Peripheral Capillary Bed Research Articles

Abstract 384: Detection of circulating melanoma cells in paired arterial and venous specimens from uveal melanoma patients with hepatic metastatic

Abstract Background: Circulating tumor cells (CTCs) represent a surrogate biomarker for hematogenous metastases. The detection of CTCs has gained increasing interest for prediction of clinical outcome. However, it remains to be determined whether uveal melanoma cells circulating in a peripheral vein predict systemic recurrence and poorer overall prognosis. Uveal melanoma, the most common primary cancer of the eye in adults, is unique in that the uveal tract is devoid of lymphatics. Since systemic recurrence develops exclusively via hematogenous spread, patients with uveal melanomas present a special opportunity to explore the prognostic potential of CTCs. Although the lung is the first organ through which venous drainage from the affected eye passes and indeed the only organ through which all venous blood must pass, 80-95% of systemic metastases are found first in the liver without development of lung metastases. To address these issues, we investigated the numbers of CTCs in paired arterial (femoral) and venous (antecubital) blood specimens obtained from uveal melanoma patients with hepatic metastases. Methods: CTCs in blood specimens were measured in 17 uveal melanoma patients with multiple hepatic metastases, including 10 patients with liver-only metastases and 7 patients with hepatic and extra-hepatic metastases. Peripheral arterial and venous blood specimens were collected at the same time prior to liver directed treatment. CTCs were analyzed using CellTracks Circulating melanoma Cell Kit by CellSearch System. The clinical information and sources of blood specimens were blinded when CTCs were analyzed. Result: CTCs were detectable from all 17 arterial blood specimens (100%) (median 5, range 1 to 168). In contrast, much smaller numbers of CTCs were detectable in 52.9% (9/17) of venous blood specimens (median 1, range 0 to 8) from the same patients. In terms of degree of tumor burden, patients who have hepatic as well as extra-hepatic metastasis showed higher numbers of arterial CTCs (median 12, range 5 to 168), compared to patients who have liver-only metastasis (median 4, range 1 to 11). More importantly, there is no significant correlation between numbers of arterial CTCs and the degree of tumor volume in the liver in patients who have liver-only metastases. Conclusions: Using this technology, the detection of uveal melanoma cells in peripheral blood is feasible. Peripheral capillary beds effectively filter CTCs from venous blood; thus venous blood might not be the best source for measurement of CTCs in patients with metastatic uveal melanoma. The paucity of clinically evident non-hepatic metastases despite the effective filtration by peripheral capillary beds remains unexplained and may be a demonstration of the “seed and soil” hypothesis. CTCs are a non-invasive source of uveal melanoma cells for evaluating tumor biology. Further investigation is warranted. Citation Format: Mizue Terai, Zhaomei Mu, David Eschelman, Carin Gonsalves, Ken Kageyama, Michael J. Mastrangelo, Marlana Orloff, Ryan Weight, Massimo Cristofanilli, Takami Sato. Detection of circulating melanoma cells in paired arterial and venous specimens from uveal melanoma patients with hepatic metastatic. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 384. doi:10.1158/1538-7445.AM2015-384

Amyloid-β efflux from the central nervous system into the plasma.

The aim of this study was to measure the flux of amyloid-β (Aβ) across the human cerebral capillary bed to determine whether transport into the blood is a significant mechanism of clearance for Aβ produced in the central nervous system (CNS). Time-matched blood samples were simultaneously collected from a cerebral vein (including the sigmoid sinus, inferior petrosal sinus, and the internal jugular vein), femoral vein, and radial artery of patients undergoing inferior petrosal sinus sampling. For each plasma sample, Aβ concentration was assessed by 3 assays, and the venous to arterial Aβ concentration ratios were determined. Aβ concentration was increased by ∼7.5% in venous blood leaving the CNS capillary bed compared to arterial blood, indicating efflux from the CNS into the peripheral blood (p < 0.0001). There was no difference in peripheral venous Aβ concentration compared to arterial blood concentration. Our results are consistent with clearance of CNS-derived Aβ into the venous blood supply with no increase from a peripheral capillary bed. Modeling these results suggests that direct transport of Aβ across the blood-brain barrier accounts for ∼25% of Aβ clearance, and reabsorption of cerebrospinal fluid Aβ accounts for ∼25% of the total CNS Aβ clearance in humans. Ann Neurol 2014;76:837-844.

Inducing a Visceral Organ to Protect a Peripheral Capillary Bed: Stabilizing Hepatic HIF-1α Prevents Oxygen-Induced Retinopathy

Activation of hypoxia-inducible factor (HIF) can prevent oxygen-induced retinopathy in rodents. Here we demonstrate that dimethyloxaloylglycine (DMOG)-induced retinovascular protection is dependent on hepatic HIF-1 because mice deficient in liver-specific HIF-1α experience hyperoxia-induced damage even with DMOG treatment, whereas DMOG-treated wild-type mice have 50% less avascular retina (P < 0.0001). Hepatic HIF stabilization protects retinal function because DMOG normalizes the b-wave on electroretinography in wild-type mice. The localization of DMOG action to the liver is further supported by evidence that i) mRNA and protein erythropoietin levels within liver and serum increased in DMOG-treated wild-type animals but are reduced by 60% in liver-specific HIF-1α knockout mice treated with DMOG, ii) triple-positive (Sca1/cKit/VEGFR2), bone-marrow-derived endothelial precursor cells increased twofold in DMOG-treated wild-type mice (P < 0.001) but are unchanged in hepatic HIF-1α knockout mice in response to DMOG, and iii) hepatic luminescence in the luciferase oxygen-dependent degradation domain mouse was induced by subcutaneous and intraperitoneal DMOG. These findings uncover a novel endocrine mechanism for retinovascular protection. Activating HIF in visceral organs such as the liver may be a simple strategy to protect capillary beds in the retina and in other peripheral tissues.

Attenuating Cardiac Pulsations within the Cochlea: Structure and Function of Tortuous Vessels Feeding Stria Vascularis

The mammalian ear has an extraordinary capacity to detect very low-level acoustic signals from the environment. Sound pressures as low as a few μPa (−10 dB SPL) can activate cochlear hair cells. To achieve this sensitivity, biological noise has to be minimized including that generated by cardiovascular pulsation. Generally, cardiac pressure changes are transmitted to most peripheral capillary beds; however, such signals within the stria vascularis of the cochlea would be highly disruptive. Not least, it would result in a constant auditory sensation of heartbeat. We investigate special adaptations in cochlear vasculature that serve to attenuate cardiac pulse signals. We describe the structure of tortuous arterioles that feed stria vascularis as seen in corrosion casts of the cochlea. We provide a mathematical model to explain the role of this unique vascular anatomy in dampening pulsatile blood flow to the stria vascularis.

Capillary filtration coefficient and urinary albumin leak at altitude.

Rapid ascent to altitude risks the development of acute mountain sickness. This study demonstrates changes in peripheral capillary filtration coefficient and renal protein loss in subjects suffering from various degrees of mountain sickness after passive ascent to 4559 m. Capillary filtration coefficient of the calf capillary bed, measured by computer-based multistep strain gauge plethysmography, increased significantly after 23.5 h at altitude when symptoms were most severe: 4.45 (2.76-6.03) to 6.31 (3.86-11.07) ml min(-1) per 100 g of tissue mmHg(-1), median (range) (P < 0.02). Urinary albumin excretion was increased after one night at altitude from 1.1 (0.6-1.5) to 2.45 (1.0-6-8) mg of albumin per mmol of creatinine (P < 0.05). These results demonstrate simultaneous leakage of a peripheral capillary bed to fluid measured by strain gauge plethysmography, and renal albumin leak, and suggest a systemic process of increased capillary leakage for different-sized molecules caused by rapid exposure to hypobaric hypoxia.

Effects of Sickle Cell Anemia on Conjunctival Oxygen Tension and Temperature

Because conjunctival vessels are affected by sickle cell disease, we wanted to see if conjunctival PO2 (partial oxygen tension) and temperature were also affected and if these measurements could aid in managing these patients. Conjunctival PO2 and temperature in 23 asymptomatic homozygous patients with sickle cell anemia did not differ significantly from those in age-matched controls. However, 12 subjects in painful sickle cell crisis had a significantly lower conjunctival PO2 than before crisis despite no significant change in hematocrit and conjunctival temperature. Supplemental oxygen therapy significantly increased conjunctival PO2. When supplemental oxygen was removed, conjunctival PO2 decreased to the admission level despite clinical improvement. This finding supports the use of supplemental oxygen in treating crisis. Measuring conjunctival PO2 can give clinicians an assessment of the effect of sickle cell disease on a peripheral capillary bed and may provide the first objective method to reliably diagnose acute painful sickle cell crisis.

Effects of sickle cell anemia on conjunctival oxygen tension and temperature

• Because conjunctival vessels are affected by sickle cell disease, we wanted to see if conjunctival Po₂(partial oxygen tension) and temperature were also affected and if these measurements could aid in managing these patients. Conjunctival Po₂and temperature in 23 asmptomatic homozygous patients with sickle cell anemia did not differ significantly from those in age-matched controls. However, 12 subjects in painful sickle cell crisis had a significantly lower conjunctival Po₂than before crisis despite no significant change in hematocrit and conjunctival temperature. Supplemental oxygen therapy significantly increased conjunctival Po₂. When supplemental oxygen was removed, conjunctival Po₂decreased to the admission level despite clinical improvement. This finding supports the use of supplemental oxygen in treating crisis. Measuring conjunctival Po₂can give clinicians an assessment of the effect of sickle cell disease on a peripheral capillary bed and may provide the first objective method to reliably diagnose acute painful sickle cell crisis. (<i>Arch Intern Med</i>1987;147:67-69)

Limb Salvage in Diabetics: Challenges and Solutions

Our current understanding of wound healing in the diabetic suggests that proper management of the blood glucose level is a necessary but not sufficient condition for containment of infection and optimal wound healing. The pathologic changes observed in the peripheral capillary bed of diabetics are somewhat variable and have no consistent relationship to the wound healing process. Occlusive disease of the arterioles is probably quite similar in significance and distribution to normoglycemic patients with peripheral vascular disease and suggests that proximal arterial occlusion is the major determinant of poor distal perfusion. These observations offer strong evidence that sufficient runoff vessels are present to support attempts at reconstruction of obstructing lesions of the aortoiliac and infrainguinal arterial segments. Noninvasive vascular laboratory data and arteriograms must be carefully interpreted in order to assess fully the degree of arterial occlusive disease that exists as well as the potential for vascular reconstruction. Clinical experience is especially helpful in proper patient selection. Aggressive attempts at distal revascularization can achieve functional limb salvage in the great majority of patients, provided that meticulous technical standards are observed. Conservative surgical debridement and minor amputations are often successful in managing problems of soft-tissue necrosis once pulsatile flow has been restored.

The metabolism of free fatty acids and chylomicron triglyceride fatty acids by isolated rat liver cells

1. 1. A study of the uptake and metabolism of chylomicron triglyceride fatty acids and free fatty acids has been carried out in a preparation of morphologically intact isolated liver cells from fasted rats. Cells incubated with chylomicrons in the presence of serum did not take up significant amounts of [ 14C]triglyceride fatty acids and oxidized less than 1% to 14CO 2 and [ 14C]Ketone bodies. When cells were incubated in the absence of serum, the recovery of 14C in the liver lipids was increased 90-fold but oxidation to 14CO 2 and [ 14C]ketone bodies was not significantly increased. These results indicate that the presence of serum in the incubation prevents adherence of chylomicrons to cell surfaces. 2. 2. Significant oxidation of [ 14C]triglyceride fatty acids to 14CO 2 and [ 14C]ketone bodies was observed only when lipoprotein lipase was added to the incubation. When 13 units of lipoprotein lipase were added to the incubation, the recoveries of [ 14C]triglyceride fatty acids in oxidation products were similar to recoveries from [ 14C]free fatty acids. 3. 3. These experiments strengthen the hypothesis that triglycerides are not taken up or metabolized by liver parenchymal cells in amounts that are physiologically significant. Triglycerides are probably metabolized by hydrolysis by lipoprotein lipase in peripheral capillary beds. The reaction products, glycerol and free fatty acids, may then recirculate to the liver in which form they readily cross the liver cell membrane.

Metabolism of chyle triglycerides in the liver: I. Studies on the mechanisms for liver uptake of intravenously injected, glycerol- and fatty acid-labeled chyle in the carbohydrate-fed rat

1. 1. Blood and liver radioactivity was studied after the intravenous injection of chyle, containing triglycerides labeled with [1- 14C]glycerol and [9, 10- 3H 2] palmitic acid or [9,10- 3H 2]oleic acid into carbohydrate-fed male rats. 2. 2. More than 25% of the fatty acid radioactivity in the livers 10 min after the injection of chyle could be washed out by an immediate perfusion in situ with saline. A major part of this radioactive material consisted of chyle triglycerides. 3. 3. Labeled palmitic acid liberated by the hydrolysis of chyle triglycerides was distributed in approximately equal amounts in liver endogenous non-phospholipids and phospholipids. Labeled oleic acid was found to a higher extent in the non-phospholipids. 4. 4. It is concluded that, after the intravenous injection of labeled chyle into carbohydrate-fed rats, chyle particles are removed by the liver intact and deposited mainly in liver extracellular spaces. The chyle triglycerides are then hydrolysed and the fatty acids and, to a smaller extent, the glycerol are used for the synthesis of liver lipids. Labeled fatty acids recirculated via the blood after hydrolysis of chyle triglycerides at peripheral capillary beds contributed less than 20% to the labeled endogenous liver lipids.

PERIPHERAL VASCULAR PHENOMENA

Early in the study of peripheral pulse volume by means of the plethysmometer described by Johnson, 1 it became evident that in persons suffering from occlusive disease of the arteries of the extremities, the pulse volume wave deviated sharply in size and contour from that obtained in normal persons. This change was found to be remarkably constant and could be repeated day after day, so that it was frequently possible to identify the patient by the appearance of the tracing (fig. 3). These changes were more uniform than were the deviations from the normal in persons with either valvular defect or myocardial impairment. 1 It will be demonstrated that the character of the wave is not dependent on changes in the peripheral capillary bed, except that as in the normal state 1 and in Raynaud's disease the size of the wave diminishes with capillary and arteriolar vasoconstriction. Immediately after the