The Higuchi model for the rate of drug release from matrix devices has been an invaluable tool in developing the modern controlled drug delivery industry.
The Higuchi model for the rate of drug ...release from matrix devices where the drug loading exceeds the solubility in the matrix medium, whose 50-year anniversary is celebrated in this issue, has proven to be a robust framework and an invaluable tool in developing a significant part of the modern controlled drug delivery industry. This paper reviews the conceptual and mathematical bases for this model and some consequences of its inherent assumptions. In addition, selected extensions of the model that have proven useful over the years are summarized. These include the effects of external mass transfer resistance and spatial variations of drug loading.
Buruli ulcer is a neglected emerging disease that has recently been reported in some countries as the second most frequent mycobacterial disease in humans after tuberculosis. Cases have been reported ...from at least 32 countries in Africa (mainly west), Australia, Southeast Asia, China, Central and South America, and the Western Pacific. Large lesions often result in scarring, contractual deformities, amputations, and disabilities, and in Africa, most cases of the disease occur in children between the ages of 4-15 years. This environmental mycobacterium, Mycobacterium ulcerans, is found in communities associated with rivers, swamps, wetlands, and human-linked changes in the aquatic environment, particularly those created as a result of environmental disturbance such as deforestation, dam construction, and agriculture. Buruli ulcer disease is often referred to as the "mysterious disease" because the mode of transmission remains unclear, although several hypotheses have been proposed. The above review reveals that various routes of transmission may occur, varying amongst epidemiological setting and geographic region, and that there may be some role for living agents as reservoirs and as vectors of M. ulcerans, in particular aquatic insects, adult mosquitoes or other biting arthropods. We discuss traditional and non-traditional methods for indicting the roles of living agents as biologically significant reservoirs and/or vectors of pathogens, and suggest an intellectual framework for establishing criteria for transmission. The application of these criteria to the transmission of M. ulcerans presents a significant challenge.
The most intensively star-forming galaxies are extremely luminous at far-infrared (FIR) wavelengths, highly obscured at optical and ultraviolet wavelengths, and lie at z ≥ 1-3. We present a programme ...of FIR spectroscopic observations with the SPIRE FTS, as well as photometric observations with PACS, both on board Herschel, towards a sample of 45 gravitationally lensed, dusty starbursts across z ∼ 1-3.6. In total, we detected 27 individual lines down to 3 σ, including nine C II 158 μm lines with confirmed spectroscopic redshifts, five possible C II lines consistent with their FIR photometric redshifts, and in some individual sources a few O III 88 μm, O III 52 μm, O I 145 μm, O I 63 μm, N II 122 μm and OH 119 μm (in absorption) lines. To derive the typical physical properties of the gas in the sample, we stack all spectra weighted by their intrinsic luminosity and by their 500μm flux densities, with the spectra scaled to a common redshift. In the stacked spectra, we detect emission lines of C II 158 μm, N II 122 μm, O III 88 μm, O III 52 μm, O I 63 μm and the absorption doublet of OH at 119 μm, at high fidelity. We find that the average electron densities traced by the N II and O III lines are higher than the average values in local star-forming galaxies and ULIRGs, using the same tracers. From the N II/C II and O I/C II ratios, we find that the C II emission is likely dominated by the photodominated regions (PDR), instead of by ionized gas or large-scale shocks.
Addressing the transmission enigma of the neglected disease Buruli ulcer (BU) is a World Health Organization priority. In Australia, we have observed an association between mosquitoes harboring the ...causative agent, Mycobacterium ulcerans, and BU. Here we tested a contaminated skin model of BU transmission by dipping the tails from healthy mice in cultures of the causative agent, Mycobacterium ulcerans. Tails were exposed to mosquito (Aedes notoscriptus and Aedes aegypti) blood feeding or punctured with sterile needles. Two of 12 of mice with M. ulcerans contaminated tails exposed to feeding A. notoscriptus mosquitoes developed BU. There were no mice exposed to A. aegypti that developed BU. Eighty-eight percent of mice (21/24) subjected to contaminated tail needle puncture developed BU. Mouse tails coated only in bacteria did not develop disease. A median incubation time of 12 weeks, consistent with data from human infections, was noted. We then specifically tested the M. ulcerans infectious dose-50 (ID50) in this contaminated skin surface infection model with needle puncture and observed an ID50 of 2.6 colony-forming units. We have uncovered a biologically plausible mechanical transmission mode of BU via natural or anthropogenic skin punctures.
In the large field of nanotechnology, polymer matrix based nanocomposites have become a prominent area of current research and development. Exfoliated clay-based nanocomposites have dominated the ...polymer literature but there are a large number of other significant areas of current and emerging interest. This review will detail the technology involved with exfoliated clay-based nanocomposites and also include other important areas including barrier properties, flammability resistance, biomedical applications, electrical/electronic/optoelectronic applications and fuel cell interests. The important question of the “nano-effect” of nanoparticle or fiber inclusion relative to their larger scale counterparts is addressed relative to crystallization and glass transition behavior. Of course, other polymer (and composite)-based properties derive benefits from nanoscale filler or fiber addition and these are addressed.
Polyethylene-clay nanocomposites were prepared by melt compounding various combinations of a maleic anhydride grafted linear low density polyethylene (LLDPE-g-MA), a linear low density polyethylene ...(LLDPE), and two organoclays. The two types of organoclay were selected to show the effect of the number of alkyl groups attached to the nitrogen of the organic modifier on exfoliation and improvement of mechanical properties. Nanocomposites derived from the organoclay having two alkyl tails, M2(HT)2, exhibited better dispersion and improvement of mechanical properties than nanocomposites based on the organoclay having one alkyl tail M3(HT)1. This result is the opposite of what is observed for nylon-6 nanocomposites. In addition, the rheological properties and gas permeability of the nanocomposites derived from the organoclay having two alkyl tails, M2(HT)2 were investigated. Both melt viscosity and melt tension (melt strength) increased with increased content of clay (MMT) and LLDPE-g-MA. Gas permeability was decreased by the addition of MMT.
The crystallization behavior of nylon 6 nanocomposites formed by melt processing was investigated. Nanocomposites were produced by extruding mixtures of organically modified montmorillonite and ...molten nylon 6 using a twin screw extruder. Isothermal and non-isothermal crystallization studies involving differential scanning calorimetry (DSC) were conducted on samples to understand how organoclay concentration and degree of clay platelet exfoliation influence the kinetics of polyamide crystallization. Very low levels of clay result in dramatic increases in crystallization kinetics relative to extruded pure polyamide. However, increasing the concentration of clay beyond these levels retards the rate of crystallization. For the pure nylon 6, the rate of crystallization decreases with increasing the molecular weight as expected; however, the largest enhancement in crystallization rate was observed for nanocomposites based on high molecular weight polyamides; this is believed to stem from a higher degree of platelet exfoliation in these nanocomposites. Wide angle X-ray diffraction (WAXD) and DSC were further used to characterize the polymer crystalline morphology of injection molded nanocomposites. The outer or skin layer of molded specimens was found to contain only γ-crystals; whereas, the central or core region contains both the α and γ-forms. The presence of clay enhanced the γ-structure in the skin; however, the clay has little effect on crystal structure in the core. Interestingly, higher levels of crystallinity were observed in the skin than in the core for the nanocomposites, while the opposite was true for the pure polyamides. In general, increasing the polymer matrix molecular weight resulted in a lower degree of crystallinity in molded samples as might be expected.
Survivors of critical illness demonstrate skeletal muscle wasting with associated functional impairment.
To perform a comprehensive prospective characterization of skeletal muscle wasting, defining ...the pathogenic roles of altered protein synthesis and breakdown.
Sixty-three critically ill patients (59% male; mean age: 54.7 years 95% CI, 50.0-59.6 years) with an Acute Physiology and Chronic Health Evaluation II score of 23.5 (95% CI, 21.9-25.2) were prospectively recruited within 24 hours following intensive care unit (ICU) admission from August 2009 to April 2011 at a university teaching and a community hospital in England. Patients were recruited if older than 18 years and were anticipated to be intubated for longer than 48 hours, to spend more than 7 days in critical care, and to survive ICU stay.
Muscle loss was determined through serial ultrasound measurement of the rectus femoris cross-sectional area (CSA) on days 1, 3, 7, and 10. In a subset of patients, the fiber CSA area was quantified along with the ratio of protein to DNA on days 1 and 7. Histopathological analysis was performed. In addition, muscle protein synthesis, breakdown rates, and respective signaling pathways were characterized.
There were significant reductions in the rectus femoris CSA observed at day 10 (−17.7% 95% CI, −25.9% to 8.1%; P < .001). In the 28 patients assessed by all 3 measurement methods on days 1 and 7, the rectus femoris CSA decreased by 10.3% (95% CI, 6.1% to 14.5%), the fiber CSA by 17.5% (95% CI, 5.8% to 29.3%), and the ratio of protein to DNA by 29.5% (95% CI, 13.4% to 45.6%). Decrease in the rectus femoris CSA was greater in patients who experienced multiorgan failure by day 7 (−15.7%; 95% CI, −27.7% to 11.4%) compared with single organ failure (−3.0%; 95% CI, −5.3% to 2.1%) (P < .001), even by day 3 (−8.7% 95% CI, −59.3% to 50.6% vs −1.8% 95% CI, −12.3% to 10.5%, respectively; P = .03). Myofiber necrosis occurred in 20 of 37 patients (54.1%). Protein synthesis measured by the muscle protein fractional synthetic rate was depressed in patients on day 1 (0.035%/hour; 95% CI, 0.023% to 0.047%/hour) compared with rates observed in fasted healthy controls (0.039%/hour; 95% CI, 0.029% to 0.048%/hour) (P = .57) and increased by day 7 (0.076% 95% CI, 0.032%-0.120%/hour; P = .03) to rates associated with fed controls (0.065%/hour 95% CI, 0.049% to 0.080%/hour; P = .30), independent of nutritional load. Leg protein breakdown remained elevated throughout the study (8.5 95% CI, 4.7 to 12.3 to 10.6 95% CI, 6.8 to 14.4 μmol of phenylalanine/min/ideal body weight × 100; P = .40). The pattern of intracellular signaling supported increased breakdown (n = 9, r = −0.83, P = .005) and decreased synthesis (n = 9, r = −0.69, P = .04).
Among these critically ill patients, muscle wasting occurred early and rapidly during the first week of critical illness and was more severe among those with multiorgan failure compared with single organ failure. These findings may provide insights into skeletal muscle wasting in critical illness.
PDF
