Comparison of thermogenic activity induced by the new sympathomimetic Ro 16-8714 between normal and obese subjects.

In a previous study, we demonstrated that the new beta-adrenoceptor agonist Ro 16-8714 possesses thermogenic property in normal male volunteers. The aim of the present study was to compare the metabolic response of lean vs obese individuals to a similar dose of this compound. Following an overnight fast, Ro 16-8714 (0.17 mg/kg fat free mass) or a placebo was given per os to six normal-weight subjects and to six moderately obese subjects. The rate of energy expenditure (EE) and the substrate utilization were determined by indirect calorimetry (hood system) before and for 6 h following the drug administration. Heart rate and blood pressure as well as plasma glucose, insulin and free fatty acid (FFA) concentrations were also measured at regular intervals throughout the study. The increment relative to base-line (mean +/- s.e.m.) in EE was similar in the two groups and averaged 4.0 +/- 1.4 per cent and 12.2 +/- 1.4 per cent with placebo and with Ro 16-8714 respectively in lean subjects, whereas the values reached 3.5 +/- 1.2 per cent and 14.4 +/- 2.0 per cent in obese subjects. Heart rate, systolic blood pressure, insulin and FFA were increased without any significant difference between the two groups. This study shows that Ro 16-8714 is a potent thermogenic agent both in normal and obese subjects.

New perspectives in the use of ink evidence in forensic science : part III : operational applications and evaluation

The research reported in this series of article aimed at (1) automating the search of questioned ink specimens in ink reference collections and (2) at evaluating the strength of ink evidence in a transparent and balanced manner. These aims require that ink samples are analysed in an accurate and reproducible way and that they are compared in an objective and automated way. This latter requirement is due to the large number of comparisons that are necessary in both scenarios. A research programme was designed to (a) develop a standard methodology for analysing ink samples in a reproducible way, (b) comparing automatically and objectively ink samples and (c) evaluate the proposed methodology in forensic contexts. This report focuses on the last of the three stages of the research programme. The calibration and acquisition process and the mathematical comparison algorithms were described in previous papers [C. Neumann, P. Margot, New perspectives in the use of ink evidence in forensic science-Part I: Development of a quality assurance process for forensic ink analysis by HPTLC, Forensic Sci. Int. 185 (2009) 29-37; C. Neumann, P. Margot, New perspectives in the use of ink evidence in forensic science-Part II: Development and testing of mathematical algorithms for the automatic comparison of ink samples analysed by HPTLC, Forensic Sci. Int. 185 (2009) 38-50]. In this paper, the benefits and challenges of the proposed concepts are tested in two forensic contexts: (1) ink identification and (2) ink evidential value assessment. The results show that different algorithms are better suited for different tasks. This research shows that it is possible to build digital ink libraries using the most commonly used ink analytical technique, i.e. high-performance thin layer chromatography, despite its reputation of lacking reproducibility. More importantly, it is possible to assign evidential value to ink evidence in a transparent way using a probabilistic model. It is therefore possible to move away from the traditional subjective approach, which is entirely based on experts' opinion, and which is usually not very informative. While there is room for the improvement, this report demonstrates the significant gains obtained over the traditional subjective approach for the search of ink specimens in ink databases, and the interpretation of their evidential value.

Tenascin-W, a new marker of cancer stroma, is elevated in sera of colon and breast cancer patients.

Tenascins are extracellular matrix proteins present during the development of organisms as well as in pathological conditions. Tenascin-W, the fourth and last member of the tenascin family remains the least well-characterized one. Our study aimed to evaluate the potential significance of tenascin-W as cancer biomarker by monitoring its presence in the serum of colorectal and breast cancer patients and its expression in colorectal tumor tissues. To measure serum tenascin-W levels, a sensitive sandwich-ELISA was established. Mean tenascin-W concentration in sera of patients with nonmetastatic colorectal cancer at time of diagnosis was highly increased compared to that of healthy volunteers. A similar tendency was observed for tenascin-C in the same patient cohort. However, the increase was much more striking for tenascin-W. We also detected elevated tenascin-W levels in sera of breast cancer patients. Furthermore, we could show a prominent expression of tenascin-W in extracts from colorectal tumor tissues by immunoblot analysis, whereas tenascin-W was not detectable in the corresponding normal colon mucosa. To confirm the western blot results, we performed immunohistochemistry of frozen sections of the same patients as well as of an additional, independently chosen collection of colorectal cancer tissues. In all cases, similarly to tenascin-C, tenascin-W was detected in the tumor stroma. Our results reveal a clear association between elevated levels of tenascin-W and the presence of cancer. These results warrant further studies to evaluate the potential value of serum and tissue tenascin-W levels as diagnostic, prognostic or monitoring biomarker in colorectal, breast and possibly other solid cancers.

The new culture of electronic publishing

Local conditions in the past often limited opportunities for scholarly exchange. But now these limits are gone and the global workplace has replaced them. It is important to react to these changes. Every academic department must now adopt new methods and rethink processes. Another is the intense national and international debate about open access to scholarly knowledge. The Open Access Initiative shows that a change is taking place in the communication process. This change is also important for service departments within research institutions. Libraries, computer centers and related units have to ask themselves how to react appropriately to the new conditions. What services must be changed or redeveloped, and in what quality and quantity should they be offered? This article focuses on changes in the scholarly publication process. It describes both technological changes and the changes needed in people's attitudes.

Preliminary report of the first season work of the International Pluridisciplinary Archaeological Expedition to Bactria 2007

A prior long-term and complex evaluation of the already available data on the geophysical prospecting during the first season work carried out at 2006, at the archaeological site of Tchinguiz Tepe of Termez, took place to decide the strategy to follow during the campaign of 2007. This previous evaluation of the information, on one hand, leaded to the decision to increase the geophysical prospecting at Tchinguiz Tepe, on the other hand, to decide the exact location of areas where the archaeological interventions.would carry out. The main objective at the beginning of this new season was to crosscheck the reliabilityof the measurements and, at the same time, to establish the unknown up to the present archaeologicaland chronological sequence of Tchinguiz Tepe. Meanwhile, the geophysical prospecting also wasextended to the outskirts of the city were the localisation of an unknown up to now Buddhist Monasterywas possible.

Preliminary report of the first season work of the International Pluridisciplinary Archaeological Expedition to Bactria 2008

This year the development of our project can be divided into two main clearly different parts, on one hand the laboratory work, where the sampled ceramic individuals has been prepared and analyzed and the elaboration of the data obtained during the excavation of 2007 has been finished and, on the other hand, the field work developed at the archaeological site during this specific year (2008).In the mark of the analytical work a significant number of ceramic individuals (144) from the different stratigraphical units from various areas of the excavation of Termez and Tchinguiz Tepe sampled duringthe new and previous field works has been archaeometrically characterized. This specific material includedindividuals dated into the Hellenistic and Sassanian period, which has been confirmed by C14dating upon organic samples.At the same time, in the mark of the field work of 2008 the archaeological record, already started tobe under study during the excavation of 2007, has been completed and two new archaeological recordshave been registered on of which is located in the area of Tchinguiz Tepe. For the archeological studythe information of the previous geophysical prospecting has been indisputably taken into considerationand the same methodology has been applied to crosscheck the latter archaeological results.

Comparison of the site distribution of melanoma in New Zealand and Canada

A comparison of the site distribution of cutaneous malignant melanoma in New Zealand and Canada was performed. This series deals with 41,331 incident cases registered between 1968 and 1990 and is the largest to date to evaluate the influence of age and gender on the site distribution of melanoma. Site-specific, age-standardized rates per unit surface area and relative tumour density were assessed by gender and country and differences compared with statistical techniques adapted to this context. The age-standardized rates for all sites were higher in New Zealand than in Canada, the ratio being 3.2 for men and 3.8 for women. Occurrence of melanoma was denser for chronically than intermittently exposed sites in both New Zealand and Canada. The highest incidence rate per unit area was for the ears in men which was more than 5 times the rate for the entire body in each country. For each gender, melanomas were relatively commoner on the trunk and the face in Canada, and on the lower limbs in New Zealand. The variations in the site distribution were similar in each country and consistent with the effect of differential patterns of sun exposure between genders. Our results show that the levels of risk of melanoma between phenotypically comparable populations exposed to different amount of UV radiation vary in a site-specific manner, especially for intermittently exposed sites. This suggests that both environmental conditions and lifestyle factors influence the site distribution of melanoma in these two populations.

Analytical progresses of the International Olympic Committee and World Anti-Doping Agency Olympic laboratories.

The Summer Olympic Games constitute the biggest concentration of human sports and activities in a particular place and time since 776 BCE, when the written history of the Olympic Games in Olympia began. Summer and Winter Olympic anti-doping laboratories, accredited by the International Olympic Committee in the past and the World Anti-Doping Agency in the present times, acquire worldwide interest to apply all new analytical advancements in the fight against doping in sports, hoping that this major human event will not become dirty by association with this negative phenomenon. This article summarizes the new analytical progresses, technologies and knowledge used by the Olympic laboratories, which for the vast majority of them are, eventually, incorporated into routine anti-doping analysis.

Two Signatures For A New Blood-Based Test For Colorectal Cancer Screening

Background: Detection rates for adenoma and early colorectal cancer (CRC) are unsatisfactory due to low compliance towards invasive screening procedures such as colonoscopy. There is a large unmet screening need calling for an accurate, non-invasive and cost-effective test to screen for early neoplastic and pre-neoplastic lesions. Our goal is to identify effective biomarker combinations to develop a screening test aimed at detecting precancerous lesions and early CRC stages, based on a multigene assay performed on peripheral blood mononuclear cells (PBMC).Methods: A pilot study was conducted on 92 subjects. Colonoscopy revealed 21 CRC, 30 adenomas larger than 1 cm and 41 healthy controls. A panel of 103 biomarkers was selected by two approaches: a candidate gene approach based on literature review and whole transcriptome analysis of a subset of this cohort by Illumina TAG profiling. Blood samples were taken from each patient and PBMC purified. Total RNA was extracted and the 103 biomarkers were tested by multiplex RT-qPCR on the cohort. Different univariate and multivariate statistical methods were applied on the PCR data and 60 biomarkers, with significant p-value (< 0.01) for most of the methods, were selected.Results: The 60 biomarkers are involved in several different biological functions, such as cell adhesion, cell motility, cell signaling, cell proliferation, development and cancer. Two distinct molecular signatures derived from the biomarker combinations were established based on penalized logistic regression to separate patients without lesion from those with CRC or adenoma. These signatures were validated using bootstrapping method, leading to a separation of patients without lesion from those with CRC (Se 67%, Sp 93%, AUC 0.87) and from those with adenoma larger than 1cm (Se 63%, Sp 83%, AUC 0.77). In addition, the organ and disease specificity of these signatures was confirmed by means of patients with other cancer types and inflammatory bowel diseases.Conclusions: The two defined biomarker combinations effectively detect the presence of CRC and adenomas larger than 1 cm with high sensitivity and specificity. A prospective, multicentric, pivotal study is underway in order to validate these results in a larger cohort.

A new measurement of energy expenditure and physical activity in patients treated by maintenance hemodialysis

Purpose: The accurate estimation of total energy expenditure (TEE) is essential to allow the provision of nutritional requirements in patients treated by maintenance hemodialysis (MHD). The measurement of TEE and resting energy expenditure (REE) by direct or indirect calorimetry and doubly labeled water are complicated, timeconsuming and cumbersome in this population. Recently, a new system called SenseWear® armband (SWA) was developed to assess TEE, physical activity and REE. This device works by measurements of body acceleration in two axes, heat production and steps counts. REE measured by indirect calorimetry and SWA are well correlated. The aim of this study was to determine TEE, physical activity and REE on patients on MHD using this new device. Methods and materials: Daily TEE, REE, step count, activity time, intensity of activity and lying time were determined for 7 consecutive days in unselected stable patients on MHD and sex, age and weightmatched healthy controls (HC). Patients with malnutrition, cancer, use of immunosuppressive drugs, hypoalbumemia <35 g/L and those hospitalized in the last 3 months, were excluded. For MHD patients, separate analyses were conducted in dialysis and non-dialysis days. Relevant parameters known to affect REE, such as BMI, albumin, pre-albumin, hemoglobin, Kt/V, CRP, bicarbonate, PTH, TSH, were recorded. Results: Thirty patients on MHD and 30 HC were included. In MHD patients, there were 20 men and 10 women. Age was 60,13 years ± 14.97 (mean ± SD), BMI was 25.77 kg/m² ± 4.73 and body weight was 74.65 kg ± 16.16. There were no significant differences between the two groups. TEE was lower in MHD patients compared to HC (28.79 ± 5.51 SD versus 32.91 ± 5.75 SD kcal/kg/day; p <0.01). Activity time was significantly lower in patients on MHD (101.3 ± 12.6SD versus 50.7 ± 9.4 SD min; p = 0.0021). Energy expenditure during the time of activity was significantly lower in MHD patients. MHD patients walked 4543 ± 643 SD vs 8537 ± 744 SD steps per day (p <0.0001). Age was negatively correlated with TEE (r = -0.70) and intensity of activity (r = -0.61) in HC, but not in patients on MHD. TEE showed no difference between dialysis and non-dialysis days (29.92 ± 2.03 SD versus 28.44 ± 1.90 SD kcal/kg/day; p = NS), reflecting a lack of difference in activity (number of steps, time of physical activity) and REE. This finding was observed in MHD patients both older and younger than 60 years. However, age stratification appeared to have an influence on TEE, regardless of dialysis day, (29.92 ± 2.07 SD kcal/kg/day for <60 years-old versus 27.41 ± 1.04 SD kcal/kg/day for ≥60 years old), although failing to reach statistical significance. Conclusion: Using SWA, we have shown that stable patients on MHD have a lower TEE than matched HC. On average, a TEE of 28.79 kcal/kg/day, partially affected by age, was measured. This finding gives support to the clinical impression that it is difficult and probably unnecessary to provide an energy amount of 30-35 kcal/kg/day, as proposed by international guidelines for this population. In addition, we documented for the first time that MHD patients exert a reduced physical activity as compared to HC. There were surprisingly no differences in TEE, REE and physical activity parameters between dialysis and non-dialysis days. This observation might be due to the fact that patients on MHD produce a physical effort to reach the dialysis centre. Age per se did not influence physical activity in MHD patients, contrary to HC, reflecting the impact of co-morbidities on physical activity in this group of patients.

Design, conduct, and analyses of Breast International Group (BIG) 1-98: a randomized, double-blind, phase-III study comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with receptor-positive, early breast cancer.

BACKGROUND: Aromatase inhibitors provide superior disease control when compared with tamoxifen as adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer. PURPOSE: To present the design, history, and analytic challenges of the Breast International Group (BIG) 1-98 trial: an international, multicenter, randomized, double-blind, phase-III study comparing the aromatase inhibitor letrozole with tamoxifen in this clinical setting. METHODS: From 1998-2003, BIG 1-98 enrolled 8028 women to receive monotherapy with either tamoxifen or letrozole for 5 years, or sequential therapy of 2 years of one agent followed by 3 years of the other. Randomization to one of four treatment groups permitted two complementary analyses to be conducted several years apart. The first, reported in 2005, provided a head-to-head comparison of letrozole versus tamoxifen. Statistical power was increased by an enriched design, which included patients who were assigned sequential treatments until the time of the treatment switch. The second, reported in late 2008, used a conditional landmark approach to test the hypothesis that switching endocrine agents at approximately 2 years from randomization for patients who are disease-free is superior to continuing with the original agent. RESULTS: The 2005 analysis showed the superiority of letrozole compared with tamoxifen. The patients who were assigned tamoxifen alone were unblinded and offered the opportunity to switch to letrozole. Results from other trials increased the clinical relevance about whether or not to start treatment with letrozole or tamoxifen, and analysis plans were expanded to evaluate sequential versus single-agent strategies from randomization. LIMITATIONS: Due to the unblinding of patients assigned tamoxifen alone, analysis of updated data will require ascertainment of the influence of selective crossover from tamoxifen to letrozole. CONCLUSIONS: BIG 1-98 is an example of an enriched design, involving complementary analyses addressing different questions several years apart, and subject to evolving analytic plans influenced by new data that emerge over time.

Loss to follow-up in an international, multicentre observational study.

OBJECTIVE: The aim of this work was to assess loss to follow-up (LTFU) in EuroSIDA, an international multicentre observational cohort study. METHODS: LTFU was defined as no follow-up visit, CD4 cell count measurement or viral load measurement after 1 January 2006. Poisson regression was used to describe factors related to LTFU. RESULTS: The incidence of LTFU in 12 304 patients was 3.72 per 100 person-years of follow-up [95% confidence interval (CI) 3.58-3.86; 2712 LTFU] and varied among countries from 0.67 to 13.35. After adjustment, older patients, those with higher CD4 cell counts, and those who had started combination antiretroviral therapy all had lower incidences of LTFU, while injecting drug users had a higher incidence of LTFU. Compared with patients from Southern Europe and Argentina, patients from Eastern Europe had over a twofold increased incidence of LTFU after adjustment (incidence rate ratio 2.16; 95% CI 1.84-2.53; P<0.0001). A total of 2743 patients had a period of >1 year with no CD4 cell count or viral load measured during the year; 743 (27.1%) subsequently returned to follow-up. CONCLUSIONS: Some patients thought to be LTFU may have died, and efforts should be made to ascertain vital status wherever possible. A significant proportion of patients who have a year with no follow-up visit, CD4 cell count measurement or viral load measurement subsequently return to follow-up.

International perspectives on general internal medicine and the case for "globalization" of a discipline.

General internal medicine (GIM) has flourished in the United States (U.S.). Unlike other subspecialties of internal medicine, however, GIM's evolution has not been global in scope, but rather appears to have occurred in isolation within countries. Here, we describe international models of GIM from Canada, Switzerland, Australia/New Zealand, Argentina, and Japan, and compare these with the U.S. model. There are notable differences in the typical clinical roles assumed by General Internists across these 7 countries, but also important overlap in clinical and academic domains. Despite this overlap, there has been a relative lack of contact among General Internists from these and other countries at a truly international GIM meeting; the time is now for increased international exchange and the "globalization" of GIM.