Clinical and genetic characteristics of late-onset Huntington's disease in a large European cohort

Background and purpose Huntington's disease (HD) is an autosomal dominant condition caused by CAG-triplet repeat expansions. CAG-triplet repeat expansion is inversely correlated with age of onset in HD and largely determines the clinical features. The aim of this study was to examine the phenotypic and genotypic correlates of late-onset HD (LoHD) and to determine whether LoHD is a more benign expression of HD. Methods This was a retrospective observational study of 5053 White European HD patients from the ENROLL-HD database. Sociodemographic, genetic and phenotypic variables at baseline evaluation of subjects with LoHD, common-onset HD (CoHD) and young-onset HD (YoHD) were compared. LoHD subjects were compared with healthy subjects (HS) aged >= 60 years. Differences between the CoHD and LoHD groups were also explored in subjects with 41 CAG triplets, a repeat number in the lower pathological expansion range associated with wide variability in age at onset. Results Late-onset HD presented predominantly as motor-onset disease, with a lower prevalence of both psychiatric history and current symptomatology. Absent/unknown HD family history was significantly more common in the LoHD group (31.2%) than in the other groups. The LoHD group had more severe motor and cognitive deficits than the HS group. Subjects with LoHD and CoHD with 41 triplets in the larger allele were comparable with regard to cognitive impairment, but those with LoHD had more severe motor disorders, less problematic behaviors and more often an unknown HD family history. Conclusions It is likely that cognitive disorders and motor symptoms of LoHD are at least partly age-related and not a direct expression of the disease. In addition to CAG-triplet repeat expansion, future studies should investigate the role of other genetic and environmental factors in determining age of onset

Immunosuppression by monocytic myeloid-derived suppressor cells in patients with pancreatic ductal carcinoma is orchestrated by STAT3

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly devastating disease with an overall 5-year survival rate of less than 8%. New evidence indicates that PDAC cells release pro-inflammatory metabolites that induce a marked alteration of normal hematopoiesis, favoring the expansion and accumulation of myeloid-derived suppressor cells (MDSCs). We report here that PDAC patients show increased levels of both circulating and tumor-infiltrating MDSC-like cells. Methods: The frequency of MDSC subsets in the peripheral blood was determined by flow cytometry in three independent cohorts of PDAC patients (total analyzed patients, n = 117). Frequency of circulating MDSCs was correlated with overall survival of PDAC patients. We also analyzed the frequency of tumor-infiltrating MDSC and the immune landscape in fresh biopsies. Purified myeloid cell subsets were tested in vitro for their T-cell suppressive capacity. Results: Correlation with clinical data revealed that MDSC frequency was significantly associated with a shorter patients' overall survival and metastatic disease. However, the immunosuppressive activity of purified MDSCs was detectable only in some patients and mainly limited to the monocytic subset. A transcriptome analysis of the immunosuppressive M-MDSCs highlighted a distinct gene signature in which STAT3 was crucial for monocyte re-programming. Suppressive M-MDSCs can be characterized as circulating STAT3/arginase1-expressing CD14+ cells. Conclusion: MDSC analysis aids in defining the immune landscape of PDAC patients for a more appropriate diagnosis, stratification and treatment

Induction of immunosuppressive functions and NF-\u3baB by FLIP in monocytes

Immunosuppression is a hallmark of tumor progression, and treatments that inhibit or deplete monocytic myeloid-derived suppressive cells could promote anti-tumor immunity. c-FLIP is a central regulator of caspase-8-mediated apoptosis and necroptosis. Here we show that low-dose cytotoxic chemotherapy agents cause apoptosis linked to c-FLIP down-regulation selectively in monocytes. Enforced expression of c-FLIP or viral FLIP rescues monocytes from cytotoxicity and concurrently induces potent immunosuppressive activity, in T cell cultures and in vivo models of tumor progression and immunotherapy. FLIP-transduced human blood monocytes can suppress graft versus host disease. Neither expression of FLIP in granulocytes nor expression of other anti-apoptotic genes in monocytes conferred immunosuppression, suggesting that FLIP effects on immunosuppression are specific to monocytic lineage and distinct from death inhibition. Mechanistically, FLIP controls a broad transcriptional program, partially by NF-\u3baB activation. Therefore, modulation of FLIP in monocytes offers a means to elicit or block immunosuppressive myeloid cells

Los cultivos intensivos y la COVID 19. Abril 2020. Efectos del primer mes de cuarentena y perspectivas a futuro para el sector

En marzo del 2020 el país debió enfrentar una serie de medidas de aislamiento social para prevenir una enfermedad de origen viral que afectó a gran parte de la humanidad, incluida la Argentina. Estas medidas afectaron a las producciones intensivas, por lo que los técnicos de INTA tuvieron que realizar tareas específicas para ayudar a los productores. Poco a poco las actividades se fueron encauzando, y se originaron cambios hacia una mayor inocuidad de los alimentos y hábitos de consumo saludables que sería beneficioso que perduren una vez superada la pandemia ocasionada por COVID19. A continuación, compartimos una crónica de aquellos días elaborada a partir de testimonios de los participantes del PE 009 provenientes de distintos puntos de nuestro vasto territorio.EEA San PedroFil: Mitidieri, Mariel Silvina. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria San Pedro; ArgentinaFil: Puch, Lilia Isabel. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Yuto; ArgentinaFil: Verón, Rodrigo Guzmán. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Bella Vista; ArgentinaFil: Lenscak, Mario Pedro. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Investigación y Desarrollo Tecnológico para la Agricultura Familiar Región Pampeana; ArgentinaFil: Trupkin, Santiago Ariel. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Investigación Floricultura; ArgentinaFil: Cuellas, Marisol Virginia. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Área Metropolitana de Buenos Aires; ArgentinaFil: Amoia, Rita Paula. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Área Metropolitana de Buenos Aires; ArgentinaFil: Morisigue, Daniel Enrique. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Investigación Floricultura; ArgentinaFil: Sordo, María Del Huerto. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Rafaela. Agencia de Extensión Rural Monte Vera; ArgentinaFil: García, Leonardo Martín. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria San Pedro. Agencia de Extensión Rural Zárate; ArgentinaFil: Montero Solito, Ramiro Ignacio. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Colonia Benítez. ArgentinaFil: González, María Virginia. Universidad Nacional de Mar del Plata. Facultad de Ciencias Agrarias; ArgentinaFil: Díaz, Beatriz María. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Concordia; ArgentinaFil: Tapia, Silvia Norma. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Yuto; ArgentinaFil: Baffoni, Patricia Andrea. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Valle Inferior de Río Negro; Argentin

Functional Movement Disorders during COVID-19: Psychological Distress, Affective Temperament and Emotional Dysregulation

Background and objective: Functional movement disorders (FMD) represent a spectrum of psychosomatic symptoms particularly sensitive to stress. The COVID-19 pandemic has increased psychological distress worldwide and may have worsened FMD. The study aimed to confirm this hypothesis and to test whether in FMD there is a relationship between affective temperament, emotional dysregulation and psychological distress due to the pandemic. Methods: We recruited individuals with FMD, diagnosed them according to validated criteria and matched them with healthy controls (HC). Psychological distress and temperament were obtained using the Kessler-10 and the Temperament Evaluation of Memphis, Pisa and San Diego Autoquestionnaire, respectively. We used bootstrapped mediation analysis to test the mediator role of emotional dysregulation on the effect of temperament on psychological distress. Results: The sample consisted of 96 individuals. During the pandemic, 31.3% of the patients reported the need for urgent neurological care, and 40.6% reported a subjective worsening neurological condition. Patients with FMD presented with more psychological distress during the COVID-19 pandemic (F = 30.15, df = 1, p ≤ 0.001) than HC. They also reported more emotional dysregulation (F = 15.80, df = 1, p ≤ 0.001) and more cyclothymic traits (F = 14.84, df = 1, p ≤ 0.001). Cyclothymic temperament showed an indirect effect on COVID-19-related psychological distress, mediated by deficits in emotion regulation mechanisms (Bootstrapped LLCI = 0.41, ULCI = 2.41). Conclusion: Our results suggest that emotional dysregulation may represent a dimension mediating cyclotimic temperament response to the stressful effect of the pandemic and provide insight for developing intervention policies

Combined isobutyryl‐CoA and multiple acyl‐CoA dehydrogenase deficiency in a boy with altered riboflavin homeostasis

In this report, we describe the case of an 11-year-old boy, who came to ourattention for myalgia and muscle weakness, associated with inappetence andvomiting. Hypertransaminasemia was also noted, with ultrasound evidence ofhepatomegaly. Biochemical investigations revealed acylcarnitine and organicacid profiles resembling those seen in MADD, that is, multiple acyl-CoA dehy-drogenase deficiencies (OMIM #231680) a rare inherited disorder of fatty acids,amino acids, and choline metabolism. The patient carried a single pathoge-netic variant in theETFDHgene (c.524G>A, p.Arg175His) and no pathoge-netic variant in the riboflavin (Rf) homeostasis related genes (SLC52A1,SLC52A2,SLC52A3,SLC25A32,FLAD1). Instead, compound heterozygosity wasfound in theACAD8gene (c.512C>G, p.Ser171Cys; c.822C>A, p.Asn274Lys),coding for isobutyryl-CoA dehydrogenase (IBD), whose pathogenic variantsare associated to IBD deficiency (OMIM #611283), a rare autosomal recessivedisorder of valine catabolism. The c.822C>A was never previously describedin a patient. Subsequent further analyses of Rf homeostasis showed reducedlevels of flavins in plasma and altered FAD-dependent enzymatic activities inerythrocytes, as well as a significant reduction in the level of the plasma mem-brane Rf transporter 2 in erythrocytes. The observed Rf/flavin scarcity in thispatient, possibly associated with a decreased ETF:QO efficiency might beresponsible for the observed MADD-like phenotype. The patient's clinical pic-ture improved after supplementation of Rf,L-carnitine, Coenzyme Q10, andalso 3OH-butyrate. This report demonstrates that, even in the absence ofgenetic defects in genes involved in Rf homeostasis, further targeted molecu-lar analysis may reveal secondary and possibly treatable biochemical alter-ations in this pattern

Polysomnographic Findings and Clinical Correlates in Huntington Disease. A Cross-sectional Cohort Study.

Study Objectives: To evaluate the sleep pattern and the motor activity during sleep in a cohort of patients affected by Huntington disease (HD). Design: Cross-sectional cohort study. Setting: Sleep laboratory. Patients: Thirty HD patients, 16 women and 14 men (mean age 57.3 \ub1 12.2 y); 30 matched healthy controls (mean age 56.5 \ub1 11.8 y). Interventions: Subjective sleep evaluation: Epworth Sleepiness Scale (ESS); Berlin's Questionnaire, interview for Restless Legs Syndrome (RLS), questionnaire for REM sleep behavior disorder (RBD). Clinical evaluation: disease duration, clinical severity (unified Huntington disease motor rating scale [UHDMRS]), genetic tests. Laboratory-based full-night attended video-polysomnography (V-PSG). Measurements and Results: The duration of the disease was 9.4 \ub1 4.4 y, UHMDRS score was 55.5 \ub1 23.4, CAG repeats were 44.3 \ub1 4.1. Body mass index was 21.9 \ub1 4.0 kg/m2. No patients or caregivers reported poor sleep quality. Two patients reported symptoms of RLS. Eight patients had an ESS score 659. Eight patients had high risk of obstructive sleep apnea. At the RBD questionnaire, two patients had a pathological score. HD patients, compared to controls, showed shorter sleep, reduced sleep efficiency Index, and increased arousals and awakenings. Four patients presented with sleep disordered breathing (SDB). Periodic limb movements (PLMs) during wake and sleep were observed in all patients. No episode of RBD was observed in the V-PSG recordings, and no patients showed rapid eye movement (REM) sleep without atonia. The disease duration correlated with ESS score (P < 0.02). UHMDRS correlated positively with the ESS score (P < 0.005), and negatively with the percentage of REM sleep. Conclusions: Patients with HD s showed a severe sleep disruption and a high prevalence of PLM, but no evidence of SDB or RBD

Subjective Assessment of Sleep in Huntington Disease: Reliability of Sleep Questionnaires Compared to Polysomnography

Introduction: The aim of the study was to evaluate the clinical reliability of subjective sleep evaluation, based on sleep and psychometric questionnaires, by comparing the results with those obtained with laboratory-based video-polysomnography (V-PSG). Patients and Methods: Thirty consecutive Huntington disease (HD) patients were enrolled. Subjective evaluation of sleep included the Pittsburgh Sleep Quality Index (PSQI), the sleep questionnaire for HD (HDQ), the Epworth Sleepiness Scale, the Bologna questionnaire for sleepiness (BQ), the Berlin questionnaire, and the RBD questionnaire; the International Restless Legs Syndrome Study Group scale was administered to patients with positive screening. The psychometric evaluation included the Zung Anxiety Scale, the short form of the Beck Depression Inventory, and the Maudsley Obsessive-Compulsive Inventory. All patients underwent V-PSG. Results: In sleepiness evaluation, the Epworth score was above the cutoff in 6 subjects, and the BQ detected a "high risk" of sleepiness in 7 cases. The results were concordant in 24 and discordant in 5 cases. In the evaluation of sleep quality, the PSQI score was above the cutoff in 18 subjects. According to the HDQ, 10 subjects were poor sleepers. The results were concordant with the PSQI in 20 subjects. Discussion: All comparisons between scale scores and PSG results showed poor or totally absent concordance between subjective and objective measures. Significance: The subjective evaluation of sleep in HD patients shows a poor correlation with PSG results

Functional Movement Disorders during COVID-19: Psychological Distress, Affective Temperament and Emotional Dysregulation

Background and objective: Functional movement disorders (FMD) represent a spectrum of psychosomatic symptoms particularly sensitive to stress. The COVID-19 pandemic has increased psychological distress worldwide and may have worsened FMD. The study aimed to confirm this hypothesis and to test whether in FMD there is a relationship between affective temperament, emotional dysregulation and psychological distress due to the pandemic. Methods: We recruited individuals with FMD, diagnosed them according to validated criteria and matched them with healthy controls (HC). Psychological distress and temperament were obtained using the Kessler-10 and the Temperament Evaluation of Memphis, Pisa and San Diego Autoquestionnaire, respectively. We used bootstrapped mediation analysis to test the mediator role of emotional dysregulation on the effect of temperament on psychological distress. Results: The sample consisted of 96 individuals. During the pandemic, 31.3% of the patients reported the need for urgent neurological care, and 40.6% reported a subjective worsening neurological condition. Patients with FMD presented with more psychological distress during the COVID-19 pandemic (F = 30.15, df = 1, p &lt;= 0.001) than HC. They also reported more emotional dysregulation (F = 15.80, df = 1, p &lt;= 0.001) and more cyclothymic traits (F = 14.84, df = 1, p &lt;= 0.001). Cyclothymic temperament showed an indirect effect on COVID-19-related psychological distress, mediated by deficits in emotion regulation mechanisms (Bootstrapped LLCI = 0.41, ULCI = 2.41). Conclusion: Our results suggest that emotional dysregulation may represent a dimension mediating cyclotimic temperament response to the stressful effect of the pandemic and provide insight for developing intervention policies