Immunosuppressive drug interactions and resistance in mononuclear cells from renal transplant patients

Existing anti-rejection drug regimes are inadequate since patients receive drugs despite serious side effects and poor response. New drugs are being developed which ultimately may allow for prescribing of rational, patient-specific immunosuppressive drug protocols. During this thesis the investigation of lymphocyte responses from renal transplant recipients to the immunosuppressant drugs Cyclosporin A (Cy A), FK506 and SDZ RAD were explored to understand the variation in sensitivity of lymphocytes to Cy A and FK506, the development of drug resistance, including resistance mechanisms, and the interactions between FK506 and SDZ RAD. Cy A and FK506 are substrates for P-glycoprotein (P-gp), the product of the multidrug-resistance (MDR1) gene in man. A hypothesis established during this thesis was that P-gp dependent mechanisms explain variations in lymphocyte sensitivities to Cy A and FK50. Lymphocytes from renal transplant recipients were assessed for their sensitivity to Cy A and FK506 and subsequently for P-gp expression and functional activity by flow cytometry. In further lymphocyte cultures the effect of the specific P-gp inhibitor, PSC 833 on sensitivity was investigated. Finally, the effects of the combination of FK506 and SDZ RAD in lymphocyte cultures were analysed. Results demonstrate a wide range in lymphocyte sensitivity to both Cy A and FK506, with the development of selective resistance to the drug used for treatment. All patients demonstrated P-gp functional activity but P-gp expression was not demonstrable. P-gp function did not account for the variation in lymphocyte sensitivity. There was no evidence of antagonism of effect of SDZ RAD in combination with FK506. In conclusion, these results suggest that non-P-gp mechanisms account for variations in lymphocyte sensitivity to Cy A and FK506. Combination therapy with SDZ RAD and FK506 is unlikely to be antagonistic in future treatment protocols

Porous silica spheres as indoor air pollutant scavengers

Porous silica spheres were investigated for their effectiveness in removing typical indoor air pollutants, such as aromatic and carbonyl-containing volatile organic compounds (VOCs), and compared to the commercially available polymer styrene-divinylbenzene (XAD-4). The silica spheres and the XAD-4 resin were coated on denuder sampling devices and their adsorption efficiencies for volatile organic compounds evaluated using an indoor air simulation chamber. Real indoor sampling was also undertaken to evaluate the affinity of the silica adsorbents for a variety of indoor VOCs. The silica sphere adsorbents were found to have a high affinity for polar carbonyls and found to be more efficient than the XAD-4 resin at adsorbing carbonyls in an indoor environment

An Evaluation of Food Insecurity & Health Behavior among Rural Community Supported Agriculture (CSA) Participants

Introduction. Access to healthy foods is a major barrier for individuals achieving a healthy diet. The literature reveals several investigations into causes of food insecurity, but few focus on Community Supported Agriculture (CSA) programs that attempt to address food insecurity and related health behaviors of participants.https://scholarworks.uvm.edu/comphp_gallery/1199/thumbnail.jp

Adolescent psychological distress, unemployment, and the Great Recession: Evidence from the National Longitudinal Study of Youth 1997

Rationale  Several studies have shown a link between psychological distress in early life and subsequent higher unemployment, but none have used sibling models to account for the unobserved family background characteristics which may explain the relationship.  Objective  This paper uses the National Longitudinal Study of Youth 1997 data to examine whether adolescent psychological distress in 2000 predicts higher unemployment over 2000–11, whether this relationship changed in the period following the Great Recession, and whether it is robust to adjustment for family effects.  Methods  7125 cohort members (2986 siblings) self-reported their mental health in 2000 and employment activities over 2000–11. This association was examined using Probit and ordinary least squares regressions controlling for intelligence, physical health, other sociodemographic characteristics and family background.  Results  After adjustment for covariates and compared to those with low distress, highly distressed adolescents were 2.7 percentage points (32%) more likely to be unemployed, 5.1 points (26%) more likely to be unemployed or out of the labor force and experienced 11 weeks (28%) more unemployment. The impact of high distress was similar to a one standard deviation decrease in intelligence, and double the magnitude of having a serious physical health problem, and these estimates were robust to adjustment for family fixed-effects. The highly distressed were also disproportionately more likely to become unemployed or exit the labor force in the years following the Great Recession.  Conclusion  These findings provide strong evidence of the unemployment penalty of early-life psychological distress and suggest that this relationship may be intensified during economic recessions. Investing in mental health in early life may be an effective way to reduce unemployment

Independent Benthic Microbial Fuel Cells Powering Sensors and Acoustic Communications with the MARS Underwater Observatory

Most oceanographic instruments on the seafloor have no connections with the surface and therefore have to run on batteries and store data until recovery. To demonstrate a developing technology, sensors and acoustic modems were powered with energy harvested from the seafloor, and data were relayed acoustically in near–real time to the Monterey Accelerated Research System (MARS) observatory in Monterey Bay, California, and to surface research vessels. MARS is a cabled observatory in deep water (~890 m) at the edge of Monterey Canyon. An acoustic modem was attached to the MARS node and configured to send out commands to, and relay data received from, remote modems. Two benthic microbial fuel cells (BMFCs) positioned approximately 0.5 km away from MARS supplied power to the remote modems and sensors. At their peak performance, these BMFCs produced continuous power densities of ~35 mW m⁻² (footprint area). The modems utilized in this study contained an integrated power management platform (PMP) designed to manage and store the electrical energy generated by each BMFC and to record BMFC performance parameters and sensor data on an hourly basis. Temperature and either oxygen or conductivity sensors were chosen because of their common use and environmental relevance. Acoustically transmitted data records show that the BMFCs renewed energy stores and that the oceanographic sensors measured dissolved oxygen, temperature, and conductivity reliably throughout the operational life of each BMFC system (~6 months). These systems remained in place for more than 12 months.Keywords: Observational techniques and algorithms, Surface observations, Ship observations, Applications, Field experiments, Remote sensing, Instrumentation/sensors, Renewable energ

Symmetric dimethylarginine (SDMA) is a stronger predictor of mortality risk than asymmetric dimethylarginine (ADMA) amongst older people with kidney disease

Background Circulating asymmetric (ADMA) and symmetric dimethylarginine (SDMA) are increased in patients with kidney disease. SDMA is considered a good marker of glomerular filtration rate (GFR) whilst ADMA is a marker of cardiovascular risk. However, a link between SDMA and all-cause mortality has been reported. In the present study we evaluated both dimethylarginines as risk and GFR markers in a cohort of elderly white individuals, both with and without CKD. Methods GFR was measured in 394 individuals aged >74 years using an iohexol clearance method. Plasma ADMA, SDMA and iohexol were measured simultaneously using isotope dilution tandem mass spectrometry. Results Plasma ADMA concentrations were increased (P60 mL/min/1.73 m², but did not differ (P>0.05) between those with GFR 30-59 mL/min/1.73 m² and <30 mL/min/1.73 m². Plasma SDMA increased consistently across declining GFR categories (P<0.0001). GFR had an independent effect on plasma ADMA concentration whilst GFR, gender, body mass index and haemoglobin had independent effects on plasma SDMA concentration. Participants were followed for a median of 33 months. There were 65 deaths. High plasma ADMA (P=0.0412) and SDMA (P<0.0001) concentrations were independently associated with reduced survival. Conclusions Amongst elderly white individuals with a range of kidney function, SDMA was a better marker of GFR and a stronger predictor of outcome than ADMA. Future studies should further evaluate the role of SDMA as a marker of outcome and assess its potential value as a marker of GFR

The Human Mitochondrial tRNAMet: Structure/Function Relationship of a Unique Modification in the Decoding of Unconventional Codons

Human mitochondrial mRNAs utilize the universal AUG and the unconventional isoleucine AUA codons for methionine. In contrast to translation in the cytoplasm, human mitochondria use one tRNA, hmtRNAMetCAU, to read AUG and AUA codons at both the peptidyl- (P-), and aminoacyl-(A-) sites of the ribosome. The hmtRNAMetCAU has a unique post-transcriptional modification, 5-formylcytidine, at the wobble position 34 (f5C34), and a cytidine substituting for the invariant uridine at position 33 of the canonical “U-turn” in tRNAs. The structure of the tRNA's anticodon stem and loop domain (hmtASLMetCAU), determined by NMR restrained molecular modeling, revealed how the f5C34 modification facilitates the decoding of AUA at the P- and A-sites. The f5C34 defined a reduced conformational space for the nucleoside, in what appears to have restricted the conformational dynamics of the anticodon bases of the modified hmtASLMetCAU. The hmtASLMetCAU exhibited a “C-turn” conformation that has some characteristics of the U-turn motif. Codon binding studies with both E. coli and bovine mitochondrial ribosomes revealed that the f5C34 facilitates AUA binding in the A-site and suggested that the modification favorably alters the ASL's binding kinetics. Mitochondrial translation by many organisms including humans sometimes initiates with the universal isoleucine codons AUU and AUC. The f5C34 enabled P-site codon binding to these normally isoleucine codons. Thus, the physicochemical properties of this one modification, f5C34, expand codon recognition from the traditional AUG to the non-traditional, synonymous codons AUU and AUC as well as AUA, in the reassignment of universal codons in the mitochondria

Bone-specific alkaline phosphatase concentrations are less variable than those of parathyroid hormone in stable hemodialysis patients

Abnormalities of bone mineral metabolism and vascular calcification are prevalent in patients with kidney failure. Clinical management is based on biochemical targets, in particular parathyroid hormone (PTH) concentrations, but this has many limitations including high biological variation. A possible alternative is bone-specific alkaline phosphatase (ALP); therefore, we evaluated the biological variation of this marker in patients undergoing hemodialysis. Bone ALP was measured in non-fasting serum samples taken twice a week over a 6-week period in 22 stable hemodialysis patients and 12 healthy volunteers. The within-individual coefficients of variance were calculated and used to derive the critical difference required to be certain that an observed change was significant. The coefficient of variance for bone ALP was significantly higher in hemodialysis patients compared to healthy individuals. Seven samples were required to estimate the homeostatic set point of bone ALP, within 10%, in a hemodialysis patient. The concentration of serial bone ALP measurements would need to change by 36% between any two measurements before it can be considered a significant change. Since the biological variation of bone ALP is less than half that reported for PTH, our study provides further support for the use of bone ALP as an alternative marker of bone mineral metabolism in the setting of chronic kidney disease–mineral and bone disorder