Cognitive and Adaptive Effects of Early Growth Hormone Treatment in Prader-Willi Syndrome Patients : A Cohort Study

Background: Prader-Willi Syndrome (PWS) is a genetically based neurodevelopmental disease characterized by obesity, hyperphagia, and mild to moderate intellectual disability. Treatment with growth hormone (GH) could provide cognitive benefits. The objective of the present study was to compare the cognitive and adaptive performance of 31 patients with genetically confirmed PWS grouped in two cohorts, one treated with GH before 2 years old (Group 1) and the other receiving the treatment later (Group 2). Method: We compared two variables necessary to diagnose intellectual disability: intellectual performance, using the Weschler scales, and adaptive behavior, using the DABS scale. The scores were analyzed by means of non-parametric statistical tests. Results: Group 1 (n = 10) obtained higher and statistically significant scores in Total Intelligence Quotient (TIQ), General Ability Index (GAI), and General Adaptive Behavior (GAB), implying better cognitive and adaptive performance compared to Group 2. Conclusions: Treatment with GH should be administered in the early stage of development (before 2 years old) to obtain greater benefits at the cognitive and adaptive levels

Gastric Dilatation and Abdominal Compartment Syndrome in a Child with Prader-Willi Syndrome

Rare disease Prader-Willi syndrome (PWS) is a genetic disorder characterized by initial muscular hypotonia and feeding difficulties, and later an insatiable appetite, hyperphagia and obesity along with mild to moderate intellectual impairment. Affected individuals' food-seeking behavior and suspected delayed gastric emptying can lead to gastric dilatation with subsequent necrosis and perforation. We present the case of a 5-year-old boy diagnosed with Prader-Willi syndrome at neonatal age due to muscular hypotonia, who started growth hormone therapy at 20 months. He presented with two episodes of a rapidly progressing gastric dilatation that led to abdominal hypertension and secondary shock at the age of 2 and 5. No large amount of food was eaten before any of the episodes, and he had abdominal pain and vomiting on both occasions. On arrival at the emergency room, a nasogastric tube was placed and aspiration of food material was performed. Abdominal X-ray and CT scan revealed massive gastric dilatation. He was admitted at the Pediatric Intensive Care Unit and after a variable period of fasting, tolerated oral intake and could be discharged. Gastric dilatation due to gastroparesis in PWS is a rare complication. However, it is a life-threatening situation and physicians should therefore maintain a high level of suspicion for gastric dilatation when patients present with warning symptoms such as abdominal pain or discomfort and vomiting

Glucagon stimulation test to assess growth hormone status in Prader-Willi syndrome

Growth hormone deficiency (GHD) must be confirmed before starting treatment in adults with Prader-Willi syndrome (PWS). Most studies use the growth-hormone-releasing hormone plus arginine (GHRH-arginine) test. No data are available on the glucagon stimulation test (GST) in PWS. We compared the utility of fixed-dose (1 mg) GST versus GHRH-arginine test in diagnosing GHD. Adults and late adolescents with PWS underwent both tests on separate days. In the GHRH-arginine test, GHD was defined according to body mass index. In the GST, two cutoffs were analyzed: peak GH concentration 90 kg). We analyzed 34 patients: 22 weighing ≤ 90 kg and 12 weighing > 90 kg. In patients weighing ≤ 90 kg, the two tests were concordant in 16 (72.72%) patients (k = 0.476, p = 0.009 with GST cutoff 90 kg, the two tests were not concordant with GST cutoff 90 kg, the < 1 ng/mL cutoff seems better. Larger studies are necessary to establish definitive glucagon doses and cutoffs, especially in extremely obese patients

Response to antipsychotic drugs in treatment-resistant schizophrenia : Conclusions based on systematic review

Peer reviewe

miRNA let-7e targeting MMP9 is involved in adipose-derived stem cell differentiation toward epithelia

miRNA let-7e is involved in stem cell differentiation, and metalloproteinases are among its potential target genes. We hypothesized that the inhibitory action of let-7e on regulation of MMP9 expression could represent a crucial mechanism during differentiation of adipose-derived stem cells (ASCs). ASCs were differentiated with all-trans retinoic acid (ATRA) to promote differentiation, and the effect of let-7 silencing during differentiation was tested. Results indicate that ASCs cultured with ATRA differentiated into cells of the epithelial lineage. We found that ASCs cultured with ATRA or transfected with miRNA let-7e expressed epithelial markers such as cytokeratin-18 and early renal organogenesis markers such as Pax2, Wt1, Wnt4 and megalin. Conversely, the specific knockdown of miRNA let-7e in ASCs significantly decreased the expression of these genes, indicating its vital role during the differentiation process. Using luciferase reporter assays, we also showed that MMP9 is a direct target of miRNA let-7e. Thus, our results suggest that miRNA let-7e acts as a matrix metalloproteinase-9 (MMP9) inhibitor and differentiation inducer in ASCs

Growth Hormone (GH) Treatment Decreases Plasma Kisspeptin Levels in GH-Deficient Adults with Prader-Willi Syndrome

Obesity and growth hormone (GH)-deficiency are consistent features of Prader-Willi syndrome (PWS). Centrally, kisspeptin is involved in regulating reproductive function and can stimulate hypothalamic hormones such as GH. Peripherally, kisspeptin signaling influences energy and metabolic status. We evaluated the effect of 12-month GH treatment on plasma kisspeptin levels in 27 GH-deficient adult PWS patients and analyzed its relationship with metabolic and anthropometric changes. Twenty-seven matched obese subjects and 22 healthy subjects were also studied. Before treatment, plasma kisspeptin concentrations in PWS and obese subjects were similar (140.20 (23.5-156.8) pg/mL vs. 141.96 (113.9-165.6) pg/mL, respectively, p = 0.979)) and higher (p = 0.019) than in healthy subjects (124.58 (107.3-139.0) pg/mL); plasma leptin concentrations were similar in PWS and obese subjects (48.15 (28.80-67.10) ng/mL vs. 33.10 (20.50-67.30) ng/mL, respectively, p = 0.152) and higher (p < 0.001) than in healthy subjects (14.80 (11.37-67.30) ng/mL). After GH therapy, lean body mass increased 2.1% (p = 0.03), total fat mass decreased 1.6% (p = 0.005), and plasma kisspeptin decreased to levels observed in normal-weight subjects (125.1(106.2-153.4) pg/mL, p = 0.027). BMI and leptin levels remained unchanged. In conclusion, 12-month GH therapy improved body composition and decreased plasma kisspeptin in GH deficient adults with PWS. All data are expressed in median (interquartile range)

The relevance of the UPS in the fatty liver graft preservation: a new approach for IGL-1 and HTK solutions

The 26S proteasome is the central proteolytic machinery of the ubiquitin proteasome system (UPS), which is involved in the degradation of ubiquitinated protein substrates. Recently, UPS inhibition has been shown to be a key factor in fatty liver graft preservation during organ cold storage using University of Wisconsin solution (UW) and Institute Georges Lopez (IGL-1) solutions. However, the merits of IGL-1 and histidine-tryptophan-ketoglutarate (HTK) solutions for fatty liver preservation have not been compared. Fatty liver grafts from obese Zücker rats were preserved for 24 h at 4 °C. Aspartate aminotransferase and alanine aminotransferase (AST/ALT), glutamate dehydrogenase (GLDH), ATP, adenosine monophosphate protein kinase (AMPK), e-NOS, proteasome activity and liver polyubiquitinated proteins were determined. IGL-1 solution prevented ATP breakdown during cold-storage preservation of steatotic livers to a greater extent than HTK solution. There were concomitant increases in AMPK activation, e-NOS (endothelial NOS (NO synthase)) expression and UPS inhibition. UPS activity is closely related to the composition of the solution used to preserve the organ. IGL-1 solution provided significantly better protection against ischemia-reperfusion for cold-stored fatty liver grafts than HTK solution. The effect is exerted through the activation of the protective AMPK signaling pathway, an increase in e-NOS expression and a dysregulation of the UPS

Mobile Phone and Wearable Sensor-Based mHealth Approach for Psychiatric Disorders and Symptoms : Systematic Review and Link to the m-RESIST Project

Background: Mobile Therapeutic Attention for Patients with Treatment-Resistant Schizophrenia (m-RESIST) is an EU Horizon 2020-funded project aimed at designing and validating an innovative therapeutic program for treatment-resistant schizophrenia. The program exploits information from mobile phones and wearable sensors for behavioral tracking to support intervention administration. Objective: To systematically review original studies on sensor-based mHealth apps aimed at uncovering associations between sensor data and symptoms of psychiatric disorders in order to support the m-RESIST approach to assess effectiveness of behavioral monitoring in therapy. Methods: A systematic review of the English-language literature, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, was performed through Scopus, PubMed, Web of Science, and the Cochrane Central Register of Controlled Trials databases. Studies published between September 1, 2009, and September 30, 2018, were selected. Boolean search operators with an iterative combination of search terms were applied. Results: Studies reporting quantitative information on data collected from mobile use and/or wearable sensors, and where that information was associated with clinical outcomes, were included. A total of 35 studies were identified; most of them investigated bipolar disorders, depression, depression symptoms, stress, and symptoms of stress, while only a few studies addressed persons with schizophrenia. The data from sensors were associated with symptoms of schizophrenia, bipolar disorders, and depression. Conclusions: Although the data from sensors demonstrated an association with the symptoms of schizophrenia, bipolar disorders, and depression, their usability in clinical settings to support therapeutic intervention is not yet fully assessed and needs to be scrutinized more thoroughly.Peer reviewe

Obstetric complications and clinical presentation in first episode of psychosis

Objective: Psychotic disorders exhibit a complex aetiology that combines genetic and environmental factors. Among the latter, obstetric complications (OCs) have been widely studied as risk factors, but it is not yet well understood how OCs relate to the heterogeneous presentations of psychotic disorders. We assessed the clinical phenotypes of individuals with a first episode of psychosis (FEP) in relation to the presence of OCs. Methods: Two-hundred seventy-seven patients with an FEP were assessed for OCs using the Lewis–Murray scale, with data stratified into three subscales depending on the timing and the characteristics of the obstetric event, namely: complications of pregnancy, abnormal foetal growth and development and difficulties in delivery. We also considered other two groups: any complications during the pregnancy period and all OCs taken altogether. Patients were clinically evaluated with the Positive and Negative Syndrome Scale for schizophrenia. Results: Total OCs and difficulties in delivery were related to more severe psychopathology, and this remained significant after co-varying for age, sex, traumatic experiences, antipsychotic dosage and cannabis use. Conclusions: Our results highlight the relevance of OCs for the clinical presentation of psychosis. Describing the timing of the OCs is essential in understanding the heterogeneity of the clinical presentation

Relationship between cognition and age at onset of first-episode psychosis: comparative study between adolescents, young adults, and adults

Psychotic disorders typically manifest from late adolescence to early adulthood, and an earlier onset might be associated with greater symptom severity and a worse long-term prognosis. This study aimed to compare the cognitive characteristics of patients with first-episode psychosis (FEP) by their age at onset. We included 298 patients diagnosed with FEP and classified them as having an early onset (EOS), youth onset (YOS), or adult onset (AOS) based on age limits of = 25 years (N = 116), respectively. Socio-demographic and clinical variables included age at baseline, gender, socio-economic status, antipsychotic medication, DSM-IV diagnoses assessed by clinical semi-structured interview, psychotic symptom severity, and age at onset. Neuropsychological assessment included six cognitive domains: premorbid intelligence, working memory, processing speed, verbal memory, sustained attention, and executive functioning. The EOS group had lower scores than the YOS or AOS groups in global cognition, executive functioning, and sustained attention. Although the scores in the YOS group were intermediate to those in the EOS and AOS groups for most cognitive factors, no statistically significant differences were detected between the YOS and AOS groups. Age at onset results in specific patterns of cognitive interference. Of note, impairment appears to be greater with EOS samples than with either YOS or AOS samples. A longitudinal study with a larger sample size is needed to confirm our findings