217 research outputs found
Trade in substandard and falsified medicines
According to WHO, 10.5% of medicines in low- and middle-income countries are substandard or falsified (SF), which has a multidimensional impact on public health as well as severe economic and socioeconomic consequences. Constrained access, weak technical capacity and poor governance contribute to the emergence of SF medicines. The increasing complexity of supply chains in our globalised world and the growing popularity of e-commerce provide numerous entry points for illegal medical products in both the Global South and the Global North. The COVID-19 pandemic led to a global surge in SF medicines. Various actors are involved in the trafficking of SF medicines. Key elements to combat SF medicines are prevention, detection and response with united, global participation of all parties involved
New Aminocoumarin Antibiotics Formed by a Combined Mutational and Chemoenzymatic Approach Utilizing the Carbamoyltransferase NovN
AbstractFive new aminocoumarin antibiotics were produced by a combined mutational and chemoenzymatic approach. For this purpose, the 3âł-carbamoyltransferase NovN from the novobiocin producer Streptomyces spheroides was overexpressed in the heterologous host S. lividans as an N-terminal His6 fusion protein and purified by nickel affinity chromatography. Five different 3âł-unsubstituted aminocoumarin derivatives were isolated from mutants of the clorobiocin producer S. roseochromogenes, carrying single or multiple gene defects. All five compounds were readily accepted as substrates by NovN, and the 3âł-carbamoylated products were isolated on a preparative scale. Their structures were elucidated by 1H-NMR and mass spectroscopy, and their inhibitory activity on gyrase in vitro as well as their antibacterial activity was determined. The results give further insight into the structure-activity relationships of aminocoumarin antibiotics
Evolutionary Relationships of Microbial Aromatic Prenyltransferases
The linkage of isoprenoid and aromatic moieties, catalyzed by aromatic prenyltransferases (PTases), leads to an impressive diversity of primary and secondary metabolites, including important pharmaceuticals and toxins. A few years ago, a hydroxynaphthalene PTase, NphB, featuring a novel ten-stranded ÎČ-barrel fold was identified in Streptomyces sp. strain CL190. This fold, termed the PT-barrel, is formed of five tandem ααÎČÎČ structural repeats and remained exclusive to the NphB family until its recent discovery in the DMATS family of indole PTases. Members of these two families exist only in fungi and bacteria, and all of them appear to catalyze the prenylation of aromatic substrates involved in secondary metabolism. Sequence comparisons using PSI-BLAST do not yield matches between these two families, suggesting that they may have converged upon the same fold independently. However, we now provide evidence for a common ancestry for the NphB and DMATS families of PTases. We also identify sequence repeats that coincide with the structural repeats in proteins belonging to these two families. Therefore we propose that the PT-barrel arose by amplification of an ancestral ααÎČÎČ module. In view of their homology and their similarities in structure and function, we propose to group the NphB and DMATS families together into a single superfamily, the PT-barrel superfamily
Out of the boxes, out of the silos: The need of interdisciplinary collaboration to reduce poor-quality medical products in the supply chain
In this paper, we argue that understanding and addressing the problem of poor-quality medical products requires a more interdisciplinary approach than has been evident to date. While prospective studies based on rigorous standardized methodologies are the gold standard for measuring the prevalence of poor-quality medical products and understanding their distribution nationally and internationally, they should be complemented by social science research to unpack the complex set of social, economic, and governance factors that underlie these patterns. In the following sections, we discuss specific examples of prospective quality surveys and of social science studies, highlighting the value of cross-sector partnerships in driving high-quality, policy-relevant research in this area
Lost Highway Not Forgotten: Satellite Tracking of a Bowhead Whale (Balaena mysticetus) from the Critically Endangered Spitsbergen Stock
The Spitsbergen bowhead whale stock is critically endangered. It is believed to number in the tens. Here we report results from the first satellite transmitter ever deployed on an individual from this stock. A female whale was tagged on 3 April 2010 (at 79Ë54' N, 01Ë03' E), but no locations were transmitted by the tag until 30 April 2010, after which data were received continuously for 86 days. Additionally, three small clusters of locations were transmitted later in the year; the latest was received 20 December 2010 (262 days after deployment). During the 86 days of continuous tracking, the whale initially remained in the middle of the Fram Strait, between 77Ë45' N, 5Ë W and 80Ë10' N, 5Ë E. For a two-week period starting around 10 June 2010, the whale traveled southwest down to 73Ë40' N (at least 950 km). Subsequently it remained at southern latitudes between ~70Ë and 73Ë N until the tag stopped continuous transmissions on 24 July. Movement patterns analyzed using first-passage times (FTP), fitted as functions of various environmental variables using Cox Proportional Hazards models, showed that the whale spent most of its time in waters close to the ice edge with modest ice coverage, over areas where the bottom slope was relatively steep. Winter positions (27 November â 20 December 2010) revealed that the whale was back in the North at about 80Ë N. This information, in combination with recent data from passive acoustic listening devices, suggests that the Spitsbergen bowhead stock overwinters at high-latitude locations. The north-south movements of this whale during summer are consistent with the patterns that early whalers described for bowhead whales in this region in the 16th and 17th centuries.La population de baleines borĂ©ales de Spitzberg est en danger critique dâextinction. Lâon croit quâelle se chiffrerait dans la dizaine. Ici, nous faisons Ă©tat des rĂ©sultats obtenus Ă lâaide du premier Ă©metteur satellite Ă nâavoir jamais Ă©tĂ© installĂ© sur un individu de cette population. Une baleine femelle a Ă©tĂ© marquĂ©e le 3 avril 2010 (Ă 79Ë54' N, 01Ë03' E), mais aucun signal nâa Ă©tĂ© transmis par ce marquage avant le 30 avril 2010, aprĂšs quoi nous avons reçu des donnĂ©es continuelles pendant 86 jours. Plus tard dans le courant de lâannĂ©e, nous avons Ă©galement reçu trois petits blocs dâinformation, dont le dernier a Ă©tĂ© transmis le 20 dĂ©cembre 2010 (262 jours aprĂšs la date du marquage). Au cours des 86 jours dâinformation continuelle, la baleine restait dâabord au milieu du dĂ©troit de Fram, entre 77Ë45' N, 5Ë O et 80Ë10' N, 5Ë E. Pendant une pĂ©riode de deux semaines commençant vers le 10 juin 2010, la baleine sâest dĂ©placĂ©e vers le sud-ouest jusquâĂ 73Ë40' N (au moins 950 km). Par la suite, elle est restĂ©e dans les latitudes du sud entre ~70Ë et 73Ë N jusquâĂ ce que le marquage cesse les transmissions continuelles le 24 juillet. Les habitudes de dĂ©placement analysĂ©es en recourant aux temps du premier passage (FTP), ajustĂ©es Ă titre de fonctions de diverses variables environnementales sâappuyant sur les modĂšles des hasards proportionnels de Cox, ont laissĂ© entrevoir que la baleine passait la plus grande partie de son temps dans les eaux Ă proximitĂ© des lisiĂšres de glace dont la couverture Ă©tait modeste par rapport aux endroits oĂč la pente du fond Ă©tait relativement abrupte. Les positions enregistrĂ©es en hiver (du 27 novembre au20 dĂ©cembre 2010) ont rĂ©vĂ©lĂ© que la baleine Ă©tait retournĂ©e dans le nord Ă environ 80Ë N. Cette information, alliĂ©e aux rĂ©centes donnĂ©es provenant dâappareils dâĂ©coute acoustique, suggĂšre que la population de baleines borĂ©ales de Spitzberg passe lâhiver Ă de hautes latitudes. Pendant lâĂ©tĂ©, les mouvements nord-sud de cette baleine sont conformes aux habitudes de dĂ©placement de la baleine borĂ©ale, telles que dĂ©crites par les anciens baleiniers dans cette rĂ©gion au cours des XVIe et XVIIe siĂšcles
<Abstract of Published Report>Geranylhydroquinone 3"-hydroxylase, a Cytochrome P-450 Monoxygenase from Lithospermum erythrorhizon Cell Suspension Cultures.
Mitogenomics and the genetic differentiation of contemporary <i>Balaena mysticetus</i> (Cetacea) from Svalbard
Full mitochondrial genomes were assembled for 12 recently sampled animals from the Svalbard bowhead whale (Balaena mysticetus) stock via high-throughput sequencing data, facilitating analysis of the demographic history of the population for the first time. The Svalbard population has retained noticeable amounts of mitochondrial genome diversity despite extreme historical harvest levels. Haplotype and nucleotide diversities were similar to those estimated earlier for other bowhead whale populations. The reconstructed demographic history was in accordance with a boomâbust scenario, combining a slight Pleistocene population growth 25 000â35 000 years ago and a Holocene decline. Employing a mutation rate of 3.418 Ă 10â8 substitutions per site per year, the time to the most recent common ancestor for the mitochondrial genomes of the contemporary Svalbard bowhead whales was estimated to be 68 782 (54 353â83 216) years before the present. Based on 370 bp fragments of the D-loop region, significant genetic differentiation was detected between all extant bowhead whale populations across the circumpolar Arctic. Thus, the Svalbard bowhead whales can be regarded as a population with its own genetic legacy
Active Cytomegalovirus Infection in Patients with Septic Shock
Cytomegalovirus reactivation occurred in one third of patients and was associated with prolonged ventilation and stay in an intensive care unit
Prophylactic Palmitoylethanolamide Prolongs Survival and Decreases Detrimental Inflammation in Aged Mice With Bacterial Meningitis
Easy-to-achieve interventions to promote healthy longevity are desired to diminish the incidence and severity of infections, as well as associated disability upon recovery. The dietary supplement palmitoylethanolamide (PEA) exerts anti-inflammatory and neuroprotective properties. Here, we investigated the effect of prophylactic PEA on the early immune response, clinical course, and survival of old mice after intracerebral E. coli K1 infection. Nineteen-month-old wild type mice were treated intraperitoneally with two doses of either 0.1 mg PEA/kg in 250 ÎŒl vehicle solution (n = 19) or with 250 ÎŒl vehicle solution only as controls (n = 19), 12 h and 30 min prior to intracerebral E. coli K1 infection. The intraperitoneal route was chosen to reduce distress in mice and to ensure exact dosing. Survival time, bacterial loads in cerebellum, blood, spleen, liver, and microglia counts and activation scores in the brain were evaluated. We measured the levels of IL-1ÎČ, IL-6, MIP-1α, and CXCL1 in cerebellum and spleen, as well as of bioactive lipids in serum in PEA- and vehicle-treated animals 24 h after infection. In the absence of antibiotic therapy, the median survival time of PEA-pre-treated infected mice was prolonged by 18 h compared to mice of the vehicle-pre-treated infected group (P = 0.031). PEA prophylaxis delayed the onset of clinical symptoms (P = 0.037). This protective effect was associated with lower bacterial loads in the spleen, liver, and blood compared to those of vehicle-injected animals (P †0.037). PEA-pre-treated animals showed diminished levels of pro-inflammatory cytokines and chemokines in spleen 24 h after infection, as well as reduced serum concentrations of arachidonic acid and of one of its metabolites, 20-hydroxyeicosatetraenoic acid. In the brain, prophylactic PEA tended to reduce bacterial titers and attenuated microglial activation in aged infected animals (P = 0.042). Our findings suggest that prophylactic PEA can counteract infection associated detrimental responses in old animals. Accordingly, PEA treatment slowed the onset of infection symptoms and prolonged the survival of old infected mice. In a clinical setting, prophylactic administration of PEA might extend the potential therapeutic window where antibiotic therapy can be initiated to rescue elderly patients
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