High-dose inhaled nitric oxide and hyperoxia increases lung collagen accumulation in piglets

Nitric oxide (NO), a pro-oxidant gas, is used with hyperoxia (O(2)) to treat neonatal pulmonary hypertension and recently bronchopulmonary dysplasia, but great concerns remain regarding NO's potential toxicity. Based on reports that exposure to oxidant gases results in pulmonary extracellular matrix injury associated with elevated lavage fluid levels of extracellular matrix components, we hypothesized that inhaled NO with or without hyperoxia will have the same effect. We measured alveolar septal width, lung collagen content, lavage fluid hydroxyproline, hyaluronan and laminin levels in neonatal piglets after 5 days' exposure to room air (RA), RA + 50 ppm NO (RA + NO), O(2) (FiO(2) > 0.96) or O(2) + NO. Matrix metalloproteinase (MMP) activity and MMP-2 mRNA were also measured. In recovery experiments, we measured lung collagen content in piglets exposed to RA + NO or O(2) + NO and then allowed to recover for 3 days. The results show that lung collagen increased 4-fold in the RA + NO piglets, the O(2) and O(2) + NO groups had only a 2-fold elevation relative to RA controls. Unlike the RA + NO piglets, the O(2) and O(2) + NO groups had more than 20-fold elevation in lung lavage fluid hydroxyproline compared to the RA group. O(2) and O(2) + NO also had increased lung MMP activity, extravascular water, and lavage fluid proteins. MMP-2 mRNA levels were unchanged. After 3 days' recovery in room air, the RA + NO groups' lung collagen had declined from 4-fold to 2-fold above the RA group values. The O(2) + NO group did not decline. Alveolar septal width increased significantly only in the O(2) and O(2) + NO groups. We conclude that 5 days' exposure to NO does not result in pulmonary matrix degradation but instead significantly increases lung collagen content. This effect appears potentially reversible. In contrast, hyperoxia exposure with or without NO results in pulmonary matrix degradation and increased lung collagen content. The observation that NO increased lung collagen content represents a new finding and suggests NO could potentially induce pulmonary fibrosis.     

1,4-Thienodiazepine-2,5-diones via MCR (I): Synthesis,Virtual Space and p53-Mdm2 Activity

1,4-Thienodiazepine-2,5-diones have been synthesized via the Ugi-Deprotection-Cyclization (UDC) approach starting from Gewald 2-aminothiophenes in a convergent and versatile manner. The resulting scaffold is unprecedented, cyclic, and peptidomimetic with four points of diversity introduced from readily available starting materials. In addition to eighteen synthesized and characterized compounds, a virtual compound library was generated and evaluated for chemical space distribution and drug-like properties. A small focused compound library of 1,4-thienodiazepine-2,5-diones has been screened for the activity against p53-Mdm2 interaction. Biological evaluations demonstrated that some compounds exhibited promising antagonistic activity.     

The volume and cost of radiologic services in the United States in 1990

Knowing the total number of radiologic services provided in the United States and their cost is important. This information can, for example, indicate the opportunities available to a radiology practice considering opening a new office or show whether high-technology radiology is, as is widely assumed, an important factor in United States health costs. However, neither the total number of procedures nor their cost is known. We developed two largely independent estimates of each total (one based principally on surveys of radiologists, the other on Medicare data) to cross-validate the estimates and provide an indication of their uncertainty. We estimate that 260-330 million radiologic procedures were performed in the United States in 1990 (including both diagnostic and therapeutic procedures and radiologic procedures performed by nonradiologists) and that payments for these services totaled $19 to $22 billion (including payments for technical components in the hospital setting). This total was approximately 3.5% of national spending on personal health care; high-technology radiology totaled less than half of this amount. The procedures numbered 1.0-1.3 per capita annually, an increase of some 10-40% since 1980. Of the spending total, $10 to $12 billion was paid to physician practices, with a substantial portion of this amount going ultimately to practice expenses, particularly in the office setting. Our results suggest that spending on high-technology radiology is too small to be a major explanation for the current level of health costs in the United States.     

Dietary protein and chronic toxicity of 1,2-dimethylhydrazine fed to mice

1,2-Dimethylhydrazine-HCl (DMH-2HCl) is derived from the natural toxin cycasin, and is extensively used to induce cancers in experiments with rodents. We examined the toxicity of DMH-2HCl, incorporated into purified diets varying in protein, to determine concentrations compatible with long-term survival in B6C3H1 mice. Initial studies showed single-dose oral LD50 values (95% confidence intervals) of 26 (18-32) mg DMH-2HCl/kg body weight for males, and 60 (53-65) for females. A 6-wk study was performed with diets containing 10 or 40% soybean protein with doses of 0, 11.25, 22.5, 45, 90, and 180 mg DMH-2HCl/kg diet. All mice fed the highest dose were removed from the study due to severe toxicity. Declines in food consumption and body weight occurred in both sexes, accelerated with increasing log(DMH) dose, and were substantially more severe in groups fed 10% protein. A 5-mo study was subsequently performed with male mice fed 10 or 40% protein diets containing doses of 0, 15, 30, or 45 mg DMH-2HCl/kg diet. In this longer study, dose-related declines of food intake and body weight were also more pronounced with 10% protein. Histopathologic examination of samples from 29 organs/tissues revealed hepatic changes most commonly, and these were more severe at higher DMH levels. Lesions ranged from focal centrilobular hepatocellular necrosis to severe toxic hepatitis, associated with lobular disorganization and hepatocellular hypertrophy. Frequent dose-dependent lesions were also found in kidneys, adrenals, and heart. Renal changes included focal subcapsular fibrosis with atrophy, and hyperplasia of the tubular epithelium. Adrenal cortical hypertrophy was noted at the two highest DMH doses. Focal cardiac myocytolysis was also noted at high DMH doses. Renal damage occurred only rarely in the absence of liver pathology, and adrenal hypertrophy only rarely without renal damage. Cardiac myocytolysis was found in 14% of mice without hepatic, renal, or adrenal damage, but in 62% of those with lesions in each of those organs. No evidence of gastrointestinal toxicity was observed. Hepatic, renal, and adrenal lesions were more frequent and severe in mice fed the low-protein diet. The protective effect of high protein was DMH-dose dependent. The lower doses in these studies could be used to investigate effects of diet, cocarcinogens, or chemopreventative agents on carcinogenesis resulting from chronic, low-level dietary exposure to DMH.     

Evidence of physical activity participation among men and women in the countries of the Gulf Cooperation Council: a review

Rapid socioeconomic development in the countries of the Gulf Cooperation Council (GCC) has resulted in demographic and epidemiological transitions, with obesity, diabetes and other chronic diseases becoming the leading causes of morbidity and mortality. This emerging disease pattern is often attributed to physically inactive lifestyles. Given that there is no consolidated evidence on physical activity participation, we reviewed studies to examine prevalence and gender differences among GCC adults. PubMed, CINAHL and reference list searches identified eight relevant studies. Based on the best‐available data, the prevalence of adults being physically active for at least 150 min week^?1 (based on the international standard definition) ranged from 39.0% to 42.1% for men and 26.3% to 28.4% for women. Men were significantly more active than were women. Prevalence estimates for participation in physical activity in the GCC States are considerably lower than those for many developed countries. Studies using standardized methodologies with nationally representative samples are urgently required. Identifying prevalence and gender variations provides the basis for understanding the unique socio‐cultural and environmental factors contributing to physical inactivity among adults in the countries of the GCC. This understanding must then inform population‐health strategies to address the rising prevalence of obesity, type 2 diabetes and other chronic diseases.