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Renin and aldosterone activity levels are low in elderly patients, raising concerns about the benefits and risks of angiotensin-converting-enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARB) use. However, data from direct comparisons of the effects of ACEIs on ARBs in the elderly population remain inconclusive. In this nationwide study, all patients aged ≥ 70 years were retrieved from the Taiwan National Health Insurance database for the period 2000 to 2009 and were followed up until the end of 2010. The ARB cohort (12,347 patients who continuously used ARBs for ≥ 90 days) was matched to ACEI cohort using high-dimensional propensity score (hdPS). Intention-to-treat (ITT) and as-treated (AT) analyses were conducted. In the ITT analysis, after considering death as a competing risk, the ACEI cohort had similar risks of myocardial infarction (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.79–1.06), ischemic stroke (HR 0.98, 95% CI 0.90–1.07), and heart failure (HR 0.93, 95% CI 0.83–1.04) compared with the ARB cohort. No difference in adverse effects, such as acute kidney injury (HR 0.99, 95% CI 0.89–1.09) and hyperkalemia (HR 1.02, 95% CI 0.87–1.20), was observed between cohorts. AT analysis produced similar results to those of ITT analysis. We were unable to demonstrate a survival difference between cohorts (HR 1.03, 95% CI 0.88–1.21) after considering drug discontinuation as a competing risk in AT analysis. Our study supports the notion that ACEI and ARB users have similar risks of major adverse cardiovascular events (MACE), even in elderly populations.

6-Arylthio and 6-arylselenoacyclonucleosides was synthesized and tested for the ability to inhibit replication of HIV-1. Lithiation of acyclonucleosides with LDA followed by reaction with the electrophiles phenyl disulfide, diphenyl diselenide, 2,2′-dipyrdyl disulfide or 2,2′-dipyridyl diselenide afforded 6-(arylthio or arylseleno)acyclonucleosides 5a-c, 6, 7, 9, 15a-c, 17a-c. Compounds 19a-c and 20a-c were obtained by deprotection of corresponding TBDMS derivatives. Dehydrated products 16a, and 18a-c were also formed during the reactions. 5-Ethyl-6-(α-pyridylthio or α-pyridylseleno) disubstituted acyclouracils 6 and 7 were more active against HIV-1 in both MT-2 and CEM-IW cell lines than AZT, DDC, DDI or D4T. The EC50 of 6 against HIV-1 in CEM-IW cell was in the nanomolar range with a therapeutic index of 1100.

Blends between poly(acrylic acid) and two different poly(oxyethylenes), (1) polyethylene glycol (PEG-1000) and (2) poly(oxyethylene) (20) sorbitan monooleate (Tween-80), were studied by differential scanning calorimetry. The glass transition temperatures, Tg, of the various compositions of these blends were found to follow Fox's equation. At room temperature, blends containing no more than 60% PEG-1000 were amorphous and exhibited only a single glass transition. For these blends with PEG-1000, the glass transition temperatures for the annealed samples were higher than for the quenched samples due to the formation of a PEG crystalline phase. It was also found that addition of an amorphous polymer such as poly(acrylic acid) significantly reduced the degree of crystallinity of a semicrystalline polymer such as poly(oxyethylene). The Tween-80 systems did not show phase separation at room temperature. The compatibility between this poly(acrylic acid) and this poly(oxyethylene) was attributed to hydrogen bonding and to the lower crystalline lattice energy of this poly(oxyethylene) through its effect on its ideal solution solubility. © 1993 John Wiley & Sons, Inc.

5-Benzyl and 5-benzyloxybenzyl-substituted 3′-azido-2′,3′-dideoxyuridine, (8a and 8b), 3′-halogeno-2′,3′-dideoxyuridine, 9a, 9b, 10a, 10b, 11a and 11b, and 2′,3′-dideoxyuridine, 12a and 12b, of Scheme I were synthesized as potential anti AIDS agents. Synthesis of epimers of 8a and 8b, 5-benzyl- and 5-benzyloxybenzyl-1-(3′-azido-2′,3′-dideoxy-β-D-threo-pentafuranosyl)uracil, 15a and 15b, and 5-benzyl- and 5-benzyloxy-5′-azido-2′,5′-dideoxyuridine, 16a and 16b, shown in Scheme II, were also reported.

1'-Halogenomethyl, 1'-azidomethyl and 1'-disubstituted aminomethyl derivatives of BAU (5-benzylacyclouridine) and BBAU (5-benzyloxybenzylacyclouridine) were synthesized in the course of our studies of benzylacyclouridines. Two new and more convenient preparations of the previously known aminomethyl-and hydroxyymethyl-parent compounds of these two series, AM-BAU, AM-BBAU and HM-BBAU are also reported. These compounds were synthesized during a search for potential antiviral agents and pyrimidine phosphorylase inhibitors

6-Arylthio and 6-arylselenoacyclonucleosides was synthesized and tested for the ability to inhibit replication of HIV-1. Lithiation of acyclonucleosides with LDA followed by reaction with the electrophiles phenyl disulfide, diphenyl diselenide, 2,2′-dipyrdyl disulfide or 2,2′-dipyridyl diselenide afforded 6-(arylthio or arylseleno)acyclonucleosides 5a-c, 6, 7, 9, 15a-c, 17a-c. Compounds 19a-c and 20a-c were obtained by deprotection of corresponding TBDMS derivatives. Dehydrated products 16a, and 18a-c were also formed during the reactions. 5-Ethyl-6-(α-pyridylthio or α-pyridylseleno) disubstituted acyclouracils 6 and 7 were more active against HIV-1 in both MT-2 and CEM-IW cell lines than AZT, DDC, DDI or D4T. The EC50 of 6 against HIV-1 in CEM-IW cell was in the nanomolar range with a therapeutic index of 1100.

A novel class of nucleosides with the C1, atom bonded to three hetero atoms was synthesized. 2′-Thia-2′,3′-dideoxycytidine was the pilot compound of this series. (±)-β-2′-Thia-1′,3′-dideoxycytidine (6) and (±)-α-2′-thia-2′,3′-dideoxycytidine (7) were synthesized from (±)-3-mercapto-1,2-propanediol. The synthesis of the enantiomerically pure 2′-thia-2′,3′-dideoxycytidines (α-D-form, β-D-form, α-1-form and β-L-form) from optically pure (S)-(2,2-dimethyl-1,3-dioxalan-yl)methyl p-toluenesulfonate (8) and its (R)-isomer 18 was also described. The preliminary biological results showed that (+)-β-D-2′-thia-2′,3′-dideoxycytidine (26) was the most active against human hepatitis B virus with an ED50 of 3 μM.

1'-Halogenomethyl, 1'-azidomethyl and 1'-disubstituted aminomethyl derivatives of BAU (5-benzylacyclouridine) and BBAU (5-benzyloxybenzylacyclouridine) were synthesized in the course of our studies of benzylacyclouridines. Two new and more convenient preparations of the previously known aminomethyl-and hydroxyymethyl-parent compounds of these two series, AM-BAU, AM-BBAU and HM-BBAU are also reported. These compounds were synthesized during a search for potential antiviral agents and pyrimidine phosphorylase inhibitors

We used a green fluorescent kidney line, Tg(wt1b:GFP), as a model to access the acetaminophen (AAP)-induced nephrotoxicity dynamically. Zebrafish (Danio rerio) embryos at different developmental stages (12-60hpf) were treated with different dosages of AAP (0-45mM) for different time courses (12-60h). Results showed that zebrafish embryos exhibited no evident differences in survival rates and morphological changes between the mock-treated control (0mM) and 2.25mM AAP-exposure (12-72hpf) groups. In contrast, after higher doses (22.5 and 45mM) of exposure, embryos displayed malformed kidney phenotypes, such as curved, cystic pronephric tube, pronephric duct, and a cystic and atrophic glomerulus. The percentages of embryos with malformed kidney phenotypes increased as the exposure dosages of AAP increased. Interestingly, under the same exposure time course (12h) and dose (22.5mM), embryos displayed higher percentages of severe defects at earlier developmental stage of exposure (12-24hpf), whereas embryos displayed higher percentages of mild defects at later exposure (60-72hpf). With an exposure time course less than 24h of 45mM AAP, no embryo survived by the developmental stage of 72hpf. These results indicated that AAP-induced nephrotoxicity depended on the exposure dose, time course and developmental stages. Immunohistochemical experiments showed that the cells' morphologies of the pronephric tube, pronephric duct and glomerulus were disrupted by AAP, and consequently caused cell death. Real-time RT-PCR revealed embryos after AAP treatment decreased the expression of cox2 and bcl2, but increased p53 expression. In conclusion, AAP-induced defects on glomerulus, pronephric tube and pronephric duct could be easily and dynamically observed in vivo during kidney development in this present model.

Purpose – The purpose of this chapter is to examine the issues of outsourcing and corresponding policy interventions by the government. Design/methodology/approach – This chapter begins with a situation in which no government interventions are allowed, and examine the government of the North, when it is allowed to intervene, can choose one of the three options: (a) to limit the quantity of each type of variety of the foreign intermediate inputs to be imported; (b) to limit the number of varieties of the foreign intermediate inputs to be imported; and (c) to impose a tariff on the imported intermediate inputs. Findings – For each policy, the optimal intervention is derived. Originality/value – The analysis can be used to examine the argument for restricting outsourcing.

It has been reported that in vitro uridine (Urd) can reverse azidothymidine (AZT) cytotoxicity without decreasing anti-human immunodeficiency virus (HIV) activity. Our studies in mice have shown that daily oral doses of benzylacyclouridine (BAU), an inhibitor of Urd breakdown, also reduces AZT hematologic toxicity, presumably by elevating the plasma concentration of Urd. We now extend these murine studies and report the effect of various doses of exogenous Urd, various doses of BAU, or the combination of BAU and Urd, administered daily, on AZT-induced toxicity. In mice receiving concomitant AZT, daily doses of Urd of 1,000 to 2,000 mg/kg increase peripheral reticulocytes and slightly reduce AZT-induced hematologic toxicity. However, the range of effective doses is narrow, and higher doses of Urd (greater than 3,000 mg/kg/d) significantly enhance hematologic toxicity. At its most effective dose, (2,000 mg/kg/d), Urd produces 28% mortality. In contrast, BAU doses up to 300 mg/kg/d reduced AZT-related hematologic toxicity in a dose-dependent manner without mortality. Higher daily doses of BAU and the combination of BAU with low doses of Urd were not more effective. Studies conducted in mice infected with the Rauscher murine leukemia virus (RLV) indicate that BAU does not impair the antiretroviral effect of AZT when administered at doses that reduce AZT-induced anemia and leukopenia. These findings may be significant for the treatment of patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex.

5-Benzyl and 5-benzyloxybenzyl-substituted 3′-azido-2′,3′-dideoxyuridine, (8a and 8b), 3′-halogeno-2′,3′-dideoxyuridine, 9a, 9b, 10a, 10b, 11a and 11b, and 2′,3′-dideoxyuridine, 12a and 12b, of Scheme I were synthesized as potential anti AIDS agents. Synthesis of epimers of 8a and 8b, 5-benzyl- and 5-benzyloxybenzyl-1-(3′-azido-2′,3′-dideoxy-β-D-threo-pentafuranosyl)uracil, 15a and 15b, and 5-benzyl- and 5-benzyloxy-5′-azido-2′,5′-dideoxyuridine, 16a and 16b, shown in Scheme II, were also reported.

Sarcoidosis is a multisystemic granulomatous disease of unknown etiology and is uncommon in Taiwan. No cases of familial sarcoidosis have been reported in Taiwan. In this article, we report a mother and son pair who had sarcoidosis. The 56-year-old mother sought medical help for chronic cough for 3 months in 1993. Enlarged mediastinal lymph nodes were demonstrated on chest computed tomography. Besides, two small erythematous papules on her face were observed. Mediastinoscopic biopsy and skin biopsy showed non-caseating granulomatous inflammation. Sarcoidosis was thus diagnosed. The human leukocyte antigen (HLA)-typing of the patient was HLA-A2, A11, B35, B39, CW4, CW7, DR8 and DQ6. Eleven years later, her son was also diagnosed with sarcoidosis proved by mediastinoscopic biopsy. His HLA-typing was HLA-A2, A24, B39, B48, CW7, CW8, DR8 and DQ6. This is the first report of familial sarcoidosis in Chinese people. More cases are needed for further investigation of genetic predisposition among Chinese people.

Spermidine synthase (putrescine aminopropyltransferase, PAPT) catalyzes the transfer of the aminopropyl group from decarboxylated S-adenosylmethionine to putrescine during spermidine biosynthesis. Helicobacter pylori PAPT (HpPAPT) has a low sequence identity with other PAPTs and lacks the signature sequence found in other PAPTs. The crystal structure of HpPAPT, determined by multiwavelength anomalous dispersion, revealed an N-terminal β-stranded domain and a C-terminal Rossmann-like domain. Structural comparison with other PAPTs showed that HpPAPT has a unique binding pocket between two domains, numerous non-conserved residues, a less acidic electrostatic surface potential, and a large buried space within the structure. HpPAPT lacks the gatekeeping loop that facilitates substrate binding in other PAPTs. PAPTs are essential for bacterial cell viability; thus, HpPAPT may be a potential antimicrobial drug target for H. pylori owing to its characteristic PAPT sequence and distinct conformation. Proteins 2007. © 2007 Wiley-Liss, Inc.

Current vendor software for authority control is found to generate negative results for nonunique Chinese headings in the local catalog. After authority control, nonunique Chinese names in the bibliographic records are found routinely altered to match authority headings established in the Library of Congress (LC) authority file that are unrelated to the Chinese script of the bibliographic record. Headings with standard diacritics in the Wade-Giles romanization scheme are the most problematic. The name headings that are negatively affected in the authority control services need to be corrected before the LC Pinyin conversion project takes place around the year 2000 to prevent headings from being distorted further in the Pinyin conversion process. In this paper, I examine the reasons why vendor software produces negative results for nonunique Chinese names, and suggest measures for Chinese-Japanese-Korean (CJK) libraries in North America and vendors who supply authority-control services that include CJK data to improve the situation. These include vendor software upgrades, modifications to CJK Name Authority Cooperative procedures, etc. The authority control service at the University of North Carolina at Chapel Hill is used to illustrate the problem.

At a nontoxic growth inhibitory concentration benzyloxyacyclouridine (BAU), a potent and specific inhibitor of uridine phosphorylase (UrdPase), enhanced 5-fluorouracil (5-FU) cytotoxic activity against human prostate cancer PC-3 and DU-145 cell lines. The BAU/5-FU combination exhibited greater antitumor activity in vivo using PC-3 human xenografts compared to 5-FU alone, with no associated increase in animal host toxicity. The mechanism(s) responsible for the enhanced in vitro and in vivo activity of this combination may involve enhanced formation of the 5-FU nucleotide metabolites FdUMP, FdUTP, and FUTP resulting in enhanced inhibition of thymidylate synthase (TS) and increased incorporation of fluoropyrimidine metabolites into tumoral RNA and DNA.

Redington Shores is located on the west coast of Florida on the barrier island, Sandy Key, in Pinellas County. A detached offshore breakwater, located to the west of Redington Shores, was constructed in 1986. The breakwater was designed by the US Army Engineer District, Jacksonville, to control beach erosion and re- duce beach nourishment requirements. This paper presents the beach response at Redington Shores to this breakwater. Initial shoreline response described in Dean and Pope (1987) for the pre- and post-construction period, september 1984 to November 1986, is summarized. The subsequent shoreline changes monitored and documented by the Jacksonville District (US Army Corps of Engineers 1989) for the post-construction period, April 1986 to February 1988, and the post- renourishment shoreline response data are analyzed and interpreted along with the regional wave climate.

The trajectory of a water particle in an oscillatory wave field has been studied by following the movement of the particle. The particle position at the end of each small time increment is calculated using the Eulerian velocity specifications. The results show the path of water particle is not a closed orbit and the calculated mass-transport velocity is in general agreement with Storkes formula. For the second-order waves, the present results demonstrate a much smaller mass-transport velocity than that predicted by the Storkes formula. In addition, the present study shows that a water particle does not return to the initial depth level at the end of each wave period. Instead, it moves in an oscillatory nature in the direction of wave propagation at a period much longer rate than the water waves.

Discussions and comparisons are provided of dynamic breaking wave forces on vertical walls predicted by Minikin and Goda methods. Normalized wave forces computed by both methods are plotted as functions of water depth to deepwater wavelength ration, seabed slope, and superstructure and foundation dimension ratio. The results exhibit distinctly different characteristics of the two predictive methods. The Minikin method is more conservative than the Goda method for large depth to wavelength ratio. With long wave or shallow water depth, the Goda method predicts conservative forces.

Nucleoside analogues of uridine, 5-bromo-, 5-iodo-, and 5-fluorouridines, thymidine and cytidine were prepared by condensing appropriately substituted 2,4-dimethoxypyrimidines with an acyclic side chain in the form of a benzoylated halo-ether, and subsequent removal of the protecting benzoyl group in base. The 2′-O-p-tosylates of these nucleoside analogues could then be modified to 2′-halo-, azido-, and amino derivatives. Many of these compounds are competitive inhibitors of uridine phosphorylase in vitro, the most active being 5-methyl-1-(2′-hydroxyethoxymethyl)uracil.

A useful, facile procedure for preparing seleno-heterocyclic compounds is reported. Treatment of cAMP, AMP, adenosine, 2-aminoadenosine, adenine arabinoside and formycin with hydrogen selenide in aqueous pyridine at 65° for 1.5-5 days gave the corresponding seleno compounds in good yield, while these compounds were relatively inert to hydrogen sulfide. A reaction mechanism is proposed.

A series of 5′-halogenated formycins, including the chloro-, bromo- and iodo- derivatives, were synthesized. These compounds are competitive inhibitors of 5′-deoxy-5′-methylthioadenosine phosphorylase (MTAPase) with Ki values in the range of 10−7 M, making them the most potent inhibitors of MTAPase reported to date. These compounds protect cells from the growth-inhibitory action of 5′-halogenated adenosines, which must be activated by MTAPase. The syntheses of 5′-halogenated formycin B derivatives, which inhibit purine nucleoside phosphorylase, are also described.

Furanosyl analogs of BAU (5-benzylacyclouridine) and BBAU (5-benzyloxybenzylacyclouridine), two potent inhibitors of uridine phosphorylase, were synthesized and evaluated as potential cancer chemotherapeutic agents. The analogs included ribosides, 2,2′-anhydro nucleosides, arabinosides and deoxyribosides. The anhydrouridine intermediates were potent inhibitors of uridine phosphorylase and good potentiators of FdUrd activity in human tumor cells in culture.

6-Chloro-9-(beta-D-arabinofuranosyl)purine served as an intermediate for the chemical synthesis of a series of 6-substituted selenopurine arabinosides. In an in vitro test using murine leukemic cells (L-5178Y) these 6-substituted selenopurine arabinosides showed some cytotoxicity. Lengthening the side chain had no effect on their cytotoxicity. Selenourea was a useful reagent for synthesizing selenopurines, selenopurine nucleosides, and selenopurine arabinoside under mild conditions.

The title compound crystallizes in the triclinic space group [Formula: see text] and the cell dimensions are a = 16.890(3), b = 9.586(2), c = 6.316(1) Å, α = 91.09(1), β = 93.50(1), γ = 93.04(1)°. X-ray intensity data were measured on a diffractometer, and the crystal structure was determined by direct methods. Least-squares refinement, which included all hydrogen atoms, converged at R = 0.056 for 3454 observed reflections. Adjacent six-membered rings are approximately perpendicular to one another. The glycosidic torsion angle [C(6)—N(1)—C(1′)—O(4′)] is 96.2(2)°. In the acyclic moiety, both C—OH bonds are gauche with respect to C(4′)—O(4′). The gauche conformation is also dominant in solution, as determined by high-resolution 1H nmr spectroscopy. Results of nuclear Overhauser experiments lead to conclusions about the flexibility of the molecule.

Eighty-seven pyrimidine base and nucleoside analogs were evaluated as inhibitors of uridine phosphorylase (UrdPase) and thymidine phosphorylase (dThdPase). These findings, together with an extensive literature review, have allowed construction of structure-activity relationships for the binding of ligands to UrdPase and dThdPase and provide a basis for the rational design of new inhibitors of these enzymes. Additionally, 2,6-pyridinediol and 6-benzyl-2-thiouracil have been identified as being potent inhibitors of UrdPase and dThdPase respectively.