Biological and environmental monitoring of occupational exposure to cyclophosphamide in industry and hospitals

The aims of the study were to clarify potential exposure situations to anticancer agents during industrial processing, drug manufacture and hospital administration, using cyclophosphamide (CP) as the model compound. CP is considered an animal and human carcinogen, and it is shown to be an indirect mutagen in various test systems using several genetic endpoints. Environmental monitoring was performed by collecting ambient air samples during the different processing and handling stages. Both stationary and personal sampling was used. CP was analyzed by liquid chromatography (HPLC) and mass spectrometry (MS). The process materials and intermediates were also analyzed for genotoxic activity using the Ames test and SCE induction in CHO cells as endpoints. Biological monitoring studies were performed on 147 persons representing 5 groups of workers, control subjects and patients. In the experimental part of the project, the intermediates in the CP manufacturing process, CP I (nor-nitrogen mustard) and CP II (phosphoroxydichloride mustard) were found directly active in the 2 genotoxicity tests. These findings led to improvements in work hygiene when handling CP I and CP II in the process. The CP measurements showed that the highest potential-exposure sites occurred during specific operations of the process, e.g., during emptying of the drying drum and during tablet mass preparation (the range of CP concentrations in air was 0.16-0.49 mg/m3). The correlation between indirect genotoxicity and chemical analyses of the ambient air samples was good, revealing the activity to be due to cyclophosphamide. However, the air samples were found mutagenic without metabolic activation also in the beginning of the process; this is obviously due to CP II particles in the ambient air, since no CP was detected chemically. The personal protection of workers in the plant collaborating in the study is efficient and the production unit is equipped with the best available techniques to protect both the personnel and the quality of the drug. Both the urine mutagenicity analyses using strain TA1535 of Salmonella typhimurium as indicator and the cytogenetic analyses of peripheral blood lymphocytes using sister-chromatid exchanges or structural chromosomal aberrations as endpoints were negative. However, a statistically nonsignificant trend in increased number of micronuclei was observed in binucleated lymphocytes of the worker groups as compared with controls. The studies on the hospital use of CP were performed in 3 oncological units and 1 pharmacy unit.(ABSTRACT TRUNCATED AT 400 WORDS)     

Quaternary Organic Solar Cells Enhanced by Cocrystalline Squaraines with Power Conversion Efficiencies >10%

The incorporation of multiple donors into the bulk‐heterojunction layer of organic polymer solar cells (PSCs) has been demonstrated as a practical and elegant strategy to improve photovoltaics performance. However, it is challenging to successfully design and blend multiple donors, while minimizing unfavorable interactions (e.g., morphological traps, recombination centers, etc.). Here, a new Förster resonance energy transfer‐based design is shown utilizing the synergistic nature of three light active donors (two small molecules and a high‐performance donor–acceptor polymer) with a fullerene acceptor to create highly efficient quaternary PSCs with power conversion efficiencies (PCEs) of up to 10.7%. Within this quaternary architecture, it is revealed that the addition of small molecules in low concentrations broadens the absorption bandwidth, induces cocrystalline molecular conformations, and promotes rapid (picosecond) energy transfer processes. These results provide guidance for the design of multiple‐donor systems using simple processing techniques to realize single‐junction PSC designs with unprecedented PCEs.     

Microscopic vs. macroscopic deformation of the pulmonary alveolar duct.

The stretch of the perimeters of alveolar ducts was measured at the surface of saline-filled specimens of human and dog lung parenchyma that were stretched biaxially. The microscopic stretch of these ducts was measured at several levels of isotropic biaxial macroscopic stretch of the parenchyma with stretch ratio (lambda x = lambda y) in the range of 1.20-1.40, which roughly corresponds to tidal breathing in humans and dogs. Alveolar walls were found to be load-carrying elements in the saline-filled lung, as seen by their straightness at all levels of stretch. Quantitatively, let l, A, L, and S denote, respectively, the duct perimeter length and area and the parenchymal target perimeter and area in the deformed state and lo, Ao, Lo, and So the corresponding variables in the undeformed state. The microscopic stretch ratio of the ducts (l/lo) was found to be approximately 4% larger than the macroscopic stretch ratio (L/Lo) in human lung and approximately 10% larger in dog lung. The microscopic area ratio of the ducts (A/Ao) was found to be approximately 10% larger than the macroscopic area ratio (S/So) in human lung and approximately 22% larger in dog lung. Ducts within human parenchyma were seen to be about twice as stiff as ducts within dog parenchyma over the range of macroscopic stretch studied. This correlates with the volume fractions of collagen and elastin being higher in the human lung than in dog lung. The observed nonuniformity in strain field at the microstructural level suggests the need to include a force balance between alveolar ducts and septal walls when modeling the mechanics of saline-filled parenchyma.     

Transcultural aspects of eating disorders: A critical literature review

A review of studies addressing anorexia nervosa and bulimia nervosa among Native Americans, African-Americans, Hispanics, Asians, Africans, and Middle Easterners yielded only 35 studies, of which 22 were qualitative case reports, three were clinical quantitative studies, and ten were non-clinical quantitative studies. The case studies reported symptoms similar to those of Caucasian patients, and eating disorders were reported in all SES classes. The clinical studies, all reported from Asian countries, described a number of cases for eating disorders quite different from one another. The non-clinical quantitative studies reported a number of cases consistent with the ranges previously reported for controlled samples of non-clinical Caucasian populations. We found few or no quantitative studies on eating disorders from Hispanic, Middle Eastern, African, or Asian countries other than Japan.     

Mixed stimuli-responsive magnetic and gold nanoparticle system for rapid purification, enrichment, and detection of biomarkers

A new diagnostic system for the enrichment and detection of protein biomarkers from human plasma is presented. Gold nanoparticles (AuNPs) were surface-modified with a diblock copolymer synthesized using reversible addition-fragmentation chain transfer (RAFT) polymerization. The diblock copolymer contained a thermally responsive poly(N-isopropylacrylamide) (pNIPAAm) block, a cationic amine-containing block, and a semi-telechelic PEG?-biotin end group. When a mixed suspension of 23 nm pNIPAAm-modified AuNPs was heated with pNIPAAm-coated 10 nm iron oxide magnetic nanoparticles (mNPs) in human plasma, the thermally responsive pNIPAAm directed the formation of mixed AuNP/mNP aggregates that could be separated efficiently with a magnet. Model studies showed that this mixed nanoparticle system could efficiently purify and strongly enrich the model biomarker protein streptavidin in spiked human plasma. A 10 ng/mL streptavidin sample was mixed with the biotinylated pNIPAAm-modified AuNPs and magnetically separated in the mixed nanoparticle system with pNIPAAm mNPs. The aggregates were concentrated into a 50-fold smaller fluid volume at room temperature where the gold nanoparticle reagent redissolved with the streptavidin target still bound. The concentrated gold-labeled streptavidin could be subsequently analyzed directly using lateral flow immunochromatography. This rapid capture and enrichment module thus utilizes the mixed stimuli-responsive nanoparticle system to achieve concentration of a gold-labeled biomarker that can be directly analyzed using lateral flow or other rapid diagnostic strategies.     

Amyloid β and impairment in multiple memory systems in older transgenic APP TgCRND8 mice

The relationship between amyloid beta and cognitive dysfunction in mouse models of Alzheimer's disease has been evaluated predominantly with the spatial reference memory version of the water maze task. However, as Alzheimer's disease encompasses decline in multiple memory systems, it is important to also utilize non-spatial tasks to fully characterize the role of amyloid on behaviour in animal models. We used the TgCRND8 mouse model of Alzheimer's disease to evaluate the effect of amyloid on spatial reference memory, as well as on the non-spatial task of acquisition of conditioned taste aversion, and on the procedural task of swimming to a visible platform. We demonstrate that 8- to 12-month-old TgCRND8 mice are significantly impaired in all three tasks, and that the levels of soluble amyloid beta are significantly correlated with impairment in spatial reference memory, but not with impairment in conditioned taste aversion or swimming to a visible platform. Insoluble fractions of amyloid, which correspond closely to amyloid plaque burden in the brain, are not associated with any behavioural measure. Our study extends the characterization of the model to stages of advanced amyloid pathology and demonstrates that older TgCRND8 mice are impaired in multiple memory systems, including procedural tasks, which are spared at younger ages. The lack of association between amyloid plaques and memory decline supports clinical findings in Alzheimer's patients.     

Blood cells from Friedreich ataxia patients harbor frataxin deficiency without a loss of mitochondrial function

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by GAA triplet expansions or point mutations in the FXN gene on chromosome 9q13. The gene product called frataxin, a mitochondrial protein that is severely reduced in FRDA patients, leads to mitochondrial iron accumulation, Fe-S cluster deficiency and oxidative damage. The tissue specificity of this mitochondrial disease is complex and poorly understood. While frataxin is ubiquitously expressed, the cellular phenotype is most severe in neurons and cardiomyocytes. Here, we conducted comprehensive proteomic, metabolic and functional studies to determine whether subclinical abnormalities exist in mitochondria of blood cells from FRDA patients. Frataxin protein levels were significantly decreased in platelets and peripheral blood mononuclear cells from FRDA patients. Furthermore, the most significant differences associated with frataxin deficiency in FRDA blood cell mitochondria were the decrease of two mitochondrial heat shock proteins. We did not observe profound changes in frataxin-targeted mitochondrial proteins or mitochondrial functions or an increase of apoptosis in peripheral blood cells, suggesting that functional defects in these mitochondria are not readily apparent under resting conditions in these cells.     

Lead optimization of purine based orally bioavailable Mps1 (TTK) inhibitors

Efforts to optimize biological activity, novelty, selectivity and oral bioavailability of Mps1 inhibitors, from a purine based lead MPI-0479605, are described in this Letter. Mps1 biochemical activity and cytotoxicity in HCT-116 cell line were improved. On-target activity confirmation via mechanism based G2/M escape assay was demonstrated. Physico-chemical and ADME properties were optimized to improve oral bioavailability in mouse.     

Long‐term monitoring of tropical alpine habitat change,Andean anurans,and chytrid fungus in the Cordillera Vilcanota,Peru: Results from a decade of study

The Cordillera Vilcanota in southern Peru is the second largest glacierized range in the tropics and home to one of the largest high‐alpine lakes, Sibinacocha (4,860 m). Here, Telmatobius marmoratus (marbled water frog), Rhinella spinulosa (Andean toad), and Pleurodema marmoratum (marbled four‐eyed frog) have expanded their range vertically within the past century to inhabit newly formed ponds created by ongoing deglaciation. These anuran populations, geographically among the highest (5,200–5,400 m) recorded globally, are being impacted by the chytrid fungus Batrachochytrium dendrobatidis (Bd), and the disease it causes, chytridiomycosis. In this study, we report results from over a decade of monitoring these three anuran species, their habitat, and Bd infection status. Our observations reveal dynamic changes in habitat including ongoing rapid deglaciation (18.4 m/year widening of a corridor between retreating glaciers from 2005 to 2015), new pond formation, changes in vegetation in amphibian habitat, and widespread occurrence of Bd in amphibians in seven sites. Three of these sites have tested positive for Bd over a 9‐ to 12‐year period. In addition, we observed a widespread reduction in T. marmoratus encounters in the Vilcanota in 2008, 2009, and 2012, while encounters increased in 2013 and 2015. Despite the rapid and dynamic changes in habitat under a warming climate, continued presence of Bd in the environment for over a decade, and a reduction in one of three anuran species, we document that these anurans continue to breed and survive in this high Andean environment. High variability in anuran encounters across sites and plasticity in these populations across habitats, sites, and years are all factors that could favor repopulation postdecline. Preserving the connectivity of wetlands in the Cordillera Vilcanota is therefore essential in ensuring that anurans continue to breed and adapt as climate change continues to reshape the environment.