Perspectives on cavitation enhanced endothelial layer permeability

Traditional drug delivery systems, where pharmaceutical agents are conveyed to the target tissue through the blood circulation, suffer of poor therapeutic efficiency and limited selectivity largely due to the low permeability of the highly specialised biological interface represented by the endothelial layer. Examples concern cancer therapeutics or degenerative disorders where drug delivery is inhibited by the blood-brain barrier (BBB). Microbubbles injected into the bloodstream undergo volume oscillations under localised ultrasound irradiation and possibly collapse near the site of interest, with no effect on the rest of the endothelium. The resulting mechanical action induces a transient increase of the inter-cellular spaces and facilitates drug extravasation. This approach, already pursed in in vivo animal models, is extremely expensive and time-consuming. On the other hand in vitro studies using different kinds of microfluidic networks are firmly established in the pharmaceutical industry for drug delivery testing. The combination of the in vitro approach with ultrasound used to control microbubbles oscillations is expected to provide crucial information for developing cavitation enhanced drug delivery protocols and for screening the properties of the biological interface in presence of healthy or diseased tissues. Purpose of the present review is providing the state of the art in this rapidly growing field where cavitation is exploited as a viable technology to transiently modify the permeability of the biological interface. After describing current in vivo studies, particular emphasis will be placed on illustrating characteristics of micro-devices, biological functionalisation, properties of the artificial endothelium and ultrasound irradiation techniques

Flexible Sigmoidoscopy and CT Colonography Screening: Patients' Experience with and Factors for Undergoing Screening-Insight from the Proteus Colon Trial

Purpose To compare the acceptability of computed tomographic (CT) colonography and flexible sigmoidoscopy (FS) screening and the factors predicting CT colonographic screening participation, targeting participants in a randomized screening trial. Materials and Methods Eligible individuals aged 58 years (n = 1984) living in Turin, Italy, were randomly assigned to be invited to screening for colorectal cancer with FS or CT colonography. After individuals who had died or moved away (n = 28) were excluded, 264 of 976 (27.0%) underwent screening with FS and 298 of 980 (30.4%) underwent CT colonography. All attendees and a sample of CT colonography nonattendees (n = 299) were contacted for a telephone interview 3-6 months after invitation for screening, and screening experience and factors affecting participation were investigated. Odds ratios (ORs) were computed by means of multivariable logistic regression. Results For the telephone interviews, 239 of 264 (90.6%) FS attendees, 237 of 298 (79.5%) CT colonography attendees, and 182 of 299 (60.9%) CT colonography nonattendees responded. The percentage of attendees who would recommend the test to friends or relatives was 99.1% among FS and 93.3% among CT colonography attendees. Discomfort associated with bowel preparation was higher among CT colonography than FS attendees (OR, 2.77; 95% confidence interval [CI]: 1.47, 5.24). CT colonography nonattendees were less likely to be men (OR, 0.36; 95% CI: 0.18, 0.71), retired (OR, 0.31; 95% CI: 0.13, 0.75), to report regular physical activity (OR, 0.37; 95% CI: 0.20, 0.70), or to have read the information leaflet (OR, 0.18; 95% CI: 0.08, 0.41). They were more likely to mention screening-related anxiety (mild: OR, 6.30; 95% CI: 2.48, 15.97; moderate or severe: OR, 3.63; 95% CI: 1.87, 7.04), erroneous beliefs about screening (OR, 32.15; 95% CI: 6.26, 165.19), or having undergone a recent fecal occult blood test (OR, 13.69; 95% CI: 3.66, 51.29). Conclusion CT colonography and FS screening are well accepted, but further reducing the discomfort from bowel preparation may increase CT colonography screening acceptability. Negative attitudes, erroneous beliefs about screening, and organizational barriers are limiting screening uptake; all these factors are modifiable and therefore potentially susceptible to interventions. (©) RSNA, 2017 Online supplemental material is available for this article

Effects of Acoustic Stimulation on Cardiovascular Regulation During Sleep

The interaction of wake-sleep states and acoustic stimulation on cardiovascular regulation was studied on rats implanted with electroencephalogram and electromyogram electrodes and an arterial catheter. Mild acoustic stimuli (1000 Hz, 90 dB, 50-ms beeps) were administered during Wakefulness (W), non-rapid eye movement (NREM) sleep and REM sleep and the changes induced in heart period (HP, ms) and mean arterial pressure (MAP, mmHg) were analyzed. Two 30-s sequences of beat-to-beat HP and MAP values were considered before (I) and after (II) acoustic stimulation, respectively. By the effect of stimulation, state-dependent stimulus-locked HP and MAP oscillations were observed, HP oscillations being grossly parallel to the MAP ones but delayed with respect to MAP in the ascending part only; HP and MAP spontaneous fluctuations (HP and MAP variability) increased in NREM and REM sleep (but not in W); HP vs MAP correlation coefficient increased in an algebraic sense. These results show that 1) acoustic stimulation primarily affects the peripheral resistance, and secondarily, through the baroreceptor reflex, HP, thereby increasing the impact of peripheral versus centrally driven autonomic influences on the heart; 2) in NREM sleep, heart excitability is higher than requested by the baroreflex function; 3) cardiac variability is increased by acoustic stimulation during sleep (but not in W); this, in addition to the effects of point 2, may favor cardiac arrhythmias in NREM sleep. Thus, mild acoustic stimuli not perturbing cardiovascular regulation during W may create a specific risk factor during sleep in pathophysiologic conditions

Sleep-Related Changes in the Regulation of Cerebral Blood Flow in Newborn Lambs

Study Objectives: The interplay between cerebral perfusion pressure (CPP) and vascular resistance leads to fluctuations in cerebral blood flow (CBF). The relationship between fluctuations in CBF and those in CPP provides insight into the impact of the regulation of vascular resistance on CBF. The aim of this work was to study sleep-related changes in CBF regulation in newborn lambs, by quantifying the extent to which variability in CBF is related to that of CPP in the different wake-sleep states. Design: Repeated-measurement within-subject. Participants: 8 newborn lambs. Interventions: Chronic instrumentation with electrodes (electrocorticogram, electrooculogram, nuchal electromyogram), an arterial catheter (arterial pressure), a subdural catheter (intracranial pressure), and an ultrasonic flow probe around the superior sagittal sinus (CBF). Measurements and Results: The CPP (difference between arterial and intracranial pressure) and CBF data sequences during quiet wakefulness, rapid-eye-movement (REM) sleep and non-REM sleep were subject to spectral analysis. The fraction of CBF variability explained by CPP variability (CPP vs CBF squared coherence in the range 0.05-0.3 Hz) was highest in REM sleep (0.653) and lowest in non-REM sleep (0.413). The CBF variability (coefficient of variation due to fluctuations in the range 0.05-0.3 Hz) was higher than CPP variability in all states, albeit not significantly in REM sleep. Conclusions: Results suggest that synchronized vasomotor fluctuations accounting for a quota of CBF variability not explained by CPP variability occur in all states in newborn lambs. Their relative contribution to CBF variability differs among wake-sleep states, being highest during non-REM sleep and lowest during REM sleep

Sleep-related brain activation does not increase the permeability of the blood–brain barrier to glucose

We compared blood-brain barrier (BBB) permeability to glucose between quiet wakefulness and rapid-eye-movement (REM) sleep to assess whether changes in BBB permeability play a role in coupling glucose supply to the physiologic metabolic needs of the brain. Male Sprague-Dawley rats were prepared with electrodes for wake-sleep state scoring and with arterial and venous catheters. Using the single-pass, dual-label indicator method, unidirectional glucose extraction by the brain and cerebral blood flow (CBF) were simultaneously measured during states of quiet wakefulness ( n = 12) or REM sleep ( n = 7). The product of BBB surface area and permeability to glucose (PS product) was computed in each state. During REM sleep, CBF significantly exceeded that during quiet wakefulness in all regions but the cerebellum, whereas the difference in the PS product between quiet wakefulness and REM sleep was not statistically significant in any brain region. In the brain as a whole, CBF significantly increased 29% from quiet wakefulness to REM sleep, while a nonsignificant 0.8% increase occurred in the PS product. During REM sleep, the increase in CBF indicates a higher rate of brain glucose consumption than in quiet wakefulness, given the tight flow-metabolism coupling in the brain. Therefore, these data show that modulation of BBB permeability to glucose is not a mechanism that provides ‘energy on demand’ during the physiologic brain activation characterising REM sleep

Sleep-Dependent Changes in the Coupling Between Heart Period and Arterial Pressure in Newborn Lambs

This study assessed whether sleep-dependent changes in the relationship between heart period (HP) and mean arterial pressure (MAP) occur in newborn life. Electrodes for electrocorticographic, electromyographic, and electrooculographic monitoring and an arterial catheter for blood pressure recordings were implanted in 11 newborn lambs. HP and MAP beat-to-beat values were computed from 120-s blood pressure recordings during quiet wakefulness, active sleep, and quiet sleep. For each recording, the time shift at which the maximum of the HP versus MAP cross-correlation function was attained was identified. For each lamb and wake-sleep state, an average correlation coefficient was then computed corresponding to the median value of such time shifts. The maximum of the cross-correlation function was attained with HP lagging behind MAP. The corresponding mean correlation coefficient was significantly higher in quiet sleep (0.51 ± 0.05) than either in quiet wakefulness (0.31 ± 0.05) or in active sleep (0.29 ± 0.03). Sleep-related differences in the correlation between HP and MAP were maintained after HP and MAP data were low-pass filtered at 0.3 Hz to remove their fast ventilatory oscillations. In conclusion, data indicate that the relationship between spontaneous fluctuations in HP and those in MAP is sleep-state dependent in newborn lambs. A positive HP versus MAP correlation with HP lagging behind MAP is consistent with baroreflex control of HP. Heart rhythm thus may be more tightly controlled by the baroreceptor reflex and less dependent on central autonomic commands in quiet sleep than either in quiet wakefulness or in active sleep

Disease-specific and general health-related quality of life in newly diagnosed prostate cancer patients: The Pros-IT CNR study

Background: The National Research Council (CNR) prostate cancer monitoring project in Italy (Pros-IT CNR) is an observational, prospective, ongoing, multicentre study aiming to monitor a sample of Italian males diagnosed as new cases of prostate cancer. The present study aims to present data on the quality of life at time prostate cancer is diagnosed. Methods: One thousand seven hundred five patients were enrolled. Quality of life is evaluated at the time cancer was diagnosed and at subsequent assessments via the Italian version of the University of California Los Angeles-Prostate Cancer Index (UCLA-PCI) and the Short Form Health Survey (SF-12). Results: At diagnosis, lower scores on the physical component of the SF-12 were associated to older ages, obesity and the presence of 3+ moderate/severe comorbidities. Lower scores on the mental component were associated to younger ages, the presence of 3+ moderate/severe comorbidities and a T-score higher than one. Urinary and bowel functions according to UCLA-PCI were generally good. Almost 5% of the sample reported using at least one safety pad daily to control urinary loss; less than 3% reported moderate/severe problems attributable to bowel functions, and sexual function was a moderate/severe problem for 26.7%. Diabetes, 3+ moderate/severe comorbidities, T2 or T3-T4 categories and a Gleason score of eight or more were significantly associated with lower sexual function scores at diagnosis. Conclusions: Data collected by the Pros-IT CNR study have clarified the baseline status of newly diagnosed prostate cancer patients. A comprehensive assessment of quality of life will allow to objectively evaluate outcomes of different profile of care

Perspectives on cavitation enhanced endothelial layer permeability

Traditional drug delivery systems, where pharmaceutical agents are conveyed to the target tissue through the blood circulation, suffer of poor therapeutic efficiency and limited selectivity largely due to the low permeability of the highly specialised biological interface represented by the endothelial layer. Examples concern cancer therapeutics or degenerative disorders where drug delivery is inhibited by the blood-brain barrier (BBB). Microbubbles injected into the bloodstream undergo volume oscillations under localised ultrasound irradiation and possibly collapse near the site of interest, with no effect on the rest of the endothelium. The resulting mechanical action induces a transient increase of the inter-cellular spaces and facilitates drug extravasation. This approach, already pursed in in vivo animal models, is extremely expensive and time-consuming. On the other hand in vitro studies using different kinds of microfluidic networks are firmly established in the pharmaceutical industry for drug delivery testing. The combination of the in vitro approach with ultrasound used to control microbubbles oscillations is expected to provide crucial information for developing cavitation enhanced drug delivery protocols and for screening the properties of the biological interface in presence of healthy or diseased tissues. Purpose of the present review is providing the state of the art in this rapidly growing field where cavitation is exploited as a viable technology to transiently modify the permeability of the biological interface. After describing current in vivo studies, particular emphasis will be placed on illustrating characteristics of micro-devices, biological functionalisation, properties of the artificial endothelium and ultrasound irradiation techniques