UT Southwestern Medical School

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Welcome to the UT Southwestern Medical School’s electronic theses and dissertations (ETD) collection.

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Body Fat Assessment and Adipocytokine Levels in the Lipodystrophy Syndrome in HIV-infected Patients
(2003-06-30) Dinges, Warren L.; Garg, Abhimanyu
The lipodystrophy syndrome in HIV-infected patients (LDHIV) is characterized by body morphologic and metabolic changes. This case-control study compared 16 male, HIV-infected, severely lipodystrophic patients on protease inhibitor (PI) therapy to 14 HIV-infected, non-lipodystrophic men not on PI-inclusive HAART. Body fat distribution was assessed using anthropometry, whole-body MRI, and DEXA analysis. Adipocytokines were compared using fasting plasma adiponectin, leptin, and insulin levels. LDHIV patients compared to control subjects had lower peripheral fat with gluteal, suprailiac and triceps skinfolds (all p<0.01, with MRI thigh subcutaneous fat (ThSCF)(mean%±SD, LDHIV 12±5 vs. Controls 22±12 p=0.01) and with DEXA leg fat (%, 12±5 vs. 22±9, p=0.0006). Dorsocervical fat (DCF) accumulation was significantly greater in LDHIV subjects by MRI depth (mm, 47±24 vs. 19±7, p=0.0009) and DEXA head fat (%, 18±3 vs. 16±1, p=0.01), but not significantly by subscapular skinfold p=0.30. In LDHIV patients, abdominal fat was greater by waist circumference (cm, 98±5 vs. 86±9 p=0.0008), nearly significantly greater by MRI Intra-abdominal fat (cm2, 218±90 vs.157±70 p=0.057), and greater by DEXA Trunk percent total fat (%TF, 65±7 vs. 53±8 p=0.0005). In the correlation analysis of LDHIV patients, MRI IAF/ThSCF showed a strong negative relationship to DCF in all three methods r<-0.80, p<0.001, implying a novel split phenotype of either DCF or IAF accumulation. Five combined lipodystrophy parameters were derived, that well delineated the two groups (all p<0.00003). LDHIV patients compared to control subjects also had lower adiponectin levels (3.2±3.1 vs. 5.9±2.9 µg/mL, p=0.01), similar leptin levels (3.5±1.5 vs. 3.0±1.6 ng/mL, p=0.49), and higher insulin levels (20±11/19 vs. 12±6/11 µU/mL, p=0.04). There was a strong negative relationship between adiponectin and insulin levels in the LDHIV group (r=-0.73, p=0.01), but not in control subjects (p=0.33). Conversely, leptin and insulin levels in the control subjects were highly correlated (r=0.86, p<0.0001), but not in LDHIV patients (p=0.82). In conclusion, plasma adiponectin levels are low in patients with LDHIV and may be a better marker than leptin for the hyperinsulinemia of LDHIV. Also, this study has defined consistent methods to quantitatively assess the regional body fat changes and lipodystrophy severity in LDHIV using Anthropometry, DEXA, and MRI.
Incidence and Clinical Relevance of Abnormal Complete Blood Counts in Survivors of Childhood Cancer
(2005-03-21) Long, Zsofia Banhegyi; Oeffinger, Kevin C.
BACKGROUND: The purpose of this study was to determine the incidence and clinical significance of abnormal complete blood counts (CBCs) obtained during follow-up of childhood cancer survivors. METHODS: A retrospective cohort study was conducted on 193 survivors, diagnosed between 1970-1986, who have been followed in our center's After Cancer Experience Program and are participants in the Childhood Cancer Survivor Study. Of these patients, 49% were female and 25% were racial/ethnic minorities. The primary outcome was determination of the cumulative percentage of patients having an abnormal CBC by 2 or 3 standard deviations (SDs). Four components of the CBC were examined and employed to define an abnormal CBC: low white blood cell count (WBC), high mean corpuscular volume (MCV), low platelet count, and low hemoglobin concentration. Association of treatment exposures to abnormal values was assessed with a multi-level logistic model. RESULTS: There were 1,376 patient visits during 1,437 person-years of follow-up. The mean number of visits per survivor was 7.2 (SD 4.5). The cumulative percentage of subjects with at least one abnormal CBC was 70%. The cumulative percent of subjects with a value abnormal by 2 SD was WBC=23%, MCV=33%, platelets=9%, hemoglobin=49%. For values abnormal by 3 SD, the frequencies were WBC=3%, MCV=18%, platelets=1%, hemoglobin=27%. None of the patients developed myelodysplastic syndrome or a secondary leukemia during the follow-up period. Exposure to epipodophyllotoxins was associated with an increased risk of having abnormally high MCV values. CONCLUSIONS: Mildly abnormal CBC values are common in survivors of childhood cancer. Abnormal values are often of questionable significance but seem to persist over time. Epipodophyllotoxin therapy was found to be associated with increased frequency of high MCV levels.
Statistical Analysis of Proposed Pediatric Asthma Screening Survey
(2005-04-15) Alexander, John C.; Oeffinger, Kevin C.
BACKGROUND: Poor asthma control is responsible for considerable morbidity and mortality among children (1). Current pharmacotherapy can suppress exacerbations of asthma symptoms. Thus, proper treatment of asthma is imperative in limiting the toll of this disease process on individuals as well as society. Treatment protocols tend to be based on measurement of asthma severity (3), but there are currently no widely accepted guidelines defining efficacy of treatment (i.e.- asthma control). OBJECTIVE: This study aimed to assess the construct validity and reliability of an asthma survey among a group of known asthmatics. Furthermore, we intended to determine the level of correlation between survey responses and asthma severity amongst survey participants as well as to discern the ability of the survey to discriminate between mild persistent, moderate persistent and severe persistent asthma. METHODS: Surveys from 207 parents/guardians of children aged 5-17 with physician-diagnosed asthma were evaluated for construct validity using Principal Components Factor Analysis. Reliability was assessed via Cronbach's alpha coefficient scale. Severity/response correlations were tested by Chi-square exact tests and the strength of each relationship was assessed using Spearman's correlation. Discriminating ability was analyzed by ROC curve, sensitivity, specificity and odds ratio. RESULTS: Construct validity testing showed that the scale is unidimensional with a Cronbach's alpha coefficient of 0.8076, indicating a high degree of reliability. Significant associations between asthma severity and each question were found, indicating that more severe asthmatics reported significantly greater symptom frequency (p-value range <0.001 - 0.019, Spearman's range = 0.152 - 0.396). ROC analysis yielded an area under the curve of 0.728. Analysis of the ROC curve indicated an optimal cutoff score of =6 to indicate moderate-to-severe asthma. This cutoff yielded a sensitivity and specificity of 65.2% and 70.2%, respectively. Odds ratio was 4.407 (95% CI of 2.366 - 8.207). CONCLUSION: Our results indicate that, among asthmatics, the survey is valid and reliable. We also noted more frequent symptoms as severity increased, indicating sub-optimal control among more severe asthmatics. Finally, the ability of the survey to predict asthma severity is not supported as the survey seems to assess asthma control, with higher scores indicating poorer control.
Understanding the Mechanism of Action of Rituximab in the Reversal of Multidrug Resistance in a Non-Hodgkins Lymphoma Cell Line
(2006-03-02) Crank, Michelle C.; Vitetta, Ellen S.
It has been previously demonstrated that an anti-CD20 monoclonal antibody (MAb) can reverse MDR in B lymphoma cells in vitro. However, the mechanisms underlying this effect are unknown. A recent study showed that anti-CD20 MAbs could induce rapid redistribution of CD20 into a detergent-insoluble embrane compartment (lipid rafts). By redistributing CD20 into rafts, Rituximab(tm) (RTX) modified their stability and organization. P-glycoprotein (P-gp) is the constituent protein of MDR tumor cells and is responsible for pumping chemotherapeutic agents out of cells. Because ~40% of P-gp is contained in lipid rafts, we hypothesized that when CD20 translocated into lipid rafts, it would displace P-gp. This displacement would lead to the reversal of MDR. To this end, we determined the function of the P-gp pump in the presence or absence of MAbs. In addition, the effects of dose and incubation time with MAbs and chemotherapeutic drugs were determined using Namalwa/MDR1 and three drug-sensitive cells. Finally, the iv distribution of P-gp and CD20 in membranes was monitored after treatment with MAbs by western blot analysis. We found that RTX inhibited the function of the P-gp pump while other anti-CD20 MAbs had no effect. RTX-mediated growth-inhibition of Namalwa/MDR1 cells was both dose- and time-dependent. Namalwa/MDR1 cells were resistant to doxorubicin and vincristine, but RTX rendered the Namalwa/MDR1 cells as chemosensitive as the parental Namalwa cells. RTX induced the translocation of CD20 into lipid rafts and the translocation of P-gp out of rafts. Our results supported our hypothesis that the ability of RTX to reverse MDR was initiated when CD20 was translocated into lipid rafts. This coincided with the translocation of P-gp out of rafts. When P-gp was no longer present in rafts, it lost activity and MDR was reversed.
Structural and Physiologic Determinants of Estrone/Estradiol Metabolism Catalyzed by Human 17beta -Hydroxysteroid Dehydrogenases Types 1 and 2
(2006-07-13) Sherbet, Daniel P.; Andersson, Stefan
The 17beta -hydroxysteroid dehydrogenases (17beta -HSDs) types 1 and 2 interconvert the weak and potent estrogens estrone and 17beta -estradiol. In intact cells, each enzyme exhibits a strong directional preference that favors either oxidation (17beta -HSD2) or reduction (17beta -HSD1). A positively charged arginine (R38) adjacent to the 2'-phosphate stabilizes NADP(H) binding to 17beta -HSD1 and favors reduction due to the high cytoplasmic NADPH/NADP+ ratio. In contrast, 17beta -HSD2 has a negatively charged glutamate (E116) at the position corresponding to R38 of 17beta -HSD1, which presumably repels the 2'-phosphate of NADP(H) and favors oxidation by harnessing the high cytoplasmic NAD+/NADH ratio. Substitution of a negatively charged aspartate, but not neutral glycine, for R38 of 17beta -HSD1 markedly reduces the affinity for NADP(H) and reverses the directional preference to oxidation in intact cells. We hypothesized that E116 confers oxidative preference to 17beta -HSD2 and that substitution of either a neutral or a positively charged residue for E116 would reverse the directional preference to favor reduction. Mutations E116G, E116R, and the double mutation E116G+N117R failed to attenuate the >95% oxidative preference of 17beta -HSD2 in intact cells. Affinity for all cofactors, as estimated by Km values, were measured for wild-type and mutant 17beta -HSD2 enzymes in yeast microsomes. For wild-type 17beta -HSD2, affinity for NAD(H) is nearly 1000-fold greater than for NADP(H), and the mutant enzymes retain high affinity for NAD(H) yet only slightly better affinity for NADP(H). We conclude that the directional preference of 17beta -HSD1 is principally governed by electrostatic interactions between R38 and the 2'-phosphate of NADP(H), but that the oxidative preference of 17beta -HSD2 is not solely due to E116 in the cofactor-binding domain. These data suggest that the directional preference of 17beta -HSD2 is controlled by other aspects of its cofactor-binding domain, such as the size of the cofactor-binding pocket.
Protective Effect of Statin Use in the Progression of Dry to Exudative Age-Related Macular Degeneration
(2006-10-13) Nettune, Gregory; Haley, Robert
PURPOSE: Age-related macular degeneration (ARMD) is a leading cause of irreversible blindness in the industrialized world. Studies suggest that HMG CoA reductase inhibitors (statins) might slow the progression of dry ARMD to the exudative stage. We set out to determine if statin use reduces the risk of progression to exudative ARMD in a matched case-control study. METHODS: An epidemiological study of 61 cases with exudative ARMD matched by age, gender, and race to 61 controls with early, high-risk ARMD determined by prospective ophthalmologic examination. RESULTS: The risk of exudative ARMD was increased by smoking within the past 20 years (OR=5.8, 95% CI 1.42-23.77) and reduced by use of statins (OR=0.2, 95% CI 0.04-0.93). Further, the duration of statin use up to four years was associated with an increasing degree of protection (9% reduction each month, 95% CI 0.85-0.98). CONCLUSION: Statin use may reduce the progression from dry to exudative ARMD.
Paw Print Gait Analysis in Rats with Spinal Cord Injury
(2007-11-02) Zinkhan, George; Tansey, Malú G.
Recovery of locomotion following spinal cord injury (SCI) in the rat may be tracked by different approaches to gait analysis, such as open field locomotor scoring and automated paw print analysis. Until recently, both of these approaches allowed the animal to walk at a self-selected speed. To further characterize gait recovery, the DigiGait system was developed to obtain video of paw prints through a clear plastic treadmill that may be set at various speeds. The DigiGait allowed the variability in gait parameters due to changes in speed to be characterized and controlled to mitigate effects of speed on these parameters. The purpose of the first study presented in this paper was to conduct a small preliminary study that uses the DigiGait with the rat model and to further characterize gait at multiple standardized treadmill speeds. A minimum treadmill speed of 10 cm/s was determined for use with the Long-Evans rat because at this speed, the rats were able to run without frequent acceleration or deceleration and it was attainable by all of the subjects by two weeks after SCI. Statistical analysis of the data was ongoing during the writing of this paper, and as a result the focus in this paper was to examine trends in the data. With increasing treadmill speed from 10 cm/s to 25 cm/s, hindlimb stride length and stride frequency were increased in injured animals by 1.3-fold and 1.9-fold, respectively; whereas, stance width was unaffected, and stance/swing ratio and hindlimb shared stance time were decreased by 1.6-fold and 2.4-fold, respectively. This study showed that certain gait parameters vary with a change speed. This variability may be reduced in future studies of gait parameters by using standardized speeds. The second study was performed three years prior to the DigiGait study. At that time, results from the DigiGait system had not yet been published. A device called the CatWalk was available for acquiring video of rats crossing a clear walkway. Analysis software for the CatWalk existed but was not available commercially. The purpose of the second study was to design software that partly automates paw print analysis of video of rats using the CatWalk. The goal of this software was to measure the same gait measures as the CatWalk analysis software. These parameters included stride length, stance width, paw print area, swing duration, and interlimb coordination. The Java computer programming language was used to incorporate open-source image analysis tools available through the National Institution of Health's (NIH) ImageJ, which is a set of Java-based plug-ins. The software was able to analyze sequential series of frames that were extracted from video clips by third party software. A proof of concept study showed that this paw print analysis software was able to identify each paw in an image as left hindpaw, right hindpaw, left forepaw, or right forepaw. The software was then able to automatically measure and save the contact area of paws and the distance between paws. Additional gait parameters may be added to this software in the future. Both of these studies contributed to the overall goal of better characterizing the efficacy of treatments that lead to improved locomotor function after SCI in the rodent model and that eventually may be used for human subjects with gait dysfunction due to SCI.
The Roles of ATP-Binding Cassette Transporters G5 and G8 in Liver X Receptor-Mediated Sterol Trafficking
(2007-12-03) York, Jennifer Lynn; Hobbs, Helen H.
The liver X receptor (LXR) is a nuclear receptor that plays a critical role in orchestrating the trafficking of sterols between tissues. Treatment of wild type mice with a potent and specific nonsteroidal LXR agonist, T0901317, is associated with increased biliary cholesterol secretion, decreased fractional cholesterol absorption, and increased fecal neutral sterol excretion. The following studies show that expression of two target genes of LXRalpha , the ATP-binding cassette (ABC) transporters Abcg5 and Abcg8, is required for the increase in sterol excretion, the decrease in fractional cholesterol absorption, and the increase in fecal neutral sterol excretion associated with LXR agonist treatment. Mice lacking ABCG5 and ABCG8 (G5G8-/- mice) and wild type littermate controls were treated for 7 days with T0901317. In control animals, the LXR agonist produced a 3-fold increase in biliary cholesterol concentration, a 25% reduction in fractional cholesterol absorption, and a 4-fold elevation in fecal neutral sterol excretion. In contrast, treatment of G5G8-/- mice with the LXR agonist did not significantly affect any of these parameters. These results demonstrate that ABCG5 and ABCG8 are required for LXR agonist-associated changes in dietary and biliary sterol trafficking and that increased expression of these proteins promotes cholesterol excretion in vivo.
Prevalence of Melasma Among Premenopausal Latino Women in Dallas and Fort Worth, TX, USA
(2007-12-03) Werlinger, Kelly D.; Pandya, Amit
BACKGROUND: The prevalence of melasma in Latino women is unknown. OBJECTIVE: The purpose of this study was to develop a valid instrument for determining the presence of melasma in Latino women and to administer this instrument by telephone to premenopausal Latino women living in Dallas-Fort Worth, Texas. METHODS: A questionnaire to investigate rates of self-reported melasma was developed and validated. This questionnaire was used to interview 500 premenopausal Latino women by telephone. RESULTS: The questionnaire was found to have a sensitivity of 93% and a specificity of 82%. The prevalence of melasma in 500 premenopausal Latino women was 8.8%. Spanish as a primary language was found to be an important risk factor for self-reporting melasma. CONCLUSION: Melasma is common among premenopausal Latino women in the Dallas-Ft. Worth area, especially among Spanish-speakers. A validated English and Spanish instrument has been developed which can be used to determine the prevalence of melasma.
Utilizing Discrepancy Theory to Quantitate Quality of Life in Chronically Ill Children
(2007-12-03) Webb, Bryn; Birod, Carlos E.
BACKGROUND: Quality of Life (QoL) is a ubiquitous yet poorly defined concept in clinical medicine. Many widely used instruments to measure QoL lack a theoretical basis and therefore may not provide accurate assessment. Multiple discrepancy theory advocates that net satisfaction is determined by evaluating the difference or gap between current life circumstances and a standard of comparison. A QoL instrument based on discrepancy theory has been developed by our research group to evaluate children with chronic diseases. OBJECTIVE: To evaluate the parent-child agreement for discrepancy theory items on the GAP QoL Questionnaire for children with chronic illness. DESIGN/METHODS: Children and parents were recruited for this pilot study when attending regularly scheduled appointments in a variety of outpatient clinics at The Hospital for Sick Children (SickKids). Trained interviewers administered the GAP Questionnaire to parents- and to their children if older than age 10. Children and parents answered the questionnaire blind to each other's answers. RESULTS: 77 participants (28 children, 49 parents: 24 parent/child pairs) were enrolled. The most important items for determining QoL generated by the GAP Questionnaire differed for children and parents (See Table). The overall weighted Kappa value for parent-child agreement on the GAP Questionnaire was 0.349 indicating moderate agreement. Items with the highest agreement were having pets (0.6962), getting along with brothers/sisters (0.5886), and the place religion has in your life (0.549).
Transcriptional Regulation of Dehydroepiandrosterone Sulfotransferase (SULT2A1) By Estrogen-Related Receptor-alpha (ERR-alpha)
(2007-12-03) Seely, Jeremiah Brent; Rainey, William
The estrogen-related receptors (ERR alpha , beta and gamma ) are a subfamily of orphan nuclear receptors (designated NR3B1, NR3B2 and NR3B3) that are structurally and functionally related to estrogen receptors alpha and beta . Herein we test the hypothesis that ERRalpha regulates transcription of the genes encoding the enzymes involved in adrenal steroid production. Real-time RT-PCR was first used to determine the levels of ERRalpha mRNA in various human tissues. Adult adrenal levels of ERRalpha transcript were similar to that seen in heart, which is known to highly express ERRalpha . Expression of ERRalpha in the adult adrenal was then confirmed using western blotting and immunohistochemistry. To examine the effects of ERRalpha on steroidogenic capacity we used reporter constructs with the 5′-flanking regions of steroidogenic acute regulatory protein (StAR), cholesterol side-chain cleavage (CYP11A), 3beta hydroxysteroid dehydrogenase type II (HSD3B2), 17alpha hydroxylase, 17,20 lyase (CYP17), and DHEA sulfotransferase (SULT2A1). Cotransfection of these reporter constructs with wild-type ERRalpha or VP16-ERRalpha expression vectors demonstrated ERRalpha enhanced reporter activity driven by flanking DNA from CYP17 and SULT2A1. SULT2A1 promoter activity was most responsive to the ERRalpha and VP16-ERRalpha , increasing activity 2.6- and 79.5-fold respectively. ERRalpha effects on SULT2A1 were greater than the stimulation seen in response to steroidogenic factor 1 (SF1). Transfection of serial deletions of the 5′-flanking DNA of the SULT2A1 gene and EMSA experiments indicated the presence of three functional regulatory cis-elements which shared sequence similarity to binding sites for SF1. Taken together, the expression of ERRalpha in the adrenal and its regulation of SULT2A1 suggest an important role for this orphan receptor in the regulation of adrenal steroid production.
The Changing Epidemiology of Musculoskeletal Infection in Children: Impact on Evaluation and Treatment at a Tertiary Pediatric Medical Center in the Southwest United States
(2007-12-03) Hollmig, S. Tyler; Copley, Lawson A. B.
BACKGROUND: Recent reports illustrate an increased incidence and severity of deep musculoskeletal infections in children. Our purpose was to review the historical experience with deep musculoskeletal infection at a tertiary pediatric medical center in the southwest United States and to compare this past experience with the more recent experience within the same institution. METHODS: A retrospective review was performed of children treated for deep musculoskeletal infection at Children's Medical Center of Dallas between January 1, 2002 and December 31, 2004. The review identified children with primary diagnoses of osteomyelitis, septic arthritis, non-tropical pyomyositis, or abscesses requiring surgical intervention. Trends were identified in terms of causative organism, anatomic location of infection, frequency of requirement of surgical debridement, and identification of adverse sequelae. These trends were compared to past experience within the same institution. RESULTS: 554 children were treated for deep musculoskeletal infection. Primary diagnoses were as follows: osteomyelitis - 212; septic arthritis - 118; pyomyositis - 20; and abscess - 204. The incidence of osteomyelitis rose from 11.7 cases per year, reported in 1982, to 70.7 cases per year, representing a six-fold increase. The incidence of septic arthritis rose from the 1982 report of 18.1 cases per year to 39 cases per year, a 2.2-fold increase. Staphylococcus aureus was responsible for the majority of infections, with methicillin resistant S. aureus representing an important cause of infection not identified in the previous study at this institution. The most common anatomic locations of infection occurred around the knee and hip joints. Deep venous thrombosis was identified as the most common major complication associated with musculoskeletal infection, with 13 cases occurring over the course of the review. DISCUSSION: We have demonstrated a change in the epidemiology among children with musculoskeletal infection at our tertiary pediatric medical center. The marked differences that are present in our current practice when compared to the experience at the same institution over twenty years ago have prompted a detailed look into this epidemiology. The emergence of methicillin resistant S. aureus, the association of deep venous thrombosis musculoskeletal infection, and the reported occurrence of non-tropical pyomyositis, were unique finding in our study. Our recent experience demonstrated trends that motivated the development of clinical practice guidelines for the evaluation and treatment of pediatric musculoskeletal infection. Future prospective work will be necessary to study the success of implementation of these evidence based guidelines as well as to ascertain their merit in terms of beneficial clinical outcomes.
Serotonin Reuptake Inhibitor Use During Pregnancy: Perinatal Outcomes
(2008-04-10) Jordan, Allison E.; Dashe, Jodi S.
OBJECTIVE: To assess severity of neonatal behavioral syndrome (NBS) in infants of serotonin reuptake inhibitor (SRI)-treated pregnancies, compared with infants of women with psychiatric illness not treated with medication. METHODS: Retrospective cohort study of pregnancies followed in a prenatal clinic for women with psychiatric illness. Infants of women who received SRI medication through delivery (SRI-treated) were compared with those who did not receive treatment or discontinued medication before the last month of pregnancy (SRI-untreated). NBS was defined as one or more of the following: jitteriness, irritability, lethargy, hypotonia, hypertonia, hyperreflexia, apnea, respiratory distress, vomiting, poor feeding, or hypoglycemia. RESULTS: Findings of NBS were identified in 28% of 46 SRI-treated pregnancies and 17% of 59 untreated pregnancies. There were no differences in rates of prematurity (4% vs. 7%), fetal growth restriction (6% vs. 2%), transfer to a higher nursery for NBS (11% vs. 10%), respiratory abnormality (7% vs. 5%), or hospitalization duration among infants with NBS findings (2 vs. 6 days). CONCLUSIONS: Findings of NBS were identified in 28% of SRI-exposed neonates. However, these infants were not more likely than unexposed infants to be admitted to a higher nursery, experience respiratory abnormalities, or have prolonged hospitalization.
The Effect of a Disease Management Algorithm and Dedicated Postacute Coronary Syndrome Clinic on Achievement of Guideline Compliance: Results from the Parkland Acute Coronary Event Treatment Study
(2008-06-13) Viswanathan, Sundeep; Yorio, Jeffrey T.; McGuire, Darren K.
BACKGROUND: The application of disease management algorithms by physician extenders has been shown to improve therapeutic adherence in selected populations. It is unknown whether this strategy would improve adherence to secondary prevention goals after acute coronary syndromes (ACSs) in a largely indigent county hospital setting. METHODS: Patients admitted for ACS were randomized at the time of discharge to usual followup care versus the same care with additional visits with physician extenders in a dedicated post- ACS clinic. Physician extender visits were conducted according to a treatment algorithm based on contemporary practice guidelines. Groups were compared using the primary end point of achievement of low-density lipoprotein treatment goals at 3 months after discharge with key secondary endpoints including the achievement of additional evidence-based practice goals with up to 1 year of follow up assessment. RESULTS: One hundred forty consecutive patients were randomized. Rates of use of all evidencebased therapies assessed were high at the time of hospital discharge, and similar between the study groups. A similar proportion of patients returned for study follow-up in both groups at 3 months (54 [79%]/68 in the usual care group vs. 57 [79%]/72 in the intervention group; P = 0.97). Among those completing the 3-month visit, a low-density lipoprotein cholesterol level less than 100 mg/dL was achieved in 37 (69%) of the usual care patients compared with 35 (57%) of those in the intervention group (P = 0.43). There was no statistical difference in implementation of therapeutic lifestyle changes (smoking cessation, cardiac rehabilitation, or exercise) between groups. Prescription rates of evidence-based therapeutics at 3 months were similar in both groups. CONCLUSION: The implementation of a post-ACS clinic run by physician extenders applying a disease management algorithm did not measurably improve adherence to evidence-based secondary prevention treatment goals. Despite initially high rates of evidence-based treatment at discharge, adherence with follow-up appointments and sustained implementation of evidence-based therapies remains a significant challenge in this high-risk cohort.
Optimizing Immunosupression in Patients Following Heart Transplantation
(2008-06-13) Mitchell, Joshua D.; DiMaio, J. Michael
BACKGROUND: Effective immunosuppression is necessary for long-term survival following heart transplantation, but it is also associated with a multitude of adverse effects. Protocols have emerged to attempt to optimize the risk-to-benefit ratio of immunosuppression. We reviewed our center's experience with two such protocols: tapering corticosteroids following heart transplantation and administering basiliximab as an induction agent. METHODS: We reviewed the records of all cardiac transplant recipients at our center between 1988 and August 2004. Patients treated with traditional triple therapy immunosuppression (cyclosporine, azathioprine, and prednisone; CAP) were compared to a similar group of patients treated with a goal of rapid (within 6 months) steroid taper and discontinuation (CAPT). Patients who received basiliximab as an induction agent were compared to a historical control group of patients who received a similar immunosuppressive protocol without basiliximab induction. RESULTS: Fifty-seven percent of the patients in the CAPT group were successfully withdrawn from steroids at six months post-transplantation. This group had a decreased freedom from acute rejection (p<0.01) and increased frequency of acute rejection (p<0.01) when compared to the CAP group. There was, however, no difference in freedom from transplant coronary artery disease (p=0.53). The CAPT group enjoyed an increased freedom from malignancy (p=0.01) and trended towards a decreased frequency of infection (p=0.10) and improved survival (p=0.06) when compared to the CAP group.One hundred forty-five patients were included in the comparison between basiliximab and control. At one and two-years post-transplantation, no difference was found between groups in the rise of serum creatinine (p=0.29). Basiliximab induction decreased the frequency of acute rejection (p=0.02) and improved the freedom from first acute rejection episode (p<0.01) during the first two years after transplantation. It had no statistically significant effect on freedom from infection, malignancy, or overall survival in our cardiac transplant population (p=0.52, p=0.85,p=0.27 respectively). CONCLUSIONS: Steroid withdrawal was possible in 57% of patients at six months posttransplantation.The institution of an early steroid taper protocol improves the overall freedom from malignancies and may decrease the frequency of infection and prolong overall survival. Basiliximab induction does not affect renal function at mid-term follow-up; however, it decreases the frequency of acute rejection and increases the freedom from first acute rejection episode. It accomplishes this without decreasing the freedom from infection, malignancy, and transplant vasculopathy. Novel medications and treatment protocols provide an opportunity for transplant teams to continue to optimize immunosuppression while simultaneously minimizing side-effects.
Effect of Perioperative Celecoxib on Patient Outcomes After Major Plastic Surgery Procedures
(2008-12-23) Sun, Tiffany B.; White, Paul F.
BACKGROUND: Controversy continues to surround the use of COX-2 inhibitors in the perioperative period. This randomized, double-blind, placebo-controlled study was designed to examine the hypothesis that administration of celecoxib preoperatively or postoperatively and for a total of 4 days after major plastic surgery would improve pain control and clinically-important patient outcomes. Another objective of the study was to determine if perioperative administration of celecoxib offered any advantages over postoperative administration alone. METHODS: One hundred and twenty healthy consenting patients undergoing major plastic surgery (e.g., breast augmentation, abdominoplasty procedures) utilizing a standardized general anesthetic technique were randomized to one of three treatment groups: (1) Control group (n=40) received two placebos orally before and after surgery, as well as one placebo BID for three days after surgery (2) Postoperative group (n=40) received two placebos before surgery and two celecoxib 200 mg po after surgery, followed by one celecoxib 200 mg po BID on POD #1, #2 and #3, and (3) Perioperative group (n=40) received two celecoxib 200 mg po 30-90 minutes before surgery and two placebos after surgery, followed by one celecoxib 200 mg po BID on POD #1, #2 and #3. Pain scores, the need for "rescue" analgesics, and side effects were recorded at specific time intervals in the postoperative period. Follow-up evaluations were performed at 24 h, 48 h, 72 h and 7 d after surgery to assess post-discharge pain, analgesic requirements, return of bowel function, resumption of normal daily activities, quality of recovery, and patients' satisfaction with their pain management. RESULTS: Compared to the Control group, the two celecoxib groups had similarly significant reductions in postoperative pain and need for opioid analgesics during the first three postoperative days (p<0.01). Patients recovered bowel function 1 d earlier and resumed normal activities 2 d earlier in the celecoxib groups. In addition, patient satisfaction with pain management and quality of recovery were significantly improved in the celecoxib (vs. control) groups (p<0.05). CONCLUSION: Celecoxib (400 mg po) administered on the day of surgery and for three days postoperatively is effective in improving postoperative pain management, as well as the speed and quality of recovery after major plastic surgery. However, perioperative administration offers no advantages over simply giving the drug after surgery.
Purification of Native and Recombinant NPC1
(2008-12-23) Dale, Jarrod Donald; Goldstein, Joseph L.
The Niemann-Pick, Type C1 protein (NPC1) is required for the transport of lipoproteinderived cholesterol from lysosomes to endoplasmic reticulum. The 1278-amino acid, polytopic membrane protein has not been purified, and its mechanism of action is unknown. We encountered NPC1 in a search for a membrane protein that binds 25-hydroxycholesterol (25-HC) and other oxysterols. Described here is the initial purification of rabbit NPC1 using a classical biochemical approach and an analysis of the sterol binding properties of native and recombinant NPC1. Our purification yielded a membrane-bound 25-HC-binding protein which was purified more than 14,000-fold from rabbit liver membranes. This protein was identified as NPC1 by mass spectroscopy. We prepared recombinant human NPC1 and confirmed its ability to bind oxysterols, including those with a hydroxyl group on the 24, 25, or 27 positions. Hydroxyl groups on the 7, 19, or 20 positions failed to confer binding. Initial characterization of the sterol binding properties showed specific binding for 25-HC; however, we were unable to demonstrate significant binding of NPC1 to cholesterol using our current experimental conditions. The availability of assays to measure NPC1 sterol binding in vitro may further the understanding of intracellular sterol transport.
The Integration of Health Care Policy in Medical Education
(2009-05-14) Nguyen-Trong, Phuong-Khanh Jessica; Wagner, James; Kirk, Lynne M.; Weber, Mary Ellen
Traditional medical school curriculums currently do not include introductory courses on various health care policy topics. The 2005-2006 U.T. Southwestern Congressional Health Care Fellowship activities are examined in this thesis, including Avian Influenza, the Ryan White Care Act reauthorization, and Massachusetts Health Care Reform Plan. It is predicted that the inclusion of several curriculum reforms in medical education will increase the participation from physicians in reforming our nation's healthcare system.
Mitophagy in Heart Failure: A Selective Autophagic Degradation of Mitochondria
(2009-06-05) Yang, Kai-Chun (Daniel); Hill, Joseph A.
INTRODUCTION: Cardiovascular disease is associated with declines in mitochondrial function. Autophagy is a lysosomal-dependent process through which cytoplasmic proteins and organelles can be degraded and has recently been shown to participate in remodeling of the myocardium in a variety of cardiac pathologies. Autophagy can be either non-selective or selective for damaged protein aggregates or organelles. Reactive oxygen species (ROS) generated in mitochondria causes mitochondrial permeability transition (MPT) and induces selective degradation of mitochondria (mitophagy). We hypothesized that mitophagy contributes to remodeling of the heart under severe oxidative stress. METHODS: Mice were subjected to hemodynamic overload by severe thoracic aortic constriction (sTAC). qPCR was used to measure the abundance of mtDNA relative to nuclear DNA. Changes in proteins and cardiac function were also assessed. RESULTS: Decreases in mtDNA abundance were time dependent after sTAC (-47%±17 at day 2, p<0.1; -73%±10 at day 4, p<0.05) (n=2 each) and correlated with increased mortality (37% at day 2; 75% at day 4). The decline in mtDNA was greater in the basal septum (-88%±2, p<0.01) than in the left ventricular free wall (- 42%±15, p<0.15) (n=4) day 8 post-sTAC. The basal septum is where we have observed the largest increases in autophagic activity and protein carbonylation, a ROS-mediated protein modification. Daily injections with cyclosporine (CsA), an inhibitor of both MPT and calcineurin, blunted load-induced mtDNA loss (-28%±2 with CsA vs -83%±10 with vehicle treatment, p<0.01) (n=3) at 4 days post-sTAC. Furthermore, CsA improved survival at 4 days-post sTAC (40% mortality with CsA vs 75% with vehicle) (n=5-8). Mice with increased ROS generation due to a disruption of the cardiac isoform of the cytochrome-c oxidase subunit COXVIaH were more sensitive to pressure overload-induced loss of mtDNA and mitochondrial proteins. CONCLUSION: MtDNA abundance declines in this model of load-induced heart failure and is associated with increased autophagic activity and ROS generation. Short-term application of CsA can blunt mtDNA loss and improve survival.
Molecular Characterization of the Human Alloimmune Response
(2009-11-18) Smith, Melody; Collins, Robert
When T lymphocytes from two individuals are placed in a mixed lymphocytic reaction (MLR) and allowed to stimulate each other a powerful proliferative response is elicited, reflecting the degree of incompatibility at the major histocompatibiltiy loci. Such in vitro proliferations translate in vivo into graft rejection of stem cell and solid organ transplants and to graft versus host disease (GvHD) in recipients of allogeneic stem cell transplants. Defining the clonal T cell responses elicited in an MLR between two individuals is complicated by the multiplicity of T cell HLA- antigen interactions. We used flow cytometry to investigate the MLR between mismatched individuals to better characterize responder T cell proliferation and the subsets involved in the alloresponse. After observing proliferation in the setting of a completely mismatched one-way MLR and ensuring that the design for the MLR was viable, we sought to characterize clonal T cell responses in a simple system. We attempted to elicit T cell responses to autologous antigen-presenting cells (APC) transfected with a single mismatched HLA-A2 molecule. We failed to detect any alloresponding T cells using a flow cytometric system, except when dendritic cells were used. We then used an HLA-A2 negative responder pre-stimulated in an MLR with an HLA-A2 positive individual for re-challenge by the responder?s own APC transfected with an HLA-A2 plasmid. In this way, we sought to identify an expanding HLA-A2 specific T cell population which could be further characterized by T cell receptor cloning. Nevertheless, we failed to detect an alloimmune response in this T cell line stimulated with HLA-A2 transfected APCs three times over a 21- day culture period. These results suggest that either the frequency of alloreactive T cells was below the limit of detection by these methods or that the particular stimulator-responder pairs used in these experiments were non-reactive. Future work will extend the study to more HLA mismatched stimulator-responder pairings to better define the characteristics of alloreactive T cells.

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