Sestrin 2 and AMPK Connect Hyperglycemia to Nox4-Dependent Endothelial Nitric Oxide Synthase Uncoupling and Matrix Protein Expression

Mesangial matrix accumulation is an early feature of glomerular pathology in diabetes. Oxidative stress plays a critical role in hyperglycemia-induced glomerular injury. Here, we demonstrate that, in glomerular mesangial cells (MCs), endothelial nitric oxide synthase (eNOS) is uncoupled upon exposure to high glucose (HG), with enhanced generation of reactive oxygen species (ROS) and decreased production of nitric oxide. Peroxynitrite mediates the effects of HG on eNOS dysfunction. HG upregulates Nox4 protein, and inhibition of Nox4 abrogates the increase in ROS and peroxynitrite generation, as well as the eNOS uncoupling triggered by HG, demonstrating that Nox4 functions upstream from eNOS. Importantly, this pathway contributes to HG-induced MC fibronectin accumulation. Nox4-mediated eNOS dysfunction was confirmed in glomeruli of a rat model of type 1 diabetes. Sestrin 2-dependent AMP-activated protein kinase (AMPK) activation attenuates HG-induced MC fibronectin synthesis through blockade of Nox4-dependent ROS and peroxynitrite generation, with subsequent eNOS uncoupling. We also find that HG negatively regulates sestrin 2 and AMPK, thereby promoting Nox4-mediated eNOS dysfunction and increased fibronectin. These data identify a protective function for sestrin 2/AMPK and potential targets for intervention to prevent fibrotic injury in diabetes.     

The cytokinesis gene KEULE encodes a Sec1 protein that binds the syntaxin KNOLLE

KEULE is required for cytokinesis in Arabidopsis thaliana. We have positionally cloned the KEULE gene and shown that it encodes a Sec1 protein. KEULE is expressed throughout the plant, yet appears enriched in dividing tissues. Cytokinesis-defective mutant sectors were observed in all somatic tissues upon transformation of wild-type plants with a KEULE-green fluorescent protein gene fusion, suggesting that KEULE is required not only during embryogenesis, but at all stages of the plant's life cycle. KEULE is characteristic of a Sec1 protein in that it appears to exist in two forms: soluble or peripherally associated with membranes. More importantly, KEULE binds the cytokinesis-specific syntaxin KNOLLE. Sec1 proteins are key regulators of vesicle trafficking, capable of integrating a large number of intra- and/or intercellular signals. As a cytokinesis-related Sec1 protein, KEULE appears to represent a novel link between cell cycle progression and the membrane fusion apparatus.     

Interface-mediated death of unconditioned Tetrahymena cells: effect of the medium composition

ABSTRACT We have previously shown that the cell death of Tetrahymena thermophila in low inocula cultures in a chemically-defined medium is not apoptotic. The death is caused by a cell lysis occurring at the medium-air interface and can be prevented by the addition of insulin or Pluronic F-68. Here, we report that cell death can also be caused by the medium. The specific effects of several medium constituents were tested in the presence and absence of an interface. Four of the 19 amino acids (arginine, aspartic acid, glutamic acid, and histidine in millimolar concentration) as well as Ca²⁺ (68 μM) and Mg²⁺ (2 mM) and trace metal ions (micromolar concentrations) are all sufficient to induce the interface-mediated death. The effect of the amino acids and the salt ions Ca²⁺ and Mg²⁺ can be abolished by the addition of insulin (10^-6 M) or Pluronic F-68 (0.01% w/v), whereas insulin/Pluronic F-68 only postpones the death induced by trace metal ions. On the basis of our findings, a new recipe for a chemically-defined medium has been formulated. Single cells can grow in this medium in the presence of medium-air interface without any supplements.     

Value of screening for intestinal and urinary parasites in non-resident permanent students in Tunisia

In order to fight digestive and urinary parasitoses, a national program of surveillance has been founded. The screening of these parasitoses among the non permanent resident students in Tunisia (ENRPTS) is one of the main actions of this program. Among 2560 ENRPTS tested in the laboratory of Parasitologie of Institut Pasteur of Tunis, between 1998 and 2002, 674 were infected by parasites, which represents a global prévalence of 26.3%. The intestinal protozoa constitute the majority of parasites identified (87.4%). Entamoeba histolytica has been isolated in 89 cases, essentially from students from tropical African countries. Urinary bilharziosis has been diagnosed in 25 cases. These results confirm the utility of the control of the ENRPTS. The precocious tracking permits to avoid the introduction and the dissemination of parasites already absent or rare in our country.     

Are there health risks for travel among Tunisians? What type of medical care should be assured?

The present work aims to assess the importance of the international travels of Tunisians, their destinations, the risks they face as well as the means to reduce them. Therefore, data related to the period from 1989 to 1998, were collected from official organisms involved in this area. Results revealed an increase of the number of Tunisians travelling outside the country of 23% between 1989 and 1998, with a mean progress of 5.7% per year since 1993. Main destinations were Maghrebin countries (65.7%), Europe (30%) and Middle East (4%). The number of persons leaving to high risk destinations remains difficult to assess and shows the importance of implementing a surveillance system to insure an adequate medical follow-up of this category of travellers. The structures actually involved in the health management of Tunisian travellers have a weak recruitment which demonstrates the importance to strengthen the sensitization of general practitioners to this subject and the promotion of the immunization ward of "Institut Pasteur" to a national centre of travelling medicine.     

The Impact of the Carer Support Needs Assessment Tool (CSNAT) in Community Palliative Care Using a Stepped Wedge Cluster Trial

Family caregiving towards the end-of-life entails considerable emotional, social, financial and physical costs for caregivers. Evidence suggests that good support can improve caregiver psychological outcomes. The primary aim of this study was to investigate the impact of using the carer support needs assessment tool (CSNAT), as an intervention to identify and address support needs in end of life home care, on family caregiver outcomes. A stepped wedge design was used to trial the CSNAT intervention in three bases of Silver Chain Hospice Care in Western Australia, 2012-14. The intervention consisted of at least two visits from nurses (2-3 weeks apart) to identify, review and address caregivers’ needs. The outcome measures for the intervention and control groups were caregiver strain and distress as measured by the Family Appraisal of Caregiving Questionnaire (FACQ-PC), caregiver mental and physical health as measured by SF-12v2, and caregiver workload as measured by extent of caregiver assistance with activities of daily living, at baseline and follow up. Total recruitment was 620. There was 45% attrition for each group between baseline and follow-up mainly due to patient deaths resulting in 322 caregivers completing the study (233 in the intervention group and 89 in the control group). At follow-up, the intervention group showed significant reduction in caregiver strain relative to controls, p=0.018, d=0.348 (95% CI 0.25 to 0.41). Priority support needs identified by caregivers included knowing what to expect in the future, having time for yourself in the day and dealing with your feelings and worries. Despite the challenges at the clinician, organisational and trial levels, the CSNAT intervention led to an improvement in caregiver strain. Effective implementation of an evidence-informed and caregiver-led tool represents a necessary step towards helping palliative care providers better assess and address caregiver needs, ensuring adequate family caregiver support and reduction in caregiver strain.     

Glut-1 Expression Correlates with Basal-like Breast Cancer

INTRODUCTION: Glucose transporter 1 (Glut-1) is a facilitative glucose transporter expressed in many cancers including breast cancer. Basal-like breast cancer (BLBC) is a high-risk disease associated with poor prognosis and lacks the benefit of targeted therapy. The aim of this study was to characterize the immunohistochemical (IHC) expression of Glut-1 in patients with BLBC compared with non-BLBC. MATERIALS AND METHODS: We identified 523 cases of invasive breast carcinoma from our database. The clinicopathologic findings and the biologic markers including estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (Her2) status were reviewed. IHC stains for cytokeratin 5/6 (CK5/6), epidermal growth factor receptor (EGFR), p53, and Glut-1 were performed on tissue microarray using standard procedures. BLBC was defined as ER-,PR-, Her2-, and CK5/6+ and/or EGFR+. RESULTS: Of informative cases, 14.7% were categorized as BLBC versus 85.3% as non-BLBC. Glut-1 was expressed in 42 (76.4%) of 55 BLBCs, whereas only 55 (23.8%) of 231 non-BLBCs showed immunostaining for Glut-1 (P < .001). Overall, Glut-1 expression was significantly associated with high histologic grade, ER negativity, PR negativity, CK5/6 positivity, EGFR expression, and high p53 expression (P < .001). However, there was no correlation between Glut-1 immunostaining and patient's outcome. CONCLUSIONS: Our results show that Glut-1 is significantly associated with BLBC and might be a potential therapeutic target for this aggressive subgroup of breast cancer, and this warrants further investigations.