Predicting particle deposition using a simplified 8-path in silico human lung prototype.

Understanding particle deposition in the human lung is crucial for the assessment of environmental pollutants and the design of new drug delivery systems. Traditionally, research has been carried out by experimental analysis, but this generally requires expensive equipment and exposure of volunteers to radiation, resulting in limited data. To overcome these drawbacks, there is an emphasis on the development of numerical models capable of accurate predictive analysis. The most advanced of these computer simulations are based on three-dimensional computational fluid dynamics. Solving the flow equations in a complete, fully resolved lung airway model is currently not feasible due to the computational resources required. In the present work, a simplified lung model is presented and validated for accurate prediction of particle deposition. Simulations are performed for an 8-path approximation to a full lung airway model. A novel boundary condition method is used to ensure accurate results in truncated flow branches. Simulations are performed at a steady inhalation flow rate of 18 l min-1, corresponding to a low activity breathing rate, while the effects of particle size and density are investigated. Comparison of the simulation results with available experimental data shows that reasonably accurate results can be obtained at a small fraction of the cost of a full airway model. The simulations clearly evaluate the effect of both particle size and particle density. Most importantly, the results show an improvement over a previously documented single-path model, both in terms of accuracy and the ability to obtain regional deposition rates. The present model represents an improvement over previously used simplified models, including single-path models. The multi-path reduced airway approach described can be used by researchers for general and patient-specific analyses of particle deposition and for the design of effective drug delivery systems.

Construction of a hybrid lung model by combining a real geometry of the upper airways and an idealized geometry of the lower airways.

BACKGROUND AND OBJECTIVE: Health care costs represent a substantial an increasing percentage of global expenditures. One key component is treatment of respiratory diseases, which account for one in twelve deaths in Europe. Computational simulations of lung airflow have potential to provide considerable cost reduction and improved outcomes. Such simulations require accurate in silico modeling of the lung airway. The geometry of the lung is extremely complex and for this reason very simple morphologies have primarily been used to date. The objective of this work is to develop an effective methodology for the creation of hybrid pulmonary geometries combining patient-specific models obtained from CT images and idealized pulmonary models, for the purpose of carrying out experimental and numerical studies on aerosol/particle transport and deposition in inhaled drug delivery. METHODS: For the construction of the hybrid numerical model, lung images obtained from computed tomography were exported to the DICOM format to be treated with a commercial software to build the patient-specific part of the model. At the distal terminus of each airway of this portion of the model, an idealization of a single airway path is connected, extending to the sixteenth generation. Because these two parts have different endings, it is necessary to create an intermediate solid to link them together. Physically realistic treatment of truncated airway boundaries in the model was accomplished by mapping of the flow velocity distribution from corresponding conducting airway segments. RESULTS: The model was verified using two sets of simulations, steady inspiration/expiration and transient simulation of forced spirometry. The results showed that the hybrid model is capable of providing a realistic description of air flow dynamics in the lung while substantially reducing computational costs relative to models of the full airway tree. CONCLUSIONS: The model development outlined here represents an important step toward computational simulation of lung dynamics for patient-specific applications. Further research work may consist of investigating specific diseases, such as chronic bronchitis and pulmonary emphysema, as well as the study of the deposition of pollutants or drugs in the airways.

Implementation of a specific boundary condition for a simplified symmetric single-path CFD lung model with OpenFOAM.

CFD modeling research about the lung airflow with a complete resolution and an adequate accuracy at all scales requires a great amount of computational resources due to the vast number of necessary grid elements. As a result, a common practice is to conduct simplifications that allows to manage it with ordinary computational power. In this study, the implementation of a special boundary condition in order to develop a simplified single conductive lung airway model, which exactly represents the effect of the removed airways, is presented. The boundary condition is programmed in the open-source software OpenFOAM®, and the developed source code is presented in the proper syntax. After this description, modeling accuracy is evaluated under different flow rate conditions typical of human breathing processes, including both inspiration and expiration movements. Afterward, a validation process is conducted using results of a Weibel's model (0-4 generations) simulation for a medium flow rate of 50 L/min. Finally, a comparison against the proposed boundary condition implemented in the commercial code ANSYS Fluent is made, which highlights the benefits of using the free code toolbox. The specific contribution of this paper will be to show that OpenFOAM® developed model can perform even better than other commercial codes due to a precise implementation and coupling of the default solver with the in-house functions by virtue of the open-source nature of the code.

Assessment of cryopreserved donor skin viability: the experience of the regional tissue bank of Siena.

Skin allografts from cadaver donors are an important resource for treating extensive burns, slow-healing wounds and chronic ulcers. A high level of cell viability of cryopreserved allografts is often required, especially in burn surgery, in Italy. Thus, we aimed to determine which conditions enable procurement of highly viable skin in our Regional Skin Bank of Siena. For this purpose, we assessed cell viability of cryopreserved skin allografts procured between 2011 and 2013 from 127 consecutive skin donors, before and after freezing (at day 15, 180, and 365). For each skin donor, we collected data concerning clinical history (age, sex, smoking, phototype, dyslipidemia, diabetes, cause of death), donation process (multi-tissue or multi-organ) and timing of skin procurement (assessment of intervals such as death-harvesting, harvesting-banking, death-banking). All these variables were analysed in the whole case study (127 donors) and in different groups (e.g. multi-organ donors, non refrigerated multi-tissue donors, refrigerated multi-tissue donors) for correlations with cell viability. Our results indicated that cryopreserved skin allografts with higher cell viability were obtained from female, non smoker, heartbeating donors died of cerebral haemorrhage, and were harvested within 2 h of aortic clamping and banked within 12 h of harvesting (13-14 h from clamping). Age, cause of death and dyslipidaemia or diabetes did not appear to influence cell viability. To maintain acceptable cell viability, our skin bank needs to reduce the time interval between harvesting and banking, especially for refrigerated donors.

Diagnostic and neural analysis of skin cancer (DANAOS). A multicentre study for collection and computer-aided analysis of data from pigmented skin lesions using digital dermoscopy.

BACKGROUND: Early detection of melanomas by means of diverse screening campaigns is an important step towards a reduction in mortality. Computer-aided analysis of digital images obtained by dermoscopy has been reported to be an accurate, practical and time-saving tool for the evaluation of pigmented skin lesions (PSLs). A prototype for the computer-aided diagnosis of PSLs using artificial neural networks (NNs) has recently been developed: diagnostic and neural analysis of skin cancer (DANAOS). OBJECTIVES: To demonstrate the accuracy of PSL diagnosis by the DANAOS expert system, a multicentre study on a diverse multinational population was conducted. METHODS: A calibrated camera system was developed and used to collect images of PSLs in a multicentre study in 13 dermatology centres in nine European countries. The dataset was used to train an NN expert system for the computer-aided diagnosis of melanoma. We analysed different aspects of the data collection and its influence on the performance of the expert system. The NN expert system was trained with a dataset of 2218 dermoscopic images of PSLs. RESULTS: The resulting expert system showed a performance similar to that of dermatologists as published in the literature. The performance depended on the size and quality of the database and its selection. CONCLUSIONS: The need for a large database, the usefulness of multicentre data collection, as well as the benefit of a representative collection of cases from clinical practice, were demonstrated in this trial. Images that were difficult to classify using the NN expert system were not identical to those found difficult to classify by clinicians. We suggest therefore that the combination of clinician and computer may potentially increase the accuracy of PSL diagnosis. This may result in improved detection of melanoma and a reduction in unnecessary excisions.

The 'common mole' from the point of view of digital dermoscopy analysis: subjective vs. objective evaluation of easy pigmented skin lesions.

BACKGROUND: The term 'common mole', often used to describe a subset of benign pigmented skin lesions, is traditionally defined on the basis of morpho-chromatic features. In recent years, certain research groups have developed equipment and methods, such as digital dermoscopy analysis, that enable objective evaluation of pigmented skin lesions. OBJECTIVE: In this study we use a digital dermoscopy analyser trained for the recognition of pigmented skin lesions to compare the subjective definition of 'common' and the mathematical concept of 'close to the mean of measurements'. METHODS: A subset (100) of digital images of flat pigmented lesions, obtained in daily practice, were classified by trained and non-expert clinicians as common moles (60) or clear-cut melanoma (40), and processed with a DB-Mips analyser. The resulting parameters, validated by a classifier, were used to evaluate Hotelling's T2 multivariate distances from the mean. RESULTS: 'Common' moles could not be clearly defined in terms of closeness to the means of objectively evaluated parameters. Their diagnosis indudes many other evaluations and clusters of variables. CONCLUSION: The clinical semantics of the term 'common' does not conform to any unambiguous mathematical definition.

Corpus callosum agenesis, multiple cysts, skin defects, and subtle ocular abnormalities with a de novo mutation [45,XX,der(5), t(5;;14) (pter;q11.2)].

We report on a 2-year-old girl with a de novo mutation [45,XX,der(5),t(5;14) (pter;q11.2)] with corpus callosum agenesis, multiple cysts (cerebral and cardiac), subtle eye abnormalities, and at least two different skin defects, strongly indicating neuroectodermal involvement, as a neuromuscular choristoma (hamartoma) and an eccrine hamartoma. Fluorescent in situ hybridization with different single-locus probes showed that chromosome 5 has a very small deletion, confined to a region composed of repetitive sequences. By contrast, the long (q) arm of chromosome 14 seems to be much more involved in the rearrangement, with partial monosomy spanning from the centromere to the D14S72 and D14S261 loci. The extent of the deleted region of chromosome 14 is approximately 16 cM. To our knowledge, this is the smallest reported deletion involving the chromosome 14q11.2 region to be associated with a developmental disorder resulting in variable eye, skin, and brain anomalies. We suggest that a new syndrome, mimicking in some ways the MLS phenotype, is caused by a deletion in the chromosome 14q11.2 region.

Differentiation between pigmented Spitz naevus and melanoma by digital dermoscopy and stepwise logistic discriminant analysis.

Epiluminescence light microscopy (ELM) has proven useful in the diagnosis of pigmented skin lesions (PSLs). However, in some cases this technique does not sufficiently increase the diagnostic accuracy in distinguishing pigmented Spitz naevi (PSNs) from melanoma. With the aim of obviating these problems of qualitative interpretation, methods based on the mathematical analysis of PSLs, such as digital dermoscopy analysis (DDA), have recently been developed. In the present study we used a digital dermoscope (DBDermo-MIPS, Dell'Eva-Burroni) to analyse PSNs and melanomas with similar clinical and dermoscopic features for any correlation between variables and to determine its discriminating power with respect to histological diagnosis. The 100 lesions underwent histological examination by three experienced dermatopathologists and were identified as PSNs (43) or melanomas (57). Thirty-six parameters were identified as possible discriminating variables and were grouped in four categories: geometry, colour, texture, and islands of colour. Statistical analysis was used to identify the variables with the highest discriminating power. Stepwise discriminant analysis selected only four variables: entropy, minimum diameter, red lesion value and peripheral dark (the means of these variables were higher in melanomas than in PSNs). Thus the combined use of digital dermoscopy and stepwise logistic discriminant analysis made it possible to single out the best objective variables for distinguishing PSN and melanoma.

Detection of telomerase activity and correlation with mitotic and apoptotic indices, Ki-67 and expression of cyclins D1 and A in cutaneous melanoma.

Telomerase plays a key role in carcinogenesis. It is activated in most immortal cell lines and human cancers, including cutaneous melanoma (CM). Increased cell proliferation and deregulation of the cell cycle occur in human cancers. Links between telomerase activity (TA), cell proliferation, cell death and expression of cell-cycle regulators have not been extensively elucidated in CM. In this study, we investigated TA, mitotic index (MI), apoptotic index (AI), Ki-67 and nuclear positivity of cyclins D1 and A (Ki-67+ N/1,000, cyclin D1+N/1,000, cyclin A+N/1,000) in 42 primary cutaneous melanomas (PCMs). TA was detected in all cases and directly correlated with MI, Ki-67+N/1,000, cyclin D1+N/1,000 and cyclin A+N/1,000 (p < 0.001); it was not correlated with AI. When subdividing PCMs into radial and vertical growth phase melanomas (RGPMs, VGPMs), a correlation was maintained only with MI (p < 0.005) and cyclin D1 +N/1,000 (p < 0.005). Although MI and Ki-67+N/1,000 were highly correlated with cyclin D1+N/1,000 and cyclin A+N/1,000 (p < 0.001) when considering all cases together, a high correlation was found in the RGPM and VGPM groups between cyclin A+N/1,000 and Ki-67+N/1,000 only (p < 0.001), thus suggesting that cyclin A is more closely correlated with cell proliferation than cyclin D1. Our results further support the association between TA, tumor cell proliferation and cyclin D1 and A expression in PCM, though it is possible that links between TA and proliferation, on the one hand, and TA and cyclin D1 expression, on the other, might occur following various pathways.

Digital dermoscopy analysis for the differentiation of atypical nevi and early melanoma: a new quantitative semiology.

OBJECTIVES: To use a digital dermoscopy analyzer with a series of "borderline" pigmentary skin lesions (ie, clinically atypical nevi and early melanoma) to find correlation between the studied variables and to determine their discriminating power with respect to histological diagnosis. DESIGN: A total of 147 pigmentary skin lesions were histologically examined by 3 experienced dermatopathologists and identified as nevi (n = 90) and melanomas (n = 57). The system evaluated 36 variables to be studied as possible discriminant variables, grouped into 4 categories: geometries, colors, textures, and islands of color. SETTING: University medical department. PATIENTS: A sample of patients with excised pigmentary skin lesions (nevi and melanomas). MAIN OUTCOME MEASURES: Sensitivity, specificity, and accuracy of the model for evaluating "borderline" pigmentary skin lesions. RESULTS: After multivariate stepwise discriminant analysis, only 13 variables were selected to compute the canonical discriminant function. CONCLUSION: The present method made it possible to determine which objective variables are important for distinguishing atypical benign pigmentary skin lesions and early melanoma.

[Variation, over time, in the pH of the materials used for pulpal-dentinal protection. A new measurement method]. / Variazione, nel tempo, del pH di materiali usati per la protezione pulpo-dentinale. Una nuova metodica di misura.

A modern AmpHel pH-meter permits the easy determination of dental materials pH. This new instrument has allowed, analysing seven cements and two varnishes used for pulpodentinal protection, continuously to specify this important parameter's modifications in the long run. The results of this study, conducted for six hours after cement mixing or varnishes application, certified glass ionomer cements' (Ketac-Cem, Fuji-Ionomer II) strong acidity, even higher than well known zinc phosphates' acidity is. A cavity liner's (Tubulitec) pH from an initial value of 6.07 decreased to 5.04 at sixth hour. On the contrary, much lower were the acidity of a modified ZOE (Temrex) and the one of a cavity varnish (Copalite): both showed a physiological pH from the beginning of the test.

[Percutaneous approach in the use of subclavian vein in pacemaker implantation]. / Utilizzo della vena succlavia per via percutanea per impianto di pacemaker.

BACKGROUND AND METHODS: We analyzed the complications of 1729 pacemakers implants (from October 1980 to December 1992) divided according to the way of leads insertion. The approaches from the subclavian vein was used in 1220 cases, the cephalic vein was used in 431 implants and the external jugular vein in 78. RESULTS: Major complications were: pocket bleeding (108 cases), pocket erosion (15 cases), infection (2 cases), lead fracture (5 cases), lead dislodgement (20 cases), pneumothorax (4 cases, only for subclavian puncture). There were no significative differences in the complications between the three approaches. On the other hand, the subclavian puncture reduces the time of the procedure, is less traumatic and allows to insert and to position several leads. CONCLUSIONS: We suggest to use the subclavian vein approach as first choice to implant one or more leads, being this way safe and fast.

[Different susceptibilities to the development of nitroglycerin tolerance in the human peripheral venous and arterial circulations]. / Differente suscettibilità allo sviluppo di tolleranza alla nitroglicerina nella circolazione venosa ed arteriosa periferica dell'uomo.

Aim of the study was to assess the relative susceptibility to the development of nitroglycerin tolerance in the arterial and venous circulation in man and to evaluate the interactions between nitroglycerin and N-acetylcysteine. Twenty patients with coronary artery disease underwent a continuous 24-h nitroglycerin infusion followed by a bolus administration of N-acetylcysteine. Forearm blood flow (ml/100 ml/min) and venous volume (ml/100 ml) were measured by strain gauge plethysmography under control conditions, at the end of nitroglycerin titration, after 24 h of infusion and after N-acetylcysteine; vascular resistance was calculated as mean cuff blood pressure/flow. After 24 h of nitroglycerin infusion, the initial increase in venous volume was reduced by 48% (p < 0.01), while the acute effects on vascular resistance were not attenuated in the whole group. N-acetylcysteine restored nitroglycerin venodilator effects in all 10 patients who developed venous tolerance but did not change significantly vascular resistance in 5 patients in whom attenuation of the arterial effects was observed during the infusion period. In conclusion, the results indicate that the susceptibility to the development of nitrate tolerance in man is higher in the venous than in the arterial circulation and that the sulphydryl group donor N-acetylcysteine is more effective in reversing nitroglycerin tolerance in the venous than in the arterial circulation.

Different susceptibility to the development of nitroglycerin tolerance in the arterial and venous circulation in humans. Effects of N-acetylcysteine administration.

BACKGROUND: Tolerance to the effects of organic nitrates develops rapidly during continuous exposure to these drugs; its main mechanism seems to be an intracellular sulfhydryl group depletion. However, the relative susceptibility to the development of nitroglycerin tolerance of the arterial or venous circulation in humans is still a matter of dispute. METHODS AND RESULTS: Twenty patients with coronary artery disease underwent a continuous 24-hour nitroglycerin infusion followed by a bolus administration of N-acetylcysteine. Forearm blood flow (ml/100 ml/min) and venous volume (ml/100 ml) were measured by strain gauge plethysmography under control conditions, at the end of nitroglycerin titration, after 24-hour infusion, and after N-acetylcysteine; vascular resistance was calculated as mean cuff blood pressure divided by flow. After 24 hours of nitroglycerin infusion, the initial increase in venous volume was reduced 48% (p less than 0.01), whereas the acute effects on vascular resistance were not attenuated in the whole group. N-Acetylcysteine completely restored nitroglycerin venodilator effects in all 10 patients in whom attenuation of the venous effects was observed during the infusion period. CONCLUSIONS: The data indicate that the susceptibility to the development of nitrate tolerance in humans is higher in the venous than in the arterial circulation, and that the sulfhydryl group donor N-acetylcysteine is extremely effective in reversing nitroglycerin tolerance in the venous circulation in humans.

[A weight and surface analysis of glass ionomer cements in the presence of acid solutions]. / Analisi ponderale e della superficie di cementi vetroionomerici in presenza di soluzioni acide.

The surface and solubility of some glass ionomer cements have been assessed after exposure to four acids (acetic, formic, lactic and propionic), that are usually present in the bacterial plaque. Therefore, we prepared 80 samples--20 for earl of 4 commercial products; after 7 days and, then after 30 other days, the samples were examined by microscope and weighed. Finally, those showing the most significant modifications were photographed.

[Hemodynamic benefits of sequential atrioventricular pacing]. / Beneficio emodinamico della stimolazione sequenziale atrio-ventricolare.

The purpose of this study was to evaluate the hemodynamic benefits of atrioventricular (A-V) sequential pacing. 30 pts implanted with DDD pacemakers underwent M-mode, B-mode and Doppler echocardiography. In each patient, left ventricular (LV) stroke volume was assessed by measuring the time-velocity integral of mitral inflow in the following modes and rates: VOO at 70 ppm or at the minimum stimulation rate and at 120 ppm; DOO at the same rates with different A-V delay (100, 150, 200, 250 and, whenever possible, 300 msec). The increase in stroke volume obtained with dual chamber pacing at the optimal A-V delay was 45 +/- 25% at 75 ppm and 29 +/- 14% at 120 ppm (p less than 0.05 75 vs 120 ppm). This increase was significantly higher in pts with than in pts without LV hypertrophy (respectively: 51.9 +/- 20.4 vs 36.9 +/- 20.8% at 75 ppm, p less than 0.05 and 33 +/- 13.4 vs 25.4 +/- 14.5% at 120 ppm, p = 0.08). Concerning the A-V delay, we noted that at 75 ppm stroke volume was significantly higher in DOO than in VOO with any A-V delay ranging +/- 100 msec from the optimal one; at 120 ppm the hemodynamic benefit of DOO pacing was observed only when the programmed A-V delay was the optimal one or very near to it. In conclusion, atrio-ventricular sequential pacing allows a significant increase in LV stroke volume over single chamber ventricular pacing both at 75 and 120 ppm. Programming the optimal A-V delay is absolutely necessary to obtain this hemodynamic benefit at the higher stimulation rate.