Domino Rh-catalyzed hydroformylation–doublecyclization of o-amino cinnamyl derivatives:applications to the formal total syntheses ofphysostigmine and physovenine

A parallel, versatile and efficient route to synthesis of pyrrolidinoindoline and tetrahydrofuranoindoline alkaloids from cinnamyl derivatives has been developed, featuring a domino Rh-catalyzed hydroformylation–double cyclization sequence. This method can be applied to the syntheses of anti-Alzheimer drugs such as physostigmine and physovenine

Clonal dissemination of the multi-drug resistant Salmonella enterica serovar Braenderup, but not the serovar Bareilly, of prevalent serogroup C1 Salmonella from Taiwan

<p>Abstract</p> <p>Background</p> <p>Nontyphoidal <it>Salmonella </it>is the main cause of human salmonellosis. In order to study the prevalent serogroups and serovars of clinical isolates in Taiwan, 8931 <it>Salmonellae </it>isolates were collected from 19 medical centers and district hospitals throughout the country from 2004 to 2007. The pulsed-field eletrophoresis types (PFGE) and antibiotic resistance profiles of <it>Salmonella enterica </it>serovars Bareilly (<it>S</it>. Bareilly) and Braenderup (<it>S</it>. Braenderup) were compared, and multi-drug resistance (MDR) plasmids were characterized.</p> <p>Results</p> <p>Over 95% of human salmonellosis in Taiwan was caused by five <it>Salmonella </it>serogroups: B, C1, C2-C3, D1, and E1. <it>S</it>. Typhymurium, <it>S</it>. Enteritidis, <it>S</it>. Stanley and <it>S</it>. Newport were the four most prevalent serovars, accounting for about 64% of isolates. While only one or two major serovars from four of the most prevalent serogroups were represented, four predominant serovars were found in serogroup C1 <it>Salmonellae</it>. The prevalence was decreasing for <it>S</it>. Choleraeuis and <it>S</it>. Braenderup, and S. Virchow and increasing for <it>S</it>. Bareilly. <it>S</it>. Braenderup mainly caused gastroenteritis in children; in contrast, <it>S</it>. Bareiley infected children and elderly people. Both serovars differed by <it>Xba</it>I-PFGE patterns. Almost all <it>S</it>. Bareilly isolates were susceptible to antibiotics of interest, while all lacked plasmids and belonged to one clone. Two distinct major clones in <it>S</it>. Braenderup were cluster A, mainly including MDR isolates with large MDR plasmid from North Taiwan, and cluster B, mainly containing susceptible isolates without R plasmid from South Taiwan. In cluster A, there were two types of conjugative R plasmids with sizes ranging from 75 to 130 kb. Type 1 plasmids consisted of replicons F1A/F1B, <it>bla</it>_TEM, IS<it>26</it>, and a class 1 integron with the genes <it>dfrA12</it>-<it>orfF</it>-<it>aadA2-qacE</it>Δ1-<it>sulI</it>. Type 2 plasmids belonged to incompatibility group Inc<it>I</it>, contained <it>tnpA</it>-<it>bla</it>_CMY-2-<it>blc</it>-<it>sugE </it>genetic structures and lacked both IS<it>26 </it>and class 1 integrons. Although type 2 plasmids showed higher conjugation capability, type 1 plasmids were the predominant plasmid.</p> <p>Conclusions</p> <p>Serogroups B, C1, C2-C3, D1, and E1 of <it>Salmonella </it>caused over 95% of human salmonellosis. Two prevalent serovars within serogroup C1, <it>S</it>. Bareilly and cluster B of S. Braenderup, were clonal and drug-susceptible. However, cluster A of <it>S</it>. Braenderup was MDR and probably derived from susceptible isolates by acquiring one of two distinct conjugative R plasmids.</p

In vitro activities of antimicrobial combinations against planktonic and biofilm forms of Stenotrophomonas maltophilia

ObjectivesTo investigate the in vitro activity of antibiotic combinations against Stenotrophomonas maltophilia isolates and their associated biofilms.MethodsThirty-two S. maltophilia clinical isolates with at least twenty-five different pulsotypes were tested. The antibacterial activity of various antibiotic combinations against seven randomly selected planktonic and biofilm-embedded S. maltophilia strains with strong biofilm formation was assessed using broth methods. Extraction of bacterial genomic DNA and PCR detection of antibiotic resistance and biofilm-related genes were also performed.ResultsThe susceptibility rates of levofloxacin (LVX), fosfomycin (FOS), tigecycline (TGC) and sulfamethoxazole-trimethoprim (SXT) against 32 S. maltophilia isolates were 56.3, 71.9, 71.9 and 90.6%, respectively. Twenty-eight isolates were detected with strong biofilm formation. Antibiotic combinations, including aztreonam-clavulanic (ATM-CLA) with LVX, ceftazidime-avibactam (CZA) with LVX and SXT with TGC, exhibited potent inhibitory activity against these isolates with strong biofilm formation. The antibiotic resistance phenotype might not be fully caused by the common antibiotic-resistance or biofilm-formation gene.ConclusionS. maltophilia remained resistant to most antibiotics, including LVX and β-lactam/β-lactamases; however, TGC, FOS and SXT still exhibited potent activity. Although all tested S. maltophilia isolates exhibited moderate-to-strong biofilm formation, combination therapies, especially ATM-CLA with LVX, CZA with LVX and SXT with TGC, exhibited a higher inhibitory activity for these isolates

Results of Fabry Disease Screening in Male Pre-End Stage Renal Disease Patients with Unknown Etiology Found Through the Platform of a Chronic Kidney Disease Education Program in a Northern Taiwan Medical Center

Background/Aims: Fabry disease (FD), a rare x-lined genetic disorder is a cause of renal deterioration. The phenotype of FD is highly variable and nonspecific, and correct diagnosis has always been delayed. We aimed to explore the prevalence and clinical presentation of FD in this high-risk male population in a Northern Taiwan medical center. Methods: This is the first study to survey the incidence of FD in this high-risk population through the platform of a chronic kidney disease (CKD) education program in Asia. A total of 1,012 male patients with unknown CKD causes were screened using an assay of alpha-galactosidase A activity (α-Gal A) by dried blood spots (DBS). A final GLA gene analysis was also done for those with low enzyme activity. Results: We identified two new patients with classic FD and four patients with late-onset FD. One novel GLA mutation with c.413 G&#x3e;A was found in one classic FD patient (index 5). The prevalence of FD is about 0.59 % (6 in 1,012) in the high-risk population group with CKD. The clinical symptoms of FD patients are nonspecific except in those with various degrees of renal failure. Those patients’ correct diagnosis was delayed, taking years and even decades. Three patients received enzyme replacement therapy and one started regular hemodialysis due to persistent renal function deterioration. Another two patients were found from family screening through a new index. In addition, a false negative result occurred in one patient who was proved to have FD by his kidney pathology as determined by this screening. Conclusion: FD is not such as rare a disease and its prevalence is greater in this high-risk male population. Clinicians need to be aware that FD should be included in the differential diagnosis in CKD with unknown etiology

Pilot Scale Production of Highly Efficacious and Stable Enterovirus 71 Vaccine Candidates

BACKGROUND: Enterovirus 71 (EV71) has caused several epidemics of hand, foot and mouth diseases (HFMD) in Asia and now is being recognized as an important neurotropic virus. Effective medications and prophylactic vaccine against EV71 infection are urgently needed. Based on the success of inactivated poliovirus vaccine, a prototype chemically inactivated EV71 vaccine candidate has been developed and currently in human phase 1 clinical trial. PRINCIPAL FINDING: In this report, we present the development of a serum-free cell-based EV71 vaccine. The optimization at each step of the manufacturing process was investigated, characterized and quantified. In the up-stream process development, different commercially available cell culture media either containing serum or serum-free was screened for cell growth and virus yield using the roller-bottle technology. VP-SFM serum-free medium was selected based on the Vero cell growth profile and EV71 virus production. After the up-stream processes (virus harvest, diafiltration and concentration), a combination of gel-filtration liquid chromatography and/or sucrose-gradient ultracentrifugation down-stream purification processes were investigated at a pilot scale of 40 liters each. Although the combination of chromatography and sucrose-gradient ultracentrifugation produced extremely pure EV71 infectious virus particles, the overall yield of vaccine was 7-10% as determined by a VP2-based quantitative ELISA. Using chromatography as the downstream purification, the virus yield was 30-43%. To retain the integrity of virus neutralization epitopes and the stability of the vaccine product, the best virus inactivation was found to be 0.025% formalin-treatment at 37 °C for 3 to 6 days. Furthermore, the formalin-inactivated virion vaccine candidate was found to be stable for >18 months at 4 °C and a microgram of viral proteins formulated with alum adjuvant could induce strong virus-neutralizing antibody responses in mice, rats, rabbits, and non-human primates. CONCLUSION: These results provide valuable information supporting the current cell-based serum-free EV71 vaccine candidate going into human Phase I clinical trials

RE-EXAMINING FACTORS INFLUENCING INFORMATION TECHNOLOGY ACCEPTANCE BY INDIVIDUAL PROFESSIONALS

This study proposed a comprehensive decomposed TPB model to understand the factors influencing the intentions of individual professionals to use information technology. A field survey was conducted to collect analysis data from physicians who have used Medline system, a kind of evidence-based medicine database, in Taiwan. After the research model was tested by the partial least square method with bootstrap estimate, we found that decomposed TPB provides effective prediction of physicians\u27 acceptance intention of the Medline system. Comparing to subjective norm and perceived behavioral control, attitudes towards using the IS provide better predictive power for behavioral intention. In addition, perceived usefulness and perceived ease of use have significant impact on attitude, respectively. Perceived ease of use has significant impact on perceived usefulness. The variance of subjective norm can be effectively explained by interpersonal influence. Personal innovativeness in IT not only directly influences perceived behavioral control, but also indirectly influences perceived behavioral control through self-efficacy. However, the facilitating conditions have no significant effect on perceived behavioral control. These findings not only provide insights for further research related to information technology acceptance by individual professionals, but also offer medical institutions practical suggestions

Using Micro-Molding and Stamping to Fabricate Conductive Polydimethylsiloxane-Based Flexible High-Sensitivity Strain Gauges

In this study, polydimethylsiloxane (PDMS) and conductive carbon nanoparticles were combined to fabricate a conductive elastomer PDMS (CPDMS). A high sensitive and flexible CPDMS strain sensor is fabricated by using stamping-process based micro patterning. Compared with conventional sensors, flexible strain sensors are more suitable for medical applications but are usually fabricated by photolithography, which suffers from a large number of steps and difficult mass production. Hence, we fabricated flexible strain sensors using a stamping-process with fewer processes than photolithography. The piezoresistive coefficient and sensitivity of the flexible strain sensor were improved by sensor pattern design and thickness change. Micro-patterning is used to fabricate various CPDMS microstructure patterns. The effect of gauge pattern was evaluated with ANSYS simulations. The piezoresistance of the strain gauges was measured and the gauge factor determined. Experimental results show that the piezoresistive coefficient of CPDMS is approximately linear. Gauge factor measurement results show that the gauge factor of a 140.0 μm thick strain gauge with five grids is the highest