Organ burden of inhaled nanoceria in a 2-year low-dose exposure study: dump or depot?

No detailed information on in vivo biokinetics of CeO2 nanoparticles (NPs) following chronic low-dose inhalation is available. The CeO2 burden for lung, lung-associated lymph nodes, and major non-pulmonary organs, blood, and feces, was determined in a chronic whole-body inhalation study in female Wistar rats undertaken according to OECD TG453 (6 h per day for 5 days per week for a 104 weeks with the following concentrations: 0, 0.1, 0.3, 1.0, and 3.0 mg/m3, animals were sacrificed after 3, 12, 24 months). Different spectroscopy methods (ICP-MS, ion-beam-microscopy) were used for the quantification of organ burden and for visualization of NP distribution patterns in tissues. After 24 months of exposure, the highest CeO2 lung burden (4.41 mg per lung) was associated with the highest aerosol concentration and was proportionally lower for the other groups in a dose-dependent manner. Imaging techniques confirmed the presence of CeO2 agglomerates of different size categories within lung tissue with a non-homogenous distribution. For the highest exposure group, after 24 months in total 1.2% of the dose retained in the lung was found in the organs and tissues analyzed in this study, excluding lymph nodes and skeleton. The CeO2 burden per tissue decreased from lungs > lymph nodes > hard bone > liver > bone marrow. For two dosage groups, the liver organ burden showed a low accumulation rate. Here, the liver can be regarded as depot, whereas kidneys, the skeleton, and bone marrow seem to be dumps due to steadily increasing NP burden over time.

[User Acceptance of an Online-Intervention for Improving Depressive Symptoms in Adults with Obesity - Results of a Pilot Study]. / Nutzungsakzeptanz einer Online-Intervention zur Verbesserung depressiver Symptome bei Menschen mit Adipositas.

OBJECTIVES: Investigating the user acceptance and associated factors regarding the use of an unguided online-intervention in people with obesity and comorbid depressive symptoms. METHODS: Quantitative longitudinal pilot study with regard to user acceptance (Baseline before access to online-intervention; Follow-up after 3 months) with n = 46 subjects. RESULTS: Moderate (usefulness, ease of use, satisfaction) to high (ease of learning) user acceptance was reported with regard to the online-intervention. Uptake-rates were 76.1 %, completion-rates were 22.9 %. Positive associations were found e. g. for people receiving invalidity pension and personality traits. CONCLUSIONS: Online-interventions for people with obesity and comorbid depressive symptoms represent a complementary treating component. Associated factors of user acceptance should be taken into account when implementing online-interventions to support high fitting accuracy and to increase the benefit for program users.

Differences in the toxicity of cerium dioxide nanomaterials after inhalation can be explained by lung deposition, animal species and nanoforms.

Considerable differences in pulmonary responses have been observed in animals exposed to cerium dioxide nanoparticles via inhalation. These differences in pulmonary toxicity might be explained by differences in lung deposition, species susceptibility or physicochemical characteristics of the tested cerium dioxide nanoforms (i.e. same chemical substance, different size, shape, surface area or surface chemistry). In order to distinguish the relative importance of these different influencing factors, we performed a detailed analysis of the data from several inhalation studies with different exposure durations, species and nanoforms, namely published data on NM211 and NM212 (JRC repository), NanoAmor (commercially available) and our published and unpublished data on PROM (industry provided). Data were analyzed by comparing the observed pulmonary responses at similar external and internal dose levels. Our analyses confirm that rats are more sensitive to developing pulmonary inflammation compared to mice. The observed differences in responses do not result purely from differences in the delivered and retained doses (expressed in particle mass as well as surface area). In addition, the different nanoforms assessed showed differences in toxic potency likely due to differences in their physicochemical parameters. Primary particle and aggregate/agglomerate size distributions have a substantial impact on the deposited dose and consequently on the pulmonary response. However, in our evaluation size could not fully explain the difference observed in the analyzed studies indicating that the pulmonary response also depends on other physicochemical characteristics of the particles. It remains to be determined to what extent these findings can be generalized to other poorly soluble nanomaterials.

[Innovative E-Health Approaches for Comorbid Depression in Patients with Obesity: Patient and Expert Perspectives on User Acceptance]. / Innovative E-Health-Ansätze für komorbide Depressionen bei Patienten mit Adipositas: Nutzungsakzeptanz aus Patienten- und Expertenperspektive.

Objective Patients with chronic somatic diseases such as obesity often suffer from comorbid depressive disorders and present a great challenge for the medical health care system. The study aims to investigate the user acceptance of an internet-based self-management program regarding depression (using the example of MoodGYM) from two different perspectives: (A) the perspective of patients as well as (B) the perspective of experts based on Rogers' 5 stages model of the innovation-decision process (2003). Methods This study is following a qualitative design including qualitative patient interviews (N = 7) and a focus group with medical experts (N = 12). Results Internet-based self-management programs represent a complementary treatment approach for patients and experts. Both groups see the need for combining the topics overweight, activity, depression and social interchange. Conclusion Patient and expert judgement showed a high degree of user acceptance for internet-based self-management programs regarding depression. The implementation of such programs within the medical care system of patients with obesity should take physical and social aspects of the illness into account.

No genotoxicity in rat blood cells upon 3- or 6-month inhalation exposure to CeO2 or BaSO4 nanomaterials.

In the course of a 2-year combined chronic toxicity-carcinogenicity study performed according to Organisation for Economic Co-operation and Development (OECD) Test Guideline 453, systemic (blood cell) genotoxicity of two OECD representative nanomaterials, CeO2 NM-212 and BaSO4 upon 3- or 6-month inhalation exposure to rats was assessed. DNA effects were analysed in leukocytes using the alkaline Comet assay, gene mutations and chromosome aberrations were measured in erythrocytes using the flow cytometric Pig-a gene mutation assay and the micronucleus test (applying both microscopic and flow cytometric evaluation), respectively. Since nano-sized CeO2 elicited lung effects at concentrations of 5mg/m3 (burdens of 0.5mg/lung) in the preceding range-finding study, whereas nano-sized BaSO4 did not induce any effect, female rats were exposed to aerosol concentrations of 0.1 up to 3mg/m3 CeO2 or 50mg/m3 BaSO4 nanomaterials (6h/day; 5 days/week; whole-body exposure). The blood of animals treated with clean air served as negative control, whereas blood samples from rats treated orally with three doses of 20mg/kg body weight ethylnitrosourea at 24h intervals were used as positive controls. As expected, ethylnitrosourea elicited significant genotoxicity in the alkaline Comet and Pig-a gene mutation assays and in the micronucleus test. By contrast, 3- and 6-month CeO2 or BaSO4 nanomaterial inhalation exposure did not elicit significant findings in any of the genotoxicity tests. The results demonstrate that subchronic inhalation exposure to different low doses of CeO2 or to a high dose of BaSO4 nanomaterials does not induce genotoxicity on the rat hematopoietic system at the DNA, gene or chromosome levels.

Blocking metabotropic glutamate receptor subtype 5 relieves maladaptive chronic stress consequences.

Etiology and pharmacotherapy of stress-related psychiatric conditions and somatoform disorders are areas of high unmet medical need. Stressors holding chronic plus psychosocial components thereby bear the highest health risk. Although the metabotropic glutamate receptor subtype 5 (mGlu5) is well studied in the context of acute stress-induced behaviors and physiology, virtually nothing is known about its potential involvement in chronic psychosocial stress. Using the mGlu5 negative allosteric modulator CTEP (2-chloro-4-[2-[2,5-dimethyl-1-[4-(trifluoromethoxy)phenyl]imidazol-4yl]ethynyl]pyridine), a close analogue of the clinically active drug basimglurant - but optimized for rodent studies, as well as mGlu5-deficient mice in combination with a mouse model of male subordination (termed CSC, chronic subordinate colony housing), we demonstrate that mGlu5 mediates multiple physiological, immunological, and behavioral consequences of chronic psychosocial stressor exposure. For instance, CTEP dose-dependently relieved hypothalamo-pituitary-adrenal axis dysfunctions, colonic inflammation as well as the CSC-induced increase in innate anxiety; genetic ablation of mGlu5 in mice largely reproduced the stress-protective effects of CTEP and additionally ameliorated CSC-induced physiological anxiety. Interestingly, CSC also induced an upregulation of mGlu5 in the hippocampus, a stress-regulating brain area. Taken together, our findings provide evidence that mGlu5 is an important mediator for a wide range of chronic psychosocial stress-induced alterations and a potentially valuable drug target for the treatment of chronic stress-related pathologies in man.

Biokinetics and effects of barium sulfate nanoparticles.

BACKGROUND: Nanoparticulate barium sulfate has potential novel applications and wide use in the polymer and paint industries. A short-term inhalation study on barium sulfate nanoparticles (BaSO4 NPs) was previously published [Part Fibre Toxicol 11:16, 2014]. We performed comprehensive biokinetic studies of ¹³¹BaSO4 NPs administered via different routes and of acute and subchronic pulmonary responses to instilled or inhaled BaSO4 in rats. METHODS: We compared the tissue distribution of ¹³¹Ba over 28 days after intratracheal (IT) instillation, and over 7 days after gavage and intravenous (IV) injection of ¹³¹BaSO4. Rats were exposed to 50 mg/m³ BaSO4 aerosol for 4 or 13 weeks (6 h/day, 5 consecutive days/week), and then gross and histopathologic, blood and bronchoalveolar lavage (BAL) fluid analyses were performed. BAL fluid from instilled rats was also analyzed. RESULTS: Inhaled BaSO4 NPs showed no toxicity after 4-week exposure, but a slight neutrophil increase in BAL after 13-week exposure was observed. Lung burden of inhaled BaSO4 NPs after 4-week exposure (0.84 ± 0.18 mg/lung) decreased by 95% over 34 days. Instilled BaSO4 NPs caused dose-dependent inflammatory responses in the lungs. Instilled BaSO4 NPs (0.28 mg/lung) was cleared with a half-life of ≈ 9.6 days. Translocated ¹³¹Ba from the lungs was predominantly found in the bone (29%). Only 0.15% of gavaged dose was detected in all organs at 7 days. IV-injected ¹³¹BaSO4 NPs were predominantly localized in the liver, spleen, lungs and bone at 2 hours, but redistributed from the liver to bone over time. Fecal excretion was the dominant elimination pathway for all three routes of exposure. CONCLUSIONS: Pulmonary exposure to instilled BaSO4 NPs caused dose-dependent lung injury and inflammation. Four-week and 13-week inhalation exposures to a high concentration (50 mg/m³) of BaSO4 NPs elicited minimal pulmonary response and no systemic effects. Instilled and inhaled BaSO4 NPs were cleared quickly yet resulted in higher tissue retention than when ingested. Particle dissolution is a likely mechanism. Injected BaSO4 NPs localized in the reticuloendothelial organs and redistributed to the bone over time. BaSO4 NP exhibited lower toxicity and biopersistence in the lungs compared to other poorly soluble NPs such as CeO2 and TiO2.

Time course of lung retention and toxicity of inhaled particles: short-term exposure to nano-Ceria.

Two Ceria nanomaterials (NM-211 and NM-212) were tested for inhalation toxicity and organ burdens in order to design a chronic and carcinogenicity inhalation study (OECD TG No. 453). Rats inhaled aerosol concentrations of 0.5, 5, and 25 mg/m(3) by whole-body exposure for 6 h/day on 5 consecutive days for 1 or 4 weeks with a post-exposure period of 24 or 129 days, respectively. Lungs were examined by bronchoalveolar lavage and histopathology. Inhaled Ceria is deposited in the lung and cleared with a half-time of 40 days; at aerosol concentrations higher than 0.5 mg/m(3), this clearance was impaired resulting in a half-time above 200 days (25 mg/m(3)). After 5 days, Ceria (>0.5 mg/m(3)) induced an early inflammatory reaction by increases of neutrophils in the lung which decreased with time, with sustained exposure, and also after the exposure was terminated (during the post-exposure period). The neutrophil number observed in bronchoalveolar lavage fluid (BALF) was decreasing and supplemented by mononuclear cells, especially macrophages which were visible in histopathology but not in BALF. Further progression to granulomatous inflammation was observed 4 weeks post-exposure. The surface area of the particles provided a dose metrics with the best correlation of the two Ceria's inflammatory responses; hence, the inflammation appears to be directed by the particle surface rather than mass or volume in the lung. Observing the time course of lung burden and inflammation, it appears that the dose rate of particle deposition drove an initial inflammatory reaction by neutrophils. The later phase (after 4 weeks) was dominated by mononuclear cells, especially macrophages. The progression toward the subsequent granulomatous reaction was driven by the duration and amount of the particles in the lung. The further progression of the biological response will be determined in the ongoing long-term study.

Epidemiology of traumatic spinal cord injury in Canada.

STUDY DESIGN: Retrospective review. OBJECTIVE: To describe the incidence, clinical features, and treatment of traumatic spinal cord injury (SCI) treated at a Canadian tertiary care center. SUMMARY OF BACKGROUND DATA: Understanding the current epidemiology of acute traumatic SCI is essential for public resource allocation and primary prevention. Recent reports suggest that the mean age of patients with SCI may be increasing. METHODS: We retrospectively reviewed hospital records on all patients with traumatic SCI between January 1997 and June 2001 (n = 151). Variables assessed included age, gender, length of hospitalization, type and mechanism of injury, associated spinal fractures, neurologic deficit, and treatment. RESULTS: Annual age-adjusted incidence rates were 42.4 per million for adults aged 15-64 years, and 51.4 per million for those 65 years and older. Motor vehicle accidents accounted for 35% of SCI. Falls were responsible for 63% of SCI among patients older than 65 years and for 31% of injuries overall. Cervical SCI was most common, particularly in the elderly, and was associated with fracture in only 56% of cases. Thoracic and lumbar SCI were associated with spinal fractures in 100% and 85% of cases, respectively. In-hospital mortality was 8%. Mortality was significantly higher among the elderly. Treatment of thoracic and lumbar fractures associated with SCI was predominantly surgical, whereas cervical fractures were equally likely to be treated with external immobilization alone or with surgery. CONCLUSION: A large proportion of injuries was seen among older adults, predominantly as a result of falls. Prevention programs should expand their focus to include home safety and avoidance of falls in the elderly.

Antiphospholipid antibodies are common in patients referred for percutaneous patent foramen ovale closure.

Very little is known about any interaction between patent foramen ovale (PFO) and various hypercoagulable disorders that have been associated with cryptogenic stroke. Percutaneous PFO closure for secondary prevention of paradoxical thromboembolization is receiving increasing attention. Hypercoagulability may affect the potential risks and expected benefits of percutaneous PFO closure. Consecutive patients undergoing percutaneous PFO closure at a single center were screened for the presence of antiphospholipid antibodies, elevated lipoprotein(a), hyperhomocysteinemia, and dysfibrinogenemia. Sixteen of 34 patients (47%) with complete arterial hypercoagulability screening had laboratory evidence of arterial hypercoagulability. Thirteen of these patients (38%) had antiphospholipid antibodies. Antiphospholipid antibodies appear to be common in patients referred for percutaneous PFO closure for secondary prevention of systemic thromboembolic events. Thorough testing based on established recommendations is warranted. Further studies are needed regarding the interaction between PFO and various hypercoagulable disorders that have been associated with cryptogenic stroke.

Early clinical and biomechanical results following cervical arthroplasty.

OBJECT: Spinal arthroplasty may become the next gold standard for the treatment of degenerative cervical spine disease. This new modality must be studied rigorously to ensure in vivo efficacy and safety. The authors review the preliminary clinical experience and radiographic outcomes following insertion of the Bryan Cervical Disc Prosthesis (Medtronic Sofamor Danek, Memphis, TN). METHODS: This prospective cohort study included 26 patients undergoing single- or two-level implantation of the Bryan artificial cervical disc for treatment of cervical degenerative disc disease resulting in radiculopathy and/or myelopathy. Radiographic and clinical assessments were made preoperatively 1.5, 3 months, and at 6, 12, and up to 24 months postoperatively. The Neck Disability Index (NDI) and Short Form-36 (SF-36) questionnaires were used to assess pain and functional outcomes. Segmental sagittal rotation from C2-3 to C6-7 was measured using quantitative motion analysis software. A total of 30 Bryan discs were placed in 26 patients. A single-level procedure was performed in 22 patients and a two-level procedure in the other four. Follow-up duration ranged from 1.5 to 27 months, with a mean duration of 12.3 months. A statistically significant improvement in the mean NDI scores was seen between pre- and late postoperative follow-up evaluations. A trend toward improvement in the SF-36 physical component was also found. Motion was preserved in the treated spinal segments (mean range of motion 7.8 degrees ) for up to 24 months postsurgery. The relative contribution of each segment to overall spinal sagittal rotation differed depending on whether the disc was placed at C5-6 or C6-7. Overall cervical motion (C2-7) was moderately increased on late follow-up evaluations. CONCLUSIONS: The Bryan artificial cervical disc provided in vivo functional spinal motion at the treated level. Overall cervical spinal motion was not significantly altered. Sagittal rotation did not change significantly at any level after surgery.