Synthesis of Isatin Based Caspase Inhibitors

Synthesis of Isatin Based Caspase Inhibitors DESIGN AND SYNTHESIS OF ISATIN BASED CASPASE INHIBITORS FOR RUTHENIUM CAGING APPLICATIONS KASUN CHINTHAKA RATNAYAKE ABSTRACT Apoptosis is the energy dependent programmed cell death. Improper function of apoptosis could lead to diseases such as cancers, strokes, alziemer’s disease. Caspases are the enzymes involved in the later stage of this process. Peptidyl and non-peptidyl caspase inhibitors have been synthesized recently. One of these non-peptidyl compound classes which consist of pyrrolidinyl-5-sulfo isatins have showed a greater potency against executioner caspases, caspase-3 and -7. According to literature and for further caging studies, two compounds were designed, synthesized and evaluated their inhibition against caspase-3 in this study. The analog in which its N-1 position alkylated with a 4-methyl pyridine moiety (7) showed a higher inhibition than the analog in which its N-1 alkylated with cyanoethyl group (8). Thus, the compound  7  was selected for further caging studies with ruthenium. Chapter 1: Introduction 1.1 Apoptosis and Caspases Apoptosis is the process of programmed cell death. This is a significant cellular process which is directly co-related with embryogenesis, immune system, ageing and various diseases including cancers, stroke, myocardial infarction and neurodegenerative disorders.1 Caspases (cysteinyl dependent aspartate directed specific proteases) are the enzymes involved in the later stage of apoptosis. Caspases are divided to different classes according to their role played in the signaling cascade of apoptosis. Caspases 6, 8, 9 and 10 are involved as initiators and caspases 2, 3 and 7 are identified as executioner caspases in the signaling cascade.2The caspases 1, 4 and 5 are found to be non-active in the cell death process. 1.2 Caspase inhibition and modified isatin sulfonamides as caspase inhibitors Caspases play a significant role in both inflammation and apoptosis. Extensive researches have been conducted on caspases and their functions because they act as potential targets in drug discovery. Various inhibitors of Caspase have been made. These inhibitors could be categorized as non-peptidyl and peptidyl based compounds. A greater selectivity could be achieved when non-peptidyl inhibitors are used for different types of caspases. Isatin sulfonamides have showed inhibition on executioner caspases (caspase-3 and -7) in recent studies. In 2000, Lee and researchers reported the x-ray structure of caspase-3 with an isatin analog, 1-methyl-5-(2-phenoxymethyl-pyrrolidine-1-sulfonyl)-1h-indole-2,3-dione (a) bound to the active site of the enzyme (Figure 1).3 Modifying isatin sulfonamide analogues with pyrrolidine groups have shown significant effect on caspase inhibition.4 For example, various pyrrolidinyl-5-sulfo isatins have been shown inhibition to caspases, 3 and 7 (Figure 2). These isatin sulfonamide analogs are modified using structure activity relationships and performed these biological assays. The following isatin sulfonamides have shown to be inhibit caspase-3. The stereochemistry of substituted pyrrolidine moiety, cyclic vs acyclic ring structures and ring sizes have been examined for these inhibition studies (figure 3).5 1.3 Ruthenium complexes for caging applications Ruthenium compounds have been reported as significant candidates for caging applications. Light activation of these metal complexes has been extensively studied. Recently, neuroactive biomolecules as well as small molecular enzyme inhibitors have been reported to be caged with these ruthenium complexes. Spatial and temporal release of these caged molecules upon light activation gives insight to develop new tools that could be used to treat various diseases in biological systems. In this study Ruthenium polypyridyl compounds are used in future studies since they have been considered as excellent candidates for caging application of small molecules. Chapter 2: Results and Data 2.1 General considerations All reagents were purchased from commercial suppliers and used as received. Varian FT-NMR Mercury-400 Spectrometer was used to record all NMR spectra. IR spectra were recorded on High resolution mass spectra were recorded on.Melting points were recorded on .Enzyme inhibition assays were done on 2.2 Designing of Caspase inhibitors Recent studies show that various 5-pyrrolidinylsulfonyl isatins act as caspase-3 inhibitors. Several factors were considered in the designing process of these analogs. First, higher caspase inhibition was considered. Use of specific stereochemistry in the pyrrolidine moiety is important since S-alkoxypyrrolidine is more potent than its R-stereoisomer which shows almost no potency against caspase-3. It is reported that methoxymethyl pyrrolidinyl analogs show higher cell toxicity than phenoxymethyl pyrrolidines, thus methoxymethyl pyrrolidine analogs were chosen for further studies. When considering the Ruthenium caging studies, the chosen analogs should contain a group which has a higher binding affinitiy towards Ruthenium. Therefore, pyridyl and cyano groups were selected to incorporate in these isatin sulfonamide analogs. These groups are chosen to be attached to N-1 position of isatin sulfonamide analog. It has been reported that higher alkyl chain on N-1 position could increase th e inhibition. Therefore 4-methylpyridine and cyanoethyl groups were selected to attach on N-1 position of these analogs and compounds 7 and 8 are designed (Figure 3). 2.3 Synthesis of designed isatin sulfonamide analogs The designed analogs were synthesized using literature and modified procedures5, 6, 7 (Scheme 1). The compound 5 was synthesized as the precursor for the final analogs 7 and 8. The compounds 7 and 8 were synthesized using modified and optimized procedures (Scheme 2 and Scheme 3). 2.4 Enzyme Inhibition Assay Caspase-3 inhibition assay was performed for compounds 6 and 7 according to the literature procedure.2 Compound 6 was found to be more potent (IC50 = .. ) of than compound 7 (IC50 = ..). Thus, compound 6 was selected for further caging studies with Ruthenium bipyridine complexes. 2.5 Experimental 2.5.1 Sodium 2,3-dioxoindoline-5-sulfonate (1) Isatin (10 g, 0.068 mol) was added carefully to a stirred solution of 20% SO3/H2SO4 (20 mL) at -15 °C. The reaction mixture was gently warmed up to 70  °C with stirring. Reaction mixture was stirred at 70  °C for another 15-20 min. The reaction mixture was carefully poured on to crushed ice and let ice to melt and then 20% NaOH was added to the reaction mixture (pH=7). The flask containing reaction mixture was kept in an ice bath to induce precipitation of the desired product. The solid was filtered, washed with ice-cold water and dried to give red-orange crystalline solid. The 1H-NMR data was compared and matched with literature data. Yield: 14.48 g (0.051 mol. 75%) 2.5.2 2,3-dioxoindoline-5-sulfonyl chloride (2) Sodium 2,3-dioxoindoline-5-sulfonate dihydrate (2 g, 70 mmol) was dissolved in tetramethylene sulfone (10 mL) under Argon environment at 60-70  °C and phosphorus oxychloride (3.36 mL, ) was added dropwise. The reaction mixture was stirred for 3 h. The reaction was cooled to room temperature and kept in an ice bath. Then ice-cold water was added to the reaction mixture carefully. A precipitate was formed, filtered, washed with ice-cold water and dried used without further purification. The desired compound is yielded as a bright yellow solid. The 1H-NMR data was compared and matched with literature data. Yield: 1.58 g (64 mmol, 92%). 2.5.3 Tert-butyl (S)-2-(methoxymethyl)pyrrolidine-1-carboxylate (3) To a solution of N-Boc-L-prolinol (5.0 g, 25 mmol) in THF (25 mL) at -78  °C, Sodium hydride (60% in mineral oil) (960 mg, 40.0 mmol) was added and stirred for 10 min. Then methyl iodide (2.65 mL, 42.5 mmol) was added dropwise and reaction was stirred for 4h at -78  °C and additional 16 h at RT. Then NH4Cl was added until all H2 evolved and EtOAc was added. The organic layer was washed with water and sat. NaCl, dried over anhyd. Na2SO4 and concentrated to give a pale yellow oil and purified with petroleum ether: ether (9:1) to give a colorless oil. The 1H-NMR data was compared and matched with literature data. Yield: 4.986 g (23.16 mmol, 92%) 2.5.4 (S)-2-(methoxymethyl)pyrrolidine (4) To a solution of tert-butyl (S)-2-(methoxymethyl)pyrrolidine-1-carboxylate (4.98 g, 23.07 mmol) in DCM (40 mL), TFA (25 mL) was added dropwise over 30 min at 0  °C. The reaction was warmed to RT and stirred for additional 1.5 h. The reaction mixture was added to 150 mL of 10% NaOH solution and extracted with DCM (50 mL x 3), dried over anhyd. Na2SO4 and concentrated to obtain a pale yellow oil. The 1H-NMR data was compared and matched with literature data. Yield: 2.657 g (23.07 mmol, 100%) 2.5.5 (S)-5-((2-(methoxymethyl)pyrrolidin-1-yl)sulfonyl)indoline-2,3-dione (5) The compound (1) was synthesized according to procedure reported by Harvan et al.1 To a stirred solution of 2,3-dioxoindoline-5-sulfonyl chloride (2 g, 8.153 mmol) in 1:1 THF/CHCl3 (80 mL), a solution of (S)-2-(methoxymethyl)pyrrolidine (1.033 g, 8.968 mmol) and DIPEA (2.84 mL, 16.310 mmol) in CHCl3 was added dropwise under Argon environment and stirred for 1 h at 0  °C. The reaction stirred for additional 1 h at RT. The reaction mixture was concentrated and purified using 1:1 EtOAc:Petroleum ether and isolated as bright yellow crystals. The 1H-NMR data was compared and matched with literature data. Yield: 1.185 g (36.53 mmol, 45%) 2.5.6 4-(bromomethyl)pyridine hydrobromide salt (6) Pyridin-4-ylmethanol (5.0 g) was dissolved in 48% HBr (50 mL) and refluxed for 24 h. (Reaction was monitored for completion using TLC). The reaction mixture was concentrated in vacuo until a thick gum appeared and treated with absolute Ethanol at 5  °C. The white crystalline solid obtained was filtered and washed thoroughly with cold absolute Ethanol. The 1H-NMR data was compared and matched with literature data. Yield: 4.74 g (18.7 mmol, 41%) 2.5.7 (S)-5-((2-(methoxymethyl) pyrrolidin-1-yl)sulfonyl)-1-(pyridin-4-ylmethyl)indoline-2,3-dione (7) To a stirred solution of (S)-5-((2-(methoxymethyl)pyrrolidin-1-yl)sulfonyl)indoline-2,3-dione (1) (168 mg, 0.518 mmol) in DMF, 60% NaH in mineral oil (51.8 mg, 1.295 mmol) was added at 0  °C under Argon atmosphere. The reaction was stirred for 30 min. Then a solution of 4-Bromomethyl pyridine (130.6 mg, 0.518 mmol) in DMF was added dropwise and stirred for 4 h at 0  °C. The reaction was diluted with EtOAc and washed with saturated NaCl (20 mLÃâ€"3). The organic layer was dried over anhyd. Na2SO4 and concentrated in vacuo. The crude product was crystallized using EtOAc:Hexanes and isolated as a yellow solid. Yield: 85.8 mg (0.207 mmol, 40%) mp = 172-174  °C, 1H NMR (400 MHz, CDCl3): ÃŽ ´ 8.64 (d, 2H, J = 6 Hz), 8.11 (s, 1H), 8.03 (d, 1H, J = 8.4 Hz), 7.27 (d, 2H, J = 3.6 Hz), 6.83 (d, 1H, J = 8.4 Hz), 4.99 (s, 2H), 3.74 (m, 1H), 3.55 (dd, 1H, J = 9.6 Hz, 4 Hz), 1H NMR (400 MHz, DMSO): ÃŽ ´ 8.51 (d, 2H, J = ..Hz), 8.01 (d, 1H, J = Hz), 7.84 (s, 1H), 7.46 (d, 2H, J = Hz), 7.07 (d, 1H, J = Hz), 4.99 (s, 2H), 3.67 (m, 1H), 3.41 (dd, 1H), 3.24 (s, 3H), 3.06 (m, 1H), 1.73 (m, 2H), 1.48 (m, 2H) 13C NMR (100 MHz, CDCl3): ÃŽ ´ 183.2, 160.8, 152.5, 150.5, 137.5, 134.9, 124.9, 122.1, 117.5, 110.8, 74.8, 59.2, 59.1, 49.3, 43.3, 28.8, 24.1 IR (ÃŽ ½max) (KBr): 3443, 2929, 2361, 2342, 1747, 1616, 1478, 1450, 1417, 1365, 1344, 1330, 1199, 1181, 1154, 1130, 1115, 1070, 1041, 994 MS (HRMS): 432 (M+Na+MeOH)+, 400 (M+Na)+ 2.5.8 (S)-3-(5-((2-(methoxymethyl) pyrrolidin-1-yl)sulfonyl)-2,3-dioxoindolin-1-yl)propanenitrile (8) To a stirred solution of (S)-5-((2-(methoxymethyl)pyrrolidin-1-yl)sulfonyl)indoline-2,3-dione (1) (200 mg, 0.620 mmol) in DMF (10 mL), KOH (4 mg, 0.062 mmol) was added and stirred for 10 min at RT. Then acrylonitrile (45  µL, 0.680 mmol) was added dropwise and stirred for 2 days under Argon environment at RT. The reaction mixture was added to H2O (30 mL), and extracted with EtOAc (20 mLÃâ€"3). The combined organic layer was washed with 10% NaCl (20 mLÃâ€"3). The organic layer was dried over anhyd. Na2SO4 and concentrated in vacuo. The crude product was purified with CH2Cl2: MeOH (99:1) to afford yellowish-orange solid. Yield: 63.6 mg (0.169 mmol, 27%) mp = 134-138  °C, 1H NMR (400 MHz, CDCl3): ÃŽ ´ 8.15 (d,1H,J=Hz), 8.11(d,1H, J=.Hz), 7.18(d,1H,J=.Hz), 4.10 (t,2H,J=), 3.77(m,2H), 3.57(dd, 2H, J= Hz), 3.43(m,H), 3.40 (s,..H), 3.38(d, H, J=Hz), 3.36 (s,3H,), 3.14(m,H), 2.98,2.96,2.94, 2.86(t,2H, J=Hz), 2.04(s,..H), 1.92(m,H), 1.69 (m,.H), 1.55(s,H) 13C NMR (100 MHz, CDCl3): ÃŽ ´ 180.8, 157.8, 152.3, 137.6, 134.7, 124.9, 117.5, 116.8, 110.4, 74.8, 59.3, 59.1, 49.4, 36.8, 28.8, 24.1, 16.7 IR (ÃŽ ½max) (KBr): 3422, 2921, 2852, 2361, 2251, 1742, 1717, 1647, 1612, 1558, 1542, 1508, 1475, 1456, 1418, 1373, 1364, 1340, 1314, 1268, 1234, 1195, 1175, 1153, 1133, 1063, 1046, 991, 970, 905, 877 MS (HRMS): 470 (M+Na+MeOH)+ Chapter 3: Conclusion and Future directions The compounds 7 and 8 were both potent for caspase-3 but compound 7 show more inhibition than that of compound 8. Thus compound 7 was selected for further ruthenium caging studies. The caged ruthenium complexes could be subjected for light activation experiments where IC50 of this complex under light and dark conditions could be determined and the dark to light inhibition ratio could be explored. Then cell toxicity studies could be done in order to explore the ability of these ruthenium complexes for prevention of apoptosis in biological systems. These combined experiments and results could lead to the final goal of this research study which is the development of novel tools to prevent apoptosis in biological systems.

Assignment 2/Developing the Evidence Matrix/PICO Essay

Catheter associated urinary tract infections (CAUTI) are the most prevalent of all nosocomial infections inflicted upon patients while hospitalized. Approximately 30% of all hospital reported infections are of the urinary tract (Joint commission: New year will usher in new CAUTI prevention requiremants, 2011). The Joint Commission estimates the annual cost of CAUTI care is in excess of $400 million; furthermore, CAUTI care is targeted by Medicaid and Medicare services as a non-reimbursable infection. For years, postoperative urinary catheter utilization has been contested regarding the appropriate criteria required for its application, maintenance, and discontinuation. Patients hospitalized for short term postoperative care, specifically, orthopedic patients, are often catheterized due to their limited immobility. The goal of therapy with surgical orthopedic procedures is to improve mobility, not render the patient immobile. Urinary catheters are often viewed as cumbersome, inconvenient instruments of immobility by the patient. Conversely, nurses have often viewed urinary catheters as an instrument of convenience and standard of care for hospitalized patients. The use of short term urinary catheter use, whether indwelling or intermittent, in orthopedic patients has been surveyed through multiple studies, resulting in evolutionary changes in the standard of care of postoperative orthopedic patients. The contrasts  in patient outcomes utilizing indwelling catheterization, intermittent straight catheterization, and non-use of catheterization will be reviewed. PICO In postoperative orthopedic patients, how does the discontinuation of an indwelling urinary catheter compare to non-catheterization in relation to the prevention of urinary tract infection? INDWELLING URINARY CATHETERS AND THE POSTOPERATIVE ORTHOPEDIC PATIENT Population: Postoperative orthopedic patients Intervention: Discontinuation of an indwelling catheter Comparison: Non-catheterization of postoperative orthopedic patients Outcome: The patient will not exhibit any symptomology of a urinary tract infection Evidenced Based Practice Models  The Johns Hopkins Nursing Evidence Based Practice Conceptual Model (JHNEBPCM) can be utilized in this area of focus as it comprises the foundations of nursing: practice, education, and research. There are three phases to this model known as the PET process: Practice question, Evidence, and Translation. The practice question identifies a problem with a current practice. Evidentiary support to answer the practice question is produced through the utilization and evaluation of research and non-research evidence. The outcome of the implemented research is then translated into practice change, the measurement of those outcomes, and the dissemination the new research (Buchko & Robinson, 2012). The Iowa Model of Evidenced Based Practice (IMEBP) is appropriate for use in this area of focus. It allows for the entire healthcare system to be utilized in determining the need for change in the delivery of care. Employing this model allows the researcher to elect to choose between a current problem and new research as the basis for change in patient care. Once the trigger has been substantiated as a priority, a team is put in place to assemble, critique, and determine if enough research has been presented to pilot a change in current practices. If there is sufficient evidence for change and the pilot  program is successful, a change in practice will occur. Once a change has been made, the data obtained from the practice change can be further  developed utilizing this model and continuing the evolutionary cycle of improving standard of care practices. INDWELLING URINARY CATHETERS AND THE POSTOPERATIVE ORTHOPEDIC PATIENT Otherwise, if there is not enough evidence, further research may be conducted to provide enough of a base to continue toward obtaining a practice change (Dontje, 2007). The differences between the JHNEBPCM and the IMEBP are minor. They both provide a common goal: to change current practices by employing evidenced based research to foster the evolution of healthcare practices. Both models use a question or a trigger to initiate a change in practice. The minor difference between the JHNEBPCM and the IMEBP is the JHNEBPCM validates its change of practice question with the application of non-research data in addition to its research data. In this way, the JHNEBPCM can consider patient preference as an indicator to best practices. Determining the Question  The National Patient Safety Guidelines, as determined by the Joint Commission, include the prevention of indwelling CAUTI, emphasizing the prompt removal of these instruments and the observation for subsequent infection (Joint commission: New year will usher in new CAUTI prevention requiremants, 2011). The initial question was, â€Å"In admitted orthopedic surgical patients, does prompt removal of an indwelling Foley catheter within 48 hours of surgery reduce the incidence of catheter associated urinary tract infection?† In order to have a broader result list in searching for articles, the PICO parameters were refined. The population parameter was reduced to â€Å"postoperative orthopedic patients.† The intervention parameter was refined to â€Å"discontinuation of an indwelling catheter.† This removed the time constraint from the initial PICO question. Using â€Å"non-catheterization,† employed the comparison tool to serve as t he basis for improved practice. The outcome parameter, â€Å"prevention of urinary  tract infection† aligns INDWELLING URINARY CATHETERS AND THE POSTOPERATIVE ORTHOPEDIC PATIENT with the Joint Commission’s National Patient Safety Guidelines to preventing CAUTI, ensuring better patient care by eliminating infections.  Search of Evidence PubMed was the first database searched for postoperative urinary catheter indications and subsequent infections. The key terms, â€Å"indwelling urinary catheter AND urinary tract infection AND surgery,† were entered into the search bar, yielding 320 results. Accordingly, a second search using the key terms, â€Å"orthopedic surgery AND catheter associated urinary tract infection,† resulted in eight articles. Of those eight, two articles were chosen for review due to their specificity to joint surgery and urinary catheterization. The Cumulated Index of Nursing and Allied Health (CINAH) database was the second database searched. The key terms, â€Å"surgical patients and urinary tract infection,† produced 14 articles, of which two retrospective cohort studies were chosen for review based on the PICO criteria of urinary catheter use in the postoperative period. Additionally, a search for the key terms, â€Å"orthopedic surgery and catheter associated urinary tract infection† resulted in zero hits. The third database searched was Science Direct. The key terms searched for in this database were, â€Å"surgical patients, indwelling catheter, sterile field, and urinary tract infection.† This search resulted in 845 articles in which they were further limited to, â€Å"infection control,† which yielded 27 articles. Of those 27 articles, two were chosen for further review; a prospective observational study with descriptive and comparative design and a randomized control trial with cost-effe ctiveness analysis. INDWELLING URINARY CATHETERS AND THE POSTOPERATIVE ORTHOPEDIC PATIENT Evidence Review The first, and oldest, article reviewed was discouraging. Knight and Pellegrini’s (1996) randomized control trial determined utilization of indwelling catheters for urinary retention in postoperative total hip arthroplasty (THA) or total knee arthroplasty (TKA) procedures was beneficial for the patient. It was also determined urinary tract infections were not a consequence of indwelling catheter usage. The level of evidence met level one criteria, yet the grade of recommendation was D due to the weak recommendations with alternative approaches likely to better suit a different group of patients, those requiring urinary catheterization for urinary retention. The next study, a retrospective cohort study, sampled 35,904 patients who underwent major cardiac, vascular, orthopedic, or gastrointestinal surgery. A urinary catheter was placed intraoperatively, resulting in the development of a urinary tract infection if left in for more than two days; these patients were twice as likely to develop a urinary tract infection compared to patients whose catheters were removed within 48 hours of surgery (Wald, Allen, Bratzler, & Kramer, 2008). That same year, another retrospective cohort study by two of the previous authors along with two additional researchers, concluded postoperative patients admitted to skilled nursing facilities where their indwelling urinary catheters were maintained over the course of their care were associated with poorer outcomes. This study was restricted to the patients in skilled nursing facilities where direct patient care was limited and ongoing surveillance was minimal (Wald, Epstein, Radcliff, & Kramer, 2008). Both of these studies level of evidence met two-b criteria, grade of recommendation A and B respectively; the first study could apply to most patients in most circumstances, while the second study could apply to most circumstances. INDWELLING URINARY CATHETERS AND THE POSTOPERATIVE ORTHOPEDIC PATIENT The final review of Nyman, et.al, (2013), resulted in a one-a level of  evidence with an A for grade of recommendation. This randomized control trial concluded the employment of indwelling catheters and intermittent straight catheterization during the postoperative period for hip surgery patients had both benefits and disadvantages, yet non-catheterization was best for postoperative patient outcomes. This study was the most recent on record and aligned with the Joint Commission’s National Patient Safety Guidelines. Summary Evidence based practices have become the cornerstone for the standard of care in healthcare facilities. Over the course of the past 20 years, healthcare providers have provided the research necessary to remove indwelling urinary catheters as the standard of care in postoperative orthopedic patients; from advocating of their use for urinary retention in the late 1990’s to limiting their utilization today. The higher incidence of CAUTI has provided Medicaid and Medicare programs support in rejecting reimbursement measures to facilities for these types of nosocomial infections. New nurse directed protocols supported by evidenced based research have decreased the incidence of CAUTI, although, if these practices are to continue to be successful, a physician culture change must be embraced. The entire healthcare team must continue to participate in an active role to eliminate unnecessary and preventable infections, specifically CAUTI’s. To appropriately act on the behalf of the patient, clinicians must ensure best practices not only for the well-being of the patient, but for the fiscal survival of a healthcare facility. INDWELLING URINARY CATHETERS AND THE POSTOPERATIVE ORTHOPEDIC PATIENT References Buchko, B., & Robinson, L. (2012). An evidenced-based approach to decrease early postoperative urinary retention following urogynecologic surgery. Urology Nursing, 32(5), 260-264. Dontje, K. (2007). Evidence-based practice:Understanding the process. Topics in Advanced Practice Nursing eJournal, 7(4). Joint commission: New year will usher in new CAUTI prevention requiremants. (2011). AIDS ALERT, 26(11), 1-2. Knight, R., & Pellegrini, V. (1996). Bladder management after total joint arthoplasty. The Journal of Arthroplasty, 11(8), 882-888. Nyman, M., Gustafsson, M., Langius-Eklof, A., Johansson, J.-E., Norlin, R., & Hagberg, L. (2013). Intermittent versus indwelling urinary catheterisation in hip surgery patients: A randomised controlled trial with cost-effectiveness analysis. International Journal of Nursing Studies, 50, 1589-1598. doi:10.1016/j.ijnurstu.2013.05.007 Wald, H., Allen, M., Bratzler, D., & Kramer, A. (2008). Indwelling urinary catheter use in the postoperative period: Analysis of teh national surgical infection prevention project data FREE. Arch Surg, 143(6), 551-557. doi:10.1001/archsurg.143.6.551 Wald, H., Epstein, A., Radcliff, T., & Kramer, A. (2008). Extended use of urianry catheters in older surgical patients: A patient safety issue? Infevtion Control and Hospital Epidemiology, 29(2), 116-124. doi:10.1086/526433

A Foundation Week Story Essay

What is Foundation week? Other students celebrate it by not going to school because for them it’s the time of their rest day but other students celebrate it by going to school and hanging out with their friends. As students of College of Nursing and Allied Health Sciences, we celebrate Foundation week by making ourselves busy. On September 22, 2014, Monday, the programme starts with the Cultural Competition and due to our Anatomy Class we’re not able to watch the competition, on the afternoon, the search for MR. and MS. Batangas State University starts. At the end of the competition, MR. Malvar and MS. CEAFA got the title for MR. and MS. BSU 2014. On the Second day of the Foundation Week, September 23, 2014, Tuesday, the programme starts with the opening talk of the University President Dr. Tirso A. Ronquillo, on the same day we perform our Bench Yell and Launched the newest symbol of valor, â€Å"The Red Spartans† , the University’s official mascot which designed by Mr. John Jeffrey Alcantara were â€Å"The Red Spartans† define the values of BatStateU; Unity, courage, and excellence. After that event we start our cooking for our Booth in the Students Fair, the third year BSND are the assigned in cooking, while second year students serves as their helping hands. On September 24, 2014, Wednesday, we need to go to school early for us to end up early our cooking session. On the same day, the opening of intramurals and cheerdance competition held, and due to our cooking we’re not able to watch the competition and according to other students who witnessed the competition, the Main Campus got the title. On September 25, 2014, Thursday, we started the day by cooking for our booth and end up the day by cleaning our booth. On September 26, 2014, Friday, Last day of the Foundation week, we started the day same as we started last Thursday, before the day ended up, the judges decided who has the best booth, and the College of Nursing and Allied Health Sciences won the title. With the theme: â€Å"BatStateU @ 111: Gearing for the ASEAN Challenge of Excellence† , Foundation Week ended up successfully yet stressful but it helps us, the students, to apply what we are learning.

Developmental Issues That Surround Title 2 And The Internet

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