Gastric cancer below the age of 55: implications for screening patients with uncomplicated dyspepsia

Several studies have reported thrombus formation and/or the release of specific vasoactive eicosanoids, suggesting that platelet activation or damage after photodynamic therapy (PDT) may contribute to blood flow stasis. The role of circulating platelets on blood flow stasis and vascular leakage of macromolecules during and after PDT was assessed in an intravital animal model. Sprague-Dawley rats bearing chondrosarcoma on the right hind limb were injected intravenously (i.v.) with 25 mg/kg Photofrin 24 h before light treatment of 135 J/cm2 at 630 nm. Thrombocytopenia was induced in animals by administration of 3.75 mg/kg of rabbit anti-rat platelet antibody i.v. 30 min before the initiation of the light treatment. This regimen reduced circulating platelet levels from 300,000/mm3 to 20,000/mm3. Reductions in the luminal diameter of the microvasculature in normal muscle and tumor were observed in control animals given Photofrin and light. Venule leakage of macromolecules was noted shortly after the start of light treatment and continued throughout the period of observation. Animals made thrombocytopenic showed none of these changes after PDT in either normal tissues or tumor. The lack of vessel response correlated with the absence of thromboxane release in blood during PDT. These data suggest that platelets and eicosanoid release are necessary for vessel constriction and blood flow stasis after PDT using Photofrin.     

Reduction of progressive burn injury by a stable prostaglandin I2 analogue, beraprost sodium (Procylin): an experimental study in rats

Beraprost sodium is a chemically stable prostaglandin I2 analogue with antiplatelet and vasodilator actions. Burn injury causes thrombosis and vessel occlusion by increasing the blood viscosity and by thermal damage to the vascular network in the dermis. A vascular response also occurs in the uninjured dermis surrounding the site of injury. Diminished blood flow and spreading tissue oedema lead to progressive ischaemia and necrosis around the burn site (zone of stasis), with the final necrotic tissue area being larger than the initial one. If blood flow could be restored in the zone of stasis, secondary tissue damage would be minimized. In this study, we examined the effects of a prostaglandin I2 analogue, beraprost sodium (Procylin, Kaken Pharmaceutical Company, Tokyo, Japan) on burn injury in rats. Twenty male Sprague-Dawley rats weighing an average of 450 g were burned with a comb-shaped brass probe that produced a row of three burns measuring 10 x 30 mm each and two intervening unburned areas measuring 5 x 30 mm each. The rats were divided into two groups of 10 animals. One group received 0.015 mg of beraprost sodium intraperitoneally immediately after burn injury, while the control group received the same volume of saline. Skin blood flow was measured with a laser Doppler flowmeter, and the development of oedema as well as the area of necrotic tissue were also determined. The extent of skin necrosis and oedema were significantly reduced in the beraprost sodium-treated rats, and blood flow in the zone of stasis was increased. These findings demonstrate that prostaglandin I2 plays an important role in burn injury and that beraprost sodium can reduce secondary necrosis in the zone of stasis.     

Regional variation in infant survival in China

Epidemiological data suggested an involvement of the progestogen component in the pathomechanism of venous and arterial diseases during intake of oral contraceptives. The influence of progestogens on haemostasis parameters depend on type and dose of the progestogen, the presence of an estrogen, the route of application, and the duration of use. Treatment of women with progestogen-only preparations caused only minor effects on coagulation and fibrinolysis. Similarly, during hormone replacement therapy with natural estrogens, the additional application of progestogens induced no unfavourable changes on haemostasis. In contrast, the use of ovulation inhibitors resulted in an acceleration of coagulation and fibrinolysis. This is primarily induced by the marked action of ethinylestradiol on hepatic and vascular function. Progestogens with androgenic properties may counteract the estrogen-induced changes in the hepatic synthesis of platelet aggregation and readiness for coagulation. Estrogen and progesterone receptors are localized in endothelial and smooth muscle cells of the vessel wall, but there are differences in the response of veins and arteries to sex steroids. Estrogens and progestogens may influence collagen and elastin synthesis, and the release of vasoactive compounds and of factors controlling fibrinolysis from endothelium. In veins, progestogens may increase distensibility and capacitance resulting in a decreased blood flow. In predisposed women, this may lead to venous stasis and thrombosis. In arteries, progestogens may act as vasoconstrictors, and may enhance vasospasms at sites of injured endothelium which finally may lead to ischemic diseases.     

Recording of unexpectedly high frequency vibrations of blood vessel walls in experimental arteriovenous fistulae of rabbits using a laser vibrometer

Because arteriovenous fistulae are associated with a palpable thrill and an audible murmur, the vibrational activity of the blood vessel walls about experimental arteriovenous fistulae in rabbits was investigated using, for the first time, a high-resolution laser vibrometer. Frequencies of mural vibrations up to 2200 Hz were recorded at different sites about the fistulae. The relationship of this vibratory activity of blood vessel walls to physiological and pathological conditions warrants further investigation.     

Newly recognized causes of atherosclerosis: the role of microorganisms and of vascular iron overload

We have hypothesized that shear stresses at sites of increased vascular turbulence may foster atherogenesis by two previously unknown mechanisms: The first involves Herpes virus activation, which can provoke direct or inflammatory cell-mediated endothelial damage while altering the vascular surface to a highly procoagulant entity. The second derives from red blood cell fragmentation, with resulting uptake by endothelium of released heme groups. In this instance the opening of the heme ring by induced endothelial heme oxygenase frees iron, which sensitizes cells to damage by oxidants--for instance, those generated by closely apposed inflammatory cells. An additional injurious effect of released heme results from its potent catalysis of LDL oxidation--a process specifically and rapidly inhibited by oral supplementation of vitamin E. Although heme-protein's deleterious actions can be counteracted by the plasma constituents haptoglobin and hemopexin, we suggest that these may not be sufficiently present in "sanctuary" sites of vessel walls such as in intramural hemorrhages associated with atherosclerotic intimal tears.     

A flexible algorithm for construction of 3-D vessel networks for use in thermal modeling

A new algorithm for the construction of artificial blood vessel networks is presented. The algorithm produces three-dimensional (3-D) geometrical representations of both arterial and venous networks. The key ingredient of the algorithm is a 3-D potential function defined in the tissue volume. This potential function controls the paths by which points are connected to existing vessels, thereby producing new vessel segments. The potential function has no physiological interpretation, but, by adjustment of parameters governing the potential, it is possible to produce networks that have physiologically meaningful geometrical properties. If desired, the veins can be generated counter current to the arteries. Furthermore, the potential function allows fashioning of the networks to the presence of bone or air cavities. The resulting networks can be used for thermal simulations of hyperthermia treatment.     

In vitro circumvention of cisplatin resistance by the novel sterically hindered platinum complex AMD473

BACKGROUND: Oral indomethacin causes villous shortening, microvascular damage, and distortion, which might induce mucosal ischaemia and necrosis. AIMS: In order to determine the early events in indomethacin induced jejunal injury we examined the temporal relations between morphological damage and changes in villous blood flow following indomethacin. METHODS: In anaesthetised rats, mid jejunal villi were exteriorised in a chamber and observed by fluorescence microscopy. Blood flow in surface capillaries was calculated from velocities and diameters. Indomethacin was applied by both luminal and intravenous routes for 90 minutes, after which the animal was perfusion fixed and the villi were processed for histological examination. Control animals received intravenous or luminal bicarbonate (1.25%). RESULTS: Blood flow slowed in individual villi at 20 minutes, and progressed to complete stasis (in another group) by 45 minutes. Histological examination at 20 minutes revealed microvascular distortion, but no villous shortening; crypt depth:villous height ratios were 0.356 (0.02) in test and 0.386 (0.01) in surrounding villi (p > 0.05). At stasis, the villi under study showed epithelial clumping and were shortened: crypt depth:villous height ratios were 0.92 (0.2) in test and 0.42 (0.06) in surrounding villi (p < 0.02). Vehicle alone had no effect on either blood flow or histology. CONCLUSIONS: Focal slowing of villous blood flow and microvascular distortion precede villus shortening and epithelial disruption, and indicate that damage to surface microvasculature is an early event in indomethacin induced mucosal injury in this model.     

The emerging role of photodynamic therapy in the management of Barrett''s oesophagus

BACKGROUND: In the rat, indomethacin causes jejunal villous shortening, microvascular distortion, and blood stasis prior to ulceration. The beta3-adrenoceptor agonist CL316,243 (CL) prevents both the early histological changes and ulceration. AIM: To test the hypothesis that the beta3-adrenoceptor agonist CL316,243 exerts its protective effect by prevention and/or reversal of blood flow changes in the rat jejunum exposed to indomethacin. METHODS: In anaesthetized rats, jejunal villous blood flow was measured in surface capillaries using fluorescence microscopy. Stasis of superficial capillary blood flow was induced by combined topical and i.v. indomethacin (100 microg/mL, 2.8 x 10(-4) M). To examine the effect of CL on blood stasis, CL was applied either i.v. (1 mg/kg) or luminally (100 microg/mL, 2.5 x 10(-5)M) at the onset of stasis. Prophylactic protection was assessed by giving i.v. CL simultaneously with indomethacin. Results were compared with controls which received luminal saline applied at blood stasis. The effect of i.v. CL (1 mg/kg) alone, or luminal CL (100 microg/mL) alone on basal villous blood flow was also examined. The small intestines were perfusion-fixed with 10% formol saline, and removed for histology, n = 5 for all groups. RESULTS: Luminal CL given at stasis reversed indomethacin-induced stasis within 10 min, whereas i.v. CL did not. Pretreatment with i.v. CL prevented the onset of stasis. Basal blood flow was raised slightly only by luminal CL. CONCLUSION: The beta-adrenoceptor agonist CL316,243 can protect against indomethacin-induced blood stasis in rat jejunal villi.     

Self-regulation of response patterning: implications for psychophysiological research and therapy

This paper develops the basic premise that learning to self-regulate a pattern of responses can have different consequences from those observed when controlling individual functions alone. It is suggested that the self-regulation of patterns of responses can be a particularly sensitive and effective procedure for (a) uncovering biological linkages and constraints between responses in the intact human, (b) investigating how multiphysiological systems combine to produce unique subjective experiences and effects on performance, and (c) enhancing the clinical effectiveness of biofeedback procedures by training patients to integrate and coordinate voluntarily specific patterns of cognitive, autonomic, and motor responses. These hypotheses are illustrated by basic research involving biofeedback training for patterns of blood pressure, heart rate and EEG activity, related experiments on the cognitive self-regulation of patterns of physiological responses using affective imagery and meditation procedures, and case studies of patients treated with biofeedback. The concept of electronic biofeedback as an "unnatural act" is presented with the goal of placing self-regulation within a more biobehavioral perspective emphasizing the natural patterning of physiological processes.     

Effect of transvascular fluid exchange on pressure-flow relationship in tumors: a proposed mechanism for tumor blood flow heterogeneity

Tumor blood flow (TBF) is characterized by spatial and temporal heterogeneities. Despite the crucial role of TBF in tumor growth, metastasis, and therapy, the mechanisms underlying these heterogeneities are not fully understood. Tumor vessels are, in general, more leaky than normal vessels and this may enhance the efficiency of fluid exchange between the vascular and the interstitial space. The coupling between transvascular fluid exchange and hemodynamics in tumors has not been explored previously. To investigate the role of transvascular fluid exchange on afferent and efferent blood flow, we modeled the tumor vasculature as an equivalent single vessel which is permeable and deformable and embedded in a fluid medium with uniform pressure. Simulations were carried out to examine the effects of vessel leakiness, vessel compliance, and interstitial fluid pressure on (a) pressure-flow relationship, (b) arterial-venous pressure relationship, and (c) pressure profile along the vessel. Experiments suggested by model simulations required an independent control of arterial and venous pressure and tumor blood flow. To this end, we perfused tissue-isolated tumors ex vivo and obtained data on perfusate flow rate vs arterial and venous pressures. The simulations predicted the following trends as a result of an enhanced fluid filtration across the vessel wall: (a) for a fixed arterial-venous pressure difference, efferent flow decreases with increasing venous pressure, (b) changes in venous pressure are not completely transmitted to the arterial side, and (c) the pressure profile along the vessel becomes less steep. The experimental results confirmed these trends and indicated that vascular and interstitial flow are coupled in isolated tumors. The implications of this coupling for the spatial and temporal heterogeneity in TBF are discussed.     

A theoretical formalism for aggregation of peroxidized lipids and plasma membrane stability during photolysis

The objective of this investigation was to examine, from a theoretical perspective, the mechanism underlying the lysis of plasma membranes by photoinduced, chemically mediated damage such as is found in photolysis. Toward this end, a model is presented which relates the membrane lifetime to the thermodynamic parameters of the membrane components based upon the kinetic theory of aggregate formation. The formalism includes a standard birth/death process for the formation of damaged membrane components (i.e., peroxidized lipids) as well as a terminating condensation process for the formation of aggregates of peroxidized plasma membrane lipids. Our theory predicts that 1) the membrane lifetime is inversely correlated with predicted rate of membrane damage; 2) an upper limit on the duration of membrane damage exists, above which the mean and variance of the membrane lifetime is independent of further membrane damage; and 3) both the mean and variance of the time of membrane lifetime distribution are correlated with the number of sites that may be damaged to form a single membrane defect. The model provides a framework to optimize the lysis of cell membranes by photodynamic therapy.     

Managing atrial fibrillation to prevent its major complication: ischemic stroke

Atrial fibrillation is an acute or chronic arrhythmia that occurs postoperatively or during intense emotional stress, exercise, or acute alcohol intoxication. More than 10% of Americans aged 75 and older have atrial fibrillation, which is common in elderly patients with cardiopulmonary disorders. During atrial fibrillation, uncoordinated electrical activity leads to ineffective atrial contraction, reduced atrial filling time, and decreasing cardiac output. Blood flow stasis may cause thrombi to form in the quivering atria. Cardioversion may be indicated to convert an unstable patient into sinus rhythm. However, if cardioversion converts the patient's status to sinus rhythm, thrombi may become dislodged and propelled into the bloodstream as emboli. Occlusion of a cerebral blood vessel often follows, leading to stroke. Because patients with longstanding atrial fibrillation are predisposed to stroke, anticoagulation therapy (usually with heparin, warfarin, or aspirin) should be initiated 3 weeks prior to cardioversion. Proper anticoagulation can usually prevent ischemic stroke.     

Superoxide dismutase and total antioxidant status of larvae and adults of Trichostrongylus colubriformis, Haemonchus contortus and Ostertagia circumcincta

By means of modern color-coded duplex sonography (CCDS) even very small vessels can be visualized. Maximum resolution nowadays is about 0.5 mm diameter of the vessel. We compared the use of CCDS and angiography in studying of acral perfusion. Besides morphologic criteria, hemodynamic criteria were recorded. Arteries in healthy fingers appear as long and straight vessels with a clearly defined border. The physiological maximal blood flow velocity exceeded 20 cm/s. CCDS revealed tortuosity of finger arteries as typical finding in thrombangiitis obliterans. Segmental stenosis can either be identified morphologically or quantified by measurement of the flow velocity with poststenotic maximal systolic velocities of less than 20 cm/s or by the acceleration of the blood flow within the stenosis, as proven by angiographic examinations. CCDS is suitable for evaluation of acral perfusion in patients suffering from secondary Raynaud's syndrome. Apart from diagnosis of disturbed acral circulation, other possible applications of CCDS are in in the surgical field, for example replantations in hand or finger surgery.     

Clinical differentiation of the patient in pain: an introductory guideline for CRNAs

The practical application of colour-coded duplex sonography shows that physico-technical artifacts of colour Doppler imaging may not be obvious in all cases and can lead to misinterpretation. Slice-thickness artifacts are due to restricted transversal resolution, as in the B-mode, and may cause false negative results in vascular occlusions. Specific problems in creating and processing the colour flow image interfere with lateral resolution and lead to errors in the quantification of stenoses from the colour Doppler image. Mirror image artifacts produce phantom pictures that can be easily identified as such in some cases, but may resemble recesses in the arterial wall in other cases. Phenomena of sound shadowing resulting from the same reasons as in B-mode may lead to assume vascular occlusions in cases of long-range stenoses. Artifacts of the sonication angle in case of blood vessel tortuosity may lead to misdiagnosis of a non-existent retrograde flow. The artifacts mentioned do restrict the capacity of colour coded duplex sonography for localising flow in the ultrasound image. Users of the method should therefore be familiar with these artifacts.     

Differential contractile response of cultured microvascular pericytes to vasoactive agents

OBJECTIVE: Microvascular pericytes may contract in two different ways: In the first, a circumferential or radial mechanical force applied at right angles to the long axis of the vessel may constrict the underlying vessel affecting blood flow and transmural pressure. Retraction and elongation of pericyte processes may also occur tangentially and at right angles to the vessel axis and alter microvessel permeability by changing the amount of ablumenal surface covered or the openness of interendothelial junctions. In this study, cultured pericytes were utilized as a model experimental system to determine if vasoactive stimulation changes their shape in a manner consistent with this hypothesis. METHODS: Pericytes cultured from isolated rate capillaries were subjected to angiotensin II and histamine. Their response was monitored by measuring the area of non-yielding substrate covered by the pericytes and the manner in which their shape changed. Shape changes were quantified by calculating the surface area: perimeter perimeter ratios. RESULTS: Histamine significantly reduced surface area covered and the surface area:perimeter ratio. The pericyte processes retracted, resulting in elongated, spindle-shaped cells. These effects were nullified by the H1 blocker diphenhydramine suggesting a receptor-specific response. Angiotensin II also elicited contraction and reduced surface area, but the cells contracted laterally and longitudinally. The surface area: perimeter ratios also decreased. CONCLUSIONS: These results indicate that pericytes are capable of two types of contractile responses in culture, depending on the specific vasoactive stimulus.     

Role of bicarbonate in blood flow-mediated protection and repair of damaged gastric mucosa in the cat

BACKGROUND/AIMS: The hyperemic response after superficial gastric mucosal damage is essential for repair of the mucosa. Only indirect evidence suggests that this is caused by supply of bicarbonate. Therefore, this study tested the effect of maintaining the availability of bicarbonate after prevention of the hyperemic response after damage by 2 mol/L NaCl. METHODS: Celiac artery flow was reduced, as monitored by Doppler ultrasonography, by gradual constriction of the vessel after mucosal damage. Saline (pH 1.0) was perfused through the stomach lumen and thereafter through a closed chamber with pH and PCO2 electrodes. RESULTS: Exposure to 2 mol/L NaCl produced a marked increase of mucosal blood flow as measured by microspheres (P < 0.025) and a high degree of mucosal restitution 90 minutes after damage as judged by microscopy, whereas prevention of the hyperemic response caused extensive erosions and much less restitution (P < 0.001). The latter effect was completely counteracted by intravenous bicarbonate. High blood concentration of bicarbonate increased luminal release of bicarbonate, whereas high mucosal blood flow did not. CONCLUSIONS: These data show that bicarbonate is an important factor in blood flow-mediated protection and repair of damaged gastric mucosa and suggest that concentration gradients are the major determinants for transport of bicarbonate across the damaged and restituted mucosa.     

The role of focal nerve ischemia and Wallerian degeneration in peripheral nerve injury producing hyperesthesia

BACKGROUND: A new model of pain associated with an experimental peripheral mononeuropathy has stimulated interest in mechanisms of pain and their structural correlates in peripheral nerve, the site of the experimental lesion. METHODS: The pathology of the neuropathy was studied and the results correlated with alterations in nerve blood flow and with the behavioral response to heat applied to the foot. The focal neuropathy was created by loosely tying several ligatures around rat sciatic nerve, which produces hyperesthesia in the ligated limb in 3-5 days. The neuropathology was striking with epineurial and endoneurial vascular stasis, edema, and extensive nerve fiber injury in the ligated segment noted at 1 week after ligation. RESULTS: Nerve blood flow was reduced significantly in the ligated segment during the development of the hyperesthesia response, suggesting that changes in nerve blood flow caused by the ligature compression of the epineurial vessels contributes to the nerve fiber injury and pathophysiology of the model. To further test this hypothesis, the epineurial vasculature was removed from 1-cm lengths of rat sciatic nerve, which reduces nerve blood flow by 58%, and by ligation of the ipsilateral femoral artery, which focally reduces nerve blood flow by 70%, and the behavioral response to heating of the paw was evaluated at 1 week. Crush injury was used as a positive control creating Wallerian degeneration without a substantial reduction in nerve blood flow. CONCLUSIONS: The results suggest that ischemia is an important initial pathogenic mechanism in the hyperesthesia associated with the loose ligature pain model, in so far as it produces Wallerian degeneration and axonal injury. Modest degrees of ischemia producing only demyelination did not produce significant hyperesthesia.     

Local nervous mechanism in regulation of blood flow in human subcutaneous tissue

The effect of local venous stasis upon blood flow in human subcutaneous adipose tissue on the distal part of the forearm was investigated in three healthy subjects and two chronically sympathectomized patients suffering from manual hyperhidrosis. The area under study was separated into two parts by means of a lead shield exerting a pressure of about 360 mmHg on the skin. The effect of venous stasis of about 40 mmHg on one side of the shield upon blood flow measured simultaneously on both sides of the shield by the local 133Xenon washout technique was investigated. During venous stasis on one side of the shield, blood flow decreased about 40% on both sides. The vasoconstrictor impulse could be transmitted over a distance of about 1-2 cm. The phenomenon was unaffected by nerve blockade induced 3 cm proximally, medially, and laterally to the area by infiltration the skin with lidocaine. Thus a vasoconstrictor impulse could be transmitted from the side of stasis to the non stasis side of the lead shield. The transmission was not affected by phentolamine but was blocked by lidocaine and chronic sympathetic denervation. The vasoconstrictor impulse elicited during venous stasis is therefore most likely transmitted by means of a local nervous mechanism involving sympathetic adrenergic vasoconstrictor fibres.     

Integrative cardiac revitalization: bypass surgery, angioplasty, and chelation. Benefits, risks, and limitations

Coronary artery disease (CAD) is still the main cause of premature death in the industrialized world. The revascularization modalities, bypass surgery and angioplasty, when successful provide restored blood flow to the myocardium. Bypass remains the most proven means for managing more severe cases of CAD, namely triple vessel disease with or without complications, while angioplasty works best for cases of single or double vessel disease with minimal complications. Both types of intervention partially relieve angina as they clear arterial blockage. Both save lives to an extent greater than medication alone. However, both are limited to being palliative since they fail to treat the underlying atherosclerotic occlusive process. EDTA chelation therapy appears to achieve revitalization of the myocardium, and is a viable alternative or adjunct to revascularization. Fish oils are now proven to help revitalize vessel wall endothelia and to partially reverse atherosclerotic damage. Being safe and having proven benefits, chelation therapy and fish oils can be integrated together with nutrients, lifestyle-dietary revision, exercise, and medications as necessary, into a cardiovascular revitalization strategy. Cardiovascular revitalization would be highly cost-effective and procedurally compatible with the revascularization modalities, while extending beyond revascularization to halt atherosclerotic progression, restore cardiac functionality, extend survival, and improve quality of life.     

Boundary layer drug delivery using a helical catheter

BACKGROUND: A catheter-based approach for local endovascular drug delivery has been developed. The catheter is deployed percutaneously, while the end of the catheter is in the form of a helix that is placed just proximal to the vascular site to be treated. The helices are in contact with the vessel wall. A number of small holes is drilled in the coils of the catheter through which drug is infused, so that the infused drug remains within the blood fluid 'boundary layer' adjacent to the vessel wall. This approach is expected to be highly efficient for administration of antithrombotic and antiproliferative agents that target processes leading to vascular occlusion, heart attacks, and strokes. METHODS: The helical catheter was qualitatively evaluated using optical dye density measurements of Evans blue dye infused using an in vitro steady flow system under a physiologic range of conditions. To further demonstrate the efficiency of the technique, its capacity to inhibit thrombosis was evaluated in a baboon thrombosis model. The catheter was inserted into a femoral arteriovenous shunt (blood flow rate = 100 ml/min) and placed proximal to a segment of highly thrombogenic Dacron vascular graft (4.0 mm i.d.). Integrelin (an inhibitor of platelet glycoprotein IIb/IIIa; doses: 0.25-1.0 microg/min) and hirudin (an antithrombin; doses: 10-100 microg/min) were used to inhibit thrombus formation. RESULTS: Experimental flow visualization studies demonstrated that high concentrations of the infused Evans blue dye were retained near the vessel wall. In the animal experiments, platelet deposition on the Dacron graft surface was reduced by 82-97% (Integrelin) and 68-92% (hirudin) over 1-2 h of blood exposure. The local antithrombotic effects produced were found to be 200-fold and 30-fold more efficient than systemic administration of the same agents. CONCLUSIONS: Local drug infusion using the helical catheter approach can achieve high drug concentration levels at target sites, may avoid systemic effects, and can reduce cost of therapy by reducing total drug requirements.