Novel Mutations in the Amyloid Precursor Protein Gene within Moroccan Patients with Alzheimer's Disease

In Morocco, Alzheimer's disease (AD) affects almost 30,000 individuals, and this number could increase to 75,000 by 2020. To our knowledge, the genes predisposing individuals to AD and predicting disease incidence remain elusive. In this study, we aimed to evaluate the genetic contribution of mutations in the amyloid precursor protein (APP) gene exons 16 and 17 to familial and sporadic AD cases. Seventeen sporadic cases and eight family cases were seen at the memory clinic of the University of Casablanca Neurology Department. These patients underwent standard somatic neurological examination, cognitive function assessment, brain imaging, and laboratory tests. Direct sequencing of exons 16 and 17 of the APP gene was performed on genomic DNA of AD patients. In this original Moroccan study, we identified seven novel frameshift mutations in exons 16 and 17 of the APP gene. Interestingly, only one novel splice mutation was detected in a family case. There is a strong correlation between clinical symptoms and genetic factors in Moroccan patients with a family history of AD. Therefore, mutations in APP gene exons 16 and 17 may eventually become genetic markers for AD predisposition.     

Predictors of Attrition From Residential Treatment for Youths With Addictive Behaviors

The present study sought to examine predictors of attrition from residential treatment for adolescents with addictive behaviors. Using data from 137 adolescents and their families, latent variable models were constructed to examine three child/adolescent factors and three parenting factors as predictors of attrition. Findings indicated that emotional/social difficulties and parental involvement in treatment, as well as their interaction, had a direct effect on attrition. In addition, parenting in adolescence interacted with both substance/behavioral problems and early caregiver discipline to predict attrition. This study provided insight into the exacerbating effects of neglectful or absent parenting practices in the successful completion of adolescent substance use treatment.     

Left superior pulmonary vein connected to superior vena cava vein in a patient with situs inversus totalis: A challenging diagnosis

We herein describe the previously unreported combination of partial anomalous venous connection to the superior vena cava combined with situs inversus totalis. Following peripheral contrast injection, bubbles appeared initially in the left atrium allowing the diagnosis of a supra‐atrial connection to be made using transthoracic echocardiography, but this timing was not anymore reproduced during transesophageal echocardiography performed minutes later. Cardiac computed tomography allowed the final diagnosis to be made. This case emphasizes the importance of performing bubble studies both during transesophageal and transthoracic echocardiography.     

Activity restrictions after gynecologic surgery: is there evidence?

Many surgeons recommend rest and restricting activities to their patients after surgery. The aim of this review is to summarize the literature regarding types of activities gynecologic surgeons restrict and intra-abdominal pressure during specific activities and to provide an overview of negative effects of sedentary behavior (rest). We searched PubMed and Scopus for years 1970 until present and excluded studies that described recovery of activities of daily living after surgery as well as those that assessed intra-abdominal pressure for other reasons such as abdominal compartment syndrome and hypertension. For our review of intra-abdominal pressure, we excluded studies that did not include a generally healthy population, or did not report maximal intra-abdominal pressures. We identified no randomized trial or prospective cohort study that studied the association between postoperative activity and surgical success after pelvic floor repair. The ranges of intra-abdominal pressures during specific activities are large and such pressures during activities commonly restricted and not restricted after surgery overlap considerably. There is little concordance in mean peak intra-abdominal pressures across studies. Intra-abdominal pressure depends on many factors, but not least the manner in which it is measured and reported. Given trends towards shorter hospital stays and off work intervals, which both predispose women to higher levels of physical activity, we urge research efforts towards understanding the role of physical activity on recurrence of pelvic organ prolapse and urinary incontinence after surgery.     

Enhanced SUMOylation and SENP-1 protein levels following oxygen and glucose deprivation in neurones

Here, we show that oxygen and glucose deprivation (OGD) causes increased small ubiquitin-like modifier (SUMO)-1 and SUMO-2/3 conjugation to substrate proteins in cultured hippocampal neurones. Surprisingly, the SUMO protease SENP-1, which removes SUMO from conjugated proteins, was also increased by OGD, suggesting that the neuronal response to OGD involves a complex interplay between SUMOylation and deSUMOylation. Importantly, decreasing global SUMOylation in cultured hippocampal neurones by overexpression of the catalytic domain of SENP-1 increased neuronal vulnerability to OGD-induced cell death. Taken together, these results suggest a neuroprotective role for neuronal SUMOylation after OGD.     

Reconstruction of an active SOCS3-based E3 ubiquitin ligase complex in vitro: identification of the active components and JAK2 and gp130 as substrates

Abstract

SOCS3 (suppressor of cytokine signaling 3) inhibits the intracellular signaling cascade initiated by exposure of cells to cytokines. SOCS3 regulates signaling via two distinct mechanisms: directly inhibiting the catalytic activity of Janus kinases (JAKs) that initiate the intracellular signaling cascade and catalysing the ubiquitination of signaling components by recruiting components of an E3 ubiquitin ligase complex. Here we investigate the latter mode-of-action biochemically by reconstructing a SOCS3-based E3 ubiquitin ligase complex in vitro using fully purified, recombinant components and examining its ability to promote the ubiquitination of molecules involved in the cytokine signaling cascade. We show that SOCS3 is an active substrate recruitment module for a Cullin5-based E3 ligase and have defined the core protein components required for ubiquitination. SOCS3-induced polyubiquitination was rapid and could proceed through a number of different ubiquitin lysines. SOCS3 catalyzed the ubiquitination of both the IL-6 receptor common chain (gp130) and JAK2.     

Acute psycho-physiological responses to perceptually regulated hypoxic and normoxic interval walks in overweight-to-obese adults

ObjectivesWe investigated psycho-physiological responses to perceptually regulated interval walks in hypoxia versus normoxia in obese individuals.DesignWithin-participants repeated measures.MethodsTen obese adults (BMI = 32 ± 3 kg/m^?2) completed a 60-min interval session (15 × 2 min walking at a rating of perceived exertion of 14 on the 6–20 Borg scale with 2 min of rest) either in hypoxia (FiO₂ = 13.0%, HYP) or normoxia (NOR). A third trial replicating the HYP speed pattern was carried out in normoxia as a control (CON). Exercise responses were analysed comparing the average of 1st to 3rd exercise bouts to those of the 4th–6th, 7th–9th, 10th–12th and 13th–15th exercise bouts (block 1 versus 2, 3, 4 and 5).ResultsTreadmill speed was slower during block 4 (6.14 ± 0.67 versus 6.24 ± 0.73 km/h^?1) and block 5 (6.12 ± 0.64 versus 6.25 ± 0.75 km/h^?1) in HYP compared to NOR or CON (p = 0.009). Compared to NOR and CON, heart rate was +6–10% higher (p = 0.001), whilst arterial oxygen saturation (?12–13%) was lower (p < 0.001) in HYP. Perceived limb discomfort was lower in HYP and CON versus NOR (?21 ± 4% and ?34 ± 6%; p = 0.004).ConclusionsIn overweight-to-obese adults, perceptually regulated interval walks in hypoxia versus normoxia leads to progressively slower speeds along with lower limb discomfort and larger physiological stress than normoxia. Walking at the speed adopted in hypoxia produces similar psycho-physiological responses at the same absolute intensity in normoxia.