Use of the Dowell Bryant Incontinence Cost Index as a post-treatment outcome measure after non-surgical therapy.

The aim of this study was to use the previously validated Dowell Bryant Incontinence Cost Index (DBICI) as a post-treatment outcome measure after non-surgical therapy and to determine whether the magnitude of reduced leakage would correlate with the magnitude of reduced personal cost. A simple urethral occlusive device (Femassist) was employed in 57 women with stress, urge, or mixed incontinence for 1 month. The DBICI was administered at baseline and after device use, along with a visual analogue scale (VAS) for severity of incontinence impact, a 3-day frequency volume chart (FVC) that documented leaks per 24 hours and pad usage, a 1-hour ICS pad test at standard volume, and two disease-specific quality of life measures (Urogenital Distress Inventory [UDI] and Incontinence Impact Questionnaire [IIQ]). The severity of leakage was significantly reduced on all parameters, and the median personal costs of incontinence fell from AU$6.52 per week (IQR 1.50-10.59) to a median of AU$ 1.57 per week (IQR 0-4.89). A significant correlation (Kendall's rank, tau) was observed between reduction in personal costs and reduction in VAS (tau = 0.24, P= 0.01), leaks/day (tau = 0.20, P = 0.03), pad test loss (tau = 0.29, P = 0.002), and quality of life scores (UDI, tau = 0.23, P = 0.01; IIQ, tau = 0.26, P = 0.005). The personal costs subset of the DBICI appears to be a useful outcome measure for urinary incontinence research and could be widely employed to assess the impact of continence treatments on the patient's economic burden.

Competence in early adult romantic relationships: a developmental perspective on family influences.

The present prospective, longitudinal study of 193 young adults (85 men, 108 women, M = 20.7 years old) and their partners in ongoing romantic relationships in 1997 was initiated in 1989, when the 193 target youths were in the 7th grade. On the basis of the model for the development of early adult romantic relationships (DEARR; C. Bryant & R. D. Conger, in press), the authors hypothesized that interactional processes in the family of origin would predict interpersonal skills by the target youths, which would be positively related to the early adult couple's relationship quality. Observational ratings showed that nurturant-involved parenting in the family of origin predicted behaviors by the target youth to a romantic partner that were warm, supportive, and low in hostility. These competent behaviors of the target youth were positively associated with relationship quality for the early adult couple and also mediated or explained the connection between parenting and relationship quality.

A combinatorial approach to the identification of dipeptide aldehyde inhibitors of beta-amyloid production.

In an effort to rapidly identify potent inhibitors of Abeta production and to probe the amino acid sequence specificity of the protease(s) responsible for the production of this peptide, a large number of dipeptide aldehydes were combinatorially synthesized and manually evaluated for their inhibitory properties. The starting point for this study was the dipeptide aldehyde carbobenzoxyl-valinyl-phenylalanal previously shown to inhibit the production of Abeta in CHO cells stably transfected with the cDNA encoding betaAPP695. Pools of related dipeptide aldehydes were combinatorially synthesized, and the most active pool was deconvoluted, resulting in the identification of the most active inhibitor of this pool. Systematic optimization of this inhibitor resulted in a series of dipeptide aldehydes with enhanced potencies relative to carbobenzoxyl-valinyl-phenylalanal. The most active dipeptide aldehydes were those that possessed hydrophobic amino acids at both the P1 and P2 positions. The most potent compound identified in this study was 3, 5-dimethoxycinnamamide-isoleucinyl-leucinal with an IC(50) of 9.6 microM, approximately 10-fold more active than carbobenzoxyl-valinyl-phenylalanal. In immunoprecipitation experiments using antibodies directed toward either Abeta1-40 or Abeta1-42, 3,5-dimethoxycinnamamide-isoleucinyl-leucinal, like carbobenzoxyl-valinyl-phenylalanal, preferentially inhibited the shorter 1-40 form of Abeta, whereas the longer 1-42 form was not as strongly inhibited. These results suggest that dipeptide aldehydes related to carbobenzoxyl-valinyl-phenylalanal inhibit Abeta through similar mechanisms and demonstrate the utility of a combinatorial synthesis approach to rapidly identify potent inhibitors of Abeta production.

Calculating the direct costs of urinary incontinence: a new test instrument.

OBJECTIVES: To develop a universally applicable test instrument to measure the total direct costs of urinary incontinence, including personal costs and treatment costs, i.e. the Dowell-Bryant Incontinence Cost Index (DBICI), and to study the construct validity and test-retest reliability of the instrument. PATIENTS AND METHODS: In a prospective observational study, 100 consecutive community-dwelling ambulatory women who presented with stress, urge or mixed incontinence were asked to complete the DBICI questionnaire on two occasions, 7 days apart, before any treatment. The construct validity of the DBICI was ascertained by correlation with other standard measures of urinary incontinence severity; (i) a visual analogue scale (VAS) to assess the impact of leakage upon lifestyle; (ii) frequency-volume charts (voids/24 h, leaks/week); (iii) urine loss during a standard 1 h pad test; and (iv) two disease-specific quality of life questionnaires. The test-retest reliability was measured by comparing the two test results and the construct validity of the individual subsets (personal and treatment) of the DBICI similarly assessed. RESULTS: Ninety-seven women completed the baseline assessment and 84 completed the re-test. The median (interquartile range) total direct incontinence cost (in Au$) was 12. 89 (5.26-22.67) per week, which comprised the median personal costs of 5.61 (1.68-10.36) and the median treatment costs of 4.96 (1.22-13. 37). The total direct incontinence cost was significantly correlated with the severity of urinary leakage on a 1 h pad test (Kendall's rank correlation, P=0.01), with the VAS impact score (P<0.001) and with the number of leaks/week (P=0.005). The correlation between the personal cost subset and other quantitative measures was also highly significant. Test-retest analysis of the personal costs subset revealed that this subset was robust and satisfied the statistical criteria of repeatability. CONCLUSIONS: The DBICI gives a detailed measure of the direct economic costs of urinary incontinence in ambulatory home-dwelling women, with the construct validity confirmed by the significant correlation with other quantitative measures of incontinence. By substituting local prices into the test format, the index should be useful in other countries. In the current climate of economic rationalization, such an index should be a part of future urinary incontinence research.

Novel anti-inflammatory compounds induce shedding of L-selectin and block primary capture of neutrophils under flow conditions.

Leumedins are small molecules that inhibit neutrophil movement into inflamed tissues. These compounds have been shown to inhibit the adherence of neutrophils in static adhesion assays mediated by beta2-integrins. We now report that leumedins, like activating agents, induce the loss of L-selectin from the neutrophil surface. The loss of L-selectin is unrelated to the inhibition of static adhesion, since neutrophils that have been pretreated with leumedins to cause shedding of L-selectin, followed by removal of drug, adhere normally in a static adhesion assay, and this adhesion is inhibited upon readdition of leumedin. In an assay of adhesion to endothelial cells under conditions of physiologic wall shear stress, leumedins prevent both primary capture of neutrophils mediated by L-selectin and firm adherence mediated by beta2-integrins.

Novel anti-inflammatory compounds prevent CD11b/CD18, alpha M beta 2 (Mac-1)-dependent neutrophil adhesion without blocking activation-induced changes in Mac-1.

Leumedins are small organic molecules with anti-inflammatory properties in vivo. We report here that leumedins inhibit the CD11b/CD18 alpha M beta 2 (Mac-1)-dependent adherence of neutrophils to serum proteins. The activation of neutrophils leading to adherence via Mac-1 is associated with an increase in cell surface Mac-1 level, and with an increased affinity of Mac-1 for adhesion partners. Inhibition of neutrophil adherence by leumedins does not require blocking the recruitment of Mac-1 from intracellular granules to the cell surface. Furthermore, leumedins do not block the expression on Mac-1 of the epitope for an "activation-specific" antibody (CBRM1/5). Time course studies show that leumedins inhibit adherence by targeting an event which occurs concurrently with changes in Mac-1 level and induction of the CBRM1/5 epitope. Therefore, leumedins block an unknown process which is permissive for Mac-1-dependent adherence.

Fluorenylalkanoic and benzoic acids as novel inhibitors of cell adhesion processes in leukocytes.

A series of fluoren-9-ylalkanoic and alkylbenzoic acids was prepared as simplified analogues of a previously reported series of antiinflammatory agents which act to inhibit neutrophil recruitment into inflamed tissue. The previous compounds ("leumedins") contained (alkoxycarbonyl)amino or benzoic acid moieties tethered to a fluorene ring. This functionality was replaced with simple structural elements. The new compounds were, in general, found to be more potent than the earlier series at inhibiting adherence of neutrophils to serum-coated wells or endothelial cells in vitro. Compound 9 was approximately 10-fold more potent than the previously reported FMOC-phenylalanine, of which it is an analogue. Similarly, compound 19 was superior in potency to its first generation progenitor, NPC 16570. The new compounds were shown to inhibit neutrophil adherence under conditions in which adherence is mediated by Mac-1 (CD11b/CD18) and LFA-1 (CD11a/CD18); they thus appear to target beta 2-integrins in their antiadhesion activity. These compounds provide a departure point for the further development of new cell adhesion inhibitors which should exhibit enhanced potency and a more selective mode of action.

CD36 is a receptor for oxidized low density lipoprotein.

The oxidation of low density lipoprotein (LDL) in the arterial wall is thought to contribute to human atherosclerotic lesion formation, in part by the high affinity uptake of oxidized LDL (OxLDL) by macrophages, resulting in foam cell formation. We have utilized cloning by expression to identify CD36 as a macrophage receptor for OxLDL. Transfection of a CD36 clone into 293 cells results in the specific and high affinity binding of OxLDL, followed by its internalization and degradation. An anti-CD36 antibody blocks 50% of the binding of OxLDL to platelets and to human macrophage-like THP cells. Furthermore, like mouse macrophages, 293 cells expressing CD36 recognize LDL which has been oxidized only 4 h, whereas more extensive oxidation of the LDL is required for recognition by the other known OxLDL receptors, the acetylated LDL (AcLDL) receptor and Fc gamma RII-B2. CD36 may play a role in scavenging LDL modified by oxidation and may mediate effects of OxLDL on monocytes and platelets in atherosclerotic lesions.

A macrophage Fc receptor for IgG is also a receptor for oxidized low density lipoprotein.

The internalization of oxidized low density lipoprotein (OxLDL) by macrophages is hypothesized to contribute to foam cell formation and eventually to atherosclerotic lesion formation. OxLDL is a ligand for the acetylated low density lipoprotein (AcLDL) receptor, however, our data show that this receptor accounts for less than half of OxLDL uptake by mouse macrophages, suggesting additional receptors for OxLDL. We have developed a novel expression cloning strategy in order to isolate clones encoding OxLDL receptors. In addition to the AcLDL receptor, we isolated a molecular clone for a structurally unrelated receptor capable of mediating the high affinity uptake of OxLDL following transfection into cells. This receptor has been identified as the mouse Fc gamma RII-B2, a member of a family of receptors known to mediate immune complex uptake through recognition of the Fc region of IgG. The uptake of OxLDL by cells transfected with the Fc gamma RII-B2 clone is not blocked by AcLDL but is blocked by the anti-Fc gamma RII monoclonal antibody, 2.4G2.