High Prevalence of Respiratory Ciliary Dysfunction in Congenital Heart Disease Patients With Heterotaxy

Patients with congenital heart disease (CHD) and heterotaxy show high postsurgical morbidity/mortality, with some developing respiratory complications. Although this finding is often attributed to the CHD, airway clearance and left-right patterning both require motile cilia function. Thus, airway ciliary dysfunction (CD) similar to that of primary ciliary dyskinesia (PCD) may contribute to increased respiratory complications in heterotaxy patients

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

The behavior of particle-reactive tracers in a high turbidity environment: 234Th and 210Pb on the Amazon continental shelf.

Excess 234Th and 210Pb seabed inventories were measured in cores collected from the Amazon continental shelf to examine particle scavenging and seabed dynamics. Typical excess 210Pb inventories range from 100 to 300 dpm cm-2, and the total excess 210Pb inventory for the Amazon shelf was determined to be 2.7 X 1017 dpm. The 210Pb measurements indicate that particle-reactive species are scavenged not only from the Amazon River but also from the lateral advection of offshore water. In order to sustain the 210Pb inventories, the volume of water supplied by the lateral advection from offshore must be approximately five to ten times the water discharge of the Amazon River. This lateral advection supplies about 67% of the total excess 210Pb to the Amazon continental shelf with relatively small contributions from riverine input (31%), atmospheric fallout (2.3%), and in-situ production (0.1%). The 234Th inventories were measured on four cruises, which occurred during periods of differing river discharge, wind stress, and flow rates of the North Brazil Current. The 234Th excess seabed inventories show large spatial and seasonal variability, with a range from 0 to 22 dpm cm-2. Ratios of predicted 234Th inventories over observed 234Th inventories indicate that a large portion of the inventories on the inner and mid shelf occur in the fluid mud layer or the suspended sediments. The 234Th excess seabed inventories are controlled by resuspension, cycling the inventories between the water column and the seabed. 210Pb and 234Th excess seabed inventories are compared directly using corrections for the different time scales and offshore concentrations. This approach indicates that for most of the shelf, the inventories of the shorter-term tracer (234Th) are less than predicted by the inventories of the longer-term tracer (210Pb). There are two explanations for this trend. The first is that a larger portion of the 234Th inventory occurs in the fluid muds or the water column relative to 210Pb. The second is that the supply of offshore water, scavenging efficiency, and/or deposition have been lower over the two year study period relative to the last one hundred years

Piecing together the Ganges-Brahmaputra-Meghna river delta: use of sediment provenance to reconstruct the history and interaction of multiple fluvial systems during Holocene delta evolution

Three main rivers—the Ganges, Brahmaputra, and Meghna—coalesce in the Bengal basin to form the world’s largest delta system, which serves as filter and gateway between the Himalayan collision and vast Bengal fan repository. New insights into the Holocene construction of the Ganges-Brahmaputra-Meghna delta, with a focus on river sedimentation, channel migration, and avulsion history, are presented here using the Sr geochemistry of bulk sediments as a provenance tracer. The sediment load of each river transmits a distinct Sr signature owing to differences in source rocks from the Himalaya, Tibet, and local regions, allowing for effective tracking of river channels and stratigraphic development within the delta. In the early Holocene, vigorous delta aggradation occurred under rapid sea-level rise and high river discharge and supported the construction of sand-dominated stratigraphy by laterally mobile, braided-stream channels. However, the vertically (i.e., temporally) uniform, but geographically distinct, Sr signatures from these deposits indicate that the Ganges, Brahmaputra, and Meghna fluvial systems remained isolated from one another and apparently constrained within their lowstand valleys. By the mid-Holocene, though, delta stratigraphy records spatially and temporally nonuniform Sr signatures that hallmark the onset of avulsions and unconstrained channel migration, like those that characterize the modern Ganges and Brahmaputra fluvial systems. Such mobility developed in the mid-Holocene despite declining discharge and sea-level rise, suggesting that earlier channel behavior had been strongly influenced by antecedent topography of the lowstand valleys. It is only after the delta had aggraded above the valley margins that the fluvial systems were able to avulse freely, resulting in numerous channel reorganizations from mid-Holocene to present. These channel-system behaviors and their role in delta evolution remain coarsely defined based only on this initial application of Sr-based provenance tools, but the approach is promising and suggests that a more complete understanding can be achieved with continued study

Inhalation delivery of topotecan is superior to intravenous exposure for suppressing lung cancer in a preclinical model

<p>Intravenous (IV) topotecan is approved for the treatment of various malignancies including lung cancer but its clinical use is greatly undermined by severe hematopoietic toxicity. We hypothesized that inhalation delivery of topotecan would increase local exposure and efficacy against lung cancer while reducing systemic exposure and toxicity. These hypotheses were tested in a preclinical setting using a novel inhalable formulation of topotecan against the standard IV dose. Respirable dry-powder of topotecan was manufactured through spray-drying technology and the pharmacokinetics of 0.14 and 0.79 mg/kg inhalation doses were compared with 0.7 mg/kg IV dose. The efficacy of four weekly treatments with 1 mg/kg inhaled vs. 2 mg/kg IV topotecan were compared to untreated control using an established orthotopic lung cancer model for a fast (H1975) and moderately growing (A549) human lung tumors in the nude rat. Inhalation delivery increased topotecan exposure of lung tissue by approximately 30-fold, lung and plasma half-life by 5- and 4-folds, respectively, and reduced the maximum plasma concentration by 2-fold than the comparable IV dose. Inhaled topotecan improved the survival of rats with the fast-growing lung tumors from 7 to 80% and reduced the tumor burden of the moderately-growing lung tumors over 5- and 10-folds, respectively, than the 2-times higher IV topotecan and untreated control (<i>p</i> < .00001). These results indicate that inhalation delivery increases topotecan exposure of lung tissue and improves its efficacy against lung cancer while also lowering the effective dose and maximum systemic concentration that is responsible for its dose-limiting toxicity.</p