Phase I/II pharmacokinetic study of pemetrexed and epirubicin in patients with locally advanced or metastatic breast cancer

BACKGROUND: Pemetrexed and epirubicin are each active in patients with advanced/metastatic breast cancer (MBC). This phase I/II study evaluated these drugs as a combination regimen. PATIENTS AND METHODS: Women with locally advanced or MBC were enrolled. Pemetrexed 400-600 mg/m2 and epirubicin 60-90 mg/m2 were administered on day 1 every 21 days. The recommended phase II dose was evaluated in a 2-stage design. RESULTS: Phase I enrolled 34 patients and evaluated 5 dose levels. Dose-limiting toxicities were neutropenia and febrile neutropenia. Patients received a median of 7.5 cycles (range, 1-8 cycles), and promising efficacy (partial response [PR], 32%; stable disease [SD], 50%) was observed. Pharmacokinetics of pemetrexed was unchanged when combined with epirubicin. Selected phase II regimen (pemetrexed 600 mg/m2 and epirubicin 75 mg/m2) was administered to 22 patients (median, 4.5 cycles; range 1-13 cycles). Five patients experienced a PR (23%), and 10 experienced SD (46%). This response was below the predefined efficacy requirements for subsequent enrollment, and accrual was stopped. Median time to progression was 5.3 months (95% CI, 3.1-8.9 months), and median time to treatment failure was 3.5 months (95% CI, 2.6-5.9 months). CONCLUSION: The regimen is safe but cannot be recommended as first-line chemotherapy in advanced breast cancer because of the low response rate.     

Telomere shortening in chronic obstructive pulmonary disease

Chronic oxidative stress and systemic inflammation contribute to the pathology of several chronic diseases, one among which is chronic obstructive pulmonary disease (COPD). In addition, increased oxidative stress and inflammation have been observed to be negatively associated with telomere length (TL). Our aim was to investigate the TL in COPD patients in relation to pulmonary and extrapulmonary disease severity. Furthermore, based on experimental evidence suggesting the effects of oxidative stress on telomere shortening, we studied the association of TL with the antioxidant enzyme superoxide dismutase (SOD). One hundred and two COPD patients with moderate to severe COPD were studied and compared with 19 healthy age-matched controls. Patients were characterized by elevated levels of inflammatory markers (CRP, sTNF-receptors) and lower SOD-activity than the controls (p<0.001), irrespective of the SOD genotype. TL was negatively associated with age (p<0.01) and was significantly shorter in COPD patients than controls (p<0.05). Within the patient group age-adjusted TL variability could not be explained by lung function and smoking history but a modest association was found with the percentage of fat mass (p<0.05). These data provide evidence for a relationship between a disturbed oxidant/antioxidant balance and telomere shortening and indicate that preservation of fat mass may be protective in delaying telomere shortening in COPD patients.     

Nutrient Status Assessment in Individuals and Populations for Healthy Aging—Statement from an Expert Workshop

A workshop organized by the University Medical Center Groningen addressed various current issues regarding nutrient status of individuals and populations, tools and strategies for its assessment, and opportunities to intervene. The importance of nutrient deficiencies and information on nutrient status for health has been illustrated, in particular for elderly and specific patient groups. The nutrient profile of individuals can be connected to phenotypes, like hypertension or obesity, as well as to socio-economic data. This approach provides information on the relationship between nutrition (nutrient intake and status) and health outcomes and, for instance, allows us to use the findings to communicate and advocate a healthy lifestyle. Nutrition is complex: a broader profile of nutrients should be considered rather than focusing solely on a single nutrient. Evaluating food patterns instead of intake of individual nutrients provides better insight into relationships between nutrition and health and disease. This approach would allow us to provide feedback to individuals about their status and ways to improve their nutritional habits. In addition, it would provide tools for scientists and health authorities to update and develop public health recommendations.     

Effect of Meal Ingestion on Ileocolonic and Colonic Transit in Health and Irritable Bowel Syndrome

Background  

Postprandial symptoms in irritable bowel syndrome (IBS) have been associated with increased bowel contractility.     

Exposure of maintenance workers to dioxin-like contaminants during the temporary shutdown of a municipal domestic solid waste incinerator: a case series

To evaluate workers' exposure to dioxin-like substances (such as polychlorinated dibenzo-p-dioxins, dibenzofurans, and polychlorinated biphenyls), the authors used a chemical-activated luciferase gene expression (CALUX) assay to determine serum dioxin-like activity in five workers before and after two different cleaning-up activities inside a municipal domestic solid-waste incinerator. The workers' mean serum concentration of dioxin-like substances before the first cleaning operation, shown as a weighted value of toxic equivalents (or TEQs) according to the CALUX test, was 17.2 pg CALUX TEQ/g fat (range = 12-22), which is comparable with concentrations found in similarly aged men in a Flemish environmental health pilot study. After cleaning work, the workers' mean serum concentration was 28.5 pg CALUX TEQ/g fat (range = 18-31). At the second plant stoppage, the workers' mean dioxin-like activity was 15.4 pg CALUX TEQ/g fat (range = 12-21) before and 16.4 pg CALUX TEQ/g fat (range = < 10-32, where 10 pg is the limit of determination) after the cleaning operation. These results indicate that workers may be exposed to dioxin-like substances during their performance of cleaning operations in a municipal domestic solid-waste incinerator.     

Protective immunization against "Candidatus Helicobacter suis" with heterologous antigens of H. pylori and H. felis

"Helicobacter (H.) heilmannii" type 1 colonizes the human stomach. It has been shown to be identical to "Candidatus H. suis", a Helicobacter species colonizing the stomach of more than 60% of slaughter pigs. This bacterium is, until now, not isolated in vitro. The effect of vaccination on "Candidatus H. suis" infection was studied in a mouse model. Mice were vaccinated intranasally or subcutaneously with whole bacterial cell lysate of Helicobacter pylori or Helicobacter felis and subsequently challenge infected with "Candidatus H. suis". Intranasal and subcutaneous immunisation caused a decrease in faecal excretion of "Candidatus H. suis" DNA. Urease tests on stomach tissue samples at 16 weeks after challenge infection were negative in all H. felis intranasally immunized animals and in the majority of the animals of the other immunisation groups. Since PCR on stomach tissue samples at 16 weeks after challenge infection could still detect "Candidatus H. suis DNA" in all immunisation-challenge groups, complete clearance of challenge bacteria was not achieved.     

De novo glutamine synthesis induced by corticosteroids in vivo in rats is secondary to weight loss

INTRODUCTION: Corticosteroid treatment affects muscle protein and glutamine metabolism. In the present study we aimed to clarify to what extent anorexia, weight loss and corticosteroids determine protein and glutamine metabolism in muscle. METHODS: The study was performed in Wistar rats (300-350 g, n = 40) given triamcinolone (0.25 mg/kg/day i.m.) treatment (CS group) for 14 days, sham treated free fed (FF group), sham treated pair fed (PF group) and sham treated pair weight (PW group). In vivo protein and glutamine turnover were measured using L-[2,6-3H]phenylalanine and L-[3,4-3H]glurtamine as tracer in a three compartment model across the hindquarter. RESULTS: Corticosteroid treatment decreased total body weight to a greater extent than can be explained by decreased food intake only, justifying the need for pair weight controls. Muscle weight loss was relatively greater in the corticosteroid treated rats than in the pair weight controls indicating specific corticosteroid induced changes in muscle protein metabolism. Pair weight rats increased muscle net protein breakdown rates from -5 +/- 3 nmol x 100 g body weight(-1) x min(-1) to -15 +/- 3 nmol x 100 g body weight(-1) x min(-1) (P < 0.05 vs FF). In the corticosteroid treated rats net protein breakdown rates increased to -22 +/- 4 nmol x 100 g body weight(-1) x min(-1) (P < 0.01 CS vs FF/PF) Net protein breakdown in corticosteroid treated rats was accompanied by increased glutamine efflux from the hindquarter (P < 0.05, CS vs FF/PF/PW). The latter could predominantly be explained by de novo synthesis. Furthermore, corticosteroid treatment induced a loss of plasma to free muscle glutamine gradient indicating down regulation of glutamine membrane transport rates into muscle. This effect was, however, similar in the pair weight control group and can thus be fully accounted for by the muscle weight loss. CONCLUSION: Two weeks treatment with triamcinolone increases net in vivo protein breakdown of muscle directly and indirectly due to secondary weight loss and decreased food intake. The amino acid residues are used for glutamine de novo synthesis which is exported from muscle to visceral organs by down regulation of glutamine transport systems. These changes were in majority related to muscle weight loss.     

Spatiotemporal properties of the BOLD response in the songbirds' auditory circuit during a variety of listening tasks

Auditory fMRI in humans has recently received increasing attention from cognitive neuroscientists as a tool to understand mental processing of learned acoustic sequences and analyzing speech recognition and development of musical skills. The present study introduces this tool in a well-documented animal model for vocal learning, the songbird, and provides fundamental insight in the main technical issues associated with auditory fMRI in these songbirds. Stimulation protocols with various listening tasks lead to appropriate activation of successive relays in the songbirds' auditory pathway. The elicited BOLD response is also region and stimulus specific, and its temporal aspects provide accurate measures of the changes in brain physiology induced by the acoustic stimuli. Extensive repetition of an identical stimulus does not lead to habituation of the response in the primary or secondary telencephalic auditory regions of anesthetized subjects. The BOLD signal intensity changes during a stimulation and subsequent rest period have a very specific time course which shows a remarkable resemblance to auditory evoked BOLD responses commonly observed in human subjects. This observation indicates that auditory fMRI in the songbird may establish a link between auditory related neuro-imaging studies done in humans and the large body of neuro-ethological research on song learning and neuro-plasticity performed in songbirds.     

In vitro antimicrobial susceptibility testing of Helicobacter felis, H. bizzozeronii, and H. salomonis

The susceptibilities of Helicobacter felis (15 strains), H. bizzozeronii (7 strains), and H. salomonis (3 strains) to 10 antimicrobial agents were investigated by determination of the MIC using the agar dilution method. No consistent differences were noticed between the different Helicobacter species, which were all highly susceptible to ampicillin, clarithromycin, tetracycline, tylosin, enrofloxacin, gentamicin, and neomycin, as demonstrated by low MICs. Higher MICs were obtained for lincomycin (up to 8 microg/ml) and spectinomycin (up to 4 microg/ml). Two H. felis strains showed a MIC of 16 microg/ml for metronidazole, suggesting acquired resistance to this antimicrobial agent.     

Muscle fiber type IIX atrophy is involved in the loss of fat-free mass in chronic obstructive pulmonary disease

BACKGROUND: Although the loss of peripheral muscle mass has been shown convincingly in chronic obstructive pulmonary disease (COPD), the underlying pathogenesis remains unclear. OBJECTIVE: The aim of the present study was to determine the relations between skeletal muscle fiber types, fiber cross-sectional area (CSA), enzyme activities, and fat-free mass (FFM) in patients with COPD and in control subjects. DESIGN: In 15 patients with COPD and 15 healthy, age-matched control subjects, FFM was determined by dual-energy X-ray absorptiometry and bioelectrical impedance analysis. In biopsy specimens from the vastus lateralis fiber types, fiber CSA and activities of cytochrome oxidase (EC 1.9.3.1), succinate dehydrogenase (EC 1.3.99.1), and glycogen phosphorylase (EC 2.4.1.1) were examined immunohistochemically and histochemically. RESULTS: Compared with control subjects, patients with COPD had less FFM (49 compared with 59 kg, P = 0.030) and lower mean fiber CSA (3839 compared with 4647 microm(2), P = 0.037). A strong correlation (r = 0.87, P < 0.001) was observed between the FFM measured by bioelectrical impedance analysis and mean fiber CSA in patients with COPD. Within fiber-type categories the mean CSA of only the IIA/IIX and IIX fiber types was lower in patients than in control subjects [3358 compared with 4428 microm(2) (P = 0.022) and 2566 compared with 4248 microm(2) (P = 0.003), respectively]. In COPD, 20% of the type IIX fibers lacked stainable activities of cytochrome oxidase, succinate dehydrogenase, and glycogen phosphorylase, and this proportion correlated negatively with type IIX fiber CSA (r = -0.65, P = 0.012). CONCLUSIONS: Muscle fiber atrophy occurs in the vastus lateralis in patients with COPD and contributes to the loss of muscle mass in COPD. Atrophy is specific to fiber types IIA/IIX and IIX and is associated with a disturbed metabolic capacity.