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Biomedical subjects

A R Young

Publications and source records attributed to A R Young.

At least 37 records · Page 2Linked to original sources
PubMed2000

Comparative quantification of IL-1beta, IL-10, IL-10r, TNFalpha and IL-7 mRNA levels in UV-irradiated human skin in vivo.

OBJECTIVE AND DESIGN: Ultraviolet (UV) exposure induces local immunosuppression and inflammation in human skin. Cytokines are, in part, responsible for these responses. To investigate the effects of UV-induced gene expression at the molecular level we established a sensitive in vivo/ex vivo method for a comparative quantification of cytokines and receptors involved in the local skin immune reactions. MATERIAL AND METHODS: Specific mRNA levels of human UV-irradiated skin were determined by real time quantification (TaqMan RT-PCR). Highly efficient PCR-reaction conditions were obtained by designing very short PCR-templates (72-87 bp). The most sensitive PCR-conditions were obtained by optimisation of primer and Mn(OAc)2-concentrations, which led to significant PCR signals (C(T)-value) of less than 36 cycles. A strong correlation between PCR efficiency of the internal control (GAPDH) compared to targets (IL-1beta, IL-10, IL-10r, TNFalpha, IL-7) allowed the use of deltadelta C(T)-method to quantify comparable mRNA levels. RESULTS: Interleukin-1beta (IL-1beta), Interleukin-10 (IL-10), and tumour necrosis factor alpha (TNFalpha) mRNA levels were increased in a time- and dose-dependent manner. Interleukin-1beta induction reached a maximum (approx. 44-fold) 6 h after a UV-dose equivalent to 3 times the minimal erythemal doses just perceptible (MEDjp). Maximal TNFalpha mRNA expression (approx. 14-fold) was also detected 6 h after UV exposure. Interleukin-10 mRNA induction reached a maximum of approximately 14-fold 24 h after UV-irradiation of 3 MEDjp. Time- and dose-dependent changes in Interleukin-7 and Interleukin-10 receptor mRNA levels did not occur after UV-irradiation. CONCLUSIONS: Time-distinct gene induction of IL-1beta, TNFalpha and IL-1beta is involved in UV-induced immune reactions, but no considerable changes were found for IL-10r or IL-7.

Adult↗
PubMed2000

Characterisation of proteases involved in egg hatching of the sheep blowfly, Lucilia cuprina.

A number of proteases were identified in the egg shell washings (ESW) collected during the egg hatching of Lucilia cuprina (sheep blowfly). Characterization of these proteases indicated a pH optima in a similar pH range that was optimal for L. cuprina egg hatching. Mechanistic characterization of these proteases indicated that they were predominantly of the serine class. Several protease inhibitors were tested for their ability to inhibit L. cuprina egg hatching in vitro. Egg hatching was significantly (P<0.05) inhibited by PMSF (61%), 1,10-Phenanthroline (42%) and Pepstatin (29%). The inhibition of egg hatching by PMSF showed a strong concentration dependence, with its effects ranging from inhibition at high concentrations to enhancement of egg hatching at low concentrations. Addition of ESW to unhatched eggs, significantly (P<0.05) enhanced their rate of hatching above untreated control eggs. This enhancement of egg hatching was significantly (P<0.05) reversed by the protease inhibitors Elastatinal (40%), 1,10-Phenanthroline (40%) and PMSF (38%). These studies indicate a role for serine and/or metallo-proteases in facilitating L. cuprina egg hatch.

Animals↗
PubMed2000

Protection by ultraviolet A and B sunscreens against in situ dipyrimidine photolesions in human epidermis is comparable to protection against sunburn.

Sunscreens prevent sunburn and may also prevent skin cancer by protecting from ultraviolet-induced DNA damage. We assessed the ability of two sunscreens, with different spectral profiles, to inhibit DNA photodamage in human epidermis in situ. One formulation contained the established ultraviolet B filter octyl methoxycinnamate, whereas the other contained terephthalylidene dicamphor sulfonic acid, a new ultraviolet A filter. Both formulations had sun protection factors of 4 when assessed with solar simulating radiation in volunteers of skin type I/II. We tested the hypothesis that sun protection factors would indicate the level of protection against DNA photodamage. Thus, we exposed sunscreen-treated sites to four times the minimal erythema dose of solar simulating radiation, whereas vehicle and control sites were exposed to one minimal erythema dose. We used monoclonal antibodies against thymine dimers and 6-4 photoproducts and image analysis to quantify DNA damage in skin sections. A dose of four times the minimal erythema dose, with either sunscreen, resulted in comparable levels of thymine dimers and 6-4 photoproducts to one minimal erythema dose +/- vehicle, providing evidence that the DNA protection factor is comparable to the sun protection factor. The lack of difference between the sunscreens indicates similar action spectra for erythema and DNA photodamage and that erythema is a clinical surrogate for DNA photodamage that may lead to skin cancer.

Adolescent↗
PubMed2000

Improved protection against solar-simulated radiation-induced immunosuppression by a sunscreen with enhanced ultraviolet A protection.

Ultraviolet radiation-induced immunosuppression is thought to play a part in skin cancer. Several studies have indicated that sunscreens that are designed to protect against erythema failed to give comparable protection against ultraviolet radiation-induced immunosuppression. One possible reason for this discrepancy is inadequate ultraviolet A protection. This study evaluated the level of immunoprotection in mice afforded by two broad-spectrum sunscreens with the same sun protection factor, but with different ultraviolet A protection factors. Both sunscreens contained the same ultraviolet B and ultraviolet A filters, in the same vehicle, but at different concentrations. Solar simulated radiation dose-response curves for erythema, edema, and systemic suppression of contact hypersensitivity were generated and used to derive protection factors for each end-point. The results of three different techniques for determining immune protection factor were compared. A comparison of the two sunscreens showed that the protection factor for erythema in mice was similar to that determined in humans (sun protection factor) but the protection factor for edema in mice was lower. Both sunscreens protected against suppression of contact hypersensitivity but the product with the higher ultraviolet A-protection factor showed significantly greater protection. The three techniques for determining immunoprotection gave very similar results for a given sunscreen, but immune protection factor was always lower than sun protection factor. These data suggest that sun protection factor may not predict the ability of sunscreens to protect the immune system and that a measure of ultraviolet A protection may also be necessary.

Animals↗
PubMed2000

Optimization and preliminary characterization of venom isolated from 3 medically important jellyfish: the box (Chironex fleckeri), Irukandji (Carukia barnesi), and blubber (Catostylus mosaicus) jellyfish.

OBJECTIVE: To optimize venom extraction and to undertake preliminary biochemical studies of venom from the box jellyfish (Chironex fleckeri), the Irukandji jellyfish (Carukia barnesi), and the blubber jellyfish (Catostylus mosaicus). METHODS: Lyophilized crude venoms from box jellyfish tentacles and whole Irukandji jellyfish were prepared in water by homogenization, sonication, and rapid freeze thawing. A second technique, consisting of grinding samples with a glass mortar and pestle and using phosphate-buffered saline, was used to prepare crude venom from isolated nematocysts of the box jellyfish, the bells of Irukandji jellyfish, and the oral lobes of blubber jellyfish. Venoms were compared by use of sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot test. Toxicity of some venoms was determined by intravenous median lethal dose assay in mice. RESULTS: Different venom extraction techniques produced significantly different crude venoms for both box and Irukandji jellyfish. Irukandji and blubber venom SDS-PAGE protein profiles were established for the first time. Analysis of Western blot tests revealed that box jellyfish antivenin reacted specifically with the venom of each jellyfish. Toxicity was found in Irukandji jellyfish venom derived by use of the mortar-and-pestle method, but not in the lyophilized venom. CONCLUSIONS: Glass mortar-and-pestle grinding and use of an appropriate buffer was found to be a simple and suitable method for the preparation of venom from each jellyfish species studied. This study contributes to biochemical investigations of jellyfish venoms, particularly the venom of the Irukandji jellyfish, for which there are, to our knowledge, no published studies. It also highlights the importance of optimizing venom extraction as the first step toward understanding the complex biological effects of jellyfish venoms.

Animals↗
PubMed1999

Epitope-specific cytotoxic T lymphocyte induction by minigene DNA immunization.

Plasmid DNA vaccines encoding full-length antigen often induce both potent antibody and cytotoxic T lymphocyte (CTL) responses. Here, we examine strategies to exclusively elicit epitope-specific CTL responses using DNA constructs expressing a minimal class I MHC-restricted epitope of the nucleoprotein (NP) of influenza virus. The effects of the addition of an ER leader sequence or cytokine combination on minigene-induced CTL responses in vivo were assessed following both delivery by needle injection into skeletal muscle and by gene gun bombardment into skin epidermis. Our data indicate that the leader sequence enhanced the magnitude of the CTL responses, whereas co-injection of the cytokine genes IL-12 and GM-CSF had a minimal effect. An antibody response against NP was not observed in any of the mice receiving the minigene constructs.

Animals↗
PubMed1999

Biochemical aspects of egg hatch in endo- and ectoparasites: potential for rational drug design.

Control of parasites through rational drug design requires a thorough understanding of the parasite's lifecycle encompassing the biochemical and physiological processes which contribute to normal parasite homeostasis. The hatching of parasite eggs for example, represents an important process in the development of a parasitic infection. Previous studies in helminths have indicated that secreted enzymes often facilitate successful endoparasite egg hatch. In contrast, there are relatively few examples demonstrating a role for secreted enzymes in the egg hatching process of insects. An analysis of this process in the ectoparasite Lucilia cuprina suggests a role for secreted enzymes in the hatching of sheep blowfly eggs. Characterisation of the proteases collected at the time of egg hatch indicates the presence of serine proteases. Further purification and characterisation of these proteases may enable the design of specific inhibitors to interfere with the egg hatch process and therefore provide a novel means of control.

Animals↗
PubMed1999

The 0.8% ultraviolet B content of an ultraviolet A sunlamp induces 75% of cyclobutane pyrimidine dimers in human keratinocytes in vitro.

Tanning lamps, emitting predominantly ultraviolet (UV) A, are used widely throughout the U.K. and other countries, but little is known about the long-term risks associated with their use, especially with respect to skin cancer. We have exposed normal human epidermal keratinocytes to a commercial tanning lamp and used the comet assay in association with DNA repair enzymes T4 endonuclease V and endonuclease III to investigate the relative yields of directly formed cyclobutane pyrimidine dimers (CPDs) and indirectly formed types of oxidative DNA damage. To put the risk of using tanning lamps into perspective, the sunbed used in this study (five Philips Performance 80W-R UVA tubes at a distance of 35 cm) was found to be approximately 0.7 times as potent at inducing CPDs as U.K. natural sunlight around noon on a fine summer day. This compares with a relative risk for CPD induction and erythema of 0.8 and 0.7 times, respectively, calculated from the relevant action spectra of tanning lamps and British noontime sunlight. To determine the relative contribution of UVB and UVA to the induction of CPDs and oxidative DNA damage, we modified the spectral output of the tanning lamps with a series of Schott WG UVB filters. The induction of CPDs was more dependent on the UVB component of the sunbed than oxidative types of damage. Schott WG UVB filters with 50% transmission at 305 nm reduced the yield of T4 endonuclease V sites by 42% while there was only a 17% decrease in the yield of endonuclease III sites. CPD induction was not completely abolished after irradiation through WG335 and WG345 nm filters despite there being no detectable UVB. From these data, it was estimated that, although the tanning lamps emitted only 0.8% of their total output in the UVB range, these wavelengths were responsible for the induction of over 75% of CPDs and 50% of the oxidative damage to DNA.

Cells, Cultured↗
PubMed1999

In situ repair of cyclobutane pyrimidine dimers and 6-4 photoproducts in human skin exposed to solar simulating radiation.

DNA repair is crucial to the integrity of the human genome. The ultraviolet radiation portion of solar radiation is responsible for the rising incidence of skin cancer, one of the most common types of cancer in humans. We applied a recently developed 32P-postlabeling technique to measure the in situ DNA repair efficiency of solar-simulated radiation induced cyclobutane pyrimidine dimers and 6-4 photoproducts in the skin of nine healthy volunteers with skin type II. Our results show about 6-fold interindividual variations in the level of DNA damage after exposure to an equal biologic dose - 2 minimal erythema doses. The kinetics of DNA repair indicated a base sequence dependence of the repair process. The DNA repair efficiency showed a 20-fold difference in volunteers. An age-related decrease of DNA repair capacity was observed; however, the data are limited due to a small number of subjects and a narrow age range. The variable response in DNA damage levels and individual differences in DNA repair efficiency suggest a susceptible subgroup of people probably with a higher skin cancer risk.

Adult↗
PubMed1999

Suppressed alloantigen presentation, increased TNF-alpha, IL-1, IL-1Ra, IL-10, and modulation of TNF-R in UV-irradiated human skin.

Cytokines induced in skin by ultraviolet radiation cause local and systemic immunosuppression. Tumor necrosis factor alpha, interleukin-1, and interleukin-10 are key mediators in the mouse, but less is known about cytokine synthesis and function in ultraviolet-irradiated human skin. We exposed human skin to 3 minimal erythema doses of solar-simulated radiation and raised suction blisters at intervals to 72 h. Alloantigen presentation was suppressed in a mixed epidermal cell-lymphocyte reaction by 69% from 4 to 15 h post-solar-simulated radiation, but recovered to control values by 24 h. Tumor necrosis factor alpha was raised at 4 h after solar-simulated radiation, reached a maximum 8-fold increase at 15 h, then rapidly declined to control values. Interleukin-1alpha and interleukin-1beta were first increased at 15 h, and remained raised to 72 h, although interleukin-1beta declined from its 15 h maximum. Interleukin-10 increased a maximum 2-fold between 15 and 24 h, coincident with recovery of mixed epidermal cell-lymphocyte reaction responses and downregulation of tumor necrosis factor alpha and interleukin-1beta. Solar-simulated radiation differentially affected soluble tumor necrosis factor alpha receptors; soluble tumor necrosis factor-RI was suppressed 33% at 8-15 h whereas soluble tumor necrosis factor-RII increased 2-fold from 15 to 48 h. Interleukin-1 receptor antagonist was raised at all times post-irradiation. Interleukin-12 was not detectable in control or irradiated skin. These kinetics suggest the tumor necrosis factor alpha network has primary importance in ultraviolet-damaged human skin. The small increase in interleukin-10 implies that 3 minimal erythema doses of solar-simulated radiation is the threshold dose for its induction and local, rather than systemic, functions for interleukin-10 in immunosuppression and regulation of other cytokines.

Adolescent↗
PubMed1999

Early postischemic hyperperfusion: pathophysiologic insights from positron emission tomography.

Early postischemic hyperperfusion (EPIH) has long been documented in animal stroke models and is the hallmark of efficient recanalization of the occluded artery with subsequent reperfusion of the tissue (although occasionally it may be seen in areas bordering the hypoperfused area during arterial occlusion). In experimental stroke, early reperfusion has been reported to both prevent infarct growth and aggravate edema formation and hemorrhage, depending on the severity and duration of prior ischemia and the efficiency of reperfusion, whereas neuronal damage with or without enlarged infarction also may result from reperfusion (so-called "reperfusion injury"). In humans, focal hyperperfusion in the subacute stage (i.e., more than 48 hours after onset) has been associated with tissue necrosis in most instances, but regarding the acute stage, its occurrence, its relations with tissue metabolism and viability, and its clinical prognostic value were poorly understood before the advent of positron emission tomography (PET), in part because of methodologic issues. By measuring both CBF and metabolism, PET is an ideal imaging modality to study the pathophysiologic mechanism of EPIH. Although only a few PET studies have been performed in the acute stage that have systematically assessed tissue and clinical outcome in relation to EPIH, they have provided important insights. In one study, about one third of the patients with first-ever middle cerebral artery (MCA) territory stroke studied within 5 to 18 hours after symptom onset exhibited EPIH. In most cases, EPIH affected large parts of the cortical MCA territory in a patchy fashion, together with abnormal vasodilation (increased cerebral blood volume), "luxury perfusion" (decreased oxygen extraction fraction), and mildly increased CMRO2, which was interpreted as postischemic rebound of cellular metabolism in structurally preserved tissue. In that study, the spontaneous outcome of the tissue exhibiting EPIH was good, with late structural imaging not showing infarction. This observation was supported by another PET study, which showed, in a few patients, that previously hypoperfused tissue that later exhibited hyperperfusion after thrombolysis did not undergo frank infarction at follow-up. In both studies, clinical outcome was excellent in all patients showing EPIH except one, but in this case the hyperperfused area coexisted with an extensive area of severe hypoperfusion and hypometabolism. These findings from human studies therefore suggest that EPIH is not detrimental for the tissue, which contradicts the experimental concept of "reperfusion injury" but is consistent with the apparent clinical benefit from thrombolysis. However, PET studies performed in the cat have shown that although hyperperfusion was associated with prolonged survival and lack of histologic infarction when following brief (30-minute) MCA occlusion, it often was associated with poor outcome and extensive infarction when associated with longer (60-minute) MCA occlusion. It is unclear whether this discrepancy with human studies reflects a shorter window for tissue survival after stroke in cats, points to the cat being more prone to reperfusion injury, or indicates that EPIH tends not to develop in humans after severe or prolonged ischemia because of a greater tendency for the no-reflow phenomenon, for example. Nevertheless, the fact that the degree of hyperperfusion in these cat studies was related to the severity of prior flow reduction suggests that hyperperfusion is not detrimental per se. Preliminary observations in temporary MCA occlusion in baboons suggest that hyperperfusion developing even after 6 hours of occlusion is mainly cortical and associated with no frank infarction, as in humans. Overall, therefore, PET studies in both humans and the experimental animal, including the baboon, suggest that hyperperfusion is not a key factor in the development of tissue infarction and that it may be a harmless phenomenon

Acute Disease↗
PubMed1999

The soluble eumelanin precursor 5,6-dihydroxyindole-2-carboxylic acid enhances oxidative damage in human keratinocyte DNA after UVA irradiation.

Soluble melanin precursors are present in serum and may act as skin chromophores contributing to UVR-induced oxidative damage. Our study aimed to determine whether the soluble eumelanin precursor 5,6-dihydroxy-indole-2-carboxylic acid (DHICA) photosensitizes DNA damage in human keratinocytes exposed to UVA irradiation. The HaCaT keratinocytes were incubated with and without DHICA, before irradiation with broadband UVA (320-400 nm). The DNA photodamage was assessed using the comet assay that detects frank single-strand breaks (SSB) and specific oxidative lesions with the addition of endonuclease III. Without DHICA incubation, there was no significant increase in SSB, compared to unirradiated cells, for doses up to 48.5 J/cm2 (< 1 minimum erythemal dose). Preincubation with 0.5 microM DHICA caused an increase in SSB at every UVA dose (significant from 12.1 to 48.5 J/cm2), while varying the DHICA concentration (0.125-2 microM) showed this effect to be concentration dependent such that SSB increased and endonuclease III-sensitive sites decreased with increasing DHICA concentration. The irradiation of cells in the presence of antioxidants (catalase, mannitol and histidine) suggests that DHICA-induced photosensitization is mediated via singlet oxygen and, to a lesser extent, hydroxyl radicals. These results indicate that DHICA can induce strand breaks with UVA at clinically relevant doses via a mechanism involving reactive oxygen species.

Antioxidants↗
PubMed1998

A single exposure of solar simulated radiation suppresses contact hypersensitivity responses both locally and systemically in humans: quantitative studies with high-frequency ultrasound.

Ultraviolet radiation (UVR)-induced suppression of cutaneous cell-mediated immunity plays an important role in the development of photocarcinogenesis in the mouse and a similar role is suspected in humans. Cell-mediated immunity is readily tested in vivo by measuring the contact hypersensitivity (CHS) response to topically applied haptens. CHS in humans is usually determine clinically, with a subjective scoring system. However, these subjective scores cannot be statistically analysed. This paper compares four methods currently used to quantify CHS elicitation responses in humans. The data show that ultrasound images provide the most accurate and reproducible measurements of the clinically observed CHS response. We also demonstrate that assessment of the primary allergic response is a useful indicator of the magnitude of the elicitation response and can be used to avoid severe CHS reactions in volunteers. There are few human studies investigating the effects of solar simulated radiation (SSR) exposure on immunosuppression. In this study we demonstrate SSR is highly immunosuppressive in all subjects tested. Irradiating a small area of skin with a single exposure to 3MEDs of SSR completely suppressed CHS both locally (12/12 volunteers) and systemically (10/12 volunteers). Our data do not support a role for a genetic susceptibility to UVR-induced immunosuppression in humans.

Adolescent↗
PubMed1998

[11C]S21007, a putative partial agonist for 5-HT3 receptors PET studies. Rat and primate in vivo biological evaluation.

We recently labeled with carbon-11, a high affinity, selective, 5-HT3 receptor (5-HT3R) ligand, S21007, for potential positron emission tomography (PET) applications. To evaluate the in vivo binding properties of [11C]S21007, its brain regional distribution, tissue and plasma pharmacokinetics and plasma metabolisation were characterized. To circumvent the problem of highly discrete brain localization of the 5-HT3R (area postrema, hippocampus), we designed an original approach combining high-resolution imaging techniques (ex vivo phosphor plate autoradiography and MRI-guided coronal PET in the rat and baboon, respectively). After i.v. injection of trace amounts of [11C]S21007 to rats, phosphorimager autoradiography failed to reveal in vivo specific binding to, nor selectivity for 5-HT3R-rich areas. PET studies in the baboon showed consistent results, i.e., there was no selective accumulation of [11C]S21007 in the area postrema or hippocampus, and neither displacement nor presaturation with cold S21007 resulted in significant changes in tissue distribution or kinetics of [11C]S21007.

Animals↗
PubMed1998

Human melanocytes and keratinocytes exposed to UVB or UVA in vivo show comparable levels of thymine dimers.

Epidemiology shows a relationship between solar exposure and all types of skin cancer. Understanding the mechanisms of skin cancer requires knowledge of the photomolecular events that occur within the relevant epidermal cell types in vivo. Studies to date have focused on UVR-induced DNA lesions in keratinocytes, the majority epidermal cell population which gives rise to most skin cancers. Malignant melanoma, arising from melanocytes (5%-10% of epidermal cells), accounts for most skin cancer deaths. We report on new techniques to detect DNA photolesions in human epidermal melanocytes in situ. Previously nonexposed buttock skin of volunteers of skin types I/II was exposed to clinically relevant doses of narrow bandwidth UVB (300 nm) and UVA (320 nm, 340 nm, 360 nm) radiation. Biopsies were taken immediately afterwards and processed for routine histology. Microscope sections were prepared and double-stained with fluorescent-tagged monoclonal antibodies for thymine dimers and melanocytes. UVR dose-response curves for dimer levels within melanocyte nuclei were determined by image analysis and compared with dimer levels in adjacent basal cell keratinocytes. Our data show that UVB and UVA readily induce thymine dimers in melanocytes at levels that are comparable with those found in adjacent keratinocytes. This new technique will enable melanocyte specific studies, such as DNA repair kinetics, to be done in vivo.

Adult↗
PubMed1998

The similarity of action spectra for thymine dimers in human epidermis and erythema suggests that DNA is the chromophore for erythema.

The location of DNA photodamage within the epidermis is crucial as basal layer cells are the most likely to have carcinogenic potential. We have determined the action spectra for DNA photodamage in different human epidermal layers in situ. Previously unexposed buttock skin was irradiated with 0.5, 1, 2, and 3 minimal erythema doses of monochromatic UVR at 280, 290, 300, 310, 320, 340, and 360 nm. Punch biopsies were taken immediately after exposure and paraffin sections were prepared for immunoperoxidase staining with a monoclonal antibody against thymine dimers that were quantitated by image analysis. Dimers were measured at two basal layer regions, the mid and the upper living epidermis. The slopes of dose-response curves were used to generate four action spectra, all of which had maxima at 300 nm. Dimer action spectra between 300 and 360 nm were independent of epidermal layer, indicating comparable epidermal transmission at these wavelengths. Furthermore, we observed 300 nm-induced dimers in dermal nuclei; however, there was a marked effect of epidermal layer between 280 and 300 nm, showing relatively poor transmission of 280 and 290 nm to the basal layer. These data indicate that solar UVB (approximately 295-320 nm) is more damaging to basal cells than predicted from transmission data obtained from human epidermis ex vivo. The epidermal dimer action spectra were compared with erythema action spectra determined from the same volunteers and ultraviolet radiation sources. Overall, these spectral comparisons suggest that DNA is a major chromophore for erythema in the 280-340 nm region.

Adult↗
PubMed1998

Evaluation of the ratio of cerebral blood flow to cerebral blood volume as an index of local cerebral perfusion pressure.

Local cerebral perfusion pressure (CPP), a crucial parameter that should allow a better assessment of the haemodynamic compromise in cerebrovascular diseases, is not currently measurable by non-invasive means. Experimental and clinical studies have suggested that the regional ratio of cerebral blood flow to cerebral blood volume (CBF:CBV), as measured by PET, represents an index of local CPP in focal ischaemia. The present study was designed to evaluate further the reliability of the CBF:CBV ratio during manipulations of CPP by deliberately varying mean arterial pressure (MAP) in the anaesthetized baboon. Cortical CBF, CBV, cerebral metabolic rate for oxygen (CMRO2) and oxygen extraction fraction were measured by PET using the (15)O steady-state technique in 10 anaesthetized baboons. Five baboons (Group A) underwent four PET examinations at different levels of MAP: base line (101 +/- 6 mmHg) followed by moderate hypotension (58 +/- 3 mmHg) and, in a separate experiment, minor hypotension (72 +/- 3 mmHg) followed by profound hypotension (34 +/- 5 mmHg). Trimetaphan was used to lower MAP to minor and moderate levels while profound hypotension was achieved by the combined effects of trimetaphan and lower-body negative pressure. Five other baboons (Group B) were subjected to hypertension (121 +/- 2 mmHg) induced by metaraminol and were compared with their base line state (81 +/- 10 mmHg). While CBF displayed significant changes with varying MAP, i.e. decrease and increase with hypotension and hypertension, respectively (-11% from base line to moderate hypotension compared with -20%, from minor to profound hypotension and +31% from base line to hypertension), CBV was more variable and did not significantly change, except with profound hypotension when the increase was significant (+13%). The CBF:CBV ratio decreased significantly at all stages of hypotension (-21 and -31%) and was significantly increased during hypertension (+30%). Importantly, the CBF:CBV ratio demonstrated a significant correlation with MAP (rho = 0.78, Spearman's rank correlation coefficient, P < 0.01). No major changes in CMRO2 were noted during either hypotension or hypertension. Our results demonstrate that, under physiological conditions, cortical CBF:CBV is significantly correlated with CPP, itself a function of MAP. In the investigated range of MAP, the relationships between CBF:CBV and MAP appear to be linear. These findings further argue for the reliability of CBF:CBV as an index of CPP in situations where increases or decreases of MAP without superimposed changes in cerebrovascular tone are encountered, and they confirm the potential usefulness of this regional ratio for clinical investigations and management in cerebrovascular diseases.

Animals↗