Lowe syndrome protein Ocrl1 is translocated to membrane ruffles upon Rac GTPase activation: a new perspective on Lowe syndrome pathophysiology

Oculocerebrorenal Lowe syndrome is a rare X-linked disorder characterized by bilateral cataract, mental retardation and renal Fanconi syndrome. The Lowe syndrome protein Ocrl1 is a PIP2 5-phosphatase, primarily localized to the trans-Golgi network (TGN), which 'loss of function' mutations result in PIP2 accumulation in patient's cells. Although PIP2 is involved in many cell functions including signalling, vesicle trafficking and actin polymerization, it has been difficult so far to decipher molecular/cellular mechanisms responsible for Lowe syndrome phenotype. We have recently shown that, through its C-terminal RhoGAP domain, Ocrl1 forms a stable complex with Rac GTPase within the cell. In line with this finding, we report here that upon epidermal growth factor induced Rac activation in COS-7 cells, a fraction of Ocrl1 translocates from TGN to plasma membrane and concentrates in membrane ruffles. In order to investigate the functionality of Ocrl1 in plasma membrane, we have analysed PIP2 distribution in human dermal fibroblasts (HDFs) from Lowe patients versus control HDFs. As revealed by both immunodetection and green fluorescent protein-PH binding, PIP2 was found strikingly to accumulate in PDGF induced ruffles in Lowe HDFs when compared with control. This suggests that Ocrl1 is active as a PIP2 5-phosphatase in Rac induced membrane ruffles. Cellular properties such as cell migration and establishment of cell-cell contacts, which depend on ruffling and lamellipodia formation, should be further investigated to understand the pathophysiology of Lowe syndrome.     

Shigella spp. with Reduced Azithromycin Susceptibility,Quebec, Canada, 2012–2013

During 2012–2013 in Montreal, Canada, 4 locally acquired Shigella spp. pulse types with the mph(A) gene and reduced susceptibility to azithromycin were identified from 9 men who have sex with men, 7 of whom were HIV infected. Counseling about prevention of enteric sexually transmitted infections might help slow transmission of these organisms.     

Clinical significance of antibodies to soluble extractable nuclear antigens (anti-ENA).

Clinical and biological manifestations have been studied in 134 patients whose serum had antibodies to soluble extractable nuclear antigens (ENA). 85 of the patients had anti-RNP antibodies, 18 had anti-Sm antibodies, and 31 had antibodies to one or more soluble nuclear antigen. In all groups, the predominant clinical manifestations were polyarthritis, Raynaud's phenomenon, fever, and skin involvement. Renal disease was less common in those patients with anti-RNP antibodies than in the other patients. Most patients with definite renal disease (13 out of 15) also had circulating anti-DNA antibodies. The final diagnoses in these 134 patients were well defined connective tissue disease in 59; overlap syndromes in 34; a limited clinical syndrome made up of polyarthritis Raynaud's phenomenon--often with swollen fingers--and/or hypergammaglobulin-aemia in 31, and various other clinical conditions in 10.     

The Maternal Adversity,Vulnerability and Neurodevelopment Project: Theory and Methodology

Objective:

To describe the theory and methodology of the multi-wave, prospective Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) study. The goal of MAVAN is to examine the pre- and postnatal influences, and their interaction, in determining individual differences in mental health.

Method:

MAVAN is a community-based, birth cohort study of pregnant Canadian mothers and their offspring. Dyads are assessed longitudinally, with multiple assessments of both mother and child in home and laboratory across the child’s development. Study measures, including assessments of cognitive and emotional function, are described. The study uses a candidate gene approach to examine gene–environment interdependence in specific developmental outcomes. Finally, the study includes measures of both brain-based phenotypes and metabolism to explore comorbidities associated with child obesity. One of the unique features of the MAVAN protocol is the extensive measures of the mother–child interaction. The relation between these measures will be discussed.

Results:

Evidence from the MAVAN project shows interesting results about maternal care, families, and child outcomes. In our review, preliminary analyses showing the correlations between measures of maternal care are reported. As predicted, early evidence suggests that maternal care measures are positively correlated, over time.

Conclusions:

This review provides evidence for the feasibility and value of laboratory-based measures embedded within a longitudinal birth cohort study. Though retention of the samples has been a challenge of MAVAN, they are within a comparable range to other studies of this nature. Indeed, the trade-off of somewhat greater participant burden has allowed for a rich database. The results yielded from the MAVAN project will not only describe typical development but also possible targets for intervention. Understanding certain endophenotypes will shed light on the pathogenesis of various mental and physical disorders, as well as their interrelation.     

Familial articular chondrocalcinosis in quebec

The existence of articular chondrocalcinosis was documented in 9 members of 3 generations of a Quebec family. No associated or secondary forms of the disease were found. The clinical manifestations appeared early in life, and extensive radiologic involvement was apparent. We determined that genetic transmission was dominant, either autosomal or sex-linked, and not related to the HLA system.     

Inhibitory effects of sigma‐1 ligands on handling‐induced tachycardia in conscious tethered rats

We used conscious tethered Sprague‐Dawley rats to evaluate the cardiovascular effects of four sigma‐1 (σ₁) agonists and five antagonists, given alone or in combination. All drugs were administered as a single intraperitoneal dose. The agonists were given at doses reported as efficacious in rodent cognition models, while the antagonists were administered at doses neutralizing agonist effects in vivo. Systolic blood pressure (SBP) and heart rate (HR) were continuously recorded for 20 min before and 60 min postadministration. Immediately after injection, a sudden, transitory increase in HR and SBP was noted in all animals, because of the stress induced by handling. For both parameters, a peak value (ΔHR_max and ΔSBP_max) and an area under the curve of changes from baseline over the period 5–20 min postinjection (ΔHR_AUC_{5–20 min} and ΔSBP_AUC_{5–20 min}) were calculated. Three of the four σ₁ agonists (SKF‐10,047, dehydroepiandrosterone (DHEAS), Compound 14) significantly reduced ΔHR_AUC_{5–20 min} value without changing ΔHR_max, while the fourth one, SA‐4503, had no significant effect. None of the antagonists (haloperidol, rimcazole, NE‐100, and BD1047) reduced, and even one (progesterone) enhanced the stress‐induced effects on HR. No changes in SBP were noted with any compound. When the antagonist NE‐100 was administered just before SKF‐10,047, it completely reversed the inhibitory effects of the σ₁ agonist on HR increase. In conclusion, we demonstrated for the first time the involvement of σ₁ receptors in the regulation of handling‐induced tachycardia in the conscious rat. Although additional investigations are needed to fully understand this role, it might offer new therapeutic perspectives to σ₁ ligands in the cardiovascular sphere.     

Carcass composition and resistance to fasting in neonatal piglets born of sows immunized against somatostatin and/or receiving growth hormone-releasing factor injections during gestation.

Thirty-eight gestating sows were either immunized against somatostatin (SRIF) and/or injected with growth hormone-releasing factor (GRF). Treatment effects on carcass composition and resistance of newborn piglets to a 60-hour fast were investigated. Protein content of carcasses at birth was increased in piglets of sows receiving GRF or immunized against SRIF, however, when sows received both treatments there was a reduction in carcass protein content (p = 0.01). Other carcass components were unaltered by treatments, and none of the treatments affected metabolic or endocrine profiles of piglets at birth. Concentrations of GH, IGF-I (p less than 0.01), glucagon and cortisol (p less than 0.05) increased linearly with duration of fast, whereas glucose values decreased. Resistance to fasting was unaltered in piglets from any treatment thereby suggesting that exogenous GRF and/or SRIF immunization of sows during gestation are unlikely to improve survival of newborn piglets.