Bioamplification as a bioaccumulation mechanism

Persistent organic pollutant (POP) bioaccumulation models have been generally formulated to predict two main processes, bioconcentration and biomagnification. A third bioaccumulation process that can mediate chemical potential in an organism is bioamplification. Bioamplification occurs when an organism loses body weight and chemical partitioning capacity faster than it can eliminate contaminants. Bioamplification causes an increase in chemical fugacity in the animal\u27s tissues and results in the redistribution of contaminants from inert storage sites to more toxicologically sensitive tissues. Further, bioamplification generally occurs when an organism experiences major bioenergetic bottlenecks or nutritional stress, frequently associated with critical periods in the animal\u27s life history. The goal of this dissertation was to characterize bioamplification as a general bioaccumulation process that is additive to bioconcentration and biomagnification mechanisms of chemical exposure. Empirical studies validating bioamplification in three different animal models each undergoing a recognizable bioenergetic bottleneck during their life history were completed. Specifically, bioamplification was validated in emergent aquatic insects, fish embryos during egg development and larval fish. Bioamplification factors in the above studies ranged from 1.9-2.1 in emergent male mayflies, 1.8-5.4 in incubating yellow perch embryos and 1.5-5.3 in larval Chinook salmon (dependent on food resource availability). To complement these studies, a literature review was completed to demonstrate the wide applicability of this concept to different animal species. Examples of bioamplification were presented in invertebrates, fishes, birds and mammals corresponding to bioenergetic bottlenecks related to migration, reproduction, early life stages, metamorphosis, over wintering weight losses and disease. Bioamplification factors summarized in the literature ranged from 1.1-14 and were similar in magnitude to biomagnification factors typically reported for aquatic and terrestrial organisms. While most of the descriptions of bioamplification in the literature have treated it as a bioaccumulation curiosity, the results of this dissertation demonstrate that bioamplification is a general bioaccumulation process that contributes to enhanced chemical fugacities of POPs across the animal kingdom. Further, the results of this dissertation showed that bioamplification is producing maximum POP fugacities at critical periods over the animal\u27s life history and as such the consequences of bioamplification may be very important to wildlife hazard and risk assessments

Reconversion of Parahydrogen Gas in Surfactant-Coated Glass NMR Tubes

The application of parahydrogen gas to enhance the magnetic resonance signals of a diversity of chemical species has increased substantially in the last decade. Parahydrogen is prepared by lowering the temperature of hydrogen gas in the presence of a catalyst; this enriches the para spin isomer beyond its normal abundance of 25% at thermal equilibrium. Indeed, parahydrogen fractions that approach unity can be attained at sufficiently low temperatures. Once enriched, the gas will revert to its normal isomeric ratio over the course of hours or days, depending on the surface chemistry of the storage container. Although parahydrogen enjoys long lifetimes when stored in aluminum cylinders, the reconversion rate is significantly faster in glass containers due to the prevalence of paramagnetic impurities that are present within the glass. This accelerated reconversion is especially relevant for nuclear magnetic resonance (NMR) applications due to the use of glass sample tubes. The work presented here investigates how the parahydrogen reconversion rate is affected by surfactant coatings on the inside surface of valved borosilicate glass NMR sample tubes. Raman spectroscopy was used to monitor changes to the ratio of the (J: 0 → 2) vs. (J: 1 → 3) transitions that are indicative of the para and ortho spin isomers, respectively. Nine different silane and siloxane-based surfactants of varying size and branching structures were examined, and most increased the parahydrogen reconversion time by 1.5×–2× compared with equivalent sample tubes that were not treated with surfactant. This includes expanding the pH2 reconversion time from 280 min in a control sample to 625 min when the same tube is coated with (3-Glycidoxypropyl)trimethoxysilane

Modest serum creatinine elevation affects adverse outcome after general surgery

Modest serum creatinine elevation affects adverse outcome after general surgery.BackgroundModest preoperative serum creatinine elevation (1.5 to 3.0 mg/dL) has been recently shown to be independently associated with morbidity and mortality after cardiac surgery. It is important to know if this association can be applied more broadly to general surgery cases.MethodsMultivariable logistic regression analyses of 46 risk variables in 49,081 cases from the Veterans Affairs National Surgical Quality Improvement Program, undergoing major general surgery from 10/1/96 through 9/30/98.ResultsThirty day mortality and several cardiac, respiratory, infectious and hemorrhagic morbidities were significantly (P < 0.001) higher in patients with a serum creatinine>1.5 mg/dL. With multivariable analysis, the adjusted odds ratio for mortality for patients with a serum creatinine of 1.5 to 3.0 mg/dL was 1.44 [95% confidence interval (95% CI) 1.22 to 1.71] and for creatinine>3.0 mg/dL was 1.93 (95% CI 1.51 to 2.46). The adjusted odds ratio for morbidity (one or more postoperative complications) for patients with a serum creatinine of 1.5 to 3.0 mg/dL was 1.18 (95% CI 1.06 to 1.32) and for creatinine>3.0 mg/dL was 1.19 (95% CI 0.99 to 1.43). Further stratification and recursive partitioning of creatinine levels revealed that a serum creatinine level>1.5 mg/dL was the approximate threshold for both increased morbidity and mortality.ConclusionsModest preoperative serum creatinine elevation (>1.5 mg/dL) is a significant predictor of risk-adjusted morbidity and mortality after general surgery. A preoperative serum creatinine of 1.5 mg/dL or higher is a readily available marker for potential adverse outcomes after general surgery

NeuroCOPE: A novel intervention to increase professional fulfillment and reduce burnout by connecting Neuro-ICU healthcare workers to their post-recovery patients

Background: Healthcare workers (HCWs) caring for patients with acute neurologic injury in the ICU rarely receive detailed information on the recovery of their patients. The missing connection between the period of acute neurologic injury and long-term outcomes is a psychological burden that contributes to moral fatigue and burnout. We hypothesize that attending an Interprofessional conference series through which patients describe their acute brain injury and recovery to Neuro-ICU HCWs may ease moral fatigue, increasing professional fulfillment and reducing burnout.https://knowledgeconnection.mainehealth.org/lambrew-retreat-2023/1014/thumbnail.jp

A prudent path forward for genomic engineering and germline gene modification

A framework for open discourse on the use of CRISPR-Cas9 technology to manipulate the human genome is urgently needed

Copepod-Associated Gammaproteobacteria Respire Nitrate in the Open Ocean Surface Layers

Microbial dissimilatory nitrate reduction to nitrite, or nitrate respiration, was detected in association with copepods in the oxygenated water column of the North Atlantic subtropical waters. These unexpected rates correspond to up to 0.09 nmol N copepod−1 d−1 and demonstrate a previously unaccounted nitrogen transformation in the oceanic pelagic surface layers. Genes and transcripts for both the periplasmic and membrane associated dissimilatory nitrate reduction pathways (Nap and Nar, respectively) were detected. The napA genes and transcripts were closely related with sequences from several clades of Vibrio sp., while the closest relatives of the narG sequences were Pseudoalteromonas spp. and Alteromonas spp., many of them representing clades only distantly related to previously described cultivated bacteria. The discovered activity demonstrates a novel Gammaproteobacterial respiratory role in copepod association, presumably providing energy for these facultatively anaerobic bacteria, while supporting a reductive path of nitrogen in the oxygenated water column of the open ocean

Pulmonary arterial remodeling induced by a Th2 immune response

Pulmonary arterial remodeling characterized by increased vascular smooth muscle density is a common lesion seen in pulmonary arterial hypertension (PAH), a deadly condition. Clinical correlation studies have suggested an immune pathogenesis of pulmonary arterial remodeling, but experimental proof has been lacking. We show that immunization and prolonged intermittent challenge via the airways with either of two different soluble antigens induced severe muscularization in small- to medium-sized pulmonary arteries. Depletion of CD4+ T cells, antigen-specific T helper type 2 (Th2) response, or the pathogenic Th2 cytokine interleukin 13 significantly ameliorated pulmonary arterial muscularization. The severity of pulmonary arterial muscularization was associated with increased numbers of epithelial cells and macrophages that expressed a smooth muscle cell mitogen, resistin-like molecule α, but surprisingly, there was no correlation with pulmonary hypertension. Our data are the first to provide experimental proof that the adaptive immune response to a soluble antigen is sufficient to cause severe pulmonary arterial muscularization, and support the clinical observations in pediatric patients and in companion animals that muscularization represents one of several injurious events to the pulmonary artery that may collectively contribute to PAH

Defining α-synuclein species responsible for Parkinson's disease phenotypes in mice.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by fibrillar neuronal inclusions composed of aggregated α-synuclein (α-syn). These inclusions are associated with behavioral and pathological PD phenotypes. One strategy for therapeutic interventions is to prevent the formation of these inclusions to halt disease progression. α-Synuclein exists in multiple structural forms, including disordered, nonamyloid oligomers, ordered amyloid oligomers, and fibrils. It is critical to understand which conformers contribute to specific PD phenotypes. Here, we utilized a mouse model to explore the pathological effects of stable β-amyloid-sheet oligomers compared with those of fibrillar α-synuclein. We biophysically characterized these species with transmission EM, atomic-force microscopy, CD spectroscopy, FTIR spectroscopy, analytical ultracentrifugation, and thioflavin T assays. We then injected these different α-synuclein forms into the mouse striatum to determine their ability to induce PD-related phenotypes. We found that β-sheet oligomers produce a small but significant loss of dopamine neurons in the substantia nigra pars compacta (SNc). Injection of small β-sheet fibril fragments, however, produced the most robust phenotypes, including reduction of striatal dopamine terminals, SNc loss of dopamine neurons, and motor-behavior defects. We conclude that although the β-sheet oligomers cause some toxicity, the potent effects of the short fibrillar fragments can be attributed to their ability to recruit monomeric α-synuclein and spread in vivo and hence contribute to the development of PD-like phenotypes. These results suggest that strategies to reduce the formation and propagation of β-sheet fibrillar species could be an important route for therapeutic intervention in PD and related disorders

Model-based evaluation of the long-term cost-effectiveness of systematic case-finding for COPD in primary care

Introduction'One-off' systematic case-finding for COPD using a respiratory screening questionnaire is more effective and cost-effective than routine care at identifying new cases. However, it is not known whether early diagnosis and treatment is beneficial in the longer term. We estimated the long-term cost-effectiveness of a regular case-finding programme in primary care.MethodsA Markov decision analytic model was developed to compare the cost-effectiveness of a 3-yearly systematic case-finding programme targeted to ever smokers aged ≥50 years with the current routine diagnostic process in UK primary care. Patient-level data on case-finding pathways was obtained from a large randomised controlled trial. Information on the natural history of COPD and treatment effects was obtained from a linked COPD cohort, UK primary care database and published literature. The discounted lifetime cost per quality-adjusted life-year (QALY) gained was calculated from a health service perspective.ResultsThe incremental cost-effectiveness ratio of systematic case-finding versus current care was £16 596 per additional QALY gained, with a 78% probability of cost-effectiveness at a £20 000 per QALY willingness-to-pay threshold. The base case result was robust to multiple one-way sensitivity analyses. The main drivers were response rate to the initial screening questionnaire and attendance rate for the confirmatory spirometry test.DiscussionRegular systematic case-finding for COPD using a screening questionnaire in primary care is likely to be cost-effective in the long-term despite uncertainties in treatment effectiveness. Further knowledge of the natural history of case-found patients and the effectiveness of their management will improve confidence to implement such an approach