Effect of aerobic training on the host systemic milieu in patients with solid tumours: an exploratory correlative study.

BACKGROUND: Few studies have investigated the effects of exercise on modulation of host factors in cancer patients. We investigated the efficacy of chronic aerobic training on multiple host-related effector pathways in patients with solid tumours. PATIENTS AND METHODS: Paired peripheral blood samples were obtained from 44 patients with solid tumours receiving cytotoxic therapy and synthetic erythropoietin (usual care; n=21) or usual care plus supervised aerobic training (n=23) for 12 weeks. Samples were characterised for changes in immune, cytokine and angiogenic factors, and metabolic intermediates. Aerobic training consisted of three supervised cycle ergometry sessions per week at 60% to 100% of peak oxygen consumption (VO2peak), 30-45 min per session, for 12 weeks following a nonlinear prescription. RESULTS: The between-group delta change in cardiopulmonary function was +4.1 ml kg (-1) min(-1), favouring aerobic training (P<0.05). Significant pre-post between-group differences for five cytokine and angiogenic factors (HGF, IL-4, macrophage inflammatory protein-1ß (MIP-1ß), vascular endothelial growth factor (VEGF), and TNF-α) also favour the aerobic training group (P's<0.05). These reductions occurred in conjunction with nonsignificant group differences for T lymphocytes CD4(+), CD8(+), and CD8(+)/CD45RA (P<0.10). For these factors, circulating concentrations generally increased from baseline to week 12 in the aerobic training group compared with decreases or no change in the usual care group. No significant changes in any metabolic intermediates were observed. CONCLUSIONS: Aerobic training alters host availability of select immune-inflammatory effectors in patients with solid tumours; larger confirmatory studies in more homogenous samples are warranted.

The estrogen receptor as a mediator of the pathological actions of cholesterol in breast cancer.

Despite increased survivorship among patients, breast cancer remains the most common cancer among women and is the second leading cause of cancer death in women. The magnitude of this problem provides a strong impetus for new chemopreventative strategies and/or lifestyle changes that reduce cancer incidence. It is of significance, therefore, that several studies positively correlate obesity to the development of breast cancer. Importantly, obesity is also highly associated with elevated cholesterol, and cholesterol itself is a risk factor for breast cancer. Furthermore, patients taking statins demonstrate a lower breast cancer incidence and decreased recurrence. The recent observation that 27-hydroxycholesterol (27HC) is produced in a stoichiometric manner from cholesterol, together with our recent demonstration that it exerts partial agonist activity on both the estrogen and liver X receptors, suggested a potential mechanistic link between hyper-cholesterolemia and breast cancer incidence. Using genetic and pharmacological approaches, we have recently shown that elevation of circulating 27HC significantly increases tumor growth and metastasis in murine models of breast cancer. Further, we have demonstrated in appropriate animal models that the impact of high-fat diet on tumor pathogenesis can be mitigated by statins or by small molecule inhibitors of CYP27A1. These findings suggest that pharmacological or dietary modifications that lower total cholesterol, and by inference 27HC, are likely to reduce the impact of obesity/metabolic syndrome on breast cancer incidence.

New insights into thyroid hormone function and modulation of reproduction in goldfish.

A number of studies have provided evidence for a link between thyroid hormones and physiological or pathophysiological conditions associated with reproduction. Most of the information available is based on clinical observations in human or research in mammals. There are also a number of studies in non-mammalian species, primarily investigating thyroid and reproductive endocrinology in isolation. The findings demonstrate that hyperthyroidism or hypothyroidism are associated with altered fertility due to changes in the levels and activities of hormones of the brain-pituitary-gonadal axis. There appears to be a consistent pattern based on a number of studies in mammalian and non-mammalian species, linking thyroid with reproduction. Results obtained in goldfish suggest that increased levels of thyroid hormones may reduce overall reproductive function. Since thyroid hormones influence metabolism and are known to stimulate growth in most species, it is likely that increased thyroid hormone levels may divert energy from reproduction and promote somatotropic functions. This is particularly important in oviparous species such as fish since energy investment in females during reproductive season is very significant, and increasing thyroid hormone levels after ovulation may be a contributing factor in promoting growth response. Thyroid hormones will likely work in concert with other hormones to influence reproduction in fish and other vertebrates.

Molecular characterization and sex-related seasonal expression of thyroid receptor subtypes in goldfish.

The thyroid hormones, acting through the nuclear thyroid receptors (TRs), play important roles in the growth and development of vertebrates. The present study investigated the molecular structure and season-related expression of the TR isoforms in the male and female goldfish pituitary, brain, liver, gonads, gut, heart, and muscle. Based on sequence alignment with other species, the results demonstrate the presence of: (1) a TRalpha (TRalpha-1) consisting of 1496 nucleotides encoding a 466 amino acid protein, (2) a novel splice variant of TRalpha (TRalpha-2) containing an out-of-frame deletion of 246 nucleotides in the ligand-binding domain consisting of 1251 nucleotides encoding a 378 amino acid protein, (3) a novel transcript resembling TRalpha, except for non-homology in the hinge region and a premature stop codon prior to the ligand-binding domain (TRalpha-truncated; 1418 nucleotides, 206 amino acid protein), and (4) TRbeta consisting of 1823 nucleotides encoding a 395 amino acid protein. The findings provide the first demonstration of the presence of a truncated TR isoform in non-mammalian vertebrates. In goldfish, the expression patterns for all TRs subtypes were found to be remarkably similar in both male and female, changing significantly before and during reproductive season. The results provide a frame work for better understanding of the functional significance of novel TR forms and TR subtypes in fish and other vertebrates.

Effects of local infusion of OP-1 on particle-induced and NSAID-induced inhibition of bone ingrowth in vivo.

Excessive polyethylene wear particles from joint replacements may lead to periprosthetic osteolysis and loosening. Nonsteroidal anti-inflammatory drugs (NSAIDs) decrease fracture healing and bone ingrowth. We hypothesized that continuous local infusion of OP-1 (BMP-7) would increase local bone formation in the presence of two different adverse stimuli, polyethylene particles, and an oral NSAID. The Drug Test Chamber (DTC) was implanted in the proximal tibia of mature rabbits. The tissue growing into the chamber was exposed to OP-1 solution (110 ng/day), which was infused via an osmotic pump. Infusion of OP-1 alone for 6 weeks enhanced local bone formation in the chamber by 80% (p < 0.05) over infusion of carrier alone. In the presence of polyethylene particles, infusion of OP-1 increased local bone formation by 38% (p < 0.05) over treatment with particles and carrier. Oral administration of NSAID reduced local bone formation by 58% (p < 0.05); this suppressive effect caused by NSAIDS was completely reversed by the infusion of OP-1 (p < 0.05). These findings underline a potential role for local treatment with OP-1 to increase bone formation in the presence of potentially adverse stimuli such as polyethylene wear particles or NSAID use.

Nalmefene to prevent epidural narcotic side effects in pediatric patients: a pharmacokinetic and safety study.

STUDY OBJECTIVE: To determine the pharmacokinetics and preliminary efficacy of nalmefene in children in preventing epidural-induced narcotic side effects. DESIGN: Double-blind, placebo-controlled study. SETTING: University-affiliated children's hospital. PATIENTS: Thirty-four children (aged 2-12 yrs) undergoing cardiothoracic surgery with epidural anesthesia. INTERVENTIONS: Patients were randomized to receive intravenous bolus nalmefene 1 microg/kg or placebo. MEASUREMENTS AND MAIN RESULTS: Six blood samples (one before nalmefene administration and five from 13 randomly designated time points) from each patient were assayed to determine plasma nalmefene concentrations. Patients were assessed for pain, nausea, vomiting, and urinary retention for 24 hours after administration. Concentration-time data were analyzed by a limited sampling strategy with adult pharmacokinetic parameters used as Bayesian priors. A two-compartment, first-order model was fitted to the data using ADAPT II. Pharmacokinetic parameter estimates in these patients were similar to values reported in adults. The initial disposition half-life (t(1/2alpha)) was 0.36+/-0.11 hour, the terminal elimination half-life (t(1/2beta)) 8.7+/-2.3 hours, clearance 0.729+/-0.172 L/kg/hr, and steady-state volume of distribution 7.21+/-2.49 L/kg. Ability to prevent epidural narcotic-induced side effects could not be documented at the 1-microg/kg dose. No statistically significant differences were noted between study and placebo groups with regard to pain, nausea, vomiting, or urinary retention. CONCLUSION: Nalmefene has similar pharmacokinetics in children as in adults. It was administered safely to these patients and did not produce unmanageable pain.

Incidence of first acute myocardial infarction in the Bangkok Adventist Hospital (1958-1985).

This present report represents an effort to find the trends in the incidence of first AMI in patients admitted to Bangkok Adventist Hospital. During a 28-year period (1958-1985), we noted a six-fold increase in the prevalence of the disease, more remarkably in males. Ethnically, there is difference in the onset of the occurrence and rate of incidence among Thai, Chinese and Indian patients. The higher incidence of AMI was found in Indians more than the Thai and Chinese. They also had earlier occurrence. The proved risk factors (hypertension, diabetes, cigarette smoking, and hypercholesterolemia) in AMI are also shown to be prominent in this investigation. The rate of hypertension and diabetes is slightly higher than that previously reported.

Homologous regulation of estrogen receptor subtypes in goldfish (Carassius auratus).

While considerable information is available on the physiological effects of estrogen, much less is known about the regulation of estrogen receptor (ER) subtypes, particularly in non-mammalian vertebrates. Using goldfish as primary experimental model, we investigated sex- and tissue-specific homologous regulation of ER subtypes (ERalpha, ERbetaI, and ERbetaII) by estradiol in vivo, in the liver and gonads. Treatment with estradiol, significantly upregulated transcript levels for all three types of ERs (ERalpha, ERbetaI, and ERbetaII) in the goldfish ovary and testis. In the goldfish liver, treatment with estradiol significantly increased ERalpha, ERbetaI transcript levels without affecting ERbetaII. In all cases increased ER transcript level was correlated with increased ER protein level determined by Western blot analysis, although we are not able to distinguish between ER subtypes. The results provide strong support for the hypothesis that homologous regulation of ERs is tissue- and gender-specific, and may be a mechanism for estrogen-mediated regulation of reproduction in goldfish.

Lower eyelid retraction following blepharoplasty.

Thirty consecutive patients with lower eyelid retraction after blepharoplasty were treated surgically with varying degrees of success. Successful outcome depended on various anatomic and pathologic factors, including the time elapsed since blepharoplasty, the prominence of the globe and its effect on eyelid contour, and the degree of septal or skin involvement. Satisfactory results were also dependent on surgical techniques used. We discuss several surgical techniques and offer advice concerning the selection of a surgical procedure in light of various pathologic parameters.

Gingival colonization with selective HACEK microbes in children with congenital heart disease.

It was previously shown that children with congenital heart disease (CHD) harbored Hemophilus, Actinobacillus, Cardiobacter, Eikenella, and Kingella (HACEK) microbes to a greater extent and had more severe gingival inflammation than a normal group of children. The purpose of this study was to determine if HACEK microbes are more prevalent in children with CHD than in normal children when there is no difference in gingival inflammation. Two groups of 12 children were matched with respect to gingival inflammation. Each child had a gingival index recorded as described by Massler. The experimental group consisted of 12 children with CHD 2.5-10 years old (average 5.5) and the control group consisted of 12 healthy children 2-13 years old (average 5.6). Subgingival samples were obtained and cultured for HACEK microbes. Fischer's exact test was performed with the significance level defined at P<0.05. The average gingival indices for the experimental and control groups were 6.5 and 6.4, respectively (N.S.). Nine of 12 children with CHD had Eikenella corrodens (E.c.) compared to 3/12 control patients ( P<0.05). Three of 12 CHD patients but no control patient had Actinobacillus actinomycetemcomitans (A.a.) (N.S.). There were no significant differences in E.c. or A.a. presence between cyanotic and acyanotic CHD patients. This study found that the greater extent of specific HACEK microbes harbored by children with CHD is not associated with cyanosis or the degree of gingival inflammation. Further study is needed to delineate fully the medical significance of this observation.

Adjuvant effect of respiratory irritation on pulmonary allergic sensitization: time and site dependency.

It has been suggested that airway irritation, by acting as an adjuvant, as well as producing damage, may be an important factor related to asthma. The present study examined the window of time following acute upper and lower airway irritant exposure to determine the period of increased risk of immunological sensitization. Brown Norway rats were exposed to 87 ppm NO2 or 1000 ppm NH3 for 1 hr. A 30-min ovalbumin (OVA) exposure of 18.14 microg/liter air was given at various times based upon the time course of irritant associated inflammatory response (either immediately prior to or 1 or 7 days after the irritant exposure). OVA-only, NO2-only or NH3-only controls, and saline controls were also studied. Weekly booster exposures of OVA (or saline) were given. Circulating OVA-specific IgE, IgA, and IgG levels were quantified periodically during the 6 weeks of the study. Bronchoalveolar lavage (BAL) was also performed to examine the inflammatory response to allergic and irritant challenge. Significant increases in OVA-specific IgE, IgG, and IgA antibody titers were seen in rats given the sensitizing OVA exposure within 1 day of the NO2, but not NH3 exposures. Enhancement of cellular infiltrate in BAL was noted in groups given the sensitizing OVA exposure within 1 day of the NO2 or NH3. It is concluded that the inflammatory and immunological response to antigen exposure can be modified by the site of respiratory tract irritation and the relative times of irritant and antigen exposure.

Ovalbumin aeroallergen exposure-response in Brown Norway rats.

A major route of exposure to allergens is through the respiratory tract. Comparatively few animal studies have used aerosolized high-molecular-weight allergens for sensitization, and in these studies, proper characterization of the aeroallergen exposure was usually missing. The purpose of this study was to profile the exposure-response relationship in Brown Norway rats (BNR) to well-characterized ovalbumin (OVA) aerosols. Rats were exposed 30 min/wk x 6 wk to respirable OVA aerosols from <1 mg/m(3) to 64 mg/m(3) air. Ovalbumin-specific circulating immunoglobulin (Ig)E, IgG, and IgA were measured throughout the study period. Rats were sacrificed 1 day after the last exposure. Pulmonary tissue was processed for histopathological and histochemical analysis. Tracheas were isolated, perfused, and assessed for in vitro responsiveness to methacholine. Serum concentrations of OVA-specific antibodies increased with both exposure concentration and number of exposures. The number of BNR with measurable titers also increased with both dose and time. Pulmonary inflammatory changes were noted only in BNR exposed to higher OVA concentrations (15 and 64 mg/m(3) air). Increased tracheal reactivity to methacholine was not found in any of the sensitized BNR. In summary, sustained aeroallergen concentration-dependent changes in specific antibody responses and pulmonary inflammation have been demonstrated.