Molecular recognition by Kluyveromyces of amphotericin B-loaded, galactose-tagged, poly (lactic acid) microspheres

In an effort to develop a new way of drug delivery, especially for polyenic antifungal molecules, we have incorporated amphotericin B (AmB) into biodegradable galactosylated poly (L-lactic acid) (L-PLA) and poly (L-lactic-co-glycolic acid) (PLGA) microspheres. These drug carriers were prepared by solvent evaporation using an oil/water (o/w) emulsion. The ratio of galactosyl spacers with different chain lengths was 1.74-2.78%. The maximal quantity of AmB encapsulated reported to 100 mg of the galactosylated microspheres was 7.14 mg for L-PLA (encapsulation rate 45% of mole) and 6.42 mg for PLGA derivatives (encapsulation rate 81% of mole). In our yeast model, drug release depended on three factors: (i) presence of galactosylated antennae, (ii) length of galactosyl antenna and (iii) nature of the polymer. More of the AmB trapped in PLGA microspheres was released than from PLA microspheres. These novel functionalised microspheres could be required for the delivering of therapeutic agents according to their recognition to specific cells.     

Relationship between esophageal muscle thickness and intraluminal pressure: an ultrasonographic study

A number of studies show a close temporal relationship between the rate of change in muscle thickness as detected by high-frequency intraluminal ultrasonography (HFIUS) and intraluminal pressure measured by manometry. There is a marked variability in esophageal contraction amplitude from one swallow to another at a given level in the esophagus and along the length of the esophagus. Furthermore, peristaltic pressures are higher in the distal compared with the proximal esophagus. The goal of this study was to evaluate the relationship between the baseline and peak muscle thickness and the contraction amplitude during swallow-induced contractions along the length of the esophagus. Fifteen normal subjects were studied using simultaneous esophageal pressures and HFIUS or HFIUS alone. Recordings were made during baseline and standardized swallows in the lower esophageal sphincter (LES) and at 2, 4, 6, 8, and 10 cm above the LES. HFIUS images were digitized, and esophageal muscle thickness and peak contraction amplitudes were measured. In the resting state, muscle thickness is higher in the LES compared with the rest of the esophagus. Baseline muscle thickness is also significantly higher at 2 cm vs. 10 cm above the LES. In a given subject and among different subjects, there is a good relationship between peak muscle thickness and peak peristaltic pressures (r = 0.55) at all sites along the length of the esophagus. The positive correlation between pressure and muscle thickness implies that the mean circumferential wall stress is fairly uniform from one swallow to another, irrespective of the contraction amplitude.     

Temporal analysis of 16 STR loci in human blood drawn from two culicid mosquitoes cultured at different temperatures

Female mosquitoes feed on human blood, which can be collected to analyze human short tandem repeat (STR) sequences; these are specific to each human individual. Analysis of STRs might help in identification of a person found near a crime scene. Aedes aegypti and Culex pipiens mosquitoes fed on human blood were cultured at 18°C or 40°C (median temperature for summer and winter time in Riyadh governorate, Saudi Arabia) for 3, 6, 12, 24, 48 and 72 h. In A. aegypti, human DNA concentration was reduced with time at both temperatures. At 18°C, we obtained full STR profiles up to 48 h post feeding on human blood while none of the 16 loci were obtained at 72 h. At 40°C, we missed six sites at 12 h after blood sucking, 12 at 24 h, and 15 at 48 h and 72 h. In C. pipiens cultured at 18°C, full profiles were developed up to 48 h following blood feeding while we could not amplify five sites at 72 h. At 40°C, mortality among females was 50% at 24 h and 100% at both 48 h and 72 h; however, we had full profiles in all samples including dead insects. This research addressed the possibility of using mosquitoes in forensic research by DNA genotyping by changing the mosquito culturing temperature and mosquito genus. Our findings proved that different types of mosquito change the temporal pattern of STR analysis and showed that the mosquito culturing temperature affects the integrity of DNA for STR analysis.     

Vascular metabolic dissipation in Murray's law

The metabolic dissipation in Murray's minimum energy hypothesis includes only the blood metabolism. The metabolic dissipation of the vascular tree, however, should also include the metabolism of passive and active components of the vessel wall. In this study, we extend the metabolic dissipation to include blood metabolism, as well as passive and active components of the vessel wall. The analysis is extended to the entire vascular arterial tree rather than a single vessel as in Murray's formulation. The calculations are based on experimentally measured morphological data of coronary artery network and the longitudinal distribution of blood pressure along the tree. Whereas the model includes multiple dissipation sources, the total metabolic consumption of a complex vascular tree is found to remain approximately proportional to the cumulative arterial volume of the unit. This implies that the previously described scaling relations for the various morphological features (volume, length, diameter, and flow) remain unchanged under the generalized condition of metabolic requirements of blood and blood vessel wall.     

Toxicological Assessment of Arsenic-Induced Hematological Alterations and Chromosomal Aberrations in Tilapia Oreochromis mossambicus

Arsenic is an environmental contaminant and potential carcinogen. Toxicological assessment of As, which causes hematological alterations and chromosomal aberrations, was studied in freshwater fish Oreochromis mossambicus. Fish were exposed to 3 ppm, 28 ppm, and 56 ppm concentrations of sodium arsenite (NaAsO₂) and blood samples were collected after 48 h, 96 h, and 192 h of exposure. Hematological assay of exposed fish revealed abnormal mature and immature erythrocytes, deformed erythrocytes (spindle-shaped and triangular erythrocytes) and erythrocytes with segmented nuclei in all treatments. Arsenic exposure induced chromosomal aberration in a concentration-dependent manner, whereas, a decreasing trend was found after 192 h exposure. Observations on blood cells of exposed fish revealed chromosome breaks, chromatid breaks, and chromatid gaps. The alterations and aberrations of these parameters can be effectively used to assess toxicological effects of As on fish in the aquatic environment and at the same time this study elucidates the potential risks to humans who live in arsenic-contaminated areas.     

MMP-13 selective alpha-sulfone hydroxamates: identification of selective P1' amides

Continuing our interest in designing compounds preferentially potent and selective for MMP-13, we report on a series of hydroxamic acids with a flexible amide P1′ substituents. We identify an amide which spares both MMP-1 and -14, and shows >500 fold selectivity for MMP-13 versus MMP-2 and -8.     

Synthesis of new 9-glycosyl-4,9-dihydropyrano [3,4-b]indole-1(3H)-ones as antibacterial agents

A series of new 9-glycosyl-4,9-dihydropyrano[3,4-b]indole-1(3H)-ones 3 was synthesized in moderate to low yields. 4,9-Dihydropyrano[3,4-b]indole-1(3H)-ones (1) were coupled with different acetobromoglycopyranoses 2 in refluxing toluene in the presence of silver oxide to afford one coupling product of the respective N-glycosides. α-L-Arabinopyranosides 3j and 3m were the most active glycosides among the tested compounds against certain Gram positive and Gram negative bacterial strains.     

Three-dimensional mechanical properties of porcine coronary arteries: a validated two-layer model

The normal coronary artery consists of two mechanically distinct layers: intima-media and adventitia. The objective of this study is to establish a two-layer three-dimensional (3-D) stress-strain relation of porcine coronary arteries. Experimental measurements were made by a series of biaxial tests (inflation and axial extension) of intact coronary arteries and, subsequently, their corresponding intima-media or adventitia layer. The Fung-type exponential strain energy function was used to describe the 3-D strain-stress relation for each layer and the intact wall. A genetic algorithm was used to determine the material constants in the Fung-type constitutive equation by curve fitting the experimental data. Because one layer must be sacrificed before the other layer can be tested, the material property of the missing layer was computed from the material constants of the intact vessel and the tested layer. A total of 20 porcine hearts were used: one group of 10 hearts for the left anterior descending artery and another group of 10 hearts for the right coronary artery. Each group was further divided into two subgroups of five specimens tested for the intact wall and the intima-media layer and for the intact wall and the adventitia layer. Our results show statistically significant differences in the material properties of the two layers. The mathematical model was validated by experimental stress-strain data for individual layers. The validated 3-D constitutive model will serve as a foundation for formulation of layer-specific boundary value problems in coronary physiology and cardiology.     

Nonuniformity of axial and circumferential remodeling of large coronary veins in response to ligation

The pressure-induced remodeling of coronary veins is important in coronary venous retroperfusion. Our hypothesis is that the response of the large coronary veins to pressure overload will depend on the degree of myocardial support. Eleven normal Yorkshire swine from either sex, weighing 31-39 kg, were studied. Five pigs underwent ligation of the left anterior descending (LAD) vein, and six served as sham-operated controls. The ligation of the coronary vein caused an increase in pressure intermediate to arterial and venous values. After 2 wk of ligation, the animals were euthanized and the coronary vessels were perfusion-fixed with glutaraldehyde. The LAD vein was sectioned, and detailed morphometric measurements were made along its length from the point of ligation near the base down to the apex of the heart. The structural remodeling of the vein was circumferentially nonuniform because the vein is partially embedded in the myocardium; it was also axially nonuniform because it is tethered to the myocardium to different degrees along its axial length. The wall area was significantly larger in the experimental group, whereas luminal area in the proximal LAD vein was significantly smaller in the same group compared with sham-operated controls. The wall thickness-to-radius ratio was also significantly larger in the experimental group in proportion to the increase in pressure. The major conclusion of this study is that the response of the vein depends on the local wall stress, which is, in part, determined by the surrounding tissue. Furthermore, the geometric remodeling of the coronary vein restores the circumferential stress to the homeostatic value.     

Axial nonuniformity of geometric and mechanical properties of mouse aorta is increased during postnatal growth

The hemodynamic conditions of aorta are relatively uniform prenatally and become more heterogeneous postnatally. Our objective was to quantify the heterogeneity of geometry and mechanical properties during growth and development. To accomplish this objective, we obtained a systematic set of data on the geometry and mechanical properties along the length of mouse aorta during postnatal development. C57BL/6 mice of ages 1-33 days were studied. The ascending aorta was cannulated in situ and preconditioned with several cyclic changes in pressure. We investigated the axial variations of geometry (diameter and length) and mechanical properties (stress-stain relation, elastic modulus and compliance) of the mouse aorta from the aortic valve to the common iliac. Our results show that the arterial blood pressure of mice increased from approximately 30 to 80 mmHg during the first 2 wk of life. The stretch ratio, diameter, wall (intima-media) thickness, and total lumen volume of mouse aorta increased with age. The aorta was transformed from a cylindrical tube at birth to a tapered structure during growth. Furthermore, we found the mechanical properties were fairly uniform along the length of the aorta at birth and become more nonuniform with age. We conclude that the rapid change of blood pressure and blood flow after birth alter the geometric and mechanical properties differentially along the length of the aorta. Hence, the axial nonuniformity of the aorta increases as the organ becomes more specialized during growth and development.