Ex vivo decrease in uranium diffusion through intact and excoriated pig ear skin by a calixarene nanoemulsion

Cutaneous contamination by radionuclides is a major concern in the nuclear industry. In case of skin exposure to uranium, no efficient emergency treatment is available to remove the actinide from the skin. For this purpose, we developed a nanoemulsion containing calixarene molecules displaying good chelating properties towards uranium. In this paper, we describe the ability of this formulation to trap uranium and limit its transfer from the cutaneous contaminated site into the blood. Uranium percutaneous diffusion kinetics was assessed with Franz cells over 24 h through intact and excoriated pig ear skin biopsies, after or without application of the nanoemulsion. Uranium distribution in the skin layers was analysed by SIMS microscopy. The results showed that prompt application of the calixarene nanoemulsion allows a 94% and 98% reduction of the amount of uranium diffused respectively through intact and excoriated skin. The formulation is still efficient in case of delayed application up to 30 minutes since the 24 h-uranium transfer through excoriated skin is reduced by 71%. Besides, no accumulation of uranium or uranium-calixarene chelate was observed in the different skin layers. In conclusion, this study demonstrated the efficiency of the calixarene nanoemulsion, which can be regarded as a promising treatment for uranium cutaneous contamination.     

Inhibition of the ubiquitin-proteasome system in Alzheimer's disease

Alzheimer's disease is the most common cause of dementia in the elderly. Although several genetic defects have been identified in patients with a family history of this disease, the majority of cases involve individuals with no known genetic predisposition. A mutant form of ubiquitin, termed Ub(+1), has been selectively observed in the brains of Alzheimer's patients, including those with nonfamilial Alzheimer's disease, but it has been unclear why Ub(+1) expression should be deleterious. Here we show that Ub(+1) is an efficient substrate for polyubiquitination in vitro and in transfected human cells. The resulting polyubiquitin chains are refractory to disassembly by deubiquitinating enzymes and potently inhibit the degradation of a polyubiquitinated substrate by purified 26S proteasomes. Thus, expression of Ub(+1) in aging brain could result in dominant inhibition of the Ub-proteasome system, leading to neuropathologic consequences.     

Sonographic evaluation of fetal abdominal growth: predictor of the large-for-gestational-age infant in pregnancies complicated by diabetes mellitus

Serial ultrasound examinations were performed during the third trimester in 79 pregnant women with diabetes to establish the onset of accelerated fetal growth. At least three ultrasound examinations were performed, with a minimum scan interval of 2 weeks. Growth curves constructed for femur length and head circumference were similar for fetuses appropriate for gestational age (n = 48) and fetuses large for gestational age (n = 31). The mean changes in femur length and head circumference (expressed as centimeters per week during the early and late third trimesters) did not differ statistically between these two groups. Abdominal circumference growth was clearly accelerated at 32 weeks' gestation in the large for gestational age group (mean +/- SD, 1.36 +/- 0.16 cm/wk) compared with the appropriate for gestational age group (0.901 +/- 0.21 cm/wk, p less than 0.001). With use of a receiver operator characteristic curve, a change in abdominal circumference of 1.2 cm/wk over the period of 32 to 39 weeks' gestation was determined to be an optimal cutoff for detecting excessive fetal growth (sensitivity 84%, specificity 85%). A change in abdominal circumference 1.2 cm/wk was present in 4/4 large-for-gestational age fetuses (less than 4000 gm), in 17/21 (81%) of fetuses with birth weights 4000 to 4499 gm, and in 5/6 (83%) whose weight exceeded 4500 gm. It appears that improved detection of the fetus large for gestational age in diabetic pregnancies may be accomplished by the use of serial ultrasonography during the third trimester.     

Maternal acetaminophen overdose at 15 weeks of gestation

Acetaminophen is a common drug used in pregnancy. A 32-year-old woman ingested 64 g of acetaminophen at 15 weeks of gestation. Treatment with N-acetylcysteine was given within 24 hours. The patient nonetheless developed severe hepatic necrosis and her hospital course was complicated by adult respiratory distress syndrome. With aggressive supportive treatment, the mother survived and delivered a viable infant at 32 weeks' gestation. The possible mechanisms of acetaminophen toxicity in the mother and the fetus are discussed.     

DX-890 (Dyax)

Dyax (formerly Protein Engineering Corp) and Debiopharm are developing DX-890, an inhibitor of human neutrophil elastase (HNE), for the potential treatment of pulmonary diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) [242806]. In December 1999, Debiopharm initiated phase I trials with an aerosol formulation of DX-890; studies were completed by October 2000 [350718], [352554], [387155]. By August 2000, DX-890 was in phase II evaluation for the potential treatment of CF [378625], and in May 2002, Dyax planned to initiate a further study, in children with CF, within the year [451044]. By June 2002, phase II trials in CF were ongoing in France and Spain, with results expected soon after this date [454485]. In September 2000, JP Morgan predicted a 2005 launch for this drug, with estimated sales in that year of 23 US dollars million rising to 63 million US dollars in 2007 [397766].     

Variation in patient-reported quality among health care organizations

Health care quality measurement initiatives often use health plans as the unit of analysis, but plans often contract with provider organizations that are managed independently. There is interest in understanding whether there is substantial variability in quality among such units. We evaluated the extent to which scores on the Consumer Assessment of Health Plans Study (CAHPS) survey vary across: health plans, regional service organizations (RSOs) (similar to independent practice associations [IPAs] and physician/hospital organizations [PHOs]), medical groups, and practice sites. There was significant variation among RSOs, groups and sites, with practice sites explaining the greatest share of variation for most measures.     

Optimization of sputum-processing methods for the measurement of interleukin-5: effects of protease inhibition

BACKGROUND: Interleukin (IL)-5 measurement in sputum samples has produced variable results that appear to be due to methodological problems. The aim of the present study was to investigate the effects of dithiothreitol (DTT), sputum protease inhibition and sample storage on IL-5 recovery in order to develop a method to accurately measure IL-5 in dispersed sputum supernatant. METHODOLOGY: Measurement of IL-5 in sputum was performed in 22 subjects with airway disease. Interleukin-5 recovery was measured in samples spiked with recombinant human IL-5 using a commercial ELISA. A mix of four protease inhibitors (PI) was added to sputum processed using the selection method with dispersion using DTT and stored with and without inhibitors. RESULTS: The addition of PI to sputum resulted in a 24% increase in IL-5 recovery. Recovery was not further increased with the addition of a blocking protein. Storage of IL-5-spiked sputum gave significantly less recovery. The addition of PI to sputum processed with DTT had no effect on total cell count, viability or cell differential. CONCLUSION: Interleukin-5 recovery is increased by the addition of PI to samples processed using the selected portion method with DTT dispersion. A protease inhibitor cocktail should be added to sputum for IL-5 assay.     

Autopsy-proven,sporadic pick disease with onset at age 25 years

CONTEXT: Pick disease is uncommon and accounts for less than 2% of adult-onset dementias. Reports of Pick disease in young adults have apparently increased in the last decade. OBJECTIVE: To document the presentation and course of a patient with tau-positive Pick disease presenting at an extremely young age. SETTING: A university hospital. PATIENT: A white woman with cognitive impairment that began at age 25 years. She experienced progressive dementia over an 8-year period with radiographic evidence of severe cerebral atrophy of the frontotemporal lobes. Autopsy findings confirmed the diagnosis of Pick disease characterized by tau-positive Pick bodies in the neurons of the fascia dentata. CONCLUSION: Pick disease should be considered in the differential diagnosis of young adults presenting with behavioral symptoms, especially those of frontal impairment.     

Age does not influence the bone response to treadmill exercise in female rats

PURPOSE: Because it is believed that bone may respond to exercise differently at different ages, we compared bone responses in immature and mature rats after 12 wk of treadmill running. METHODS: Twenty-two immature (5-wk-old) and 21 mature (17-wk-old) female Sprague Dawley rats were randomized into a running (trained, P = 10 immature, 9 mature) or a control group (controls, P = 12 immature, 12 mature) before sacrifice 12 wk later. Rats ran on a treadmill five times per week for 60-70 min at speeds up to 26 m.min. Both at baseline and after intervention, we measured total body, lumbar spine, and proximal femoral bone mineral, as well as total body soft tissue composition using dual-energy x-ray absorptiometry (DXA). After sacrificing the animals, we measured dynamic and static histomorphometry and three-point bending strength of the tibia. RESULTS: Running training was associated with greater differences in tibial subperiosteal area, cortical cross-sectional area, peak load, stiffness, and moment of inertia in immature and mature rats (P < 0.05). The trained rats had greater periosteal bone formation rates (P < 0.01) than controls, but there was no difference in tibial trabecular bone histomorphometry. Similar running-related gains were seen in DXA lumbar spine area (P = 0.04) and bone mineral content (BMC; P = 0.03) at both ages. For total body bone area and BMC, the immature trained group increased significantly compared with controls (P < 0.05), whereas the mature trained group gained less than did controls (P < 0.01). CONCLUSION: In this model, where a similar physical training program was performed by immature and mature female rats, we demonstrated that both age groups were sensitive to loading and that bone strength gains appeared to result more from changes in bone geometry than from improved material properties.