Safety and Availability of Clofazimine in the Treatment of Multidrug and Extensively Drug-Resistant Tuberculosis: Analysis of Published Guidance and Meta-Analysis of Cohort Studies

Objectives: Given the spread of multidrug-resistant tuberculosis (MDR-TB), new therapies are urgently needed, including the repurposing of existing drugs. We aimed to assess key considerations for the clinical and programmatic use of clofazimine (Cfz), a riminophenazine with anti-mycobacterial activity currently used to treat leprosy. Design: Fixed and random effects meta-analysis of cohort studies and systematic review Setting: Electronic and manual searches were combined. Inclusion criteria: Observational studies on treatment of multidrug- and extremely drug- resistant tuberculosis with clofazimine or a clofazimine-containing regimen, and published guidance and documents relating to cost and availability were eligible. Results: Five observational studies enrolled 861 patients, of which 602 received Cfz. The pooled proportion of adverse drug reactions requiring discontinuation of Cfz treatment was 0.1% (95% CI: [0.0, 0.6%]), and the median frequency of all adverse events was 5.1%. Cfz showed in vitro efficacy against Mycobacterium tuberculosis, and Cfz-containing regimens may have had a useful role in the treatment of patients with drug-resistant strains and who had limited alternative treatment options. However, Cfz uptake remains insufficient to meet global needs; there is only one internationally quality-assured manufacturer, which produces a limited quantity of the drug prioritised for treatment of leprosy, the only indication for which the drug is registered. Conclusions: While the data were limited, Cfz was associated with a risk for adverse drug reactions comparable to that of first-line TB treatment, which could be reasonably managed under programmatic conditions. However, low market availability and high cost are important barriers to access to Cfz for MDR-TB patients.Other Research Uni

The Catholic Bohemian German dialect of Ellis, Kansas

Ph.D. University of Kansas, Germanic Languages and Literatures 1998Beginning in the 1880s, many German speaking immigrants left the Austrian settlements in Bukovina for the United States. The Bukovina immigrants to the Ellis area in west central Kansas formed two distinct groups in Ellis. The Lutheran "Swabian" Germans, who speak a Palatine type of dialect, came from southwest Germany. The Catholic Bohemian Germans, which represent the focus of my research, found their way to America and Kansas via Bukovina from the Bohemian Forest, today situated in the Czech Republic. The Catholic Bohemian Germans retained the native dialect for the first two generations following their arrival in Kansas. The pressure of assimilation into the American mainstream society and the subsequent decline of the German dialect grew with increasing anti-German animosity between the two World Wars. This dissertation provides a written documentation of what is left of the Catholic Bohemian German dialect of Ellis, Kansas, which, like other remaining German dialects in Kansas, faces its linguistic demise. The linguistic data for this study were gathered by tape recorded interviews with eleven informants. The main source for the recorded interview sessions were a series of forty Wenker sentences and a number of isolated vocabulary items used for the compilation of the Deutscher Wortatlas (the German word atlas). Recordings of free conversations and picture descriptions of rural scenes in the dialect also provided data for this project. In addition, anecdotes and jokes were obtained from some informants. The interview materials were presented in English with the informants answering in the native dialect. The language of the Catholic Bohemian Germans has dialect features which are mainly associated with Central Bavarian, but it also shows characteristics of the Central-North Bavarian dialect transition zone. In addition to the historical background of the Bukovina Germans, the phonology, morphology, and syntactic structure of the Ellis Catholic Bohemian German dialect are described in detail. Other linguistic issues dealt with are lexical forms, borrowing, the linguistic history and dialect geographical origin. Finally, implications on language death and the revival of heritage awareness of Bukovina Germans are discussed

Recent trends in microdialysis sampling integrated with conventional and microanalytical systems for monitoring biological events: A review

Microdialysis (MD) is a sampling technique that can be employed to monitor biological events both in vivo and in vitro. When it is coupled to an analytical system, microdialysis can provide near realtime information on the time-dependent concentration changes of analytes in the extracellular space or other aqueous environments. Online systems for the analysis of microdialysis samples enable fast, selective and sensitive analysis while preserving the temporal information. Analytical methods employed for online analysis include liquid chromatography (LC), capillary (CE) and microchip electrophoresis and flow-through biosensor devices. This review article provides an overview of microdialysis sampling and online analysis systems with emphasis on in vivo analysis. Factors that affect the frequency of analysis and, hence, the temporal resolution of these systems are also discussed

Continuous monitoring of adenosine and its metabolites using microdialysis coupled to microchip electrophoresis with amperometric detection

Rapid monitoring of concentration changes of neurotransmitters and energy metabolites is important for understanding the biochemistry of neurological disease as well as for developing therapeutic options. This paper describes the development of a separation-based sensor using microchip electrophoresis (ME) with electrochemical (EC) detection coupled to microdialysis (MD) sampling for continuous on-line monitoring of adenosine and its downstream metabolites. The device was fabricated completely in PDMS. End-channel electrochemical detection was accomplished using a carbon fiber working electrode embedded in the PDMS. The separation conditions for adenosine, inosine, hypoxanthine, and guanosine were investigated using a ME-EC chip with a 5 cm long separation channel. The best resolution was achieved using a background electrolyte consisting of 35 mM sodium borate at pH 10, 15% dimethyl sulfoxide (DMSO), and 2 mM sodium dodecyl sulphate (SDS), and a field strength of 222 V cm−1. Under these conditions, all four purines were separated in less than 85 s. Using a working electrode detection potential of 1.4 V vs. Ag/AgCl, the limits of detection were 25, 33, 10, and 25 μM for adenosine, inosine, hypoxanthine, and guanosine, respectively. The ME-EC chip was then coupled to microdialysis sampling using a novel all-PDMS microdialysis–microchip interface that was reversibly sealed. This made alignment of the working electrode with the end of the separation channel much easier and more reproducible than could be obtained with previous MD-ME-EC systems. The integrated device was then used to monitor the enzymatic conversion of adenosine to inosine in vitro

Separation and Detection of Tyrosine and Phenylalanine-derived Oxidative Stress Biomarkers Using Microchip Electrophoresis with Electrochemical Detection

This is the peer reviewed version of the following article: D. B. Weerasekara, S. M. Lunte, Electroanalysis 2022, 34, 1913, which has been published in final form at https://doi.org/10.1002/elan.202100580. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.A method for the determination of selected aromatic amino acid biomarkers of oxidative stress using microchip electrophoresis with electrochemical detection is described. The separation of the major reaction products of phenylalanine and tyrosine with reactive nitrogen and oxygen species was accomplished using ligand exchange micellar electrokinetic chromatography with a PDMS/glass hybrid chip. Electrochemical detection was achieved using a pyrolyzed photoresist film working electrode. The system was evaluated for the analysis of the products of the Fenton reaction with tyrosine and phenylalanine, and the reaction of peroxynitrite with tyrosine

A review of microdialysis coupled to microchip electrophoresis for monitoring biological events

Microdialysis is a powerful sampling technique that enables monitoring of dynamic processes in vitro and in vivo. The combination of microdialysis with chromatographic or electrophoretic methods yields along with selective detection methods yields a “separation-based sensor” capable of monitoring multiple analytes in near real time. Analysis of microdialysis samples requires techniques that are fast (<1 min), have low volume requirements (nL–pL), and, ideally, can be employed on-line. Microchip electrophoresis fulfills these requirements and also permits the possibility of integrating sample preparation and manipulation with detection strategies directly on-chip. Microdialysis coupled to microchip electrophoresis has been employed for monitoring biological events in vivo and in vitro. This review discusses technical considerations for coupling microdialysis sampling and microchip electrophoresis, including various interface designs, and current applications in the field

Determination of Methylarginines in Infant Plasma by CE-LIF

Methylarginines (MAs) are a class of nitric oxide synthase inhibitors that have been implicated in respiratory complications of critically ill infants. This paper describes the development of an analytical method to measure these compounds in the plasma of newborns using capillary electrophoresis (CE). The CE separation method was optimized to enable complete baseline resolution of the four MA analogues of interest. Sample preparation concerns for infant-derived samples were addressed by validating a heat-assisted extraction method for the analysis of low volume (≤100 µL) samples from a plasma matrix. It was determined that the sample matrix (plasma versus serum) did not affect the measured MA concentrations, while extracting smaller volumes of plasma that underwent heat-induced gelation afforded higher MA recoveries than larger volume samples. These methods were then applied to blood samples collected from infants housed in the neonatal intensive care unit. It was discovered that these newborns had significantly elevated concentrations of MAs at younger ages (< 6 months) while amounts were similar between infants 6 months old and adults. The data are preliminary, but demonstrate an interesting age dependence on the concentrations of these nitric oxide inhibitors, which has not been previously reported

Impulse der Christlichen Soziallehre für die EU. Personen und Themen

ZusammenfassungImpulse Christlicher Soziallehre für die Europäische Union können persönlicher und theoretisch-konzeptioneller Natur sein. Den persönlichen Aspekt konkretisiert der Essay am Beispiel wichtiger europäischer Protagonisten. Mit ihrer gemeinsamen geistigen Grundlage in der Christlichen Soziallehre stehen diese Persönlichkeiten stellvertretend für viele Akteure auf unterschiedlichen Ebenen der EU. Aber auch die vertragliche Gestalt der EU ist von der Christlichen Sozialethik geprägt und es gibt demnach ebenfalls einen theoretisch-konzeptionellen Impuls christlich-sozialethischer Ideen in der EU. Diese Beobachtung führt der Text anhand der Themen »Stellung der Arbeit«, »Solidarität« sowie »Subsidiarität« weiter aus. Abschließend fragt er, inwiefern auch die EU Einfluss auf die Weiterentwicklung der Christlichen Sozialethik habe.AbstractThis paper illustrates the impacts of Christian social ethics on the European Union. These suggestions have a personal as well as a theoretical-conceptual focus. The personal focus is realised through the example of important European protagonists. Having in common their spiritual grounding in Christian social ethics, the quoted personalities are representative of a great many actors at various levels within the EU. Since the contractual framework of the EU is also informed by Christian social ethics, there is also an impact at the theoretical-conceptual level. This observation will be further elaborated on the basis of such topics as “status of labour”, “solidarity” and “principle of subsidiarity”. Finally, there will be an investigation of the question in how far the EU, in turn, impacts on the development of Christian social ethics.urn:nbn:de:hbz:6:3-201201272

Separation and Detection of Peroxynitrite Using Microchip Electrophoresis with Amperometric Detection

Peroxynitrite (ONOO-) is a highly reactive species implicated in the pathology of several cardiovascular and neurodegenerative diseases. It is generated in vivo by the diffusion-limited reaction of nitric oxide (NO•) and superoxide anion (•O2-) and is known to be produced during periods of inflammation. Detection of ONOO- is made difficult by its short half-life under physiological conditions (∼1 s). Here we report a method for the separation and detection of ONOOfrom other electroactive species utilizing a microchip electrophoresis device incorporating an amperometric detection scheme. Microchip electrophoresis permits shorter separation times (∼25 s for ONOO-) and higher temporal resolution than conventional capillary electrophoresis (several minutes). This faster analysis allows ONOO- to be detected before substantial degradation occurs, and the increased temporal resolution permits more accurate tracking of dynamic changes in chemical systems

Stoßinduzierte Strömungsablösung in transitionellen Grenzschichten

Die Auswirkungen von transitionellen Stoß-Grenzschicht-Wechselwirkungen (SGWW) auf die induzierten Wärmelasten und den Verlauf des laminar-turbulenten Umschlags sind Thema dieser Arbeit. Experimentelle Untersuchungen wurden bei Mach 6 am Rohrwindkanal Göttingen an einer ebenen Platte durchgeführt. Die Strömungstopologie wurde mittels Schattenaufnahmen untersucht und die Wärmestromdichte über quantitative Infrarotthermographie bestimmt. Zusätzlich wurden die Druck- und Dichteschwankungen innerhalb der Grenzschicht mittels Drucksensoren bzw. fokussierter Laser-Differentialinterferometrie detektiert. Verschiedene Verfahren zur Quantifizierung des Transitionsfortschrittes wurden anhand der Messdaten verglichen und lieferten systematische Abweichungen in der Intermittenzverteilung. Die Abweichungen ließen sich anhand der experimentellen Implementierung erklären und liegen im Rahmen der Messgenauigkeit. Unter Verwendung eines zweidimensionalen einfallenden Stoßes wurde systematisch und unabhängig die Stoßauftreffposition (x_imp), die Stoßintensität sowie die Lage der natürlichen Transition variiert. Die Messungen zeigen einen systematischen Einfluss der variierten Parameter auf die räumliche Verteilung der Wärmestromdichte. Hierbei korreliert die maximale stoßinduzierte dimensionslose Wärmestromdichte St_max mit dem Transitionsende der Grenzschicht. Die Entfernung bis zum Transitionsende und derWert von St_max hängen maßgeblich von der Kombination aus Stoßintensität und dem Grenzschichtzustand bei x_imp ab. Durch eine Skalierung der relativen Lage der Stoßauftreffposition mit der Länge des ungestörten Transitionsgebietes ergibt sich eine einheitliche Verteilung der normierten St_max-Werte. Für die Normierung wird zum einen der Einfluss der Stoßintensität mit dem Skalierungsgesetz von Holden (1977) berücksichtigt und zum anderen ein aus der ungestörten St-Verteilung abgeleiteter Referenzwert verwendet. Die höchsten Wärmestromverstärkungen werden bei transitionellen SGWW beobachtet