MRI newsletter 8: Georeferenced biological databases - A tool for understanding mountain biodiversity

The Mountain Research Initiative invited Dr Eva Spehn, Director of the Global Mountain Biodiversity Assessment (GMBA), and Dr Antoine Guisan, head of the Spatial Ecology Group at the University of Lausanne, to introduce the reader to their coordinated efforts to advance understanding and prediction of mountain biodiversity. Antoine Guisan's EUROMONT project is one of the many scientific projects that may potentially provide data for the new GMBA initiative for a GIS mountain biodiversity database.

Oxidative folding of synthetic polypeptides S-protected as tert-butylthio derivatives.

A new method for oxidative folding of synthetic polypeptides assembled by stepwise solid phase synthesis is introduced. Folding is obtained in excellent yields by reacting S-tert-butylthiolated polypeptides with a 100-fold molar excess of cysteine at 37 degrees C in a slightly alkaline buffer containing chaotropic salts, and in the presence of air-oxygen. This novel protocol has been applied to the folding of S-tert-butylthiolated human thymus and activation-regulated chemokine (hu-TARC) derivatives as well as to larger segments of Plasmodium falciparum and Plasmodium berghei circumsporozoite proteins. Folded P. falciparum polypeptides have been used as substrates of endoproteinase Glu-C (Glu-C) and endoproteinase Asp-N (Asp-N) in an attempt to identify their disulfide connectivities. Particular practical advantages of the present method are (i) easy purification and storage of the S-protected peptide derivatives, (ii) elimination of the risk of cysteine alkylation during the acidolytic cleavage deprotection and resin cleavage steps, (iii) possibility to precisely evaluate the extent of folding and disulfide bond formation by mass spectrometry, and (iv) facile recovery of the final folded product.

Promises of apoptosis-inducing peptides in cancer therapeutics.

Until recently, most research efforts aimed at developing anti-cancer tools were focusing on small molecules. Alternative compounds are now being increasingly assessed for their potential anti-cancer properties, including peptides and their derivatives. One earlier limitation to the use of peptides was their limited capacity to cross membranes but this limitation was alleviated with the characterization of cell-permeable sequences. Additionally, means are designed to target peptides to their malignant targets. Most anti-cancer peptidic compounds induce apoptosis of tumor cells by modulating the activity of Bcl-2 family members that control the release of death factors from the mitochondria or by inhibiting negative regulators of caspases, the proteases that mediate the apoptotic response in cells. Some of these peptides have been shown to inhibit the growth of tumors in mouse models. Hopefully, pro-apoptotic anti-tumor peptides will soon be tested for their efficacy in patients with cancers.

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Objective: To assess the factorial validity of the Portuguese version of the Maslach Burnout Inventory - Human Services Survey (MBI-HSS). Methods: Between November 2010 and November 2011 a Portuguese version of the MBI-HSS was applied to 151 Portuguese family doctors (55% women, median age 54 years). The factorial structure of the MBI-HSS was examined by principal component analysis (PCA) and confirmatory factor analysis (CFA). Internal consistency estimates of the MBI-HSS were determined with Cronbach's alpha. Results: The fit of the hypothesized three-factor model to the data was superior to the alternative two-factor and four-factor models. CFA supported MBI-HSS as an acceptable measure to evaluate burnout and deletion of items 12 and 16 improved the goodness of fit of the model. In PCA, the three-factor model explained 50.58% of the variance and the four-factor model did not lead to understandable components. Item 12 was also found to be problematic in PCA. The Cronbach's alpha was satisfactory for emotional exhaustion (alpha=0.90), lack of personal accomplishment (alpha=0.73), and depersonalization (alpha=0.64). Conclusion: The Portuguese version of the MBI-HSS was found to be reliable to measure burnout among Portuguese medical doctors. We also recommend the deletion of items 12 and 16 from the MBI-HSS.

Mediastinal lymph node clearance after docetaxel-cisplatin neoadjuvant chemotherapy is prognostic of survival in patients with stage IIIA pN2 non-small-cell lung cancer: a multicenter phase II trial.

PURPOSE: A multicenter, phase II trial investigated the efficacy and toxicity of neoadjuvant docetaxel-cisplatin in locally advanced non-small-cell lung cancer (NSCLC) and examined prognostic factors for patients not benefiting from surgery. PATIENTS AND METHODS: Ninety patients with previously untreated, potentially operable stage IIIA (mediastinoscopically pN2) NSCLC received three cycles of docetaxel 85 mg/m2 day 1 plus cisplatin 40 mg/m2 days 1 and 2, with subsequent surgical resection. RESULTS: Administered dose-intensities were docetaxel 85 mg/m2/3 weeks (range, 53 to 96) and cisplatin 95 mg/m2/3 weeks (range, 0 to 104). The 265 cycles were well tolerated, and the overall response rate was 66% (95% confidence interval [CI], 55% to 75%). Seventy-five patients underwent tumor resection with positive resection margin and involvement of the uppermost mediastinal lymph node in 16% and 35% of patients, respectively (perioperative mortality, 3%; morbidity, 17%). Pathologic complete response occurred in 19% of patients with tumor resection. In patients with tumor resection, downstaging to N0-1 at surgery was prognostic and significantly prolonged event-free survival (EFS) and overall survival (OS; P =.0001). At median follow-up of 32 months, the median EFS and OS were 14.8 months (range, 2.4 to 53.4) and 33 months (range, 2.4 to 53.4), respectively. Local relapse occurred in 27% of patients with tumor resection, with distant metastases in 37%. Multivariate analyses identified mediastinal clearance (hazard ratio, 0.22; P =.0003) and complete resection (hazard ratio, 0.26; P =.0006) as strongly prognostic for increased survival. CONCLUSION: Neoadjuvant docetaxel-cisplatin is effective and tolerable in stage IIIA pN2 NSCLC. Resection is recommended only for patients with mediastinal downstaging after chemotherapy.

Gastric outlet obstruction by Brunner's gland hyperplasia in an 8-year-old child.

Several cases of Brunner's gland hyperplasia causing hemorrhage, obstruction, or intussusception have been published in the adult literature. Similar cases in the pediatric population are very rare and have only been described twice, always associated with chronic renal failure. We report the third and youngest case of gastric outlet obstruction because of Brunner's gland hyperplasia focusing on histopathologic condition and treatment based on a review of the literature.

Evaluation of C-reactive protein, procalcitonin, tumor necrosis factor alpha, interleukin-6, and interleukin-8 as diagnostic parameters in sepsis-related fatalities.

The aims of this study were to investigate the usefulness of serum C-reactive protein, procalcitonin, tumor necrosis factor alpha, interleukin-6, and interleukin-8 as postmortem markers of sepsis and to compare C-reactive protein and procalcitonin values in serum, vitreous humor, and cerebrospinal fluid in a series of sepsis cases and control subjects, in order to determine whether these measurements may be employed for the postmortem diagnosis of sepsis. Two study groups were formed, a sepsis group (eight subjects coming from the intensive care unit of two university hospitals, with a clinical diagnosis of sepsis in vivo) and control group (ten autopsy cases admitted to two university medicolegal centers, deceased from natural and unnatural causes, without elements to presume an underlying sepsis as the cause of death). Serum C-reactive protein and procalcitonin concentrations were significantly different between sepsis cases and control cases, whereas serum tumor necrosis factor alpha, interleukin-6, and interleukin-8 values were not significantly different between the two groups, suggesting that measurement of interleukin-6, interleukin-8, and tumor necrosis factor alpha is non-optimal for postmortem discrimination of cases with sepsis. In the sepsis group, vitreous procalcitonin was detectable in seven out of eight cases. In the control group, vitreous procalcitonin was clearly detectable only in one case, which also showed an increase of all markers in serum and for which the cause of death was myocardial infarction associated with multi-organic failure. According to the results of this study, the determination of vitreous procalcitonin may be an alternative to the serum procalcitonin for the postmortem diagnosis of sepsis.

Parameters for successful monthly extended dosing of darbepoetin-alpha in patients undergoing hemodialysis.

AIM: To document the feasibility and report the results of dosing darbepoetin-alpha at extended intervals up to once monthly (QM) in a large dialysis patient population. MATERIAL: 175 adult patients treated, at 23 Swiss hemodialysis centres, with stable doses of any erythropoiesis-stimulating agent who were switched by their physicians to darbepoetin-alpha treatment at prolonged dosing intervals (every 2 weeks [Q2W] or QM). METHOD: Multicentre, prospective, observational study. Patients' hemoglobin (Hb) levels and other data were recorded 1 month before conversion (baseline) to an extended darbepoetin-alpha dosing interval, at the time of conversion, and once monthly thereafter up to the evaluation point (maximum of 12 months or until loss to follow-up). RESULTS: Data for 161 evaluable patients from 23 sites were included in the final analysis. At 1 month prior to conversion, 73% of these patients were receiving darbepoetin-alpha weekly (QW) and 27% of the patients biweekly (Q2W). After a mean follow-up of 9.5 months, 34% received a monthly (QM) dosing regimen, 52% of the patients were receiving darbepoetin-alpha Q2W, and 14% QW. The mean (SD) Hb concentration at baseline was 12.3 +/- 1.2 g/dl, compared to 11.9 +/- 1.2 g/dl at the evaluation point. The corresponding mean weekly darbepoetin-alpha dose was 44.3 +/- 33.4 microg at baseline and 37.7 +/- 30.8 microg at the evaluation point. CONCLUSIONS: Conversion to extended darbepoetin-alpha dosing intervals of up to QM, with maintenance of initial Hb concentrations, was successful for the majority of stable dialysis patients.

"La vie et l'oeuvre"? : Recherches sur le biographique : Actes du colloque de relève organisé à l'Université de Lausanne les 8-9 novembre 2007

La réflexion sur la biographie a connu un renouvellement important ces vingt dernières années dans plusieurs disciplines. Florissant sur le marché ditorial, ce genre ancien trouve aujourd'hui des formes nouvelles, nourries de la galaxie des sciences humaines contemporaines, comme en témoigne l'ouvrage de François Dosse, Le Pari biographique (La Découverte, 2005). Genre fondateur en histoire de l'art, la biographie est pratiquée peu ou prou dans la plupart des disciplines des lettres. Bonne raison pour se pencher de manière interdisciplinaire sur le genre et sa pratique. La vogue des éloges académiques au XVIIIe siècle, et la profusion du discours biographique sur les artistes à l'orée du Romantisme ont ouvert la voie à la fameuse «méthode biographique» de Sainte-Beuve, et à sa reconversion dans les programmes d'enseignement, par le biais de Gustave Lanson et de ses émules. Inculqué à des générations d'élèves, devenu une structure invisible de l'entendement universitaire dans les disciplines littéraires, le couple « la vie et l'oeuvre » a été sévèrement reconsidéré, au XXe siècle, par les approches formalistes, structuralistes ou sociologiques. Qu'en est-il de ce genre actuellement? Comment les travaux de littéraires, d'historiens, d'historiens de l'art, de philosophes envisagent-ils les données biographiques?

Tenofovir use is associated with an increase in serum alkaline phosphatase in the Swiss HIV Cohort Study.

BACKGROUND: Tenofovir (TDF) use has been associated with proximal renal tubulopathy, reduced calculated glomerular filtration rates (cGFR) and losses in bone mineral density. Bone resorption could result in a compensatory osteoblast activation indicated by an increase in serum alkaline phosphatase (sAP). A few small studies have reported a positive correlation between renal phosphate losses, increased bone turnover and sAP. METHODS: We analysed sAP dynamics in patients initiating (n = 657), reinitiating (n = 361) and discontinuing (n = 73) combined antiretroviral therapy with and without TDF and assessed correlations with clinical and epidemiological parameters. RESULTS: TDF use was associated with a significant increase of sAP from a median of 74 U/I (interquartile range 60-98) to a plateau of 99 U/I (82-123) after 6 months (P < 0.0001), with a prompt return to baseline upon TDF discontinuation. No change occurred in TDF-sparing regimes. Univariable and multivariable linear regression analyses revealed a positive correlation between sAP and TDF use (P < or = 0.003), but no correlation with baseline cGFR, TDF-related cGFR reduction, changes in serum alanine aminotransferase (sALT) or active hepatitis C. CONCLUSIONS: We document a highly significant association between TDF use and increased sAP in a large observational cohort. The lack of correlation between TDF use and sALT suggests that the increase in sAP is because of the bone isoenzyme and indicates stimulated bone turnover. This finding, together with published data on TDF-related renal phosphate losses, this finding raises concerns that TDF use could result in osteomalacia with a loss in bone mineral density at least in a subset of patients. This potentially severe long-term toxicity should be addressed in future studies.