Acute Vascular Changes Research Articles

#220 Acute vascular response to hemodialysis as measured by serum syndecan-1 and endothelin-1 levels, as well as vascular stiffness

Abstract Background and Aims End-stage kidney disease (ESKD) patients on chronic hemodialysis (HD) have very high cardiovascular risk. Acute vascular changes during dialysis mediated partially by factors of the endothelium may have a crucial role in the cardiovascular (CV) disease of HD patients. Aim To study acute vascular changes during HD measured by applanation tonometry and to assess the role of syndecan-1 (SDC-1), endothelin-1 (ET-1), and traditional and non-traditional CV risk factors in these changes. Method 29 consecutive chronic HD patients (median age: 65.6 ± 10.4 years; 52% men) were included in the study. Pre-, mid-, and post-HD plasma SDC-1 and ET-1 levels and routine biochemical parameters were measured. Applanation tonometry (SphygmoCor, AtCor Medical) was performed before HD. Results As assessed by trend analysis, SDC-1 levels increased significantly during HD (p = 0.004). ET-1 levels were decreasing during HD. Male patients had significantly higher ET-1 levels than women. Patients were divided into 2 groups based on their pulse wave velocity (PWV): PWV ≥12 m/s and PWV <12 m/s. Pre-HD and mid-HD SDC-1 levels were significantly higher in the group with PWV ≥12 m/s (10.174 ± 2.568 vs. 7.928 ± 1.794 ng/ml, p = 0.013, and 10.319 ± 3.482 vs. 8.248 ± 1.793 ng/ml, p = 0.044, respectively). Post-HD ET-1 levels were significantly higher in the patient group having PWV ≥12 m/s (10.88 ± 3.00 vs. 8.05 ± 3.48 pg/l, p = 0.027). Patients having PWV ≥12 m/s had significantly higher pre-HD peripheral and aortic systolic blood pressure than the patients having lower PWV (147.4 ± 73.3 vs. 134.1 ± 72.2 mmHg, p = 0.038, and 130.7 ± 16.6 vs. 122.5 ± 14.9 mmHg, p = 0.016, respectively). Mid-HD and post-HD blood pressures were not different. We found a positive correlation between total cholesterol and the decrease in SDC-1 levels during HD (r = 0.539; p = 0.008). Pre-, mid-, and post-HD SDC-1 correlated significantly with the ultrafiltration volume during HD (r = 0.432, p = 0.019; r = 0.377, p = 0.044; and r = 0.401, p = 0.012, respectively). Conclusion SDC-1 and ET-1 may contribute to the vascular changes observed during HD, and they have correlations with some traditional and non-traditional CV risk factors.

Acute Vascular Response to Hemodialysis as Measured by Serum Syndecan-1 and Endothelin-1 Levels as Well as Vascular Stiffness

Background: Chronic hemodialysis (HD) patients have a very high cardiovascular risk. Acute vascular changes during dialysis mediated by factors of the endothelium may have a crucial role in this. The aim of this article is to study the acute vascular changes during HD. Methods: In 29 consecutive chronic HD patients (age: 65.6 ± 10.4 years), their pre-, mid-, and post-HD plasma syndecan-1 (SDC-1) and endothelin-1 (ET-1) levels were measured. Applanation tonometry was performed before HD. Results: Their SDC-1 levels increased during HD (p = 0.004). Males had higher ET-1 levels. The patients were divided into two groups based on their pre-HD pulse wave velocity (PWV): PWV ≥ 12 m/s and PWV < 12 m/s. The pre-HD and mid-HD SDC-1 levels were higher in the group with a PWV ≥ 12 m/s (10.174 ± 2.568 vs. 7.928 ± 1.794 ng/mL, p = 0.013, and 10.319 ± 3.482 vs. 8.248 ± 1.793 ng/mL, p = 0.044, respectively). The post-HD ET-1 levels were higher in the patient group with a PWV ≥ 12 m/s (10.88 ± 3.00 vs. 8.05 ± 3.48 pg/l, p = 0.027). Patients with a PWV ≥ 12 m/s had higher pre-HD peripheral and aortic systolic blood pressures (p < 0.05). The total cholesterol correlated with the SDC-1 decrease during HD (r = 0.539; p = 0.008). The pre-, mid-, and post-HD SDC-1 correlated with ultrafiltration (r = 0.432, p = 0.019; r = 0.377, p = 0.044; and r = 0.401, p = 0.012, respectively). Conclusion: SDC-1 and ET-1 contribute to the vascular changes observed during HD, and they have correlations with some cardiovascular risk factors.

Joint injury-induced angiogenesis and thrombospondin 2

Purpose: It is controversial whether inhibition of angiogenesis slows the progression of post-traumatic osteoarthritis (PTOA). The matricellular protein thrombospondin-2 (TSP2) is a candidate for inhibiting intraarticular angiogenesis after joint injury as it is a well-characterized endogenous anti-angiogenic protein. In addition, prior literature demonstrates the inhibition of matrix metalloproteinase (MMP) bioavailability by TSP2. However, little is known of the involvement of TSP2 in joint trauma, injury-induced angiogenesis and MMP activity, and PTOA progression. The purpose of this study was to characterize the endogenous TSP2 response following traumatic joint injury in mice. Methods: With IACUC approval, noninvasive ACLR was induced in adult TSP2-GFP reporter mice and C57Bl/6 mice via tibial compression. Limbs were processed for histology at 3d, 14d, and 28d post-ACLR (n=3-4/timepoint). The proportion of TSP2+ cells in synovium was quantified in injured and contralateral limbs of TSP2-GFP mice using k-means clustering of reporter intensity. ACLR-induced angiogenesis was assessed in C57Bl/6 mice via CD31 immunostaining and in vivo near-infrared imaging (NIR) utilizing the AngioSense-agent (Perkin Elmer), which enables in vivo assessment of vascular changes. Synovia from C57Bl/6 ACLR and contralateral knees were dissected, homogenized in Trizol, and analyzed for TSP2, MMP2, MMP3, MMP13 gene expression via rtPCR at 3d and 14d post-ACLR (n=5-8/timepoint), representing timepoints of early and late inflammation. To determine which cytokines induce TSP2 in fibroblast-like synoviocytes (FLS) and whether ACLR-associated in vivo inflammation affects the in vitro FLS cytokine response, primary mouse FLS were isolated from knee synovium of 7d post-ACLR and contralateral knees (n=3/group). FLS were induced with IL-1β and TNFα (10 ng/ml) for 48 hours and analyzed for TSP2 and MMP13 gene expression. Gene expression was normalized to ATP5b and paired t-tests performed. Results: ACLR induced intraarticular angiogenesis at 14d and 28d, assessed by influx of CD31+ cells. Abundant CD31+ staining was observed in synovium, menisci, and osteophytes of injured knees up to 28d post-ACLR (Figure. 1 A-C). An observed increase in in vivo AngioSense signal of the injured knee 7d post-ACLR (P=0.021) corroborates this finding and indicates acute vascular changes (Figure. 1D-E). ACLR also induced significant upregulation of MMP-2, -3, and -13 mRNA by synovium at 3d and 14d post-ACLR (Figure. 2K). In TSP2-GFP reporter mice, injured knees exhibited abundant synovial TSP2 expression, as early as 3d and up to 28d (at which point mice exhibit moderate PTOA severity; data not shown). At 3d and 14d, TSP2 expression is confined to the synovium, and by 28d, developing osteophytes are also TSP2(+). At all timepoints, synovial TSP2 expression is localized to the subintima. The intima of injured joints, although hyperplastic, remains TSP2(-). The cruciate ligaments, menisci, articular cartilage, and subchondral bone remain TSP2(-) (Figure. 2A-H). Quantitative image analysis indicates ACLR-induced TSP2-GFP expression in ∼27% of synovial cells at 14d (P=0.017) and ∼24% at 28d (P=0.018) post-ACLR, compared to near-zero expression in contralateral synovia (Figure. 2J). rtPCR confirms strong TSP2 upregulation in injured C57Bl/6 synovium at 3d (P=.006) and 14d (P=.007) (Figure. 2I). Surprisingly, both IL-1β and TNFα downregulated TSP2 in FLS from healthy (IL-1β - P=.009; TNFα - P=.001) and injured (IL-1β - P=.001; TNFα - P=.10) joints. TNFα-treated FLS from injured joints exhibited significantly less downregulation compared to healthy FLS (P=0.025) (Figure. 3B). Both IL-1β and TNFα induced a strong MMP13 response in healthy (P=0.002; P=0.004) and injured (P=0.001; P=0.006) FLS (Figure 3A), and there was no difference in the magnitude of MMP13 expression between healthy and injured FLS. Conclusions: TSP2 is strongly upregulated by the synovium following ACLR. This coincides with a synovial MMP-2, -3, and -13 response, increased intraarticular angiogenesis, and the time course of post-injury inflammation. Interestingly, TSP2 expression is confined to the subintimal region of the synovium. Our in vitro data shows that primary FLS do not upregulate TSP2 in response to IL-1β or TNFα, and interestingly, FLS from injured joints do not exhibit differentially-elevated TSP2 compared to FLS from contralateral joints, despite abundant in vivo synovial TSP2 expression following ACLR. Thus, ongoing work is identifying local TSP2+ cell populations and ligands that induce TSP2 expression in FLS. Given evidence on the anti-angiogenic capacity of TSP2, ongoing work is assessing angiogenesis, inflammation, catabolism, and PTOA severity in global TSP2-KO mice. Our ultimate objective is to mitigate injury-induced angiogenesis with exogenous TSP2 treatment.View Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT)

A-42 Case of Persistent Amnestic Syndrome due to Small Right-Sided Retrosplenial Lacunes

Abstract Objective Lesions to the retrosplenial cortex secondary to acute stroke or tumor have been shown to disrupt Papez’s circuit due to disconnection between the anterior thalamus and hippocampus, via the posterior cingulate, producing an amnestic syndrome. This case demonstrates how small but strategic lacunes in this region may produce memory deficits. Method The patient is a 52-year-old, right-handed, African-American woman with 18 years of education who reported memory changes over the last 8 years (e.g., misplacing items, forgetting details of conversations). Her medical history was notable for BMI of 31 and borderline diabetes. She completed structural magnetic resonance imaging 6 years prior to, and concordant with, her neuropsychological evaluation. Both scans showed two small (2-3 mm) right-sided retrosplenial lacunes, without evidence of hippocampal or global volume loss over the 6-year span. Results Her neurocognitive profile was characterized by impairments in both verbal (stories, word-list) and figural memory, with relative strengths in attention, processing speed, and executive functioning. Across memory measures, she performed in the low average-to-mildly impaired range on immediate recall, mildly-to-severely impaired range on delayed recall, and did not benefit from yes-no recognition format. She demonstrated additional features of an amnestic profile, including flat learning slope, recency effect, elevated cued recall intrusion errors, and very elevated false positive errors on recognition. Conclusions Findings expand upon the existing literature to show that chronic, small retrosplenial lacunes can disrupt the connection between the anterior thalamus and hippocampus, resulting in a clinical presentation of circumscribed memory impairment that persists years beyond acute vascular changes.

Cardiovascular Responses to Skeletal Muscle Stretching: "Stretching" the Truth or a New Exercise Paradigm for Cardiovascular Medicine?

Stretching is commonly prescribed with the intended purpose of increasing range of motion, enhancing muscular coordination, and preventing prolonged immobilization induced by aging or a sedentary lifestyle. Emerging evidence suggests that acute or long-term stretching exercise may modulate a variety of cardiovascular responses. Specifically, at the onset of stretch, the mechanical deformation of the vascular bed coupled with stimulation of group III muscle afferent fibers initiates a cascade of events resulting in both peripheral vasodilation and a heart rate-driven increase in cardiac output, blood pressure, and muscle blood flow. This potential to increase shear stress and blood flow without the use of excessive muscle energy expenditure may hold important implications for future therapeutic vascular medicine and cardiac health. However, the idea that a cardiovascular component may be involved in human skeletal muscle stretching is relatively new. Therefore, the primary intent of this review is to highlight topics related to skeletal muscle stretching and cardiovascular regulation and function. The current evidence suggests that acute stretching causes a significant macro- and microcirculatory event that alters blood flow and the relationship between oxygen availability and oxygen utilization. These acute vascular changes if performed chronically may result in improved endothelial function, improved arterial blood vessel stiffness, and/or reduced blood pressure. Although several mechanisms have been postulated, an increased nitric oxide bioavailability has been highlighted as one promising candidate for the improvement in vessel function with stretching. Collectively, the evidence provided in this review suggests that stretching acutely or long term may serve as a novel and alternative low intensity therapeutic intervention capable of improving several parameters of vascular function.

The Examination of the Acute Vascular Changes after Short-Term Smoking Cessation Using Second Derivative of Photoplethysmogram in the Adult Men

The Examination of the Acute Vascular Changes after Short-Term Smoking Cessation Using Second Derivative of Photoplethysmogram in the Adult Men

Omphalitis Leading to Urachitis and Acute Vascular Changes in a Buffalo Calf: An Insight into Macro and Microscopic Pathologic Changes

Omphalitis in domestic animals being considered as commonest ailment after birth, are in general, poorly reported for its uneventful recovery. Several previously reported cases endeavoured to highlight involvement of pathogenic organism in progression of the condition with little elaboration to pathologic changes occurred. Moreover, description of omphalitis in buffalo calf was never been attempted. Therefore this report intends to elaborate the pathology noted around umbilical zone in a buffalo calf possibly arisen to infectious etiology with special reference to complicated involvement of urachus, eventual haemoperitoneum and striking acute vascular changes of multi-systemic organs. Intriguingly, this report also attempted to review few recent cases of omphalitis seen in different animals along with their paramount etiologic causes.

Chemotherapy-induced Vascular Toxicity - Real-time <em>In vivo</em> Imaging of Vessel Impairment

Certain classes of chemotherapies may exert acute vascular changes that may progress into long-term conditions that may predispose the patient to an increased risk of vascular morbidity. Yet, albeit the mounting clinical evidence, there is a paucity of clear studies of vascular toxicity and therefore the etiology of a heterogeneous group of vascular/cardiovascular disorders remains to be elucidated. Moreover, the mechanism that may underlie vascular toxicity can completely differ from the principles of chemotherapy-induced cardiotoxicity, which is related to direct myocyte injury. We have established a real-time, in vivo molecular imaging platform to evaluate the potential acute vascular toxicity of anti-cancer therapies. We have set up a platform of in vivo, high-resolution molecular imaging in mice, suitable for visualizing vasculature within confined organs and reference blood vessels within the same individuals whereas each individual serve as its own control. Blood vessel walls were impaired after doxorubicin administration, representing a unique mechanism of vascular toxicity that may be the early event in end-organ injury. Herein, the method of fibered confocal fluorescent microscopy (FCFM) based imaging is described, which provides an innovative mode to understand physiological phenomena at the cellular and sub-cellular levels in animal subjects.

Chemotherapy-induced Vascular Toxicity - Real-time <em>In vivo</em> Imaging of Vessel Impairment

Certain classes of chemotherapies may exert acute vascular changes that may progress into long-term conditions that may predispose the patient to an increased risk of vascular morbidity.Yet, albeitthe mounting clinical evidence, there is a paucity of clear studies of vascular toxicity and therefore the etiology of a heterogeneous group of vascular/cardiovascular disorders remains to be elucidated. Moreover, the mechanism that may underlie vascular toxicity can completely differ from the principles of chemotherapy-induced cardiotoxicity, which is related to direct myocyte injury. We have established a real-time, in vivo molecular imaging platformto evaluatethe potentialacutevascular toxicity of anti-cancer therapies. We have set up a platform of in vivo, high-resolution molecular imagingin mice,suitable for visualizing vasculature within confined organs and reference blood vessels within the same individuals whereas each individual serve as its own control. Blood vessel walls were impaired after doxorubicin administration, representing a unique mechanism of vascular toxicity that may be the early event in end-organ injury. Herein, the method of fibered confocal fluorescent microscopy (FCFM) based imaging is described, which provides an innovative mode to understand physiological phenomena at the cellular and sub-cellular levels in animal subjects.

Acute Vascular Changes Following Prolonged Live Firefighting

Acute Vascular Changes Following Prolonged Live Firefighting

The Examination of the Acute Vascular Changes Due to Smoking Using Second Derivative of Photoplethysmogram

Background: Although smoking is the major risk factor for atherosclerosis under the age of 40, the smoking rate of adolescent and young adult has been is increasing. In case of young adults, there is no available clinical indices reflecting harmful effects of smoking. The aim of this study was to investigate whether any second derivative of photoplethysmogram (SDPTG) index can be used as a clinical index of acute effects of smoking. Methods: Twenty smoking and eighteen never-smoking males ages between 20-39 without medical history of atherosclerotic disease nor peripheral vascular diseases were selected for this study. We investigated the life styles and risk factors of atherosclerosis through a questionnaire, laboratory test and physical examination. We measured SDPTG at baseline, 3, 5, 10, 15, and 20 minutes for smokers after smoking and walking and for never-smokers after walking. Repeated measures ANOVA and ANCOVA were used for analysing the changes of SDPTG according to time. Results: The heart rate and blood vessel tension (BVT) were different between the smokers and never-smokers after adjusting age, fasting blood sugar, body mass index, depression, and exercise (P < 0.05, P < 0.05, respectively). In contrast to never-smokers, heart rate of smokers at 3 minutes after smoking was increased for 10.1 per minute (P < 0.001) and higher than never-smokers until 15 minutes (P < 0.05). BVT in smokers was decreased at 3 minutes (P < 0.05) from baseline and lower than never-smokers at 3 minutes (P < 0.05). Differential pulse wave index, stress power, remained blood volume, and the changes of these indices according to time were not significantly different between the two groups. Conclusion: BVT and heart rate reflected the acute effect of smoking on blood vessels and could be used to provide motivation to quit smoking and make people more concerned about their own health especially to the young smokers who has no symptoms yet.

Acute vascular changes in renal arterial anatomy after cryosurgery

IntroductionCryosurgery is gaining importance as an optional curative or palliative treatment technique for urological cancers. The aim is to indicate which part of the microcirculation is acutely destroyed by this technique.MethodsIn 6 anesthetized pigs kidney cryoablation was applied for 20 minutes using a triple needle probe configuration (Cryoneedle TM). The kidneys where allowed to thaw in situ and then excised., its main artery was flushed with saline and filled with a fluorescence dyed elastomere. The kidney was, frozen and processed in an imaging cryomicrotome. After each slice the fluorescence in the cutting plane was measured applying a 2000 by 2000 pixel digital camera. 3 D image processing revealed information about arterial structure down to 20 μm vessels. As a statistical measure the summed length, Ld of all segments having a diameter, d, were summed for regions of interest, ROI.ResultsThe ablated zones were clearly noticeable in the white light and 3‐D fluorescent images. The histograms of Ld versus d as well as dPeak (d where Ld is maximal) where independent of the selection of non‐ablated ROI. For ablated areas dPeak shifted to larger diameters by 70 microns and Ld at dPeak without ablation reduced by a factor of 10.ConclusionAfter cryoablation, acute injury of the renal arterial vessels induced destruction of the vessels smaller than 200 μm leaving the structure of larger vessels intact.

Antivascular effects of combretastatin A4 phosphate in breast cancer xenograft assessed using dynamic bioluminescence imaging and confirmed by MRI

Bioluminescence imaging (BLI) has found significant use in evaluating long-term cancer therapy in small animals. We have now tested the feasibility of using BLI to assess acute effects of the vascular disrupting agent combretastatin A4 phosphate (CA4P) on luciferase-expressing MDA-MB-231 human breast tumor cells growing as xenografts in mice. Following administration of luciferin substrate, there is a rapid increase in light emission reaching a maximum after about 6 min, which gradually decreases over the following 20 min. The kinetics of light emission are highly reproducible; however, following i.p. administration of CA4P (120 mg/kg), the detected light emission was decreased between 50 and 90%, and time to maximum was significantly delayed. Twenty-four hours later, there was some recovery of light emission following further administration of luciferin substrate. Comparison with dynamic contrast-enhanced MRI based on the paramagnetic contrast agent Omniscan showed comparable changes in the tumors consistent with the previous literature. Histology also confirmed shutdown of tumor vascular perfusion. We believe this finding provides an important novel application for BLI that could have widespread application in screening novel therapeutics expected to cause acute vascular changes in tumors.

CHICAGO and RIO-Diabetes

CHICAGO and RIO-Diabetes

Antenatal corticosteroids: the controversy continues

Purpose of review Maternal administration of glucocorticoids remains the mainstay of perinatal medicine for the fetus at risk of premature delivery. The reductions of severity of respiratory distress syndrome, incidence of intraventricular hemorrhage, and neonatal death have all been well documented. Findings from both experimental studies in animals as well as clinical investigation in humans have raised issues of concern and controversy. These include the use of repetitive courses of corticosteroids. Questions have been raised regarding the postnatal neurobehavioral and prenatal cardiovascular responses to corticosteroids. The purpose of this review is to address the current data pertaining to these controversies. Recent findings Animal studies reflect the concerns of the use of multiple courses of steroids with alterations of brain growth and histology. Human data suggest that multiple courses of corticosteroids might reduce the risk of respiratory distress syndrome, but at the expense of alterations of lung architecture. There are concerns about decreased somatic and head size. Neurobehavioral abnormalities are more frequently seen in children exposed to multiple courses. In growth-restricted fetuses with evidence of placental dysfunction, there may be a risk of sudden in-utero decompensation. Summary Repetitive courses of corticosteroids have deleterious effects with little improvement in neonatal outcome. A ‘rescue dose’ given to a fetus previously yet remotely treated may be of some benefit. Animal studies suggest acute vascular changes with maternal steroids. This has not been consistently borne out with the indirect assessment using Doppler in the human. A select group of severely growth restricted fetuses with umbilical artery absent end diastolic flow may actually deteriorate with maternal corticosteroids.

Tranilast reduces mesenteric vascular collagen deposition and chymase-positive mast cells in experimental diabetes

The mast cell has a central role in the pathogenesis of fibrosis a common feature of diabetic microvascular complications. Increased mast cell numbers have been demonstrated in diabetic nephropathy in association with renal fibrosis, and diabetes acutely increases mast cell infiltration in the mesentery. Antimast cell agents such as tranilast may ameliorate the acute vascular changes in diabetes due to stabilisation of mast cells and/or reduction in mast cell numbers. After 3 weeks of streptozotocin diabetes, light microscopy techniques were used to estimate mesenteric vessel fibrosis and mast cell infiltration. Mast cells were identified by toluidine blue staining and tryptase, chymase and TGF-β immunohistochemistry in three study groups of rats: control, diabetic and plus tranilast. Diabetes was associated with an increase in both mesenteric vessel fibrosis and mast cell numbers. Administration of tranilast to diabetic rats reduced mesenteric vessel fibrosis and this was associated with a reduction in chymase-positive mast cells. These changes were independent of mast cell TGF-β and were not associated with a reduction in tryptase-positive mast cells. The amelioration of diabetes-induced vessel fibrosis may be due to a reduction in the liberation of angiotensin II by inhibiting mast cell chymase.

Oxidative cell membrane alteration. Evidence for surfactant-mediated sealing.

Exposure to very intense ionizing irradiation produces acute tissue sequelae including inflammation, pain, and swelling that often results in tissue fibrosis and/or necrosis. Acute tissue necrosis occurs in hours when sufficiently rapid damage to membrane lipids and proteins leads to altered membrane structure, disrupting the vital electrochemical diffusion barrier necessary for cell survival. This damage mechanism is thought to underlie the interphase death of lethally irradiated postmitotic cells such as neurons, but it has also been implicated in the rapid cell death of lymphocytes and acute vascular changes due to capillary epithelium dysfunction. It is not known whether sealing of radiation-permeabilized cell membranes will prolong survival of lethally irradiated cells or perhaps lead to repair of damaged nucleic acids. The purpose of this study is to begin to address the first question.

Characteristics and fate of vascular fibrin deposition: An electron microscopic study of hyalinosis

The characteristics and fate of fibrin deposition were followed by electron microscopy in arterioles and arteries of heart, pancreas, and mesentery, as well as in subdiaphragmatic segments of aorta of rats killed at intervals ranging from 2 to 65 days after surgical induction of malignant hypertension. Acute vascular changes were characterized by the formation of highly organized crystalline fibrin bodies within compartments of arteriolar and arterial wall and loose fibrillar fibrin in perivascular areas. Whereas perivascular fibrin was readily replaced by proliferating fibroblasts and collagen, masses of crystalline fibrin within vascular compartments limited by basement or elastic laminae persisted and then evolved into acellular fields of hyalin. During the period of observation, two processes could be followed in these vascular compartments: (1) a slow structural modification in the crystalline fibrin bodies, resulting in a granular electron-dense substance and (2) parallel new formation of basement-membrane-like material. Endothelial and smooth muscle cells seemed to play a role in both processes.

The cerebrospinal fluid pressure response to certain acute vascular changes.

A perfused cat preparation is described which permits controlled and independent alterations of certain major vascular variables. The effects of such alterations upon the cerebrospinal fluid pressure are examined. The information obtained together with that derived from experiments on non-perfused animals is used to explain the cerebrospinal fluid pressure response to temporary obstruction of a vena cava. An increase in a caval pressure produces a sustained rise of cerebrospinal fluid pressure which resists lowering, and the rise of the latter pressure accompanying an increase in cardiac input is due mainly to the increase of central venous pressures. A decrease of cardiac input produces first a fall followed by a rise of cerebrospinal fluid pressure. When the input is restored the pressure rises steeply, ex­ceeding the resting level. None of these effects is due to changes in central venous pressures. In the non-perfused animal a caval obstruction produces a rise of distal caval pressure and a fall of cardiac input and the result of these two opposing influences is usually an increase of cerebrospinal fluid pressure. The rise of caval pressure raises the cerebrospinal fluid pressure by increasing the regional intracraniovertebral venous sinus pressure. On releasing an obstructed inferior vena cava a supernormal rise of cerebrospinal fluid pressure is observed, as after restoration of a reduced cardiac input. This response is dependent upon a mechanism restricted to the cranial end of the neuraxis and appears to be caused by a brief increase of cerebral blood flow. On releasing an obstructed superior vena cava a supernormal rise of cerebrospinal fluid pressure is not seen.