Tracking cocrystallization of active pharmaceutical ingredients with Bbenzoic acid coformer using Broadband Acoustic resonance Dissolution Spectroscopy (BARDS)

This study investigates the use of Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS) as a detection method for the formation of cocrystals. BARDS is a novel approach that uses reproducible changes in the compressibility of a solvent as a sample dissolves to characterize and differentiate between materials and in this case cocrystallization. Two cocrystal systems with a 1:1 stoichiometry were examined, which used benzoic acid as a coformer with isonicotinamide and with theophylline. Cocrystals were prepared using dry and wet milling for periods from 1 to 40 min, and samples were analyzed using infrared spectroscopy, powder X-ray diffraction, and BARDS. Comparison of the BARDS data with the IR and PXRD data cross-validated the BARDS results. This study shows that BARDS can be used to rapidly assess the formation of these cocrystals at-line when milling or as a relatively low cost tool in preformulation product development. The data can also be used to gauge the unique entrained gas and gas volume generation of the cocrystal samples during dissolution and their dissolution kinetics

Pathomechanics of calcaneal apophysitis

Sever's disease is a common cause of activity-related heel pain in children. However, little is known about its development and scientific support regarding potential risk factors is often contradictory. This thesis aimed to understand the role of biomechanical risk factors anecdotally linked to the condition. The findings suggest that foot mobility, Achilles tendon mechanics and ground reaction forces during walking and running does not differ in children with and without Sever's disease. Though, children with Sever's disease possess greater ankle joint movement during running. This thesis questions the rationale behind many common biomechanical interventions used in children with Sever's disease

Tolerance mechanisms of streptococci to hydrolysable and condensed tannins

Copyright © 2005 Published by Elsevier B.V.Denis O. Krause, Wendy J.M. Smith, John D. Brooker and Christopher S. McSweeneyhttp://www.elsevier.com/wps/find/journaldescription.cws_home/503299/description#descriptio

Methane inhibition alters the microbial community, hydrogen flow and fermentation response in the rumen of cattle

Management of metabolic hydrogen ([H]) in the rumen has been identified as an important consideration when reducing ruminant CH4 emissions. However, little is known about hydrogen flux and microbial rumen population responses to CH4 inhibition when animals are fed with slowly degradable diets. The effects of the anti-methanogenic compound, chloroform, on rumen fermentation, microbial ecology and H2 /CH4 production were investigated in vivo. Eight rumen fistulated Brahman steers were fed a roughage hay diet (Rhode grass hay) or roughage hay:concentrate diet (60:40) with increasing levels (low, mid and high) of chloroform in a cylcodextrin matrix. The increasing levels of chloroform resulted in an increase in H2 expelled as CH4 production decreased with no effect on dry matter intakes. The amount of expelled H2 per mole of decreased methane, was lower for the hay diet suggesting a more efficient redirection of hydrogen into other microbial products compared with hay:concentrate diet. A shift in rumen fermentation towards propionate and branched-chain fatty acids was observed for both diets. Animals fed with the hay:concentrate diet had both higher formate concentration and H2 expelled than those fed only roughage hay. Metabolomic analyses revealed an increase in the concentration of amino acids, organic and nucleic acids in the fluid phase for both diets when methanogenesis was inhibited. These changes in the rumen metabolism were accompanied by a shift in the microbiota with an increase in Bacteroidetes:Firmicutes ratio and a decrease in Archaea and Synergistetes for both diets. Within the Bacteroidetes family, some OTUs assigned to Prevotella were promoted under choloroform treatment. These bacteria may be partly responsible for the increase in amino acids and propionate in the rumen. No significant changes were observed for abundance of fibrolytic bacteria, protozoa and fungi, which suggests that fibre degradation was not impaired. The observed 30% decrease in methanogenesis did not adversely affect rumen metabolism and the rumen microbiota was able to adapt and redirect [H] into other microbial end-products for both diets. However, it is also required dietary supplements or microbial treatments to capture the additional H2 expelled by the animal to further improve rumen digestive efficiency

A phase I study of the combination of TZT-1027 (soblidotin) and gemcitabine administered on day 1 and 8 every three weeks to patients with advanced or metastatic solid tumors

Background: TZT-1027 is a dolastatin 10 analog interfering with microtubule assembly, with increased antitumor activity when combined with gemcitabine in animal models. Patients and Methods: Eligible patients with refractory solid tumors received gemcitabine followed by TZT-1027 on Days 1 and 8 every 21 days, with pharmacokinetic sampling during the first 24 hours. Results: Fourteen patients received at least one course of study drug (10 at TZT-1027 dose 1.6 mg/m2 and 4 at 2.0 mg/m2). There were 36% male, median age 59 years, median PS 0, median number of prior treatments 2. Reasons for withdrawal included: progression of disease (n=12) and adverse events (n=2). A total of 66 courses were administered. Of 12 instances of dose delay, 8 were due to neutropenia. Grade 3/4 adverse events included neutropenia (50%), thrombocytopenia (14%), fatigue (14%), and anorexia (7%). Cmax and AUCinf were 181 mcg/L (CV% 38.2) and 537 ng.h/mL (n=10 in cohort 1), and peaked at 1.05 hours after the end of TZT-1027 infusion, with a biphasic elimination. T1/2 was 5.12 h, clearance 3.9 L/h/m2, and VSS 16.5 L/m2. Conclusions: The recommended phase II dose is 1.6 mg/m2 of TZT and 800 mg/m2 of gemcitabine. Pharmacokinetics are consistent between studies.C. F. Verschraegen, H. Raftopoulos, K. Feit, R. De Jager, S. Joon Lee & C. Sweene

A genomic catalog of Earth’s microbiomes

The reconstruction of bacterial and archaeal genomes from shotgun metagenomes has enabled insights into the ecology and evolution of environmental and host-associated microbiomes. Here we applied this approach to >10,000 metagenomes collected from diverse habitats covering all of Earth’s continents and oceans, including metagenomes from human and animal hosts, engineered environments, and natural and agricultural soils, to capture extant microbial, metabolic and functional potential. This comprehensive catalog includes 52,515 metagenome-assembled genomes representing 12,556 novel candidate species-level operational taxonomic units spanning 135 phyla. The catalog expands the known phylogenetic diversity of bacteria and archaea by 44% and is broadly available for streamlined comparative analyses, interactive exploration, metabolic modeling and bulk download. We demonstrate the utility of this collection for understanding secondary-metabolite biosynthetic potential and for resolving thousands of new host linkages to uncultivated viruses. This resource underscores the value of genome-centric approaches for revealing genomic properties of uncultivated microorganisms that affect ecosystem processes.</p