate the influence that introducing a routine daily use of lung ultrasound in critically ill patients may have on the number of CXRs and as a consequence, on medical costs and radiation exposure. Methods: Data were collected by conducting a retrospective evaluation of the medical records of adult patients who needed thoracic imaging and were admitted to our academic polyvalent ICU. We compared the number of CXRs and relative costs before and after the introduction of lung ultrasound in our ICU. Results: A total of 4134 medical records were collected from January 2010 to December 2014. We divided our population into two groups, before (Group A, 1869 patients) and after (Group B, 2265 patients) the introduction of a routine use of LUS in July 2012. Group A performed a higher number of CXRs compared to Group B (1810 vs 961, P = 0.012), at an average of 0.97 vs 0.42 exams per patient. The estimated reduction of costs between Groups A and B obtained after the introduction of LUS, was 57%. No statistically significant difference between the outcome parameters of the two groups was observed. Conclusions: Lung ultrasound was effective in reducing the number of CXRs and relative medical costs and radiation exposure in ICU, without affecting patient outcome

Risk of Seven-Day Worsening and Death: A New Clinically Derived COVID-19 Score

This monocentric, retrospective, two-stage observational study aimed to recognize the risk factors for a poor outcome in patients hospitalized with SARS-CoV-2 infection, and to develop and validate a risk score that identifies subjects at risk of worsening, death, or both. The data of patients with SARS-CoV-2 infection during the first wave of the pandemic were collected and analyzed as a derivation cohort. Variables with predictive properties were used to construct a prognostic score, which was tried out on a validation cohort enrolled during the second wave. The derivation cohort included 494 patients; the median age was 62 and the overall fatality rate was 22.3%. In a multivariable analysis, age, oxygen saturation, neutrophil-to-lymphocyte ratio, C-reactive protein and lactate dehydrogenase were independent predictors of death and composed the score. A cutoff value of 3 demonstrated a sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) of 93.5%, 68.5%, 47.4% and 97.2% for death, and 84.9%, 84.5%, 79.6% and 87.9% for worsening, respectively. The validation cohort included 415 subjects. The score application showed a Se, Sp, PPV and NPV of 93.4%, 61.6%, 29.5% and 98.1% for death, and 81%, 76.3%, 72.1% and 84.1% for worsening, respectively. We propose a new clinical, easy and reliable score to predict the outcome in hospitalized SARS-CoV-2 patients

Clinical course of Coronavirus Disease-19 in patients with haematological malignancies is characterized by a longer time to respiratory deterioration compared to non-haematological ones: results from a case-control study

Background We evaluated clinical features and risk factors for mortality in patients with haematological malignancies and COVID-19. Methods Retrospective, case-control (1:3) study in hospitalized patients with COVID-19. Cases were patients with haematological malignancies and COVID-19, controls had COVID-19 without haematological malignancies. Patients were matched for sex, age and time of hospitalization. Results Overall, 66 cases and 198 controls were included in the study. Cases had higher prior corticosteroid use, infection rates, thrombocytopenia and neutropenia and more likely received corticosteroids and antibiotics than controls. Cases had higher respiratory deterioration than controls (78.7% vs 65.5%, p = 0.04). Notably, 29% of cases developed respiratory worsening > 10 days after hospital admission, compared to only 5% in controls. Intensive Care Unit admission and mortality were higher in cases than in controls (27% vs 8%, p = 0.002, and 35% vs 10%, p < 0.001). At multivariable analysis, having haematological malignancy [OR4.76, p < 0.001], chronic corticosteroid therapy [OR3.65, p = 0.004], prior infections [OR57.7, p = 0.006], thrombocytopenia [OR3.03, p < 0.001] and neutropenia [OR31.1, p = 0.001], low albumin levels [OR3.1, p = 0.001] and >= 10 days from hospital admission to respiratory worsening [OR3.3, p = 0.002] were independently associated with mortality. In cases, neutropenia [OR3.1, p < 0.001], prior infections [OR7.7, p < 0.001], >= 10 days to respiratory worsening [OR4.1, p < 0.001], multiple myeloma [OR1.5, p = 0.044], the variation of the CT lung score during hospitalization [OR2.6, p = 0.006] and active treatment [OR 4.4, p < 0.001] all were associated with a worse outcome. Conclusion An underlying haematological malignancy was associated with a worse clinical outcome in COVID-19 patients. A prolonged clinical monitoring is needed, since respiratory worsening may occur later during hospitalization

Effect of ceftazidime/avibactam plus fosfomycin combination on 30 day mortality in patients with bloodstream infections caused by KPC-producing Klebsiella pneumoniae. Results from a multicentre retrospective study

Introduction The primary outcome of the study was to evaluate the effect on 30 day mortality of the combination ceftazidime/avibactam + fosfomycin in the treatment of bloodstream infections (BSIs) caused by KPC-producing Klebsiella pneumoniae (KPC-Kp). Materials and methods From October 2018 to March 2021, a retrospective, two-centre study was performed on patients with KPC-Kp BSI hospitalized at Sapienza University (Rome) and ISMETT-IRCCS (Palermo) and treated with ceftazidime/avibactam-containing regimens. A matched cohort (1:1) analysis was performed. Cases were patients receiving ceftazidime/avibactam + fosfomycin and controls were patients receiving ceftazidime/avibactam alone or in combination with in vitro non-active drugs different from fosfomycin (ceftazidime/avibactam +/- other). Patients were matched for age, Charlson comorbidity index, ward of isolation (ICU or non-ICU), source of infection and severity of BSI, expressed as INCREMENT carbapenemase-producing Enterobacteriaceae (CPE) score. Results Overall, 221 patients were included in the study. Following the 1:1 match, 122 subjects were retrieved: 61 cases (ceftazidime/avibactam + fosfomycin) and 61 controls (ceftazidime/avibactam +/- other). No difference in overall mortality emerged between cases and controls, whereas controls had more non-BSI KPC-Kp infections and a higher number of deaths attributable to secondary infections. Almost half of ceftazidime/avibactam + fosfomycin patients were prescribed fosfomycin without MIC fosfomycin availability. No difference in the outcome emerged after stratification for fosfomycin susceptibility availability and dosage. SARS-CoV-2 infection and ICS >= 8 independently predicted 30 day mortality, whereas an appropriate definitive therapy was protective. Conclusions Our data show that fosfomycin was used in the treatment of KPC-Kp BSI independently from having its susceptibility testing available. Although no difference was found in 30 day overall mortality, ceftazidime/avibactam + fosfomycin was associated with a lower rate of subsequent KPC-Kp infections and secondary infections than other ceftazidime/avibactam-based regimens

Discontinuation of alpha-interferon treatment in patients with chronic myeloid leukemia in long-lasting complete molecular response

To evaluate follow-up after α-interferon (IFN) discontinuation, 23 patients with chronic myeloid leukemia (CML) in stable complete molecular response (CMolR) with IFN were revisited. After a median IFN treatment of 105.8 months (IR 56.1 - 127.3), all patients discontinued IFN for prolonged CMolR (12), intolerance (8) or planned ABMT (3). After 12.5 months, one patient developed an extramedullar blast crisis. Four patients needed to start imatinib, all achieving again molecular response. Eighteen patients are still off-therapy (median time from IFN discontinuation 125.5 months, IR 86.9-205.3); among these, five are BCR-ABL negative, six present with a sporadic positivity (BCR-ABL ratio < 0.1) and seven show a stable and long-lasting mild positivity (BCR-ABL ratio < 0.5). Patients in prolonged CMolR with IFN have low risk of recurrence after discontinuation; the reappearance of a BCR-ABL positivity < 0.5 did not always precede a relapse, suggesting mechanisms of immunological control induced by IFN

The novel mu-opioid antagonist, GSK1521498, reduces ethanol consumption in C57BL/6J mice.

RATIONALE Using the drinking-in-the-dark (DID) model, we compared the effects of a novel mu-opioid receptor antagonist, GSK1521498, with naltrexone, a licensed treatment of alcohol dependence, on ethanol consumption in mice. OBJECTIVE We test the ability of GSK1521498 to reduce alcohol consumption and compare its intrinsic efficacy to that of naltrexone by comparing the two drugs at doses matched for equivalent receptor occupancy. METHODS Thirty-six C57BL/6J mice were tested in a DID procedure. In 2-day cycles, animals experienced one baseline, injection-free session, and one test session when they received two injections, one of test drug and one placebo. All animals received GSK1521498 (0, 0.1, 1 and 3 mg/kg, i.p., 30 min pre-treatment) and naltrexone (0, 0.1, 1 and 3 mg/kg, s.c. 10 min pre-treatment) in a cross-over design. Receptor occupancies following the same doses were determined ex vivo in separate groups by autoradiography, using [3H]DAMGO. Binding in the region of interest was measured integrally by computer-assisted microdensitometry and corrected for non-specific binding. RESULTS Both GSK1521498 and naltrexone dose-dependently decreased ethanol consumption. When drug doses were matched for 70-75 % receptor occupancy, GSK1521498 3 mg/kg, i.p., caused a 2.5-fold greater reduction in alcohol consumption than naltrexone 0.1 mg/kg, s.c. Both GSK1521498 and naltrexone significantly reduced sucrose consumption at a dose of 1 mg/kg but not 0.1 mg/kg. In a test of conditioned taste aversion, GSK1521498 (3 mg/kg) reduced sucrose consumption 24 h following exposure to a conditioning injection. CONCLUSIONS Both opioid receptor antagonists reduced alcohol consumption but GK1521498 has higher intrinsic efficacy than naltrexone