Evaluating the swelling,erosion, and compaction properties of cellulose ethers

Swelling, erosion, deformation, and consolidation properties can affect the performance of cellulose ethers, the most commonly used matrix former in hydrophilic sustained tablet formulations. The present study was designed to comparatively evaluate the swelling, erosion, compression, compaction, and relaxation properties of the cellulose ethers in a comprehensive study using standardised conditions. The interrelationship between various compressional models and the inherent deformation and consolidation properties of the polymers on the derived swelling and erosion parameters are consolidated. The impact of swelling (K_w) on erosion rates (K_E) and the inter-relationship between Heckel and Kawakita plasticity constants was also investigated. It is evident from the findings that the increases in both substitution and polymer chain length led to higher K_w, but a lower K_E; this was also true for all particle size fractions regardless of polymer grade. Smaller particle size and high substitution levels tend to increase the relative density of the matrix but reduce porosity, yield pressure (P_y), Kawakita plasticity parameter (b^?1) and elastic relaxation. Both K_W versus K_E (R²?=?0.949–0.980) and P_y versus. b^?1 correlations (R²?=?0.820–0.934) were reasonably linear with regards to increasing hydroxypropyl substitution and molecular size. Hence, it can be concluded that the combined knowledge of swelling and erosion kinetics in tandem with the in- and out-of-die compression findings can be used to select a specific polymer grade and further to develop and optimize formulations for oral controlled drug delivery applications.     

Graft-versus-host disease after liver transplantation is associated with bone marrow failure,hemophagocytosis, and DNMT3A mutations

Graft-versus-host disease after liver transplantation (LT-GVHD) is rare, frequently fatal, and associated with bone marrow failure (BMF), cytopenias, and hyperferritinemia. Given hyperferritinemia and cytopenias are present in hemophagocytic lymphohistiocytosis (HLH), and somatic mutations in hematopoietic cells are associated with hyperinflammatory responses (clonal hematopoiesis of indeterminate potential, CHIP), we identified the frequency of hemophagocytosis and CHIP mutations in LT-GVHD. We reviewed bone marrow aspirates and biopsies, quantified blood/marrow chimerism, and performed next-generation sequencing (NGS) with a targeted panel of genes relevant to myeloid malignancies, CHIP, and BMF. In all, 12 marrows were reviewed from 9 LT-GVHD patients. In all, 10 aspirates were evaluable for hemophagocytosis; 7 had adequate DNA for NGS. NGS was also performed on marrow from an LT cohort (n = 6) without GVHD. Nine of 10 aspirates in LT-GVHD patients showed increased hemophagocytosis. Five (71%) of 7 with LT-GVHD had DNMT3A mutations; only 1 of 6 in the non-GVHD LT cohort demonstrated DNMT3A mutation (p = .04). Only 1 LT-GVHD patient survived. BMF with HLH features was associated with poor hematopoietic recovery, and DNMT3A mutations were over-represented, in LT-GVHD patients. Identification of HLH features may guide prognosis and therapeutics. Further studies are needed to clarify the origin and impact of CHIP mutations on the hyperinflammatory state.

     

Germ‐free mice as a model to study effect of gut microbiota on host physiology

The alterations in resident gut microbiota seen in chronic gastrointestinal disorders have led to an increasing interest in the role of gut bacteria in maintaining intestinal barrier function. While acute alterations in colonic secretomotor function in response to pathogens have been well described, the effect of commensal bacteria on intestinal barrier function and colonic secretomotor function still remains poorly understood. Germ‐free mice represent a model system to study effect of gut microbes on host gastrointestinal physiology. The study by Lomasney et al. represents an important step in this direction by demonstrating that the colonic secretomotor function is largely preserved in germ‐free mice, hence making them a suitable model to study effect of gut microbiota on host function.     

Expression of Hedgehog ligand and signal transduction components in mutually distinct isocitrate dehydrogenase mutant glioma cells supports a role for paracrine signaling

DNA methylation plays an important role in cancer biology and methylation events are important prognostic and predictive markers in many tumor types. We have used methylation-specific multiplex ligation-dependent probe amplification to survey the methylation status of MGMT and 25 tumor suppressor genes in 73 glioblastoma cases. The data obtained was correlated with overall survival and response to treatment. The study revealed that methylation of promoter regions in TP73 (seven patients), THBS1 (eight patients) and PYCARD (nine patients) was associated with improved outcome, whereas GATA5 (21 patients) and WT1 (24 patients) promoter methylation were associated with poor outcome. In patients treated with temozolomide and radiation MGMT and PYCARD promoter methylation events remained associated with improved survival whereas GATA5 was associated with a poor outcome. The identification of GATA5 promoter methylation in glioblastoma has not previously been reported. Furthermore, a cumulative methylation score separated patients into survival groups better than any single methylation event. In conclusion, we have identified specific methylation events associated with patient outcome and treatment response in glioblastoma, and these may be of functional and predictive/prognostic significance. This study therefore provides novel candidates and approaches for future prospective validation.     

Impact of Stimulus Integrity on Age Differences in Letter Matching

Young and older adults were tested in both a letter-identification and a letter-matching task in which the integrity of the letter stimuli was manipulated through contrast reduction and low-pass spatial frequency filtering. The use of the contrast and filtering manipulations was an attempt to increase encoding difficulty in an effort to examine whether stimulus integrity impacts more than just the initial encoding of the letter pairs in a letter-matching task, namely the comparison process as indexed by fast-same and false-different effects. Of interest in terms of aging is whether a decline in information-processing performance often reported in the aging literature is related to the known encoding deficits of older adults. In the letter-identification task, both contrast reduction and filtering slowed letter-identification speed for both groups, with the effect being larger for the older adults. In the letter-matching task, decreased processing efficiency produced by the contrast-reduction and low-pass-filtering manipulations led to an overall increase in reaction time and errors, but it did not interact with the magnitude of the fast-same effect or false-different effects for either subject group. These findings suggest that the stimulus integrity manipulations only impact the encoding of the letter pairs in the matching task and not the comparison process. The results of the present study support a dual-process model of the matching task consisting of separate encoding and comparison processes. The finding of a larger fast-same effect for older adults suggests that the age effect is occurring at the comparison stage, but it is not impacted by the stimulus integrity manipulations. The findings are described within a generalized slowing framework.     

Factors Affecting the Longevity and Strength in an <Emphasis Type="Italic">In Vitro</Emphasis> Model of the Bone–Ligament Interface

The interfaces between musculoskeletal tissues with contrasting moduli are morphologically and biochemically adapted to allow the transmission of force with minimal injury. Current methods of tissue engineering ligaments and tendons do not include the interface and this may limit the future clinical success of engineered musculoskeletal tissues. This study aimed to use solid brushite cement anchors to engineer intact ligaments from bone-to-bone, creating a functional musculoskeletal interface in vitro. We show here that modifying anchor shape and cement composition can alter both the longevity and the strength of an in vitro model of the bone–ligament interface: with values reaching 23 days and 21.6 kPa, respectively. These results validate the use of brushite bone cement to engineer the bone–ligament interface in vitro and raise the potential for future use in ligament replacement surgery.     

Antimicrobial susceptibility pattern and prevalence of extended spectrum beta-lactamase (ESBLs) producing strains of Klebsiella pneumoniae from a major hospital in New Delhi

Extended spectrum beta-lactamases (ESBLs) are plasmid mediated enzymes capable of hydrolyzing penicillins, broad spectrum-cephalosporins and monobactams. The ESBL producing K. pneumoniae strains are being reported from around the world including India. The present study was taken up to evaluate the ESBL production and in-vitro susceptibility of K. pneumoniae isolates from a hospital. The bacterial isolates collected during 2003 included 51 K. pneumoniae biochemically confirmed isolates from 395 patients admitted in various wards of a major hospital in New Delhi. The isolates were from pus, wound, pleural fluid, urine and tracheal aspirate of patients attending respiratory, urology and burns wards. Antimicrobial susceptibility was carried out by Kirby Bauer's disc diffusion technique using NCCLS criteria. A screening of ESBL production was done by Double-disc synergy test (DDST) and using E-test ESBL strips. The frequency of resistance among K. pneumoniae for the cephalosporins (cefoxitin, cefuroxime, cefotaxime, ceftazidime, and cefepime) and non-cephalosporins (aztreonam, piperacillin, chloramphenicol and trimethoprim-sulfamethoxazole) were in the range of 39.2-88.0% and 51.0-90.2% respectively. 14 different antimicrobial resistance profiles were recognized ranging from resistance to only four (n=6, 11.7%) to as many as ten (n=9, 17.7%). Among the 51 isolates of K. pneumoniae strains, a total of 36 (70.6%) could be identified as ESBL producers, that correlates with the high frequency of multi-drug resistant K. pneumoniae The study shows alarming rise in ESBL production among K. pneumoniae strains and high rate of resistance to a wide range of cephalosporin and non-cephalosporin group of antimicrobials.     

Regional oxygen supply and consumption balance in experimental left ventricular hypertrophy

Summary The aim of the present study was to determine if the relationship between myocardial O₂ supply and O₂ consumption was preserved after prolonged pressure overload due to aortic valve stenosis. This was examined in anesthetized open-chest dogs in which the aortic valve was plicated 6 months previously. We measured coronary blood flow with radioactive microspheres and regional small vessel O₂ saturation with microspectrophotometry, to obtain O₂ supply, and O₂ consumption. Regional O₂ consumption was calculated as the product of flow and O₂ extraction. The left ventricular weight/body weight ratio was 81% greater in the dogs with aortic valve stenosis. There were no hemodynamic differences between the groups except that left ventricular systolic pressure was 38±22 mm Hg greater than aortic in the hypertrophied group. Coronary blood flow did not differ between the control and hypertrophied groups nor were there subepicardial vs subendocardial differences. When maximal coronary flow was determined with chromonar (10 mg/kg), the flow increase was significantly attenuated in the hypertrophied subendocardium (242.1±82.3 (hypertrophy) vs 512.4±204.1 ml·min^–1·100 g^–1 (control)). There were no significant differences in O₂ extraction or O₂ consumption/g between control and hypertrophied animals. There was a significantly lower O₂ supply/consumption ratio in the subendocardium compared to the subepicardium of both groups. However, the O₂ supply/consumption ratio was not decreased by hypertrophy. Thus, despite significant hypertrophy, a loss of flow reserve and a high left ventricular pressure, O₂ supply/consumption balance is preserved in valvular aortic stenosis at rest.     

Development and evaluation of a microdevice for amino acid biomarker detection and analysis on Mars

The Mars Organic Analyzer (MOA), a microfabricated capillary electrophoresis (CE) instrument for sensitive amino acid biomarker analysis, has been developed and evaluated. The microdevice consists of a four-wafer sandwich combining glass CE separation channels, microfabricated pneumatic membrane valves and pumps, and a nanoliter fluidic network. The portable MOA instrument integrates high voltage CE power supplies, pneumatic controls, and fluorescence detection optics necessary for field operation. The amino acid concentration sensitivities range from micromolar to 0.1 nM, corresponding to part-per-trillion sensitivity. The MOA was first used in the lab to analyze soil extracts from the Atacama Desert, Chile, detecting amino acids ranging from 10-600 parts per billion. Field tests of the MOA in the Panoche Valley, CA, successfully detected amino acids at 70 parts per trillion to 100 parts per billion in jarosite, a sulfate-rich mineral associated with liquid water that was recently detected on Mars. These results demonstrate the feasibility of using the MOA to perform sensitive in situ amino acid biomarker analysis on soil samples representative of a Mars-like environment.