International prescribing patterns and polypharmacy in older people with advanced chronic kidney disease: results from the European Quality study.

BACKGROUND: People with chronic kidney disease (CKD) are at high risk of polypharmacy. However, no previous study has investigated international prescribing patterns in this group. This article aims to examine prescribing and polypharmacy patterns among older people with advanced CKD across the countries involved in the European Quality (EQUAL) study. METHODS: The EQUAL study is an international prospective cohort study of patients ≥65 years of age with advanced CKD. Baseline demographic, clinical and medication data were analysed and reported descriptively. Polypharmacy was defined as ≥5 medications and hyperpolypharmacy as ≥10. Univariable and multivariable linear regressions were used to determine associations between country and the number of prescribed medications. Univariable and multivariable logistic regression were used to determine associations between country and hyperpolypharmacy. RESULTS: Of the 1317 participants from five European countries, 91% were experiencing polypharmacy and 43% were experiencing hyperpolypharmacy. Cardiovascular medications were the most prescribed medications (mean 3.5 per person). There were international differences in prescribing, with significantly greater hyperpolypharmacy in Germany {odds ratio (OR) 2.75 [95% confidence interval (CI) 1.73-4.37]; P < 0.001, reference group UK}, the Netherlands [OR 1.91 (95% CI 1.32-2.76); P = 0.001] and Italy [OR 1.57 (95% CI 1.15-2.15); P = 0.004]. People in Poland experienced the least hyperpolypharmacy [OR 0.39 (95% CI 0.17-0.87); P = 0.021]. CONCLUSIONS: Hyperpolypharmacy is common among older people with advanced CKD, with significant international differences in the number of medications prescribed. Practice variation may represent a lack of consensus regarding appropriate prescribing for this high-risk group for whom pharmacological treatment has great potential for harm as well as benefit.

An association between occupancy rates in the emergency department and rates of violence toward staff.

BACKGROUND: Studies have explored possible causes of violent acts in the emergency department (ED), however, the association of violence with ED crowding has not been studied. Although the total number of violent acts would be expected to increase, it is not clear if the rate of violent acts also increases as occupancy levels rise. OBJECTIVE: The purpose of this study was to determine if there is an association between occupancy rates in the ED and rates of violence toward staff. METHODS: This was a retrospective chart review study. Violent incidents in a community, Level I trauma center ED were identified from review of orders of emergency detainment, adverse event forms, physical restraint logs, and pharmacy records from January 1, 2005 to June 1, 2008. Occupancy rates for all days were calculated and violent vs. non-violent days were compared using a standard two-sample t-test. Logistic regression analysis was then used to investigate other factors associated with violent incidents. RESULTS: A rate of violence of 1.3 incidents per 1000 patients was found. When comparing the occupancy rates of violent days (mean 95%, SD 26%) with non-violent days (mean 86%, SD 24%), a statistically significant association was found (p<0.0001). Multivariate logistic regression confirmed a significant association between crowding and violence toward staff (odds ratio 4.290, 95% confidence interval 2.137-8.612). CONCLUSION: These results suggest another possible negative effect that crowding has on ED staff and physicians. Policies and recommendations regarding ED operating procedures and staff safety during times of higher occupancy levels should be discussed.

Change in treatment burden among people with multimorbidity: a follow-up survey.

BACKGROUND: Treatment burden is the effort required of patients to look after their health and the impact this has on their functioning and wellbeing. Little is known about change in treatment burden over time for people with multimorbidity. AIM: To quantify change in treatment burden, determine factors associated with this change, and evaluate a revised single-item measure for high treatment burden in older adults with multimorbidity. DESIGN AND SETTING: A 2.5-year follow-up of a cross-sectional postal survey via six general practices in Dorset, England. METHOD: GP practices identified participants of the baseline survey. Data on treatment burden (measured using the Multimorbidity Treatment Burden Questionnaire; MTBQ), sociodemographics, clinical variables, health literacy, and financial resource were collected. Change in treatment burden was described, and associations assessed using regression models. Diagnostic test performance metrics evaluated the revised single-item measure relative to the MTBQ. RESULTS: In total, 300 participants were recruited (77.3% response rate). Overall, there was a mean increase of 2.6 (standard deviation 11.2) points in treatment burden global score. Ninety-eight (32.7%) and 53 (17.7%) participants experienced an increase and decrease, respectively, in treatment burden category. An increase in treatment burden was associated with having >5 long-term conditions (adjusted ß 8.26, 95% confidence interval [CI] = 4.20 to 12.32) and living >10 minutes (versus ≤10 minutes) from the GP (adjusted ß 3.88, 95% CI = 1.32 to 6.43), particularly for participants with limited health literacy (mean difference: adjusted ß 9.59, 95% CI = 2.17 to 17.00). The single-item measure performed moderately (sensitivity 55.7%; specificity 92.4%. CONCLUSION: Treatment burden changes over time. Improving access to primary care, particularly for those living further away from services, and enhancing health literacy may mitigate increases in burden.

The Utility of Pain Scale to Assess Verifiable vs Non-Verifiable Pain in United States Emergency Departments.

INTRODUCTION: We sought to examine the utility of self-reported pain scale by comparing emergency department (ED) triage pain scores of self-reported but non-verifiable painful conditions with those of verifiable painful conditions using a large, nationally representative sample. METHODS: We analyzed the National Hospital Ambulatory Medical Care Survey (NHAMCS) 2015. Verifiable painful conditions were identified based on the final diagnoses in the five included International Classification of Diseases 9th revision codes. Non-verifiable painful conditions were identified by the five main reasons for visit. Only adults 18 years of age or older were included. The primary outcome variable was the pain scale from 0 to 10 at triage. We performed descriptive and multivariate analyses to investigate the relationships between the pain scale and whether the painful condition was verifiable, controlling for patient characteristics. RESULTS: There were 55 million pain-related adult ED visits in 2015. The average pain scale was 6.49. For verifiable painful diagnoses, which were about 24% of the total visits, the average was 6.27, statistically significantly lower than that for non-verifiable painful conditions, 6.56. Even after controlling for the confounding of patient characteristics and comorbidities, verifiable painful diagnoses still presented less pain than those with non-verifiable painful complaints. Older age, female gender, and urban residents had significantly higher pain scores than their respective counterparts, controlling for other confounding factors. Psychiatric disorders were independently associated with higher pain scores by about a half point. CONCLUSION: Self-reported pain scales obtained at ED triage likely have a larger psychological component than a physiological one. Close attention to clinical appropriateness and overall patient comfort are more likely to lead to better health outcomes and patient experiences than focusing on self-reported pain alone.

Treatment burden for patients with multimorbidity: cross-sectional study with exploration of a single-item measure.

BACKGROUND: Treatment burden is the effort required of patients to look after their health, and the impact this has on their wellbeing. Quantitative data on treatment burden for patients with multimorbidity are sparse, and no single-item treatment burden measure exists. AIM: To determine the extent of, and associations with, high treatment burden among older adults with multimorbidity, and to explore the performance of a novel single-item treatment burden measure. DESIGN AND SETTING: Cross-sectional postal survey via general practices in Dorset, UK. METHOD: Patients ≥55 years, living at home, with three or more long-term conditions (LTCs) were identified by practices. Treatment burden was measured using the Multimorbidity Treatment Burden Questionnaire. Data collected were sociodemographics, LTCs, medications, and characteristics including health literacy and financial resource. Associations with high treatment burden were investigated via logistic regression. Performance of a novel single-item measure of treatment burden was also evaluated. RESULTS: A total of 835 responses were received (response rate 42%) across eight practices. Patients' mean age was 75 years, 55% were female (n = 453), and 99% were white (n = 822). Notably, 39% of patients self-reported fewer than three LTCs (n = 325). Almost one-fifth (18%) of responders reported high treatment burden (n = 150); making lifestyle changes and arranging appointments were particular sources of difficulty. After adjustment, limited health literacy and financial difficulty displayed strong associations with high treatment burden; more LTCs and more prescribed regular medications were also independently associated. The single-item measure discriminated moderately between high and non-high burden with a sensitivity of 89%, but a specificity of 58%. CONCLUSION: High treatment burden was relatively common, underlining the importance of minimising avoidable burden. More vulnerable patients, with less capacity to manage, are at greater risk of being overburdened. Further development of a single-item treatment burden measure is required.

Change in treatment burden among people with multimorbidity: Protocol of a follow up survey and development of efficient measurement tools for primary care.

BACKGROUND: Treatment burden is the effort required of patients to look after their health and the impact this has on their functioning and wellbeing. It is likely treatment burden changes over time as circumstances change for patients and health services. However, there are a lack of population-level studies of treatment burden change and factors associated with this change over time. Furthermore, there are currently no practical screening tools for treatment burden in time-pressured clinical settings or at population level. METHODS AND ANALYSIS: This is a three-year follow-up of a cross-sectional survey of 723 people with multimorbidity (defined as three or more long-term conditions; LTCs) registered at GP practices in in Dorset, England. The survey will repeat collection of information on treatment burden (using the 10-item Multimorbidity Treatment Burden Questionnaire (MTBQ) and a novel single-item screening tool), sociodemographics, medications, LTCs, health literacy and financial resource, as at baseline. Descriptive statistics will be used to compare change in treatment burden since the baseline survey in 2019 and associations of treatment burden change will be assessed using regression methods. Diagnostic test accuracy metrics will be used to evaluate the single-item treatment burden screening tool using the MTBQ as the gold-standard. Routine primary care data (including demographics, medications, LTCs, and healthcare usage data) will be extracted from medical records for consenting participants. A forward-stepwise, likelihood-ratio logistic regression model building approach will be employed in order to assess the utility of routine data metrics in quantifying treatment burden in comparison to self-reported treatment burden using the MTBQ. IMPACT: To the authors' knowledge, this will be the first study investigating longitudinal aspects of treatment burden. Findings will improve understanding of the extent to which treatment burden changes over time for people with multimorbidity and factors contributing to this change, as well as allowing better identification of people at risk of high treatment burden.

Recurrent ocular syphilis in a patient living with HIV.

A 26-year-old male living with human immunodeficiency virus (HIV) and who had previously been treated for ocular syphilis presented to the Emergency Department with progressive vision loss and uveitis. The efficacy of standard management for neurosyphilis in HIV and recurrence was examined.

Health-related quality of life, functional impairment and comorbidity in people with mild-to-moderate chronic kidney disease: a cross-sectional study.

OBJECTIVES: To determine the associations between comorbidities, health-related quality of life (HRQoL) and functional impairment in people with mild-to-moderate chronic kidney disease (CKD) in primary care. DESIGN: Cross-sectional analysis at 5-year follow-up in a prospective cohort study. SETTING: Thirty-two general practitioner surgeries in England. PARTICIPANTS: 1008 participants with CKD stage 3 (of 1741 people recruited at baseline in the Renal Risk in Derby study) who survived to 5 years and had complete follow-up data for HRQoL and functional status (FS). PRIMARY AND SECONDARY OUTCOME MEASURES: HRQoL assessed using the 5-level EQ-5D version (EQ-5D-5L, with domains of mobility, self-care, usual activities, pain/discomfort and anxiety/depression and index value using utility scores calculated from the English general population), and FS using the Karnofsky Performance Status scale (functional impairment defined as Karnofksy score ≤70). Comorbidity was defined by self-reported or doctor-diagnosed condition, disease-specific medication or blood result. RESULTS: Mean age was 75.8 years. The numbers reporting some problems in EQ-5D-5L domains were: 582 (57.7%) for mobility, 166 (16.5%) for self-care, 466 (46.2%) for usual activities, 712 (70.6%) for pain/discomfort and 319 (31.6%) for anxiety/depression. Only 191 (18.9%) reported no problems in any domain. HRQoL index values showed greater variation among those with lower FS (eg, for those with Karnofsky score of 60, the median (IQR) EQ-5D index value was 0.45 (0.24 to 0.68) compared with 0.94 (0.86 to 1) for those with Karnofsky score of 90). Overall, 234 (23.2%) had functional impairment.In multivariable logistic regression models, functional impairment was independently associated with experiencing problems for all EQ-5D-5L domains (mobility: OR 16.87 (95% CI 8.70 to 32.79, p<0.001, self-care: OR 13.08 (95% CI 8.46 to 20.22), p<0.001, usual activities: OR 8.27 (95% CI 5.43 to 12.58), p<0.001, pain/discomfort: OR 2.94 (95% CI 1.86 to 4.67), p<0.001, anxiety/depression: 3.08 (95% CI 2.23 to 4.27), p<0.001). Higher comorbidity count and obesity were independently associated with problems in mobility, self-care, usual activities and pain/discomfort: for three or more comorbidities versus none: (mobility: OR 2.10 (95% CI 1.08 to 4.10, p for trend 0.002), self-care: OR 2.64 (95% CI 0.72 to 9.67, p for trend 0.05), usual activities: OR 4.20 (95% CI 2.02 to 8.74, p for trend <0.001), pain/discomfort: OR 3.06 (95% CI 1.63 to 5.73, p for trend <0.001)), and for obese (body mass index (BMI) ≥30 kg/m2) versus BMI <25 kg/m2: (mobility: OR 2.44 (95% CI 1.61 to 3.69, p for trend <0.001), self-care: OR 1.98 (95% CI 1.06 to 3.71, p for trend 0.003), usual activities: OR 1.82 (95% CI 1.19 to 2.76, p for trend 0.019), pain/discomfort: OR 2.37 (95% CI 1.58 to 3.55, p for trend <0.001)). Female sex, lower FS and lower educational attainment were independently associated with anxiety/depression (ORs 1.60 (95% CI 1.18 to 2.16, p 0.002), 3.08 (95% CI 2.23 to 4.27, p<0.001) and 1.67 (95% CI 1.10 to 2.52, p 0.009), respectively). Older age, higher comorbidity count, albuminuria (≥30 mg/mmol vs <3 mg/mmol), lower educational attainment (no formal qualifications vs degree level) and obesity were independently associated with functional impairment (ORs 1.07 (95% CI 1.04 to 1.09, p<0.001), 2.18 (95% CI 0.80 to 5.96, p for trend <0.001), 1.74 (95% CI 0.82 to 3.68, p for trend 0.005), 2.08 (95% CI 1.26 to 3.41, p for trend <0.001) and 4.23 (95% CI 2.48 to 7.20), respectively). CONCLUSIONS: The majority of persons with mild-to-moderate CKD reported reductions in at least one HRQoL domain, which were independently associated with comorbidities, obesity and functional impairment. TRIAL REGISTRATION NUMBER: National Institute for Health Research Clinical Research Portfolio Study Number 6632.

HFE mutation and dietary iron content interact to increase ischemia/reperfusion injury of the heart in mice.

Hereditary hemochromatosis is an inherited pathological condition characterized by iron overload in several vital organs including heart. To increase our understanding of the underlying pathogenic mechanisms of hereditary hemochromatosis, we used a HFE gene knockout mouse model that replicates hereditary hemochromatosis. A group of mice with no copies of HFE gene and corresponding wild-type mice were maintained either on low-iron (30 ppm) or high-iron (300 ppm) diet since birth. The results of our study revealed that HFE gene knockout mouse hearts were susceptible to ischemia-reperfusion injury as evidenced by increased postischemic ventricular dysfunction, increased myocardial infarct size and cardiomyocyte apoptosis compared with wild-type control hearts. The degree of injury increased in the hearts of the mice fed high-iron diet. The hearts of the HFE knockout mice showed increased iron deposition, increased content of reactive oxygen species (ROS) as evidenced by the increased formation of malondialdehyde, and reduced antioxidant enzymes including superoxide dismutase, catalase, and glutathione peroxidase. The results suggest that increased amount of ROS and reduced antioxidant reserve secondary to iron overloading may be instrumental for the susceptibility of the HFE gene knockout mice to cardiac injury.

Oxidative damage in colon and mammary tissue of the HFE-knockout mouse.

The HFE mutation is common and, when homozygous, can lead to a morbid accumulation of body iron and the disease hereditary hemochromatosis. Heterozygotes compose 10-15% of the European-American population, and have evidence of elevated body iron compared to homozygous normal people. Dietary iron content was hypothesized to interact with the HFE genotype to influence oxidative damage in mammary and colon tissue. Two groups of HFE-knockout mice were fed a standard iron diet (300 ppm) or a low iron diet (30 ppm). There was a significantly elevated concentration of malondialdehyde (by HPLC) in mammary (305 pmol/g vs. 166, p =.04) and colon (349 pmol/g vs. 226, p =.02) tissue among those mice on the standard iron diet compared to those on the low iron diet. These results suggest that dietary modification may affect the course of iron overload from HFE mutations.

Genotoxic potential of 1.6 GHz wireless communication signal: in vivo two-year bioassay.

Timed-pregnant Fischer 344 rats (from nineteenth day of gestation) and their nursing offspring (until weaning) were exposed to a far-field 1.6 GHz Iridium wireless communication signal for 2 h/day, 7 days/week. Far-field whole-body exposures were conducted with a field intensity of 0.43 mW/cm(2) and whole-body average specific absorption rate (SAR) of 0.036 to 0.077 W/kg (0.10 to 0.22 W/kg in the brain). This was followed by chronic, head-only exposures of male and female offspring to a near-field 1.6 GHz signal for 2 h/day, 5 days/week, over 2 years. Near-field exposures were conducted at an SAR of 0.16 or 1.6 W/kg in the brain. Concurrent sham-exposed and cage control rats were also included in the study. At the end of 2 years, all rats were necropsied. Bone marrow smears were examined for the extent of genotoxicity, assessed from the presence of micronuclei in polychromatic erythrocytes. The results indicated that the incidence of micronuclei/2000 polychromatic erythrocytes were not significantly different between 1.6 GHz-exposed, sham-exposed and cage control rats. The group mean frequencies were 5.6 +/- 1.8 (130 rats exposed to 1.6 GHz at 0.16 W/kg SAR), 5.4 +/- 1.5 (135 rats exposed to 1.6 GHz at 1.6 W/kg SAR), 5.6 +/- 1.7 (119 sham-exposed rats), and 5.8 +/- 1.8 (100 cage control rats). In contrast, positive control rats treated with mitomycin C exhibited significantly elevated incidence of micronuclei/2000 polychromatic erythrocytes in bone marrow cells; the mean frequency was 38.2 +/- 7.0 (five rats). Thus there was no evidence for excess genotoxicity in rats that were chronically exposed to 1.6 GHz compared to sham-exposed and cage controls.

Establishment of a novel clonal murine bone marrow stromal cell line for assessment of p53 responses to genotoxic stress.

The p53 protein is widely regarded as an important sensor of genotoxic damage in cells, and mutations in p53 are the most frequent observed in human cancers. Rapid assays for evaluating the potential of a chemical or physical agent to alter the transcriptional regulatory role of p53 may therefore serve as useful tools in toxicological research. In this study, the use of enhanced green fluorescent protein (EGFP) as a live cell reporter to assess the transactivation response of p53 to chemical and physical agents was evaluated. A stable murine bone marrow stromal cell line (D2XRIIGFP24) expressing EGFP under control of p53 response elements was established. D2XRIIGFP24 cells displayed low constitutive background fluorescence which was significantly enhanced in response to exposure to agents that induced p53 protein levels. Increases in EGFP fluorescence in response to oxidative and nitrosative stress as well as UVC irradiation were dose-dependent, detectable within 3 h of exposure and correlated closely with the amount of p53 protein accumulated within the cell. The results demonstrate the potential for rapid and early detection of p53 transactivation using the EGFP reporter approach and indicate this approach is adaptable to a variety of fluorescent assay techniques and a useful cell model for molecular toxicology research.

Microfluidic investigation of the deposition of asphaltenes in porous media.

The deposition of asphaltenes in porous media, an important problem in science and macromolecular engineering, was for the first time investigated in a transparent packed-bed microreactor (µPBR) with online analytics to generate high-throughput information. Residence time distributions of the µPBR before and after loading with ~29 µm quartz particles were measured using inline UV-Vis spectroscopy. Stable packings of quartz particles with porosity of ~40% and permeability of ~500 mD were obtained. The presence of the packing materials reduced dispersion under the same velocity via estimation of dispersion coefficients and the Bodenstein number. Reynolds number was observed to influence the asphaltene deposition mechanism. For larger Reynolds numbers, mechanical entrapment likely resulted in significant pressure drops for less pore volumes injected and less mass of asphaltenes being retained under the same maximum dimensionless pressure drop. The innovation of packed-bed microfluidics for investigations on asphaltene deposition mechanisms could contribute to society by bridging macromolecular science with microsystems.

Aminothiol receptors for decorporation of intravenously administered (60)Co in the rat.

This report provides a comparison of the oral decorporation efficacy of L-glutathione (GSH), L-cysteine (Cys), and a liposomal GSH formulation (ReadiSorb) toward systemic (60)Co to that observed following intravenous administration of GSH and Cys in F344 rats. Aminoacid L-histidine (His) containing no thiol functionality was tested intravenously to compare in vivo efficacy of the aminothiol (GSH, Cys) chelators with that of the aminoimidazole (His) chelator. In these studies, (60)Co was administered to animals by intravenous injection, followed by intravenous or oral gavage doses of a chelator repeated at 24-h intervals for a total of 5 doses. The results suggest that GSH and Cys are potent decorporation agents for (60)Co in the rat model, although the efficacy of treatment depends largely on the systemic availability of the chelator. The intravenous route of administration of GSH or Cys was most effective in reducing tissue (60)Co levels and in increasing excretion of radioactivity compared to control animals. Liposomal encapsulation was found to markedly enhance the oral bioavailability of GSH compared to non-formulated GSH. The oral administration of liposomal GSH reduced (60)Co levels in nearly all tissues by 12-43% compared to that observed for non-formulated GSH. Efficacy of oral Cys was only slightly reduced in comparison with intravenous Cys. Further studies to optimize the dosing regimen in order to maximize decorporation efficiency are warranted.

Biomaterials for the decorporation of (85)Sr in the rat.

Although four stable isotopes of strontium occur naturally, Sr is produced by nuclear fission and is present in surface soil around the world as a result of fallout from atmospheric nuclear weapons tests. It can easily transfer to humans in the event of a nuclear/radiological emergency or through the plant-animal-human food chain causing long-term exposures. Strontium is chemically and biologically similar to calcium, and is incorporated primarily into bone following internal deposition. Alginic acid (alginate) obtained from seaweed (kelp) extract selectively binds ingested strontium in the gastrointestinal tract blocking its systemic uptake and reducing distribution to bone in rats, while other natural polysaccharides including chitosan and hyaluronic acid had little in vivo affinity for strontium. Alginate exhibits the unique ability to discriminate between strontium and calcium and has been previously shown to reduce intestinal absorption and skeletal retention of strontium without changing calcium metabolism. In our studies, the effect of commercially available alginate on intestinal absorption of strontium was examined. One problem associated with alginate treatment is its limited solubility and gel formation in water. The aqueous solubility of sodium alginate was improved in a sodium chloride/sodium bicarbonate electrolyte solution containing low molecular weight polyethylene glycol (PEG). Furthermore, oral administration of the combined alginate/electrolyte/PEG solution accelerated removal of internal strontium in rats when compared to treatment with individual sodium alginate/electrolyte or electrolyte/PEG solutions. Importantly, both alginate and PEG are nontoxic, readily available materials that can be easily administered orally in case of a national emergency when potentially large numbers of the population may require medical treatment for internal depositions. Our results suggest further studies to optimize in vivo decorporation performance of engineered alginate material via modification of its chemical and physicochemical properties are warranted.

Evaluation of Cuprimine and Syprine for decorporation of (60)Co and (210)Po.

The acknowledged risk of deliberate release of radionuclides into local environments by terrorist activities has prompted a drive to improve novel materials and methods for removing internally deposited radionuclides. These decorporation treatments will also benefit workers in the nuclear industry, should an exposure occur. Cuprimine and Syprine are oral therapeutics based on the active ingredients D-penicillamine and N,N'-bis-(2-aminoethyl)-1,2-ethanediamine dihydrochloride, respectively. These therapeutic drugs have been used for several decades to treat Wilson's disease, a genetic defect leading to copper overload, by chelation and accelerated excretion of internally deposited copper. Studies were undertaken to evaluate these FDA-approved drugs for the in vivo decorporation of radioactive cobalt (Co) and polonium (Po) using male Wistar-Han rats. In these studies, Co or Po was administered to animals by IV injection, followed by oral gavage doses of either Cuprimine or Syprine. Control animals received the radionuclide alone. For Co studies, animals received a single dose of Cuprimine or Syprine, while for Po studies animals were repeatedly dosed at 24-h intervals for a total of 5 doses. Results show that Syprine significantly increased urinary elimination and skeletal concentrations of Co compared to controls. While Cuprimine had little effect on total excretion of Co, the skeletal, kidney, liver, muscle, and stomach tissues had significantly lower radioactivity compared to control animals. The low overall excretion of Po made it difficult to reliably measure urinary or fecal radioactivity and draw a definitive conclusion on the effect of Cuprimine or Syprine treatment on excretion. However, Cuprimine treatment was effective at reducing spleen levels of Po compared to controls. Similarly, Syprine treatment produced statistically significant reductions of Po in the spleen and skeletal tissues compared to control animals. Based on these promising findings, further studies to evaluate the dose-response pharmacokinetic profiles for decorporation are warranted.

Investigation of chitosan for decorporation of 60Co in the rat.

With the increased threat of terrorist release of radioactive materials, there is a need for non-toxic decorporation agents to treat internal contamination with radionuclides. In this study, low molecular weight chitosan was evaluated for decorporation of radioactive cobalt (60Co). The affinity of chitosan for Co(II) was tested in vitro using spectrophotometric and potentiometric titration techniques. For in vivo studies, the effect of chitosan on ingested 60Co was evaluated using F344 rats administered a single dose followed by oral chitosan. Chitosan was also evaluated for systemic decorporation of 60Co following intravenous injection with repeated chitosan administration over 5 d. Control animals received 60Co without chelation treatment. Excreta and tissues were collected for analysis using gamma-counting techniques. Results from in vitro experiments confirmed the binding of Co(II) to chitosan, with the postulated formation of a mixed cobalt-chitosan-hydroxide complex species; a stability constant was calculated for this complex. For in vivo studies, oral administration of chitosan significantly reduced systemic absorption of orally administered 60Co as evidenced by an increase in fecal elimination and decrease in urinary elimination. However, oral administration of chitosan lactate slightly decreased fecal excretion of 60Co. Further, oral administration of chitosan significantly reduced 60Co levels in kidney, liver, and skeleton compared to control animals receiving 60Co alone. By the i.v. route, chitosan slightly reduced levels of 60Co in tissues compared to controls, although statistically significant reductions were only observed for blood and kidney. Overall, this commercially available chitosan oligosaccharide exhibited promising potential; further studies are warranted to evaluate the optimal dosing regimen and chemical modifications to increase effectiveness.

Platelet activation in cystic fibrosis.

Cystic fibrosis (CF) is caused by a mutation of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). We examined platelet function in CF patients because lung inflammation is part of this disease and platelets contribute to inflammation. CF patients had increased circulating leukocyte-platelet aggregates and increased platelet responsiveness to agonists compared with healthy controls. CF plasma caused activation of normal and CF platelets; however, activation was greater in CF platelets. Furthermore, washed CF platelets also showed increased reactivity to agonists. CF platelet hyperreactivity was incompletely inhibited by prostaglandin E(1) (PGE(1)). As demonstrated by Western blotting and reverse-transcriptase-polymerase chain reaction (RT-PCR), there was neither CFTR nor CFTR-specific mRNA in normal platelets. There were abnormalities in the fatty acid composition of membrane fractions of CF platelets. In summary, CF patients have an increase in circulating activated platelets and platelet reactivity, as determined by monocyte-platelet aggregation, neutrophil-platelet aggregation, and platelet surface P-selectin. This increased platelet activation in CF is the result of both a plasma factor(s) and an intrinsic platelet mechanism via cyclic adenosine monophosphate (cAMP)/adenylate cyclase, but not via platelet CFTR. Our findings may account, at least in part, for the beneficial effects of ibuprofen in CF.