Event-Related Potentials in ADHD Associated With Tuberous Sclerosis Complex:A Possible Biomarker of Symptoms Severity?

Background and Aim:Tuberous sclerosis complex (TSC) is associated with a high rate of attention deficit-hyperactivity disorder (ADHD), usually with more severe symptoms than in idiopathic cases. Event-related potentials have been used in idiopathic ADHD, and they have been proposed as a possible biomarker of symptoms severity. Aim of this study was to investigate event-related potential (ERP) characteristics in patients with ADHD secondary to TSC, compared to patients with drug-naive idiopathic ADHD and healthy controls (HCs), to investigate whether (1) distinct clinical features can be due to different pathophysiological mechanisms, and (2) ERPs may reliably predict ADHD symptoms severity in TSC. Materials and Methods:We enrolled 13 patients with idiopathic ADHD (iADHD), 6 patients with ADHD associated with TSC (tscADHD), and 14 age-matched HCs (7-17 years). All of them underwent ERP recording, with mismatch negativity (MMN) preceding the P300 recording. All patients underwent neurocognitive evaluations. Results:Mismatch negativity latency was shorter in iADHD (P= 0.04) and tscADHD (P= 0.06) than in HC, with no difference between patients' groups. Mismatch negativity amplitude was significantly higher in patients (both iADHD and tscADHD) than in HC. The P300 amplitude was significantly lower in iADHD patients than in both tscADHD patients (P= 0.03) and HCs (P< 0.001). No difference was found between tscADHD patients and HCs (P= 0.2). Conclusion:While patients with iADHD present lower P300 amplitude than HC, in tscADHD patients P300 amplitude was not different from that in HC, suggesting that in TSC P300 amplitude does not really reflect symptom severity

A cohort study on acute ocular motility disorders in pediatric emergency department

Background: Acute ocular motility disorders (OMDs) in children admitted to Emergency Department (ED) represents a not so rare condition with a wide spectrum of different etiologies. The emergency physician must be skilled in rapidly identifying patients with potentially life threatening (LT) forms, requiring further diagnostic procedures. The aim of the study was to assess characteristics of children with acute Ocular Motility Disorders (OMDs), and to identify "red flags" for recognition of underlying life-threatening (LT) conditions. Methods: A retrospective cohort study evaluated children (2 months-17 years) admitted to a tertiary Emergency Department in 2009-2014. A subgroup analysis was performed comparing children with and without LT conditions. Results: Of 192 visits for OMDs, the isolated strabismus occurred most frequently (55.6%), followed by pupil disorders (31.8%), ptosis (5.2%) and combined OMDs (11.5%). The majority of acute OMDs involved no underlying LT conditions (n = 136) and most of them were infants or toddlers (50%). In a multivariable analysis, LT conditions included especially children over 6 years of age, increasing the odds ratio by 2% for each months of age (p = 0.009). LT etiologies were 16 times more likely in combined OMDs (p = 0.018), were over 13 times more likely to report associated extra-ocular signs/symptoms (p = 0.017) and over 50 times more likely to report co-morbidity (p = 0.017). Conclusion: OMDs are not an uncommon presentation at ED. Although most of them involve non-LT conditions, the ED physician should consider potential "red flags" for appropriate management of children such as age > 6 years, combined OMDs, extra-ocular symptoms and co-morbidity

Nitrogen and chlorophyll status determination in durum wheat as influenced by fertilization and soil management: Preliminary results.

Handheld chlorophyll meters as Soil Plant Analysis Development (SPAD) have proven to be useful tools for rapid, no-destructive assessment of chlorophyll and nitrogen status in various crops. This method is used to diagnose the need of nitrogen fertilization to improve the efficiency of the agricultural system and to minimize nitrogen losses and deficiency. The objective of this study is to evaluate the effect of repeated conservative agriculture practices on the SPAD readings, leaves chlorophyll concentration and Nitrogen Nutrition Index (NNI) relationships in durum wheat under Mediterranean conditions. The experimental site is a part of a long-term-experiment established in 1994 and is still on-going where three tillage managements and three nitrogen fertilizer treatments were repeated in the same plots every year. We observed a linear relationship between the SPAD readings performed in the central and distal portion of the leaf (R2 = 0.96). In fertilized durum wheat, we found all positive exponential relationships between SPAD readings, chlorophyll leaves concentration (R2 = 0.85) and NNI (R2 = 0.89). In the unfertilized treatment, the SPAD has a good attitude to estimate leaves chlorophyll concentration (R2 = 0.74) and NNI (R2 = 0.77) only in crop grow a soil with relative high content of soil organic matter and nitrogen availability, as observed in the no tilled plots. The results show that the SPAD can be used for a correct assessment of chlorophyll and nitrogen status in durum wheat but also to evaluate indirectly the content of soil organic matter and nitrogen availability during different growth stages of the crop cycle

Case report:A pediatric case of Bickerstaff brainstem encephalitis after COVID-19 vaccination and Mycoplasma pneumoniae infection: Looking for the culprit

Bickerstaff brainstem encephalitis (BBE) is a rare, immune-mediated disease characterized by the acute onset of external ophthalmoplegia, ataxia, and consciousness disturbance. It has a complex multifactorial etiology, and a preceding infectious illness is seen in the majority of cases. Immune-mediated neurological syndromes following COVID-19 vaccination have been increasingly described. Here we report the case of a child developing BBE 2 weeks after COVID-19 vaccination. Despite nerve conduction studies and CSF analysis showing normal results, BBE was diagnosed on clinical ground and immunotherapy was started early with a complete recovery. Later, diagnosis was confirmed by positive anti-GQ1b IgG in serum. Even if there was a close temporal relationship between disease onset and COVID-19 vaccination, our patient also had evidence of a recent Mycoplasma pneumoniae infection that is associated with BBE. Indeed, the similarity between bacterial glycolipids and human myelin glycolipids, including gangliosides, could lead to an aberrantly immune activation against self-antigens (i.e., molecular mimicry). We considered the recent Mycoplasma pneumoniae infection a more plausible explanation of the disease onset. Our case report suggests that suspect cases of side effects related to COVID-19 vaccines need a careful evaluation in order to rule out well-known associated factors before claiming for a causal relationship

Mutations in KCNK4 that Affect Gating Cause a Recognizable Neurodevelopmental Syndrome

Aberrant activation or inhibition of potassium (K+) currents across the plasma membrane of cells has been causally linked to altered neurotransmission, cardiac arrhythmias, endocrine dysfunction, and (more rarely) perturbed developmental processes. The K+ channel subfamily K member 4 (KCNK4), also known as TRAAK (TWIK-related arachidonic acid-stimulated K+ channel), belongs to the mechano-gated ion channels of the TRAAK/TREK subfamily of two-pore-domain (K2P) K+ channels. While K2P channels are well known to contribute to the resting membrane potential and cellular excitability, their involvement in pathophysiological processes remains largely uncharacterized. We report that de novo missense mutations in KCNK4 cause a recognizable syndrome with a distinctive facial gestalt, for which we propose the acronym FHEIG (facial dysmorphism, hypertrichosis, epilepsy, intellectual disability/developmental delay, and gingival overgrowth). Patch-clamp analyses documented a significant gain of function of the identified KCNK4 channel mutants basally and impaired sensitivity to mechanical stimulation and arachidonic acid. Co-expression experiments indicated a dominant behavior of the disease-causing mutations. Molecular dynamics simulations consistently indicated that mutations favor sealing of the lateral intramembrane fenestration that has been proposed to negatively control K+ flow by allowing lipid access to the central cavity of the channel. Overall, our findings illustrate the pleiotropic effect of dysregulated KCNK4 function and provide support to the hypothesis of a gating mechanism based on the lateral fenestrations of K2P channels

Serum Albumin Is Inversely Associated With Portal Vein Thrombosis in Cirrhosis

We analyzed whether serum albumin is independently associated with portal vein thrombosis (PVT) in liver cirrhosis (LC) and if a biologic plausibility exists. This study was divided into three parts. In part 1 (retrospective analysis), 753 consecutive patients with LC with ultrasound-detected PVT were retrospectively analyzed. In part 2, 112 patients with LC and 56 matched controls were entered in the cross-sectional study. In part 3, 5 patients with cirrhosis were entered in the in vivo study and 4 healthy subjects (HSs) were entered in the in vitro study to explore if albumin may affect platelet activation by modulating oxidative stress. In the 753 patients with LC, the prevalence of PVT was 16.7%; logistic analysis showed that only age (odds ratio [OR], 1.024; P = 0.012) and serum albumin (OR, -0.422; P = 0.0001) significantly predicted patients with PVT. Analyzing the 112 patients with LC and controls, soluble clusters of differentiation (CD)40-ligand (P = 0.0238), soluble Nox2-derived peptide (sNox2-dp; P < 0.0001), and urinary excretion of isoprostanes (P = 0.0078) were higher in patients with LC. In LC, albumin was correlated with sCD4OL (Spearman's rank correlation coefficient [r(s)], -0.33; P < 0.001), sNox2-dp (r(s), -0.57; P < 0.0001), and urinary excretion of isoprostanes (r(s), -0.48; P < 0.0001) levels. The in vivo study showed a progressive decrease in platelet aggregation, sNox2-dp, and urinary 8-iso prostaglandin F2 alpha-III formation 2 hours and 3 days after albumin infusion. Finally, platelet aggregation, sNox2-dp, and isoprostane formation significantly decreased in platelets from HSs incubated with scalar concentrations of albumin. Conclusion: Low serum albumin in LC is associated with PVT, suggesting that albumin could be a modulator of the hemostatic system through interference with mechanisms regulating platelet activation

Clinical features and outcomes of elderly hospitalised patients with chronic obstructive pulmonary disease, heart failure or both

Background and objective: Chronic obstructive pulmonary disease (COPD) and heart failure (HF) mutually increase the risk of being present in the same patient, especially if older. Whether or not this coexistence may be associated with a worse prognosis is debated. Therefore, employing data derived from the REPOSI register, we evaluated the clinical features and outcomes in a population of elderly patients admitted to internal medicine wards and having COPD, HF or COPD + HF. Methods: We measured socio-demographic and anthropometric characteristics, severity and prevalence of comorbidities, clinical and laboratory features during hospitalization, mood disorders, functional independence, drug prescriptions and discharge destination. The primary study outcome was the risk of death. Results: We considered 2,343 elderly hospitalized patients (median age 81 years), of whom 1,154 (49%) had COPD, 813 (35%) HF, and 376 (16%) COPD + HF. Patients with COPD + HF had different characteristics than those with COPD or HF, such as a higher prevalence of previous hospitalizations, comorbidities (especially chronic kidney disease), higher respiratory rate at admission and number of prescribed drugs. Patients with COPD + HF (hazard ratio HR 1.74, 95% confidence intervals CI 1.16-2.61) and patients with dementia (HR 1.75, 95% CI 1.06-2.90) had a higher risk of death at one year. The Kaplan-Meier curves showed a higher mortality risk in the group of patients with COPD + HF for all causes (p = 0.010), respiratory causes (p = 0.006), cardiovascular causes (p = 0.046) and respiratory plus cardiovascular causes (p = 0.009). Conclusion: In this real-life cohort of hospitalized elderly patients, the coexistence of COPD and HF significantly worsened prognosis at one year. This finding may help to better define the care needs of this population

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation