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We report the first observations of Opheodrys vernalis (Smooth Greensnake) communal oviposition of 137 eggs within an active nest mound of Lasius interjectus (Citronella Ant) in a northern Illinois prairie. This is the first North American documentation of snake oviposition, and communal oviposition, within an active ant nest. The communal Smooth Greensnake nest is also the largest reported to date. We observed other instances of Smooth Greensnakes nesting in proximity to Citronella Ant nests beneath artificial cover objects, which may indicate a facultative inquiline relationship. Other documented North American associations between snakes and ants have been with Formica mound-building ants in which snakes used mounds as refugia or hibernacula. The only other North American observation of a reptile nesting within an active ant mound was with Anolis carolinensis (Green Anole) and Odontomachus brunneus ants in Florida (Kwapich 2021). Other accounts of inquiline oviposition by snakes within active ant nests have been from Central America, South America, and Africa, predominantly within the fungal-farming chambers of leaf-cutter ant genera Acromyrmex, Anochetus, Apterostigma, Atta, Camponotus, Platythyrea, and Strumigenys. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) is a major cause of complications and death in many countries. The possible causal relation between T2D and cancer has been the aim of many research investigations. In view of the importance of the topic we carried out a narrative review of observational studies to summarize the available evidence of the association between T2D and cancer. To deal with the problem of abundance of published studies, we reviewed up to December 2017, the literature of meta-analyses of observational studies first, then we reviewed cohort studies not reported in meta-analyses because of more recent publication. We found that the association of T2D with risk of colorectal cancer was robust, whereas the evidence of the associations with other cancer sites was lower. Some of the observed associations could be overestimated, due to publication bias, unmeasured confounders (such as obesity) and surveillance bias. In conclusion a probable causal association of T2D with risk of colorectal cancer was confirmed. A possible causal association with pancreatic, endometrial, hepatocellular and gallbladder carcinoma was also found. Substantial uncertainty exists for other cancer sites. [ABSTRACT FROM AUTHOR]

Complex networks in different areas exhibit degree distributions with a heavy upper tail. A preferential attachment mechanism in a growth process produces a graph with this feature. We herein investigate a variant of the simple preferential attachment model, whose modifications are interesting for two main reasons: to analyze more realistic models and to study the robustness of the scale-free behavior of the degree distribution. We introduce and study a model which takes into account two different attachment rules: a preferential attachment mechanism (with probability 1 − p ) that stresses the rich get richer system, and a uniform choice (with probability p ) for the most recent nodes, i.e. the nodes belonging to a window of size w to the left of the last born node. The latter highlights a trend to select one of the last added nodes when no information is available. The recent nodes can be either a given fixed number or a proportion ( α n ) of the total number of existing nodes. In the first case, we prove that this model exhibits an asymptotically power-law degree distribution. The same result is then illustrated through simulations in the second case. When the window of recent nodes has a constant size, we herein prove that the presence of the uniform rule delays the starting time from which the asymptotic regime starts to hold. The mean number of nodes of degree k and the asymptotic degree distribution are also determined analytically. Finally, a sensitivity analysis on the parameters of the model is performed. [ABSTRACT FROM AUTHOR]

Background: An increased risk of cardiovascular diseases (CVD) has been associated with women's parity, but whether or not this association reflects a direct pregnancy effect, or exposure to factors related to childrearing, still appears unclear. We assessed the CVD risk associated with number of children separately by gender and tested effect modification by socioeconomic position (SEP) and employment status, in order to elucidate the possible mechanisms underlying this association. Methods: The study population was composed of 20,904 men and 25,246 women who were interviewed in one of two National Health Surveys conducted in 2000 and 2005 in Italy. These subjects were followed for CVD incidence up to 2014 through record-linkage with national archives of mortality and hospitalisations. CVD risk was estimated by Cox regression models that were adjusted for socio-demographics, perceived health, lifestyles, biological CVD risk factors and for other potential confounders. Results: CVD incidence was significantly increased among men with 3 or more children (HR = 1.26, 95% CI: 1.02–1.56) and among women with 2 and with 3 or more children (HR = 1.42, 95% CI: 1.10–1.83; and HR = 1.39, 95% CI: 1.03–1.87, respectively) compared to subjects without children and no significant gender differences were observed. Subjects with lower SEP displayed stronger associations with parity and a higher number of children for both genders; by contrast, no modifying effect of employment status was observed. Conclusions: Taken together, the significant association between higher parity and CVD risk in both genders, and the higher risk of CVD associated with higher parity among lower SEP parents, suggests that childrearing has a potential effect on the development of CVD that is more pronounced among disadvantaged families, although a concurrent effect of childbearing cannot be completely excluded. [ABSTRACT FROM AUTHOR]

To overcome some limits of classical neuronal models, we propose a Markovian generalization of the classical model based on Jacobi processes by introducing downwards jumps to describe the activity of a single neuron. The statistical analysis of interspike intervals is performed by studying the first passage times of the proposed Markovian Jacobi process with jumps through a constant boundary. In particular, we characterize its Laplace transform, which is expressed in terms of some generalization of hypergeometric functions that we introduce, and deduce a closed-form expression for its expectation. Our approach, which is original in the context of first-passage-time problems, relies on intertwining relations between the semigroups of the classical Jacobi process and its generalization, which have been recently established in [P. Cheridito et al., J. Ec. Polytech. - Math., 8 (2021), pp. 331--378]. A numerical investigation of the firing rate of the considered neuron is performed for some choices of the involved parameters and of the jump distributions. [ABSTRACT FROM AUTHOR]

Prokineticins (PK) 1 and 2 belong to a new family of chemokines capable to interact with two different G coupled receptors: Prokineticin receptor (PKR)1 and 2. Both prokineticins and their receptors are widely distributed in different tissues and regulate several biological functions. In particular, a role of the PK system in inflammation and nociception has been established. PKRs are expressed in regions of the nervous system associated with pain and in primary sensitive neurons they colocalize with transient potential receptor vanilloid-TRPV1 providing an anatomical interaction in nociceptor sensitization. Moreover, PKs are strongly upregulated in immune and glial cells and sustain a proinflammatory loop in inflamed tissues. Recent evidences indicate that the block of the PK system represents a promising strategy to contrast inflammation and pain. [ABSTRACT FROM AUTHOR]

Prokineticins (PK) 1 and 2 belong to a new family of chemokines capable to interact with two different G coupled receptors: Prokineticin receptor (PKR)1 and 2. Both prokineticins and their receptors are widely distributed in different tissues and regulate several biological functions. In particular, a role of the PK system in inflammation and nociception has been established. PKRs are expressed in regions of the nervous system associated with pain and in primary sensitive neurons they colocalize with transient potential receptor vanilloid-TRPV1 providing an anatomical interaction in nociceptor sensitization. Moreover, PKs are strongly upregulated in immune and glial cells and sustain a proinflammatory loop in inflamed tissues. Recent evidences indicate that the block of the PK system represents a promising strategy to contrast inflammation and pain. [ABSTRACT FROM AUTHOR]

Background: A consistent association has been reported between low socioeconomic status (SES) and cardiovascular events (CE), whereas the association between SES and cerebrovascular events (CBVD) is less clear. The aim of this study was to investigate the association between SES (measured using education) and CE/CBVD in a cohort study, as well as to investigate lifestyle and clinical risk factors, to help to clarify the mechanisms by which SES influences CE/CBVD. Material and Methods: We searched for diagnoses of CE and CBVD in the clinical records of 47,749 members of the EPICOR cohort (average follow-up time: 11 years). SES was determined by the relative index of inequality (RII). Results: A total of 1,156 CE and 468 CBVD were found in the clinical records. An increased risk of CE was observed in the crude Cox model for the third tertile of RII compared to the first tertile (hazard ratio [HR] = 1.39; 95% confidence interval [CI] 1.21–1.61). The increased risk persisted after adjustment for lifestyle risk factors (HR = 1.19; 95%CI 1.02–1.38), clinical risk factors (HR = 1.35; 95%CI 1.17–1.56), and after full adjustment (HR = 1.17; 95%CI 1.01–1.37). Structural equation model showed that lifestyle rather than clinical risk factors are involved in the mechanisms by which education influences CE. No significant association was found between education and CBVD. A strong relationship was observed between education and diabetes at baseline. Conclusion: The most important burden of inequality in CE incidence in Italy is due to lifestyle risk factors. [ABSTRACT FROM AUTHOR]

Statistical properties of spike trains as well as other neurophysiological data suggest a number of mathematical models of neurons. These models range from entirely descriptive ones to those deduced from the properties of the real neurons. One of them, the diffusion leaky integrate-and-fire neuronal model, which is based on the Ornstein-Uhlenbeck (OU) stochastic process that is restricted by an absorbing barrier, can describe a wide range of neuronal activity in terms of its parameters. These parameters are readily associated with known physiological mechanisms. The other model is descriptive, Gamma renewal process, and its parameters only reflect the observed experimental data or assumed theoretical properties. Both of these commonly used models are related here. We show under which conditions the Gamma model is an output from the diffusion OU model. In some cases, we can see that the Gamma distribution is unrealistic to be achieved for the employed parameters of the OU process. [ABSTRACT FROM AUTHOR]

Given a two-dimensional correlated diffusion process, we determine the joint density of the first passage times of the process to some constant boundaries. This quantity depends on the joint density of the first passage time of the first crossing component and of the position of the second crossing component before its crossing time. First we show that these densities are solutions of a system of Volterra–Fredholm first kind integral equations. Then we propose a numerical algorithm to solve it and we describe how to use the algorithm to approximate the joint density of the first passage times. The convergence of the method is theoretically proved for bivariate diffusion processes. We derive explicit expressions for these and other quantities of interest in the case of a bivariate Wiener process, correcting previous misprints appearing in the literature. Finally we illustrate the application of the method through a set of examples. [ABSTRACT FROM AUTHOR]

The continuous infusion of the opioid peptide β-endorphin prolongs skin allograft survival in mice, while the opiate receptor antagonist naloxone, administered together with the opioid at the time of transplantation, abolishes the effect of the opioid. Consistently, naloxone, when given alone at the time of transplantation, but not later, accelerates graft rejection and increases splenocyte IL-2 and interferon-gamma (IFN-γ) production. Splenocyte β-endorphin concentrations are lower in transplanted animals. The effects of exogenous β-endorphin and naloxone suggest that the endogenous opioid peptide β-endorphin exerts a tonic inhibitory effect over early events of T cell-mediated immune responses in vivo. The effects of β-endorphin and naloxone are consistent with the previously shown role of the opioid system in the modulation of the Th1/Th2 cytokine pattern. [ABSTRACT FROM AUTHOR]

Headstarting is a conservation technique for improving survival of species with high juvenile mortality by accelerating growth rate and increasing body size of captive-born young. With reptiles, headstarts are often kept active year-round to achieve body size goals and increase survival, omitting overwintering (brumation). As brumation is part of the life cycle of reptiles, there may be tradeoffs related to temperature response post-release when reptiles are kept active. Upon release into habitats, reptiles are either soft released, where acclimation is provided with in situ enclosures, or hard released without acclimation, directly into habitat. Soft releases have resulted in greater survival and site fidelity than hard releases, but evaluations with snakes are rare. We used a comparative approach to examine effects of brumation versus year-round activity on prerelease growth and survival of smooth green snake O pheodrys vernalis headstarts. We estimated short-term post-release daily survival rates of headstarts and compared movements of hard and soft released snakes. Despite decreases in body mass during brumation, prerelease body size, growth rate and survival did not differ among brumation treatments. Brumated headstarts exhibited rapid compensatory growth, attaining the size of active headstarts within 2 months of brumation. We observed qualitative evidence of reproductive potential in brumated snakes with the production of spermatozoa and unfertilized eggs, which was absent in active headstarts. The short-term survival rate of all headstarts during post-release tracking was 0.83 (±0.01), but we lacked power to examine differences in survival among release treatments. Daily movements did not differ among release treatments. Soft releases had slightly greater recaptures, facilitating monitoring. Although brumation comparisons produced equivalent prerelease growth and survival, as a precautionary measure for post-release survival, we recommend incorporating brumation into headstarting efforts. While further study with other reptiles is warranted, we recommend a comparative framework in planning headstarting efforts with additional species. [ABSTRACT FROM AUTHOR]

We consider the multivariate point process determined by the crossing times of the components of a multivariate jump process through a multivariate boundary, assuming to reset each component to an initial value after its boundary crossing. We prove that this point process converges weakly to the point process determined by the crossing times of the limit process. This holds for both diffusion and deterministic limit processes. The almost sure convergence of the first passage times under the almost sure convergence of the processes is also proved. The particular case of a multivariate Stein process converging to a multivariate Ornstein–Uhlenbeck process is discussed as a guideline for applying diffusion limits for jump processes. We apply our theoretical findings to neural network modeling. The proposed model gives a mathematical foundation to the generalization of the class of Leaky Integrate-and-Fire models for single neural dynamics to the case of a firing network of neurons. This will help future study of dependent spike trains. [ABSTRACT FROM AUTHOR]

Background:There is growing evidence of the protective role of dietary intake of flavonoids and lignans on cancer, but the association with bladder cancer has not been thoroughly investigated in epidemiological studies. We evaluated the association between dietary intakes of total and subclasses of flavonoids and lignans and risk of bladder cancer and its main morphological type, urothelial cell carcinoma (UCC), within the European Prospective Investigation into Cancer and Nutrition (EPIC) study.Methods:A cohort of 477 312 men and women mostly aged 35-70 years, were recruited in 10 European countries. At baseline, dietary flavonoid and lignan intakes were estimated using centre-specific validated questionnaires and a food composition database based on the Phenol-Explorer, the UK Food Standards Agency and the US Department of Agriculture databases.Results:During an average of 11 years of follow-up, 1575 new cases of primary bladder cancer were identified, of which 1425 were UCC (classified into aggressive (n=430) and non-aggressive (n=413) UCC). No association was found between total flavonoid intake and bladder cancer risk. Among flavonoid subclasses, significant inverse associations with bladder cancer risk were found for intakes of flavonol (hazard ratio comparing fifth with first quintile (HRQ5-Q1) 0.74, 95% confidence interval (CI): 0.61-0.91; P-trend=0.009) and lignans (HRQ5-Q1 0.78, 95% CI: 0.62-0.96; P-trend=0.046). Similar results were observed for overall UCC and aggressive UCC, but not for non-aggressive UCC.Conclusions:Our study suggests an inverse association between the dietary intakes of flavonols and lignans and risk of bladder cancer, particularly aggressive UCC. [ABSTRACT FROM AUTHOR]

We demonstrate novel direct effects of an invasive plant metabolite on embryo development in the native Western Chorus Frog ( Pseudacris triseriata) and a model organism, African Clawed Frog ( Xenopus laevis). European buckthorn ( Rhamnus cathartica) exhibits aggressive growth in amphibian breeding sites and releases the secondary metabolite, emodin, into soil and water. Emodin is known to have several deleterious, bioactive properties in mammals and birds, but its effects on amphibians have not been assessed. We used the FETAX (Frog Embryo Teratogenesis Assay- Xenopus) protocol to assess the effect of emodin on amphibian development in X. laevis, and modified the assay with P. triseriata to determine whether effects were consistent in a native species occurring within the range of the invasive R. cathartica. We detected and quantified emodin at amphibian breeding ponds that were infested heavily with buckthorn and have experienced recent declines in amphibian diversity and abundance. The X. laevis assay demonstrated significant embryo mortality and malformation in the presence of a gradient of concentrations of emodin including those detected in the environment. Teratogenicity indices (TI) >2 indicate the strong development-disrupting potential of emodin in amphibians. The P. triseriata assay produced similar patterns of embryo mortality and malformation as observed in the X. laevis assay. However, P. triseriata were more sensitive to emodin than X. laevis with TIs >40. Such effects may contribute to amphibian declines through depressed hatching success and poor larval survival and may represent an unrecognized impact of invasive plants more generally. [ABSTRACT FROM AUTHOR]

The article offers information of the Opheodrys vernalis known as Smooth Greensnake in Lake and DuPage counties, Illinois, U.S, observed multiple incidences of eggs being preyed upon by both adults and larvae of Necrophila Americana between June 2017 and July 2020.

A new, non-parametric and binless estimator for the mutual information of a d-dimensional random vector is proposed. First of all, an equation that links the mutual information to the entropy of a suitable random vector with uniformly distributed components is deduced. When d = 2 this equation reduces to the well known connection between mutual information and entropy of the copula function associated to the original random variables. Hence, the problem of estimating the mutual information of the original random vector is reduced to the estimation of the entropy of a random vector obtained through a multidimensional transformation. The estimator we propose is a two-step method: first estimate the transformation and obtain the transformed sample, then estimate its entropy. The properties of the new estimator are discussed through simulation examples and its performances are compared to those of the best estimators in the literature. The precision of the estimator converges to values of the same order of magnitude of the best estimator tested. However, the new estimator is unbiased even for larger dimensions and smaller sample sizes, while the other tested estimators show a bias in these cases. [ABSTRACT FROM AUTHOR]

Abstract: We consider a bivariate Gauss–Markov process and we study the first passage time of one component through a constant boundary. We prove that its probability density function is the unique solution of a new integral equation and we propose a numerical algorithm for its solution. Convergence properties of this algorithm are discussed and the method is applied to the study of the integrated Brownian motion and to the integrated Ornstein–Uhlenbeck process. Finally a model of neuroscience interest is discussed. [Copyright &y& Elsevier]

Products of different origin, time of collection, and activities fall under the general term of colostrum and, therefore, great variability in composition as well as in the concentration of its components has been reported in the literature. In the present study, we describe the standardization of a bovine colostrum derivative and the characterization of its bioactive components. Evaluation of the most representative agents (lactoferrin, transferrin, IL-2, IFN-γ, tumor necrosis factor, IgG, and IgA) showed that a marked decrease in active components occurs after the first few hours. Bovine colostrum was, therefore, collected up to the fifth hour after delivery from Holstein cows, in the presence of preservatives, and immediately frozen. A protocol of centrifugation, filtration, and lyophilization was then applied to pools of colostrum from at least 30 cows to obtain a stable, sterile, standardized product. Preservatives were removed by dialysis. Evaluation of the active biological components of colostrum showed that the final product of colostrums contained significant and reproducible amounts of bioactive factors, including cytokines, immunomodulating factors, growth factors, and immunoglobulins. The final product appeared, therefore, as a sterile, pyrogen-free, standardized derivative of bovine colostrum with a high concentration of bioactive components. [ABSTRACT FROM AUTHOR]

Background: It has been documented that variations exist in breast cancer treatment despite wide dissemination of clinical practice guidelines. The aim of this population-based study was to evaluate the impact of regional guidelines (Piedmont guidelines, PGL) for breast cancer diagnosis and treatment on quality-of-care indicators in the Northwestern Italian region of Piedmont. Methods: We included two samples of women aged 50-69 years with incident breast cancer treated in Piedmont before and after the introduction of PGL: 600 in 2002 (pre-PGL) and 621 in 2004 (post-PGL). Patients were randomly selected among all incident breast cancer cases identified through the hospital discharge records database. We extracted clinical data on breast cancer cases from medical charts and ascertained vital status through linkage with town offices. We assessed compliance with 14 quality-of-care indicators from PGL recommendations, before and after their introduction in clinical practice. Results: Among patients with invasive lesions, 77.1% (N = 368) and 77.5% (N = 383) in the pre-PGL and post-PGL groups, respectively, received breast conservative surgery (BCS) as a first-line treatment. Following BCS, 87.7% received radiotherapy in 2002, compared to 87.9% in 2004. Of all patients at medium-to-high risk of distant metastasis, 65.5% (N = 268) and 63.6% (N = 252) received chemotherapy in 2002 and in 2004, respectively. Among the 117 patients with invasive lesions and negative estrogen receptor status in 2002, hormonal therapy was prescribed in 23 of them (19.6%). The incorrect prescription of hormonal therapy decreased to 10.8% (N = 10) among the 92 estrogen receptor-negative patients in 2004 (p < 0.01). Compliance with PGL recommendations was already high in the pre-PGL group, although some quality-of-care indicators did not reach the standard. In the pre/post analysis, 8 out of 14 quality-of-care indicators showed an improvement from 2002 to 2004, but only 4 out of 14 reached statistical significance. We did not find any change in the risk of mortality in the post-PGL versus the pre-PGL group (adjusted hazard ratio 0.94, 95%CI 0.56-1.56). Conclusions: These results highlight the need to continue to improve breast cancer care and to measure adherence to PGL. [ABSTRACT FROM AUTHOR]

Surgical reconstruction of the anterior cruciate ligament (ACL) does not necessarily decrease the risk of developing osteoarthritis (OA). The inflammatory response and relative changes in pro- and anti-inflammatory cytokines could participate in triggering the development of OA. To test this hypothesis we measured the concentrations of IL-1β, IL-1ra, IL-6, IL-8, IL-10, and TNF-α at different times after ACL rupture. The sample population consisted of 48 patients with ACL tear which were assigned to different groups according to the time elapsed from the injury: 22 acute (A), 7 early sub-acute (ESA), 11 late sub-acute (LSA), and 8 chronic (C). In group A, there were high levels of IL-1β, IL-6, and IL-8, whereas levels of IL-1ra and TNF-α were significantly lower than usually reported. IL-1β and IL-8 concentrations returned with time to normal levels in the ESA group. Interestingly, IL-1ra levels remained always significantly lower than normally reported levels, and TNF-α levels did not increase after trauma. Our data show increased level of pro-inflammatory cytokines (IL-6 and IL-8) in the acute phase of inflammation which could be responsible for triggering cartilage catabolism and suggest that prompt neutralization of IL-6 and IL-8 accumulations in synovial fluid could help prevent development of OA in ACL-injured knees. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 315-321, 2013 [ABSTRACT FROM AUTHOR]

One-dimensional leaky integrate and fire neuronal models describe interspike intervals (ISIs) of a neuron as a renewal process and disregarding the neuron geometry. Many multi-compartment models account for the geometrical features of the neuron but are too complex for their mathematical tractability. Leaky integrate and fire two-compartment models seem a good compromise between mathematical tractability and an improved realism. They indeed allow to relax the renewal hypothesis, typical of one-dimensional models, without introducing too strong mathematical difficulties. Here, we pursue the analysis of the two-compartment model studied by Lansky and Rodriguez (Phys D 132:267–286, 1999), aiming of introducing some specific mathematical results used together with simulation techniques. With the aid of these methods, we investigate dependency properties of ISIs for different values of the model parameters. We show that an increase of the input increases the strength of the dependence between successive ISIs. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases worldwide. In high-income countries, low socioeconomic status seems to be related to a high incidence of T2DM, but very little is known about the intermediate factors of this relationship. Method We performed a case-cohort study in eight Western European countries nested in the EPIC study (n = 340, 234, 3.99 million person-years of follow-up). A random sub-cohort of 16,835 individuals and a total of 12,403 incident cases of T2DM were identified. Crude and multivariate-adjusted hazard ratios (HR) were estimated for each country and pooled across countries using meta-analytical methods. Age-, gender- and country-specific relative indices of inequality (RII) were used as the measure of educational level and RII tertiles were analysed.Results: Compared with participants with a high educational level (RII tertile 1), participants with a low educational level (RII tertile 3) had a higher risk of T2DM [HR: 1.77, 95% confidence interval (CI): 1.69-1.85; P-trend < 0.01]. The HRs adjusted for physical activity, smoking status and propensity score according to macronutrient intake were very similar to the crude HR (adjusted HR: 1.67, 95% CI: 1.52-1.83 in men; HR: 1.88, 95% CI: 1.73-2.05 in women). The HRs were attenuated only when they were further adjusted for BMI (BMI-adjusted HR: 1.36, 95% CI: 1.23-1.51 in men; HR: 1.32, 95% CI: 1.20-1.45 in women).Conclusion: This study demonstrates the inequalities in the risk of T2DM in Western European countries, with an inverse relationship between educational level and risk of T2DM that is only partially explained by variations in BMI. [ABSTRACT FROM AUTHOR]

Background Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases worldwide. In high-income countries, low socioeconomic status seems to be related to a high incidence of T2DM, but very little is known about the intermediate factors of this relationship.Method We performed a case-cohort study in eight Western European countries nested in the EPIC study (n = 340 234, 3.99 million person-years of follow-up). A random sub-cohort of 16 835 individuals and a total of 12 403 incident cases of T2DM were identified. Crude and multivariate-adjusted hazard ratios (HR) were estimated for each country and pooled across countries using meta-analytical methods. Age-, gender- and country-specific relative indices of inequality (RII) were used as the measure of educational level and RII tertiles were analysed.Results Compared with participants with a high educational level (RII tertile 1), participants with a low educational level (RII tertile 3) had a higher risk of T2DM [HR: 1.77, 95% confidence interval (CI): 1.69–1.85; P-trend < 0.01]. The HRs adjusted for physical activity, smoking status and propensity score according to macronutrient intake were very similar to the crude HR (adjusted HR: 1.67, 95% CI: 1.52–1.83 in men; HR: 1.88, 95% CI: 1.73–2.05 in women). The HRs were attenuated only when they were further adjusted for BMI (BMI-adjusted HR: 1.36, 95% CI: 1.23–1.51 in men; HR: 1.32, 95% CI: 1.20–1.45 in women).Conclusion This study demonstrates the inequalities in the risk of T2DM in Western European countries, with an inverse relationship between educational level and risk of T2DM that is only partially explained by variations in BMI. [ABSTRACT FROM PUBLISHER]

BACKGROUND AND PURPOSE The amphibian peptide Bv8 induces potent nociceptive sensitization in rodents. Its mammalian homologue, prokineticin 2 (PROK2), is strongly up-regulated in inflamed tissues and is a major determinant in triggering inflammatory pain. Bv8 and PROK2 activate two closely related GPCRs, PK1 and PK2, in a relatively non-selective fashion. To characterize better the roles of the two receptors in hyperalgesia and to obtain ligands whose binding affinity and efficacy differed for the two receptors, we modified the Bv8 molecule in regions essential for receptor recognition and activation. EXPERIMENTAL APPROACH We modified the Bv8 molecule by substituting Trp in position 24 with Ala (A-24) and compared it with Bv8 for binding and activating PK1 and PK2 receptors in cell preparations and in affecting nociceptive thresholds in rodents. KEY RESULTS A-24 preferentially bound to PK2 receptors and activated them with a lower potency (5-fold) than Bv8. When systemically injected, A-24 induced Bv8-like hyperalgesia in rats and in mice, at doses 100 times higher than Bv8. Locally and systemically injected at inactive doses, A-24 antagonized Bv8-induced hyperalgesia. In rat and mouse models of inflammatory and post-surgical pain, A-24 showed potent and long-lasting anti-hyperalgesic activity. Unlike Bv8, A-24 increased β-endorphin levels in mouse brain. CONCLUSIONS AND IMPLICATIONS A-24 induced its anti-hyperalgesic effect in rodents by directly blocking nociceptor PK1 receptors and by activating the central opioid system and the descending pain control pathway through brain PK2 receptors. [ABSTRACT FROM AUTHOR]

Abstract: The dynamics of a neuron are influenced by the connections with the network where it lies. Recorded spike trains exhibit patterns due to the interactions between neurons. However, the structure of the network is not known. A challenging task is to investigate it from the analysis of simultaneously recorded spike trains. We develop a non-parametric method based on copulas, that we apply to simulated data according to different bivariate Leaky Integrate and Fire models. The method discerns dependencies determined by the surrounding network, from those determined by direct interactions between the two neurons. Furthermore, the method recognizes the presence of delays in the spike propagation. This article is part of a Special Issue entitled “Neural Coding”. [Copyright &y& Elsevier]

Adrenal hemorrhage is rarely suspected clinically, exhibits no specific clinical symptoms or laboratory findings, and yet is immediately life-threatening when bilateral. Recognition of adrenal hematomas is complicated by the variable appearance of these lesions. We survey the ways in which adrenal hematomas can appear on CT and provide strategies for differentiating hematomas from other adrenal pathologies. [ABSTRACT FROM AUTHOR]

Current evidence supports the central role of neuropeptides in the molecular mechanisms underlying dental pain. In particular, substance P, a neuropeptide produced in neuron cell bodies localised in dorsal root and trigeminal ganglia, contributes to the transmission and maintenance of noxious stimuli and inflammatory processes. Themajor role of substance P in the onset of dental pain and inflammation is increasingly being recognised. Well-grounded experimental and clinical observations have documented an increase in substance P concentration in patients affected by caries, pulpitis, or granulomas and in those undergoing standard orthodontic or orthodontic/dental care procedures. This paper focuses on the role of substance P in the induction and maintenance of inflammation and dental pain, in order to define future lines of research for the evaluation of therapeutic strategies aimed at modulating the complex effects of this mediator in oral tissues. [ABSTRACT FROM AUTHOR]

Background: The present study focuses on the analysis of social, clinical and hospital characteristics that can lead to disparities in the management and outcome of care. To that end, indicators of the quality of initial treatment delivered to newly-diagnosed colorectal cancer patients in a North-Western Region of Italy, were investigated using administrative data. Methods: The cohort includes all incident colorectal cancer patients (N = 24,187) selected by a validated algorithm from the Piedmont Hospital Discharge Record system over an 8-year period (2000-2007). Three indicators of quality of care in this population-based cohort were evaluated: the proportion of preoperative radiotherapy (RT) and of abdominoperineal (AP) resection in rectal cancer patients, and the proportion of postoperative in-hospital mortality in colorectal cancer patients. Results: Among rectal cancers, older patients were less likely to have preoperative RT, and more likely to receive an AP resection compared to younger patients. The probability of undergoing preoperative RT and AP resection was reduced in females compared to males (odds ratio (OR) 0.77, 95% confidence interval (CI) 0.64-0.93 and OR 0.78, 95%CI 0.69-0.89, respectively). However, there was a trend of increasing RT over time (p for trend <0.01). The probability of undergoing AP resection was increased in less-educated patients and in hospitals with a low caseload. A higher risk of postoperative in-hospital mortality was found among colorectal cancer patients who were older, male, (female versus male OR 0.71, 95%CI 0.60-0.84), unmarried (OR 1.32, 95%CI 1.09-1.59) or with unknown marital status. Conclusions: The study provides evidence of the importance of social, clinical and hospital characteristics on the equity and quality of care in a Southern European country with an open-access public health care system. [ABSTRACT FROM AUTHOR]

Abstract: Aim: To provide evidence based recommendations for optimal care diabetes care in the elderly. Background: Diabetes affects approximately 25% of the population ≥65 years, and that percentage is increasing rapidly, particularly in minorities who represent an important fraction of the uninsured/underinsured. Diabetes is an important cause of hospital admissions and a co-morbidity in as high as 50% of hospital inpatients. It impacts mortality and quality of life. While tools have become available to improve glycemic control, enthusiasm for their application must be tempered with the sober realization of the risks involved in intensification of glycemic control, chiefly hypoglycemia. Methods: Weighted review from PubMed and other literature search tools in descending order of randomized control trials, observational studies, pilot studies, published guidelines, the authors’ clinical experience, and expert opinion. Results/conclusions: [•] HbA1c targets should be stratified according to the frailty of the elderly diabetic patient: <7.0% in the generally well elderly and < 8.0% in the frail elderly. [•] Therapies are available that achieve glycemic goals, while minimizing the risk of hypoglycemia, taking into consideration such factors as cognitive function, renal and hepatic function, bone density, fall risk, and hypoglycemia unawareness. [•] When insulin is used determir or glargine are safer choices than NPH. [•] Ultra-short acting prandial insulins are safer than regular insulin. [•] Pen devices for insulin delivery significantly reduce dosing errors and the risk of hypoglycemia. [•] Sudden managed care formulary changes that disrupt patients’ diabetes treatment should be prevented through national policy initiatives. [•] Up to date home medication lists help prevent dangerous medication errors. [•] Widespread adoption of telehealth approaches can significantly improve glycemic control and render it safer. [Copyright &y& Elsevier]

Neural membrane potential data are necessarily conditional on observation being prior to a firing time. In a stochastic leaky integrate-and-fire model, this corresponds to conditioning the process on not crossing a boundary. In the literature, simulation and estimation have almost always been done using unconditioned processes. In this letter, we determine the stochastic differential equations of a diffusion process conditioned to stay below a level S up to a fixed time t1 and of a diffusion process conditioned to cross the boundary for the first time at t1.This allows simulation of sample paths and identification of the corresponding mean process. Differences between the mean of free and conditioned processes are illustrated, as well as the role of noise in increasing these differences. [ABSTRACT FROM AUTHOR]

Abstract: Neuropathic pain refers to pain that originates from pathology of the nervous system. Diabetes, infection (herpes zoster), nerve compression, nerve trauma, and autoimmune diseases are examples of diseases that may cause neuropathic pain. Unfortunately no satisfactory treatment is yet available for this type of pain. This consideration has led to an explosion of interest for the underlying mechanisms, accompanied by a growing number of animal models. In recent years, most of the neuropathic pain models initially developed in the rat have been translated to mice in order to exploit the resource represented by genetically modified mice. Obviously the most useful animal models of pain would be ones in which the etiology of the pain would be endogenous and not induced by the experimenters: together with the classic models based on peripheral nerve ligation, in the last years other techniques are being developed that mimic more closely clinical pain syndromes, often by attempting to induce the disease associated to neuropathic pain. Although several variables must be taken into account when using animal models for mimicking clinical neuropathic pain, the huge number of models that are now reproducible and well characterized should help to reach important goals in the comprehension of mechanisms and to discover novel therapeutic target for this disease. [ABSTRACT FROM AUTHOR]

Abstract: Simultaneous recordings from groups of neurons request to improve models. To switch from single unit description to multivariate models describing the coding activity of two or more neurons, we propose to use the copula notion. This mathematical object catches the coupling properties and allows a mathematical description of the dependencies between two or more random variables. Its use is here illustrated by means of toy examples and further applications are discussed. [Copyright &y& Elsevier]

The Bayesian approach to significance testing, that makes use of prior information, has been studied in the last years, particularly to allow the detection of deformations which are small with respect to measurement errors from repeated surveys. Some investigations showed up to now that, under particular conditions concerning both the parameters of the prior distribution and the structure of the control network, Bayesian tests give stronger results than tests based on the frequentist approach, with regard to the detectability of deformations. In the present paper, after illustrating the essential developments and the most relevant results of previous works, new analytical developments and numerical simulations are carried out, to illustrate some critical aspects and advantages of the frequentist and Bayesian methods. It is shown, starting from simple examples involving only Gaussian and truncated Gaussian distributions and from a simplified formulation of the prior deformationmodel, that the testing procedures based on the frequentist approach, which do not introduce any a priori information, are in many cases of practical interest insensitive to internal consistencies of the displacements (e.g., to the fact that they have a common direction). It is also illustrated that the introduction of prior information, even in a non Bayesian context, more easily allows the detection of little displacements. Besides it is noted that in some cases Bayesian tests detect displacements in the presence of observed non-coherent movements, even if prior probability densities describing coherent movements are introduced. [ABSTRACT FROM AUTHOR]

Abstract: The proinflammatory cytokine tumor necrosis factor-α (TNF) is an important mediator in neuropathic pain. We investigated the temporal pattern of TNF mRNA expression in the sciatic nerve, in dorsal root ganglia (DRG) and spinal cord in the mouse chronic constriction injury model of neuropathy with quantitative real-time polymerase chain reaction. Neuropathic pain-like behaviour was monitored by evaluating thermal hyperalgesia and mechanical allodynia. Pain-related behaviour and TNF expression were evaluated 6h, 1, 3, 7 and 14 days after injury. Naive animals and sham-operated mice were used as controls. We found an early upregulation of sciatic nerve TNF mRNA levels in chronic constriction injury (CCI) and sham-operated animals 6h after surgery: 1 day later TNF overexpression was present in CCI mice only and disappeared 3 days after injury. The mRNA cytokine levels were elevated in DRG 1 and 3 days after surgery in CCI animals only, while the cytokine was not modulated in the spinal cord. A significant hyperalgesia was present in CCI and sham-operated mice at 6h and 1 day, while at later time point only CCI mice presented lower thresholds. Mechanical allodynia was already present only in CCI animals 6h from surgery and remained constant up to the 14th day. The results indicate that a transient early TNF upregulation takes place in peripheral nervous system after CCI that can activate a cascade of proinflammatory/pronociceptive mediators. [Copyright &y& Elsevier]

Abstract: Opiate addiction influences many physiological functions including immune responses. The objective of this study was to investigate the immune system function in heroin addicted patients submitted to methadone or buprenorphine maintenance treatment compared to untreated heroin addicts and healthy controls. Four groups were studied: group A included nine heroin addicted subjects, who were still injecting heroin; groups B and C were composed of 12 patients previously addicted to heroin, being treated with methadone (mean dosage 58±12.7mg/day) or buprenorphine (mean dose 9.3±2.3mg/day) since at least 6 months; group D was composed of 15 sex and age matched healthy controls. Lymphoproliferation and peripheral mononuclear cell cultures production of the Th1 cytokines IL-2 and IFN-γ, the Th2 cytokine IL-4, and of the pro-inflammatory cytokine TNF-α were evaluated in all the patients and controls. PHA-lymphoproliferation was lower in untreated heroin addicts than in controls, while it was normal in methadone and buprenorphine treated patients. An altered Th1/Th2 balance, characterized by reduced IL-4, IFN-γ and TNF-α but normal IL-2 levels, was present in untreated heroin addicted subjects, while the Th1/Th2 balance was well conserved in the methadone and buprenorphine groups. These findings suggest that the immune system abnormalities in heroin addicted patients can be restored to almost normal values by controlled treatment with methadone and buprenorphine. [Copyright &y& Elsevier]

Abstract: The functionality of structural light alloy castings can be considerably improved by inserting into them upon moulding iron base local reinforcements. A necessary condition to obtain tight joints with good load transfer is that a sound metallurgical bond is formed at the insert/alloy interface. However, many physical–chemical factors play an important part in the mechanical behaviour of the joint. To acquire a better insight into this issue, bimetallic samples were prepared by immersing a mild steel bar (5mm in diameter) in magnesium base Mg–Al alloy melts held at 650–750°C in a graphite crucible (mean diameter 19mm). Different processing conditions were used to vary the degree of chemical interaction at the insert/alloy interface. After melt solidification, the bimetallic samples were cut into slices (2–10mm thick) and push out testing was performed on these slices. Attempts have been made to relate the main features of the load–displacement curves thus obtained with the nature and extent of the transition zones formed at the insert/alloy interface. [Copyright &y& Elsevier]

Opioid compounds such as morphine produce powerful analgesia that is effective in treating various types of pain. In addition to their therapeutic efficacy, opioids can produce several well known adverse events, and, as has recently been recognized, can interfere with the immune response. The immunomodulatory activities of morphine have been characterized in animal and human studies. Morphine can decrease the effectiveness of several functions of both natural and adaptive immunity, and significantly reduces cellular immunity. Indeed, in animal studies morphine is consistently associated with increased morbidity and mortality due to infection and worsening of cancer. However, from several animal studies it emerges that not all opioids induce the same immunosuppressive effects, and evaluating each opioid’s profile is important for appropriate analgesic selection. Buprenorphine is a potent opioid that is frequently prescribed for chronic pain. Acute intracerebroventricular administration of buprenorphine has been shown in rats not to affect cellular immune responses, while a statistically significant inhibition of the immune response was observed with morphine. In mouse studies, chronic administration of buprenorphine led to immune parameters important for antimicrobial responses or for anti-tumour surveillance (lymphoproliferation, natural killer (NK)-lymphocyte activity, cytokine production, lymphocyte number) being unaffected. In contrast, levels of these immune markers were significantly reduced when the potent μ-agonist fentanyl was administered, but recovered after longer periods as tolerance developed. Because the intrinsic immunosuppressive activity varies between individual opioids, predicting the outcome on immunity can be difficult. To study this, the effects of morphine, fentanyl and buprenorphine on NK-lymphocyte activity depressed by experimental surgery were examined in rats. Treating animals immediately after surgery with equianalgesic doses of morphine and buprenorphine significantly reduced surgery-induced immunosuppression. However, buprenorphine reverted NK-lymphocyte activity to preoperative levels, while in morphine-treated rats NK-lymphocyte activity was ameliorated, although not completely. In contrast, fentanyl did not prevent immunosuppression induced by surgery. Overall, from several animal studies it emerges that buprenorphine has the more favourable profile, being a potent analgesic devoid of intrinsic immunosuppressive activity. [ABSTRACT FROM PUBLISHER]

We present a computational algorithm aimed to classify single unit spike trains on the basis of observed interspikes intervals (ISI). The neuronal activity is modeled with a stochastic leaky integrate and fire model and the inverse first passage time method is extended to the Ornstein-Uhlenbeck (OU) process. Differences between spike trains are detected in terms of the boundary shape. The proposed classification method is applied to the analysis of multiple single units recorded simultaneously in the thalamus and in the cerebral cortex of unanesthetized rats during spontaneous activity. We show the existence of at least three different firing patterns that could not be classified using the usual statistical indices. [ABSTRACT FROM AUTHOR]

Opioid compounds such as morphine produce powerful analgesia that is effective in treating various types of pain. In addition to their therapeutic efficacy, opioids can produce several well known adverse events, and, as has recently been recognized, can interfere with the immune response. The immunomodulatory activities of morphine have been characterized in animal and human studies. Morphine can decrease the effectiveness of several functions of both natural and adaptive immunity, and significantly reduces cellular immunity. Indeed, in animal studies morphine is consistently associated with increased morbidity and mortality due to infection and worsening of cancer. However, from several animal studies it emerges that not all opioids induce the same immunosuppressive effects, and evaluating each opioid's profile is important for appropriate analgesic selection. Buprenorphine is a potent opioid that is frequently prescribed for chronic pain. Acute intracerebroventricular administration of buprenorphine has been shown in rats not to affect cellular immune responses, while a statistically significant inhibition of the immune response was observed with morphine. In mouse studies, chronic administration of buprenorphine led to immune parameters important for antimicrobial responses or for anti-tumour surveillance (lymphoproliferation, natural killer (NK)-lymphocyte activity, cytokine production, lymphocyte number) being unaffected. In contrast, levels of these immune markers were significantly reduced when the potent μ-agonist fentanyl was administered, but recovered after longer periods as tolerance developed. Because the intrinsic immunosuppressive activity varies between individual opioids, predicting the outcome on immunity can be difficult. To study this, the effects of morphine, fentanyl and buprenorphine on NK-Iymphocyte activity depressed by experimental surgery were examined in rats. Treating animals immediately after surgery with equianalgesic doses of morphine and buprenorphine significantly reduced surgery-induced immunosuppression. However, buprenorphine reverted NK-lymphocyte activity to preoperative levels, while in morphine-treated rats NK-Iymphocyte activity was ameliorated, although not completely. In contrast, fentanyl did not prevent immunosuppression induced by surgery. Overall, from several animal studies it emerges that buprenorphine has the more favourable profile, being a potent analgesic devoid of intrinsic immunosuppressive activity. [ABSTRACT FROM AUTHOR]

Nutrient uptake by a primitive cell would have been limited by the permeability characteristics of its membrane. We measured the permeabilities of model protocellular membranes to water, five of the six pentoses, and selected aldohexoses, ketohexoses, and three to six carbon alditols by following volume changes of vesicles after the addition of solute to the external medium. Solute hydrophobicities correlated poorly with permeability coefficients within one structural class of compounds. The permeability coefficients of diastereomeric sugars differed by as much as a factor of 10, with ribose being the most permeable aldopentose. Flexible alditols and sugars, sugars biased toward or restricted to furanose forms, and sugars having anomers with hydrophobic faces permeated more quickly than compounds lacking these features. Among the aldo-pentoses, only ribose possesses all of these properties. Ribose permeated both fatty acid and phospholipid membranes more rapidly than the other aldopentoses or hexoses. The enhanced permeability conferred by the unique conformational preferences of ribose would have allowed faster assimilation of ribose by primitive cells as they passively absorbed materials from the environment. The kinetic advantage of ribose over the other aldopentoses in crossing membranes may therefore have been one factor that facilitated the emergence of the RNA world. [ABSTRACT FROM AUTHOR]

Abstract: Cannabidiol is the main nonpsychoactive component of marijuana. We examined the ability of in vivo and in vitro cannabidiol to interfere with the production of interleukin (IL)-12 and IL-10 by murine macrophages and to modulate macrophage chemotaxis. Cannabidiol added in vitro to peritoneal macrophages significantly increased IL-12 and decreased IL-10 production. The CB1 and CB2 receptor antagonists prevented this modulation. Macrophages from animals treated with cannabidiol at the dose of 30 mg kg−1 either orally or i.p. produced higher levels of IL-12 and lower levels of IL-10 in comparison to controls, and the CB receptor antagonists did not prevent these effects. Cannabidiol dose-dependently decreased fMLP-induced chemotaxis of macrophages, and the CB2 receptor antagonist prevented this decrease. [Copyright &y& Elsevier]

Abstract: To relate the noise intensity with a periodically modulated input signal in a single neuron stochastic model we introduce a diffusion model with both time modulated drift and diffusion coefficient. Such a model is the continuous version of a Stein model with time oscillating frequencies for the Poisson processes describing the inputs impinging on the neuron. We focus here on some aspects of the resonance phenomenon for such a model. We compare the corresponding interspike interval distribution with the analogous distribution for a model sharing the same parameter values, but with constant noise intensity. Examples with two different levels for this noise intensity are discussed. The enhancement of the height of the peaks in the interspike interval distribution appearing at the modulation period, the improvement of the phase locking behavior and an enlargement of the noise ranges where a resonance like behavior arises are the main features observed in the considered cases. [Copyright &y& Elsevier]

Interleukin-6 (IL-6) is a cytokine shown to affect brain function and to be involved in pathological neurodegenerative disorders such as Alzheimer’s disease (AD). In the present study we investigated the cognitive function in transgenic mice not expressing IL-6 (IL-6 KO) and in wild type (WT) genotype at 4 and 12 months of age, using a passive avoidance and an eight-arm radial maze tasks. Motor function was quantified using an Animex apparatus. Hippocampal choline acetyltransferase (ChAT) activity was evaluated in both genotypes. No difference was observed in both genotypes for spontaneous motor activity. The mean latency (s) to re-enter the shock box, was similar in both young mutant and WT mice. However, a decreased sensitivity (50%) to scopolamine (1 mg/kg) in mutant compared to WT mice, was obtained. IL-6 KO mice exhibited a facilitation of radial maze learning over 30 days, in terms of a lower number of working memory errors and a higher percentage of animals reaching the criterion as compared with WT genotype tested at both ages. Furthermore, mutant mice, at the age of 12 months, showed a faster acquisition (22 days versus 30 days to reach the criterion). The pattern of arm entry exhibited by IL-6 KO mice showed a robust tendency to enter an adjacent arm at both ages, while WT only at the age of 4 months. ChAT activity was inversely correlated with memory performance. These findings suggest a possible involvement of IL-6 on memory processes, even if the mechanism remains still unclear. [Copyright &y& Elsevier]

The effect of chronic stress on immune functions is strongly biased by individual factors. Mice were subjected to a new model of chronic psychosocial stress in which four different subcategories of stressed animals may be identified: Resident Dominants (RD), Resident Subordinates (RS), Intruder Dominants (InD), and Intruder Subordinates (InS). After 7 days of stress, mice were immunized with keyhole limpet hemocyanine (KLH). Their immune functions were investigated 14 days later with stress continuing trough. Importantly, RS mice, which are mice losing territory ownership, were the more affected, having lower IgG, proliferation, and IL-2. RD and InD showed lower IgG while InS showed no immune alteration. In conclusion, loss of resources could be a key factor in determining individual vulnerability to stressful events. [Copyright &y& Elsevier]

The problem of global geoid determination is usually solved using satellite altimetry data on the oceans, together with an oceanographic model of sea surface topography, and gravity anomaly data on the continents. Such data, however, enable to obtain only potential differences with respect to a reference surface whose absolute potential is unknown. This situation suggests to modify the classical mixed boundary-value problem of physical geodesy by inserting into the boundary conditions an unknown additive constant, that must be determined by imposing a suitable additional constraint. Yet, such formulation of the boundary-value problem, from the point of view of its mathematical properties, is not unconditionally well-posed, and, furthermore, does not reflect faithfully the available physical model, as the present knowledge of ocean circulation does not allow to connect along coastlines the reference surfaces defined on the oceans and on the continents. The introduction of two different unknown additive constants, one for the oceans and one for the earth, to be determined by imposing two additional constraints, gives rise to a more faithful picture of the present physical knowledge, and, at the same time, to a new well-posed formulation of the boundary-value problem. [ABSTRACT FROM AUTHOR]

The stochastic leaky integrate-and-fire (LIF) continuous model is studied under the condition that the amplitude of noise is a function of the input signal. The coefficient of variation (CV) of interspike intervals (ISIs) is investigated for different types of dependencies between the noise and the signal. Finally, we present the CV and the ISI density resulting from the special choice of parameters of the input that gave rise to a contra-intuitive behavior of the transfer function in La´nsky´ and Sacerdote [Phys. Lett. A 285 (2001) 132]. [Copyright &y& Elsevier]

The effects of taking into account in a perfect integrate and fire model of neuronal activity the spatial localization of the synapses are studied by superposing to the diffusion a simple discrete jump component. Different criteria are employed to assess the role of excitatory and inhibitory discrete contributions. Comparisons are performed with respect to the case where contributions coming from synapses more distal from the trigger zone are summed up in a continuous model. A systematic study of the output frequency and of the inter spike interval coefficient of variation (CV) is performed by means of examples as the model parameters are varied. [Copyright &y& Elsevier]