Interpericyte tunnelling nanotubes regulate neurovascular coupling.

Signalling between cells of the neurovascular unit, or neurovascular coupling, is essential to match local blood flow with neuronal activity. Pericytes interact with endothelial cells and extend processes that wrap capillaries, covering up to 90% of their surface area1,2. Pericytes are candidates to regulate microcirculatory blood flow because they are strategically positioned along capillaries, contain contractile proteins and respond rapidly to neuronal stimulation3,4, but whether they synchronize microvascular dynamics and neurovascular coupling within a capillary network was unknown. Here we identify nanotube-like processes that connect two bona fide pericytes on separate capillary systems, forming a functional network in the mouse retina, which we named interpericyte tunnelling nanotubes (IP-TNTs). We provide evidence that these (i) have an open-ended proximal side and a closed-ended terminal (end-foot) that connects with distal pericyte processes via gap junctions, (ii) carry organelles including mitochondria, which can travel along these processes, and (iii) serve as a conduit for intercellular Ca2+ waves, thus mediating communication between pericytes. Using two-photon microscope live imaging, we demonstrate that retinal pericytes rely on IP-TNTs to control local neurovascular coupling and coordinate light-evoked responses between adjacent capillaries. IP-TNT damage following ablation or ischaemia disrupts intercellular Ca2+ waves, impairing blood flow regulation and neurovascular coupling. Notably, pharmacological blockade of Ca2+ influx preserves IP-TNTs, rescues light-evoked capillary responses and restores blood flow after reperfusion. Our study thus defines IP-TNTs and characterizes their critical role in regulating neurovascular coupling in the living retina under both physiological and pathological conditions.

In silico model of the early effects of radiation therapy on the microcirculation and the surrounding tissues.

BACKGROUND: Radiation-induced organ dysfunction are frequently described by Normal Tissue Complication Probability models. The approximations of this radiobiological approach do not allow to consider the important role played by the microvasculature not only in the dose-response of the blood vessels but also of the organs where it is located. To this purpose, we presented a computational model that describes the fluid dynamics of microcirculation when the parameters of the network and the surrounding tissues are affected by radio-induced changes. MATERIALS AND METHODS: The effects of the ionizing radiation on the capillary bed are mediated by the inflammatory response. We derived from a literature search the possible morphological and functional variations of the network due to the process of the acute inflammation. Specifically, we considered vasodilation, increased membrane permeability with consequent fluid extravasation and increased wall elasticity. These perturbations to the system were included in a computational model, already able to describe the physics of the microcirculation and its exchanges with the surrounding tissues. RESULTS: Two computational descriptions were considered. In the first one, we changed a set of 4 parameters associated with the increased fluid exchange from the health scenario at the baseline to a seriously compromised scenario with the edema formation. The second study investigated the effect of a perturbation to the vessel wall elasticity. CONCLUSIONS: These simulations represent a first step towards the challenging objective of understanding and describing in a mechanistic way the effects of radiation on the vascular microenvironment.

Variation of Diagnostic Ultrasound-Induced Pulmonary Capillary Hemorrhage with Fraction of Inspired Oxygen.

Pulmonary capillary hemorrhage induction by diagnostic ultrasound (DUS-PCH) was investigated with respect to the influence of the fraction of inspired oxygen (FiO2). Sprague-Dawley rats were anesthetized with Telazol only (TO) or Telazol plus xylazine (TX), which can enhance DUS-PCH. A linear array probe (10 L, GE Vivid 7 Dimension) was used in B-mode at 7.5 MHz to expose the right lung. FiO2 at 10%, 20%, 60% and 100% was delivered through a nose cone. On the ultrasound images, the PCH effect was observed as growing comet tail (B-line) artifacts and as subpleural consolidated segments at higher FiO2. PCH for TO with 20% and 60% FiO2 were significantly greater (p < 0.05) than for the 10% FiO2. PCHs with TX at 10% and 20% FiO2 were significantly greater (p < 0.02) than those for TO anesthesia. Added xylazine and high percentages of FiO2 reduced PCH thresholds, but xylazine and high percentages of FiO2 together did not lower the PCH threshold further. The lowest threshold observed, 1.4 MPa, corresponded to an in situ mechanical index of 0.5.

Efficacy and Safety of the 532-nm KTP and Long-Pulsed 1064-nm Neodymium-doped Yttrium Aluminum Garnet Laser for Treatment of Vascular Malformations.

BACKGROUND: Pulsed dye lasers (PDLs) are well-established for treatment of capillary malformations but are unable to penetrate the depth needed to treat deeper vascular lesions. A combined approach using a deeper penetrating wavelength with a "superficial" wavelength could more comprehensively treat vascular malformations than PDL alone. OBJECTIVE: To evaluate the safety and efficacy of the long-pulsed 1064-nm neodymium:yttrium-aluminum-garnet (LP 1064-nm Nd:YAG) in conjunction with the 532-nm potassium titanyl phosphate (532-nm KTP) laser wavelengths for treatment of capillary venous and venous malformations. METHODS: In this retrospective single-center study, we queried patient records who underwent treatment with the 532-nm KTP and LP 1064-nm Nd:YAG laser wavelengths. A blinded panel of 3 physicians evaluated improvement in lesion color, elevation, texture, and overall architecture on a four-point scale: 0% to 25%; 26% to 50%, 51% to 75%, and 76% to 100%. RESULTS: Our cohort consisted of 23 cases. Sixteen cases had sufficient information for clinical assessment. Treatment number and parameters varied depending on lesion, skin type, and end point. Clinical assessment of treatment effectiveness revealed average scores of 51% to 75% improvement for color, elevation, texture, and overall architecture. CONCLUSION: This study illustrates that 2 wavelengths, 532-nm KTP to target superficial components and LP 1064-nm Nd:YAG for deeper components, can safely and effectively treat both capillary venous and venous malformations.

Nailfold Capillaroscopic Findings in an Orthopedic Surgeon: Reversible Abnormalities after the Cessation of Radiation Exposure.

Interventional fluoroscopy is a leading source of occupational ionizing radiation exposure for medical personnel. For example, orthopedic surgeons represent one occupation where the risk of exposure is large. This occupational hazard is the result of a cumulative dose of radiation over time. Adverse health effects induced by low-dose radiation exposure can arise from daily procedures performed over an entire career. Many of the radiation-induced effects that may develop are transient erythema, permanent epilation, dry desquamation, dermal necrosis and telangiectasia; these effects have occurred on the skin of fingers of interventionalists. Nailfold videocapillaroscopy (NVC) is a non-invasive technique useful for early detection of radiation-induced effects on microcirculation of fingernails. Here we report on a case of an orthopedic surgeon exposed to radiation for 30 years during his professional career. He performed NVC before and after the end of his professional career, and regression of the microcirculatory abnormalities were documented after cessation of radiation exposure. To our knowledge, this is the first published work in which the regression of chronic low-dose radiation-induced alterations of finger microvessels have been described and documented.

A Model of Indirect Cell Death Caused by Tumor Vascular Damage after High-Dose Radiotherapy.

There is increasing evidence that high doses of radiotherapy, like those delivered in stereotactic body radiotherapy (SBRT), trigger indirect mechanisms of cell death. Such effect seems to be two-fold. High doses may trigger an immune response and may cause vascular damage, leading to cell starvation and death. Development of mathematical response models, including indirect death, may help clinicians to design SBRT optimal schedules. Despite increasing experimental literature on indirect tumor cell death caused by vascular damage, efforts on modeling this effect have been limited. In this work, we present a biomathematical model of this effect. In our model, tumor oxygenation is obtained by solving the reaction-diffusion equation; radiotherapy kills tumor cells according to the linear-quadratic model, and also endothelial cells (EC), which can trigger loss of functionality of capillaries. Capillary death will affect tumor oxygenation, driving nearby tumor cells into severe hypoxia. Capillaries can recover functionality due to EC proliferation. Tumor cells entering a predetermined severe hypoxia status die according to a hypoxia-death model. This model fits recently published experimental data showing the effect of vascular damage on surviving fractions. It fits surviving fraction curves and qualitatively reproduces experimental values of percentages of functional capillaries 48 hours postirradiation, and hypoxic cells pre- and 48 hours postirradiation. This model is useful for exploring aspects of tumor and EC response to radiotherapy and constitutes a stepping stone toward modeling indirect tumor cell death caused by vascular damage and accounting for this effect during SBRT planning. SIGNIFICANCE: A novel biomathematical model of indirect tumor cell death caused by vascular radiation damage could potentially help clinicians interpret experimental data and design better radiotherapy schedules.

Patient-Side Appraisal of Late Radiation-Induced Oral Microvascular Changes.

PURPOSE: To determine the clinical feasibility of examining and measuring late irradiation changes in the oral microcirculation of head and neck (HN) cancer patients using the novel CytoCam video microscope system. METHODS AND MATERIALS: In 30 HN cancer patients and 30 age-matched controls, bilateral video images were recorded noninvasively of the oral microcirculation of the buccal mucosa and mandibular gingiva. Tissue perfusion parameters, such as functional capillary density (FCD), buccal blood vessel diameter, and microcirculatory flow index, were analyzed. RESULTS: No difference was observed for mean buccal mucosa FCD in irradiated versus healthy tissue, whereas a lower mean gingival FCD in irradiated versus healthy tissue was observed (34 ± 17 capillaries per millimeter squared [cpll/mm2] vs 68 ± 19 cpll/mm2; P < .001). A significant difference in mean buccal blood vessel diameter of 16 ± 3 µm was measured, compared with 14 ± 1 µm in control buccal mucosa (P < .001). No significant difference in microcirculatory flow index was observed between the 2 groups. CONCLUSIONS: Quantifying oral microcirculatory injury associated with late irradiation effects using the CytoCam was feasible in HN cancer patients. Results indicate that marked differences in tissue-specific microcirculatory measurements of angioarchitecture, diminished capillary density, and extensively dilated blood vessel diameters are associated with late irradiation effects in HN cancer patients.

Comparison of Emla cream and topical lidocaine tape for pain relief of V-beam laser treatment.

The authors compared the analgesic effects of two topical applications; Emla® cream (Sato Pharmaceutical Co. Ltd., Tokyo, Japan) and 60% lidocaine tape (Penles® tape; Maruho, Osaka, Japan). The authors examined 20 outpatients with capillary malformations. Emla® cream or Penles® tape was applied 1 h before laser irradiation using V-Beam. After V-Beam irradiation, pain intensity was measured using Pain Vision® (NIPRO, Osaka, Japan), while subjective pain was converted into numerical values using the VAS system. In the assessment using Pain Vision®, pain was significantly lower in patients who received Emla® cream (Welch test), whereas no difference was observed in VAS ratings between the two applications (student's t test). The objective system showed that Emla® cream had a significantly greater analgesic effect. We plan to evaluate the analgesic effects of these topical anesthetics by applying them to other anatomical areas.

Enhanced radiation dose and DNA damage associated with iodinated contrast media in diagnostic X-ray imaging.

A review was undertaken of studies reporting increased DNA damage in circulating blood cells and increased organ doses, for X-ray exposures enhanced by iodinated contrast media (ICM), compared to unenhanced imaging. This effect may be due to ICM molecules acting as a source of secondary radiation (Auger/photoelectrons, fluorescence X-rays) following absorption of primary X-ray photons. It is unclear if the reported increase in DNA damage to blood cells necessarily implies an increased risk of developing cancer. Upon ICM-enhancement, the attenuation properties of blood differ substantially from surrounding tissues. Increased energy deposition is likely to occur within very close proximity to ICM molecules (within a few tens of micrometres). Consequently, in many situations, damage and dose enhancement may be restricted to the blood and vessel wall only. Increased cancer risks may be possible, in cases where ICM molecules are given sufficient time to reach the capillary network and interstitial fluid at the time of exposure. In all situations, the extrapolation of blood cell damage to other tissues requires caution where contrast media are involved. Future research is needed to determine the impact of ICM on dose to cells outside the blood itself and vessel walls, and to determine the concentration of ICM in blood vessels and interstitial fluid at the time of exposure.

Ionizing radiation reduces ADAM10 expression in brain microvascular endothelial cells undergoing stress-induced senescence.

Cellular senescence is associated with aging and is considered a potential contributor to age-associated neurodegenerative disease. Exposure to ionizing radiation increases the risk of developing premature neurovascular degeneration and dementia but also induces premature senescence. As cells of the cerebrovascular endothelium are particularly susceptible to radiation and play an important role in brain homeostasis, we investigated radiation-induced senescence in brain microvascular endothelial cells (EC). Using biotinylation to label surface proteins, streptavidin enrichment and proteomic analysis, we analyzed the surface proteome of stress-induced senescent EC in culture. An array of both recognized and novel senescence-associated proteins were identified. Most notably, we identified and validated the novel radiation-stimulated down-regulation of the protease, a disintegrin and metalloprotease 10 (ADAM10). ADAM10 is an important modulator of amyloid beta protein production, accumulation of which is central to the pathologies of Alzheimer's disease and cerebral amyloid angiopathy. Concurrently, we identified and validated increased surface expression of ADAM10 proteolytic targets with roles in neural proliferation and survival, inflammation and immune activation (L1CAM, NEO1, NEST, TLR2, DDX58). ADAM10 may be a key molecule linking radiation, senescence and endothelial dysfunction with increased risk of premature neurodegenerative diseases normally associated with aging.

Low-dose ionizing radiation induces therapeutic neovascularization in a pre-clinical model of hindlimb ischemia.

AIMS: We have previously shown that low-dose ionizing radiation (LDIR) induces angiogenesis but there is no evidence that it induces neovascularization in the setting of peripheral arterial disease. Here, we investigated the use of LDIR as an innovative and non-invasive strategy to stimulate therapeutic neovascularization using a model of experimentally induced hindlimb ischemia (HLI). METHODS AND RESULTS: After surgical induction of unilateral HLI, both hindlimbs of female C57BL/6 mice were sham-irradiated or irradiated with four daily fractions of 0.3 Gy, in consecutive days and allowed to recover. We demonstrate that LDIR, significantly improved blood perfusion in the murine ischemic limb by stimulating neovascularization, as assessed by laser Doppler flow, capillary density, and collateral vessel formation. LDIR significantly increased the circulating levels of VEGF, PlGF, and G-CSF, as well as the number of circulating endothelial progenitor cells (EPCs) mediating their incorporation to ischemic muscles. These effects were dependent upon LDIR exposition on the ischemic niche (thigh and shank regions). In irradiated ischemic muscles, these effects were independent of the recruitment of monocytes and macrophages. Importantly, LDIR induced a durable and simultaneous up-regulation of a repertoire of pro-angiogenic factors and their receptors in endothelial cells (ECs), as evident in ECs isolated from the irradiated gastrocnemius muscles by laser capture microdissection. This specific mechanism was mediated via vascular endothelial growth factor (VEGF) receptor signaling, since VEGF receptor inhibition abrogated the LDIR-mediated gene up-regulation and impeded the increase in capillary density. Finally, the vasculature in an irradiated non-ischemic bed was not affected and after 52 week of LDIR exposure no differences in the incidence of morbidity and mortality were seen. CONCLUSIONS: These findings disclose an innovative, non-invasive strategy to induce therapeutic neovascularization in a mouse model of HLI, emerging as a novel approach in the treatment of critical limb ischemia patients.

Semiparametric profile likelihood estimation for continuous outcomes with excess zeros in a random-threshold damage-resistance model.

Continuous outcome data with a proportion of observations equal to zero (often referred to as semicontinuous data) arise frequently in biomedical studies. Typical approaches involve two-part models, with one part a logistic model for the probability of observing a zero and some parametric continuous distribution for modeling the positive part of the data. We propose a semiparametric model based on a biological system with competing damage manifestation and resistance processes. This allows us to derive a closed-form profile likelihood based on the retro-hazard function, leading to a flexible procedure for modeling continuous data with a point mass at zero. A simulation study is presented to examine the properties of the method in finite samples. We apply the method to a data set consisting of pulmonary capillary hemorrhage area in lab rats subjected to diagnostic ultrasound. Copyright © 2017 John Wiley & Sons, Ltd.

Analysis of the variation in low-level laser energy density on the crushed sciatic nerves of rats: a morphological, quantitative, and morphometric study.

The objective of this study was to evaluate three energy densities of low-level laser therapy (LLLT, GaAlAs, 780 nm, 40 mW, 0.04 cm2) for the treatment of lesions to peripheral nerves using the sciatic nerve of rats injured via crushing model (15 kgf, 5.2 MPa). Thirty Wistar rats (♂, 200-250 g) were divided into five groups (n = 6): C-control, not injured, and irradiated; L0-injured nerve without irradiation; L4-injured nerve irradiated with LLLT 4 J/cm2 (0.16 J); L10-injured nerve irradiated with LLLT 10 J/cm2 (0.4 J); and L50-injured nerve irradiated with LLLT 50 J/cm2 (2 J). The animals were sacrificed 2 weeks after the injury via perfusion with glutaraldehyde (2.5%, 0.1 M sodium cacodylate buffer). The nerve tissue was embedded in historesin, cut (3 µm), mounted on slides, and stained (Sudan black and neutral red). The morphological and quantitative analysis (myelin and blood capillary densities) and morphometric parameters (maximum and minimum diameters of nerve fibers, axon diameter, G-ratio, myelin sheath thickness) were assessed using the ImageJ software. ANOVA (parametric) or Kruskal-Wallis (nonparametric) tests were used for the statistical analysis. Groups L0, L4, L10, and L50 exhibited diminished values of all the quantitative and morphometric parameters in comparison to the control group. The morphological, quantitative, and morphometric data revealed improvement after injury in groups L4, L10, and L50 (irradiated groups) compared to the injured-only group (L0); the best results, in general, were observed for the L10 group after 15 days of nerve injury.

Irradiation as a hazard for mucociliary clearance.

OBJECTIVES: In this paper we study effects of irradiation to pulmonary tissue on a micro and ultrastructural level to get insights into the dynamics of morphological changes and associated post-radiative physiological conditions. METHODS: Animal and human pulmonary tissue with and without radiation damage was subject to light, transmission, scanning and polarization microscopy and morphometric evaluation. RESULTS: The present investigations on the influence of irradiation on experimental and human lung tissue demonstrate that complex changes are induced in the cells which are essential for mucociliary clearance. These changes are a shortage of alveolar macrophages, cell apoptosis, proliferation of collagen ligament in the barrier of gaseous exchange, retraction of endothelial lining of capillaries and significant broadening of the gaseous exchange barrier, resulting in serious damage for the O2 and CO2 exchange. CONCLUSIONS: These changes at microscopic, cellular, and ciliary level trigger conditions for various diseases of the respiratory system, which is further assessed by a simultaneous computer aided estimation of ciliary function. With the concurrent world-wide increase of respiratory diseases, these findings are important knowledge for the clinical practice.

Microvascular injury in persistent gastric ulcers after yttrium-90 microsphere radioembolization for liver malignancies.

Yttrium-90 microsphere radioembolization ((90)Y MRE) is a therapy for liver malignancies by permanently implanting (90)Y-containing microspheres into tumors via hepatic artery. The etiology of persistent gastric ulcerations in patients presenting months after treatment remains unclear. Three patients who presented with gastric ulceration 4 to 13 months after (90)Y MRE were examined by esophagogastroduodenoscopy and biopsies. Pathological examinations showed multiple (90)Y microspheres scattered within the lamina propria and submucosa. Most of the microspheres were distributed in a linear fashion, consistent with an intravascular location; however, the vascular lumen and endothelial cells were not present. The microspheres were surrounded by fibrotic tissue infiltrated by chronic inflammatory cells and rare neutrophils. Epithelial granulation without pititis and miniaturized glands with intervening fibrosis were noted, compatible with chronic ischemic changes. These findings suggest that the persistent gastric ulceration is a result of localized ischemic injury in response to (90)Y MRE-induced vascular damage.

Sestrin2 protects the myocardium against radiation-induced damage.

The purpose of this study was to investigate the role of Sestrin2 in response to radiation-induced injury to the heart and on the cardiomyopathy development in the mouse. Mice with genetic deletion of the Sestrin2 (Sestrin2 knockout mice [Sestrin2 KO]) and treatment with irradiation (22 or 15 Gy) were used as independent approaches to determine the role of Sestrin2. Echocardiography (before and after isoproterenol challenge) and left ventricular (LV) catheterization were performed to evaluate changes in LV dimensions and function. Masson's trichrome was used to assess myocardial fibrosis. Immunohistochemistry and Western blot were used to detect the capillary density. After 22 or 15 Gy irradiation, the LV ejection fraction (EF) was impaired in wt mice at 1 week and 4 months after irradiation when compared with sham irradiation. Compared to wt mice, Sestrin2 KO mice had significant reduction in reduced LVEF at 1 week and 4 months after irradiation. A significant increase in LV end-diastolic pressure and myocardial fibrosis and a significant decrease in capillary density were observed in irradiation-wt mice, as well as in irradiation-Sestrin2 KO mice. Sestrin2 involved in the regulation of cardiomyopathy (such as myocardial fibrosis) after irradiation. Overexpression of Sestrin2 might be useful in limiting radiation-induced myocardial injury.

The Influence of Dexmedetomidine on Ultrasound-induced Pulmonary Capillary Hemorrhage in Rats.

The use of xylazine, a veterinary sedative, with ketamine for rat anesthesia has been shown to enhance the pulmonary capillary hemorrhage (PCH) effect of diagnostic ultrasound. This study was undertaken to assess whether the sedative/analgesic dexmedetomidine, commonly used in the intensive care unit, can also enhance ultrasound-induced PCH. Female Sprague Dawley rats were anesthetized with various combinations of ketamine plus xylazine or dexmedetomidine. The dosage of dexmedetomidine was reduced for some groups to doses relevant to human clinical usage. The right thorax of all rats was shaved and depilated for ultrasound transmission and the rats were scanned with diagnostic ultrasound using a 7.6-MHz linear array in a 38°C de-gassed water bath. There was no significant difference in PCH results for the recommended anesthetic dosages of ketamine plus xylazine and ketamine plus 500 µg/kg dexmedetomidine. The varied doses of dexmedetomidine enhanced the PCH, even for the lowest dose of 4 µg/kg, equivalent to a low human dose of 0.64 µg/kg. There was no significant difference in PCH for 500 µg/kg dexmedetomidine with or without ketamine. Further research is needed to identify and characterize other factors that may modify the patient risk from ultrasound-induced PCH.

Pulmonary Capillary Hemorrhage Induced by Fixed-Beam Pulsed Ultrasound.

The induction of pulmonary capillary hemorrhage (PCH) by pulsed ultrasound was discovered 25 y ago, but early research used fixed-beam systems rather than actual diagnostic ultrasound machines. In this study, results of exposure of rats to fixed-beam focused ultrasound for 5 min at 1.5 and 7.5 MHz were compared with recent research on diagnostic ultrasound. One exposure condition at each frequency used 10-µs pulses delivered at 25-ms intervals. Three conditions involved Gaussian modulation of the pulse amplitudes at 25-ms intervals to simulate diagnostic scanning: 7.5 MHz with 0.3- and 1.5-µs pulses at 100- and 500-µs pulse repetition periods, respectively, and 1.5 MHz with 1.7-µs pulses at 500-µs repetition periods. Four groups were tested for each condition to assess PCH areas at different exposure levels and to determine occurrence thresholds. The conditions with identical pulse timing resulted in smaller PCH areas for the smaller 7.5-MHz beam, but both had thresholds of 0.69-0.75 MPa in situ peak rarefactional pressure amplitude. The Gaussian modulation conditions for both 7.5 MHz with 0.3-µs pulses and 1.5 MHz with 1.7-µs pulses had thresholds of 1.12-1.20 MPa peak rarefactional pressure amplitude, although the relatively long 1.5-µs pulses at 7.5 MHz yielded a threshold of 0.75 MPa. The fixed-beam pulsed ultrasound exposures produced lower thresholds than diagnostic ultrasound. There was no clear tendency for thresholds to increase with increasing ultrasonic frequency when pulse timing conditions were similar.

A Monte Carlo approach to small-scale dosimetry of solid tumour microvasculature for nuclear medicine therapies with (223)Ra-, (131)I-, (177)Lu- and (111)In-labelled radiopharmaceuticals.

The small-scale dosimetry of radionuclides in solid-tumours is directly related to the intra-tumoral distribution of the administered radiopharmaceutical, which is affected by its egress from the vasculature and dispersion within the tumour. The aim of the present study was to evaluate the combined dosimetric effects of radiopharmaceutical distribution and range of the emitted radiation in a model of tumour microvasculature. We developed a computational model of solid-tumour microenvironment around a blood capillary vessel, and we simulated the transport of radiation emitted by (223)Ra, (111)In, (131)I and (177)Lu using the GEANT4 Monte Carlo. For each nuclide, several models of radiopharmaceutical dispersion throughout the capillary vessel were considered. Radial dose profiles around the capillary vessel, the Initial Radioactivity (IR) necessary to deposit 100 Gy of dose at the edge of the viable tumour-cell region, the Endothelial Cell Mean Dose (ECMD) and the Tumour Edge Mean Dose (TEMD), i.e. the mean dose imparted at the 250-µm layer of tissue, were computed. The results for beta and Auger emitters demonstrate that the photon dose is about three to four orders of magnitude lower than that deposited by electrons. For (223)Ra, the beta emissions of its progeny deliver a dose about three orders of magnitude lower than that delivered by the alpha emissions. Such results may help to characterize the dose inhomogeneities in solid tumour therapies with radiopharmaceuticals, taking into account the interplay between drug distribution from vasculature and range of ionizing radiations.