The retinoid fenretinide inhibits proliferation and downregulates cyclooxygenase-2 gene expression in human colon adenocarcinoma cell lines

Fenretinide [N-(4-Hydroxyphenyl)retinamide, 4-HPR] (10(-10)-10(-6) M) treatment of HT-29 human colon cancer cells for 24-72 h significantly inhibited their growth. Using HCT-15 cells, 4-HPR had limited inhibitory effects on cell proliferation over the same concentration range and time period. The inhibitory effects of 4-HPR on cell growth in HT-29 cells were markedly reduced in the presence of exogenously added prostaglandins (PGs), suggesting a possible role for inhibition of PG synthesis as a mechanism for 4-HPR's antiproliferative effects. Inhibition of PGE(2) production was caused by 4-HPR in a concentration-dependent manner and decreased COX-2 but not COX-1 mRNA levels; this is the first indication that 4-HPR selectively inhibits COX-2 gene expression. Our findings suggest a possible mechanism for the chemopreventive and anti-proliferative effects of 4-HPR.     

Soluble CD4-PE40 is cytotoxic for a transfected mammalian cell line stably expressing the envelope protein of human immunodeficiency virus (HIV-1), and cytotoxicity is variably inhibited by the sera of HIV-1-infected patients.

Sera were obtained from 50 individuals infected with human immunodeficiency virus type 1 or from HIV-1-uninfected individuals before or after vaccination with recombinant gp160. These sera were evaluated for activity antagonistic to the cell-killing activity of the chimeric Pseudomonas exotoxin hybrid protein, sCD4-PE40. For these studies, Chinese hamster ovary (CHO) cells were transfected with a chimeric plasmid encoding the tat, rev, and envelope genes of HIV-1 and a cell line was selected for stable expression of the envelope glycoproteins at the cell surface (CHO-env). Cytotoxicity of sCD4-PE40 for CHO-env in the presence or absence of added human serum was quantitated spectrophometrically following enzymatic reduction of a tetrazolium bromide within the mitochondria of viable cells (MTT assay). Several HIV+ sera inhibited the cytotoxic activity of sCD4-PE40; the antagonist had properties consistent with those of immunoglobulins in that it was heat stable, absorbed by protein A, and reversible by increasing the concentration of sCD4-PE40. Of 15 HIV+ sera which strongly reacted with gp120, 11 (73%) also potently inhibited sCD4-PE40 cytotoxicity, and cytotoxicity was inhibited by sera from some HIV- individuals after, but not before, immunization with gp160. These data suggested a role for antibody to gp120 in the antagonistic activity. However, not all sera with antibody to gp120 antagonized sCD4-PE40 cytotoxicity and high levels of antagonist activity were frequently (40%) found in HIV+ sera lacking immunoblot-detectable antibody to gp120, or antibody to either CD4 or PE40. Grouping of the HIV+ sera according to the patients' absolute number of CD4+ cells revealed that the degree of inhibition of sCD4-PE40 cytotoxicity approached a Gaussian distribution, suggesting that persons with CD4+ cell counts between 200 and 700/mm3 may be more likely to possess significant levels of serum antagonist. This data have implications for the clinical development of sCD4-PE40 or other sCD4-based therapeutics in the management of HIV-1 infection.     

Sensitization induced in guinea pigs with beta-propiolactone-treated serum albumin: experimental evidence for the cause of allergic reactions in humans receiving human diploid cell rabies vaccines

beta-Propiolactone-treated (BPL-T) homologous serum albumin caused anaphylaxis in guinea pigs with a frequency and severity equal to that of guinea pigs inoculated with human albumin. Untreated guinea pig serum albumin did not cause any reactions in these animals. Some recipients of current rabies vaccine produced in human diploid cells available in the USA develop systemic allergic reactions, usually following booster immunization. The BPL-T human albumin component of the vaccines was believed to be the cause of the complications. Our studies support this conclusion.     

The prevalence of selected physical activities and their relation with coronary heart disease risk factors in elderly men: the Zutphen Study, 1985

Physical activity patterns and their relation with coronary heart disease risk factors are described for a representative sample of 863 Dutch men, 65-84 years old, who participated in the 1985 survey of the Zutphen cohort of the Seven Countries Study. Cross-sectional results revealed a median total of reported physical activity of about 1 hour and 20 minutes per day; only 5.8% reported no physical activity. The percentage of participation and total weekly time spent in physical activity decreased as age increased; the decrease was less pronounced for walking, bicycling, gardening, and doing odd jobs than for sports, hobbies, and work. Statistically significant mean differences were found among quartiles of total weekly physical activity for both total cholesterol and high-density lipoprotein cholesterol (HDL cholesterol); however, only the differences for HDL cholesterol remained significant (p = 0.045) after adjusting for potential confounders. Statistically significant regression coefficients (p less than 0.05) were found for the independent association between walking and total cholesterol and between gardening and total cholesterol, HDL cholesterol, and systolic blood pressure, after adjusting for confounders. Total weekly physical activity and specific activities, e.g., gardening and walking, demonstrated generally favorable associations with cholesterol and systolic blood pressure.     

Sources of hepatic glucose production by 2H2O ingestion and Bayesian analysis of 2H glucuronide enrichment

The contribution of gluconeogenesis to hepatic glucose production (GP) was quantified after ²H₂O ingestion by Bayesian analysis of the position 2 and 5 ²H‐NMR signals (H2 and H5) of monoacetone glucose (MAG) derived from urinary acetaminophen glucuronide. Six controls and 10 kidney transplant (KTx) patients with cyclosporine A (CsA) immunosuppressant therapy were studied. Seven KTx patients were lean and euglycemic (BMI = 24.3 ± 1.0 kg/m²; fasting glucose = 4.7 ± 0.1 mM) while three were obese and hyperglycemic (BMI = 30.5 ± 0.7 kg/m²; fasting glucose = 7.1 ± 0.5 mM). For the 16 spectra analyzed, the mean coefficient of variation for the gluconeogenesis contribution was 10% ± 5%. This uncertainty was associated with a mean signal‐to‐noise ratio (SNR) of 79:1 and 45:1 for the MAG H2 and H5 signals, respectively. For control subjects, gluconeogenesis contributed 54% ± 7% of GP as determined by the mean and standard deviation (SD) of individual Bayesian analyses. For the lean/normoglycemic KTx subjects, the gluconeogenic contribution to GP was 62% ± 7% (P = 0.06 vs. controls), while hyperglycemic/obese KTx patients had a gluconeogenic contribution of 68% ± 3% (P < 0.005 vs. controls). These data suggest that in KTx patients, an increased gluconeogenic contribution to GP is strongly associated with obesity and hyperglycemia. Magn Reson Med 60:517–523, 2008. © 2008 Wiley‐Liss, Inc.     

Preoperative lumbar epidural morphine improves postoperative analgesia and ventilatory function after transsternal thymectomy in patients with myasthenia gravis

OBJECTIVE: To test the hypothesis that preoperative lumbar epidural morphine improves postoperative pain control and ventilatory function after transsternal thymectomy in patients with myasthenia gravis. DESIGN: The study design was randomized, placebo-controlled, and double-blind. SETTING: After surgery, all patients were admitted to the Neuroscience Critical Care Unit for evaluation and treatment. PATIENTS: All patients with myasthenia gravis who presented to the hospital for thymectomy were asked to participate in the study. Twenty patients were randomized to either the placebo or epidural morphine groups. INTERVENTIONS: Patients received either epidural morphine (7 mg in 14 mL of sterile saline) or saline (14 mL) before induction of anesthesia. Supplemental iv opioids were administered intraoperatively, with need determined by the anesthesiologist. MAIN OUTCOME MEASURES: The main outcome measures were indicators of postoperative pain (e.g., Visual Analog Pain Score, requirement for supplemental opioid administration, respiratory rate) and ventilatory function (e.g., forced vital capacity, negative inspiratory pressure). RESULTS: Immediately after surgery, the Visual Analog Pain Score in the placebo group was twice as high as the score in the epidural morphine group (placebo 7.0 +/- 1.3; epidural morphine 3.5 +/- 1.2, p less than or equal to .05). During the first eight postoperative hours, the placebo group required more opioids (0.22 +/- 0.03 vs. 0.12 +/- 0.04 mg/kg morphine equivalents, p less than or equal to .06) than the epidural morphine group. Later, both groups received similar amounts of opioids. Patients receiving epidural morphine had better initial recovery of forced vital capacity (at 8 hrs: 55 +/- 6% [epidural morphine] vs. 34 +/- 5% [placebo] of preoperative value, p less than or equal to .05). Respiratory rate was lower for the first 12 postoperative hours in the epidural morphine group, without a difference in PaCO2. There was no difference between groups for the duration of postoperative intubation or ventilation. CONCLUSIONS: Preoperative lumbar epidural morphine facilitates postoperative analgesia and improves initial postoperative ventilatory performance.     

Effect of volume and dose on the pulmonary distribution of exogenous surfactant administered to normal rabbits or to rabbits with oleic acid lung injury

Administration of exogenous lung surfactant to infants with or at risk for respiratory distress syndrome has been demonstrated to improve gas exchange and survival; administration of surfactant to patients with the adult respiratory distress syndrome is currently undergoing clinical evaluation. Although it is currently assumed the optimal effect will occur when administered surfactant is distributed homogeneously throughout the lung, little is known of the influence of variables inherent in the administration procedure on subsequent distribution. To address this question, we studied the effect of the volume size in which the surfactant is suspended for instillation, and demonstrated a marked relationship in the normal rabbit lung between this volume and the subsequent homogeneity of surfactant distribution. In the rabbit lung that was acutely injured by oleic acid, this relationship was not evident. Concentration of administered surfactant was not demonstrated to be of major influence on its distribution after administration. Our results focus attention on the importance of parameters of the administration procedure, and also demonstrate the usefulness of the techniques used for determination of surfactant distribution.     

Exercise compliance and the gym ball: a case study

Manipulation and exercise are recommended by chiropractors for treatment and prevention of low back problems. Many patients stop their exercise program with improvement in their symptoms. The success of exercises for the prevention of low back pain is dependent on several factors, one being continued compliance to the program. Only a small percentage of the general population do regular exercise; therefore, it is essential that patients recognize the importance of regular exercise in reducing the recurrence of their low back pain. This case study shows how the use of a gym ball appears to have improved compliance and reduced the incidence of low back pain for one patient with a history of re-occurring low back pain and a poor record of exercise compliance. The question must be asked, is this an case incident or is use of the gym ball an appropriate treatment for low back pain?