NANOPARTICLE AGGLOMERATES FOR PULMONARY DRUG DELIVERY

The Pulmonary route has been traditionally used to treat diseases of the respiratory tract. However, important research within the last two decades have shown that in addition to treating local diseases, a wide range of systemic diseases can be treated by delivering drugs to the lungs. The recent FDA approval to market Exubera, an inhalable form of insulin developed by Pfizer, to treat Diabetes, may just be the stepping stone that the pharmaceutical industry needs to market other drugs to treat systemic diseases via the lungs. However, this technology still needs repeated drug doses to control glucose levels, as the inhaled drug is cleared rapidly. Technologies have been developed where inhaled particles are capable of controlled release of drug from the lungs. An important feature of these technologies is the large geometric size of the particles that makes it difficult for the lung macrophages to clear these particles, which results in longer residence times for the particles in the lungs. Owing to the porosity, these particles have lower densities making them deliverable to the deep lungs. However, no modulation of drug release can be achieved with these technologies when more drug release may be required. This additional requirement can only be assuaged by additional dosing of the drug formulation, which can have undesirable effects due to excess loading of excipients in the lungs. In an attempt to bring about modulation of release from long residence time particles, a novel concept was developed in our laboratory that has been termed as the Agglomerated Vesicle Technology (AVT). Liposomes with encapsulated drug were agglomerated using well known cross linking chemistries to form agglomerates in the micron sized range. The large particles exhibited aerodynamic sizes in the respirable size range with minimal damage to the particles upon nebulization. By breaking the cross links between the liposomes with a cleaving agent, it was anticipated that triggered release of drug from the AVT particles could be achieved. In vivo studies done in healthy rabbits showed that post-administration modulation of drug release is possible from the AVT particles after the introduction of the cleaving agent. This study has important implications for the future development of this technology, where the AVT particles can be made “sensitive” to the product of disease. It is envisaged that a single dose of AVT containing the appropriate drug when administered to the lungs would maintain drug levels at a controlled rate over an extended period of time. When the need for more drug arises, the product of the disease would trigger the AVT particles to release more drug as needed to control the condition, thus eliminating the need for repeated drug doses and improved compliance amongst patients.

Noble gas, CFC and other geochemical evidence for the age and origin of the Bath thermal waters, UK

The city of Bath is a World Heritage site and its thermal waters, the Roman Baths and new spa development rely on undisturbed flow of the springs (45 °C). The current investigations provide an improved understanding of the residence times and flow regime as basis for the source protection. Trace gas indicators including the noble gases (helium, neon, argon, krypton and xenon) and chlorofluorocarbons (CFCs), together with a more comprehensive examination of chemical and stable isotope tracers are used to characterise the sources of the thermal water and any modern components. It is shown conclusively by the use of 39Ar that the bulk of the thermal water has been in circulation within the Carboniferous Limestone for at least 1000 years. Other stable isotope and noble gas measurements confirm previous findings and strongly suggest recharge within the Holocene time period (i.e. the last 12 kyr). Measurements of dissolved 85Kr and chlorofluorocarbons constrain previous indications from tritium that a small proportion (<5%) of the thermal water originates from modern leakage into the spring pipe passing through Mesozoic valley fill underlying Bath. This introduces small amounts of O2 into the system, resulting in the Fe precipitation seen in the King’s Spring. Silica geothermometry indicates that the water is likely to have reached a maximum temperature of between 69–99 °C, indicating a most probable maximum circulation depth of ∼3 km, which is in line with recent geological models. The rise to the surface of the water is sufficiently indirect that a temperature loss of >20 °C is incurred. There is overwhelming evidence that the water has evolved within the Carboniferous Limestone formation, although the chemistry alone cannot pinpoint the geometry of the recharge area or circulation route. For a likely residence time of 1–12 kyr, volumetric calculations imply a large storage volume and circulation pathway if typical porosities of the limestone at depth are used, indicating that much of the Bath-Bristol basin must be involved in the water storage.

Dating groundwater in the Bohemian Cretaceous Basin: Understanding tracer variations in the subsurface

The northern section of the Bohemian Cretaceous Basin has been the site of intensive U exploitation with harmful impacts on groundwater quality. The understanding of groundwater flow and age distribution is crucial for the prediction of the future dispersion and impact of the contamination. State of the art tracer methods (3H, 3He, 4He, 85Kr, 39Ar and 14C) were, therefore, used to obtain insights to ageing and mixing processes of groundwater along a north–south flow line in the centre of the two most important aquifers of Cenomanian and middle Turonian age. Dating of groundwater is particularly complex in this area as: (i) groundwater in the Cenomanian aquifer is locally affected by fluxes of geogenic and biogenic gases (e.g. CO2, CH4, He) and by fossil brines in basement rocks rich in Cl and SO4; (ii) a thick unsaturated zone overlays the Turonian aquifer; (iii) a periglacial climate and permafrost conditions prevailed during the Last Glacial Maximum (LGM), and iv) the wells are mostly screened over large depth intervals. Large disagreements in 85Kr and 3H/3He ages indicate that processes other than ageing have affected the tracer data in the Turonian aquifer. Mixing with older waters (>50 a) was confirmed by 39Ar activities. An inverse modelling approach, which included time lags for tracer transport throughout the unsaturated zone and degassing of 3He, was used to estimate the age of groundwater. Best fits between model and field results were obtained for mean residence times varying from modern up to a few hundred years. The presence of modern water in this aquifer is correlated with the occurrence of elevated pollution (e.g. nitrates). An increase of reactive geochemical indicators (e.g. Na) and radiogenic 4He, and a decrease in 14C along the flow direction confirmed groundwater ageing in the deeper confined Cenomanian aquifer. Radiocarbon ages varied from a few hundred years to more than 20 ka. Initial 14C activity for radiocarbon dating was calibrated by means of 39Ar measurements. The 14C age of a sample recharged during the LGM was further confirmed by depleted stable isotope signatures and near freezing point noble gas temperature. Radiogenic 4He accumulated in groundwater with concentrations increasing linearly with 14C ages. This enabled the use of 4He to validate the dating range of 14C and extend it to other parts of this aquifer. In the proximity of faults, 39Ar in excess of modern concentrations and 14C dead CO2 sources, elevated 3He/4He ratios and volcanic activity in Oligocene to Quaternary demonstrate the influence of gas of deeper origin and impeded the application of 4He, 39Ar and 14C for groundwater dating.

Lability of Proteinaceous Material in Estuarine Seston and Subcellular Fractions of Phytoplankton

The rate of proteolysis of amino acids was used to assess the nutritional lability of various materials making up estuarine seston in 3 Maine, USA, estuaries. Physical separations of subcellular fractions of phytoplankton cells led to higher proteolysis rate constants for the cytoplasmic fraction (>1.2 h(-1)) than for the membrane fraction (0.2 to 1 h(-1)). Whole cells, copepod fecal pellets, bottom sediments, and estuarine seston had overlapping ranges of rate constants of 0.17 to 1.3 h(-1), which were indistinguishable from one another. Protein pools in the seston of these estuaries throughout the seasons were dominated by phytoplankton production and its fresh detrital products. Inverse relationships between proteolysis rate constants for estuarine seston and the ratios of pheopigments to chlorophyll indicates that the average lability of seston decreases with the disappearance of cytoplasmic material in suspension. This kinetic approach to the quality of food resources implies the existence of different pools of digestible protein for estuarine heterotrophs with different gut residence times. Preferential enrichment of membrane components in sestonic detritus may result from the differential lability of proteins in cytoplasm versus membrane components of cells.

Natural Tracers in recent groundwaters from different Alpine aquifers

Groundwater with underground residence times between days and a few years have been investigated over more than 20 years from 487 remote sites located in different aquifer types in the Alpine belt. Analysis of the data reveals that groundwaters evolved in crystalline, evaporite, carbonate, molasse, and flysch aquifers can be clearly distinguished based on their major and trace element composition and degree of mineralisation. A further subdivision can be made even within one aquifer type based on the trace element compositions, which are characteristic for the lithologic environment. Major and trace element concentrations can be quantitatively described by interaction of the groundwater with the aquifer- specific mineralogy along the flow path. Because all investigated sites show minimal anthropogenic influences, the observed concentration ranges represent the natural background concentrations and can thus serve as a “geo-reference” for recent groundwaters from these five aquifer types. This “geo-reference” is particularly useful for the identification of groundwater contamination. It further shows that drinking water standards can be grossly exceeded for critical elements by purely natural processes

Tracer applications of noble gas radionuclides in the geosciences

Noble gas radionuclides, including 81Kr (t1/2 = 229,000 years), 85Kr (t1/2 = 10.8 years), and 39Ar (t1/2 = 269 years), possess nearly ideal chemical and physical properties for studies of earth and environmental processes. Recent advances in Atom Trap Trace Analysis (ATTA), a laser-based atom counting method, have enabled routine measurements of the radiokrypton isotopes, as well as the demonstration of the ability to measure 39Ar in environmental samples. Here we provide an overview of the ATTA technique, and a survey of recent progress made in several laboratories worldwide.We review the application of noble gas radionuclides in the geosciences and discuss how ATTA can help advance these fields, specifically: determination of groundwater residence times using 81Kr, 85Kr, and 39Ar; dating old glacial ice using 81Kr; and an 39Ar survey of the main water masses of the oceans, to study circulation pathways and estimate mean residence times. Other scientific questions involving a deeper circulation of fluids in the Earth's crust and mantle are also within the scope of future applications. We conclude that the geoscience community would greatly benefit from an ATTA facility dedicated to this field, with instrumentation for routine measurements, as well as for research on further development of ATTA methods.

Multiple sources of Greenland dust throughout the Holocene

It is contested that the mineral dust found in Greenlandic ice cores during the Holocene stems from multiple source areas. Particles entrained above a more productive, primary source dominate the signal’s multi-seasonal average. Data in sub-annual resolution, however, reveal at least one further source. Whereas distinct inputs from the primary source are visible in elevated concentration levels, various inputs of the secondary source(s) are reflected by multiple maxima in the coarse particle percentage. As long as the dust sources’ respective seasonal cycles are preserved, primary and secondary source can be distinguished. Since the two source’s ejecta eventually detected differ in size, which can be attributed to a change in atmospheric residence times, it is suggested that the secondary source is located in closer proximity to the drilling site than the primary one.

The role of climate-driven chemical weathering on soil production

Climate plays an important role in controlling rates of weathering and weathered regolith production. Regolith production functions, however, seldom take climate parameters into account. Based on a climate-dependent weathered regolith production model, at low denudation rates, relative regolith thicknesses are less sensitive to changes in precipitation rates, while at high denudation rates, small changes in climatic parameters can result in complete stripping of hillslopes. This pattern is compounded by the long residence times and system response times associated with low denudation rates, and vice versa. As others have shown, the transition between regolith-mantled and bedrock slopes is dependent on the ratio of denudation to production. Here, we further suggest that this is itself a function of precipitation rate and temperature. We suggest that climatic parameters can be easily incorporated into existing soil production models and that such additions improve the predictive power of soil production models. (C) 2013 Elsevier B.V. All rights reserved.

Plutonium and americium concentrations in sea water and in sinking particles

Vertical fluxes of 239+240Pu and 241Am and temporal changes in their inventories in the northwestern Mediterranean Sea have been examined through high-resolution water column sampling coupled with direct measurements of the vertical flux of particle-bound transuranics using time-series sediment traps. Water column profiles of both radionuclides showed well-defined sub-surface maxima (2391240Pu between 100-400 m; 241Am at 100-200 m and 800 m), the depths of which are a result of the different biogeochemical scavenging behavior of the two radionuclides. Comparison of deep water column (0-2,000 m) transuranic inventories with those derived from earlier measurements demonstrate that the total 2391240Pu inventory had not substantially changed between 1976-1990 whereas 241Am had decreased by approximately 24%. Enhanced scavenging of 241Am and a resultant, more rapid removal from the water column relative to 239+240Pu was also supported by the observation of elevated Am/Pu activity ratios in sinking particles collected in sediment traps at depth. Direct measurements of the downward flux of particulate 239+240Pu and 241Am compared with transuranic removal rates derived from observed total water column inventory differences over time, show that particles sinking out of deep waters (1,000-2,000 m) could account for 26-72% of the computed total annual 239+240Pu loss and virtually all of the 241Am removal from the water column. Upper water column (0-200 m) residence times based on direct flux measurements ranged from 20-30 yr for 239+240Pu and 5-10 yr for 241Am. The observation that 241Am/239+240Pu activity ratios in unfiltered Mediterranean seawater are six times lower than those in the north Pacific suggests the existence of a specific mechanism for enhanced scavenging and removal of 241Am from the generally oligotrophic waters of the open Mediterranean. It is proposed that atmospheric inputs of aluminosilicate particles transported by Saharan dust events which frequently occur in the Mediterranean region could enhance the geochemical scavenging and resultant removal of 241Am to the sediments.

Sediment and pore fluid chemistry for IODP Sites 311-U1325 and 311-U1329

Analytical challenges in obtaining high quality measurements of rare earth elements (REEs) from small pore fluid volumes have limited the application of REEs as deep fluid geochemical tracers. Using a recently developed analytical technique, we analyzed REEs from pore fluids collected from Sites U1325 and U1329, drilled on the northern Cascadia margin during the Integrated Ocean Drilling Program (IODP) Expedition 311, to investigate the REE behavior during diagenesis and their utility as tracers of deep fluid migration. These sites were selected because they represent contrasting settings on an accretionary margin: a ponded basin at the toe of the margin, and the landward Tofino Basin near the shelf's edge. REE concentrations of pore fluid in the methanogenic zone at Sites U1325 and U1329 correlate positively with concentrations of dissolved organic carbon (DOC) and alkalinity. Fractionations across the REE series are driven by preferential complexation of the heavy REEs. Simultaneous enrichment of diagenetic indicators (DOC and alkalinity) and of REEs (in particular the heavy elements Ho to Lu), suggests that the heavy REEs are released during particulate organic carbon (POC) degradation and are subsequently chelated by DOC. REE concentrations are greater at Site U1325, a site where shorter residence times of POC in sulfate-bearing redox zones may enhance REE burial efficiency within sulfidic and methanogenic sediment zones where REE release ensues. Cross-plots of La concentrations versus Cl, Li and Sr delineate a distinct field for the deep fluids (z > 75 mbsf) at Site U1329, and indicate the presence of a fluid not observed at the other sites drilled on the Cascadia margin. Changes in REE patterns, the presence of a positive Eu anomaly, and other available geochemical data for this site suggest a complex hydrology and possible interaction with the igneous Crescent Terrane, located east of the drilled transect.

Geochemistry of plagioclase from the Mid-Atlantic Ridge

We have studied the chemical zoning of plagioclase phenocrysts from the slow-spreading Mid-Atlantic Ridge and the intermediate-spreading rate Costa Rica Rift to obtain the time scales of magmatic processes beneath these ridges. The anorthite content, Mg, and Sr in plagioclase phenocrysts from the Mid-Atlantic Ridge can be interpreted as recording initial crystallisation from a primitive magma (~11 wt% MgO) in an open system. This was followed by crystal accumulation in a mush zone and later entrainment of crystals into the erupted magma. The initial magma crystallised plagioclase more anorthitic than those in equilibrium with any erupted basalt. Evidence that the crystals accumulated in a mush zone comes from both: (1) plagioclase rims that were in equilibrium with a Sr-poor melt requiring extreme differentiation; and (2) different crystals found in the same thin section having different histories. Diffusion modelling shows that crystal residence times in the mush were <140 years, whereas the interval between mush disaggregation and eruption was ?1.5 years. Zoning of anorthite content and Mg in plagioclase phenocrysts from the Costa Rica Rift show that they partially or completely equilibrated with a MgO-rich melt (>11 wt%). Partial equilibration in some crystals can be modelled as starting <1 year prior to eruption but for others longer times are required for complete equilibration. This variety of times is most readily explained if the mixing occurred in a mush zone. None of the plagioclase phenocrysts from the Costa Rica Rift that we studied have Mg contents in equilibrium with their host basalt even at their rims, requiring mixing into a much more evolved magma within days of eruption. In combination these observations suggest that at both intermediate- and slow-spreading ridges: (1) the chemical environment to which crystals are exposed changes on annual to decadal time scales; (2) plagioclase crystals record the existence of melts unlike those erupted; and (3) disaggregation of crystal mush zones appears to precede eruption, providing an efficient mechanism by which evolved interstitial melt can be mixed into erupted basalts.

Geochemistry of tephra layers in ODP Site 121-758

A tephrochronology of the past 5 Ma is constructed with ash layers recovered from Neogene sediments during drilling at ODP Leg 121 Site 758 on northern Ninetyeast Ridge. The several hundred tephra layers observed in the first 80 m of cores range in thickness from a few millimeters to 34 cm. Seventeen tephra layers, at least 1 cm thick, were sampled and analyzed for major elements. Relative ages for the ash layers are estimated from the paleomagnetic and d18O chronostratigraphy. The ash layers comprise about 1.7% by volume of the sediments recovered in the first 72 m. The median grain size of the ashes is about 75 ?m, with a maximum of 150 ?m. The ash consists of rhyolitic bubble junction and pumice glass shards. Blocky and platy shards are in even proportion (10%-30%) and are dominated by bubble wall shards (70%-90%). The crystal content of the layers is always less than 2%, with Plagioclase and alkali feldspar present in nearly every layer. Biotite was observed only in the thickest layers. The major element compositions of glass and feldspar reflect fractionation trends. Three groupings of ash layers suggest different provenances with distinct magmatic systems. Dating by d18O and paleomagnetic reversals suggests major marine ash-layer-producing eruptions (marine tephra layers > 1 cm in thickness) occur roughly every approximately 414,000 yr. This value correlates well with landbased studies and dates of Pleistocene Sumatran tuffs (average 375,000-yr eruptive interval). Residence times of the magmatic systems defined by geochemical trends are 1.583, 2.524, and 1.399 Ma. The longest time interval starts with the least differentiated magma. The Sunda Arc, specifically Sumatra, is inferred to be the source region for the ashes. Four of the youngest five ash layers recovered correlate in time and in major element chemistry to ashes observed on land at the Toba caldera.

Stable isotope composition of Holocene benthic foraminifers from the Eastern Mediterranean Sea

Temporal and regional changes in paleoproductivity and paleoceanography in the eastern Mediterranean Sea during the past 12 kyr were reconstructed on the basis of the stable oxygen and carbon isotope composition of the epibenthic Planulina ariminensis and the shallow endobenthic Uvigerina mediterranea from three sediment cores of the Aegean Sea and Levantine Basin. The Younger Dryas is characterized by high d18O values, indicating enhanced salinities and low temperatures of deep water masses at all investigated sites. With the onset of the Holocene, d18O records show a continuous decrease towards the onset of sapropel S1 formation, mainly caused by a freshening and warming of surface waters at deep water formation sites. In the middle and late Holocene, the similarity of d18O values from the southern Aegean Sea and Levantine Basin suggests the influence of isotopically identical deep water masses. By contrast, slightly higher d18O values are observed the northern Aegean Sea, which probably point to lower temperatures of North Aegean deep waters. The epifaunal d13C records reveal clear changes in sources and residence times of eastern Mediterranean deep waters associated with period of S1 formation. Available data for the early and late phase of sapropel S1 formation and for the interruption around 8.2 kyr display drops by 0.5 and 1.5 per mil, indicating the slow-down of deep water circulation and enhanced riverine input of isotopically light dissolved inorganic carbon from terrestrial sources into the eastern Mediterranean Sea. The decrease in epifaunal d13C signals is particularly expressed in the southern Aegean Sea and Levantine Basin, while it is less pronounced in the northern Aegean Sea. This points to a strong reduction in deep water exchange rates in the southern areas, but the persistence of local deep water formation in the northern Aegean Sea. The d13C values of U. mediterranea records reveal temporal and regional differences in paleoproductivity during the past 12 kyr, with rather eutrophic and mesotrophic conditions in the North Aegean Sea and southeast Levantine Basin, respectively, while the South Aegean Sea is characterized by rather oligotrophic conditions. After S1 formation, increasing d13C values reflect a progressive decrease in surface water productivity in the eastern Mediterranean Sea during the middle and late Holocene. In the northern Aegean Sea, this time interval is marked by repetitive changes in organic matter fluxes documented by significant fluctuations in the d13C signal of U. mediterranea on millennial- to multi-centennial time scales. These fluctuations can be linked to short-term changes in river runoff driven by northern hemisphere climatic variability.

Physical oceanography and hydrochemistry from the Laptev Sea, Arctic Ocean

Combined d18O/salinity data reveal a distinctive water mass generated during winter sea ice formation which is found predominantly in the coastal polynya region of the southern Laptev Sea. Export of the brine-enriched bottom water shows interannual variability in correlation with atmospheric conditions. Summer anticyclonic circulation is favoring an offshore transport of river water at the surface as well as a pronounced signal of brine-enriched waters at about 50 m water depth at the shelf break. Summer cyclonic atmospheric circulation favors onshore or an eastward, alongshore water transport, and at the shelf break the river water fraction is reduced and the pronounced brine signal is missing, while on the middle Laptev Sea shelf, brine-enriched waters are found in high proportions. Residence times of bottom and subsurface waters on the shelf may thereby vary considerably: an export of shelf waters to the Arctic Ocean halocline might be shut down or strongly reduced during "onshore" cyclonic atmospheric circulation, while with "offshore" anticyclonic atmospheric circulation, brine waters are exported and residence times may be as short as 1 year only.

Radiocarbon-age differences among coexisting planktic foraminifera shells

For slowly accumulating sediments, a major contrast exists in the radiocarbon-age differences among coexisting shells of planktic foraminifera between those experiencing little dissolution and those experiencing significant dissolution. In the former, the ages generally agree to within a couple of hundred years. In the latter, age differences as large as 1000 years are common. The most likely explanation appears to be the Barker Effect, which involves the preferential fragmentation of dissolution-prone G. sacculifer and G. ruber. The whole shells of these species picked for radiocarbon dating have shorter residence times in the bioturbation zone than those for dissolution-resistant species (including benthics). As low accumulation rate sediment cores often fail to yield reliable radiocarbon-based ocean ventilation ages, where possible, such studies should be conducted on high accumulation rate cores.