Functional Transcranial Doppler (fTCD) investigation of brain lateralization following visual stimuli.

This preliminary investigation of the local cerebral perfusion evaluated by Transcranial Doppler (TCD) monitoring of the Posterior Cerebral Arteries shows that selective stimulation of visual hemifields evokes significantly different vascular responses. TCD can therefore allow for functional evaluation of lateralized enhancements in cerebral metabolism.Clinical Relevance-The cerebral lateralization evaluated with the functional TCD can be a useful and low-cost approach to evaluate the effectiveness of the rehabilitation therapy in post stroke subjects experiencing hemianopia or to assess cerebral reorganization after cerebrovascular accidents.

A Compartmental Model for the Iron Trafficking Across the Blood-Brain Barriers in Neurodegenerative Diseases.

Iron accumulation in the brain is supposed to play a central role in the induction of oxidative stress and consequently in neurodegeneration. The sensitive balance of iron in the brain is maintained by the brain barriers system, i.e., the blood-brain barrier between the blood and brain interstitial fluid and the blood-cerebrospinal fluid barrier between the blood and cerebrospinal fluid (CSF). In this work, we proposed a three-compartmental mathematical model simulating iron trafficking between blood, CSF, and cerebral space, describing the direction of fluxes based on the structural and functional characteristics of the brain barriers system. Different techniques of sensitivity analysis were used to evaluate the most important parameters, providing an indication for the most relevant biological functions that potentially affect the physiological transport of iron across brain barriers.

A mathematical model for the evaluation of iron transport across the blood-cerebrospinal fluid barrier in neurodegenerative diseases.

Iron plays important roles in healthy brain but altered homeostasis and concentration have been correlated to aging and neurodegenerative diseases. Iron enters the central nervous system by crossing the brain barrier systems: the Blood- Brain Barrier separating blood and brain and the Blood-Cerebrospinal Fluid Barrier (BCSFB) between blood and CSF, which is in contact with the brain by far less selective barriers. Herein, we develop a two-compartmental model for the BCSFB, based on first-order ordinary differential equations, performing numerical simulations and sensitivity analysis. Furthermore, as input parameters of the model, experimental data from patients affected by Alzheimer's disease, frontotemporal dementia, mild cognitive impairment and matched neurological controls were used, with the aim of investigating the differences between physiological and pathological conditions in the regulation of iron passage between blood and CSF which can be possibly targeted by therapy.

Low-dose curcuminoid-loaded in dextran nanobubbles can prevent metastatic spreading in prostate cancer cells.

Preventing recurrences and metastasis of prostate cancer after prostatectomy by administering adjuvant therapies is quite a controversial issue. In addition to effectiveness, absence of side effects and long term toxicity are mandatory. Curcuminoids (Curc) extracted with innovative techniques and effectively loaded by polymeric nanobubbles (Curc-NBs) satisfy such requirements. Curc-NBs showed stable over 30 d, were effectively internalized by tumor cells and were able to slowly release Curc in a sustained way. Significant biological effects were detected in PC-3 and DU-145 cell lines where Curc-NBs were able to inhibit adhesion and migration, to promote cell apoptosis and to affect cell viability and colony-forming capacity in a dose-dependent manner. Since the favourable effects are already detectable at very low doses, which can be reached at a clinical level, the actual drug concentration can be visualized and monitored by US or MRI, Curc-NBs can be proposed as an effective adjuvant theranostic tool.

Long-term response to recombinant human growth hormone treatment: a new predictive mathematical method.

INTRODUCTION: Recombinant GH has been offered to GH-deficient (GHD) subjects for more than 30 years, in order to improve height and growth velocity in children and to enhance metabolic effects in adults. AIM: The aim of our work is to describe the long-term effect of rhGH treatment in GHD pediatric patients, suggesting a growth prediction model. MATERIAL AND METHODS: A homogeneous database is defined for diagnosis and treatment modalities, based on GHD patients afferent to Hospital Regina Margherita in Turin (Italy). In this study, 232 GHD patients are selected (204 idiopathic GHD and 28 organic GHD). Each measure is shown in terms of mean with relative standard deviations (SD) and 95% confidence interval (95% CI). To estimate the final height of each patient on the basis of few measures, a mathematical growth prediction model [based on Gompertzian function and a mixed method based on the radial basis functions (RBFs) and the particle swarm optimization (PSO) models] was performed. RESULTS: The results seem to highlight the benefits of an early start of treatment, further confirming what is suggested by the literature. Generally, the RBF-PSO method shows a good reliability in the prediction of the final height. Indeed, RMSE is always lower than 4, i.e., in average the forecast will differ at most of 4 cm to the real value. CONCLUSIONS: In conclusion, the large and accurate database of Italian GHD patients allowed us to assess the rhGH treatment efficacy and compare the results with those obtained in other Countries. Moreover, we proposed and validated a new mathematical model forecasting the expected final height after therapy which was validated on our cohort.

Is there still a role for computed tomography and bone scintigraphy in prostate cancer staging? An analysis from the EUREKA-1 database.

PURPOSE: According to the current guidelines, computed tomography (CT) and bone scintigraphy (BS) are optional in intermediate-risk and recommended in high-risk prostate cancer (PCa). We wonder whether it is time for these examinations to be dismissed, evaluating their staging accuracy in a large cohort of radical prostatectomy (RP) patients. METHODS: To evaluate the ability of CT to predict lymph node involvement (LNI), we included 1091 patients treated with RP and pelvic lymph node dissection, previously staged with abdomino-pelvic CT. As for bone metastases, we included 1145 PCa patients deemed fit for surgery, previously staged with Tc-99m methylene diphosphonate planar BS. RESULTS: CT scan showed a sensitivity and specificity in predicting LNI of 8.8 and 98 %; subgroup analysis disclosed a significant association only for the high-risk subgroup of 334 patients (P 0.009) with a sensitivity of 11.8 % and positive predictive value (PPV) of 44.4 %. However, logistic multivariate regression analysis including preoperative risk factors excluded any additional predictive ability of CT even in the high-risk group (P 0.40). These data are confirmed by ROC curve analysis, showing a low AUC of 54 % for CT, compared with 69 % for Partin tables and 80 % for Briganti nomogram. BS showed some positivity in 74 cases, only four of whom progressed, while 49 patients with negative BS progressed during their follow-up, six of them immediately after surgery. CONCLUSIONS: According to our opinion, the role of CT and BS should be restricted to selected high-risk patients, while clinical predictive nomograms should be adopted for the surgical planning.

Review: Feto-placental vascularization: a multifaceted approach.

Doppler Ultrasound allows the in vivo study of feto-placental hemodynamics. Doppler flow velocity waveforms (FVW's) obtained from the umbilical arteries reflect downstream blood flow impedance, thus giving indirect evidence of vascular villous tree characteristics. Pulsatility Index, which quantifies FVW's, decreases throughout normal pregnancy, indicating decreasing impedance and is often higher in cases of fetal growth restriction (FGR). Different approaches (morphometrical, morphological, mathematical, immunohistochemical and molecular) have contributed to elucidation of which anomalies of the vascular villous tree underlie Doppler findings. 3D ultrasound may be useful in the study of feto-placental perfusion. However, the unsolved question is why developmental villous tree anomalies occur. Crucial to the success of future research is definition of the population studied based on the uniform and correct definition of FGR.

Non-linear recurrence analysis of NREM human sleep microstructure discloses deterministic oscillation patterns related to sleep stage transitions and sleep maintenance.

Sleep is a dynamic process aimed at obtaining the required neurophysiological states at certain times, according to circadian and homeostatic needs and despite external or internal interfering stimuli. In this context, peculiar transient synchronized EEG patterns (TSEP) are supposed to play the main role in the building up of EEG synchronization and in the flexible adaptation against perturbations Our study aimed at disclosing and quantifying attractor driven, hidden periodicity or, conversely, chaotic oscillation patterns in the series of these TSEP related to sleep stage transitions and sleep maintenance. At first we devised a multistep algorithm, able to capture TSEP from EEG during sleep in 10 healthy volunteers. The time series of TSEP were then analyzed according to the Recurrence Plot (RP). TSEP series showed to form a pseudo-periodic series which becomes progressively denser and more stable until steady slow wave NREM sleep is reached, but looses stability just before REM sleep starts. This suggests that deterministic oscillatory patterns maybe adequate descriptors of the balance between homeostatic needs for NREM sleep and REM sleep pressure, supported by different cortical neuronal populations interactions.

Oscillations in growth of multicellular tumour spheroids: a revisited quantitative analysis.

OBJECTIVES: Multicellular tumour spheroids (MTS) provide an important tool for study of the microscopic properties of solid tumours and their responses to therapy. Thus, observation of large-scale volume oscillations in MTS, reported several years ago by two independent groups (1,2), in our opinion represent a remarkable discovery, particularly if this could promote careful investigation of the possible occurrence of volume oscillations of tumours 'in vivo'. MATERIALS AND METHODS: Because of high background noise, quantitative analysis of properties of observed oscillations has not been possible in previous studies. Such an analysis can be now performed, thanks to a recently proposed approach, based on formalism of phenomenological universalities (PUN). RESULTS: Results have provided unambiguous confirmation of the existence of MTS volume oscillations, and quantitative evaluation of their properties, for two tumour cell lines. Proof is based not only on quality of fitting of the experimental datasets, but also on determination of well-defined values of frequency and amplitude of the oscillations for each line investigated, which would not be consistent with random fluctuation. CONCLUSIONS: Biological mechanisms, which can be directly responsible for observed oscillations, are proposed, which relates also to recent work on related topics. Further investigations, both at experimental and at modelling levels, are also suggested. Finally, from a methodological point of view, results obtained represent further confirmation of applicability and usefulness of the PUN approach.

Preparation and characterization of dextran nanobubbles for oxygen delivery.

Dextran nanobubbles were prepared with a dextran shell and a perfluoropentan core in which oxygen was stored. To increase the stability polyvinylpirrolidone was also added to the formulation as stabilizing agent. Rhodamine B was used as fluorescent marker to obtain fluorescent nanobubbles. The nanobubble formulations showed sizes of about 500nm, a negative surface charge and a good capacity of loading oxygen, no hemolytic activity or toxic effect on cell lines. The fluorescent labelled nanobubbles could be internalized in Vero cells. Oxygen-filled nanobubbles were able to release oxygen in different hypoxic solutions at different time after their preparation in in vitro experiments. The oxygen release kinetics could be enhanced after nanobubble insonation with ultrasound at 2.5MHz. The oxygen-filled nanobubble formulations might be proposed for therapeutic applications in various diseases.

Radio hyperthermia for re-treatment of superficial tumours.

PURPOSE: Relapse remains an unsolved problem for previously radio-treated patients. Our purpose is to evaluate the role of radio-hyperthermia (RT-HT) in the retreatment of superficial recurrences. MATERIALS AND METHODS: From 1998 to 2007, 51 patients affected by four histological types (breast recurrences (group A), melanoma recurrences (group B), head and neck recurrences (group C), and others (group D)) of 76 superficial lesions, were enrolled at Mauriziano Hospital at the Research Institute of Cancer Care Candiolo (IRCC) in Turin. All patients had previously undergone RT except 6 patients of group B. The total mean retreatment dose was 31.8 Gy (20-60 Gy), while the mean of HT sessions was 5 (1 to 8), temperature ranged from 38.5 degrees C (T min) to 44 degrees C (T max). RESULTS: Acute cutaneous toxicity was 77.6% G1, 22.4% G2, none for G3. Forty-five days later we observed: for group A 65.9% complete response (CR), 29.5% partial response (PR), 4.5% non-response (NR); for group B 33.3% CR, 25% PR and 41.7% NR; for group C 40% CR, 13.3% PR, 46.7% NR, for group D 60% CR and 40% NR. 18 months later group A presented 72.7% local control (LC), 20.5% stable disease (SD) and 6.8% non-control (NC), group B 50% LC, 16,7% SD and 33.3% NC, group C 33.3% LC, 40% SD and 26.7% NC, group D 40% LC and 60% NC. Early response, size of lesions < or =3 cm, T max > or =42 degrees C and RT doses > or =40 Gy were predictive outcome factors. CONCLUSIONS: We confirmed that radio-hyperthermia is useful in re-irradiation with a very high patient compliance.

Cancer metabolism and the dynamics of metastasis.

Cancer growth dynamics, commonly simulated with a Gompertzian model, is analyzed in the framework of a more recent and realistic model. In particular, we consider the setting of a tumor embedded in a host organ and investigate their interaction. We assume that, at least in some cases, tumor metastasis may be triggered by an 'energetic crisis', when the tumor exceeds the 'carrying capacity' of the host organ. As a consequence, dissemination of clusters of cancer cells is set in motion, with a statistical probability given by a Poisson distribution. The model, although still at a preclinical level, is fully quantitative and is applied, as an example, to the case of prostate cancer. The results confirm that, at least for the more aggressive cancers, metastasis starts very early during tumorigenesis and a quantitative link is found between the tumor's doubling time, its 'aggressiveness' and the metastatic potential.

Is three-dimensional power Doppler ultrasound useful in the assessment of placental perfusion in normal and growth-restricted pregnancies?

OBJECTIVES: To investigate three-dimensional (3D) power Doppler ultrasound indices in the assessment of placental perfusion and their relationship to gestational age (GA), placental position and umbilical artery Doppler flow velocity waveform (FVW) patterns in normal and intrauterine growth-restricted (IUGR) pregnancies. METHODS: Forty-five pregnant women at 23-37 weeks' gestation were studied, of whom 30 had IUGR and 15 were controls. Nine of the IUGR group had normal umbilical FVWs (NED), nine had abnormal patterns but positive end-diastolic velocities (PED) and 12 had absent or reversed end-diastolic velocities (AED). Placental position was assessed as being posterior, anterior or lateral. 3D power Doppler indices related to placental perfusion (vascularization index (VI), vascularization flow index (VFI) and flow index (FI)) were obtained from five different sampling sites in each placenta. RESULTS: VI, VFI and FI were not significantly dependent on GA or placental position. VI and VFI were significantly lower in PED and AED cases compared with controls, while FI was reduced in the AED group only. VI and VFI showed high variability between different sampling sites within each placenta, while the variability of FI was much lower. CONCLUSIONS: 3D power Doppler sonography can provide new insights into placental pathophysiology. FI, which identifies the most severe cases of placental impairment, appears to be the most reliable index because of its low intraplacental variability. Further studies are needed to verify its accuracy when applied in clinical practice as a substitute for or an adjunct to umbilical artery Doppler studies.

Automatic detection of transient EEG events during sleep can be improved using a multi-channel approach.

OBJECTIVE: Automatic methods developed to detect transient EEG events during sleep may present a degree of arbitrariness in the choice of appropriate channels or amplitude thresholds for the analysis. To overcome these limitations, we propose a multi-channel and temporal coincidences approach. METHODS: A two-step automatic detection (AD) of peculiar transient synchronized EEG events (TE) was performed in stage 2 and stage 3 sleep periods obtained from 10 normal sleep recordings and included: (a) detection of candidate TE from all the EEG traces and averaged signals, based on amplitude thresholds selections in both the time and frequency domains; (b) cross-checking of TE by evaluation of the coincidences in different EEG traces. TE found by AD but not confirmed by visual analysis (false positives, FP) and TE evidenced by visual analysis and missed by AD (false negatives, FN) were then counted. RESULTS: AD performed in averaged signals significantly reduced the number of FP but slightly increased FN, compared to single-channel analysis. However, when TE were confirmed by inter-channel temporal coincidences, a significant reduction of total errors (FN+FP) was achieved. The minimum error was obtained after C3-A2 and C4-A1 averaging and signal cross-checking with at least three channels (C3-A2 or C4-A1, plus both O1-A2 and O2-A1). CONCLUSIONS: This study describes a novel method for automatic detection of transient EEG events occurring during sleep that takes into account all the available channels. SIGNIFICANCE: This approach reduces the need of human supervision and may overcome most of the difficulties encountered by automatic methods based on single-channel analysis.

Growth laws in cancer: implications for radiotherapy.

Comparing the conventional Gompertz tumor growth law (GL) with the "Universal" law (UL), which has recently been proposed and applied to cancer, we have investigated the implications of the growth laws for various radiotherapy regimens. According to the GL, the surviving tumor cell fraction could be reduced ad libitum, independent of the initial tumor mass, simply by increasing the number of treatments. In contrast, if tumor growth dynamics follows the Universal scaling law, there is a lower limit of the surviving fraction that cannot be reduced further regardless of the total number of treatments. This finding can explain the so-called tumor size effect and re-emphasizes the importance of early diagnosis because it implies that radiotherapy may be successful provided that the tumor mass at treatment onset is rather small. Taken together with our previous work, the implications of these findings include revisiting standard radiotherapy regimens and treatment protocols overall.

Thermal response of contrast agent microbubbles: preliminary results from physico-chemical and US-imaging characterization.

Hyperthermia (HT) is a therapeutic strategy based on the selective damaging of tumoral cells when heated at temperatures in the range 41-45 degrees C. We are currently investigating the feasibility of Ultrasound (US) imaging to perform a non-invasive, efficient and cost effective temperature monitoring of heated tissues. Commercial US contrast agents (Sonovue, Bracco), consisting in microbubbles of SF(6) coated with a phospholipidic shell, greatly improve the US echo signal from tissues. Further investigations have been performed, consisting in physico-chemical and US-imaging characterization. In conclusion, we demonstrate that Sonovue microbubbles reach their maximal diameter at 40 degrees C, and then a sharp decrease is observed, possible due to the occurrence of gel-sol transition of the phospholipidic shell. At the same temperature the maximal backscattering intensity is predicted and actually experimentally observed. Sonovue, as well as other contrast agents based only on phospholipids, are, therefore, not suitable for use as non-invasive temperature monitoring medium since it is sensitive to temperatures below the hyperthermic range. Although microbubbles are in principle thermally effective, other coating materials should be investigated in order to increase their operative thermal range.

Classification scheme for phenomenological universalities in growth problems in physics and other sciences.

A classification in universality classes of broad categories of phenomenologies, belonging to physics and other disciplines, may be very useful for a cross fertilization among them and for the purpose of pattern recognition and interpretation of experimental data. We present here a simple scheme for the classification of nonlinear growth problems. The success of the scheme in predicting and characterizing the well known Gompertz, West, and logistic models, suggests to us the study of a hitherto unexplored class of nonlinear growth problems.

Curvature affects Doppler investigation of vessels: implications for clinical practice.

In clinical practice, blood velocity estimations from Doppler examination of curved vascular segments are normally different from those of nearby straight segments. The observed "accelerations," sometimes considered as a sort of stochastic disturbances, can actually be related to very specific physical effects due to vessel curvature (i.e., the development of nonaxial velocity [NAV] components) and the spreading of the axial velocity direction in the Doppler sample volume with respect to the insonation axis. The relevant phenomena and their dependence on the radius of curvature of the vessels and on the insonation angle are investigated with a beam-vessel geometry as close as possible to clinical setting, with the simplifying assumptions of steady flow, mild vessel curvature, uniform ultrasonic beam and complete vessel insonation. The insonation angles that minimize the errors are provided on the basis of the study results.

Assessment of the effect of vessel curvature on Doppler measurements in steady flow.

Blood vessel curvature is responsible for the appearance of nonaxial velocity components and for minor changes in the pattern of the axial flow. All the velocity components are expected to contribute to the Doppler signal produced by the ultrasound (US) backscattered by the insonated blood cells, the axial velocity, contributing to the actual volumetric blood flow, and the transverse velocity, causing the recirculating vortices. A detailed, separate analysis of the velocity components is, therefore, mandatory to quantify how vessel curvature can affect results and clinical diagnosis. Both experimental in vitro measures and numerical simulations were performed on a curved tube and the Doppler power spectra so obtained were compared. The satisfactorily agreement of the above spectra shows that the nonaxial velocity components are easily detectable with clinical equipment and that their amplitude, as expected, is not negligible and can bias Doppler measurements and resulting clinical diagnosis.