Brain-penetrant cyanoindane and cyanotetralin inhibitors of G2019S-LRRK2 kinase activity.

The G2019S variant of LRRK2, which causes an increase in kinase activity, is associated with the occurrence of Parkinson's disease (PD). Potent, mutation-selective, and brain penetrant inhibitors of LRRK2 can suppress the biological effects specific to G2019S-LRRK2 that cause pathogenicity. We report the discovery of a series of cyanoindane and cyanotetralin kinase inhibitors culminating in compound 34 that demonstrated selective inhibition of phosphorylation of LRRK2 in the mouse brain. These novel inhibitors may further enable the precision medicine path for future PD therapeutics.

Late Onset of ANCA Vasculitis as a Side Effect of Levamisole Treatment in Nephrotic Syndrome.

Levamisole is effectively used in steroid-dependent nephrotic syndrome and the more frequent side effects reported are cytopenia and liver enzymes alterations. Several studies have demonstrated that this drug can induce high titers of circulating perinuclear antineutrophil cytoplasmic autoantibodies (ANCA) and vasculitis, most of them occurring in the case of prolonged use. A four-year-old boy that was affected with steroid-dependent nephrotic syndrome was treated with Levamisole as a steroid-sparing agent at a dose of 2 mg/kg/48 h. After initiation of the treatment, the number of relapses drastically decreased, enabling a significant reduction in the cumulative steroid dose. Levamisole was well tolerated, and was therefore administered for several years. At the age of 15, he was also diagnosed with celiac disease. After nine years of continuous Levamisole treatment, he presented with a high fever, hand and foot joint arthritis, and increased levels of total and direct bilirubin. Since the symptoms started two days after the injection of the second dose of the COVID-19 vaccine, it was initially concluded that these manifestations were rare vaccination side effects. Therefore, he did not receive any specific treatments, and Levamisole was continued at the same dose. After an initial improvement, two months later, the patient presented with the same symptoms. Suspecting Levamisole-induced vasculitis, an ANCA titer was measured and this returned positive. Clinical manifestations and double positivity for both myeloperoxidase (MPO) and anti-proteinase 3 (PR3) antibodies argued against the fact that that these findings were secondary to vaccination, cocaine abuse, or celiac disease. Assuming that we were facing a rare drug reaction, Levamisole was promptly interrupted. This resulted in a rapid remission of fever and arthritis improvement, and a decrease in ANCA titers. By reporting this case, we want to raise awareness among clinicians regarding a rare complication of treatment with Levamisole that is often misdiagnosed due to the fact that the current literature lacks univocal guidelines regarding the precise timing of ANCA titrations and the duration of the treatment.

Eculizumab in patients with severe coronavirus disease 2019 (COVID-19) requiring continuous positive airway pressure ventilator support: Retrospective cohort study.

BACKGROUND: Complement activation contributes to lung dysfunction in coronavirus disease 2019 (COVID-19). We assessed whether C5 blockade with eculizumab could improve disease outcome. METHODS: In this single-centre, academic, unblinded study two 900 mg eculizumab doses were added-on standard therapy in ten COVID-19 patients admitted from February 2020 to April 2020 and receiving Continuous-Positive-Airway-Pressure (CPAP) ventilator support from ≤24 hours. We compared their outcomes with those of 65 contemporary similar controls. Primary outcome was respiratory rate at one week of ventilator support. Secondary outcomes included the combined endpoint of mortality and discharge with chronic complications. RESULTS: Baseline characteristics of eculizumab-treated patients and controls were similar. At baseline, sC5b-9 levels, ex vivo C5b-9 and thrombi deposition were increased. Ex vivo tests normalised in eculizumab-treated patients, but not in controls. In eculizumab-treated patients respiratory rate decreased from 26.8±7.3 breaths/min at baseline to 20.3±3.8 and 18.0±4.8 breaths/min at one and two weeks, respectively (p<0.05 for both), but did not change in controls. Between-group changes differed significantly at both time-points (p<0.01). Changes in respiratory rate correlated with concomitant changes in ex vivo C5b-9 deposits at one (rs = 0.706, p = 0.010) and two (rs = 0.751, p = 0.032) weeks. Over a median (IQR) period of 47.0 (14.0-121.0) days, four eculizumab-treated patients died or had chronic complications versus 52 controls [HRCrude (95% CI): 0.26 (0.09-0.72), p = 0.010]. Between-group difference was significant even after adjustment for age, sex and baseline serum creatinine [HRAdjusted (95% CI): 0.30 (0.10-0.84), p = 0.023]. Six patients and 13 controls were discharged without complications [HRCrude (95% CI): 2.88 (1.08-7.70), p = 0.035]. Eculizumab was tolerated well. The main study limitations were the relatively small sample size and the non-randomised design. CONCLUSIONS: In patients with severe COVID-19, eculizumab safely improved respiratory dysfunction and decreased the combined endpoint of mortality and discharge with chronic complications. Findings need confirmation in randomised controlled trials.

Ultrasound: a suitable technology to improve the extraction and techno-functional properties of vegetable food proteins.

Vegetable-based proteins may be extracted from different sources using different extraction methods, among them, ultrasound-assisted extraction stands out. This review presents the current knowledge on ultrasound-assisted extraction (UAE) and the functional properties of extracted vegetable proteins. Ultrasound generates cavitation in a liquid medium, defined as gas and vapor microbubbles collapse under pressure changes large enough to separate them in the medium. Cavitation facilitates the solvent and solid interaction, increasing yield and reducing extraction periods and temperature used. Moreover, ultrasound treatment changed extracted protein properties such as solubility, hydrophobicity, emulsifying and foam, water and oil absorption capacity, viscosity, and gelatinization. Ultrasound-assisted extraction is a promising technique for the food technology sector, presenting low environmental impact, lower energy and solvent consumption, and it is in accordance with green chemistry technology and sustainable concepts.

Selective Inhibitors of G2019S-LRRK2 Kinase Activity.

Pathogenic variants in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified that increase the risk for developing Parkinson's disease in a dominantly inherited fashion. These pathogenic variants, of which G2019S is the most common, cause abnormally high kinase activity, and compounds that inhibit this activity are being pursued as potentially disease-modifying therapeutics. Because LRRK2 regulates important cellular processes, developing inhibitors that can selectively target the pathogenic variant while sparing normal LRRK2 activity could offer potential advantages in heterozygous carriers. We conducted a high-throughput screen and identified a single selective compound that preferentially inhibited G2019S-LRRK2. Optimization of this scaffold led to a series of novel, potent, and highly selective G2019S-LRRK2 inhibitors.

The Geometry of Abstraction in the Hippocampus and Prefrontal Cortex.

The curse of dimensionality plagues models of reinforcement learning and decision making. The process of abstraction solves this by constructing variables describing features shared by different instances, reducing dimensionality and enabling generalization in novel situations. Here, we characterized neural representations in monkeys performing a task described by different hidden and explicit variables. Abstraction was defined operationally using the generalization performance of neural decoders across task conditions not used for training, which requires a particular geometry of neural representations. Neural ensembles in prefrontal cortex, hippocampus, and simulated neural networks simultaneously represented multiple variables in a geometry reflecting abstraction but that still allowed a linear classifier to decode a large number of other variables (high shattering dimensionality). Furthermore, this geometry changed in relation to task events and performance. These findings elucidate how the brain and artificial systems represent variables in an abstract format while preserving the advantages conferred by high shattering dimensionality.

Evaluation of novel coronavirus disease (COVID-19) using quantitative lung CT and clinical data: prediction of short-term outcome.

BACKGROUND: Computed tomography (CT) enables quantification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, helping in outcome prediction. METHODS: From 1 to 22 March 2020, patients with pneumonia symptoms, positive lung CT scan, and confirmed SARS-CoV-2 on reverse transcription-polymerase chain reaction (RT-PCR) were consecutively enrolled. Clinical data was collected. Outcome was defined as favourable or adverse (i.e., need for mechanical ventilation or death) and registered over a period of 10 days following CT. Volume of disease (VoD) on CT was calculated semi-automatically. Multiple linear regression was used to predict VoD by clinical/laboratory data. To predict outcome, important features were selected using a priori analysis and subsequently used to train 4 different models. RESULTS: A total of 106 consecutive patients were enrolled (median age 63.5 years, range 26-95 years; 41/106 women, 38.7%). Median duration of symptoms and C-reactive protein (CRP) was 5 days (range 1-30) and 4.94 mg/L (range 0.1-28.3), respectively. Median VoD was 249.5 cm3 (range 9.9-1505) and was predicted by lymphocyte percentage (p = 0.008) and CRP (p < 0.001). Important variables for outcome prediction included CRP (area under the curve [AUC] 0.77), VoD (AUC 0.75), age (AUC 0.72), lymphocyte percentage (AUC 0.70), coronary calcification (AUC 0.68), and presence of comorbidities (AUC 0.66). Support vector machine had the best performance in outcome prediction, yielding an AUC of 0.92. CONCLUSIONS: Measuring the VoD using a simple CT post-processing tool estimates SARS-CoV-2 burden. CT and clinical data together enable accurate prediction of short-term clinical outcome.

Feasibility of ultrasound-assisted optimized process of high purity rice bran protein extraction / Viabilidade do processo otimizado assistido por ultrassom para extração de proteína de farelo de arroz de alta pureza

ABSTRACT: Rice bran is a by-product of the rice milling process, found worldwide in abundance and highlighted due its protein content. This study optimized the conditions for ultrasonic-assisted extraction of protein from defatted rice bran (DRB) and characterized the rice bran protein concentrate (RBPC). A sequential strategy of experimental design was employed; the effect of pH, temperature, ultrasound exposure time, and amplitude were evaluated regarding the percentage of protein extraction by a Full factorial design (FFD) with a fixed frequencies (FFD-A: 37 kHz; FFD-B: 80 kHz). Subsequently, the percentage of protein extracted was optimized employing a Central composite rotatable design (variables: pH and ultrasound exposure time) and RBPC obtained was characterized regarding chemical and functional properties. The pH and ultrasound exposure time had positive effect (P ≤ 0.05) on percentage of protein extraction; moreover, 37 kHz frequency was more effective in protein extraction. The optimized condition (frequency: 37 kHz; temperature: 30 °C; pH: 10; ultrasound exposure time: 30 min; and amplitude: 100%) allowed 15.07% of protein recovery and the RBPC presented 84.76 g 100 g-1 of protein. Magnesium and copper were the main mineral in RBPC (34.4 and 25.5 µg g-1, respectively), while leucine was the limiting amino acid (0.42) and threonine presented the highest chemical score (1.0). The RBPC solubility was minimal at pH 4 and higher at pHs 6-10; the water and oil absorption capacity were higher than bovine serum albumin (BSA) and the emulsifying capacity was comparable to BSA, with a suitable stability. It was possible to obtain a higher purity RBPC than described in the literature, due to the optimization in the extraction process steps, with functional properties suitable for application in food products, especially emulsified ones.

RESUMO: O farelo de arroz é um subproduto do processo de moagem do arroz, encontrado em abundância em todo o mundo e destacado devido ao seu teor de proteínas. Este estudo otimizou as condições para a extração assistida por ultrassom da proteína do farelo de arroz desengordurado (DRB) e caracterizou o concentrado de proteína do farelo de arroz (RBPC). Uma estratégia sequencial de desenho experimental foi empregada; o efeito do pH, temperatura, tempo de exposição ao ultrassom e amplitude foram avaliados em relação à porcentagem de extração proteica por um Delineamento Fatorial Completo (FFD) com frequências fixas (FFD -A: 37 kHz; FFD-B: 80 kHz). Posteriormente, a porcentagem de proteína extraída foi otimizada empregando um Planejamento Composto Central (variáveis: pH e tempo de exposição ao ultrassom) e o RBPC obtido foi caracterizado quanto às propriedades químicas e funcionais. O pH e o tempo de exposição ao ultrassom tiveram efeito positivo (P ≤ 0,05) na porcentagem de extração proteica. Além disso, a frequência de 37 kHz foi mais eficaz na extração de proteínas. A condição otimizada (frequência: 37 kHz; temperatura: 30 °C; pH: 10; tempo de exposição ao ultrassom: 30 min; e amplitude: 100%) permitiu 15,07% de recuperação de proteínas e o RBPC apresentou 84,76 g 100 g-1 de proteína. Magnésio e cobre foram os principais minerais da RBPC (34,4 e 25,5 µg g-1, respectivamente), enquanto a leucina foi o aminoácido limitante (0,42) e a treonina apresentou o maior escore químico (1,0). A solubilidade do RBPC foi mínima em pH 4 e superior em pH 6-10; a capacidade de absorção de água e óleo foi maior que a albumina sérica bovina (BSA) e a capacidade de emulsificação foi comparável à BSA, com uma estabilidade adequada. Assim, foi possível obter um RBPC com elevada pureza, maior do que o descrito na literatura, devido à otimização nas etapas do processo de extração, com propriedades funcionais adequadas para aplicação em produtos alimentícios, principalmente emulsificados.

The contribution of nonhuman primate research to the understanding of emotion and cognition and its clinical relevance.

Psychiatric disorders are often conceptualized as arising from dysfunctional interactions between neural systems mediating cognitive and emotional processes. Mechanistic insights into these interactions have been lacking in part because most work in emotions has occurred in rodents, often without concurrent manipulations of cognitive variables. Nonhuman primate (NHP) model systems provide a powerful platform for investigating interactions between cognitive operations and emotions due to NHPs' strong homology with humans in behavioral repertoire and brain anatomy. Recent electrophysiological studies in NHPs have delineated how neural signals in the amygdala, a brain structure linked to emotion, predict impending appetitive and aversive stimuli. In addition, abstract conceptual information has also been shown to be represented in the amygdala and in interconnected brain structures such as the hippocampus and prefrontal cortex. Flexible adjustments of emotional behavior require the ability to apply conceptual knowledge and generalize to different, often novel, situations, a hallmark example of interactions between cognitive and emotional processes. Elucidating the neural mechanisms that explain how the brain processes conceptual information in relation to emotional variables promises to provide important insights into the pathophysiology accounting for symptoms in neuropsychiatric disorders.

Noninvasive liver fibrosis assessment in chronic viral hepatitis C: agreement among 1D transient elastography, 2D shear wave elastography, and magnetic resonance elastography.

PURPOSE: To assess the agreement of one-dimensional transient elastography (1D-TE), two-dimensional shear wave elastography (2D-SWE), and magnetic resonance elastography (MRE) in a consecutive cohort of patients affected by hepatitis C virus (HCV) and to understand which patient-related factors are associated with disagreement. METHODS: Ninety-one consecutive patients with current or previous chronic HCV infection were enrolled between March 2017 and September 2018. We assessed the correlation between stiffness measurements expressed in kilopascals (kPa). After converting kPa values in three groups of increasing fibrosis burden using validated cut-off values, we assessed the agreement among the different techniques. Factors influencing inter-modality disagreement were examined by employing multivariate logistic regression analysis. RESULTS: Seventy-seven patients met the inclusion criteria and had reliable measurements by all stiffness imaging techniques. At the quantitative analysis, a strong correlation between stiffness measurements was found (Spearman's rho values ranging from 0.7 to 0.89 in all pairs of techniques). Complete concordance among MRE, 1D-TE, and 2D-SWE was found in 64.9% of patients, and the agreement was highest between MRE and 1D-TE, with κ value of 0.801. In only 2/77 patients (2.6%), there was complete disagreement. High body mass index (BMI) was the only factor significantly associated with inter-modality discordance. CONCLUSIONS: MRE, 1D-TE, and 2D-SWE assigned the majority of patients to the same fibrosis group. The agreement was at least good, and there was a strong correlation between kPa values in all three pairs of techniques. Highest agreement was found between MRE and 1D-TE. High BMI was associated with discordance among the techniques.

Assessment of environmental impact of biomass power plants to increase the social acceptance of renewable energy technologies.

OBJECTIVE: The objectives of the European Union (EU) policy agenda are to reduce the greenhouse gas emissions and to decrease the dependence of EU member countries from fossil fuel sources. In order to achieve these policy objectives, in the last decades the number of biomass power plants has increased throughout the EU. This study analyzed the environmental impacts of the bioenergy systems at global and local level to support communication and information strategies to increase social acceptance and to reduce conflicts between stakeholders. The environmental impacts were estimated to a sample of biomass power plants in North Italy selected based on the size, feedstock and type (cogeneration or heating). The study aims to identify and evaluate the environmental impacts associated with the thermal energy production in biomass power plants using a Life Cycle Assessment (LCA) approach. MATERIALS AND METHODS: For each biomass district plant an LCA analysis was performed to: compare the environmental impacts associated with the production of the same functional unit, quantifying and valuating the environmental performance deriving from the production process life cycle, and highlighting the production phases with greater impact. RESULTS: The results show an average climate change impact by biomass energy plant of 45.84 gCO2eq MJ-1 and a range between 14.93 gCO2eq MJ-1 and 90.70 gCO2eq MJ-1. The results show that the size of the biomass energy plant (less than 1 MW or more than 1 MW) and the feedstock used (forest or sawmill woodchip) are two main variables that influence many categories of environmental impact.

Hyponatremia in infants with community-acquired infections on hospital admission.

Acute moderate to severe gastroenteritis is traditionally associated with hypernatremia but recent observations suggest that hypernatremia is currently less common than hyponatremia. The latter has sometimes been documented also in children with acute community-acquired diseases, such as bronchiolitis and pyelonephritis. We investigated the prevalence of dysnatremia in children with acute moderate severe gastroenteritis, bronchiolitis and pyelonephritis. This prospective observational study included 400 consecutive previously healthy infants ≥4 weeks to ≤24 months of age (232 males and 168 females): 160 with gastroenteritis and relevant dehydration, 160 with moderate-severe bronchiolitis and 80 with pyelonephritis admitted to our emergency department between 2009 and 2017. Circulating sodium was determined by means of direct potentiometry. For analysis, the Kruskal-Wallis test and the Fisher's exact test were used. Hyponatremia was found in 214 of the 400 patients. It was common in gastroenteritis (43%) and significantly more frequent in bronchiolitis (57%) and pyelonephritis (68%). Patients with hyponatremia were significantly younger than those without hyponatremia (3.9 [1.6-13] versus 7.5 [3.4-14] months). The gender ratio was similar in children with and without hyponatremia. Hyponatremia was associated with further metabolic abnormalities (hypokalemia, hyperkalemia, metabolic acidosis or metabolic alkalosis) in gastroenteritis (71%) and pyelonephritis (54%), and always isolated in bronchiolitis. In conclusion, hyponatremia is common at presentation among previously healthy infants with gastroenteritis, bronchiolitis or pyelonephritis. These data have relevant consequences for the nutrition and rehydration management in these conditions.

Complete tetraglycosylation of a calix[4]arene by a chemo-enzymatic approach.

Polyglycosylated calixarenes are efficient and selective multivalent ligands for lectins. However, the chemical decoration of these macrocyclic scaffolds with saccharides of increasing complexity is hampered by the highly complex chemistry of carbohydrates. An alternative to the conventional approach is the enzymatic diversification of simple glycocluster-presented glycans. In this work, we present a highly efficient chemo-enzymatic approach to tetra-N-acetyl-lactosaminylcalix[4]arene via glycan extension catalyzed by a human ß-1,4-galactosyltransferase. This demonstrates that calixarenes can be exhaustively processed by enzymatic glycosyl transfer despite the heavy steric crowding, paving the way to the design and achievement of multivalent ligands based on these macrocyclic scaffolds having complex branched glycans.

Advanced Power Doppler Technique Increases Synovial Vascularity Detection in Patients with Rheumatoid Arthritis.

We compared the diagnostic performance of an advanced power Doppler technique (superb microvascular imaging [SMI]) with that of power Doppler Imaging (PDI) and B-mode ultrasound (US) in patients with early rheumatoid arthritis (RA) and RA under treatment with rituximab. Thirty patients (21 women aged 45 ± 11 y) affected by RA with remission to moderate disease activity were examined. Both hand joints were evaluated using US, PDI and SMI. Two radiologists reviewed all video clips and evaluated synovial vascularity intensity using a semi-quantitative scoring system. SMI revealed the presence of synovial vascularity in a significantly larger number of patients than PDI (p = 0.02). Inter-observer agreement for US, PDI and SMI was moderate (κ = 0.59), very good (κ = 0.87) and very good (κ = 0.82), respectively. We conclude that SMI detects more vessels than PDI in RA patients. This may allow increased sensitivity for early diagnosis of synovial inflammation, monitoring of its dynamic changes under therapy and evaluation of true imaging remission.

In vivo feasibility of real-time MR-US fusion imaging lumbar facet joint injections.

OBJECTIVES: Traditionally, facet joint injections (FJI) are performed under fluoroscopic or computed tomography (CT) guidance, mainly due to the deep anatomical location and the presence of bony landmarks. Fusion imaging technology, which couples the ultrasound scan with the corresponding CT or magnetic resonance (MR) image obtained from the diagnostic examination and reformatted in real time according to the ultrasound scanning plane, allows to combine the panoramic view and the elevated anatomical detail of MR or CT with the ease of use of ultrasound without patient exposure to ionizing radiation. METHODS: Thirty eight patients (24 females; mean age ± SD: 64 ± 9 years) received MR fusion-assisted ultrasound-guided FJI of 1 ml of a mixture of local anaesthetic and corticosteroid using a ultrasound machine (Logiq E9, GE Healthcare) equipped with a GPS-enhanced fusion imaging technology which couples real-time B-mode images with those of the previous recent diagnostic MR examination. Low-dose CT needle positioning confirmation was performed in the first 28 patients. Patients' pain was recorded using a visual analogue scale (VAS), at baseline and at 2, 4 and 8 weeks. RESULTS: All fusion imaging-guided injections were performed successfully. Out of 112, 96 FJI had optimal intra-articular needle positioning (accuracy: 85.7%). Patients VAS significantly decreases after the procedure with no differences among who received CT needle positioning control and who did not receive it. No major complications were observed. CONCLUSIONS: Ultrasound needle guidance with MR fusion assistance allows for safe and effective injection of degenerative facet joint disease.

Gender differences in adult attention-deficit/hyperactivity disorder: results from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC).

BACKGROUND: Gaining insight into possible gender differences in the clinical presentation of adults with attention-deficit/hyperactivity disorder (ADHD) is of relevance in order to conduct appropriate screening and treatment interventions in both genders. METHOD: The analyses compared (1) prevalence and sociodemographic correlates, (2) frequency of ADHD core symptoms, (3) rates of subtypes, (4) prevalence of comorbid mental health conditions, and (5) rates of risky/impulsive behaviors, as well as health and social correlates, in men and women with ADHD in a nationally representative, US population-based sample. Face-to-face psychiatric interviews were conducted according to DSM-IV criteria in 34,653 adults from the US National Epidemiologic Survey on Alcohol and Related Conditions (Wave 2, 2004-2005). RESULTS: While the prevalence of lifetime ADHD was significantly higher in men than in women (OR = 1.46, 95% CI = 1.22-1.76), the rate of persistent ADHD did not significantly differ across genders (OR = 1.23, 95% CI = 0.96-1.58). Compared to men with persistent ADHD, women with persistent ADHD, despite having lower rates of hyperactive symptoms, presented with similar ADHD subtypes profile and rates of risky behaviors (except for reckless driving), as well as with significantly more anxiety and perceived mental health impairment (P = .032). Results were similar when considering lifetime ADHD. CONCLUSIONS: Our findings show that, despite different symptom profiles and comorbidities, men and women have similar rates of current ADHD and of risky behaviors associated with the disorder. Women with ADHD should receive as much attention as their male counterparts.

Prevalence and correlates of anger in the community: results from a national survey.

INTRODUCTION: Little is known about the prevalence and correlates of anger in the community. METHODS: We used data derived from a large national sample of the U.S. population, which included more than 34,000 adults ages 18 years and older. We defined inappropriate, intense, or poorly controlled anger by means of self-report of the following: (1) anger that was triggered by small things or that was difficult to control, (2) frequent temper outbursts or anger that lead to loss of control, or (3) hitting people or throwing objects in anger. RESULTS: The overall prevalence of inappropriate, intense, or poorly controlled anger in the U.S. population was 7.8%. Anger was especially common among men and younger adults, and was associated with decreased psychosocial functioning. Significant and positive associations were evident between anger and parental factors, childhood, and adulthood adverse events. There were strong associations between anger and bipolar disorder, drug dependence, psychotic disorder, borderline, and schizotypal personality disorders. There was a dose-response relationship between anger and a broad range of psychopathology. CONCLUSIONS: A rationale exists for developing screening tools and early intervention strategies, especially for young adults, to identify and help reduce anger.