Explain the concept of wellbeing and factors that influence it Describe downstream consequences of burnout and distress Analyze personal wellbeing across multiple domains Evaluate the extent to which wellbeing is supported across organization levels Describe interventions that could be implemented to foster a culture of wellbeing

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Oral vitamin K is administered to patients who have very high INR lab values and are on warfarin therapy. Due to the inability of some patients to swallow tablets, and the commercial formulation of vitamin K being available only as a tablet or an injectable emulsion, it may be necessary to compound an oral liquid formulation. When compounding batches of oral solutions, it is sometimes convenient to measure the product in unit doses. In this project, we compared liquid vitamin K in sterile water (1mg/mL) verses liquid vitamin K in Ora-Sweet (1mg/mL) stored in amber plastic syringes. Vitamin K is light sensitive and is best stored in amber containers. Vitamin K is also lipophilic and may adsorb to the plastic syringes. In this study, we investigated the feasibility of bulk compounding oral vitamin K solutions, and aliquoting them for storage in amber plastic syringes. The Vitamin K in sterile water syringes were made by mixing 45 mL of sterile water and 5 ampules, each containing 10mg/mL of vitamin K emulsion, together in an amber glass bottle for a final concentration of 1mg/mL. Thirty 1mL plastic amber syringes were filled with the mixture, capped, and placed in the refrigerator. The same process was repeated using Ora-Sweet instead of sterile water to fill thirty more plastic amber syringes. Three syringes of vitamin K in sterile water mixture, three syringes of vitamin K in Ora-Sweet mixture, and one Vitamin K reference standard were all analyzed using HPLC-UV on the day of compounding, and at day 1, 2, 4, 7, 14, 21, 30, 60, and 90. If stability is defined as 90-110% active ingredient, then Vitamin K in sterile water is stable to fourteen days, 95.3±3.5% recovery, but some samples fell below 90% recovery after 14 days. By day ninety, the recovery in SWFI syringes was 84.2±8.9%. For vitamin K in Ora-Sweet, the within-day variability was very high due to limitations in drug dissolution; as such the average concentration was not consistently above 90%. On the day of compounding, the percent recovery in the Ora-Sweet syringes was 92.7±9.9%, despite 1 hour of stirring. In conclusion, the Vitamin K in sterile water mixture can be stored in refrigerated, amber oral plastic syringes for 14 days, but plastic amber syringes were not appropriate for storage of the Vitamin K in Ora-Sweet mixture.

The effects of a physiologically balanced mixture of amino acids on the synthesis of proteins has been investigated. The roles of leucine and tryptophan, both implicated in the regulation of protein synthesis, were also studied. The balance of amino acids is important under specific rate-limiting conditions; the physiological balance "protects" the protein synthesizing system from the stressed condition of leucine limitation. Leucine is an important regulator of protein synthesis and the tryptophan effect on translation is dependent on the concentration of leucine. Thus tryptophan is a secondary regulator. The relative concentration of amino acids, described as balance, alterned the synthesis of protein in cell-free and intact cell culture experiments, when leucine was limiting. Both qualitative and quantitative differences were observed. The effect of the amino acid mixture decreased when the concentration of leucine was physiological. Two different components were sensitive to added leucine. This sensitivity was indicated by different kinetics; one component showed low Km and Vmax values while the other showed high Km and Vmax values. The initial rate of protein synthesis was first order with respect to leucine when it was limiting and mixed order when it was physiological. The effect of tryptophan on stimulation of protein synthesis was small in comparison to the effect of leucine, and was dependent on the ooncentration of leucine. The incorporation of leucine into protein was changed as the tryptophan concentration changed when leucine was limiting; synthesis of albumin was slightly stimulated. The ribosome distribution did not change as indicated by polysome analysis. The incorporation of leucine into protein did not change when· leucine was physiological and tryptophan was. varied. However, the ribosome distribution was altered. A low molecular weight inhibitor of protein synthesis was found in cell extracts which acted independently of amino acid or leucine concentrations. It could be partially removed by treatment with G-25 Sephadex, but has not been purified. Several nucleotide effects independent of amino acid concentration were also observed. ATP, at increasing concentrations, significantly depressed levels of synthesis and concentrations greater than 4 mM caused 100% inhibition of the protein synthesizing system. The phosphodiesterase inhibitor, theophyllin~ enhanced synthesis of albumin, although the cyclic nucleotide, cAMP, did not itself alter synthesis of protein. Finally, the concentrations of amino acids in plasma of C3HeB/FeJ mice were determined. The two amino acids examined in the protein synthesis experiments, tryptophan and leucine, were found to remain relatively constant, regardless of the fed or fasted condition of the animals, but showed changes with the age of the animals.

Until the past few years, cellulose derivatives, (e.g., cellophane, collodion, and parchment) and animal membranes (e.g., goldbeater’s skin) have been the only dialysis membranes employed commercially. Cellophane has been used as the dialysis membrane in the artificial kidney since the machine’s inception in 1914. It continues to serve in this capacity, even though, in the last few years, attempts have been made to develop better films. An appreciation of both the “solution theory” and the “pore theory” is in order for this discussion. By incorporating the dynamics of these theories in the techniques of membram formulation, improved membrane performance can be exhibited. In the following discussion which considers membrane formulation, improved membrane performance can be displayed by higher particle transfer rates and greater particle selectivity.

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To investigate the mechanism of polyamine- and acetylpolyamine-induced vasodilation, aortic rings from anesthetized New Zealand white rabbits (2.0-2.5 kg) were incubated in modified Krebs-Henseleit buffer, precontracted with phenylephrine (PE), and isometric tension measured. Concentration-response curves were constructed for polyamines (putrescine, spermidine, and spermine) and acetylpolyamines ($N\sp1$-acetylputrescine, $N\sp1$-acetylspermidine, $N\sp8$-acetylspermidine, and $N\sp1$-acetylspermine) in both endothelium-intact and -denuded rings. In both types of rings, all polyamines and acetylpolyamines except $N\sp1$-acetylputrescine produced concentration-dependent relaxation (potency, spermine $>$ spermidine $>$ putrescine for polyamines; $N\sp1$-acetylspermine $>\ N\sp1$-acetylspermidine $>$ $N\sp8$-acetylspermidine for acetylpolyamines). The inhibition of endothelium-derived relaxing factor (EDRF)/nitric oxide (NO) by reduced hemoglobin and $N\sp\omega$-nitro- sc L-arginine methyl ester (sc L-NAME), and the inhibition of soluble guanylate cyclase by methylene blue did not affect the ability of polyamines or acetylpolyamines to relax vascular smooth muscle with and without endothelium, respectively. Indomethacin had no effect on polyamine- or acetylpolyamine-induced vasodilation in endothelium-intact aortic rings. In endothelium-denuded rings, Ca$\sp{2+}$ agonist, Bay K 8644, induced concentration-dependent contraction in segments of rabbit aorta, partially depolarized with 15 mM KCl. This was blocked by Ca$\sp{2+}$ antagonists, nifedipine and verapamil, and polyamines and acetylpolyamines in a concentration-dependent manner, shifting the concentration-response curve of Bay K 8644 to the right. Polyamines and acetylpolyamines as nifedipine and verapamil shifted concentration-response curves of K$\sp+$ and PE to the right in a concentration-dependent manner. Polyamines and acetylpolyamines also decreased contractions invoked by the Ca$\sp{2+}$ ionophore A23187. The concentration-dependent contraction curve for exogenous Ca$\sp{2+}$ in K$\sp+$-depolarization medium (K$\sp+$ = 120 mM) was shifted to the right by polyamines and acetylpolyamines. Both polyamines and acetylpolyamines also reduced the potentiation of K$\sp+$-induced contraction and Ca$\sp{2+}$ concentration-dependent contraction induced by Bay K 8644. The results indicate that polyamines and acetylpolyamines, as endogenous vasodilators, dilate vascular smooth muscle independent of EDRF/NO, vasodilatory prostaglandins, and by activation of soluble guanylate cyclase. Furthermore, these results suggest that polyamines and acetylpolyamines may relax vascular smooth muscle at the plasma membrane level by a mechanism that involves Ca$\sp{2+}$ influx, although may other mechanism may be possible. Further studies are needed to determine if polyamines and acetylpolyamines have calcium antagonistic properties that are involved in the mechanism of vasodilation of rabbit aortic vascular smooth muscle.

The bZIP transcription factors make up a family of long α-helical proteins that dimerize based on a pattern of hydrophobic residues and bind to DNA through a region of basic residues. Because binding specificity is a particular topic of interest, the dimerization interaction is attractive as a possible candidate to better understand protein quaternary structure. Use of the Knob-Socket (KS) model for determination of packing structure provides a novel approach to analyze protein-protein interactions. A KS analysis of the protein-protein interface provides unique insight into the specificity of the classical leucine zipper pseudo-7mer repeat. From an analysis of the KS packing maps, this research provides evidence of a general framework for defining the specificity between coiled-coils. The KS maps show how hydrophobic specificity is defined in the coiled-coil interface, where knobs are centralized in the middle of the socket packing, while the peripheral socket residues are hydrophilic. Based on this KS analysis, the KS model will be used to design proteins that mimic the leucine zipper region of bZIP proteins. The proteins will be purified into E. coli and its 2º structure will be confirmed through circular dichroism. Binding specificity will be studied through mutations of the designed proteins and compared using the BACTH (bacterial adenylate cyclase two-hybrid) system.

Peptides have been used as targeting ligands in targeted drug delivery. Conjugating peptides to cytotoxicity agents via a linker to build peptide-drug conjugate (PDC) is a promising targeting strategy. The binding affinity of the peptide ligand and the receptor plays a crucial role in the PDC targeted drug delivery. Although the ligand binding which can be used in targeted drug delivery has been established conceptually, the quantitative or semi-quantitative contribution of binding affinity in targeting efficiency has not been fully explored. The optimal range of binding affinity of the peptide for targeted delivery remains unknown. Therefore, there is a lack of knowledge on the relationship between the peptide binding affinity and targeted drug delivery efficiency. The major steps in peptide drug delivery include cellular binding, cellular internalization, and tumor cells killing. In this study, three EGFR-targeting peptides with binding affinity levels ranging from 22 nM to 1.25 μM were selected to study their targeted drug delivery efficiency. The cellular binding study of FITC labeled peptides showed that peptide GE11 with the highest binding affinity had the highest cellular binding among three peptides. PEP11 peptide showed enhanced cellular binding compared to the L1 peptide. Moreover, GE11 also showed the selectivity of cellular binding between EGFR-positive cells and EGFR-negative cells. The cellular distribution showed that GE11-FITC could be successfully internalized into cells. The uptake mechanism studies demonstrated that the cellular uptake of GE11-FITC was based on receptor-mediated endocytosis, meaning that the cellular binding of GE11 was able to trigger the endocytosis. MMAE, a non-selective anticancer agent, was conjugated to the peptides through a protease-sensitive linker. The cytotoxicity assay showed that GE11-MMAE had the highest drug delivery efficiency and selectivity of three peptides, with 200 folds lower IC50 value than MMAE in EGFR-positive cells and 1000 times lower in EGFR-negative cells. PEP11-MMAE also showed an enhanced drug delivery than MMAE and L1-MMAE. L1-MMAE failed to show a significant difference with MMAE. Cellular binding kinetics results revealed that GE11-FITC had a higher rate of cellular uptake than PEP11-FITC. In conclusion, in the range from micromolar to the nanomolar, higher binding affinity of peptide ligand will contribute to higher cellular binding, targeted drug delivery efficiency, and cellular uptake rate. These results suggest that in EGFR-targeting delivery, the nanomolar level binding affinity is necessary for peptides to be used as targeting moiety in the targeted drug delivery. This study provides a starting point for further quantitative probing of the optimal binding affinity for designing and developing peptide ligand-based targeted delivery.