IN VITRO INTERACTION OF AMINOGLYCOSIDES AND BETA-LACTAM PENICILLINS

The aminoglycoside antibiotics are often used in combination with a f3-lactam antibiotic, to provide either a wider spectrum of activity against gram-negative bacilli or a synergistic antimicrobial effect against Pseudomonas aeruginosa and various enterobacteria. In 1971, MacLaughlin & Reeves found that the combined use of gentamicin and carbenicillin resulted in an interaction and loss of activity of both antibiotics. Since then more studies, in vitro and in vivo, have been performed to study the effect of medium, temperature, concentration, time, pH and different penicillin-aminoglycoside combinations on the interaction. The purpose of this study was to investigate the kinetics of the interaction in vitro. Four different concentrations of aminoglycosides (A) (5, 10, 15 & 20 pg/mL of gentamicin or tobramycin) and penicillins (P) (100, 200, 400 & 600 pg/mL of carbenicillin or ticarcillin) were incubated in plasma at 37°C for 3 days. Samples taken at 12 h intervals were analyzed for both aminoglycoside and penicillin by radioimmunoassay and high pressure liquid chromatography, respectively. Degradation of all four antibiotics in controls were first order reactions. The degradation of penicillins was faster than the aminoglycosides, with only 50% of the original concentration remaining at 24 h. In incubation mixtures, the rate of loss of penicillins was not significantly different from the controls and still appeared as a first order reaction. The interaction did not contribute significantly to the loss of penicillin. However, the rate of loss of aminoglycosides was greater than in controls and appeared as a second order reaction dependent on the concentration of both penicillin and aminoglycoside. The loss of aminoglycoside was due to its degradation in plasma and its interaction with penicillin. The degradation constants of penicillins (Kp) were calculated as dP/dt = -K PP and averaged 1.8 x 10 -2 h -1 for carbenicillin and 2.6 x 10 -2 h -1 for ticarcillin in controls and averaged 2.2 x 10 -2 h -1 for carbenicillin and 3.0 x 10 -2 h -1 for ticarcillin in antibiotic mixtures. In both controls and mixtures, the time required for loss of 50% of initial analyzed concentration (t50) was 30 & 55% larger, for carbenicillin and ticarcillin respectively, at higher penicillin concentrations of 400 & 600 µg/mL compared to lower penicillin concentrations of 100 & 200 µg/mL. The degradation constants of aminoglycosides (KA) in controls were calculated as dA/dt = -K A A and averaged 0.9 x 10 -3 h -1 for gentamicin and 1.2 x 10 -3 h -1 for tobramycin. The degradation constants of aminoglycosides in antibiotic mixtures and the interaction rate constants (K.) were determined by computer fitting of the aminoglycoside concentrations in incubation mixtures to a model incorporating a second order loss of aminoglycoside and a first order loss of penicillin from the mixtures. The degradation constants of aminoglycosides in antibiotic mixture were less than 1 x 10 -8 h -1 . The t 50 values of aminoglycosides in antibiotic mixtures were shorter than in controls (> 25 days) and were related to the concentration of penicillin. The t50 values of aminoglycosides were longer than 72 h at a penicillin concentration of 100 µg/mL. As the concentration of penicillin became higher, the t50 values became shorter and were less than 10 h for a penicillin concentration of 600 µg/mL. The interaction rate constants averaged 2.2 x 10-4 mL/µgxh and 1.6 x 10 -4 mL/µgxh for both carbenicillin and ticarcillin interactions with gentamicin and tobramycin, respectively. The "effective" interaction rate constants (K. x P) were larger for the higher penicillin concentrations. Examination of both the t 50 values of aminoglycosides and the K. indicated that there was no significant difference between the interaction rate produced by carbenicillin and ticarcillin and gentamicin was inactivated more by carbenicillin and ticarcillin than tobramycin. The effect of the interaction in vivo was examined by computer simulation using the kinetic parameters determined in vitro. The interaction of penicillin and aminoglycoside would be significant in patients with impaired renal function and might be significant in patients with normal renal function when the concentration of penicillin is very high

IDENTIFICATION OF ACTIVITIES INVOLVED IN CAG/CTG REPEAT INSTABILITY

CAG/CTG repeat instability is associated with at least 14 neurological disorders, including Huntington’s disease and Myotonic dystrophy type 1. In vitro and in vivo studies have showed that CAG/CTG repeats form a stable hairpin that is believed to be the intermediate for repeat expansion and contraction. Addition of extra DNA is essential for repeat expansion, so DNA synthesis is one of the keys for repeat expansion. In vivo studies reveal that 3’ CTG slippage with subsequent hairpin formation (henceforth called the 3’ CTG slippage hairpin) occurs during DNA synthesis. It is proposed that hairpin tolerance machinery is activated because prolonged stalling of DNA polymerase triggers severe DNA damage. As a means toward studying the hairpin-mediated expansion, we created a special hairpin substrate, mimicking the 3’ CTG slippage hairpin, to determine which polymerase promotes hairpin bypass. Our studies reveal polymerase β (pol β) is involved in the initial hairpin synthesis while polymerase δ (pol δ) is responsible for the resumption of DNA synthesis beyond the hairpin (extension step). Surprisingly, we also found that the pol δ can remove the short CTG hairpin by excision of the hairpin with its 3’ to 5’ exonuclease activity. Besides repairing the hairpin directly, resolving the hairpin is an alternative pathway to maintain CAG/CTG repeat stability. With limited understanding of which human helicase is responsible for resolving CAG/CTG hairpins, we conducted a screening approach to identify the human helicase involved. Werner Syndrome Protein (WRN) induces the hairpin repair activity when (CTG)35 hairpin is formed on the template strand. Primer extension assay reveals that WRN stimulates pol δ synthesis on (CAG)35/(CTG)35 template and such induction was still found in the presence of accessory factors. Helicase assay confirms that WRN unwinds CTG hairpin structures. Our studies provide a better understanding of how polymerases and helicases play a role in CAG/CTG repeat instability. Considering CAG/CTG repeat instability associated disorders are still incurable, our studies can provide several potential therapeutic targets for treating and/or preventing CAG/CTG repeat associated disorders

Differ in Socio-Cognitive Processes? Some Comparisons Between Paper and Video Triggered PBL

This paper investigates whether paper and video triggers stimulate different social and cognitive processes during PBL. The study focused on how medical students identified and described problems, and how they built shared cognitions that lead them to diagnose and solve problems. The results showed that students who used video triggers put more effort into communicating their understanding of the problem and relevant knowledge than students who used paper triggers. The findings contribute to discussions on how to evaluate the effectiveness of different PBL triggers in order to better integrate them into the curriculum

Continuous Monitoring of Distributed Data Streams over a Time-based Sliding Window

The past decade has witnessed many interesting algorithms for maintaining statistics over a data stream. This paper initiates a theoretical study of algorithms for monitoring distributed data streams over a time-based sliding window (which contains a variable number of items and possibly out-of-order items). The concern is how to minimize the communication between individual streams and the root, while allowing the root, at any time, to be able to report the global statistics of all streams within a given error bound. This paper presents communication-efficient algorithms for three classical statistics, namely, basic counting, frequent items and quantiles. The worst-case communication cost over a window is $O(\frac{k} {\epsilon} \log \frac{\epsilon N}{k})$ bits for basic counting and $O(\frac{k}{\epsilon} \log \frac{N}{k})$ words for the remainings, where $k$ is the number of distributed data streams, $N$ is the total number of items in the streams that arrive or expire in the window, and $\epsilon < 1$ is the desired error bound. Matching and nearly matching lower bounds are also obtained.Comment: 12 pages, to appear in the 27th International Symposium on Theoretical Aspects of Computer Science (STACS), 201

Cross-Talk between PPARs and the Partners of RXR: A Molecular Perspective

The PPARs are integral parts of the RXR-dependent signaling networks. Many other nuclear receptor subfamily 1 members also require RXR as their obligatory heterodimerization partner and they are often co-expressed in any given tissue. Therefore, the PPARs often complete with other RXR-dependent nuclear receptors and this competition has important biological implications. Thorough understanding of this cross-talk at the molecular level is crucial to determine the detailed functional roles of the PPARs. At the level of DNA binding, most RXR heterodimers bind selectively to the well-known “DR1 to 5” DNA response elements. As a result, many heterodimers share the same DR element and must complete with each other for DNA binding. At the level of heterodimerization, the partners of RXR share the same RXR dimerization interface. As a result, individual nuclear receptors must complete with each other for RXR to form functional heterodimers. Cross-talk through DNA binding and RXR heterodimerization present challenges to the study of these nuclear receptors that cannot be adequately addressed by current experimental approaches. Novel tools, such as engineered nuclear receptors with altered dimerization properties, are currently being developed. These tools will enable future studies to dissect specific RXR heterodimers and their signaling pathways

Chinese herbal medicine research in eczema treatment

Eczema is a chronic relapsing atopic dermatitis (AD) associated with pruritus, sleep disturbance and poor quality of life of the patient. Treatment of eczema includes use of emollient, topical and systemic antimicrobial agents, corticosteroid or immunomodulating agents. Many patients also seek alternative treatments such as dietary avoidance, supplementation or both. This article reviews the basic pathophysiology of eczema and clinical trials involving Chinese medicine in the treatment of eczema. Research reports on Chinese herbal medicine for eczema were retrieved from PubMed and the Cochrane Database for Systematic Reviews for this review. Only a few RCTs demonstrated the efficacy (or lack of efficacy) of Chinese medicinal herbs in treating atopic eczema. Further larger scale trials are warranted

Online Searching in PBL Tutorials

This study aims to explore how online searching plays a role during PBL tutorials in two undergraduate health sciences curricula, Medicine and Dentistry. Utilizing Interactional Ethnography (IE) as an organizing framework for data collection and analysis, and drawing on a critical theory of technology as an explanatory lens, enabled a textured understanding of student practices and beliefs regarding online searching during face-to-face PBL tutorials. Two event maps trace key transitions in learning regarding online searching in one cycle of problem-based learning in each program. From a critical perspective, analysis of students’ stimulated recall interviews indicated that the use of students’ personal mobile devices with online searching capacity is considered a dynamic pedagogically and socially constructed process. Online searching during the PBL process is also viewed as a “site-of-struggle” where there are challenges for first-year undergraduates when implementing such learning technologies in PBL tutorials

A systematic review on ankle injury and ankle sprain in sports

This article systematically reviews epidemiological studies on sports injury from 1977 to 2005 in which ankle injury was included. A total of 227 studies reporting injury pattern in 70 sports from 38 countries were included. A total of 201 600 patients were included, with 32 509 ankle injuries. Ankle injury information was available from 14 098 patients, with 11 847 ankle sprains. Results show that the ankle was the most common injured body site in 24 of 70 included sports, especially in aeroball, wall climbing, indoor volleyball, mountaineering, netball and field events in track and field. Ankle sprain was the major ankle injury in 33 of 43 sports, especially in Australian football, field hockey, handball, orienteering, scooter and squash. In sports injuries throughout the countries studied, the ankle was the second most common injured body site after the knee, and ankle sprain was the most common type of ankle injury. The incidence of ankle injury and ankle sprain was high in court games and team sports, such as rugby, soccer, volleyball, handball and basketball. This systematic review provides a summary of the epidemiology of ankle injury in sports

Genome-wide association studies of metabolites in Finnish men identify disease-relevant loci

The Finnish population is enriched for genetic variants which are rare in other populations. Here, the authors find new genetic loci associated with 1391 circulating metabolites in 6136 Finnish men, demonstrating that metabolite genetic associations can help elucidate disease mechanisms. Few studies have explored the impact of rare variants (minor allele frequency < 1%) on highly heritable plasma metabolites identified in metabolomic screens. The Finnish population provides an ideal opportunity for such explorations, given the multiple bottlenecks and expansions that have shaped its history, and the enrichment for many otherwise rare alleles that has resulted. Here, we report genetic associations for 1391 plasma metabolites in 6136 men from the late-settlement region of Finland. We identify 303 novel association signals, more than one third at variants rare or enriched in Finns. Many of these signals identify genes not previously implicated in metabolite genome-wide association studies and suggest mechanisms for diseases and disease-related traits.Peer reviewe