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.     

Ovarian metastases of digestive cancers. Diagnostic and therapeutic management

Although ovarian metastasis of digestive cancers were well known since more 80 years, the management of ovaries is still discussed. The authors reviewed 112 cases of digestive tumors in female patients operated between 1973 and 1987, excluding the peritoneal carcinomatosis, and report 7 cases of ovarian metastasis. The primary carcinoma was gastric (2 cases) colonic (2 cases) appendicular (1 case) small bowel (1 case) and biliary tract (1 case). Because the severe prognosis and the frequent revealing and isolated feature of the ovarian metastases the authors review the literature in order to propose recommendations regarding the diagnosis and treatment according to the localisation, the grading of the primary tumor particularly in non menopausal patients. When the primary tumor is a mucinous signet-ring carcinoma with spread to the serosa and a gross abnormality of an ovary is discovered the oophorectomy should be performed. In every cases an immediate histological examination is absolutely necessary. Clinical and sonographic findings are included in the operative staging and the follow up of patients operated for a digestive adenocarcinoma. Especially if the ovarian tumor is bilateral a complete digestive check-up including appendix and biliary tract is necessary.     

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.     

Evaluation of a decision aid and a personal risk profile in community pharmacy for patients considering options to improve cardiovascular health: the OPTIONS pilot study

Objective In a pilot study, to assess the feasibility and relevance of providing a community pharmacist consultation supplemented by a decision aid (DA) or a personal risk profile (PRP) to patients on lipid‐lowering or antihypertensive pharmacotherapy. Preliminary data on the clinical effectiveness of these interventions were collected. Method Patients were randomised to DA or PRP and evaluated before, two weeks after, and three months after a pharmacist consultation. No differences were observed between DA and PRP groups; results are reported for all patients combined. The quality of the patients' decision to initiate or maintain lifestyle change and/or pharmacological treatment was evaluated at baseline and two weeks after the consultation by measuring their knowledge, risk perception, decisional conflict and satisfaction with the decision process. The stage of change for various lifestyles and changes in cardiovascular disease (CVD)‐risk factors were evaluated at baseline and at three months. Setting Ten community pharmacies. Key findings Twenty‐six of 42 patients (62%) agreed to participate. Patients reported as excellent or very good the way the information was presented (79%), the amount of information (88%), and the usefulness of the tools (100%). The quality of the patients' decision at baseline was low; one‐third of participants correctly estimated their CVD risks and laboratory results, and 54% had high decisional conflict. After the intervention, the satisfaction scores for role in decision making, amount of information provided and pharmacist's attitude were 69%, 81% and 85% respectively, and the proportion of participants with high decisional conflict declined to 25% (P = 0.02). CVD knowledge and risk perception did not change after the intervention. Improvements in low‐density lipoprotein cholesterol (LDL)‐C, total‐C/high‐density lipoprotein (HDL)‐C ratio, body mass index, and estimated 10‐year CVD risk were observed. Conclusion Providing pharmacist consultation supplemented by a DA or a PRP in community pharmacies is feasible and relevant. However, it did not improve CVD knowledge or risk perception.     

Development and preliminary testing of a patient decision aid to assist pharmaceutical care in the prevention of cardiovascular disease

STUDY OBJECTIVE: To develop and test a decision aid for patients with hypertension and/or dyslipidemia because a decision aid may assist in pharmaceutical care by providing relevant evidence-based information. DESIGN: Before and after use of a decision aid. SETTING: Hypertension clinic of a university hospital and a specialized coronary heart disease-prevention clinic. PATIENTS: A convenience sample of 16 patients receiving pharmacologic treatment for hypertension and/or dyslipidemia. INTERVENTION: A face-to-face interview was conducted before using the decision aid. This was followed by a telephone interview after the patient used the decision aid to assess the acceptability of the decision aid to the patient, as well as the patient's knowledge, risk perception, and decisional conflict. MEASUREMENTS AND MAIN RESULTS: The decision aid consists of a booklet containing general, evidence-based information and a personal worksheet. The worksheet provides information on patient risk factors, personal estimates of cardiovascular disease (CVD) risk, the benefits of treatment options, and values clarification exercise. It invites patients to specify an action plan and follow their own progress over time. Most patients (86-93%) rated the presentation of the information as excellent or very good, 80% judged the information about lifestyle changes and drug therapy to be balanced, 93% rated the amount of information "just right," and 100% found the decision aid useful. After using the decision aid, patients had higher knowledge scores for general risk factors (before, 91%; after, 100%, p=0.014), personal risk factors (73%, 92%, p=0.016), and treatment options (68%, 99%, p<0.001). More patients were able to estimate correctly their CVD risk category (50%, 93%, p=0.03) and their absolute 10-year CVD risk (0%, 93%, p<0.001), whereas the overall decisional conflict score decreased (p=0.007). CONCLUSION: The decision aid was acceptable to patients and improved their knowledge, risk perception, and decisional conflict. Therefore, the feasibility and impact of using the decision aid in community pharmacies and medical clinics should be assessed.     

Vitamin A prevents high fat diet-induced ACF development and modifies the pattern of expression of peroxisome proliferator and retinoic acid receptor m-RNA

Some dietary compounds, among them fats, are modulators of colon cancer risk. This study reports the modulating effects of n-6, with or without vitamin A, on promotion of colon preneoplasic lesions induced by 1,2-dimethylhydrazine (DMH) and on the expression of nuclear receptors (PPARgamma, RXRalpha, and RARbeta). One group of male Fisher rats was fed a basic diet (5% safflower oil) and two groups were fed a high-fat diet (HFD, 25% safflower oil). Of these, one was supplemented with 200 IU vitamin A for 5 mo. The safflower oil contained polyunsaturated fatty acids, mainly linoleic acid (73%). The data showed an increasing effect of safflower oil-enriched diet on aberrant crypt foci occurrence and multiplicity. This effect was impaired by vitamin A supplementation. In addition, an HFD-related up-regulation of PPARgamma and a concomitant down-regulation of RARbeta mRNA expression were observed with or without chemical initiation and were prevented by vitamin A. Moreover, when treated with DMH, HFD rats exhibited a dramatically decreased expression of RXRalpha mRNA (-49%). It was hypothesized that HFD, leading to hyperexpression of PPARgamma, would produce an alteration of retinoic acid signaling and, in this way, create a background modulating colon cancer risk.     

Quercetin induces apoptosis of Trypanosoma brucei gambiense and decreases the proinflammatory response of human macrophages

In addition to parasite spread, the severity of disease observed in cases of human African trypanosomiasis (HAT), or sleeping sickness, is associated with increased levels of inflammatory mediators, including tumor necrosis factor (TNF)-alpha and nitric oxide derivatives. In the present study, quercetin (3,3',4',5,7-pentahydroxyflavone), a potent immunomodulating flavonoid, was shown to directly induce the death of Trypanosoma brucei gambiense, the causative agent of HAT, without affecting normal human cell viability. Quercetin directly promoted T. b. gambiense death by apoptosis as shown by Annexin V binding. In addition to microbicidal activity, quercetin induced dose-dependent decreases in the levels of TNF-alpha and nitric oxide produced by activated human macrophages. These results highlight the potential use of quercetin as an antimicrobial and anti-inflammatory agent for the treatment of African trypanomiasis.