Self-care behaviors in a primarily low SES sample of children with Insulin-dependent Diabetes Mellitus (IDDM; N = 41) from Puerto Rico were examined using the 24-hour recall interview (Johnson, Silverstein, Rosenbloom, Carter, & Cunningham, 1986). Children (6-17 years of age) and their mothers were interviewed independently on three separate occasions concerning daily self-care behaviors. Measures of 11 different adherence behaviors were constructed based on information obtained from the interviews. Results indicated that children from Puerto Rico came close to achieving many of the self-care guidelines recommended by the American Diabetes Association (ADA). For example, they consumed 29% of their daily calories from fat and 52% from carbohydrates, achieving the ideal for fat intake and approaching the ideal for carbohydrate intake recommended by the ADA. In contrast, Puerto Rican children exercised approximately 18 minutes once a day, indicating great difficulty attaining ADA recommended exercise goals of six times daily for approximately 30 minutes each time. Children from Puerto Rico took their insulin 7.4 minutes before eating, much later than recommended by the ADA (30-60 minutes before meal). In comparison to a sample of children from the United States, Puerto Rican children displayed better self-care behaviors for blood glucose testing frequency, eating frequency, ideal percentage of calories from fat, and ideal percentage of calories from carbohydrates. In contrast, the U.S. sample of children exercised more frequently and for longer periods of time on average than did children from Puerto Rico. Results indicated that parent-child agreement for the Puerto Rican sample was strong for 8 of the 11 measures, similar to previous research (Johnson, et al., 1986). Predictors of self-care behavior in the Puerto Rican sample indicated that child gender and disease duration significantly predicted different self-care behaviors, but age did not, contrary to the literature. Overall, this study provided a description of diabetes self-care behaviors in a primarily low SES sample of children from Puerto Rico. Children appeared to meet most of the ADA recommendations, indicating that despite poor economic conditions in Puerto Rico and the overburdened health care system, the sample of children in this study engaged in relatively good self-care / acase@tulane.edu

Historians studying healing in the seventeenth century have concluded that there was no formalized medical profession in that century 1, yet by the end of the eighteenth century, a new standard caregiver of the sick had taken hold: the university-educated physician.2 This new breed was more educated, respected, and autonomous than healers of past centuries. Although the rise of the profession of medicine and the medical man has been well documented, historians have not explained why people increasingly enlisted the services of licensed practitioners. This dissertation will examine one crucial but under-analyzed aspect of illness and its treatment: the moral dimension, to argue that religious attitudes and beliefs played a vital role in society's conception of illness and the options available to alleviate suffering In early modern England, bodily health and the health of one's soul were inexorably entwined. It was therefore imperative that physicians be seen as capable of caring for both in order to be trusted with the whole health of the individual. Their ability to embrace the nexus of physical and spiritual health is what began to set the learned physician apart from all other types of healers over the course of the seventeenth century. They were able to combine the legacy of their university training with an emerging sense that their skills were ordained by God to cure disease, particularly those considered punishment for sin, in order to present themselves as protectors of a bodily health that was dependent on both physical and spiritual wellness In a society in which disease was largely interpreted in terms of moral agency, and the physical and spiritual world were so intimately connected, the responsibility of caring for the entire patient, both body and soul, was a matter of public trust. To assume such trust required the highest degree of moral authority, a trait which physicians argued was connected to being learned. Their ability to convince the public of their moral authority is what ultimately proved to be their most powerful weapon against lay and popular healers at a time when there were so many other viable options for health care 1Margaret Pelling, The Common Lot: Sickness, Medical Occupations and the Urban Poor in Early Modern England (New York: Longman, 1998), 244. Similar notions have been expressed by Roy Porter and Dorothy Porter, In Sickness and in Health: The British Experience 1650-1850 (London: Fourth Estate, 1988) and Lucinda Beier, 'In Sickness and in Health: A Seventeenth Century Family's Experience,' in Patients and Practitioners: Lay Perceptions of Medicine in Pre-Industrial Society, ed. Roy Porter (Cambridge: Cambridge University Press, 1985), 4-5. 2The group of medical men upon which this dissertation focuses are those who were considered in the seventeenth century to be 'learned physicians,' meaning they had earned university degrees in medicine, either in England or on the Continent. Such individuals were a fairly new group in England, the product of what Harold Cook has termed the intellectual and educational changes of the late fifteenth and sixteenth centuries. They are not necessarily fellows, licentiates, or even extra-licentiates of the College of Physicians, as this would restrict the group to a scant number. They are, moreover, individuals who considered themselves to be medical professionals, rather than those who merely dabbled in or 'topped off' their salaries through medicine / acase@tulane.edu

Decompression Sickness (DCS) is caused by a change in atmospheric pressure, as is experienced by scuba divers. This illness has gone from a small, predominately military existence into the larger civilian population as scuba diving continues to grow in popularity. The treatment for DCS is recompression in a hyperbaric chamber with oxygen (HBO). However, over a third of recreational divers treated for DCS report residual symptoms after treatment is complete. Although there have been numerous studies on the type of treatment in a hyperbaric chamber as well as the effects of delay to recompression on the treatment outcome, the effect of presenting symptoms of DCS on the outcome of HBO is not well understood. This study examined potential relationships between presenting symptoms of DCS and the final outcome post-complete HBO therapy Data were obtained from Divers Alert Network, which collects comprehensive data on U.S. recreational diving injuries. Among the 3,437 reported cases of DCS treated in HBO chambers from 1987--1995, 43.8% had residual symptoms after HBO. Approximately three-fourths of the cases were men. Due to possible confounding, analysis was stratified by gender Logistic and polytomous regression were used to predict residual symptoms after HBO. Controlling for age and delay from symptom onset to time of treatment, experiencing a bladder problem was highly associated with residuals post-HBO where persons with bladder problems were 5 times more likely to have residuals than those without the symptom Final models predicting residuals indicated that numbness/tingling [OR 1.74 (95% CI = 1.30, 2.33)] and muscle twitching [OR = 3.27 (95% CI = 1.51, 7.04)] were prognostic for women whereas difficulty walking/standing [OR 2.17 (95% CI = 1.565, 3.01)] and visual disturbance [OR = 2.47 (95% CI = 1.47, 4.15)] were prognostic for men. Predicted sensitivity of prognostic models ranged from 66 percent to 73 percent The results of this study found individual predictors to be of limited use in the clinical setting, as with these models, 30 percent of the time, cases with residuals were unexplained (unpredicted). This study did find that women and men appear to have different presenting symptoms of DCS and different predictive symptoms of residuals. This study should be generalizable to similar U.S. recreational divers / acase@tulane.edu

Megalin and the Angiotensin type 1 receptor (AT1R) are coexpressed in several polarized epithelia including the renal proximal tubule and the yolk sac where megalin is heavily involved in receptor-mediated protein endocytosis. Because angiotensin II uptake by proximal tubule cells and yolk sac cells was only partially inhibited by AT1R specific blockers, we tested to see if megalin interacts with angiotensin peptides. Angiotensin II and Angiotensin-(1-7) were chosen on the basis of their physiological relevance and their dissimilar affinity for the AT1R. Cell experiments were conducted on several proximal tubule cell lines (HRCEs, IRPPT cells and NRK-52E cells) and BN/MSV cells. Uptake experiments were performed in cell monolayers exposed to fluorescent-labeled angiotensin II or angiotensin-(1-7) +/- different competitors, and the amount of cell-associated fluorescence (an indication of internalized angiotensin) was determined by flow cytometry. Anti-megalin antisera and AT1R blockers (olmesartan or candesartan) were used to interfere with uptake via megalin and the AT1R respectively. Anti-megalin antisera universally interfered with angiotensin II uptake by proximal tubule and BN/MSV cells, but the degree of reduction was cell type-dependent (ranging from 80 to 30% in reduction, p < 0.05 in all cases vs. positive control). Angiotensin-(1-7) uptake by BN/MSV cells was also prevented by anti-megalin antisera (63%, p < 0.001). Angiotensin II interfered with uptake of metallothionein (a known ligand for megalin) by BN/MSV cells. Flow cytometry analysis of binding experiments performed in brush border membrane vesicles freshly isolated from kidney cortices of CD-1 mice showed that anti-megalin antisera interfered with angiotensin II and Angiotensin-(1-7) binding (27% and 30% respectively, p < 0.05 vs. positive control). Molecular interactions of megalin with angiotensin II and angiotensin-(1-7) were studied by surface plasmon resonance. Angiotensin II and angiotensin-(1-7) bind megalin dose and time-dependently and with a similar affinity (&sim;3 mM). Collectively, the data from these studies demonstrate that megalin binds and internalizes angiotensin II and angiotensin-(1-7). These results also indicate that angiotensin II or angiotensin-(1-7) internalization in the proximal tubule might be megalin-dependent and that the scavenger receptor megalin may play a role in regulating proximal tubule and therefore intrarenal angiotensin peptide levels / acase@tulane.edu

The purpose of this study was to determine whether pregnancy is associated with an acceleration of HIV disease progression in women who have a pregnancy while HIV-infected. A retrospective review of all women fifteen to thirty-five years of age who attended an HIV outpatient program from January 1989 through August 1995 was undertaken. The 192 women who had a term pregnancy after testing positive for HIV were compared to 164 women who were not pregnant during the same period. In addition, disease progression in the 45 women who had a CD4 count available before their pregnancy and 45 non-pregnant women matched on CD4 count at entry was compared. The main outcome measures were death, the occurrence of a first AIDS defining condition, or a condition indicative of symptomatic HIV. Disease progression was assessed using the Kaplan-Meier method and multivariate proportional hazards models The median follow-up in the cohort and matched analysis was 32 and 46 months respectively. Women with a term pregnancy were significantly more likely to be African-American (88% vs 78%, p $<$.05), younger than 22 years of age (51% vs 11%, p$<$.001), and to have entered the clinic with a higher median CD4 count (519 vs 433 cells/$\mu$l, p $<$.001). After adjusting for entry CD4 count, age, and anti-retroviral use, pregnancy was not associated with progression to symptomatic HIV (RR = 0.9, 0.6-1.3), AIDS (RR = 1.1, 0.6-2.0), or death (RR = 0.6, 0.3-1.3). In the matched analysis adjusting for demographic differences, there was also no significant increase in risk of progression to symptomatic HIV (RR = 1.6, 0.7-4.0), AIDS (RR = 1.3, 0.4-4.1), or death (RR = 1.0, 0.3-3.6). A CD4 count below 200 cells/$\mu$l and an AIDS defining condition at entry were predictive of death; a low CD4 count was also associated with progression to symptomatic HIV and AIDS. A repeated measures analysis of CD4 count in the year following pregnancy found a trend towards an increase in CD4 count in the pregnant women as compared to the non-pregnant women Pregnancy does not appear to accelerate the progression of HIV disease in women attending a publicly funded clinic / acase@tulane.edu

Objectives. To investigate the association between HPV infection, cervical dysplasia (CD) and progression of HIV Methods. All eligible adult and adolescent women attending a public HIV outpatient clinic from January 1990 to October 1994 were followed. Demographic and clinical information was abstracted from the medical records. The Kaplan-Meier product limit and Cox proportional hazards model were utilized to evaluate the association between HPV infection at entry into the cohort, ever evidence of HPV infection, and CD on progression of HIV. Two distinct models were used; time to death and time to AIDS Results. (1) Time to death: After adjusting for CD4 counts, pneumocystis carinni pneumonia (PCP) prophylaxis and age, women with CD were 1.8 times more likely to die (95% CI = 0.9, 3.5), women with HPV at entry were 3.3 times more likely to die (95% CI = 1.4, 8.3), and women ever diagnosed with HPV were 1.6 times more likely to die (95% CI = 0.8, 3.3). In the Cox analysis, there was no consistent association between HPV infection, CD and survival. (2) Time to AIDS: After adjusting for CD4 counts, PCP prophylaxis and age, women with CD were 2.1 times more likely to develop AIDS (95% CI = 1.4, 4.7), women with HPV at entry were 4.2 times more likely to develop AIDS (95% CI = 1.6, 10.9), and women ever diagnosed with HPV were 2.5 times more likely to develop AIDS (95% CI = 1.3, 5.0). In the Cox analysis, women with CD (HR 1.7, 95% CI = 1.0, 2.8), HPV at entry (HR 2.4, 95% CI = 1.2, 4.6), and ever HPV infection (HR 1.6, 95% CI = 0.9, 2.8) progressed to AIDS more rapidly Conclusion. Evidence of HPV infection and SIL in women with HIV appears to be associated with progression time to AIDS but not death / acase@tulane.edu

Arylsulfatase A (ASA) is a lysosomal enzyme whose primary physiological function is desulfation of cerebroside sulfate. Deficiency of ASA leads to metachromatic leukodystrophy (MLD) with different ages of onset. Some healthy individuals also show low ASA activity which is sometimes indistinguishable from that in MLD patients. These so-called ASA pseudodeficient (PD) individuals bring complications to the diagnosis of MLD. This dissertation attempts to establish a model to study the relationships between genotype and phenotype for the PD individuals and MLD patients with different ages of onset Mutations were identified in the ASA-deficient variants using the direct solid-phase sequencing method. These base changes lead to amino acid alterations. Three novel mutations were confirmed by restriction analyses of more than 100 normal alleles. ASA was purified from human liver and the rabbit anti-human ASA antiserum was obtained. Attempts were made to produce monoclonal antibodies against ASA and two of the monoclonal antibodies reacted with ASA in Western blots. ASA from fibroblasts of normals and ASA-deficient variants was partially purified. Western blots were performed after sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), isoelectric focusing (IEF), and dot blot of fractions from the purification procedure. The Western blotting patterns were different among the controls and ASA-deficient variants The K$\sb{\rm m}$ and heat-inactivation profiles were established from normals and an PD individual. The K$\sb{\rm m}$ of the PD individual was three times that of the controls. The half-lives of ASA from normal subjects were three times that of the PD individual at 60$\sp\circ$C and double that of the PD individual at 65$\sp\circ$C The genotype and phenotype relationships were analyzed and this study provides information for diagnosis, prognosis, genetic counseling and gene therapy for MLD patients / acase@tulane.edu

Despite significant improvements in the diagnosis and treatment of breast carcinoma over the past several decades, resistance and toxicity in response to therapy remains the primary cause of breast cancer treatment failure today. Recent studies have indicated that aberrant sphingolipid metabolism resulting in a decrease in endogenous ceramides and increase in sphingosine-1-phosphate (S1P) is an important mediator of both chemo- and endocrine therapy-resistance. The balance between these lipids is tightly regulated by the enzyme sphingosine kinase, which converts pro-apoptotic, antiproliferative ceramide into its pro-survival and mitogenic metabolite S1P. The term Ceramide-S1P rheostat, refers to the concept that it is the relative ratio of ceramide to S1P that determines cell fate. Therefore, sphingosine kinase has been proposed to be a 'switch' turning cells from an anti-growth state into a proliferative one. In many cancers, increased expression and activity of sphingosine kinase alters the rheostat, resulting in malignancy. Similarly, decreased ceramide generation in response to chemotherapy and increased activity of sphingosine kinase has been shown to be a key mechanism of drug resistance in breast cancer Utilizing a number of ceramide analogs and sphingosine kinase inhibitors, we examined the effects of targeting the Ceramide-S1P rheostat in the treatment of drug sensitive and drug resistant breast cancer. Our results indicate that modifying the amide bond of short chain ceramides can increase their potency resulting in enhanced antiviability and anti-proliferative effects in both chemoresistant and endocrine therapy resistant breast cancers. These ceramide analogs altered the sphingolipid profile and induced apoptosis to exert their effects and exhibited additive anti-viability properties when using in combination with current clinical chemotherapeutics, such as etoposide and doxorubicin. These results suggest that using short-chain ceramide analogs have therapeutic potential in treating drug resistant breast cancer Two novel sphingosine kinase-2 inhibitors, SKI-II and ABC294640, were shown to block formation and downstream signaling of S1P. These inhibitors exhibit low-micromolar efficacy in viability, clonogenic survival and proliferation assays in drug resistant breast cancer. Furthermore, both inhibitors can induce apoptosis through the mitochondrial pathway in a wide variety of breast cancer cell lines. In ER-positive breast cancer, both SKI-II and ABC294640 can directly bind the estrogen receptor in an antagonistic fashion and decrease ER transcriptional activity to block estrogen signaling both in vitro and in vivo. Furthermore, in both ER-positive and ER-negative cancer, these drugs diminish NF-kappaB transcription factor signaling through blockade of p65 phosphorylation, resulting in decreased p65 transcriptional activity. Finally, using xenograft animal models, the inhibitor ABC294640 was shown to decrease drug sensitive, endocrine therapy resistant and chemotherapy resistant tumor growth in vivo. Taken together, these results indicate that targeting sphingosine kinase is a viable and promising approach in the treatment of drug sensitive and refractory breast cancer / acase@tulane.edu

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