The apoptotic and proliferation rate of tumour budding cells in colorectal cancer outlines a heterogeneous population of cells with various impacts on clinical outcome

AIMS In colorectal cancer (CRC), tumour buds represent an aggressive cell type at the invasive front with apparently low proliferation. The aim of this study was to determine proliferation and apoptotic rates of buds in comparison to tumour centre, front and mucosa. METHODS AND RESULTS Whole tissue sections from 188 CRC patients underwent immunohistochemistry for Ki67. Ten high-power fields (HPFs) were evaluated in mucosa, tumour centre, tumour front and tumour buds (total = 40 HPFs/case). Caspase-3 and M30 immunohistochemistry were performed on a multipunch tissue microarray from the same cohort. Ki67, caspase-3 and M30 immunoreactivity were correlated with outcome. The average percentage of cells showing Ki67 positivity was 5.2% in mucosa, and was not significantly different between the centre and front of the tumour (38.2% and 34.9%; P < 0.0001); 0.3% of buds showed Ki67 positivity (P < 0.0001). Caspase-3 expression was similar in mucosa, tumour centre and tumour front, but lower in tumour buds (<0.1%; P < 0.0001). M30 staining in buds was decreased (0.01%; P < 0.0001) in comparison to other areas. Ki67 positivity in buds was detrimental to survival in univariate (P = 0.0352) and multivariate (P = 0.0355) analysis. Caspase-3-positive tumours showed better outcome than negative tumours (P = 0.0262); but tumours with caspase-3-positive buds showed a worse outcome than those with caspase-3-negative buds (P = 0.0235). CONCLUSIONS Ki67, caspase-3 and M30 staining is absent in most tumour buds, suggesting decreased proliferation and apoptosis. However, the fact that Ki67 and caspase-3 immunoreactivity was associated with unfavourable prognosis points to a heterogeneous population of tumour buds.

A new sulfonamide resistance gene (sul3) in Escherichia coli is widespread in the pig population of Switzerland

A new gene, sul3, which specifies a 263-amino-acid protein similar to a dihydropteroate synthase encoded by the 54-kb conjugative plasmid pVP440 from Escherichia coli was characterized. Expression of the cloned sul3 gene conferred resistance to sulfamethoxazole on E. coli. Two copies of the insertion element IS15Delta/26 flanked the region containing sul3. The sul3 gene was detected in one-third of the sulfonamide-resistant pathogenic E. coli isolates from pigs in Switzerland.

Scent-marking behaviour and social dynamics in a wild population of Eurasian lynx Lynx lynx.

Scent-marking is widespread among mammals and has been observed in many felid species. Although the behaviour is well-described, little is known about its function in wild felid populations. We investigated patterns of scent-marking and its role in intra- and intersexual communication among resident and non-resident Eurasian lynx Lynx lynx by observing interactions among wild lynx at natural marking sites by means of infrared camera traps. Marking activity of resident animals showed a peak during the mating season and was lowest during the time when females gave birth and lactated. Both sexes scent-marked, but male lynx visited marking sites much more often than females and marked relatively more often when visiting a site. Most visits to marking sites were by residents but we also observed scent-marking by non-residents. Juveniles were never observed marking. We found no evidence of lynx regularly renewing scent-marks after a certain 'expiry date' but the presence of a strange scent-mark triggered over-marking. Males responded similarly to the presence of another individual's scent-mark, irrespective of whether it was the top- or the underlying scent-mark in a mixture of scent-marks they encountered. Our results suggest that marking sites could serve as 'chemical bulletin boards', where male lynx advertise their presence and gain information on ownership relationships in a given area. Females placed their urine marks on top of the ones left by resident males, but further studies are needed to explain the functions of over-marking in females.

A regional climate palaeosimulation for Europe in the period 1500–1990 – Part 2: Shortcomings and strengths of models and reconstructions

This study compares gridded European seasonal series of surface air temperature (SAT) and precipitation (PRE) reconstructions with a regional climate simulation over the period 1500–1990. The area is analysed separately for nine subareas that represent the majority of the climate diversity in the European sector. In their spatial structure, an overall good agreement is found between the reconstructed and simulated climate features across Europe, supporting consistency in both products. Systematic biases between both data sets can be explained by a priori known deficiencies in the simulation. Simulations and reconstructions, however, largely differ in the temporal evolution of past climate for European subregions. In particular, the simulated anomalies during the Maunder and Dalton minima show stronger response to changes in the external forcings than recorded in the reconstructions. Although this disagreement is to some extent expected given the prominent role of internal variability in the evolution of regional temperature and precipitation, a certain degree of agreement is a priori expected in variables directly affected by external forcings. In this sense, the inability of the model to reproduce a warm period similar to that recorded for the winters during the first decades of the 18th century in the reconstructions is indicative of fundamental limitations in the simulation that preclude reproducing exceptionally anomalous conditions. Despite these limitations, the simulated climate is a physically consistent data set, which can be used as a benchmark to analyse the consistency and limitations of gridded reconstructions of different variables. A comparison of the leading modes of SAT and PRE variability indicates that reconstructions are too simplistic, especially for precipitation, which is associated with the linear statistical techniques used to generate the reconstructions. The analysis of the co-variability between sea level pressure (SLP) and SAT and PRE in the simulation yields a result which resembles the canonical co-variability recorded in the observations for the 20th century. However, the same analysis for reconstructions exhibits anomalously low correlations, which points towards a lack of dynamical consistency between independent reconstructions.

Dynamics of a Tularemia Outbreak in a Closely Monitored Free-Roaming Population of Wild House Mice.

Infectious disease outbreaks can be devastating because of their sudden occurrence, as well as the complexity of monitoring and controlling them. Outbreaks in wildlife are even more challenging to observe and describe, especially when small animals or secretive species are involved. Modeling such infectious disease events is relevant to investigating their dynamics and is critical for decision makers to accomplish outbreak management. Tularemia, caused by the bacterium Francisella tularensis, is a potentially lethal zoonosis. Of the few animal outbreaks that have been reported in the literature, only those affecting zoo animals have been closely monitored. Here, we report the first estimation of the basic reproduction number R0 of an outbreak in wildlife caused by F. tularensis using quantitative modeling based on a susceptible-infected-recovered framework. We applied that model to data collected during an extensive investigation of an outbreak of tularemia caused by F. tularensis subsp. holarctica (also designated as type B) in a closely monitored, free-roaming house mouse (Mus musculus domesticus) population in Switzerland. Based on our model and assumptions, the best estimated basic reproduction number R0 of the current outbreak is 1.33. Our results suggest that tularemia can cause severe outbreaks in small rodents. We also concluded that the outbreak self-exhausted in approximately three months without administrating antibiotics.

Code-switching: a touchstone of models of bilingual language production

The goal of the present thesis was to investigate the production of code-switched utterances in bilinguals’ speech production. This study investigates the availability of grammatical-category information during bilingual language processing. The specific aim is to examine the processes involved in the production of Persian-English bilingual compound verbs (BCVs). A bilingual compound verb is formed when the nominal constituent of a compound verb is replaced by an item from the other language. In the present cases of BCVs the nominal constituents are replaced by a verb from the other language. The main question addressed is how a lexical element corresponding to a verb node can be placed in a slot that corresponds to a noun lemma. This study also investigates how the production of BCVs might be captured within a model of BCVs and how such a model may be integrated within incremental network models of speech production. In the present study, both naturalistic and experimental data were used to investigate the processes involved in the production of BCVs. In the first part of the present study, I collected 2298 minutes of a popular Iranian TV program and found 962 code-switched utterances. In 83 (8%) of the switched cases, insertions occurred within the Persian compound verb structure, hence, resulting in BCVs. As to the second part of my work, a picture-word interference experiment was conducted. This study addressed whether in the case of the production of Persian-English BCVs, English verbs compete with the corresponding Persian compound verbs as a whole, or whether English verbs compete with the nominal constituents of Persian compound verbs only. Persian-English bilinguals named pictures depicting actions in 4 conditions in Persian (L1). In condition 1, participants named pictures of action using the whole Persian compound verb in the context of its English equivalent distractor verb. In condition 2, only the nominal constituent was produced in the presence of the light verb of the target Persian compound verb and in the context of a semantically closely related English distractor verb. In condition 3, the whole Persian compound verb was produced in the context of a semantically unrelated English distractor verb. In condition 4, only the nominal constituent was produced in the presence of the light verb of the target Persian compound verb and in the context of a semantically unrelated English distractor verb. The main effect of linguistic unit was significant by participants and items. Naming latencies were longer in the nominal linguistic unit compared to the compound verb (CV) linguistic unit. That is, participants were slower to produce the nominal constituent of compound verbs in the context of a semantically closely related English distractor verb compared to producing the whole compound verbs in the context of a semantically closely related English distractor verb. The three-way interaction between version of the experiment (CV and nominal versions), linguistic unit (nominal and CV linguistic units), and relation (semantically related and unrelated distractor words) was significant by participants. In both versions, naming latencies were longer in the semantically related nominal linguistic unit compared to the response latencies in the semantically related CV linguistic unit. In both versions, naming latencies were longer in the semantically related nominal linguistic unit compared to response latencies in the semantically unrelated nominal linguistic unit. Both the analysis of the naturalistic data and the results of the experiment revealed that in the case of the production of the nominal constituent of BCVs, a verb from the other language may compete with a noun from the base language, suggesting that grammatical category does not necessarily provide a constraint on lexical access during the production of the nominal constituent of BCVs. There was a minimal context in condition 2 (the nominal linguistic unit) in which the nominal constituent was produced in the presence of its corresponding light verb. The results suggest that generating words within a context may not guarantee that the effect of grammatical class becomes available. A model is proposed in order to characterize the processes involved in the production of BCVs. Implications for models of bilingual language production are discussed.

Population pharmacokinetics of sevoflurane in conjunction with the AnaConDa: toward target-controlled infusion of volatiles into the breathing system

BACKGROUND: The Anesthetic Conserving Device (AnaConDa) uncouples delivery of a volatile anesthetic (VA) from fresh gas flow (FGF) using a continuous infusion of liquid volatile into a modified heat-moisture exchanger capable of adsorbing VA during expiration and releasing adsorbed VA during inspiration. It combines the simplicity and responsiveness of high FGF with low agent expenditures. We performed in vitro characterization of the device before developing a population pharmacokinetic model for sevoflurane administration with the AnaConDa, and retrospectively testing its performance (internal validation). MATERIALS AND METHODS: Eighteen females and 20 males, aged 31-87, BMI 20-38, were included. The end-tidal concentrations were varied and recorded together with the VA infusion rates into the device, ventilation and demographic data. The concentration-time course of sevoflurane was described using linear differential equations, and the most suitable structural model and typical parameter values were identified. The individual pharmacokinetic parameters were obtained and tested for covariate relationships. Prediction errors were calculated. RESULTS: In vitro studies assessed the contribution of the device to the pharmacokinetic model. In vivo, the sevoflurane concentration-time courses on the patient side of the AnaConDa were adequately described with a two-compartment model. The population median absolute prediction error was 27% (interquartile range 13-45%). CONCLUSION: The predictive performance of the two-compartment model was similar to that of models accepted for TCI administration of intravenous anesthetics, supporting open-loop administration of sevoflurane with the AnaConDa. Further studies will focus on prospective testing and external validation of the model implemented in a target-controlled infusion device.

The stigma of mental illness in Southern Ghana: attitudes of the urban population and patients' views

PURPOSE: Stigma is a frequent accompaniment of mental illness leading to a number of detrimental consequences. Most research into the stigma connected to mental illness was conducted in the developed world. So far, few data exist on countries in sub-Saharan Africa and no data have been published on population attitudes towards mental illness in Ghana. Even less is known about the stigma actually perceived by the mentally ill persons themselves. METHOD: A convenience sample of 403 participants (210 men, mean age 32.4 ± 12.3 years) from urban regions in Accra, Cape Coast and Pantang filled in the Community Attitudes towards the Mentally Ill (CAMI) questionnaire. In addition, 105 patients (75 men, mean age 35.9 ± 11.0 years) of Ghana's three psychiatric hospitals (Accra Psychiatry Hospital, Ankaful Hospital, Pantang Hospital) answered the Perceived Stigma and Discrimination Scale. RESULTS: High levels of stigma prevailed in the population as shown by high proportions of assent to items expressing authoritarian and socially restrictive views, coexisting with agreement with more benevolent attitudes. A higher level of education was associated with more positive attitudes on all subscales (Authoritarianism, Social Restrictiveness, Benevolence and Acceptance of Community Based Mental Health Services). The patients reported a high degree of experienced stigma with secrecy concerning the illness as a widespread coping strategy. Perceived stigma was not associated with sex or age. DISCUSSION: The extent of stigmatising attitudes within the urban population of Southern Ghana is in line with the scant research in other countries in sub-Saharan Africa and mirrored by the experienced stigma reported by the patients. These results have to be seen in the context of the extreme scarcity of resources within the Ghanaian psychiatric system. Anti-stigma efforts should include interventions for mentally ill persons themselves and not exclusively focus on public attitudes.

Minimization of Intra-Operative Shaping of Orthopaedic Fixation Plates: A Population-Based Design

In this paper we present a new population-based method for the design of bone fixation plates. Standard pre-contoured plates are designed based on the mean shape of a certain population. We propose a computational process to design implants while reducing the amount of required intra-operative shaping, thus reducing the mechanical stresses applied to the plate. A bending and torsion model was used to measure and minimize the necessary intra-operative deformation. The method was applied and validated on a population of 200 femurs that was further augmented with a statistical shape model. The obtained results showed substantial reduction in the bending and torsion needed to shape the new design into any bone in the population when compared to the standard mean-based plates.

Irradiated disks and planet population synthesis

Recent planet population synthesis models (Alibert et al. 2010, submitted) have emphasized the key role played by the proto-planetary disk properties in determining the overall planet population characteristics. We present a disk model that takes into account viscous heating and irradiation by a central star. We consider the case of an equilibrium flaring angle. We illustrate the consequences of the resulting changes in the disk structure on the planet population by the synthetic populations corresponding to each of the different structures.

Spatio-Temporal Credit Assignment in Neuronal Population Learning

n learning from trial and error, animals need to relate behavioral decisions to environmental reinforcement even though it may be difficult to assign credit to a particular decision when outcomes are uncertain or subject to delays. When considering the biophysical basis of learning, the credit-assignment problem is compounded because the behavioral decisions themselves result from the spatio-temporal aggregation of many synaptic releases. We present a model of plasticity induction for reinforcement learning in a population of leaky integrate and fire neurons which is based on a cascade of synaptic memory traces. Each synaptic cascade correlates presynaptic input first with postsynaptic events, next with the behavioral decisions and finally with external reinforcement. For operant conditioning, learning succeeds even when reinforcement is delivered with a delay so large that temporal contiguity between decision and pertinent reward is lost due to intervening decisions which are themselves subject to delayed reinforcement. This shows that the model provides a viable mechanism for temporal credit assignment. Further, learning speeds up with increasing population size, so the plasticity cascade simultaneously addresses the spatial problem of assigning credit to synapses in different population neurons. Simulations on other tasks, such as sequential decision making, serve to contrast the performance of the proposed scheme to that of temporal difference-based learning. We argue that, due to their comparative robustness, synaptic plasticity cascades are attractive basic models of reinforcement learning in the brain.

The future of osteoporosis treatment - a research update

Osteoporosis is characterised by a progressive loss of bone mass and microarchitecture which leads to increased fracture risk. Some of the drugs available to date have shown reductions in vertebral and non-vertebral fracture risk. However, in the ageing population of industrialised countries, still more fractures happen today than are avoided, which highlights the large medical need for new treatment options, models, and strategies. Recent insights into bone biology, have led to a better understanding of bone cell functions and crosstalk between osteoblasts, osteoclasts, and osteocytes at the molecular level. In the future, the armamentarium against osteoporotic fractures will likely be enriched by (1.) new bone anabolic substances such as antibodies directed against the endogenous inhibitors of bone formation sclerostin and dickkopf-1, PTH and PTHrp analogues, and possibly calcilytics; (2.) new inhibitors of bone resorption such as cathepsin K inhibitors which may suppress osteoclast function without impairing osteoclast viability and thus maintain bone formation by preserving the osteoclast-osteoblast crosstalk, and denosumab, an already widely available antibody against RANKL which inhibits osteoclast formation, function, and survival; and (3.) new therapeutic strategies based on an extended understanding of the pathophysiology of osteoporosis which may include sequential therapies with two or more bone active substances aimed at optimising the management of bone capital acquired during adolescence and maintained during adulthood in terms of both quantity and quality. Finally, one of the future challenges will be to identify those patients and patient populations expected to benefit the most from a given drug therapy or regimen. The WHO fracture risk assessment tool FRAX® and improved access to bone mineral density measurements by DXA will play a key role in this regard.

Prevalence of vitamin B12 depletion and deficiency in Liechtenstein

OBJECTIVE: Data about vitamin B12 (B12) deficiency in the general population are scarce. The present study was performed to determine the prevalence of B12 deficiency in the general population of the Principality of Liechtenstein, as well as to identify sub-populations potentially at high risk. DESIGN: Retrospective study. SETTING: Ambulatory setting, population of the Principality of Liechtenstein. SUBJECTS: Seven thousand four hundred and twenty-four patients seeking medical attention whose serum samples were referred for routine work-up in an ambulatory setting were consecutively enrolled. Serum total B12 was determined in all patients in this cohort. In addition, for a subgroup of 1328 patients, serum holotranscobalamin was also measured. Prevalence of B12 deficiency was calculated. Further, multivariate logistical regression models were applied to identify covariates independently associated with B12 deficiency and depletion. RESULTS: Nearly 8 % of the general population was suffering from either B12 depletion or deficiency. The ratio between B12 depletion and deficiency was 2:1 for all age ranges. Pathological changes were detected predominantly in older people. Female gender was a significant predictor of B12 depletion. In the cohort, nearly 40 % exhibited either depletion or deficiency of B12. CONCLUSIONS: B12 depletion and deficiency are common in Liechtenstein, a Central European country. The measurement of biochemical markers represents a cost-efficient and valid assessment of the B12 state. When a deficiency of B12 is diagnosed at an early stage, many cases can be treated or prevented, with beneficial effects on individual outcomes and subsequent potential reductions in health-care costs.

Association between conventional risk factors and different ultrasound-based markers of atherosclerosis at carotid and femoral levels in a middle-aged population

Ultrasound detection of sub-clinical atherosclerosis (ATS) may help identify individuals at high cardiovascular risk. Most studies evaluated intima-media thickness (IMT) at carotid level. We compared the relationships between main cardiovascular risk factors (CVRF) and five indicators of ATS (IMT, mean and maximal plaque thickness, mean and maximal plaque area) at both carotid and femoral levels. Ultrasound was performed on 496 participants aged 45-64 years randomly selected from the general population of the Republic of Seychelles. 73.4 % participants had ≥ 1 plaque (IMT thickening ≥ 1.2 mm) at carotid level and 67.5 % at femoral level. Variance (adjusted R2) contributed by age, sex and CVRF (smoking, LDL-cholesterol, HDL-cholesterol, blood pressure, diabetes) in predicting any of the ATS markers was larger at femoral than carotid level. At both carotid and femoral levels, the association between CVRF and ATS was stronger based on plaque-based markers than IMT. Our findings show that the associations between CVRF and ATS markers were stronger at femoral than carotid level, and with plaque-based markers rather than IMT. Pending comparison of these markers using harder cardiovascular endpoints, our findings suggest that markers based on plaque morphology assessed at femoral artery level might be useful cardiovascular risk predictors.

Stable virulence levels in the HIV epidemic of Switzerland over two decades

OBJECTIVE: To determine whether the virulence of HIV-1 has been changing since its introduction into Switzerland. DESIGN: A prospective cohort study of HIV-1 infected individuals with well-characterized pre-therapy disease history. METHODS: To minimize the effect of recently imported viruses and ethnicity-associated host factors, the analysis was restricted to the white, north-west-European majority population of the cohort. Virulence was characterized by the decline slope of the CD4 cell count (n = 817 patients), the decline slope of the CD4:CD8 ratio (n = 815 patients) and the viral setpoint (n = 549 patients) in untreated patients with sufficient data points. Linear regression models were used to detect correlations between the date of diagnosis (ranging between 1984 and 2003) and the virulence markers, controlling for gender, exposure category, age and CD4 cell count at entry. RESULTS: We found no correlation between any of the virulence markers and the date of diagnosis. Inspection of short-term trends confirmed that virulence has fluctuated around a stable level over time. CONCLUSIONS: The lack of long-term time trends in the virulence markers indicates that HIV-1 is not evolving towards increasing or decreasing virulence at a perceptible rate. Both highly virulent and attenuated strains have apparently been unable to spread at the population level. This result suggests that either the evolution of virulence may be slow or inhibited due to evolutionary constraints, or HIV-1 may have already evolved to optimal virulence in the human host.