STAT4 contributes to adipose tissue inflammation and atherosclerosis.

Adipose tissue (AT) inflammation is an emerging factor contributing to cardiovascular disease. STAT4 is a transcription factor expressed in adipocytes and in immune cells and contributes to AT inflammation and insulin resistance in obesity. The objective of this study was to determine the effect of STAT4 deficiency on visceral and peri-aortic AT inflammation in a model of atherosclerosis without obesity. Stat4(-/-)Apoe(-/-) mice and Apoe(-/-) controls were kept either on chow or Western diet for 12 weeks. Visceral and peri-aortic AT were collected and analyzed for immune composition by flow cytometry and for cytokine/chemokine expression by real-time PCR. Stat4(-/-)Apoe(-/-) and Apoe(-/-) mice had similar body weight, plasma glucose, and lipids. Western diet significantly increased macrophage, CD4+, CD8+, and NK cells in peri-aortic and visceral fat in Apoe(-/-) mice. In contrast, in Stat4(-/-)Apoe(-/-) mice, a Western diet failed to increase the percentage of immune cells infiltrating the AT. Also, IL12p40, TNFa, CCL5, CXCL10, and CX3CL1 were significantly reduced in the peri-aortic fat in Stat4(-/-)Apoe(-/-) mice. Importantly, Stat4(-/-)Apoe(-/-) mice on a Western diet had significantly reduced plaque burden vs Apoe(-/-) controls. In conclusion, STAT4 deletion reduces inflammation in peri-vascular and visceral AT and this may contribute via direct or indirect effects to reduced atheroma formation.

Vitamin D analogs as anti-carcinogenic agents.

Deltanoids are the class of compounds comprising all natural and synthetic vitamin D molecules. The anti-proliferative, pro-differentiation, and pro-apoptotic properties of deltanoids have garnered interest in the fields of cancer chemoprevention and chemotherapy. The naturally occurring, biologically active form of vitamin D, 1,25(OH)2D3, causes hypercalcemia at pharmacologically relevant doses which forms a major obstacle in the clinical development of this compound. Design of new deltanoids has shown promise in separating the beneficial effects from the toxic effects. The Vitamin D receptor (VDR) is a major target for deltanoid design, and the structural features of deltanoid binding have been described. Effective compounds must also exhibit beneficial pharmacokinetic properties in vivo, and the plasma vitamin D binding protein (DBP) is likely to play an important role in the success of deltanoids in the clinic. Further, dual strategies of avoiding vitamin D toxicity through altering the dosing schedule and using less toxic deltanoids are in development. The three main categories of structural modification to the vitamin D backbone include the C,D-ring, the A-ring, and the C,D-ring side chain, and the ways each area has impacted efficacy and toxicity have been described through structure-activity relationships (SARs). Lastly, there is evidence that deltanoids can enhance the activity of other chemopreventive agents. The use of a cocktail approach will be discussed as a potential avenue for deltanoids in chemoprevention and chemotherapy.

Parasite control methods used by horse owners: factors predisposing to the development of anthelmintic resistance in nematodes.

One hundred and fifty horse owners, primarily private owners and riding schools, replied to a questionnaire concerning the practices they used to control parasites. Twenty-seven had experienced a parasite problem. Faecal samples from 188 horses selected at random showed that worm control practices were generally successful; however, many owners were not following recommendations for slowing the development of resistant parasites. In 1996, 86 per cent of the owners were using either three or two classes of anthelmintic a year, and they used a median of six doses with a range from one to 11. Approximately half the owners, more commonly owners of up to five horses, picked up their horses' faeces at least once a week, but these owners also used more doses of anthelmintic a year than owners who did not pick up faeces. One-third of the owners manually removed Gasterophilus species eggs from the horses' hairs, but 94 per cent of them also used ivermectin. Many owners treated specifically for Anoplocephala species, cyathostome larvae and Gasterophilus species, and these owners were the most likely to use three classes of anthelmintic a year. One-hundred-and-seven owners replied to a second questionnaire asking for information about the factors that influenced their anthelmintic control practices. Many owners, particularly private owners, were not influenced by the cost of the anthelmintic. For the timing and frequency of treatment, and the choice of drug, owners were most influenced by advertisements, magazine articles and veterinary surgeons. In two magazines aimed at horse owners, the brands of drugs most frequently advertised were the brands most commonly used by the owners, and articles in the magazines recommended the use of three classes of drug per year. These results are discussed in relation to their influence on the development of anthelmintic-resistant nematodes.

Pancreatic cancer: treatment with neutron irradiation alone and with chemotherapy.

PURPOSE: To evaluate neutron irradiation alone and with chemotherapy to treat inoperable pancreatic cancer. MATERIALS AND METHODS: Between 1977 and 1994, 173 patients (60 men, 113 women, aged 43-77 years [mean, 59 years]) with unresectable adenocarcinoma of the exocrine pancreas were treated, 106 with neutron irradiation alone and 67 with concomitant chemotherapy (fluorouracil [5-FU]). At follow-up, which was performed at 2-month intervals until death (range, 4-64 months), clinical status was recorded, noting the presence of overt metastasis and the onset of any major complications. Actuarial (Kaplan-Meier) survival tables were computed for both groups. RESULTS: For neutron irradiation alone and neutron irradiation plus chemotherapy, median survival times were 6 months and 9 months, respectively; actuarial survival rates at 3 years were 0 and 7%, respectively; major reactions (grade 3 or higher [scale of the Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer]) occurred in 19 (18%) and 17 (25%) patients, respectively; and severe complications (grade 4) occurred in five (5%) and four (6%) patients, respectively. Most deaths were due to metastatic disease rather than to failure of local control. CONCLUSIONS: Neutron irradiation obliterated pancreatic adenocarcinoma at the primary site but has no effect on long-term survival. With more effective concomitant chemotherapy to prevent metastasis, local control of pancreatic cancer with neutron irradiation could lead to increased long-term survival.

Neutron irradiation of human pelvic tissues yields a steep dose-response function for late sequelae.

PURPOSE: Analysis of the dose-response function in normal tissues following pelvic irradiation for carcinoma of the prostate. METHODS AND MATERIALS: A homogeneous group of 136 patients with locally advanced carcinoma of the prostate were treated with the Fermilab high-energy neutron beam at three dose levels: 19, 20.4, and 21 Gy, using the same treatment plan and fractionation scheme for all patients. RESULTS: Tumor control rates were about 83% at the three dose levels studied. However, the normal tissue complication rate (late sequelae) varied with dose: 0 out of 5 at 19 Gy, 5 out of 58 (8.6%) at 20.4 Gy, and 9 out of 73 (12.3%) at 21 Gy. CONCLUSIONS: Neutron therapy to the pelvis reveals a steep dose-response function for late effects with a coefficient of variation of only 11%. This is lower than that usually observed with photons or with less uniform clinical data sets, and may be characteristic for well-planned high-LET radiotherapy.