Virtual cycling effort is dependent on power update rate.

Cycling ergometer protocols are commonly integrated with a virtual reality environment (VRE), especially because of its static position that also allows multiple exercise experiments. Concerning VRE scenarios, visually delayed situations like the ones produced at excessive low update rates can also affect the sense of presence and physiological responses. However, the main interface between the subject and a cycling VRE is the power applied over the crank, and there are only a few experiments to evaluate the effect of delayed situations on this particular interface. Thus, this work aims to investigate the effects of the power update rate (PUR) over the subject`s performance on an avatar-based simulator during a drafting task. A custom cycling VRE was built, and 21 male recreational cyclists (175.9 ± 7.5 cm; 76.5 ± 13.9 kg) were tested at six different PUR levels from 100 to 3000 ms. As a result, PUR affects performance scores (virtual distance, efficiency, and heart rate, p < 0.01) at the given VRE conditions. The case-by-case analysis of the groups reveals that higher update rates always lead to a statistical equivalent or superior performance. Nevertheless, no parameter shows any group difference between 500 ms and lower PUR. These results suggest that virtual cycling protocols should consider PUR and other delay-related mechanisms as possible intervening factors over physiological responses and performance scores.

Lung assist devices influence cardio-energetic parameters: Numerical simulation study.

We aim at an analysis of the effects mechanical ventilators (MVs) and thoracic artificial lungs (TALs) will have on the cardiovascular system, especially on important quantities, such as left and right ventricular external work (EW), pressure-volume area (PVA) and cardiac mechanical efficiency (CME). Our analyses are based on simulation studies which were carried out by using our CARDIOSIM(©) software simulator. At first, we carried out simulation studies of patients undergoing mechanical ventilation (MV) without a thoracic artificial lung (TAL). Subsequently, we conducted simulation studies of patients who had been provided with a TAL, but did not undergo MV. We aimed at describing the patient's physiological characteristics and their variations with time, such as EW, PVA, CME, cardiac output (CO) and mean pulmonary arterial/venous pressure (PAP/PVP). We were starting with a simulation run under well-defined initial conditions which was followed by simulation runs for a wide range of mean intrathoracic pressure settings. Our simulations of MV without TAL showed that for mean intrathoracic pressure settings from negative (-4 mmHg) to positive (+5 mmHg) values, the left and right ventricular EW and PVA, right ventricular CME and CO decreased, whereas left ventricular CME and the PAP increased. The simulation studies of patients with a TAL, comprised all the usual TAL arrangements, viz. configurations "in series" and in parallel with the natural lung and, moreover, hybrid configurations. The main objective of the simulation studies was, as before, the assessment of the hemodynamic response to the application of a TAL. We could for instance show that, in case of an "in series" configuration, a reduction (an increase) in left (right) ventricular EW and PVA values occurred, whereas the best performance in terms of CO can be achieved in the case of an in parallel configuration.

The role of antennae in the thermopreference and biting response of haematophagous bugs.

Insects sense thermal cues mainly through thermoreceptors located in the antenna. To analyse the impact of antennectomy on the thermal behaviour of the haematophagous bug Triatomainfestans, we studied the distribution of intact and antennectomised bugs in an experimental arena where a temperature gradient was established, as well as the biting response of insects with and without antennae to objects at the temperature of a potential host. Antennectomy did not abolish thermopreference, but modified the temperature at which the insects preferred to stay. In the arena, antennectomised insects chose to remain at a higher temperature (ca. 3°C higher in unfed bugs), and exhibited a larger dispersion around that preferred temperature, than intact bugs. In addition, ablated insects temporarily lost their ability to bite an object at the temperature of a potential host, but that ability was gradually recovered after the fifth day post-antennectomy. Results presented here show that thermoreceptors other than those located on the antennae can also guide thermal behaviours. We conclude that the function of antennal thermoreceptors can be taken over by other receptors located in different regions of the body. Those receptors have a different sensitivity and confer the insects with a different responsiveness.

[Implementing clinical pathways: some practical notes]. / L'implementazione dei percorsi: note pratiche.

The traditional biomedical paradigm is no longer a guarantee of quality for health care, facing increasingly difficult challenges caused by chronic diseases and increasingly fragmented resources that current healthcare systems are dealing with. Health care organizations, considered to be the most complex enterprises of the modern era, must be able to focus on the flow of patients, integrating primary and secondary care through tools such as the Integrated Care Pathways (ICP). This brief discussion attempts to define the ICP its purposes, the elements that characterize it, its limitations and the mechanisms to push for a successful implementation. In order to highlight the elements and basic steps for the creation of an ICP, the authors have compared five different clinical pathways, whose implementation they have contributed to. The comparison was made using two grids: the first showing the essential elements for the definition of lCP and the second one with features that can facilitate their effectiveness. The conclusions of the work show what, pursuing the construction of a pathway, we must never forget: to analyze the gap between the clinical-care activities performed and the theoretical framework provided by the evidence; to see the barriers to change that may impede the implementation; to involve all actors in the system, with particular attention to patients and their associations, and finally to provide a plan for information and education, addressed to health professionals and patients as well.

Associations between ABCC2 polymorphisms and cisplatin disposition and efficacy.

ABCC2 (MRP2, cMOAT) expression has been implicated in cisplatin resistance in vitro. In mice, cisplatin disposition and toxicity were unaffected by Abcc2 knockout (Abcc2−/−). Moreover, in cancer patients (n = 237), cisplatin pharmacokinetics (P > 0.12) and efficacy (P > 0.41) were not associated with seven of the single-nucleotide polymorphisms (SNPs) in ABCC2. These SNPs were also not correlated with ABCC2 expression in the NCI60 panel (P > 0.26) or with cisplatin-induced cytotoxicity (P = 0.21). These findings highlight the importance of verifying drug-transporter interactions with in vitro tests in humans.

HIPK2 phosphorylates ΔNp63α and promotes its degradation in response to DNA damage.

Homeodomain-interacting protein kinase 2 (HIPK2) is an emerging player in cell response to genotoxic agents that senses damage intensity and contributes to the cell's choice between cell cycle arrest and apoptosis. Phosphorylation of p53 at S46, an apoptosis-specific p53 posttranslational modification, is the most characterized HIPK2 function in response to lethal doses of ultraviolet (UV), ionizing radiation or different anticancer drugs, such as cisplatin, roscovitine and doxorubicin (DOX). Indeed, like p53, HIPK2 has been shown to contribute to the effectiveness of these treatments. Interestingly, p53-independent mechanisms of HIPK2-induced apoptosis were described for UV and tumor growth factor-ß treatments; however, it is unknown whether these mechanisms are relevant for the responses to anticancer drugs. Because of the importance of the so-called 'p53-independent apoptosis and drug response' in human cancer chemotherapy, we asked whether p53-independent factor(s) might be involved in HIPK2-mediated chemosensitivity. Here, we show that HIPK2 depletion by RNA interference induces resistance to different anticancer drugs even in p53-null cells, suggesting the involvement of HIPK2 targets other than p53 in response to chemotherapy. In particular, we found that HIPK2 phosphorylates and promotes proteasomal degradation of ΔNp63α, a prosurvival ΔN isoform of the p53 family member, p63. Indeed, effective cell response to different genotoxic agents was shown to require phosphorylation-induced proteasomal degradation of ΔNp63α. In DOX-treated cells, we show that HIPK2 depletion interferes with ΔNp63α degradation, and expression of a HIPK2-resistant ΔNp63α-Δ390 mutant induces chemoresistance. We identify T397 as the ΔNp63α residue phosphorylated by HIPK2, and show that the non-phosphorylatable ΔNp63α-T397A mutant is not degraded in the face of either HIPK2 overexpression or DOX treatment. These results indicate ΔNp63α as a novel target of HIPK2 in response to genotoxic drugs.

The role of extracellular conditions during CaCo-2 cells growth: a preliminary study for numerical model validation.

OBJECTIVES: One important limitation in cell therapy protocols, and regenerative medicine (an innovative and promising strategy for different pathologies treatment), is the lack of knowledge about cells engraftment, proliferation and differentiation. In order to allow an efficient and successful cell transplant, it is necessary to predict the logistics, economic and timing issues during cellular injection. It has been reported that several parameters, such as cells number, temperature and extracellular pH (pH0) value can influence metabolic pathways and cellular growth. Numerical analysis and model can help to reduce and understand the effects of the above environmental conditions on cell survival. The aim of this paper is to develop the first step of cells transplantation in order to identify "in vitro", which parameters can be useful to develop and validate a numerical model, able to evaluate "in vivo" cells engraftment and proliferation. MATERIAL AND METHODS: We studied the variation of extracellular parameters--such as medium volume, buffer system, nutrient concentrations and temperature on human colon carcinoma cells (CaCo-2) "in vitro culture"--pursuing the goal of understanding in deeper details cellular processes such as growth, metabolic activity, survival and pH0. RESULTS: Results showed that CaCo-2 cells growth and mortality increase after two days in culture when cells were suspended in 3.5 ml volume to respect of 10 ml volume. Different temperature values influenced CaCo-2 cells growth and metabolic activity showing a direct relationship with the volume of the medium. CONCLUSIONS: Our results describe as CaCo-2 cell growth, metabolic activity, mortality and extracellular pH were influenced by extracellular parameters, enabling us to develop and validate a numerical model to be use to predict cells engraftment and proliferation.

The morphology and fine structure of the giant interneurons of the wood cricket Nemobius sylvestris.

The structural and ultrastructural characteristics of giant interneurons in the terminal abdominal ganglion of the cricket Nemobius sylvestris were investigated by means of cobalt and fluorescent dye backfilling and transmission electron microscopy. The projections of the 8 eight pairs of the biggest ascending interneurons (giant interneurons) are described in detail. The somata of all interneurons analyzed are located contralateral to their axons, which project to the posterior region of the terminal ganglion and arborise in the cercal glomerulus. Neuron 7-1a is an exception, because its arborisation is restricted to the anterior region of the ganglion. The fine structure of giant interneurons shows typical features of highly active cells. We observed striking indentations in the perineural layer, enabling the somata of the giant interneurons to be very close to the haemolymph. The cercal glomerulus exhibits a high diversity of synaptic contacts (i.e. axo-dendritic, axo-axonic, dendro-axonic, and dendro-dendritic), as well as areas of tight junctions. Electrical synapses seem to be present, as well as mixed synapses. The anatomical organization of the giant interneurons is finally discussed in terms of functional implications and on a comparative basis.

[An organizational model for safety management in health services]. / Un modello organizzativo per la gestione della sicurezza in Sanità.

The authors are reporting a practical experience about safety management of health workers through the adoption of a management model inspired to the indications of International Standard for Quality Management. In the discussion they describe the integration path between the Prevention and protection Service and the Quality Office of the University Hospital of Bologna in order to promote the accomplishment of a progressive spirit of collaboration through the implementation of a shared and common management system which helped in the adoption of appropriate Improvement solutions in order to protect the safety of the health workers.

Cardiac resynchronization therapy: could a numerical simulator be a useful tool in order to predict the response of the biventricular pacemaker synchronization?

BACKGROUND AND OBJECTIVES: Cardiac resynchronization therapy (CRT) can be considered as an established therapy for patients with moderate or severe heart failure (HF), depressed systolic function and a wide QRS complex. Biventricular stimulation through the CRT is applied at patients with an intra and/or inter-ventricular conduction delay. The goal of this technique is to resynchronize contraction between and within ventricles. A numerical model of the cardiovascular system, together with the numerical model of the biventricular pacemaker (BPM), can be an useful tool to study the better synchronization of the BPM in order to reduce the inter-ventricular and/or intra-ventricular conduction delay. SUBJECTS AND METHODS: Within a group of patients which were representative of the most common disease etiologies of heart failure, seven patients, affected by dilated cardiomyopathy undergoing CRT with BPM, were studied and simulated using the numerical model of the cardiovascular system CARDIOSIM. The patients were submitted to echocardiographic evaluation (with pulsate Doppler and tissue Doppler imaging) and electrocardiography evaluation in order to evaluate intra-ventricular and/or inter-ventricular dyssynchrony. These evaluations were made three times: the first one before BPM implantation, the second and the third one respectively within seven days and six months after BPM implantation. Also haemodynamic parameters were measured. Using the software simulator, the pathological conditions before CRT, within seven days and within six months since CRT were reproduced for each patients in order to evaluate the following haemodynamic parameters: the end-systolic and end-diastolic left ventricular volume, the systolic pulmonary arterial pressure, the systolic, diastolic and mean aortic blood pressure and the ejection fraction. Also the trend of the left ventricular elastance was studied for each patient in order to evaluate the benefits produced by the CRT. RESULTS: The results obtained by means the numerical simulator were in good agreement with clinical data measured on the patients. For each patient also the evolution of the left ventricular elastance was in accordance with the literature data. CONCLUSION: The cardiovascular numerical model seems to be a useful tool to study the synchronization of the BPM in order to reduce the inter-ventricular and/or intra-ventricular conduction delay and to reproduce the condition of a patient.

HIPK2 is involved in cell proliferation and its suppression promotes growth arrest independently of DNA damage.

INTRODUCTION/OBJECTIVES: The serine/threonine kinase homeodomain-interacting protein kinase 2 (HIPK2) is a co-regulator of an increasing number of transcription factors and cofactors involved in DNA damage response and development. We and others have cloned HIPK2 as an interactor of the p53 oncosuppressor, and have studied the role of this interaction in cell response to stress. Nevertheless, our original cloning of HIPK2 as a p53-binding protein, was aimed at discovering partners of p53 involved in cell differentiation and development, still controversial p53 functions. To this aim, we used p53 as bait in yeast two-hybrid screening of a cDNA library from mouse embryo (day 11 postcoitus) when p53 is highly expressed. METHODS AND RESULTS: In this study, we directly explored whether HIPK2 and p53 cooperate in cell differentiation. By measuring HIPK2 expression and activity in skeletal muscle and haemopoietic differentiation, we observed inverse behaviour of HIPK2 and p53--excluding cooperation activity of these two factors in this event. However, by HIPK2 depletion experiments, we showed that drastic HIPK2 suppression promotes cell-cycle arrest by induction of the cyclin-dependent kinase inhibitor p21(Waf-1/Cip-1). HIPK2 activity is independent of DNA damage and takes place in cell-cycle-arresting conditions, such as terminal differentiation, growth factor deprivation, and G(0) resting. CONCLUSIONS: HIPK2 was found to be involved in cell-cycle regulation dependent on p21(Waf-1/Cip-1) and independent of DNA damage.

Application of a user-friendly comprehensive circulatory model for estimation of hemodynamic and ventricular variables.

PURPOSE: Application of a comprehensive, user-friendly, digital computer circulatory model to estimate hemodynamic and ventricular variables. METHODS: The closed-loop lumped parameter circulatory model represents the circulation at the level of large vessels. A variable elastance model reproduces ventricular ejection. The circulatory model has been modified embedding an algorithm able to adjust the model parameters reproducing specific circulatory conditions. The algorithm reads input variables: heart rate, aortic pressure, cardiac output, and left atrial pressure. After a preliminary estimate of circulatory parameters and ventricular elastance, it adjusts the amount of circulating blood, the value of the systemic peripheral resistance, left ventricular elastance, and ventricular rest volume. Input variables and the corresponding calculated variables are recursively compared: the procedure is stopped if the difference between input and calculated variables is within the set tolerance. At the procedure end, the model produces an estimate of ventricular volumes and Emaxl along with systemic and pulmonary pressures (output variables). The procedure has been tested using 4 sets of experimental data including left ventricular assist device assistance. RESULTS: The algorithm allows the reproduction of the circulatory conditions defined by all input variable sets, giving as well an estimate of output variables. CONCLUSIONS: The algorithm permits application of the model in environments where the simplicity of use and velocity of execution are of primary importance. Due to its modular structure, the model can be modified adding new circulatory districts or changing the existing ones. The model could also be applied in educational applications.

[Prospective observational study of pneumonia in an Italian hospital]. / Studio osservazionale prospettico delle polmoniti in un ospedale italiano.

A prospective observational study was conducted during a two-year period to evaluate the prevalence of hospitalized pneumonia in six hospital units of the Bologna S.Orsola-Malpighi hospital (Italy). The selected units were: general surgery, general medicine, internal medicine, geriatrics, respiratory physiopathology and pneumology, with a total of 205 beds and around 4,800 admissions per year. Data were collected from the clinical cards and cases of pneumonia were distinguished by origin (community-acquired or hospital-acquired according to CDC definition), individual and clinical characteristics, and aetiology. The study involved 486 cases of pneumonia: 75 hospital-acquired and 411 community-acquired (84.6%). Patients affected by hospital-acquired pneumonia were older (average age 77 years) compared to community-acquired cases (74 years) and show a more homogeneous gender distribution (males: 48.0% vs 59.4%). Hospital stays (42 vs 21 days) and mortality rates (24.0% vs 11.7%) were significantly higher in hospital-acquired pneumonia. The incidence rate of nosocomial pneumonia was 7.4 per 1000 hospitalized patients and increased to 17-23 per 1000 in the pneumology and respiratory physiopathology units. Only 16.9% of cases had an aetiological diagnosis (14.1% community-acquired; 31.8% hospital-acquired); the most common isolates were S. aureus and P. aeruginosa. The hospital-acquired cases were caused by Gram-negative bacilli more often than the community-acquired cases, and infections were more frequently polymicrobial (37.5% vs 3.4%). In order to reduce morbidity and mortality due to pneumonia it is important to implement prevention measures in the community (i.e. specific vaccination campaigns), improve clinical protocols for aetiological diagnosis in hospitalised patients and increase epidemiological surveillance of hospital-acquired infections.

Right ventricular assistance by continuous flow device. A numerical simulation.

OBJECTIVES: This work is another step in the development of the circulatory model CARDIOSIM and of its model library. Continuous flow assistance is often used to support the right ventricular failure. Computer simulation is one of the methods to study the effect of this assistance on the failing ventricle. The purpose of this study was to evaluate the effect of this support on some hemodynamic variables, when different right ventricular end-systolic elastance and pump speed values were applied. METHODS: The rotary blood pump model was included into the software package CARDIOSIM, which reproduces the cardiovascular system. Lumped parameters models were used to reproduce the circulatory phenomena. Variable elastance models reproduced the Starling's law of the heart for both ventricles. In the study right ventricular end-systolic elastance (EmaxRIGHT) and the rotational speed of the pump took three different values. All the other parameters of the model were constants. RESULTS: The rotational speed of the pump had a significant influence on right ventricular end-diastolic and end-systolic volumes, right atrial pressure (Pra), right ventricular (Qro) and pump flows. The effects on pulmonary arterial pressure (Pap) were more evident when the right ventricular end-systolic elastance was low. When the speed of the device increased the mean value of Pra decreased for each value of EmaxRIGHT. The total flow (Qro+pump flow) increased when the speed of the pump increased. CONCLUSIONS: Our simulation (in good agreement with the results presented in literature) showed that Hemopump produces a rise in total flow, a drop in blood flow pumped out by the right ventricle and a drop in right atrial pressure.

The impact of rotary blood pump in conjunction with mechanical ventilation on ventricular energetic parameters - numerical simulation.

OBJECTIVES: Aim of this work is to study the impact of left ventricular rotary blood pump assistance, on energetic variables, when mechanical ventilation (MV) of the lungs is applied. METHODS: Computer simulation was used to perform this study. Lumped parameter models reproduce the circulatory system. Variable elastance models reproduce the Starling's law of the heart for each ventricle. After the reproduction of ischemic heart disease left ventricular assistance was applied using a model of rotary blood pump. The pump speed was changed in steps and was assumed to be constant during each step. The influence of mechanical ventilation was introduced by different values of positive mean thoracic pressure. RESULTS: The increase of the rotational speed has a significant influence on some ventricular energetic variables. In fact it decreased left ventricular external work, left and right ventricular pressure-volume area and the left ventricular efficiency. Finally, it increased the right ventricular efficiency but had no influence on the right ventricular external work. The increase of thoracic pressure from -2 to +5 mmHg caused a significant decrease of external work, pressure-volume area (right ventricular pressure-volume area dropped up to 50%) and an increase of right ventricular efficiency (by 40%) while left ventricular efficiency remained almost stable. CONCLUSIONS: Numerical simulation is a very suitable tool to predict changes of not easily measurable parameters such as energetic ventricular variables when mechanical assistance of heart and/or lungs is applied independently or simultaneously.

Orientation response of haematophagous bugs to CO2: the effect of the temporal structure of the stimulus.

Carbon dioxide is generally recognized as an important cue used by haematophagous insects to locate a food source. When the mammalian hosts of these insects breathe, they normally emanate considerable amounts of CO2 at discrete intervals, i.e. with each exhalation. In this work, we analysed the effect of temporally pulsing CO2 on the host-seeking behaviour of Triatoma infestans. We investigated the ability of T. infestans to follow continuous and intermittent air pulses of 0.25, 0.5 and 1 Hz that included different concentrations of CO2. We found that insects were attracted to pulsed airstreams of 0.25 and 0.5 Hz transporting 400 ppm of CO2 above the ambient levels and to continuous streams added with the same amount of CO2. On the other hand, insects walked away from streams pulsed at rates of 1 Hz regardless of the amount of CO2 they bear. The walking trajectories displayed by bugs to attractive CO2-pulsed streams were as rectilinear and accurate as those to CO2-continuous streams. Our results are discussed in the frame of the interaction between olfactory and mechanoreceptive inputs as affecting the behavioural response of bugs.

Modelling in the study of interaction of Hemopump device and artificial ventilation.

The aim of this work is to evaluate in different ventricular conditions the influence of joint mechanical ventilation (MV) and Hemopump assistance. To perform this study, we used a computer simulator of human cardiovascular system where the influence of MV was introduced changing thoracic pressure to positive values. The simulation confirmed that haemodynamic variables are highly sensitive to thoracic pressure changes. On the other hand, Hemopump assistance raises, among the others, mean aortic pressure, total cardiac output (left ventricular output flow plus Hemopump flow) and coronary flow. The simulation showed that the joint action of Hemopump and positive thoracic pressure diminishes these effects.