Exogenous Aß seeds induce Aß depositions in the blood vessels rather than the brain parenchyma, independently of Aß strain-specific information.

Little is known about the effects of parenchymal or vascular amyloid ß peptide (Aß) deposition in the brain. We hypothesized that Aß strain-specific information defines whether Aß deposits on the brain parenchyma or blood vessels. We investigated 12 autopsied patients with different severities of Aß plaques and cerebral amyloid angiopathy (CAA), and performed a seeding study using an Alzheimer's disease (AD) mouse model in which brain homogenates derived from the autopsied patients were injected intracerebrally. Based on the predominant pathological features, we classified the autopsied patients into four groups: AD, CAA, AD + CAA, and less Aß. One year after the injection, the pathological and biochemical features of Aß in the autopsied human brains were not preserved in the human brain extract-injected mice. The CAA counts in the mice injected with all four types of human brain extracts were significantly higher than those in mice injected with PBS. Interestingly, parenchymal and vascular Aß depositions were observed in the mice that were injected with the human brain homogenate from the less Aß group. The Aß and CAA seeding activities, which had significant positive correlations with the Aß oligomer ratio in the human brain extracts, were significantly higher in the human brain homogenate from the less Aß group than in the other three groups. These results indicate that exogenous Aß seeds from different Aß pathologies induced Aß deposition in the blood vessels rather than the brain parenchyma without being influenced by Aß strain-specific information, which might be why CAA is a predominant feature of Aß pathology in iatrogenic transmission cases. Furthermore, our results suggest that iatrogenic transmission of Aß pathology might occur due to contamination of brain tissues from patients with little Aß pathology, and the development of inactivation methods for Aß seeding activity to prevent iatrogenic transmission is urgently required.

TAMEP are brain tumor parenchymal cells controlling neoplastic angiogenesis and progression.

Aggressive brain tumors like glioblastoma depend on support by their local environment and subsets of tumor parenchymal cells may promote specific phases of disease progression. We investigated the glioblastoma microenvironment with transgenic lineage-tracing models, intravital imaging, single-cell transcriptomics, immunofluorescence analysis as well as histopathology and characterized a previously unacknowledged population of tumor-associated cells with a myeloid-like expression profile (TAMEP) that transiently appeared during glioblastoma growth. TAMEP of mice and humans were identified with specific markers. Notably, TAMEP did not derive from microglia or peripheral monocytes but were generated by a fraction of CNS-resident, SOX2-positive progenitors. Abrogation of this progenitor cell population, by conditional Sox2-knockout, drastically reduced glioblastoma vascularization and size. Hence, TAMEP emerge as a tumor parenchymal component with a strong impact on glioblastoma progression.

Differential expression of receptors mediating receptor-mediated transcytosis (RMT) in brain microvessels, brain parenchyma and peripheral tissues of the mouse and the human.

Receptor-mediated transcytosis (RMT) is a principal pathway for transport of macromolecules essential for brain function across the blood-brain barrier (BBB). Antibodies or peptide ligands which bind RMT receptors are often co-opted for brain delivery of biotherapeutics. Constitutively recycling transferrin receptor (TfR) is a prototype receptor utilized to shuttle therapeutic cargos across the BBB. Several other BBB-expressed receptors have been shown to mediate transcytosis of antibodies or protein ligands including insulin receptor (INSR) and insulin-like growth factor-1 receptor (IGF1R), lipid transporters LRP1, LDLR, LRP8 and TMEM30A, solute carrier family transporter SLC3A2/CD98hc and leptin receptor (LEPR). In this study, we analyzed expression patterns of genes encoding RMT receptors in isolated brain microvessels, brain parenchyma and peripheral organs of the mouse and the human using RNA-seq approach. IGF1R, INSR and LRP8 were highly enriched in mouse brain microvessels compared to peripheral tissues. In human brain microvessels only INSR was enriched compared to either the brain or the lung. The expression levels of SLC2A1, LRP1, IGF1R, LRP8 and TFRC were significantly higher in the mouse compared to human brain microvessels. The protein expression of these receptors analyzed by Western blot and immunofluorescent staining of the brain microvessels correlated with their transcript abundance. This study provides a molecular transcriptomics map of key RMT receptors in mouse and human brain microvessels and peripheral tissues, important to translational studies of biodistribution, efficacy and safety of antibodies developed against these receptors.

Quantitative Assessment of Salivary Gland Parenchymal Vascularization Using Power Doppler Ultrasound and Superb Microvascular Imaging: A Potential Tool in the Diagnosis of Sjögren's Syndrome

Background: Primary Sjögren's syndrome is a chronic inflammatory autoimmune disease. Minor salivary gland biopsy is the gold standard for the diagnosis of primary Sjögren's syndrome. Superb microvascular imaging, power Doppler ultrasound, and color Doppler of the salivary glands represent non-invasive, non-irradiating modality for evaluating the vascularity of the salivary glands in the diagnosis and follow-up of primary Sjögren's syndrome. Aims: To evaluate the efficacy of superb microvascular imaging and vascularity index in salivary glands for the sonographic diagnosis of primary Sjögren's syndrome. Study Design: Prospective case-control study. Methods: Twenty participants with primary Sjögren's syndrome and 20 healthy subjects were included in the study. Both parotid glands and submandibular glands were evaluated by superb microvascular imaging, power Doppler ultrasound, and color Doppler. The diagnostic accuracy of superb microvascular imaging was compared using these techniques. Results: In the patient group, the vascularity index values of superb microvascular imaging in parotid glands and submandibular glands were 3.5±1.66, 5.06±1.94, respectively. While the same values were 1.0±0.98 and 2.44±1.34 in the control group (p≤0.001). In the patient group, the vascularity index values of power Doppler ultrasound in parotid glands and submandibular glands were 1.3±1.20 and 2.59±1.82, respectively. While the same values were 0.3±0.32 and 0.85±0.68 in the control group (p≤0.001). The superb microvascular imaging vascularity index cut-off value for the diagnosis of primary Sjögren's syndrome in parotid glands that maximizes the accuracy was 1.85 (area under the curve: 0.906; 95% confidence interval: 0.844, 0.968), and its sensitivity and specificity were 87.5% and 72.5%, respectively. While the superb microvascular imaging vascularity index cut-off value for the diagnosis of primary Sjögren's syndrome in submandibular gland that maximizes the accuracy was 3.35 (area under the curve: 0.873; 95% confidence interval: 0.800, 0.946), its sensitivity and specificity were 82.5% and 70%, respectively. Conclusion: Superb microvascular imaging with high reproducibility of the vascularity index has a higher sensitivity and specificity than the power Doppler ultrasound in the diagnosis of primary Sjögren's syndrome. It can be a noninvasive technique in the diagnosis of primary Sjögren's syndrome when used with clinical, laboratory and other imaging methods.

Hypertension and Its Impact on Stroke Recovery: From a Vascular to a Parenchymal Overview.

Hypertension is the first modifiable vascular risk factor accounting for 10.4 million deaths worldwide; it is strongly and independently associated with the risk of stroke and is related to worse prognosis. In addition, hypertension seems to be a key player in the implementation of vascular cognitive impairment. Long-term hypertension, complicated or not by the occurrence of ischemic stroke, is often reviewed on its vascular side, and parenchymal consequences are put aside. Here, we sought to review the impact of isolated hypertension or hypertension associated to stroke on brain atrophy, neuron connectivity and neurogenesis, and phenotype modification of microglia and astrocytes. Finally, we discuss the impact of antihypertensive therapies on cell responses to hypertension and functional recovery. This attractive topic remains a focus of continued investigation and stresses the relevance of including this vascular risk factor in preclinical investigations of stroke outcome.

The softness of tumour-cell-derived microparticles regulates their drug-delivery efficiency.

Extracellular microparticles (MPs) can function as drug-delivery vehicles for anticancer drugs. Here, we show that the softness of MPs derived from tumour-repopulating cells (TRCs) isolated from three-dimensional fibrin gels enhances the MPs' drug-delivery efficiency. We found that, compared with MPs derived from tumour cells cultured in conventional tissue-culture plastic, TRC-derived MPs intravenously injected in tumour-xenograft-bearing mice showed enhanced accumulation in tumour tissues, enhanced blood-vessel crossing and penetration into tumour parenchyma, and preferential uptake by highly tumorigenic TRCs. We also show that the cytoskeleton-related protein cytospin-A plays a critical role in the regulation of TRC-derived MP softness. The modulation of the mechanical properties of TRC-derived MPs could aid the efficiency of delivery of anticancer drugs.

Renal intraparenchymal resistive index: the ultrasonographic answer to many clinical questions.

The use of renal resistive indices (RRIs) for the study of renal microcirculation has in the past been proposed for the identification of renal organ damage or even to specifically identify injury to some areas of the renal parenchyma. Nevertheless, according to the most recent evidences from literature this organ-based conception of RRIs has been proven to be partial and unable to explain the RRIs variations in clinical settings of sepsis or combined organ failure of primitively extrarenal origin or, more generally, the deep connection between RRIs and hemodynamic factors such as compliance and pulsatility of the large vessels. The aim of this review is to explain the physiopathological basis of RRIs determination and the most common interpretative errors in their analysis. Moreover, through a comprehensive vision of these Doppler indices, the traditional and emerging clinical application fields for RRIs are discussed.

Vanishing spleen syndrome post right partial nephrectomy in a sicklemic patient.

Splenic infarction after contralateral laparoscopic renal surgery has not, to our knowledge, been reported. The spleen is the most affected organ in sickle cell disease and the mechanism of auto infarction is thought to result from the crystallization of abnormal hemoglobin during periods of hypoxia or acidosis resulting in parenchymal ischemia and ultimately tissue necrosis. We report a case of 45 year old female with sickle cell disease who had an unremarkable spleen at the time of a laparoscopic right partial nephrectomy and was subsequently found to have marked diminution in her splenic volume.

Elimination of substances from the brain parenchyma: efflux via perivascular pathways and via the blood-brain barrier.

This review considers efflux of substances from brain parenchyma quantified as values of clearances (CL, stated in µL g-1 min-1). Total clearance of a substance is the sum of clearance values for all available routes including perivascular pathways and the blood-brain barrier. Perivascular efflux contributes to the clearance of all water-soluble substances. Substances leaving via the perivascular routes may enter cerebrospinal fluid (CSF) or lymph. These routes are also involved in entry to the parenchyma from CSF. However, evidence demonstrating net fluid flow inwards along arteries and then outwards along veins (the glymphatic hypothesis) is still lacking. CLperivascular, that via perivascular routes, has been measured by following the fate of exogenously applied labelled tracer amounts of sucrose, inulin or serum albumin, which are not metabolized or eliminated across the blood-brain barrier. With these substances values of total CL ≅ 1 have been measured. Substances that are eliminated at least partly by other routes, i.e. across the blood-brain barrier, have higher total CL values. Substances crossing the blood-brain barrier may do so by passive, non-specific means with CLblood-brain barrier values ranging from < 0.01 for inulin to > 1000 for water and CO2. CLblood-brain barrier values for many small solutes are predictable from their oil/water partition and molecular weight. Transporters specific for glucose, lactate and many polar substrates facilitate efflux across the blood-brain barrier producing CLblood-brain barrier values > 50. The principal route for movement of Na+ and Cl- ions across the blood-brain barrier is probably paracellular through tight junctions between the brain endothelial cells producing CLblood-brain barrier values ~ 1. There are large fluxes of amino acids into and out of the brain across the blood-brain barrier but only small net fluxes have been observed suggesting substantial reuse of essential amino acids and α-ketoacids within the brain. Amyloid-ß efflux, which is measurably faster than efflux of inulin, is primarily across the blood-brain barrier. Amyloid-ß also leaves the brain parenchyma via perivascular efflux and this may be important as the route by which amyloid-ß reaches arterial walls resulting in cerebral amyloid angiopathy.

Impaired function of cerebral parenchymal arterioles in experimental preeclampsia.

Preeclampsia (PE), a dangerous hypertensive complication of pregnancy, is associated with widespread maternal vascular dysfunction. However, the effect of PE on the cerebral vasculature that can lead to stroke and cognitive decline is not well understood. We hypothesized that function of cortical parenchymal arterioles (PAs) would be impaired during PE. Using a high cholesterol diet to induce experimental PE in rats (ePE), we studied the function and structure of isolated and pressurized PAs supplying frontoparietal white matter (WM) tracts and cortex and compared to normal pregnant (Preg) and nonpregnant (Nonpreg) Sprague Dawley rats (n = 8/group). Myogenic reactivity and tone were similar between groups; however, constriction to intermediate-conductance calcium-activated potassium (IK) channel inhibition was diminished and dilation to inward-rectifying K+ (KIR) channel activation was impaired in PAs from ePE rats, suggesting altered ion channel function. Conducted vasodilation was significantly delayed in response to 12 mM KCl, but not 10 µM adenosine, in PAs from ePE rats versus Preg and Nonpreg rats (940 ±â€¯300 ms vs. 70 ±â€¯50 ms and 370 ±â€¯90 ms; p < 0.05). Overall, dysfunction of PAs supplying frontoparietal WM and gray matter was present in ePE. If persistent these changes could potentiate neuronal injury that over time could contribute to WM lesions and early-onset cognitive decline.

Carotid artery stenosis in hypertensive rats impairs dilatory pathways in parenchymal arterioles.

Hypertension is a leading risk factor for vascular cognitive impairment and is strongly associated with carotid artery stenosis. In normotensive rats, chronic cerebral hypoperfusion induced by bilateral common carotid artery stenosis (BCAS) leads to cognitive impairment that is associated with impaired endothelium-dependent dilation in parenchymal arterioles (PAs). The aim of this study was to assess the effects of BCAS on PA function and structure in stroke-prone spontaneously hypertensive rats, a model of human essential hypertension. Understanding the effects of hypoperfusion on PAs in a hypertensive model could lead to the identification of therapeutic targets for cognitive decline in a model that reflects the at-risk population. We hypothesized that BCAS would impair endothelium-dependent dilation in PAs and induce artery remodeling compared with sham rats. PAs from BCAS rats had endothelial dysfunction, as assessed using pressure myography. Inhibition of nitric oxide and prostaglandin production had no effect on PA dilation in sham or BCAS rats. Surprisingly, inhibition of epoxyeicosatrienoic acid production increased dilation in PAs from BCAS rats but not from sham rats. Similar results were observed in the presence of inhibitors for all three dilatory pathways, suggesting that epoxygenase inhibition may have restored a nitric oxide/prostaglandin-independent dilatory pathway in PAs from BCAS rats. PAs from BCAS rats underwent remodeling with a reduced wall thickness. These data suggest that marked endothelial dysfunction in PAs from stroke-prone spontaneously hypertensive rats with BCAS may be associated with the development of vascular cognitive impairment. NEW & NOTEWORTHY The present study assessed the structure and function of parenchymal arterioles in a model of chronic cerebral hypoperfusion and hypertension, both of which are risk factors for cognitive impairment. We observed that impaired dilation and artery remodeling in parenchymal arterioles and abolished cerebrovascular reserve capacity may mediate cognitive deficits.

[THE STRUCTURE OF THE ILEUM AFTER THE RESECTION OF LIVER PARENCHYMA].

The ileum was morphologically examined in 45 sexually mature white male rats, which were divided into 3 groups: I group included 15 intact animals, II - 15 rats, in which 31.5% of the liver parenchyma was removed, III - 15 animals after resection 58,1% of liver parenchyma. Euthanasia of rats was performed by bloodletting under the conditions of thiopental anesthesia 1 month after the beginning of the experiment. Histological micropreparations were made from the ileum, which were studied morphometrically. Quantitative indicators were processed statistically. It was revealed that after resection of 31.5% of the parenchyma of the liver, the morphometric parameters studied were insignificantly altered. Resection of 58.1% of the liver parenchyma lead to postresectional portal hypertension, which was characterized by venous full-blood in the veins of the portal hepatic vein system and morphological changes in the ileum. Venous thrombosis, edema, dystrophic, necrotic, infiltrative, sclerotic and atrophic processes were observed in the investigated organ. The relative volume of the damaged epitheliocytes of the mucous membrane of the ileum reached 64.50±0.72%, and myocytes in the muscular membrane - 41.10±0.54%. The pronounced changes in nuclear-cytoplasmic relations in epitheliocytes and stromal-myocytic muscle tissue testified to violations of tissue and cellular structural homeostasis. Thus, the removal of large volumes of liver parenchyma leads to postresectional portal hypertension expressed by remodeling of the structures of the ileum, which is characterized by uneven disproportional changes in the spatial characteristics of the organ structures, disturbances between them, vascular disorders, edema, dystrophic, necrobiotic changes in epitheliocytes, endothelial cells, myocytes, stromal elements, infiltrative, sclerotic and atrophic processes.

Focal 18F-DOPA Uptake in Brain Parenchyma Surrounding Developmental Venous Anomalies.

We report the finding of increased F-DOPA uptake within parenchyma surrounding a developmental venous anomaly, found incidentally in a 64-year-old woman undergoing PET scan to assess for Parkinson's disease. Not identified on previous T1/T2 MRI, susceptibility-weighted imaging MRI performed post-PET scan demonstrated the presence of developmental venous anomaly within the left cerebellar hemisphere. Focal uptake of F-DOPA may suggest the presence of a brain tumor and prompt invasive diagnostic investigations. Nuclear medicine physicians should be aware of this finding when interpreting F-DOPA PET and consider appropriate imaging to identify venous anomalies prior to more invasive investigations for possible brain tumors.

Functional Comparison of Renal Tumor Enucleation Versus Standard Partial Nephrectomy.

BACKGROUND: Tumor enucleation (TE) optimizes parenchymal preservation and could yield better function than standard partial nephrectomy (SPN), although data on this are conflicting. OBJECTIVE: To compare functional outcomes for TE and SPN strategies. DESIGN, SETTING, AND PARTICIPANTS: Patients managed with partial nephrectomy (PN) with necessary data for analysis of preservation of ipsilateral parenchymal mass (IPM) and global glomerular filtration rate (GFR) from two centers were included. All studies were required <2 mo before and 3-12 mo after surgery. Patients with a solitary kidney or multifocal tumors were excluded. INTERVENTION: Partial nephrectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Vascularized IPM was estimated from contrast-enhanced CT scans preoperatively and postoperatively. Serum creatinine-based estimates of global GFR were also obtained in the same timeframes. Univariable and multivariable linear regression evaluated factors associated with new-baseline global GFR. RESULTS/LIMITATIONS: Analysis included 71 TE and 373 SPN cases. The median preoperative global GFR was comparable for TE and SPN (75 vs 78ml/min/1.73m2; p=0.6). The median tumor size was 3.0cm for TE and 3.3cm for SPN (p=0.03). The median RENAL score was 7 in both cohorts. For TE, warm ischemia and zero ischemia were used in 51% and 49% of cases, respectively. For SPN, warm ischemia and cold ischemia were used in 72% and 28% of patients, respectively. Capsular closure was performed in 46% of TE and 100% of SPN cases (p<0.001). Positive margins were found in 8.5% of TE and 4.8% of SPN patients (p=0.2). The median vascularized IPM preserved was 95% (interquartile range [IQR] 91-100%) for TE and 84% (IQR 76-92%) for SPN (p<0.001). The median global GFR preserved was 101%(IQR 93-111%) and 89% (IQR 81-96%) for TE and SPN, respectively (p<0.001). On multivariable analysis, resection strategy, preoperative GFR, and vascularized IPM preserved were all significantly associated (p<0.001) with new-baseline global GFR. Limitations include the retrospective design and the lack of resection outcome data. CONCLUSIONS: Our analysis suggests that TE has potential for maximum IPM preservation compared to SPN and may provide optimized functional recovery. Further investigation will be required to evaluate the clinical significance of these findings. PATIENT SUMMARY: Tumor enucleation for kidney cancer involves dissection along the tumor capsule and optimally preserves normal kidney tissue, which may lead to better functional recovery. The importance of this approach in various clinical settings will require further investigation.

The Pathology of Chronic Obstructive Pulmonary Disease: Progress in the 20th and 21st Centuries.

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and is the fourth leading cause of death worldwide. There has been significant progress in the pathologic description and pathophysiologic analysis of COPD in the 20th and 21st centuries. We review the history, progression, and significance of pathologic alterations in COPD, including emphysematous changes, airway alterations, and vascular alterations. We also indicate what pathologic features of COPD the practicing pathologist should be describing in standard surgical and autopsy specimens.

DOCA-salt hypertension impairs artery function in rat middle cerebral artery and parenchymal arterioles.

OBJECTIVE: Chronic hypertension induces detrimental changes in the structure and function of surface cerebral arteries. Very little is known about PAs, which perfuse distinct neuronal populations in the cortex and may play a role in cerebrovascular disorders. We investigated the effect of DOCA-salt induced hypertension on endothelial function and artery structure in PAs and MCAs. METHODS: Uninephrectomized male Sprague-Dawley rats were implanted with a subcutaneous pellet containing DOCA (150 mg/kg b.w.) and drank salt water (1% NaCl and 0.2% KCl) for 4 weeks. Sham rats were uninephrectomized and drank tap water. Vasoreactivity and passive structure in the MCAs and the PAs were assessed by pressure myography. RESULTS: Both MCAs and PAs from DOCA-salt rats exhibited impaired endothelium-dependent dilation (P<.05). In the PAs, addition of NO and COX inhibitors enhanced dilation in DOCA-salt rats (P<.05), suggesting that dysfunctional NO and COX-dependent signaling could contribute to impaired endothelium-mediated dilation. MCAs from DOCA-salt rats exhibited inward remodeling (P<.05). CONCLUSIONS: Hypertension-induced MCA remodeling coupled with impaired endothelium-dependent dilation in both the MCAs and PAs may exacerbate the risk of cerebrovascular accidents and the associated morbidity and mortality.

Uncoupling of neurovascular communication after transient global cerebral ischemia is caused by impaired parenchymal smooth muscle Kir channel function.

Transient global cerebral ischemia is often followed by delayed disturbances of cerebral blood flow, contributing to neuronal injury. The pathophysiological processes underlying such disturbances are incompletely understood. Here, using an established model of transient global cerebral ischemia, we identify dramatically impaired neurovascular coupling following ischemia. This impairment results from the loss of functional inward rectifier potassium (KIR) channels in the smooth muscle of parenchymal arterioles. Therapeutic strategies aimed at protecting or restoring cerebrovascular KIR channel function may therefore improve outcomes following ischemia.

Early Impact on Renal Parenchymal Vascularization of Chimney Grafts Versus Fenestrated Grafts.

OBJECTIVE: The primary objective of this retrospective study was to analyze the early impact of chimney (CG) versus fenestrated grafts (FG) on renal parenchymal vascularization and function. METHODS: All consecutive patients with juxta-renal abdominal aortic aneurysm (JR-AAA) treated by endovascular repair from December 2013 to July 2014 at the vascular unit, Pellegrin University Hospital, Bordeaux, France, were included. Serum creatinine (SCr) and estimated glomerular filtration rate (eGFR) were reported at baseline and at J2 for acute kidney injury (AKI) incidence, and at J7 for AKI staging (KDIGO criteria); renal resistive indices (RRI) were reported for renal parenchymal repercussion at J-1, J0, and J1. RESULTS: Ten patients were included in the CG group and 25 in the FG group, with 13 and 50 renal target vessels, respectively. Successful target vessel revascularization was achieved in 92.3% and 100.0% of patients. The incidence of AKI (10% and 32%), baseline SCr, and eGFR did not differ significantly. SCr was more elevated in the FG group at J1 (p = .025), J2 (p = .051), and J7 (p = .052), and eGFR was significantly lower from baseline to J1 (p = .015) and J2 (p = .014). RRI did not differ significantly between both groups. RRI augmentation was only noted in the FG group from J-1 to J0 (p = .039) and J-1 to J1 (p = .059). Patients with a KDIGO score <2 versus ≥2 showed significantly different RRI at J0 (p = .038) and J1 (p = .007). ROC curve analysis showed that RRI measures could be a predictive factor for AKI at J0 (cutoff = 0.72, sensitivity [Se] = 50%, specificity [Sp] = 86%) and J1 (cutoff = 0.71, Se = 70%, Sp = 84%). CONCLUSIONS: This study showed no significant difference in terms of RRI, eGFR, and the incidence of AKI or CKD between CG and FG. However, post-operative SCr levels were higher with FG, which was corroborated by comparison between pre- and post-operative RRI. Results are limited by the small sample size, but early repeated measures of RRI could be helpful in alerting the clinician to post-operative renal degradation, allowing better-informed attempts to preserve renal function.