Abstract Local drug delivery into cartilage remains a challenge due to its dense extracellular matrix of negatively charged proteoglycans enmeshed within a collagen fibril network. The high negative ...fixed charge density of cartilage offers the unique opportunity to utilize electrostatic interactions to augment transport, binding and retention of drug carriers. With the goal of developing particle-based drug delivery mechanisms for treating post-traumatic osteoarthritis, our objectives were, first, to determine the size range of a variety of solutes that could penetrate and diffuse through normal cartilage and enzymatically treated cartilage to mimic early stages of OA, and second, to investigate the effects of electrostatic interactions on particle partitioning, uptake and binding within cartilage using the highly positively charged protein, Avidin, as a model. Results showed that solutes having a hydrodynamic diameter ≤10 nm can penetrate into the full thickness of cartilage explants while larger sized solutes were trapped in the tissue's superficial zone. Avidin had a 400-fold higher uptake than its neutral same-sized counterpart, NeutrAvidin, and >90% of the absorbed Avidin remained within cartilage explants for at least 15 days. We report reversible, weak binding ( KD ∼ 150 μ m ) of Avidin to intratissue sites in cartilage. The large effective binding site density ( NT ∼ 2920 μ m ) within cartilage matrix facilitates Avidin's retention, making its structure suitable for particle based drug delivery into cartilage.
Abstract
Background
The increasing incidence of pediatric inflammatory bowel disease (IBD), along with more extensive and severe disease in children, raises concern for related health care ...expenditures.
Aim
The aim of this study was to quantify and characterize costs of pediatric IBD in the year following diagnosis.
Methods
We identified all patients diagnosed with IBD at Connecticut Children’s Medical Center in 2016 with a minimum of 1 year follow-up. Clinical and demographic factors were recorded at diagnosis. We examined paid service and professional costs related to outpatient medications and infusions, outpatient procedures and radiology imaging, inpatient services, and outpatient visits. Actual dollar reimbursements were from private and public payers. Data is reported as mean ± SD and median (IQR).
Results
First-year cost data were collected on 67 patients (43 Crohn’s disease CD, 24 ulcerative colitis UC, mean age 13 years SD 3.22) revealing a mean cost of $45,753 (SD $37,938), with $43,095 (SD $30,828) for CD and $50,516 (SD $48,557) for UC. Severe CD (n = 11) had a mean cost of $71,176 (SD $43,817) and severe UC (n = 5) $134,178 (SD $40,920). Patients receiving infusion therapy had a mean cost of $59,376 (SD $38,724) compared with $27,903 (SD $28,795) for those not receiving infusions. Overall cost distribution showed 37% from infusion costs, 25% hospital costs, 18% outpatient procedures, 10% outpatient oral medications, 7% outpatient imaging, and 3% outpatient visits.
Conclusions
Infusion therapy is a key driver of first-year costs for children newly diagnosed with IBD. Understanding cost distribution in relation to disease presentation can be helpful to anticipate future related costs.
Pediatric inflammatory bowel disease is increasing in incidence and severity, which raises concern for related health care expenditures. Severity of disease at time of diagnosis and use of biologic infusion therapy dramatically increase costs in the first year after diagnosis.
Wetlands are prominent landscapes throughout North America. The general characteristics of wetlands are controversial, thus there has not been a systematic assessment of different types of wetlands ...in different parts of North America, or a compendium of the threats to their conservation. Wetland Habitats of North America adopts a geographic and habitat approach, in which experts familiar with wetlands from across North America provide analyses and syntheses of their particular region of study. Addressing a broad audience of students, scientists, engineers, environmental managers, and policy makers, this book reviews recent, scientifically rigorous literature directly relevant to understanding, managing, protecting, and restoring wetland ecosystems of North America.
genomic basis of trophic strategy in marine bacteria Lauro, Federico M; McDougald, Diane; Thomas, Torsten ...
Proceedings of the National Academy of Sciences - PNAS,
09/2009, Volume:
106, Issue:
37
Journal Article
Peer reviewed
Open access
Many marine bacteria have evolved to grow optimally at either high (copiotrophic) or low (oligotrophic) nutrient concentrations, enabling different species to colonize distinct trophic habitats in ...the oceans. Here, we compare the genome sequences of two bacteria, Photobacterium angustum S14 and Sphingopyxis alaskensis RB2256, that serve as useful model organisms for copiotrophic and oligotrophic modes of life and specifically relate the genomic features to trophic strategy for these organisms and define their molecular mechanisms of adaptation. We developed a model for predicting trophic lifestyle from genome sequence data and tested >400,000 proteins representing >500 million nucleotides of sequence data from 126 genome sequences with metagenome data of whole environmental samples. When applied to available oceanic metagenome data (e.g., the Global Ocean Survey data) the model demonstrated that oligotrophs, and not the more readily isolatable copiotrophs, dominate the ocean's free-living microbial populations. Using our model, it is now possible to define the types of bacteria that specific ocean niches are capable of sustaining.
Abstract
Primary human hepatocytes (PHHs) are commonly used for in vitro studies of drug-induced liver injury. However, when cultured as 2D monolayers, PHH lose crucial hepatic functions within ...hours. This dedifferentiation can be ameliorated when PHHs are cultured in sandwich configuration (2Dsw), particularly when cultures are regularly re-overlaid with extracellular matrix, or as 3D spheroids. In this study, the 6 participating laboratories evaluated the robustness of these 2 model systems made from cryopreserved PHH from the same donors considering both inter-donor and inter-laboratory variability and compared their suitability for use in repeated-dose toxicity studies using 5 different hepatotoxins with different toxicity mechanisms. We found that expression levels of proteins involved in drug absorption, distribution, metabolism, and excretion, as well as catalytic activities of 5 different CYPs, were significantly higher in 3D spheroid cultures, potentially affecting the exposure of the cells to drugs and their metabolites. Furthermore, global proteomic analyses revealed that PHH in 3D spheroid configuration were temporally stable whereas proteomes from the same donors in 2Dsw cultures showed substantial alterations in protein expression patterns over the 14 days in culture. Overall, spheroid cultures were more sensitive to the hepatotoxic compounds investigated, particularly upon long-term exposures, across testing sites with little inter-laboratory or inter-donor variability. The data presented here suggest that repeated-dosing regimens improve the predictivity of in vitro toxicity assays, and that PHH spheroids provide a sensitive and robust system for long-term mechanistic studies of drug-induced hepatotoxicity, whereas the 2Dsw system has a more dedifferentiated phenotype and lower sensitivity to detect hepatotoxicity.
Comparison of eight iron experiments shows that maximum Chl a, the maximum DIC removal, and the overall DIC/Fe efficiency all scale inversely with depth of the wind mixed layer (WML) defining the ...light environment. Moreover, lateral patch dilution, sea surface irradiance, temperature, and grazing play additional roles. The Southern Ocean experiments were most influenced by very deep WMLs. In contrast, light conditions were most favorable during SEEDS and SERIES as well as during IronEx‐2. The two extreme experiments, EisenEx and SEEDS, can be linked via EisenEx bottle incubations with shallower simulated WML depth. Large diatoms always benefit the most from Fe addition, where a remarkably small group of thriving diatom species is dominated by universal response of Pseudo‐nitzschia spp. Significant response of these moderate (10–30 μm), medium (30–60 μm), and large (>60 μm) diatoms is consistent with growth physiology determined for single species in natural seawater. The minimum level of “dissolved” Fe (filtrate < 0.2 μm) maintained during an experiment determines the dominant diatom size class. However, this is further complicated by continuous transfer of original truly dissolved reduced Fe(II) into the colloidal pool, which may constitute some 75% of the “dissolved” pool. Depth integration of carbon inventory changes partly compensates the adverse effects of a deep WML due to its greater integration depths, decreasing the differences in responses between the eight experiments. About half of depth‐integrated overall primary productivity is reflected in a decrease of DIC. The overall C/Fe efficiency of DIC uptake is DIC/Fe ∼ 5600 for all eight experiments. The increase of particulate organic carbon is about a quarter of the primary production, suggesting food web losses for the other three quarters. Replenishment of DIC by air/sea exchange tends to be a minor few percent of primary CO2 fixation but will continue well after observations have stopped. Export of carbon into deeper waters is difficult to assess and is until now firmly proven and quite modest in only two experiments.
The mucosal origins hypothesis of rheumatoid arthritis (RA) proposes a central role for mucosal immune responses in the initiation or perpetuation of the systemic autoimmunity that occurs with ...disease. However, the connection between the mucosa and systemic autoimmunity in RA remains unclear. Using dual immunoglobulin A (IgA) and IgG family plasmablast-derived monoclonal autoantibodies obtained from peripheral blood of individuals at risk for RA, we identified cross-reactivity between RA-relevant autoantigens and bacterial taxa in the closely related families
and
. After generating bacterial isolates within the
genus
from the feces of an individual, we confirmed monoclonal antibody binding and CD4
T cell activation in individuals with RA compared to control individuals. In addition, when
isolate 7 but not isolate 1 colonized germ-free mice, it stimulated T
17 cell expansion, serum RA-relevant IgG autoantibodies, and joint swelling reminiscent of early RA, with histopathology characterized by antibody deposition and complement activation. Systemic immune responses were likely due to mucosal invasion along with the generation of colon-isolated lymphoid follicles driving increased fecal and serum IgA by isolate 7, because B and CD4
T cell depletion not only halted intestinal immune responses but also eliminated detectable clinical disease. In aggregate, these findings demonstrate a mechanism of RA pathogenesis through which a specific intestinal strain of bacteria can drive systemic autoantibody generation and joint-centered antibody deposition and immune activation.
The blooming cosmopolitan coccolithophore Emiliania huxleyi and its viruses (EhVs) are a model for density-dependent virulent dynamics. EhVs commonly exhibit rapid viral reproduction and drive host ...death in high-density laboratory cultures and mesocosms that simulate blooms. Here we show that this system exhibits physiology-dependent temperate dynamics at environmentally relevant E. huxleyi host densities rather than virulent dynamics, with viruses switching from a long-term non-lethal temperate phase in healthy hosts to a lethal lytic stage as host cells become physiologically stressed. Using this system as a model for temperate infection dynamics, we present a template to diagnose temperate infection in other virus-host systems by integrating experimental, theoretical, and environmental approaches. Finding temperate dynamics in such an established virulent host-virus model system indicates that temperateness may be more pervasive than previously considered, and that the role of viruses in bloom formation and decline may be governed by host physiology rather than by host-virus densities.
We previously reported the unexpected finding of significantly improved survival for newly diagnosed glioblastoma in patients when radiation therapy (RT) was initiated later (>4 wk post-op) compared ...with earlier (≤2 wk post-op). In that analysis, data were analyzed from 2855 patients from 16 NRG Oncology/Radiotherapy Oncology Group (RTOG) trials conducted prior to the era of concurrent temozolomide (TMZ) with RT. We now report on 1395 newly diagnosed glioblastomas from 2 studies, treated with RT and concurrent TMZ followed by adjuvant TMZ. Our hypothesis was that concurrent TMZ has a synergistic/radiosensitizing mechanism, making RT timing less significant.
Data from patients treated with TMZ-based chemoradiation from NRG Oncology/RTOG 0525 and 0825 were analyzed. An analysis comparable to our prior study was performed to determine whether there was still an impact on survival by delaying RT. Overall survival (OS) was investigated using the Kaplan-Meier method and Cox proportional hazards model. Early progression (during time of diagnosis to 30 days after RT completion) was analyzed using the chi-square test.
Given the small number of patients who started RT early following surgery, comparisons were made between >4 and ≤4 weeks delay of radiation from time of operation. There was no statistically significant difference in OS (hazard ratio = 0.93; P = 0.29; 95% CI: 0.80-1.07) after adjusting for known prognostic factors (recursive partitioning analysis and O6-methylguanine-DNA methyltransferase methylation status). Similarly, the rate of early progression did not differ significantly (P = 0.63).
We did not observe a significant prognostic influence of delaying radiation when given concurrently with TMZ for newly diagnosed glioblastoma. The effects of early (1-3 wk post-op) or late (>5 wk) initiation of radiation tested in our prior study could not be replicated.
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