Profiles of polychlorinated biphenyl congeners, organochlorine pesticides, and butyltins in southern sea otters and their prey

Concentrations of organochlorine pesticides, polychlorinated biphenyl (PCB) congeners, and butyltins were measured in sea otters and selected prey species (invertebrates) collected from the California (USA) coast. Polychlorinated biphenyls, DDTs (sum of p,p'-dichlorodiphenyldichloroethylene [p,p'-DDE], p,p'-dichlorodiphenyldichloroethane [p,p'-DDD], and p,p'-DDT), and butyltins were the major contaminants found in sea otters and their prey. Lipid-normalized concentrations of PCBs and DDT in sea otter livers were 60- and 240-fold greater than those found in the prey. Great biomagnification of PCBs and DDT in sea otters is suggested to result from their high per-capita intake of diet compared with those of other marine mammals. Profiles of PCB congeners in sea otters and prey species suggest a great capacity of sea otters to biotransform lower-chlorinated congeners. Sea otters seem to possess a greater ability than cetaceans to metabolize PCBs. The 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents of non- and mono-ortho PCBs in sea otters and certain prey species were at or above the theoretical threshold for toxic effects.     

The new staging system for heart failure. What every primary care physician should know

The primary care physician is in a unique position to have a major impact on the prevention of heart failure. Using the new system of classifying heart failure, the primary care physician can better evaluate and treat patients in the primary care setting. The new American College of Cardiology/American Heart Association staging system for heart failure emphasizes the structural condition of the heart as well as the prevention, evolution, and progression of heart failure. It is meant to complement the NYHA classification system, which has been used to describe functional limitations, not structural abnormalities.     

Haptoglobin elutes from human atherosclerotic coronary arteries--a potential marker of arterial pathology

BACKGROUND: Molecules which egress from atherosclerotic arteries may function as plasma markers of arterial pathology, but such egress has not been proven with living human coronary arteries. We hypothesised that proteins eluting from the arterial wall may discriminate between atherosclerotic and non-atherosclerotic coronary arteries. METHODS AND RESULTS: During cardiac bypass surgery, 155 sequential fractions of antegradely flushed coronary cardioplegia solution were collected by balloon-cuffed catheter from the coronary sinus in subjects with angiographically extensive (n=30) or minor (n=7) coronary disease. Although plasma was the major source of protein in heavily blood-contaminated samples, under conditions of low blood contamination (<0.5 mg/ml red cell Haemoglobin) coronary circulation-derived protein was detected. N-terminal sequencing of a major 40 kDa band detected by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) demonstrated 100% homology with beta chain of Haptoglobin (Hpt). Comparison of perfusates from patients with and without significant coronary disease found that the concentration of Hpt was markedly increased in perfusates from atherosclerotic coronary arteries (0.099+/-0.017 microg Hpt/microg Hb) relative to controls (0.016+/-0.008 microg Hpt/microg Hb, P=0.0027). Analysis of peripheral plasma samples of the same subjects, and of a separate cohort of patients, confirmed greater Hpt in those with angiographic coronary disease than in those without disease. CONCLUSIONS: Proteins such as Hpt elute from the human coronary vascular bed and may differentiate between arteries with minor or extensive atherosclerosis. Although the suitability of Hpt as a circulating plasma marker for atherosclerosis remains to be established, the approach used in the present study may permit identification of diverse plasma-detectable markers of atherosclerosis, and the subsequent non-invasive evaluation of in vivo arterial pathology.     

Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction

BACKGROUND: Surgical resection of adenocarcinoma of the stomach is curative in less than 40 percent of cases. We investigated the effect of surgery plus postoperative (adjuvant) chemoradiotherapy on the survival of patients with resectable adenocarcinoma of the stomach or gastroesophageal junction. METHODS: A total of 556 patients with resected adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to surgery plus postoperative chemoradiotherapy or surgery alone. The adjuvant treatment consisted of 425 mg of fluorouracil per square meter of body-surface area per day, plus 20 mg of leucovorin per square meter per day, for five days, followed by 4500 cGy of radiation at 180 cGy per day, given five days per week for five weeks, with modified doses of fluorouracil and leucovorin on the first four and the last three days of radiotherapy. One month after the completion of radiotherapy, two five-day cycles of fluorouracil (425 mg per square meter per day) plus leucovorin (20 mg per square meter per day) were given one month apart. RESULTS: The median overall survival in the surgery-only group was 27 months, as compared with 36 months in the chemoradiotherapy group; the hazard ratio for death was 1.35 (95 percent confidence interval, 1.09 to 1.66; P=0.005). The hazard ratio for relapse was 1.52 (95 percent confidence interval, 1.23 to 1.86; P<0.001). Three patients (1 percent) died from toxic effects of the chemoradiotherapy; grade 3 toxic effects occurred in 41 percent of the patients in the chemoradiotherapy group, and grade 4 toxic effects occurred in 32 percent. CONCLUSIONS: Postoperative chemoradiotherapy should be considered for all patients at high risk for recurrence of adenocarcinoma of the stomach or gastroesophageal junction who have undergone curative resection.     

Going the distance: Developing shared web-based learning programmes

Despite a high demand for continuing professional education, it is becoming more challenging to provide education in a resource-limited environment that meets the varied needs of learners. The advent of user-friendly, interactive communication technology led the University of British Columbia in Canada to explore the feasibility of developing a web-based distance learning programme shared by undergraduate and practising therapists to address this problem. Potential benefits and challenges of distance learning, undergraduate web-learning, pilot-test results and an assessment of therapists’ interests and needs are profiled.     

Sodium nitroprusside enhances TRAIL-induced apoptosis via a mitochondria-dependent pathway in human colorectal carcinoma CX-1 cells

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, Apo-2L) is a recently characterized member of the family of programmed cell death-inducing ligands that includes TNF-alpha and CD95L (FasL). It is well known that TRAIL binds to the death signaling receptors, DR4 and DR5, and initiates the TRAIL death pathway. Activation of this pathway, mediated through a caspase cascade, causes apoptosis. In this study, we hypothesized that oxidative stress facilitates TRAIL-induced apoptosis by promoting caspase activity through cytochrome c release from mitochondria. Human colorectal carcinoma CX-1 cells were treated with various concentrations of TRAIL (12.5-200 ng/ml) and/or sodium nitroprusside (SNP; 0.03-1 mM) for 12 h. SNP, a nitric oxide donor, which had little toxic effect by itself, enhanced TRAIL-induced cytotoxicity. For example, TRAIL-induced apoptosis (200 ng/ml) was increased by a factor of 2.5-fold in the presence of 1 mM SNP. The combined treatment also caused an increase in cytochrome c release, caspase-3 activity, and PARP cleavage. Overexpression of Bcl-2 completely blocked the SNP-promoting effects, but only moderately inhibited TRAIL-induced apoptosis. Similar results were observed in the presence of hydrogen peroxide or peroxynitrite. Taken together, the present studies suggest that SNP enhances TRAIL-induced cytotoxicity by facilitating the mitochondria-mediated caspase signal transduction pathway.     

Calorie restriction in nonhuman primates: mechanisms of reduced morbidity and mortality

Long term chronic calorie restriction (CR) of adult nonhuman primates significantly reduces morbidity and increases median age of death. The present review is focused upon an ongoing study of sustained adult- onset calorie restriction, which has been underway for 15 years. Monkeys, initially calorie restricted at about 10 years of age, are now approximately 25 years old. The median life span of these restricted monkeys is increasing, now exceeding that of ad libitum (AL)-fed monkeys. In our laboratory, maximum life span for AL-fed monkeys appears to be about 40 years. Thus, whether CR can also increase maximal life span, as it does in rodents, cannot be determined for at least another 15 years. The earliest detectable positive benefit on morbidity in these monkeys was previously reported as the prevention of obesity. Current evidence, as reviewed here, suggests that much obesity- associated morbidity is also mitigated by sustained calorie restraint in nonhuman primates. Furthermore, probably because of the prevention of obesity, diabetes has also been prevented. Recent findings include the identification of extraordinary changes in the glycogen synthesis pathway, and on the phosphorylation of glycogen synthase in response to insulin. This calorie restriction-induced prevention of morbidity does not require excessive leanness, but is clearly present when body fat is within the normal range of 10 to 22%, and this is likely to be true in humans as well.      

Reactive nitrogen and oxygen radicals formed during hepatic ischemia-reperfusion kill weakly metastatic colorectal cancer cells

Microscopic infarcts develop within the livers of athymic nude mice during the first 24 h after human colorectal carcinoma (CRC) cells arrest within hepatic sinusoids. Because these regions are reperfused, essentially all weakly metastatic clone A and MIP-101 CRC cells die, whereas many highly metastatic CX-1 CRC cells survive. Because hepatic sinusoidal endothelial cells kill tumor cells in vitro by producing nitric oxide, superoxide anion, and other reactive oxygen and nitrogen species, our purpose was to determine whether reoxygenation of ischemic hepatic cultures in vitro forms toxic oxygen and nitrogen radicals that kill weakly but not highly metastatic CRC cells. CRC cells (10(7)) were labeled with rhodamine-dextran and calcein AM, cultured with cells from one mouse liver in a rotating suspension culture system for up to 24 h, and the metabolic activity of the CRC cells was determined. Liver fragments oxygenated normally before harvest were not toxic to either CRC cell line, but coculture with liver made ischemic by a 3-min ligation of the portal vein and hepatic artery in vivo before harvest and then cultured in oxygenated medium killed 50-70% of weakly metastatic clone A and MIP-101 cells at 24 h but <15% of highly metastatic CX-1 cells. Inhibition of nitric oxide synthase, addition of exogenous superoxide dismutase, but not catalase or hypoxia, during coculture blocked the killing of weakly metastatic CRC cells. Thus, reoxygenation of hepatic parenchymal and nonparenchymal cells after ischemia may form toxic species that eliminate weakly metastatic CRCs within 24 h of their arrest in the liver.     

Apolipoprotein A-I, cyclodextrins and liposomes as potential drugs for the reversal of atherosclerosis. A review

Several studies have revealed that high-density lipoprotein (HDL) is the most reliable predictor for susceptibility to cardiovascular disease. Since apolipoprotein A-I (apoA-I) is the major protein of HDL, it is worthwhile evaluating the potential of this protein to reduce the lipid burden of lesions observed in the clinic. Indeed, apoA-I is used extensively in cell culture to induce cholesterol efflux. However, while there is a large body of data emanating from in-vitro and cell-culture studies with apoA-I, little animal data and scant clinical trials examining the potential of this apolipoprotein to induce cholesterol (and other lipid) efflux exists. Importantly, the effects of oxysterols, such as 7-ketocholesterol (7KC), on cholesterol and other lipid efflux by apoA-I needs to be investigated in any attempt to utilise apoA-I as an agent to stimulate efflux of lipids. Lessons may be learnt from studies with other lipid acceptors such as cyclodextrins and phospholipid vesicles (PLVs, liposomes), by combination with other effluxing agents, by remodelling the protein structure of the apolipoprotein, or by altering the composition of the lipoprotein intended for administration in-vivo. Akin to any other drug, the usage of this apolipoprotein in a therapeutic context has to follow the traditional sequence of events, namely an evaluation of the biodistribution, safety and dose-response of the protein in animal trials in advance of clinical trials. Mass production of the apolipoprotein is now a simple process due to the advent of recombinant DNA technology. This review also considers the potential of cyclodextrins and PLVs for use in inducing reverse cholesterol transport in-vivo. Finally, the potential of cyclodextrins as delivery agents for nucleic acid-based constructs such as oligonucleotides and plasmids is discussed.