Lysophosphatidic acid-induced proliferation in opossum kidney proximal tubular cells: role of PI 3-kinase and ERK

Lysophosphatidic acid-induced proliferation in opossum kidney proximal tubular cells: Role of PI 3-kinase and ERK. BACKGROUND: Lysophosphatidic acid (LPA) is a mitogenic lipid bound to albumin in the circulation and implicated in the induction of proximal tubular cell (PTC) injury in proteinuric states. In this study, we investigated the effect of LPA on proliferation of opossum kidney (OK) cells and the roles of the p85/p110 phosphatidylinositol 3-kinase (PI 3-kinase) and extracellular signal-regulated kinases (ERKs) ERK-1 and ERK-2 in LPA-induced proliferation. METHODS: [3H]-thymidine incorporation was used as an index of OK cell proliferation. PI 3-kinase and ERK activities were measured by in vitro kinase assays of immunoprecipitates from both wild-type OK cells and OK cells expressing a dominant negative p85 (Deltap85) subunit of PI 3-kinase in an inducible vector. RESULTS: LPA stimulated a marked increase in [3H]-thymidine uptake in wild-type and Deltap85 OK cells. OK cell PI 3-kinase activity was stimulated by LPA and was inhibited by expression of Deltap85. LPA-induced proliferation was inhibited by wortmannin and the induction of Deltap85 expression. These data suggest that LPA stimulates PI 3-kinase activity, which is essential for signaling the induction of proliferation. LPA also stimulated ERK activity (peak at 5 min, return to baseline by 60 min) maximally at a dose of 100 microM LPA. This increase was approximately 600% above basal and was similar to the effects of 10% fetal calf serum. The proliferative effect of LPA was decreased by the ERK-kinase (MEK) inhibitor PD98059 (5 microM), therefore suggesting that ERK as well as PI 3-kinase activation is important for proliferation. ERK activation by LPA was not affected by pretreatment with wortmannin or by the expression of Deltap85. PI 3-kinase activation by LPA was not affected by pretreatment with PD98059. CONCLUSIONS: We conclude that activation of PI 3-kinase is essential for the LPA-induced proliferation of OK cells and that ERK activation is also important. Therefore, they are both vital elements in separate signaling pathways leading to cell proliferation. LPA filtered into the proximal tubule in proteinuric states is likely to have profound effects on PTC growth.     

Measuring health-related quality of life in patients with venous leg ulcers

Introduction: The effect on quality of life by healing leg ulcers is not known and no validated disease-specific tool is available for measuring health-related quality of life (HRQoL) for people with venous leg ulcers. The objective of this paper was to compare four generic instruments [MOS 36-Item Short-Form Health Survey (SF-36); EuroQol (EQ); McGill Short Form Pain Questionnaire (SF-MPQ) and the Frenchay Activities Index (FAI)] used for measuring HRQoL in people with venous leg ulcers, and to offer guidance on the most appropriate tool for researchers. Methods: Two hundred and thirty-three patients with venous leg ulcers were recruited as part of a randomised controlled trial of the cost-effectiveness of community leg ulcer clinics. Subjects completed questionnaires containing the four instruments on three occasions (initial assessment, 3 and 12 months). The discriminative and evaluative properties of the four instruments were compared. Results: All four instruments were acceptable to patients, taking a mean of 19.3 (SD 6.3) min to complete. At initial assessment, the SF-MPQ had poorer discriminative properties than the other three instruments and was not able to distinguish between the different patient groups in relation to age and ulcer duration. The FAI was good at discriminating between the different patient groups (at initial assessment) in relation to age, mobility and ulcer size. At the three-month follow-up, the SF-MPQ was more responsive than the other measures and detected changes in HRQoL, whereas the EQ and SF-36 did not. At 12 months, the SF-MPQ still identified differences and the SF-36 and EQ also did at this stage. Conclusion: In the absence of a validated condition-specific tool for measuring changes in general health status for patients with venous leg ulcers, we make the following recommendations. For evaluating the outcome of interventions with a short-term follow-up (three months) in a clinical study we recommend the SF-MPQ and for 12-month follow-up in a clinical study the SF-36, with or without the SF-MPQ.     

The safety of ranitidine bismuth citrate in controlled clinical studies

Ranitidine bismuth citrate (Pylorid, Tritec) is a novel drug which heals peptic ulcers and when co-prescribed with either clarithromycin or amoxycillin eradicatesHelicobacter pylori. In controlled clinical studies it was well-tolerated when given alone or when co-prescribed with either antibiotic. Data from 20 clinical studies are reported in this analysis of safety with almost 5000 patients having received ranitidine bismuth citrate (200, 400, or 800 mg twice daily). The incidence of adverse events reported with this new drug, either alone or with an antibiotic, was not different from or lower than in patients given placebo and was independent of the dose of ranitidine bismuth citrate tested. Most commonly reported events (>1% of patients) were upper respiratory tract infection, constipation, diarrhoea, nausea and vomiting, dizziness, and headache, the latter being the only event reported by >2% of patients who received ranitidine bismuth citrate alone. Adverse events considered by the clinical investigator to be adverse reactions occurred with a similar frequency amongst patients given ranitidine bismuth citrate (8%), ranitidine hydrochloride (6%), or placebo (6%). The incidence of adverse reactions was greater when co-prescribed with amoxycillin (11%) or clarithromycin (20%) although it was not different from that noted with the antibiotics alone. Serious adverse events were reported in similar proportions of patients given placebo, ranitidine bismuth citrate alone or with an antibiotic, and ranitidine hydrochloride (range: <1-2%). The safety profile of ranitidine bismuth citrate was thus comparable to that of ranitidine hydrochloride (Zantac), a drug with a well-established record of safety in clinical use.     

Medical and dental implications of cocaine abuse

With the ever-increasing supply of cocaine and use of "crack," the potent and smokeable form of cocaine, the dangers of cocaine abuse, with its high morbidity and mortality, have become recognized. Oral and maxillofacial surgeons may frequently and unknowingly be treating patients who use cocaine, and, therefore, they must be educated about cocaine-related problems and be prepared to deal with the complications. This article discusses the nature of cocaine, its pharmacology, systemic affects, the oral manifestations of cocaine abuse, and recommended clinical management of the patient.     

The diagnostic and therapeutic impact of MRI: an observational multi-centre study

AIM: To provide information about the diagnostic and therapeutic impact of magnetic resonance imaging (MRI) and to compare the findings across diagnostic groups. MATERIALS AND METHODS: A prospective, observational study of 2017 consecutive referrals for MRI of the head, spine or knee at four imaging centres. Clinicians completed questionnaires before MRI stating initial diagnoses, diagnostic confidence and treatment plans. After imaging, a second questionnaire evaluated clinicians' revised diagnosis and treatment plans in the light of imaging findings. Patients were grouped into nine diagnostic categories for analysis. Comparison between pre- and post-imaging was used to assess the diagnostic and therapeutic impact of MRI. RESULTS: In seven of nine diagnostic groups MRI findings were associated with a diagnostic impact. Diagnoses were revised or discarded following normal MR findings and diagnostic confidence was increased by confirmative MR findings. There was no statistically significant diagnostic impact for suspected pituitary or cerebello-pontine angle lesions. In five of nine diagnostic groups (knee meniscus, knee ligament, multiple sclerosis, lumbar and cervical spine) MRI findings had a clear impact on treatment plans. CONCLUSION: This study demonstrates that in most diagnostic categories, MRI influences diagnosis and treatment. However, experimental studies are needed to prove that these diagnostic and therapeutic impacts lead to improved health.Hollingworth (2000). Clinical Radiology55, 825-831.     

Atelosteogenesis syndromes: a review, with comments on their pathogenesis

The clinical, radiographic, and morphological findings in 25 cases of atelosteogenesis and boomerang dysplasia have been reviewed. The review confirms the nosologic grouping of atelosteogenesis type I with boomerang dysplasia and the clinical and radiographic overlap of features between atel- osteogenesis I and atelosteogene- sis II (synonymous with De la Chapelle dysplasia) and a group of patients with atelosteogenesis type III. A common pathogenesis is suggested for atelosteogenesis type I and boomerang dysplasia. A marked excess of male fetuses with boomerang dysplasia was observed. Atelosteogenesis type II shows distinctive chondro-osseous histopathology with a major disturbance in cartilage matrix macromolecules. An overlap of phenotypic, radiographic, morphological, and cartilage histochemical features with those observed in diastrophic dysplasia and achondrogenesis type IB suggests that atelosteogenesis type II has common pathogenetic features with disorders of sulfation of connective tissue matrix macro- molecules. Received/accepted: 8 December 1995