Mutational analysis of a highly conserved proline residue in MRP1, MRP2, and MRP3 reveals a partially conserved function.

The ATP-binding cassette multidrug resistance protein 1 MRP1 (ABCC1) mediates the cellular efflux of organic anions including conjugated metabolites, chemotherapeutic agents, and toxicants. We previously described a mutation in cytoplasmic loop 7 (CL7) of MRP1, Pro1150Ala, which reduced leukotriene C(4) (LTC(4)) transport but increased 17beta-estradiol 17beta-d-glucuronide (E(2)17betaG) and methotrexate (MTX) transport. Vanadate-induced trapping of [alpha-(32)P]8N(3)ADP by the Pro1150Ala mutant in the absence of substrate was also greatly reduced compared with wild-type MRP1 suggesting an uncoupling of ATP hydrolysis and transport activity. To determine whether the functional importance of MRP1-Pro(1150) is conserved, the analogous Pro(1158) and Pro(1147) residues in the MRP2 and MRP3 transporters, respectively, were mutated to Ala. Expression levels of the three mutants were unaffected; however, the vesicular transport activity of at least one organic anion substrate was significantly altered. As observed for MRP1-Pro1150Ala, LTC(4) transport by MRP2-Pro1158Ala was decreased. However, E(2)17betaG and MTX transport was comparable with that of wild-type MRP2 rather than increased as was observed for MRP1-Pro1150Ala. In the case of MRP3-Pro1147Ala, LTC(4) transport was increased, whereas E(2)17betaG transport was unaffected. MTX transport by MRP3-Pro1147Ala was also increased but to a lesser extent than for MRP1-Pro1150Ala. In contrast, all three mutants showed a marked reduction in levels of vanadate-induced trapped [alpha-(32)P]8N(3)ADP. We conclude that MRP1-Pro(1150), MRP2-Pro(1158), and MRP3-Pro(1147) in CL7 differ in their influence on substrate specificity but share a common role in the nucleotide interactions of these transporters.     

The check-up: in-person, computerized, and telephone adaptations of motivational enhancement treatment to elicit voluntary participation by the contemplator

Countless barriers come between people who are struggling with substance abuse and those charged with providing substance abuse treatment. The check-up, a form of motivational enhancement therapy, is a harm reduction intervention that offers a manner of supporting individuals by lowering specific barriers to reaching those who are untreated. The check-up was originally developed to reach problem drinkers who were neither seeking treatment nor self-initiating change. The intervention, marketed as an opportunity to take stock of one's experiences, involves an assessment and personalized feedback delivered with a counseling style termed motivational interviewing. Check-ups can be offered in care settings to individuals who, as a result of screening, manifest risk factors for specific disorders such as alcoholism. They can also be free-standing and publicized widely to the general public. This paper will discuss illustrations of in-person, computerized, in-school, and telephone applications of the free-standing type of check-up with reference to alcohol consumers, adult and adolescent marijuana smokers, and gay/bisexual males at risk for sexual transmission of HIV. The paper's major focus is to highlight how unique features of each application have the potential of reducing barriers to reaching specific at-risk populations. Also considered are key policy issues such as how check-up services can be funded, which venues are appropriate for the delivery of check-up interventions, pertinent competency criteria in evaluating staff who deliver this intervention, how marketing can be designed to reach contemplators in untreated at-risk populations, and how a check-up's success ought to be defined.     

Nutritional factors as predictors of response to radio-chemotherapy and survival in unresectable squamous head and neck carcinoma

BACKGROUND AND PURPOSE: This study sought to evaluate nutritional prognostic factors before treatment in patients with unresectable head and neck cancer treated by concomitant radio-chemotherapy. METHODS AND MATERIALS: Seventy-two consecutive patients were treated. We studied the potential effects of CRP, Alb, preAlb, orosomucoid, weight, weight history, BMI, PINI, OPR and NRI on response to treatment, Event-Free Survival (EFS) and Overall Survival (OS). Effects of potential risk factors on OS and on EFS were analyzed by computing Kaplan-Meier estimates, and curves were compared using the log-rank test. RESULTS: All biological nutritional factors were statistically correlated with the response to radio-chemotherapy. In multivariate analysis, only CRP (p=0.004) remained statistically significant. A statistical correlation was found between Alb and EFS in multivariate analysis (p=0.04). The factors influencing OS in univariate analysis were Alb (p=0.008), CRP (p=0.004), orosomucoid (p=0.01) and NRI (p=0.01), response to radio-chemotherapy (p<0.001) and staging (p=0.04). In multivariate analysis, only the response to radio-chemotherapy (p<0.001) remained significant. CONCLUSIONS: This study illustrates the prognostic value of nutritional status. CRP and Alb may be useful in the assessment of advanced head and neck cancer patients at diagnosis and for stratifying patients taking part in randomized trials.     

Uric Acid in Pregnancy and Preeclampsia: An Alternative Hypothesis

EDITORIAL COMMENT: This hypothesis that the rise in serum uric acid in patients with preeclampsia is secondary to placental damage rather than alteration in renal function will interest readers. A major problem with the hypothesis is acceptance that raised serum uric acid levels are a feature of normal pregnancy although this was the finding in a careful study recently reported in this Journal (Carter J, Child A. Serum uric acid levels in normal pregnancy. Aust NZ J Obstet Gynaecol 1989; 29: 313–431). This hypothesis could be tested by performing uric acid clearance studies in normal pregnancy and in patients with preeclampsia and relating it to creatinine clearance.     

Intrapartum Cardiotocography and the Expert Witness

Summary: Fetal heart rate changes occur in the majority of labours and correlate poorly with perinatal outcome and subsequent neurological development. Obstetricians giving expert evidence related to the interpretation of intrapartum cardiotocographs are advised to exercise caution when expressing their opinions.     

“Marden-Walker Syndrome”: Neuropathologic Findings in Two Siblings

Neuropathologic examination of two siblings with phenotypic features consistent with Marden-Walker syndrome revealed central nervous system abnormalities which include reduction in the number of spinal anterior horn cells. The occurrence of these changes in a sibling pair provides strong evidence for a genetic etiology. The relationship between the neuropathologic changes and other phenotypic manifestations in this syndrome and in the closely related syndrome of Pena-Shokeir are discussed.     

Pathological Features of Multiple Endocrine Neoplasia Type IIb in Childhood

The features of two patients with multiple endocrine neoplasia type IIb are described. Patient 1, a 9-year-old boy with marfanoid features, presented with chronic constipation and failure to thrive since infancy. Patient 2, a 12-year-old boy with marfanoid features, presented with a five-year history of persistent cervical lymphadenopathy. In patient 1, the myenteric and submucosal nerve plexuses at all levels of the small and large intestines were comprised of diffusely disorganized, hyperplastic, mature ganglion cells and nonmyelinated nerve fibers. Nerve plexus dissection with morphometric analysis showed marked thickening of the myenteric plexus with a quantitative increase in neural tissue. Patient 2 had a submucosal neuroma of the tongue. Both patients had occult medullary thyroid carcinoma, and patient 2 had cervical lymph node metastases. Both neoplasms showed positive staining for cytokeratin, carcinoembryonic antigen, calcitonin, bombesin, chromogranin, serotonin, and Leu 7. Electron microscopy showed membrane-bound, intermediate-sized, dense-core neurosecretory granules in tumor cells. In patient 2, calcitonin-positive amyloid was present with localization of calcitonin by immunoelectron microscopy to cytoplasmic secretory granules and to extracellular amyloid fibrils. These cases illustrate the potential for missed or delayed diagnosis in multiple endocrine neoplasia syndromes.     

Neonatal nosocomial infection at a pediatric resuscitation and intensive care unit

During 1989, a nosocomial infection rate of 3.15% was observed among the 412 neonates hospitalised for more than 2 days in the paediatric intensive care unit and a special care baby unit in the medical centre of Nice. Certain factors only partially explain the above, and it is probable that the non-invasive methods of monitoring and care and the experienced nursing staff contribute to a great extent to this low frequency of infection.     

Current therapeutic indications in laryngeal stenoses in children]

Among pediatric patients with laryngeal stenosis, acquired forms are now more common than congenital forms. External surgery is not always warranted except in complete or tight obstructions. After establishing the diagnosis by endoscopy, consequences on respiration and phonation should be assessed before deciding on the most appropriate treatment: abstention, medical therapy, endoscopic treatment, or surgical treatment by the cervical route. Surgical laryngoplasty techniques have changed radically over the last twenty years. The Cotton procedure is the most widely used. Another available method is the cricoid-split technique. These laryngoplasty procedures can be performed from birth and tracheostomy is now warranted only after failure of initial surgery.