Modulation of chemokine gene expression by Shiga-toxin producing Escherichia coli belonging to various origins and serotypes

Infection with Shiga-toxin producing Escherichia coli (STEC) may result in the development of the haemolytic-uremic syndrome (HUS), the main cause of acute renal failure in children. While O157:H7 STEC are associated with large outbreaks of HUS, it is difficult to predict whether a non-O157:H7 isolate can be pathogenic for humans. The mucosal innate immune response plays a central role in the pathogenesis of HUS; therefore, we compared the induction of IL-8 and CCL20 in human colon epithelial cells infected with strains belonging to different serotypes, isolated from cattle or from HUS patients. No correlation was observed between strain virulence and chemokine gene expression. Rather, the genetic background of the strains seems to determine the chemokine gene expression profile. Investigating the contribution of different bacterial factors in this process, we show that the type III secretion system of O157:H7 bacteria, but not the intimate adhesion, is required to stimulate the cells. In addition, H7, H10, and H21 flagellins are potent inducers of chemokine gene expression when synthesized in large amount.

Interrelation of peri-operative morbidity and ASA class assignment in patients undergoing gynaecological surgery

OBJECTIVE: The aim of this study was to estimate intra- and post-operative risk using the American Society of Anaesthesiologists (ASA) classification which is an important predictor of an intervention and of the entire operating programme. STUDY DESIGN: In this retrospective study, 4435 consecutive patients undergoing elective and emergency surgery at the Gynaecological Clinic of the University Hospital of Zurich were included. The ASA classification for pre-operative risk assessment was determined by an anaesthesiologist after a thorough physical examination. We observed several pre-, intra- and post-operative parameters, such as age, body-mass-index, duration of anaesthesia, duration of surgery, blood loss, duration of post-operative stay, complicated post-operative course, morbidity and mortality. The investigation of different risk factors was achieved by a multiple linear regression model for log-transformed duration of hospitalisation. RESULTS: Age and obesity were responsible for a higher ASA classification. ASA grade correlates with the duration of anaesthesia and the duration of the surgery itself. There was a significant difference in blood loss between ASA grades I (113+/-195 ml) and III (222+/-470 ml) and between classes II (176+/-432 ml) and III. The duration of post-operative hospitalisation could also be correlated with ASA class. ASA class I=1.7+/-3.0 days, ASA class II=3.6+/-4.3 days, ASA class III=6.8+/-8.2 days, and ASA class IV=6.2+/-3.9 days. The mean post-operative in-hospital stay was 2.5+/-4.0 days without complications, and 8.7+/-6.7 days with post-operative complications. Multiple linear regression model showed that not only the ASA classification contained an important information for the duration of hospitalisation. Parameters such as age, class of diagnosis, post-operative complications, etc. also have an influence on the duration of hospitalisation. CONCLUSION: This study shows that the ASA classification can be used as a good and early available predictor for the planning of an intervention in gynaecological surgery. The ASA classification helps the surgeon to assess the peri-operative risk profile of which important information can be derived for the planning of the operation programme.

Renal allografts with IF/TA display distinct expression profiles of metzincins and related genes

Chronic renal allograft injury is often reflected by interstitial fibrosis (IF) and tubular atrophy (TA) without evidence of specific etiology. In most instances, IF/TA remains an irreversible disorder, representing a major cause of long-term allograft loss. As members of the protease family metzincins and functionally related genes are involved in fibrotic and sclerotic processes of the extracellular matrix (ECM), we hypothesized their deregulation in IF/TA. Gene expression and protein level analyses using allograft biopsies with and without Banff'05 classified IF/TA illustrated their deregulation. Expression profiles of these genes differentiated IF/TA from Banff'05 classified Normal biopsies in three independent microarray studies and demonstrated histological progression of IF/TA I to III. Significant upregulation of matrix metalloprotease-7 (MMP-7) and thrombospondin-2 (THBS-2) in IF/TA biopsies and sera was revealed in two independent patient sets. Furthermore, elevated THBS-2, osteopontin (SPP1) and beta-catenin may play regulatory roles on MMP. Our findings further suggest that deregulated ECM remodeling and possibly epithelial to mesenchymal transition (EMT) are implicated in IF/TA of kidney transplants, and that metzincins and related genes play an important role in these processes. Profiling of these genes may be used to complement IF/TA diagnosis and to disclose IF/TA progression in kidney transplant recipients.

Age modeling of young non-varved lake sediments: methods and limits. Examples from two lakes in Central Chile

High-resolution and highly precise age models for recent lake sediments (last 100–150 years) are essential for quantitative paleoclimate research. These are particularly important for sedimentological and geochemical proxies, where transfer functions cannot be established and calibration must be based upon the relation of sedimentary records to instrumental data. High-precision dating for the calibration period is most critical as it determines directly the quality of the calibration statistics. Here, as an example, we compare radionuclide age models obtained on two high-elevation glacial lakes in the Central Chilean Andes (Laguna Negra: 33°38′S/70°08′W, 2,680 m a.s.l. and Laguna El Ocho: 34°02′S/70°19′W, 3,250 m a.s.l.). We show the different numerical models that produce accurate age-depth chronologies based on 210Pb profiles, and we explain how to obtain reduced age-error bars at the bottom part of the profiles, i.e., typically around the end of the 19th century. In order to constrain the age models, we propose a method with five steps: (i) sampling at irregularly-spaced intervals for 226Ra, 210Pb and 137Cs depending on the stratigraphy and microfacies, (ii) a systematic comparison of numerical models for the calculation of 210Pb-based age models: constant flux constant sedimentation (CFCS), constant initial concentration (CIC), constant rate of supply (CRS) and sediment isotope tomography (SIT), (iii) numerical constraining of the CRS and SIT models with the 137Cs chronomarker of AD 1964 and, (iv) step-wise cross-validation with independent diagnostic environmental stratigraphic markers of known age (e.g., volcanic ash layer, historical flood and earthquakes). In both examples, we also use airborne pollutants such as spheroidal carbonaceous particles (reflecting the history of fossil fuel emissions), excess atmospheric Cu deposition (reflecting the production history of a large local Cu mine), and turbidites related to historical earthquakes. Our results show that the SIT model constrained with the 137Cs AD 1964 peak performs best over the entire chronological profile (last 100–150 years) and yields the smallest standard deviations for the sediment ages. Such precision is critical for the calibration statistics, and ultimately, for the quality of the quantitative paleoclimate reconstruction. The systematic comparison of CRS and SIT models also helps to validate the robustness of the chronologies in different sections of the profile. Although surprisingly poorly known and under-explored in paleolimnological research, the SIT model has a great potential in paleoclimatological reconstructions based on lake sediments

A real time simulation model of glucose-insulin metabolism for type 1 diabetes patients

In this paper, a simulation model of glucose-insulin metabolism for Type 1 diabetes patients is presented. The proposed system is based on the combination of Compartmental Models (CMs) and artificial Neural Networks (NNs). This model aims at the development of an accurate system, in order to assist Type 1 diabetes patients to handle their blood glucose profile and recognize dangerous metabolic states. Data from a Type 1 diabetes patient, stored in a database, have been used as input to the hybrid system. The data contain information about measured blood glucose levels, insulin intake, and description of food intake, along with the corresponding time. The data are passed to three separate CMs, which produce estimations about (i) the effect of Short Acting (SA) insulin intake on blood insulin concentration, (ii) the effect of Intermediate Acting (IA) insulin intake on blood insulin concentration, and (iii) the effect of carbohydrate intake on blood glucose absorption from the gut. The outputs of the three CMs are passed to a Recurrent NN (RNN) in order to predict subsequent blood glucose levels. The RNN is trained with the Real Time Recurrent Learning (RTRL) algorithm. The resulted blood glucose predictions are promising for the use of the proposed model for blood glucose level estimation for Type 1 diabetes patients.

The Bcl-2 Protein Family Member Bok Binds to the Coupling Domain of Inositol 1,4,5-Trisphosphate Receptors and Protects Them from Proteolytic Cleavage

Bok is a member of the Bcl-2 protein family that controls intrinsic apoptosis. Bok is most closely related to the pro-apoptotic proteins Bak and Bax, but in contrast to Bak and Bax, very little is known about its cellular role. Here we report that Bok binds strongly and constitutively to inositol 1,4,5-trisphosphate receptors (IP3Rs), proteins that form tetrameric calcium channels in the endoplasmic reticulum (ER) membrane and govern the release of ER calcium stores. Bok binds most strongly to IP3R1 and IP3R2, and barely to IP3R3, and essentially all cellular Bok is IP3R bound in cells that express substantial amounts of IP3Rs. Binding to IP3Rs appears to be mediated by the putative BH4 domain of Bok and the docking site localizes to a small region within the coupling domain of IP3Rs (amino acids 1895–1903 of IP3R1) that is adjacent to numerous regulatory sites, including sites for proteolysis. With regard to the possible role of Bok-IP3R binding, the following was observed: (i) Bok does not appear to control the ability of IP3Rs to release ER calcium stores, (ii) Bok regulates IP3R expression, (iii) persistent activation of inositol 1,4,5-trisphosphate-dependent cell signaling causes Bok degradation by the ubiquitin-proteasome pathway, in a manner that parallels IP3R degradation, and (iv) Bok protects IP3Rs from proteolysis, either by chymotrypsin in vitro or by caspase-3 in vivo during apoptosis. Overall, these data show that Bok binds strongly and constitutively to IP3Rs and that the most significant consequence of this binding appears to be protection of IP3Rs from proteolysis. Thus, Bok may govern IP3R cleavage and activity during apoptosis.

Osteocyte lacunar density and area in newly formed bone of the augmented sinus

OBJECTIVES Osteocytes, the most common cells of the bone, are buried in lacunae. Density and area of the osteocyte lacunae change with increasing maturation of the newly formed bone. Evaluation of osteocyte lacunae can therefore provide insights into the process of graft consolidation. MATERIALS AND METHODS Here, we determined the osteocyte lacunar density (number of osteocyte lacunae per bone area; N.Ot/BAr) and the osteocyte lacunar area in μm(2) (Lac.Ar) in histological specimens 6 and 12 weeks after the sinuses of 10 minipigs were augmented with Bio-Oss(®) , a deproteinized bovine bone mineral, and Ostim(®) , an aqueous paste of synthetic nanoparticular hydroxyapatite. The region of interest was defined by the following criteria: (i) >1 mm from the host bone, (ii) >0.5 mm from the sinus mucosa, (iii) minimum area of 0.2 mm(2) , and (iv) bone tissue spanning at least two bone substitute particles. RESULTS The overall osteocyte lacunar density was significantly higher in the Bio-Oss(®) group than in the Ostim(®) group and decreased during the observation period at a similar range in both groups. The osteocyte lacunar area was smaller in the Bio-Oss(®) group than the Ostim(®) group but there was no significant change within the groups over time. CONCLUSIONS These results suggest that bone substitutes affect the osteocyte lacunar density and the osteocyte lacunar area in the newly formed bone within the augmented sinus in this particular model situation. These measures can provide insights into the maturation of newly formed bone in the augmented sinus.

Exemestane Versus Anastrozole in Postmenopausal Women With Early Breast Cancer: NCIC CTG MA.27—A Randomized Controlled Phase III Trial

PURPOSE In patients with hormone-dependent postmenopausal breast cancer, standard adjuvant therapy involves 5 years of the nonsteroidal aromatase inhibitors anastrozole and letrozole. The steroidal inhibitor exemestane is partially non-cross-resistant with nonsteroidal aromatase inhibitors and is a mild androgen and could prove superior to anastrozole regarding efficacy and toxicity, specifically with less bone loss. PATIENTS AND METHODS We designed an open-label, randomized, phase III trial of 5 years of exemestane versus anastrozole with a two-sided test of superiority to detect a 2.4% improvement with exemestane in 5-year event-free survival (EFS). Secondary objectives included assessment of overall survival, distant disease-free survival, incidence of contralateral new primary breast cancer, and safety. RESULTS In the study, 7,576 women (median age, 64.1 years) were enrolled. At median follow-up of 4.1 years, 4-year EFS was 91% for exemestane and 91.2% for anastrozole (stratified hazard ratio, 1.02; 95% CI, 0.87 to 1.18; P = .85). Overall, distant disease-free survival and disease-specific survival were also similar. In all, 31.6% of patients discontinued treatment as a result of adverse effects, concomitant disease, or study refusal. Osteoporosis/osteopenia, hypertriglyceridemia, vaginal bleeding, and hypercholesterolemia were less frequent on exemestane, whereas mild liver function abnormalities and rare episodes of atrial fibrillation were less frequent on anastrozole. Vasomotor and musculoskeletal symptoms were similar between arms. CONCLUSION This first comparison of steroidal and nonsteroidal classes of aromatase inhibitors showed neither to be superior in terms of breast cancer outcomes as 5-year initial adjuvant therapy for postmenopausal breast cancer by two-way test. Less toxicity on bone is compatible with one hypothesis behind MA.27 but requires confirmation. Exemestane should be considered another option as up-front adjuvant therapy for postmenopausal hormone receptor-positive breast cancer.

Relative survival is an adequate estimate of cancer-specific survival: baseline mortality-adjusted 10-year survival of 771 rectal cancer patients.

BACKGROUND The objective of the present investigation is to assess the baseline mortality-adjusted 10-year survival of rectal cancer patients. METHODS Ten-year survival was analyzed in 771 consecutive American Joint Committee on Cancer (AJCC) stage I-IV rectal cancer patients undergoing open resection between 1991 and 2008 using risk-adjusted Cox proportional hazard regression models adjusting for population-based baseline mortality. RESULTS The median follow-up of patients alive was 8.8 years. The 10-year relative, overall, and cancer-specific survival were 66.5% [95% confidence interval (CI) 61.3-72.1], 48.7% (95% CI 44.9-52.8), and 66.4% (95% CI 62.5-70.5), respectively. In the entire patient sample (stage I-IV) 47.3% and in patients with stage I-III 33.6 % of all deaths were related to rectal cancer during the 10-year period. For patients with AJCC stage I rectal cancer, the 10-year overall survival was 96% and did not significantly differ from an average population after matching for gender, age, and calendar year (p = 0.151). For the more advanced tumor stages, however, survival was significantly impaired (p < 0.001). CONCLUSIONS Retrospective investigations of survival after rectal cancer resection should adjust for baseline mortality because a large fraction of deaths is not cancer related. Stage I rectal cancer patients, compared to patients with more advanced disease stages, have a relative survival close to 100% and can thus be considered cured. Using this relative-survival approach, the real public health burden caused by rectal cancer can reliably be analyzed and reported.

Microfabric memory of vein quartz for strain localization in detachment faults: A case study on the Simplon fault zone

This manuscript deals with the adaptation of quartz-microfabrics to changing physical deformation conditions, and discusses their preservation potential during subsequent retrograde deformation. Using microstructural analysis, a sequence of recrystallization processes in quartz, ranging from Grain-Boundary Migration Recrystallization (GBM) over Subgrain-Rotation Recrystallization (SGR) to Bulging Nucleation (BLG) is detected for the Simplon fault zone (SFZ) from the low strain rim towards the internal high strain part of the large-scale shear zone. Based on: (i) the retrograde cooling path; (ii) estimates of deformation temperatures; and (iii) spatial variation of dynamic recrystallization processes and different microstructural characteristics, continuous strain localization with decreasing temperature is inferred. In contrast to the recrystallization microstructures, crystallographic preferred orientations (CPO) have a longer memory. CPO patterns indicative of prism and rhomb glide systems in mylonitic quartz veins, overprinted at low temperatures (�400 �C), suggest inheritance of a high-temperature deformation. In this way, microstructural, textural and geochemical analyses provide information for several million years of the deformation history. The reasons for such incomplete resetting of the rock texture is that strain localization is caused by change in effective viscosity contrasts related to temporal large- and small-scale temperature changes during the evolution of such a long-lived shear zone. The spatially resolved, quantitative investigation of quartz microfabrics and associated recrystallization processes therefore provide great potential for an improved understanding of the geodynamics of large-scale shear zones.

Molecular Epidemiology Issues of BVDV Infection in the Eastern Ukraine

Aim. This study was focused on (i) detection of specific BVDV-antibodies within selected cattle farms, (ii) identification of persistently infected (PI) animals and (iii) genetic typing of selected BVDV isolates. Methods. RNA extraction, real-time polymerase chain reaction, ELISA technique, sequencing. Results. Specific BVDV-antibodies were detected in 713 of 1,059 analyzed samples (67.3 per cent). This number is in agreement with findings in many cattle herds around the world. However, the number of positive samples differed in the herds. While 57 samples out of 283 (20.1 per cent) were identified in the first herd, 400 out of 475 (84.2 per cent) and 256 out of 301 (85 per cent) animals were positive in the second and third herd. High number of animals with BVDV RNA was detected in all herds. The real-time PCR assay detected BVDV RNA in 5 of 1068 samples analyzed (0.5 per cent). 4 positive samples out of 490 (0.8 per cent) and 1 out of 301 (0.33 per cent) were found in the second and third herd. The genetic materials of BVDV were not found in the first herd. Data on the number of PI animals were in accord with serological findings in the cattle herds involved in our study. The genetic typing of viral isolates revealed that only BVDV, Type 1 viruses were present. The hylogenetic analysis confirmed two BVDV-1 subtypes, namely b and f and revealed that all 4 viruses from the second farm were typed as BVDV-1b and all of them were absolutely identical in 5’-UTR, but virus from the third farm was typed as BVDV-1f. Conclusion. Our results indicated that the BVDV infection is widespread in cattle herds in the eastern Ukraine, that requires further research and development of new approaches to improve the current situation.

Achieving a more realistic assessment of rockfall hazards by coupling three-dimensional process models and field-based tree-ring data

Sound knowledge of the spatial and temporal patterns of rockfalls is fundamental for the management of this very common hazard in mountain environments. Process-based, three-dimensional simulation models are nowadays capable of reproducing the spatial distribution of rockfall occurrences with reasonable accuracy through the simulation of numerous individual trajectories on highly-resolved digital terrain models. At the same time, however, simulation models typically fail to quantify the ‘real’ frequency of rockfalls (in terms of return intervals). The analysis of impact scars on trees, in contrast, yields real rockfall frequencies, but trees may not be present at the location of interest and rare trajectories may not necessarily be captured due to the limited age of forest stands. In this article, we demonstrate that the coupling of modeling with tree-ring techniques may overcome the limitations inherent to both approaches. Based on the analysis of 64 cells (40 m × 40 m) of a rockfall slope located above a 1631-m long road section in the Swiss Alps, we illustrate results from 488 rockfalls detected in 1260 trees. We illustrate that tree impact data cannot only be used (i) to reconstruct the real frequency of rockfalls for individual cells, but that they also serve (ii) the calibration of the rockfall model Rockyfor3D, as well as (iii) the transformation of simulated trajectories into real frequencies. Calibrated simulation results are in good agreement with real rockfall frequencies and exhibit significant differences in rockfall activity between the cells (zones) along the road section. Real frequencies, expressed as rock passages per meter road section, also enable quantification and direct comparison of the hazard potential between the zones. The contribution provides an approach for hazard zoning procedures that complements traditional methods with a quantification of rockfall frequencies in terms of return intervals through a systematic inclusion of impact records in trees.

Glacial–interglacial temperature change in the tropical West Pacific: A comparison of stalagmite-based paleo-thermometers

In the tropics, geochemical records from stalagmites have so far mainly been used to qualitatively reconstruct changes in precipitation, but several new methods to reconstruct past temperatures from stalagmite material have emerged recently: i) liquide vapor homogenization of fluid inclusion water ii) noble gas concentrations in fluid inclusion water, iii) the partitioning of oxygen isotopes between fluid inclusion water and calcite, and iv) the abundance of the 13C18O16O(‘clumped’) isotopologue in calcite. We present, for the first time, a direct comparison of these four paleo-thermometers by applying them to a fossil stalagmite covering nearly two glaciale interglacial cycles (Marine Isotope Stages (MIS) 12 e 9) and to two modern stalagmites, all from northern Borneo. The temperature estimates from the different methods agree in most cases within errors for both the old and recent samples; reconstructed formation temperatures of the recent samples match within 2-sigma errors with measured cave temperatures. However, slight but systematic deviations are observed between noble gas and liquide vapor homogenization temperatures. Whereas the temperature sensitivity of fluid inclusion d18O and clumped isotopes is currently debated, we find that the calibration of Tremaine et al. (2011) for fluid inclusion d18O and a synthetic calcite-based clumped isotope calibration (Ziegler et al., in prep.) yield temperature estimates consistent with the other methods. All methods (with the potential exception of clumped isotopes) show excellent agreement on the amplitude of glaciale interglacial temperature change, indicating temperature shifts of 4-5 C°. This amplitude is similar to the amplitude of Mg/Ca-based regional sea surface temperature records, when correcting for sea level driven changes in cave elevation. Our reconstruction of tropical temperature evolution over the time period from 440 to 320 thousand years ago (ka) adds support to the view that climate sensitivity to varying greenhouse forcing is substantial also in the deep tropics.

First thoughts on surface tonal patterns in Amawaka, a Panoan language of Peru and Brazil

Amawaka ([ɑmɨ̃ˈwɐkɑ]) is a highly endangered and underdocumented tonal language of the Headwaters (Fleck 2011) subgroup of the Panoan family in the Southwest Amazon Basin, spoken by approximately 200 people. Undocumented phonetic and phonological phenomena of Amawaka include its tonal structure, both in terms of surface realizations and the patterns underlying these realizations. Original audiovisual data from the author’s fieldwork in various Amawaka communities at the Peru-Brazil border will illuminate the as-yet obscure tonal systematicity of the language. Unlike other elements, monosyllabic bimoraic phonological nominal words with long vowels display variation in their surface realization. All the words with the open back unrounded /ɑ/, like /ˈkɑ̀:/ (patarashca, a traditional Amazonian dish), /ˈnɑ̀:/ “mestizo” etc. [with the exception of /ˈtɑ:/ “reed”, which surfaces with either a H or L tone] bear a low tone in isolation. This realization contrasts with all the encountered nominal monosyllables with vowels from the close and close-mid front and central spectrum /i, ɘ, ɨ, ɨ̃/, which clearly surface as high tone words in isolation, for example /ˈmɨ̃́:/ (a clay-lick for animals), /ˈwí:/ “Anopheles, spp. mosquito”. Monosyllables with close-mid back rounded /o/ have a less restrictive pitch that varies among speakers from low to high realizations, and sometimes even across the speech tokens from an individual speaker, e.g. /wó:/ or /wō:/ “hair”, /ɧō:/ or /ɧò:/ (a type of tarantula). Phrasal tonal phonology is more complex, when these three kinds of monosyllables appear in larger noun phrases. Some retain the same surface tones as their isolation form, while others seem to vary freely in their surface realization, e.g. /ˈtɘ́:.nɑ̀:/ or /ˈtɘ́:.nɑ́:/ ‘one mestizo’. Yet other monosyllables, e.g. /mɑ̀:/, exhibit a falling tone when preceded by a H syllable, suggesting probably latent tone sandhi phenomena, e.g /ˈtɘ́:.mɑ̂:/ (one clay-lick for parrots). In disyllabic, trisyllabic and quadrisyllabic nouns, tonal and stress patterns generally seem to be more consistent and tend to be retained both in isolation and in larger intonational phrases. Disyllabic nouns, for instance, surface as L-H or L-L when a glottal stop is in coda position. The association of L with a glottal stop is a feature that occurs in other Panoan languages as well, like Capanahua (Loos 1969), and more generally it is an areal feature, found in other parts of Amazonia (Hyman 2010). So, tone has significant interactions with the glottal stop and glottalization, which generally co-occurs with L. The data above suggest that the underlying tonal system of Amawaka is much more complex than the privative one-tone analysis (/H/ vs. Ø, i.e. lack of tone) that was proposed by Russell and Russell (1959). Evidence from field data suggests either an equipollent (Hyman 2010) two-tone opposition between /H/ and /L/, or a hybrid system, with both equipollent and privative features; that is, /H/ vs. /L/ vs. either Ø or /M/. This first systematic description of Amawaka tone, in conjunction with ongoing research, is poised to address broader questions concerning interrelationships between surface/underlying tone and other suprasegmental features, such as nasality, metrical stress, and intonation. References Fleck, David W. 2011. Panoan languages and linguistics. In Javier Ruedas and David W. Fleck (Eds.), Panoan Histories and Interethnic Identities, To appear. Hyman, Larry. 2010. Amazonia and the typology of tone systems. Presented at the conference Amazonicas III: The structure of the Amazonian languages. Bogotá. Loos, Eugene E. 1969. The phonology of Capanahua and its grammatical basis. Norman: SIL and U. Oklahoma. Russell, Robert & Dolores. 1959. Syntactotonemics in Amahuaca (Pano). Série Lingüistica Especial, 128-167. Publicaçoes do Museu Nacional, Rio de Janeiro, Brasil.