Testosterone does not affect lower urinary tract symptoms while improving markers of prostatitis in men with benign prostatic hyperplasia: a randomized clinical trial.

PURPOSE: Benign Prostatic Hyperplasia (BPH) is a result of prostate inflammation, frequently occurring in metabolic syndrome (MetS). Low testosterone is common in MetS. A randomized clinical trial was designed to evaluate if 24 weeks of testosterone therapy (TTh) in BPH men with MetS and low testosterone improve urinary symptoms and prostate inflammation. METHODS: One-hundred-twenty men with MetS waitlisted for BPH surgery were enrolled. They were categorized into normal testosterone (TT ≥ 12 nmol/L and cFT ≥ 225 pmol/L; n = 48) and testosterone deficient (TD) (TT < 12 nmol/L and/or cFT < 225 pmol/L; n = 72) then randomized to testosterone gel 2% (5 g/daily) or placebo for 24 weeks. At baseline and follow-up, questionnaires for urinary symptoms and trans-rectal ultrasound were performed. Prostate tissue was collected for molecular and histopathological analyses. RESULTS: No differences in the improvement of urinary symptoms were found between TTh and placebo (OR [95% CI] 0.96 [0.39; 2.37]). In TD + TTh, increase in prostate but not adenoma volume was observed (2.64 mL [0.07; 5.20] and 1.82 mL [- 0.46; 0.41], respectively). Ultrasound markers of inflammation were improved. In a subset of 61 men, a hyper-expression of several pro-inflammatory genes was found in TD + placebo when compared with normal testosterone. TTh was able to counteract this effect. For 80 men, the inflammatory infiltrate was higher in TD + placebo than in normal testosterone (0.8 points [0.2; 1.4]) and TD + TTh men (0.9 points [0.2; 1.5]). CONCLUSIONS: Twenty-four weeks of TTh in TD men with BPH and MetS improves ultrasound, molecular and histological proxies of prostate inflammation. This does not result in symptom improvement.

Testosterone positively regulates vagina NO-induced relaxation: an experimental study in rats.

PURPOSE: Female sexual response involves a complex interplay between neurophysiological mechanisms and the nitric oxide (NO)-mediated relaxation of clitoris and vagina. The aim of this study was to evaluate sex steroids regulation of the relaxant pathway in vagina, using a validated animal model. METHODS: Subgroups of OVX Sprague-Dawley rats were treated with 17ß-estradiol, testosterone, or testosterone and letrozole, and compared with a group of intact animals. Masson's trichrome staining was performed for morphological evaluation of the distal vaginal wall, in vitro contractility studies investigated the effect of OVX and in vivo treatments on vaginal smooth muscle activity. RNA from vaginal tissue was analyzed by semi-quantitative RT-PCR. RESULTS: Immunohistochemical analysis showed that OVX induced epithelial and smooth muscle structural atrophy, testosterone and testo + letrozole increased the muscle bundles content and organization without affecting the epithelium while 17ß-estradiol mediated the opposite effects. In vitro contractility studies were performed on noradrenaline pre-contracted vaginal strips from each experimental group. Acetylcholine (0.001-10 µM) stimulation induced a concentration-dependent relaxation, significantly reduced by NO-synthase inhibitor L-NAME and by guanylate cyclase inhibitor ODQ. OVX resulted in a decreased responsiveness to acetylcholine, restored by testosterone, with or without letrozole, but not by 17ß-estradiol. OVX sensitivity to the NO-donor SNP was higher than in the control. Vardenafil, a PDE5 inhibitor, enhanced SNP effect in OVX + testosterone as well as in control, as supported by RNA expression analysis. CONCLUSIONS: Our study demonstrates that testosterone improves the NO-mediated smooth muscle vaginal cells relaxation confirming its role in maintaining the integrity of muscular relaxant machinery.

Sexual function in men undergoing androgen deprivation therapy.

Androgen deprivation therapy (ADT) has a deleterious effect on sexual functions and general well-being in men. Despite this evidence, however, patient and couple knowledge about ADT side effects as well as their management is poor. Similar considerations can be made for physician endorsement of management strategies. In this paper, we summarize and critically discuss available evidence regarding the possible associations between ADT and sexual dysfunction as well as the best therapeutical options. Preclinical data show that ADT is associated with penile contractility impairment as well as lower response to phosphodiesterase type 5 inhibitors (PDE5i). Available data indicate that ADT resulted in a five to sixfold increased risk of reduced libido and in a threefold increased risk of ED confirming the main role of testosterone in regulating sexual desire. Despite this evidence, sexuality remains an important aspect of health and well-being for men and their partner. The best therapeutical options depend on patient and couple desires and needs. When nonpenetrative erections are still possible, nonpenetrative activities should be encouraged to maintain sexual intimacy. A combined and personal educational program including the collaboration of different professional figures (including general physicians, oncologists, andrologists, sexologists, and psychologists) trained in sexual medicine is advisable in order to provide the best support to subjects undergoing ADT.

Treatment potential of LPCN 1144 on liver health and metabolic regulation in a non-genomic, high fat diet induced NASH rabbit model.

PURPOSE: Low free testosterone (T) level in men is independently associated with presence and severity of Non-Alcoholic Steatohepatitis (NASH). The histological and molecular effects of oral testosterone prodrug LPCN 1144 treatment on hepatic fibrosis and NASH features are unknown. A metabolic syndrome-induced NASH model in rabbits consuming high fat diet (HFD) has been previously used to assess treatment effects of injectable T on hepatic fibrosis and NASH features. Here we present results on LPCN 1144 in this HFD-induced, NASH preclinical model. METHODS: Male rabbits were randomly assigned to five groups: regular diet (RD), HFD, HFD + 1144 vehicle (HFD + Veh), HFD + 1144 (1144), and HFD + 1144 + α-tocopherol (1144 + ALPHA). Rabbits were sacrificed after 12 weeks for liver histological, biochemical and genetic analyses. Histological scores were obtained through Giemsa (inflammation), Masson's trichrome (steatosis and ballooning), and Picrosirius Red (fibrosis) staining. RESULTS: Compared to RD, HFD and HFD + Veh significantly worsened NASH features and hepatic fibrosis. Considering HFD and HFD + Veh arms, histological and biomarker features were not significantly different. Both 1144 and 1144 + ALPHA arms improved mean histological scores of NASH as compared to HFD arm. Importantly, percentage of fibrosis was improved in both 1144 (p < 0.05) and 1144 + ALPHA (p = 0.05) treatment arms vs. HFD. Both treatment arms also reduced HFD-induced inflammation and fibrosis mRNA markers. Furthermore, 1144 treatments significantly improved HFD-induced metabolic dysfunctions. CONCLUSIONS: Histological and biomarker analyses demonstrate that LPCN 1144 improved HFD-induced hepatic fibrosis and NASH biochemical, biomolecular and histochemical features. These preclinical findings support a therapeutic potential of LPCN 1144 in the treatment of NASH and of hepatic fibrosis.

A Multiscale Approach to Axon and Nerve Stimulation Modeling: A Review.

Electrical nerve fiber stimulation is a technique widely used in prosthetics and rehabilitation, and its study from a computational point of view can be a useful instrument to support experimental tests. In the last years, there was an increasing interest in computational modeling of neural cells and numerical simulations on nerve fibers stimulation because of its usefulness in forecasting the effect of electrical current stimuli delivered to tissues through implanted electrodes, in the design of optimal stimulus waveforms based on the specific application (i.e., inducing limb movements, sensory feedback or physiological function restoring), and in the evaluation of the current stimuli properties according to the characteristics of the nerves surrounding tissue. Therefore, a review study on the main modeling and computational frameworks adopted to investigate peripheral nerve stimulation is an important instrument to support and drive future research works. To this aim, this paper deals with mathematical models of neural cells with a detailed description of ion channels and numerical simulations using finite element methods to describe the dynamics of electrical stimulation by implanted electrodes in peripheral nerve fibers. In particular, we evaluate different nerve cell models considering different ion channels present in neurons and provide a guideline on multiscale numerical simulations of electrical nerve fibers stimulation.

Testosterone treatment is associated with reduced adipose tissue dysfunction and nonalcoholic fatty liver disease in obese hypogonadal men.

PURPOSE: In both preclinical and clinical settings, testosterone treatment (TTh) of hypogonadism has shown beneficial effects on insulin sensitivity and visceral and liver fat accumulation. This prospective, observational study was aimed at assessing the change in markers of fat and liver functioning in obese men scheduled for bariatric surgery. METHODS: Hypogonadal patients with consistent symptoms (n = 15) undergoing 27.63 ± 3.64 weeks of TTh were compared to untreated eugonadal (n = 17) or asymptomatic hypogonadal (n = 46) men. A cross-sectional analysis among the different groups was also performed, especially for data derived from liver and fat biopsies. Preadipocytes isolated from adipose tissue biopsies were used to evaluate insulin sensitivity, adipogenic potential and mitochondrial function. NAFLD was evaluated by triglyceride assay and by calculating NAFLD activity score in liver biopsies. RESULTS: In TTh-hypogonadal men, histopathological NAFLD activity and steatosis scores, as well as liver triglyceride content were lower than in untreated-hypogonadal men and comparable to eugonadal ones. TTh was also associated with a favorable hepatic expression of lipid handling-related genes. In visceral adipose tissue and preadipocytes, TTh was associated with an increased expression of lipid catabolism and mitochondrial bio-functionality markers. Preadipocytes from TTh men also exhibited a healthier morpho-functional phenotype of mitochondria and higher insulin-sensitivity compared to untreated-hypogonadal ones. CONCLUSIONS: The present data suggest that TTh in severely obese, hypogonadal individuals induces metabolically healthier preadipocytes, improving insulin sensitivity, mitochondrial functioning and lipid handling. A potentially protective role for testosterone on the progression of NAFLD, improving hepatic steatosis and reducing intrahepatic triglyceride content, was also envisaged. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02248467, September 25th 2014.

Key aspects for effective mathematical modelling of fractional-diffusion in cardiac electrophysiology: a quantitative study.

Microscopic structural features of cardiac tissue play a fundamental role in determining complex spatio-temporal excitation dynamics at the macroscopic level. Recent efforts have been devoted to the development of mathematical models accounting for non-local spatio-temporal coupling able to capture these complex dynamics without the need of resolving tissue heterogeneities down to the micro-scale. In this work, we analyse in detail several important aspects affecting the overall predictive power of these modelling tools and provide some guidelines for an effective use of space-fractional models of cardiac electrophysiology in practical applications. Through an extensive computational study in simplified computational domains, we highlight the robustness of models belonging to different categories, i.e., physiological and phenomenological descriptions, against the introduction of non-locality, and lay down the foundations for future research and model validation against experimental data. A modern genetic algorithm framework is used to investigate proper parameterisations of the considered models, and the crucial role played by the boundary assumptions in the considered settings is discussed. Several numerical results are provided to support our claims.

Therapeutic effects of the selective farnesoid X receptor agonist obeticholic acid in a monocrotaline-induced pulmonary hypertension rat model.

BACKGROUND: Activation of the farnesoid X receptor (FXR), a member of the nuclear receptor steroid superfamily, leads to anti-inflammatory and anti-fibrotic effects in several tissues, including the lung. We have recently demonstrated a protective effect of the farnesoid X receptor (FXR) agonist obeticholic acid (OCA) in rat models of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) and bleomycin-induced pulmonary fibrosis. The aim of the present study was to investigate whether the positive effects of OCA treatment could be exerted also in established MCT-induced PAH, i.e., starting treatment 2 weeks after MCT administration. METHODS: Rats with MCT-induced PAH were treated, 2 weeks after MCT administration, with OCA or tadalafil for two additional weeks. Pulmonary functional tests were performed at week 2 (before treatment) and four (end of treatment). At the same time points, lung morphological features and expression profile of genes related to smooth muscle relaxation/contraction and tissue remodeling were also assessed. RESULTS: 2 weeks after MCT-induced injury, the treadmill resistance (a functional parameter related to pulmonary hypertension) was significantly decreased. At the same time point, we observed right ventricular hypertrophy and vascular remodeling, with upregulation of genes related to inflammation. At week 4, we observed a further worsening of the functional and morphological parameters, accompanied by dysregulation of inflammatory and extracellular matrix markers mRNA expression. Administration of OCA (3 or 10 mg/kg/day), starting 2 weeks after MCT-induced injury, significantly improved pulmonary function, effectively normalizing the exercise capacity. OCA also reverted most of the lung alterations, with a significant reduction of lung vascular wall thickness, right ventricular hypertrophy, and restoration of the local balance between relaxant and contractile pathways. Markers of remodeling pathways were also normalized by OCA treatment. Notably, results with OCA treatment were similar, or even superior, to those obtained with tadalafil, a recently approved treatment for pulmonary hypertension. CONCLUSIONS: The results of this study demonstrate a significant therapeutic effect of OCA in established MCT-induced PAH, improving exercise capacity associated with reduction of right ventricular hypertrophy and lung vascular remodeling. Thus, OCA dosing in a therapeutic protocol restores the balance between relaxant and contractile pathways in the lung, promoting cardiopulmonary protective actions in MCT-induced PAH.

Therapeutic effects of obeticholic acid (OCA) treatment in a bleomycin-induced pulmonary fibrosis rat model.

PURPOSE: We recently demonstrated a protective effect of the farnesoid X receptor agonist obeticholic acid (OCA) in rat models of bleomycin-induced pulmonary fibrosis (PF). Aim of the present study was to investigate whether the positive effects of OCA treatment are apparent also on ongoing bleomycin-induced PF, i.e., after 2 weeks of bleomycin administration. METHODS: Bleomycin-induced PF rats were treated 2 weeks after bleomycin administration with OCA or pirfenidone for two additional weeks. Pulmonary function test was performed at 2 and 4 weeks in all experimental groups. At the same time points, lung morphological features and mRNA expression profile of genes related to fibrosis, inflammation and epithelial-mesenchymal transition were also assessed. RESULTS: After 2 weeks, bleomycin significantly increased the pressure at the airway opening (PAO), a functional parameter related to fibrosis-induced lung stiffness, and induced diffuse lung interstitium fibrosis, with upregulation of inflammation (IL1ß, MCP1) and tissue remodeling (COL1A1, COL3A1, ET1, MMP7, PDGFa, αSMA, SNAI1) markers. At week four, a further increase of lung fibrosis and PAO was observed, accompanied by upregulation of extracellular matrix-related mRNA expression. OCA administration, even after the establishment of PF, significantly improved pulmonary function, normalizing PAO, and reverted the bleomycin-induced lung alterations, with significant reduction of markers of inflammation (CD206, COX2, HIF1, IL1ß, MCP1), epithelial proliferation (CTGF, PDGFa) and fibrosis (COL1A1, COL3A1, ET1, FN1, MMPs, αSMA, SNAIs, TGFß1, TIMPs). Results with OCA were similar or superior to those obtained with pirfenidone. CONCLUSIONS: In conclusion, our results demonstrate a significant therapeutic effect of OCA in already established PF.

Access to direct-acting antivirals for the treatment of hepatitis C in a country with limited resources. / Evaluación del acceso a antivirales para el tratamiento de la hepatitis C en un país con recursos limitados.

AIMS: To estimate the number of patients that have access to treatment of hepatitis C with direct-acting antivirals in Argentina and evaluate the factors associated with the lack of access. MATERIALS AND METHODS: A cross-sectional cohort study was conducted that included all the consecutive prescriptions of direct-acting antivirals issued at health centers that participated in the ECHOTM telemedicine project directed by the Hospital Italiano de Buenos Aires, within the time frame of January 2016 and February 2017. RESULTS: A total of 143 treatment prescriptions were included and overall access was 70% (95% CI 62-77%). The only independent factor associated with a lack of treatment access was coverage by a public healthcare system (OR 4.98 [95% CI 2.05- 12.09]). CONCLUSION: Patients with hepatitis C that were covered by a public healthcare system had a 4 times higher chance of not having access to treatment with direct-acting antivirals than patients covered by other healthcare systems (private insurance or the social welfare system).

Viscoelastic computational modeling of the human head-neck system: Eigenfrequencies and time-dependent analysis.

A subject-specific 3-dimensional viscoelastic finite element model of the human head-neck system is presented and investigated based on computed tomography and magnetic resonance biomedical images. Ad hoc imaging processing tools are developed for the reconstruction of the simulation domain geometry and the internal distribution of bone and soft tissues. Material viscoelastic properties are characterized point-wise through an image-based interpolating function used then for assigning the constitutive prescriptions of a heterogenous viscoelastic continuum model. The numerical study is conducted both for modal and time-dependent analyses, compared with similar studies and validated against experimental evidences. Spatiotemporal analyses are performed upon different exponential swept-sine wave-localized stimulations. The modeling approach proposes a generalized, patient-specific investigation of sound wave transmission and attenuation within the human head-neck system comprising skull and brain tissues. Model extensions and applications are finally discussed.

Nonlinear diffusion and thermo-electric coupling in a two-variable model of cardiac action potential.

This work reports the results of the theoretical investigation of nonlinear dynamics and spiral wave breakup in a generalized two-variable model of cardiac action potential accounting for thermo-electric coupling and diffusion nonlinearities. As customary in excitable media, the common Q10 and Moore factors are used to describe thermo-electric feedback in a 10° range. Motivated by the porous nature of the cardiac tissue, in this study we also propose a nonlinear Fickian flux formulated by Taylor expanding the voltage dependent diffusion coefficient up to quadratic terms. A fine tuning of the diffusive parameters is performed a priori to match the conduction velocity of the equivalent cable model. The resulting combined effects are then studied by numerically simulating different stimulation protocols on a one-dimensional cable. Model features are compared in terms of action potential morphology, restitution curves, frequency spectra, and spatio-temporal phase differences. Two-dimensional long-run simulations are finally performed to characterize spiral breakup during sustained fibrillation at different thermal states. Temperature and nonlinear diffusion effects are found to impact the repolarization phase of the action potential wave with non-monotone patterns and to increase the propensity of arrhythmogenesis.

Multi-band decomposition analysis: application to cardiac alternans as a function of temperature.

OBJECTIVE: It has long been known that variations in temperature can facilitate the development of cardiac arrhythmias. Here, we aim to quantify the effects of temperature on cardiac alternans properties. APPROACH: in this work, we use optical mapping recordings of canine ventricular epicardial preparations to demonstrate that hypothermia can promote the formation of alternans, which is an important precursor to potentially lethal arrhythmias like fibrillation. We then present a novel quantification of alternans properties for a broad range of cycle lengths under different thermal states. Specifically, we apply the recently developed multi-band-decomposition analysis (MBDA) in the context of cardiac action potential dynamics. MAIN RESULTS: We show that the MBDA offers several advantages compared with traditional analysis of action potential durations. First, MBDA allows a depiction and quantification of the magnitude of alternans at all threshold values simultaneously and thus offers more information about how alternans relates to the action potential morphology while also removing the necessity of choosing a single threshold value. Second, the MBDA technique offers simple ways for assessing action potential amplitude alternans. Finally, MBDA provides a quantification of signal quality without any additional processing. SIGNIFICANCE: We find that the MBDA technique shows promise in leading to a deeper understanding of cardiac alternans properties.

Computational comparison of aortic root stresses in presence of stentless and stented aortic valve bio-prostheses.

We provide a computational comparison of the performance of stentless and stented aortic prostheses, in terms of aortic root displacements and internal stresses. To this aim, we consider three real patients; for each of them, we draw the two prostheses configurations, which are characterized by different mechanical properties and we also consider the native configuration. For each of these scenarios, we solve the fluid-structure interaction problem arising between blood and aortic root, through Finite Elements. In particular, the Arbitrary Lagrangian-Eulerian formulation is used for the numerical solution of the fluid-dynamic equations and a hyperelastic material model is adopted to predict the mechanical response of the aortic wall and the two prostheses. The computational results are analyzed in terms of aortic flow, internal wall stresses and aortic wall/prosthesis displacements; a quantitative comparison of the mechanical behavior of the three scenarios is reported. The numerical results highlight a good agreement between stentless and native displacements and internal wall stresses, whereas higher/non-physiological stresses are found for the stented case.

Gap-junction coupling and ATP-sensitive potassium channels in human ß-cell clusters: Effects on emergent dynamics.

The importance of gap-junction coupling between ß cells in pancreatic islets is well established in mouse. Such ultrastructural connections synchronize cellular activity, confine biological heterogeneity, and enhance insulin pulsatility. Dysfunction of coupling has been associated with diabetes and altered ß-cell function. However, the role of gap junctions between human ß cells is still largely unexplored. By using patch-clamp recordings of ß cells from human donors, we previously estimated electrical properties of these channels by mathematical modeling of pairs of human ß cells. In this work we revise our estimate by modeling triplet configurations and larger heterogeneous clusters. We find that a coupling conductance in the range 0.005-0.020 nS/pF can reproduce experiments in almost all the simulated arrangements. We finally explore the consequence of gap-junction coupling of this magnitude between ß cells with mutant variants of the ATP-sensitive potassium channels involved in some metabolic disorders and diabetic conditions, translating studies performed on rodents to the human case. Our results are finally discussed from the perspective of therapeutic strategies. In summary, modeling of more realistic clusters with more than two ß cells slightly lowers our previous estimate of gap-junction conductance and gives rise to patterns that more closely resemble experimental traces.

Experimental evidence and mathematical modeling of thermal effects on human colonic smooth muscle contractility.

It has been shown, in animal models, that gastrointestinal tract (GIT) motility is influenced by temperature; nevertheless, the basic mechanism governing thermal GIT smooth muscle responses has not been fully investigated. Studies based on physiologically tuned mathematical models have predicted that thermal inhomogeneity may induce an electrochemical destabilization of peristaltic activity. In the present study, the effect of thermal cooling on human colonic muscle strip (HCMS) contractility was studied. HCMSs were obtained from disease-free margins of resected segments for cancer. After removal of the mucosa and serosa layers, strips were mounted in separate chambers. After 30 min, spontaneous contractions developed, which were measured using force displacement transducers. Temperature was changed every hour (37, 34, and 31°C). The effect of cooling was analyzed on mean contractile activity, oscillation amplitude, frequency, and contraction to ACh (10(-5) M). At 37°C, HCMSs developed a stable phasic contraction (~0.02 Hz) with a significant ACh-elicited mean contractile response (31% and 22% compared with baseline in the circular and longitudinal axis, respectively). At a lower bath temperature, higher mean contractile amplitude was observed, and it increased in the presence of ACh (78% and 43% higher than the basal tone in the circular and longitudinal axis, respectively, at 31°C). A simplified thermochemomechanical model was tuned on experimental data characterizing the stress state coupling the intracellular Ca(2+) concentration to tissue temperature. In conclusion, acute thermal cooling affects colonic muscular function. Further studies are needed to establish the exact mechanisms involved to better understand clinical consequences of hypothermia on intestinal contractile activity.

Opposite effects of tamoxifen on metabolic syndrome-induced bladder and prostate alterations: a role for GPR30/GPER?

BACKGROUND: BPH and LUTS have been associated to obesity, hypogonadism, and metabolic syndrome (MetS). MetS-induced prostate and bladder alterations, including inflammation and tissue remodeling, have been related to a low-testosterone and high-estrogen milieu. In addition to ERs, GPR30/GPER is able to mediate several estrogenic non-genomic actions. METHODS: Supplementing a subgroup of MetS rabbits with tamoxifen, we analyzed the in vivo effects on MetS-induced prostate and bladder alterations. The effects of selective ER/GPER ligands and GPER silencing on prostate inflammation were also studied in vitro using hBPH cells. RESULTS: ERα, ERß, and PR expression was upregulated in MetS bladder, where tamoxifen decreased ERα and PR expression, further stimulating ERß. In addition, tamoxifen-dosing decreased MetS-induced overexpression of inflammatory and tissue remodeling genes. In prostate, sex steroid receptors, pro-inflammatory and pro-fibrotic genes were upregulated in MetS. However, tamoxifen did not affect them and even increased COX-2. In hBPH cells, 17ß-estradiol increased IL-8 secretion, an effect blunted by co-treatment with GPER antagonist G15 but not by ER antagonist ICI 182,780, which further increased it. GPER agonist G1 dose-dependently (IC50 = 1.6 nM) induced IL-8 secretion. In vitro analysis demonstrated that GPER silencing reverted these stimulatory effects. CONCLUSIONS: GPER can be considered the main mediator of estrogen action in prostate, whereas in bladder the mechanism appears to rely on ERα, as indicated by in vivo experiments with tamoxifen dosing. Limiting the effects of the MetS-induced estrogen action via GPER could offer new perspectives in the management of BPH/LUTS, whereas tamoxifen dosing showed potential benefits in bladder.

A stochastic mathematical model to study the autoimmune progression towards type 1 diabetes.

BACKGROUND: The integrity of the interactions and the 3D architecture among beta cell populations in pancreatic islets is critical for proper biosynthesis, storage and release of insulin. The aim of this study was to evaluate the effect on electrophysiological signalling of beta cells that is produced by progressive lymphocytic islet cell infiltration (insulitis), by modelling the disruption of pancreatic islet anatomy as a consequence of insulitis and altered glucose concentrations. METHODS: On the basis of histopathological images of murine islets from non-obese diabetic mice, we simulated the electrophysiological dynamics of a 3D cluster of mouse beta cells via a stochastic model. Progressive damage was modelled at different glucose concentrations, representing the different glycaemic states in the autoimmune progression towards type 1 diabetes. RESULTS: At 31% of dead beta cells (normoglycaemia) and 69% (hyperglycaemia), the system appeared to be biologically robust to maintain regular Ca(2+) ion oscillations guaranteeing an effective insulin release. Simulations at 84%, 94% and 98% grades (severe hyperglycemia) showed that intracellular calcium oscillations were absent. In such conditions, insulin pulsatility is not expected to occur. CONCLUSIONS: Our results suggest that the islet tissue is biophysically robust enough to compensate for high rates of beta cell loss. These predictions can be experimentally tested in vitro by quantifying space and time electrophysiological dynamics of animal islets kept at different glucose gradients. The model indicates the necessity of maintaining glycaemia within the physiological range as soon as possible after diabetes onset to avoid a dramatic interruption of Ca(2+) pulsatility and the consequent drop of insulin release.

Computational modeling and stress analysis of columellar biomechanics.

The open approach for rhinoplasty offers excellent exposure of the various components of the nose in situ. The biggest advantage of the external approach is the complete anatomic exposure, which allows the surgeon to inspect the osteo-cartilagineous framework, while the biggest disadvantage is represented by the transcolumellar scar. The goal of this study is to numerically quantify the stress induced on the scar of a human columella by a constant load, through a fine tuned finite elasticity continuum model. Specifically we want to determine the best shape of incision which would minimize this stress. The columellar portion of the nose, together with the various constituting tissues, has been modeled in a first approximation as a hyperelastic body and seven types of scars have been studied. The determination of the best incision must be a compromise among different factors: shape and size primarily, but also position with respect to the internal structures and external loads. From this point of view, the best class of scar appears to be, both at simulated and real levels, the V-shaped one, inducing a maximum logarithmic von Mises stress in tissue of 4.67 Pa, and an absolute minimum stress distribution on the scar of 4.17 Pa. Numerical simulations appear to be in agreement with the evidence-based results coming from surgical practice, thus confirming the necessity to minimize local stresses on the tissue. A parameters' sensitivity analysis further highlighted our optimal choice. The proposed mathematical model can be applied both to theoretically designed and numerically verified new non-conventional scar geometries.