Changes in blood lipids and their associations with changes in measures of height, weight and body mass index from age 8 to 18 years: Project Heartbeat!

A variety of studies indicate that the process of athrosclerosis begins in childhood. There was limited information on the association of the changes in anthropometric variables to blood lipids in school age children and adolescents. Previous longitudinal studies of children typically with insufficient frequency of observation could not provide sound inference on the dynamics of change in blood lipids. The aims of this analysis are (1) to document the sex- and ethnic-specific trajectory and velocity curves of blood lipids (TC, LDL-C, HDL-C and TG); (2) to evaluate the relationship of changes in anthropometric variables, such as height, weight and BMI, to blood lipids from age 8 to 18 years. ^ Project HeartBeat! is a longitudinal study designed to examine the patterns of serial change in major cardiovascular risk factors. Cohort of three different age levels, 8, 11 and 14 years at baseline, with a total of 678 participants were enrolled. Each member of these cohorts was examined three times per year for up to four years. ^ Sex- and ethnic-specific trajectory and velocity curves of blood lipids; demonstrated the complex and polyphasic changes in TC, LDL-C, HDL-C and TG longitudinally. The trajectory curves of TC, LDL-C and HDL-C with age showed curvilinear patterns of change. The velocity change in TC, HDL-C and LDL-C showed U-shaped curves for non-Blacks, and nearly linear lines in velocity of TG for both Blacks and non-Blacks. ^ The relationship of changes in anthropometric variables to blood lipids was evaulated by adding height, weight, or BMI and associated interaction terms separately to the basic age-sex models. Height or height gain had a significant negative association with changes in TC, LDL-C and HDL-C. Weight or BMI gain showed positive associations with TC, LDL-C and TC, and a negative relationship with HDL-C. ^ Dynamic changes of blood lipids in school age children and adolescents observed from this analysis suggested that using fixed screening criteria under the current NCEP guidelines for all ages 2–19 may not be appropriate for this age group. The association of increasing BMI or weight to an adverse blood lipid profile found in this analysis also indicated that weight or BMI monitoring could be a future intervention to be implemented in the pediatric population. ^

The development and characterization of two types of chronic responses in irradiated mouse colon

The hypothesis to be tested is that there are two distinct types of chronic responses in irradiated normal tissues, each resulting from damage to different cell populations in the tissue. The first is a sequala of chronic epithelial depletion in which the tissue's integrity cannot be maintained, i.e. a "consequential" chronic response. The other response is due to cell loss in the connective tissue and/or vascular stroma, i.e. a "primary" chronic response. The purpose of this study was to test the hypothesis in the murine colon by first, establishing a model of each chronic response and then, by determining whether the responses differed in timing of expression, histology, and expression of specific collagen types. The model of late damage used was colonic obstructions/strictures induced by a single dose of 27 Gy ("consequential" response) and two equal doses of 14.75 Gy (t = 10 days) ("primary" response). "Consequential" lesions appeared as early as 5 weeks after 27 Gy and were characterized by a deep mucosal ulceration and a thickened fibrotic serosa containing excessive accumulations of collagen types I and III. Both types were commingled in the scar at the base of the ulcer. Fibroblasts were synthesizing pro-collagen types I and III mRNA 10 weeks prior to measurable increases in collagen. A significant decrease in the ratio of collagen types I:III was associated with the "consequential" response at 4-5 months post-irradiation. The "primary" response, on the other hand, did not appear until 40 weeks after the split dose even though the total dose delivered was approximately the same as that for the "consequential" response. The "primary" response was characterized with an intact mucosa and a thickened fibrotic submucosa which contained excessive amounts of only collagen type I. An increased number of fibroblasts were synthesizing pro-collagen type I mRNA nearly 25 weeks before collagen type I levels were increased. The "primary" response lesion had a significantly elevated collagen type I:III ratio at 10-13 months post-irradiation. These data show a clear difference between the two chronic response and suggest that not all chronic responses share a common pathogenesis, but depend on the cell population in the tissue that is damaged. ^

Strange bedfellows: The ethics and politics of medical futility in Texas

Background: Futile medical treatments are interventions that are not associated with a benefit to the patient. The definition and concept of medical futility are controversial. The Texas Advance Directives Act (TADA) was passed in 1999 to address medically inappropriate interventions by allowing providers to withdraw inappropriate interventions against a surrogate decision maker's wishes following a review, attempt to transfer the patient, and 10-day waiting period. The original legislation was a negotiated compromise by players across the political spectrum. However, in recent years there has been increasing controversy regarding TADA and attempts to alter its applicability in Texas. ^ Purpose: The purpose of this project was to apply Paul Sabatier's advocacy coalition framework (ACF) to gain understanding into the historical, ethical, and political basis of the initial compromise, and determine the sources of conflict that have led to increased opposition to TADA. ^ Methods: Using the ACF model, key actors within the medical futility policy debate in Texas were aggregated into coalitions based on shared beliefs. A narrative summary based analysis identified the core elements of the policy subsystem, as well as the constraints and resources of the subsystem actors. Externalities that promoted adjustments to coalition beliefs and tactics used by coalition participants were analyzed. Data sources included review of the published literature regarding medical futility, as well as analysis of published newspaper accounts and editorials regarding the medical futility issue in Texas, legislative testimony, and review of weblogs and online commentaries dealing with the issue. ^ Results: Primary coalition participants in developing compromise legislation in 1999 were the Providers and Vitalists, with Autonomists gaining a prominent role starting in 2006. Internal factors associated with the breakdown of consensus included changes to the makeup of the governing coalition and changes in individual case information available to the Vitalist coalition. Externalities related to the intertwining of the Sun Hudson case and the Terri Schiavo case generated negative publicity for the TADA from progressive and conservative viewpoints. Dissemination of information in various venues regarding contentious cases was associated with more polarization of viewpoints, and realignment of coalition alliances. ^ Conclusions: The ACF provided an outline for the initial compromise over the creation of the Texas Advance Directives Act as well as the eventual loss of consensus. The debate between the Provider, Vitalist, and Autonomist coalitions has been affected by internal policy evolution, changes in the governing coalition, and important externalities. The debate over medical futility in Texas has had much broader implications in the dispute over Health Care Reform.^

Study on the effect of metformin in patients of metastatic renal cell cancer with diabetes receiving tyrosine kinase inhibitor therapy

Objective: The primary objective of our study was to study the effect of metformin in patients of metastatic renal cell cancer (mRCC) and diabetes who are on treatment with frontline therapy of tyrosine kinase inhibitors. The effect of therapy was described in terms of overall survival and progression free survival. Comparisons were made between group of patients receiving metformin versus group of patients receiving insulin in diabetic patients of metastatic renal cancer on frontline therapy. Exploratory analyses were also done comparing non-diabetic patients of metastatic renal cell cancer receiving frontline therapy compared to diabetic patients of metastatic renal cell cancer receiving metformin therapy. ^ Methods: The study design is a retrospective case series to elaborate the response rate of frontline therapy in combination with metformin for mRCC patients with type 2 diabetes mellitus. The cohort was selected from a database, which was generated for assessing the effect of tyrosine kinase inhibitor therapy associated hypertension in metastatic renal cell cancer at MD Anderson Cancer Center. Patients who had been started on frontline therapy for metastatic renal cell carcinoma from all ethnic and racial backgrounds were selected for the study. The exclusion criteria would be of patients who took frontline therapy for less than 3 months or were lost to follow-up. Our exposure variable was treatment with metformin, which comprised of patients who took metformin for the treatment of type 2 diabetes at any time of diagnosis of metastatic renal cell carcinoma. The outcomes assessed were last available follow-up or date of death for the overall survival and date of progression of disease from their radiological reports for time to progression. The response rates were compared by covariates that are known to be strongly associated with renal cell cancer. ^ Results: For our primary analyses between the insulin and metformin group, there were 82 patients, out of which 50 took insulin therapy and 32 took metformin therapy for type 2 diabetes. For our exploratory analysis, we compared 32 diabetic patients on metformin to 146 non-diabetic patients, not on metformin. Baseline characteristics were compared among the population. The time from the start of treatment until the date of progression of renal cell cancer and date of death or last follow-up were estimated for survival analysis. ^ In our primary analyses, there was a significant difference in the time to progression of patients receiving metformin therapy vs insulin therapy, which was also seen in our exploratory analyses. The median time to progression in primary analyses was 1259 days (95% CI: 659-1832 days) in patients on metformin therapy compared to 540 days (95% CI: 350-894) in patients who were receiving insulin therapy (p=0.024). The median time to progression in exploratory analyses was 1259 days (95% CI: 659-1832 days) in patients on metformin therapy compared to 279 days (95% CI: 202-372 days) in non-diabetic group (p-value <0.0001). ^ The median overall survival was 1004 days in metformin group (95% CI: 761-1212 days) compared to 816 days (95%CI: 558-1405 days) in insulin group (p-value<0.91). For the exploratory analyses, the median overall survival was 1004 days in metformin group (95% CI: 761-1212 days) compared to 766 days (95%CI: 649-965 days) in the non-diabetic group (p-value<0.78). Metformin was observed to increase the progression free survival in both the primary and exploratory analyses (HR=0.52 in metformin Vs insulin group and HR=0.36 in metformin Vs non-diabetic group, respectively). ^ Conclusion: In laboratory studies and a few clinical studies metformin has been proven to have dual benefits in patients suffering from cancer and type 2-diabetes via its action on the mammalian target of Rapamycin pathway and effect in decreasing blood sugar by increasing the sensitivity of the insulin receptors to insulin. Several studies in breast cancer patients have documented a beneficial effect (quantified by pathological remission of cancer) of metformin use in patients taking treatment for breast cancer therapy. Combination of metformin therapy in patients taking frontline therapy for renal cell cancer may provide a significant benefit in prolonging the overall survival in patients with metastatic renal cell cancer and diabetes. ^

Molecular mechanisms involved in the regulation of cell polarity and genome stability by the p21 -activated kinase, Shk1, in the fission yeast, Schizosaccharomyces pombe

The essential p21-activated kinase (PAK), Shk1, is a critical component of a Ras/Cdc42/PAK complex required for cell viability, normal cell polarity, proper regulation of cytoskeletal dynamics, and sexual differentiation in the fission yeast, Schizosaccharomyces pombe. While cellular functions of PAKs have been described in eukaryotes from yeasts to mammals, the molecular mechanisms of PAK regulation and function are poorly understood. This study has characterized a novel Shk1 inhibitor, Skb15, and, in addition, identified the cell polarity regulator, Tea1, as a potential biological substrate of Shk1 in S. pombe. Skb15 is a highly conserved WD repeat protein that was discovered from a two-hybrid screen for proteins that interact with the catalytic domain of Shk1. Molecular data indicate that Skb15 negatively regulates Shk1 kinase activity in S. pombe cells. A null mutation in the skb15 gene is lethal and results in deregulation of actin polymerization and localization, microtubule biogenesis, and the cytokinetic machinery, as well as a substantial uncoupling of these processes from the cell cycle. Loss of Skb15 function is suppressed by partial loss of Shk1, demonstrating that negative regulation of Shk1 by Skb15 is required for proper execution of cytoskeletal remodeling and cytokinetic functions. A mouse homolog of Skb15 can substitute for its counterpart in fission yeast, demonstrating that Skb15 protein function has been substantially conserved through evolution. ^ Our laboratory has recently demonstrated that Shk1, in addition to regulating actin cytoskeletal organization, is required for proper regulation of microtubule dynamics in S. pombe cells. The Shk1 protein localizes to interphase and mitotic microtubules, the septum-forming region, and cell ends. This pattern of localization overlaps with that of the cell polarity regulator, Tea1, in S. pombe cells. The tea1 gene was identified by Paul Nurse's laboratory from a screen for genes involved in the control of cell morphogenesis in S. pombe. In contrast to wild type S. pombe cells, which are rod shaped, tea1 null cells are often bent and/or branched in shape. The Tea1 protein localizes to the cell ends, like Shk1, and the growing tips of interphase microtubules. Thus, experiments were performed to investigate whether Tea1 interacts with Shk1. The tea1 null mutation strongly suppresses the loss of function of Skb15, an essential inhibitor of Shk1 function. All defects associated with the skb15 mutation, including defects in F-actin organization, septation, spindle elongation, and chromosome segregation, are suppressed by tea1Δ, suggesting that Tea1 may function in these diverse processes. Consistent with a role for Tea1 in cytokinesis, tea1Δ cells have a modest cell separation defect that is greatly exacerbated by a shk1 mutation and, like Shk1, Tea1 localizes to the septation site. Molecular analyses showed that Tea1 phosphorylation is significantly dependent on Shk1 function in vivo and that bacterially expressed Tea1 protein is directly phosphorylated by recombinant Shk1 kinase in vitro. Taken together, these results identify Tea1 as a potential biological substrate of Shk1 in S. pombe. ^ In summary, this study provides new insights into a conserved regulatory mechanism for PAKs, and also begins to uncover the molecular mechanisms by which the Ras/Cdc42/PAK complex regulates the microtubule and actin cytoskeletons and cell growth polarization in fission yeast. ^

The Rise and Fall of the Doctor-Patient Relationship

This talk will outline the history of the doctor-patient relationship in the West. It will touch briefly on medicine in Greek and Roman antiquity, using key texts from Hippocrates and Galen. It will also sketch the changing balance of the religious and the secular in medieval medicine. Finally, it will outline the rise of the modern personal doctor-patient relationship in the 18th century and analyze the chronic dissatisfaction that settled over relations between doctors and patients in the last quarter of the 20th century.