Impaired Decision Making and Loss of Inhibitory-Control in a Rat Model of Huntington Disease

Cognitive deficits associated with Huntington disease (HD) are generally dominated by executive function disorders often associated with disinhibition and impulsivity/compulsivity. Few studies have directly examined symptoms and consequences of behavioral disinhibition in HD and its relation with decision-making. To assess the different forms of impulsivity in a transgenic model of HD (tgHD rats), two tasks assessing cognitive/choice impulsivity were used: risky decision-making with a rat gambling task (RGT) and intertemporal choices with a delay discounting task (DD). To assess waiting or action impulsivity the differential reinforcement of low rate of responding task (DRL) was used. In parallel, the volume as well as cellular activity of the amygdala was analyzed. In contrast to WT rats, 15 months old tgHD rats exhibited a poor efficiency in the RGT task with difficulties to choose advantageous options, a steep DD curve as delays increased in the DD task and a high rate of premature and bursts responses in the DRL task. tgHD rats also demonstrated a concomitant and correlated presence of both action and cognitive/choice impulsivity in contrast to wild type (WT) animals. Moreover, a reduced volume associated with an increased basal cellular activity of the central nucleus of amygdala indicated a dysfunctional amygdala in tgHD rats, which could underlie inhibitory dyscontrol. In conclusion, tgHD rats are a good model for impulsivity disorder that could be used more widely to identify potential pharmacotherapies to treat these invasive symptoms in HD

Pressure injury prevalence in Australian intensive care units: A secondary analysis

Background: Pressure injuries (PIs) are an enduring problem for patients in the intensive care unit (ICU) because of their vulnerability and numerous risk factors. Method: This study reports Australian data as a subset of data from an international 1-day point prevalence study of ICU-acquired PI in adult patients. Patients aged 18 years or older and admitted to the ICU on the study day were included. The outcome measure was the identification of a PI by direct visual skin assessment on the study day. Data collected included demographic data and clinical risk factors, PI location and stage, and PI prevention strategies used. Descriptive statistics were used to describe PI characteristics, and odds ratios (ORs) were used to identify factors associated with the development of a PI. Results: Data were collected from 288 patients from 16 Australian ICUs. ICU-acquired PI prevalence was 9.7%, with 40 PIs identified on 28 patients. Most PIs were of stage 1 and stage 2 (26/40, 65.0%). Half of the ICU-acquired PIs were found on the head and face. The odds of developing an ICU-acquired PI increased significantly with renal replacement therapy (OR: 4.25, 95% confidence interval [CI]: 1.49–12.11), impaired mobility (OR: 3.13, 95% CI: 1.08–9.12), fastest respiratory rate (OR: 1.05 [per breath per minute], 95% CI: 1.00–1.10), longer stay in the ICU (OR: 1.04 [per day], 95% CI: 1.01–1.06), and mechanical ventilation on admission (OR: 0.36, CI: 0.14–0.91). Conclusion: This study found that Australian ICU-acquired PI prevalence was 9.7% and these PIs were associated with many risk factors. Targeted PI prevention strategies should be incorporated into routine prevention approaches to reduce the burden of PIs in the Australian adult ICU patient population.</p

GM3 synthase deficiency in non-Amish patients

International audiencePURPOSE: Biallelic loss-of-function variants in ST3GAL5 cause GM3 synthase deficiency (GM3SD) responsible for Amish infantile epilepsy syndrome. All Amish patients carry the homozygous p.(Arg288Ter) variant arising from a founder effect. To date only 10 patients from 4 non-Amish families have been reported. Thus, the phenotypical spectrum of GM3SD due to other variants and other genetic backgrounds is still poorly known. METHODS: We collected clinical and molecular data from 16 non-Amish patients with pathogenic ST3GAL5 variants resulting in GM3SD. RESULTS: We identified 12 families originating from Reunion Island, Ivory Coast, Italy, and Algeria and carrying 6 ST3GAL5 variants, 5 of which were novel. Genealogical investigations and/or haplotype analyses showed that 3 of these variants were founder alleles. Glycosphingolipids quantification in patients' plasma confirmed the pathogenicity of 4 novel variants. All patients (N = 16), aged 2 to 12 years, had severe to profound intellectual disability, 14 of 16 had a hyperkinetic movement disorder, 11 of 16 had epilepsy and 9 of 16 had microcephaly. Other main features were progressive skin pigmentation anomalies, optic atrophy or pale papillae, and hearing loss. CONCLUSION: The phenotype of non-Amish patients with GM3SD is similar to the Amish infantile epilepsy syndrome, which suggests that GM3SD is associated with a narrow and severe clinical spectrum

Individual trial analysis evidences clock and non-clock based conditioned suppression behaviors in rats

International audienceWe analyzed the temporal pattern of conditioned suppression of lever-pressing for food in rats conditioned with tone-shock pairings using either a 10 or 15s conditioned stimulus (CS)-unconditioned stimulus (US) interval with a CS duration that was three times the CS-US interval. The analysis of average suppression and of individual trials was performed during Probe CS-alone trials and when a short gap was inserted during the CS. The pattern of suppression followed the classical temporal rules: (1) scalar property, (2) a shift in peak suppression due to a gap, compatible with a Stop rule, (3) a three-state pattern of lever-pressing in individual trials, with abrupt start and stop of suppression. The peak of the average suppression curve, but not the middle time, was anticipatory to the programmed US time. The pattern of lever-pressing in individual trials unraveled two types of start of suppression behavior: a clock-based biphasic responding, with a burst of lever-pressing before suppression, and a non-clock based monophasic reduction of lever-pressing close to the CS onset. The non-clock based type of behavior may be responsible for the anticipatory peak time, and the biphasic pattern of lever-pressing may reflect the decision stage described in clock models

Cardiac expression of Brn-3a and Brn-3b POU transcription factors and regulation of Hsp27 gene expression

The Brn-3 family of transcription factors play a critical role in regulating expression of genes that control cell fate, including the small heat shock protein Hsp27. The aim of this study was to investigate the relationship between Brn-3a and Brn-3b and Hsp27 expression in the developing rodent heart. Brn-3a and Brn-3b were detected from embryonic days 9.5–10.5 (E9.5–E10.5) in the mouse heart, with significant increases seen later during development. Two isoforms (long and short) of each protein were detected during embryogenesis and postnatally. Brn-3a messenger RNA (mRNA) and protein were localized by E13.0 to the atrio-ventricular (AV) valve cushions and leaflets, outflow tract (OFT), epicardium and cardiac ganglia. By E14.5, Brn-3a was also localised to the septa and compact ventricular myocardium. An increase in expression of the long Brn-3a(l) isoform between E17 and adult coincided with a decrease in expression of Brn-3b(l) and a marked increase in expression of Hsp27. Hearts from Brn-3a−/− mice displayed a partially penetrant phenotype marked by thickening of the endocardial cushions and AV valve leaflets and hypoplastic ventricular myocardium. Loss of Brn-3a was correlated with a compensatory increase in Brn-3b and GATA3 mRNA but no change in Hsp27 mRNA. Reporter assays in isolated cardiomyocytes demonstrated that both Brn-3a and Brn-3b activate the hsp27 promoter via a consensus Brn-3-binding site. Therefore, Brn-3 POU factors may play an important role in the development and maintenance of critical cell types and structures within the heart, in part via developmental regulation of myocardial Hsp27 expression. Furthermore, Brn-3a may be necessary for correct valve and myocardial remodelling and maturation