bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of Dopamine D1 Receptors and Extracellular Signal Regulated Kinase in the Motivational Properties of Acetaldehyde as Assessed by Place Preference Conditioning
Authors: Spina Liliana , Longoni Rosanna , Vinci Stefania , Ibba Federico , Peana Alessandra T. , Muggironi Giulia , Spiga Saturnino , Acquas Elio
Published: January 2010

Background:  The role of dopamine D1 receptors and Extracellular signal Regulated Kinase (ERK) in the motivational properties of drugs can be studied by place‐conditioning. Recent advances have shown that the motivational properties of ethanol, determined by place‐conditioning, are mediated by its metabolic conversion into acetaldehyde. To date, the role of D1 receptors and ERK activation in acetaldehyde‐elicited place preference has not been determined. The aim of this study was to assess the role of D1 receptors blockade and MEK inhibition in the acquisition of acetaldehyde‐elicited conditioned place preference.

Methods:  Male Sprague–Dawley rats were subjected to repeated pairings with 1 compartment of the conditioning apparatus immediately following acetaldehyde (20 mg/kg i.g.) or ethanol (1 g/kg i.g.) administration. The D1 receptor antagonist, SCH 39166 (50 μg/kg s.c.), was administered 10 minutes before acetaldehyde or ethanol administration. In order to study the role of activated ERK in the acetaldehyde‐elicited place preference, rats were administered the MEK inhibitor, PD98059 (1, 30, and 90 μg i.c.v.), 10 or 30 minutes before acetaldehyde. To verify the specificity of these effects, we also studied whether PD98059 pretreatment could affect morphine (1 mg/kg s.c.)‐elicited place preference.

Results:  Both acetaldehyde and ethanol elicited significant place preferences and these were prevented by pretreatment with SCH 39166. In addition, pretreatment with PD98059, dose (30 and 90 but not 1 μg i.c.v.) and time (10 but not 30 minutes before) dependently, prevented the acquisition of acetaldehyde‐ and significantly reduced the acquisition of morphine‐elicited conditioned place preference.

Conclusions:  These results confirm that acetaldehyde and ethanol elicit conditioned place preference and demonstrate that D1 receptors are critically involved in these effects. Furthermore, the finding that PD98059 prevents the acquisition of acetaldehyde‐elicited conditioned place preference highlights the importance of the D1 receptor–ERK pathway in its motivational effects.
Altered Motor Cortex Excitability to Magnetic Stimulation in Alcohol Withdrawal Syndrome
Authors: Nardone Raffaele , Bergmann Jürgen , Kronbichler Martin , Caleri Francesca , Lochner Piergiorgio , Tezzon Frediano , Ladurner Gunther , Golaszewski Stefan
Published: January 2010

Background: Alcohol addiction is a complex brain disease caused by alterations in crucial neurotransmitter systems, including gamma‐aminobutyric acid (GABA) and glutamate. These disturbances could be revealed by changes in cortical excitability parameters, as assessed by transcranial magnetic stimulation (TMS). This study was aimed to further investigate the complex pathophysiology of alcohol withdrawal syndrome (AWS).

Methods: Motor cortex excitability was examined in 13 subjects with AWS in a mild predelirial state, in 12 chronic alcoholics and in 15 age‐matched control subjects, using a range of TMS protocols. Central motor conduction time, resting and active motor threshold, duration of the cortical silent period, short latency intracortical inhibition (SICI), and intracortical facilitation (ICF) to paired TMS were examined.

Results: Intracortical facilitation was significantly increased in the AWS patients when compared with the chronic alcoholics and the control subjects. The other TMS parameters did not differ significantly from the controls. Administration of a single oral dose of the glutamatergic antagonist riluzole in a subgroup of 8 patients significantly reduced ICF; motor threshold and SICI were not affected by riluzole.

Conclusion: Transcranial magnetic stimulation shows a selective increase in intracortical facilitation after ethanol withdrawal. Our findings support the theory that altered glutamatergic receptor function plays an important role in the pathogenesis of human alcohol withdrawal. This study provides further physiological evidence that antiglutamatergic approaches represent an efficacious alternative for treating alcohol withdrawal symptoms.
Does Alcohol Involvement Increase the Severity of Intimate Partner Violence?
Authors: McKinney Christy M. , Caetano Raul , Rodriguez Lori A. , Okoro Ngozi
Published: January 2010

Background:  Most studies that have examined alcohol use immediately prior to intimate partner violence (IPV) have been limited to male‐to‐female partner violence (MFPV) and are subject to a number of methodological limitations. We add new information concerning the relationship between alcohol involvement and severity of IPV, MFPV, and female‐to‐male partner violence (FMPV).

Methods:  We analyzed data from a 1995 U.S. national population‐based survey of couples ≥18 years old. We examined 436 couples who reported IPV and had information on alcohol involvement with IPV. We measured IPV using a revised Conflict Tactics Scale, Form R that asked respondents about 11 violent behaviors in the past year. Respondents were classified into mutually exclusive categories as having experienced mild only or mild + severe (“severe”) IPV, MFPV or FMPV. Respondents were also asked if they or their partner were drinking at the time the violent behavior occurred and were classified as exposed to IPV with or without alcohol involvement. We estimated proportions, odds ratios, 95% confidence intervals, and p‐values of the proposed associations, accounting for the complex survey design.

Results:  Overall, 30.2% of couples who reported IPV reported alcohol involved IPV; 69.8% reported no alcohol involvement. In adjusted analyses, those reporting severe (vs. mild only) IPV were more than twice as likely to report alcohol involvement. In adjusted analyses, those reporting severe (vs. mild) MFPV or FMPV were more likely to report female but not male alcohol involvement. Though estimates were positive and strong, most confidence intervals were compatible with a wide range of estimates including no association.

Conclusions:  Our findings suggest alcohol involvement of either or both in the couple increases the risk of severe IPV. Our findings also suggest female alcohol use may play an important role in determining the severity of IPV, MFPV or FMPV.
GABRA2 and Alcohol Use Disorders: No Evidence of an Association in an Italian Case–Control Study
Authors: Onori Nicoletta , Turchi Chiara , Solito Giovanni , Gesuita Rosaria , Buscemi Loredana , Tagliabracci Adriano
Published: January 2010

Background: Alcoholism is a major health and social issue, a highly frequent disease and a cause of premature death. It is also the most expensive addictive disorder being related to high morbidity and mortality, violence, accidents, and social and legal problems. It is a quantitative disorder, where the combined incidence of environmental and multiple genetic factors varies from 1 subject to another. Recent association studies have identified several genes as candidates for alcoholism, including GABAAreceptor genes, due to their role in mediating several behavioral effects of alcohol, such as motor incoordination, anxiolysis, sedation, and withdrawal. The proposed association between the 3′ half of the gene encoding the alpha‐2 subunit of GABA receptor (3′‐GABRA2) and alcohol use disorders (AUDs) has received several independent confirmations.

Methods: In this study, 10 single nucleotide polymorphisms (SNPs) of the 3′‐GABRA2 gene, previously reported to be implicated in alcohol dependence, were used to evaluate the linkage between selected SNPs and AUDs in an Italian sample and to compare findings with those of previous studies.

Results: No evidence of an association was found at the allele, genotype, haplotype, or diplotype levels between the 3′‐GABRA2 polymorphisms investigated and alcoholism in 149 Italian alcoholics (98 alcohol dependents and 51 alcohol abusers) and 278 controls.

Conclusions: Despite previous reports, we did not find an association between AUDs and 3′‐GABRA2 polymorphisms. This is probably due to the minimal comorbidity of our Italian sample suggesting that this gene is implicated in polysubstance dependence rather than in alcoholism alone.
Anti‐Inflammatory and Anti‐Apoptotic Roles of Endothelial Cell STAT3 in Alcoholic Liver Injury
Authors: Miller Andrew M. , Wang Hua , Park Ogyi , Horiguchi Norio , Lafdil Fouad , Mukhopadhyay Partha , Moh Akira , Fu Xin Yuan , Kunos George , Pacher Pal , Gao Bin
Published: January 2010

Background:  It is generally believed that the hepatoprotective effect of interleukin‐6 (IL‐6) is mediated via activation of signal transducer and activator of transcription 3 (STAT3) in hepatocytes. IL‐6‐deficient mice are more susceptible to alcohol‐induced hepatocyte apoptosis and steatosis and elevation of serum alanine transaminase (ALT); however, whereas hepatocyte‐specific STAT3 knockout mice are more susceptible to alcohol‐induced hepatic steatosis, they have similar hepatocyte apoptosis and serum ALT after alcohol feeding compared with wild‐type mice. This suggests that the hepatoprotective effect of IL‐6 in alcoholic liver injury may be mediated via activation of STAT3‐independent signals in hepatocytes, activation of STAT3 in nonparenchymal cells, or both. We have previously shown that IL‐6 also activates STAT3 in sinusoidal endothelial cells (SECs). Thus, the purpose of this study was to investigate whether STAT3 in endothelial cells also plays a protective role in alcoholic liver injury.

Methods:  Wild‐type and endothelial cell‐specific STAT3 knockout (STAT3E−/−) mice were pair‐fed and fed ethanol containing diet for 4 weeks. Liver injury and inflammation were determined.

Results:  Feeding mice with ethanol‐containing diet for 4 weeks induced greater hepatic injury (elevation of serum ALT) and liver weight in STAT3E−/− mice than wild‐type control groups. In addition, ethanol‐fed STAT3E−/− mice displayed greater hepatic inflammation and substantially elevated serum and hepatic levels of IL‐6 and TNF‐α compared with wild‐type mice. Furthermore, ethanol‐fed STAT3E−/− mice displayed a greater abundance of apoptotic SECs and higher levels of serum hyaluronic acid than wild‐type controls.

Conclusions:  These data suggest that endothelial cell STAT3 plays important dual functions of attenuating hepatic inflammation and SEC death during alcoholic liver injury.
Prevalence of Alcohol‐Related Problems in an Elderly Population and Their Association With Cognitive Impairment and Dementia
Authors: Lopes Marcos A. , Furtado Erikson F. , Ferrioli Eduardo , Litvoc Júlio , De Campos Bottino Cássio M.
Published: January 2010

Background:  Studies investigating the association between alcohol use and cognitive disorders in the elderly population have produced divergent results. Moreover, the role of alcohol in cognitive dysfunction is not clear. The aims of this study were to estimate the prevalence of alcohol‐related problems in an elderly population from Brazil and to investigate their association with cognitive and functional impairment (CFI) and dementia.

Methods:  A community‐based cross‐sectional study was performed. A sample of 1,145 elderly people was examined in 2 phases. Several instruments were utilized in the first phase: the CAGE questionnaire was used to identify potential cases of alcohol‐related problems, and a screening test for dementia was used to estimate CFI. The CAMDEX interview (Cambridge Examination) and DSM‐IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) criteria were used for the clinical diagnosis of dementia in the second phase.

Results:  “Heavy alcohol use” (CAGE ≥ 2) was found in 92 subjects (prevalence: 8.2%). It was associated with gender (males, p < 0.001), low education (only in females, p = 0.002), and low socioeconomic level (p = 0.001, in females; p = 0.002, in males). The Mini Mental State Examination exhibited a nonlinear relationship with alcohol‐related problems in females; “mild–moderate alcohol use” (CAGE < 2) presented the highest score. A significant association between alcohol‐related problems and cognitive dysfunction was found only in females. “Heavy alcohol use” was associated with higher CFI and dementia rates compared to “mild–moderate alcohol use” (p = 0.003 and p < 0.001, respectively). “Mild–moderate alcohol use” had a tendency of association with lower CFI and dementia rates when compared to “no alcohol use” (p = 0.063 and 0.050, respectively).

Conclusion:  Our findings suggest that alcohol use does not have a linear relationship with cognitive decline.
Adolescent C57BL/6J (but not DBA/2J) Mice Consume Greater Amounts of Limited‐Access Ethanol Compared to Adults and Display Continued Elevated Ethanol Intake into Adulthood
Authors: Moore Eileen M. , Mariani John N. , Linsenbardt David N. , Melón Laverne C. , Boehm Stephen L.
Published: January 2010

Background:  Alcohol use is common during the adolescent period, a time at which a number of crucial neurobiological, hormonal, and behavioral changes occur (Spear, 2000). In order to more fully understand the complex interaction between alcohol use and these age‐typical neurobiological changes, animal models must be utilized. Rodents experience a developmental period similar to that of adolescence. Although rat models have shown striking adolescent‐specific differences in sensitivity to ethanol, little work has been done in mice despite the fact that the C57BL/6J (B6) and DBA2/J (D2) mice have been shown to markedly differ in ethanol preference drinking and exhibit widely different sensitivities to ethanol.

Methods:  The current study examined ethanol intake in adolescent and adult B6 and D2 mice using a limited access alcohol exposure paradigm called Drinking in the Dark (DID). Additionally, the effect of adolescent (or adult) ethanol exposure on subsequent adult ethanol intake was examined by re‐exposing the mice to the same paradigm once the adolescents reached adulthood. We hypothesized that adolescent (P25–45) mice would exhibit greater binge‐like alcohol intake compared to adults (P60–80), and that B6 mice would exhibit greater binge‐like alcohol intake compared to D2 mice. Moreover, we predicted that relative difference in binge‐like alcohol intake between adolescents and adults would be greater in D2 mice.

Results:  Adolescent B6 mice consumed more ethanol than adults in the DID model. There was no difference between adolescent and adult D2 mice.

Conclusions:  This work adds to the literature suggesting that adolescents will consume more ethanol than adults and that this exposure can result in altered adult intake. However, this effect seems largely dependent upon genotype. Future work will continue to examine age‐related differences in ethanol intake, preference, and sensitivity in inbred mouse strains.
Willingness of Older Korean‐American Adults to Use Hospice
Authors: Jang Yuri , Chiriboga David A. , Allen Jessica Y. , Kwak Jung , Haley William E.
Published: January 2010

Responding to an urgent need for more research on end‐of‐life concerns of racial and ethnic minorities, the present study explored predictors of willingness of older Korean‐American adults (N=675) to use hospice. Guided by Andersen's behavioral health model, the study considered predisposing factors (age, sex, marital status, education), potential health needs (chronic conditions, functional disability), and enabling factors (health insurance, acculturation, prior awareness of hospice). Nearly three‐quarters of the sample answered yes to the following statement and question, “Hospice is a program that helps people who are dying by making them feel comfortable and free of pain when they can no longer be cured of their disease. If you needed hospice services, would you use them?” A greater willingness was observed in younger persons (odds ratio (OR)=0.96, 95% confidence interval (CI)=0.93–0.98) and those with higher levels of education (OR=1.67, 95% CI=1.12–2.48), more chronic conditions (OR=1.23, 95% CI=1.05–1.44), health insurance (OR=0.59, 95% CI=0.37–0.94), higher levels of acculturation (OR=1.07, 95% CI=1.03–1.10), and prior awareness of hospice (OR=4.43, 95% CI=2.85–6.90). The present study highlights the role of prior awareness in shaping individuals' attitudes toward services, calling attention to a need for community education and outreach programs for racial and ethnic minorities, with specific emphasis on dissemination of information and greater awareness of hospice services.
Situated Learning: Conceptualization and Measurement
Authors: Goel Lakshmi , Johnson Norman , Junglas Iris , Ives Blake
Published: January 2010

A focus on the interaction between cognitive schemas and context in situ has been suggested as fundamental in organizational decision making and information interpretation. Past research suggests that the situation and the social interaction that occur during learning at the cognitive level consist of factors that affect the process, but the research lacks a coherent explanation for how those factors affect it. We propose a conceptualization of learning, termed situated learning, which accounts for these factors. By drawing on situated cognition theory, social learning theory, and the theory of mental models, we identify and measure four components of situated learning, that is, thematic focus, cognitive absorption, social structure, and participation. Among the most important lessons for researchers and practitioners is the need to consider learning as a constellation of the four components instead of an indivisible phenomenon. This perspective can enhance our understanding of cognitive processes, such as information interpretation and decision making.
The G‐20 Moment
Authors: LULA DA SILVA LUIZ INÁCIO
Published: January 2010

Thanks to the draining effects of the Iraq war and the financial meltdown emanating from Wall Street, a powershift away from American dominance is taking place. Caught between a rising China and an America in relative decline, the new leadership in Japan is recalibrating its post‐World War II relationships. The G‐20 has usurped the role once played by the G‐8 as the governing committee of globalization. And the symbiotic coupling of “Chimerica”, born out of the credit bubble built up over the past two decades, is being put to the test.

In this section, the new prime minister of Japan, the president of the European Union, the president of Brazil and a leading economic historian assess these shifts.
Obama, China and Wishful Thinking About American Jobs
Authors: REICH ROBERT
Published: January 2010

Thanks to the draining effects of the Iraq war and the financial meltdown emanating from Wall Street, a powershift away from American dominance is taking place. Caught between a rising China and an America in relative decline, the new leadership in Japan is recalibrating its post‐World War II relationships. The G‐20 has usurped the role once played by the G‐8 as the governing committee of globalization. And the symbiotic coupling of “Chimerica”, born out of the credit bubble built up over the past two decades, is being put to the test.

In this section, the new prime minister of Japan, the president of the European Union, the president of Brazil and a leading economic historian assess these shifts.
Integration of Intestinal Structure, Function, and Microvascular Regulation
Authors: BOHLEN H. GLENN
Published: January 2010

Without an increase in blood flow to provide additional oxygen, intestinal absorption of nutrients cannot proceed. Studies of the intestinal microvascular structure and distribution of resistances indicated that most of the microvascular regulation must occur outside the mucosal tissues. This requires a communication system from the mucosa to resistance vessels unlike that of any other organ. The various mechanisms involved and their communication from mucosal to arteriolar cells has required an integrated study of intestinal structure, physiology, and microvascular regulation. The results of this analysis using diverse approaches have revealed some of the major physical and cellular mechanisms that couple intestinal absorption and microvascular function.
Distribution of Cellular Proliferation in Skeletal Muscle Transverse Arterioles During Maturation
Authors: PRICE RICHARD J. , SKALAK THOMAS C.
Published: January 2010

Objective: To investigate the spatial and phenotypic origin of the new smooth muscle (SM) cells that are necessary for transverse arteriolar (TA) remodeling by establishing the distribution of cellular proliferation in TA trees during maturation.

Methods: Whole‐mount gracilis muscles from rats at 4 and 9 weeks of age were immunolabeled for SM myosin heavy chain to denote arterioles and for bromodeoxyuridine to denote S‐phase (DNA synthesizing) nuclei. The dimensions of each clearly visible segment in TA trees were measured. S‐phase cells in the wall of, or within 5 µm of, TA segments were identified as (1) endothelium or intimal fibroblasts, (2) SM, or (3) interstitial cells. The relative percentages of each cell type in S‐phase, the distribution of arteriolar diameters containing S‐phase SM, and the density of S‐phase interstitial cells (per unit length and per unit surface area of TA) were determined. Alcian blue counterstaining was used to discern the percentage of interstitial cells that were mast cells.

Results: At 4 and 9 weeks, respectively, 3.7% and 2.1% of S‐phase cells were endothelium or intimal fibroblasts, 3.0% and 4.2% were SM, and 93.3% and 93.7% were interstitial cells. No S‐phase interstitial cells within 5 µm of TAs were mast cells. The mean diameter of TA segments containing an S‐phase SM nucleus was 15.22 ± 1.2 µm at 4 weeks of age, with the minimum diameter being 8.9 µm. From 4 to 9 weeks of age, the number of interstitial cells per unit length of TA decreased 10‐fold from 15.2 (n = 115) to 1.5 (n = 182) cells/mm. At 4 weeks, the density of S‐phase interstitial cells was greatest surrounding the most terminal arterioles.

Conclusions: When coupled with the result that S‐phase SM is absent in the most terminal segments, the relatively high density of S‐phase interstitial cells surrounding the smallest diameter terminal segments at 4 weeks of age is consistent with the hypothesis that fibroblast hyperplasia is a component of terminal arteriolar development.
Observations on the Accuracy of Photometric Techniques Used to Measure Some In Vivo Microvascular Blood Flow Parameters
Authors: COKELET GILES R. , PRIES AXEL R. , KIANI MOHAMMAD F.
Published: January 2010

Objective: The accuracy of optical methods used to measure in vivo microvascular blood flow parameters is investigated using measurements made in all vessels of microvascular networks of the rat mesentery.

Methods: The principle of mass conservation was applied to in vivo blood flow rate and discharge hematocrit data, which were determined by photometric methods. One of the several implied assumptions of most interpretations of in vivo optical data is that the vessels are circular in cross‐section; to see the impact of vessel lumen shape on one of these measurements, the average velocity of blood flowing through a d‐shaped glass capillary tube was measured by the dual‐slit method.

Results: For in vivo data, significant imbalance exists in a large number of bifurcations, and the correlation between the blood flow imbalance and the red cell flux imbalance is very small (r2 = 0.39), indicating multiple sources of error. Furthermore, the measured discharge hematocrits were consistent with the observed flow directions at bifurcations in only 39% to 46% of the bifurcations in a network. The imbalance at these bifurcations is not simply caused by the inaccuracy of measurements in only a few microvessels that join such bifurcations, i.e., the inaccuracies are evenly distributed among the vessels. The results of the in vitro study of blood velocity measurement in d‐shaped tubes indicates that the ratio of dual‐slit velocity to the actual average blood velocity is sensitive to the shape of the vessel lumen, and is a function of blood flow rate, hematocrit, vessel lumen shape, and orientation.

Conclusions: Significant inaccuracies exist in the flow and hematocrit data obtained by current methods of interpretation of in vivo photometric measurements. These inaccuracies must be considered when making vessel‐to‐vessel comparisons, or vessel‐by‐vessel comparisons between in vivo observations and model predictions, even though the inaccuracies are greatly reduced when comparing averaged data.
Mice Lacking E‐Selection Show Normal Numbers of Rolling Leukocytes but Reduced Leukocyte Stable Arrest on Cytokine‐Activated Microvascular Endothelium
Authors: MILSTONE DAVID S. , FUKUMURA DAI , PADGETT RICHARD C. , O'DONNELL PETER E. , DAVIS VANNESSA M. , BENAVIDEZ OSCAR J. , MONSKY WAYNE L. , MELDER ROBERT J. , JAIN RAKESH K. , GIMBRONE MICHAEL A.
Published: January 2010

Objective: Previous work indicated that E‐selectin mediates transient interactions between leukocytes and cytokine‐activated endothelium in vitro. Here we examine the role of E‐selectin in blood leukocyte interactions with microvascular endothelium in vivo.

Methods: E‐selectin‐deficient (E−/− mice were produced by gene targeting. The effect of this null mutation on leukocyte‐endothelial interactions was determined by intravital microscopy before and 4 to 5 hours after local administration of the proinflammatory cytokine tumor necrosis factor α (TNFα) in dermal microvessels with low blood flow (dorsal skin‐fold chambers, intact ear skin), and after endotoxin activation in exteriorized mesenteric microvessels with higher blood flow.

Results: E−/− mice were viable, fertile with normal circulating leukocyte and platelet profiles. Approximately 60% of circulating leukocytes rolled in dermal microvessels of both normal (E+/+) and E−/− mice without inflammatory stimulation. After local administration of TNFα, rolling increased modestly and equivalently in both genotypes. The main effect of TNFα was a dramatic increase in leukocyte stable adhesion and, unlike rolling, this manifestation of endothelial activation was significantly reduced in E−/− animals. This reflected fewer dermal microvessels supporting higher adhesion densities in E−/− mice, and a similar trend was observed in mesenteric microvessels.

Conclusions: E‐selectin plays a previously unappreciated role in facilitating and/or mediating stable adhesion of leukocytes to inflamed microvascular endothelium.
In vivo Tissue pO2 Measurements in Hamster Skinfold by Recessed pO2 Microelectrodes and Phosphorescence Quenching Are in Agreement
Authors: BUERK DONALD G. , TSAI AMY G. , INTAGLIENTTA MACROS , JOHNSON PAUL C.
Published: January 2010

Objective: Phosphorescence quenching has been used successfully to optically measure in vivo blood pO2 in the microvasculature. Optical measurements have also been made in some tissues, but it is not clear whether these results accurately reflect tissue pO2.

Methods: Recessed pO2 microelectrodes and the phosphorescence quenching technique were used simultaneously to measure in vivo tissue pO2 in hamster skinfold. The optical window for phosphorescence quenching was focused around the tips of microelectrodes that were positioned in tissue regions at least 100 µm from large microvessels.

Results: Mean tissue pO2 measured by recessed pO2 microelectrodes was 18.4 ± 1.7 (SE) Torr, and mean tissue pO2 determined from the time course of phosphorescence decay was 18.8 ± 2.0 Torr (no significant difference). The two tissue pO2 measurements agreed over a wide range, from 2 to 46 Torr (r = 0.93, 39 paired measurements from six sites in 3 animals). There was no systematic change in the microelectrode tissue pO2 during the period of light excitation used for the optical method.

Conclusions: Under the conditions of our study, sufficient amounts of porphyrin dye leaked from the vasculature and diffused into tissue, allowing accurate measurements of tissue pO2 by the phosphorescence quenching technique. Furthermore, the optical method did not deplete significant amounts of O2 from tissue during light excitation.
The Mechanics of Vascular Cell Motility
Authors: SHUSTER C.B. , HERMAN I.M.
Published: January 2010

Alterations in vascular cell shape and motility occur during developmental processes and in response to injury. Similarly, during tumor vascularization and atherogenesis, endothelial and smooth muscle cells undergo motile and proliferative responses to extracellular cues. Recent inroads into our understanding of signal transduction have identified several candidate pathways by which the extracellular matrix‐ and growth factor‐mediated stimulation of vascular cell motility may be mediated. The multiple and divergent extracellular stimuli that stimulate vascular motile responses may converge on the cytoskeleton via a family of ras‐related GTPases. Biochemical analyses as well as examination of cytoskeletal dynamics in vivo indicate that actin polymerization at the forward aspects of spreading cytoplasm is capable of driving forward protrusion formation in the absence of a conventional actin motor. Actin polymerization at the plasma membrane of leading lamellae may be mediated both by de novo nucleation of actin filaments and the generation of free filament ends by uncapping the barbed ends of existing actin filaments. This review summarizes the most recent findings in extracellular‐cytoskeletal‐signal transduction, therein, providing a framework to explain the remarkable remodeling seen in the vasculature during developmental and disease‐related processes.
Effect of Flow on Hydraulic Conductivity and Reflection Coefficient of Rabbit Mesentery
Authors: PARAMESWARAN SANDHYA , BROWN LAURA V. , LAI‐FOOK STEPHEN J.
Published: January 2010

Objective: To measure the hydraulic conductivity and reflection coefficient for albumin, as defined by the Starling equation, in rabbit mesentery.

Methods: A section of rabbit mesentery was fixed between two chambers filled with lactated Ringer solution. Flow (Q) of Ringer solution was measured across the mesentery at driving pressures (ΔP) between 1 and 6 cm H2O. Hydraulic conductivity was proportional to the slope of the Q‐ΔP curve. At constant ΔP (∼−2, −4, or −6 cm H2O), flow was measured at three different albumin concentration differences (0.5, 1, and 1.5/g/dl). Unstirred layer effects were minimized by magnetic stirrers. Reflection coefficient was the negative of the slope of the Q‐Δπ curve divided by the slope of the Q‐ΔP curve, where Δπ was the albumin osmotic pressure difference. Hydraulic conductivity was measured before and after testicular hyaluronidase was added to the Ringer solution.

Results: There was no significant difference in conductivity per unit area (Lp) for the three different driving pressures. Hyaluronidase increased hydraulic conductivity significantly (p< 0.01) by 72 ± 56 %, indicating that hyaluronan and other glycosaminoglycans contributed to tissue fluid resistance. Reflection coefficient (σ) increased from 0.02 to 0.14 as flow increased eightfold.

Conclusions: The results suggest that the mesentery tissue provides little restriction to the passage of albumin. The increase in conductivity in the presence of hyaluronidase indicates that tissue hyaluronan and other glycosaminoglycans provide fluid resistance to bulk flow.
Prediction of Permeability‐Surface Area Product Data by Continuous‐Distribution Pore Models
Authors: MCNAMEE JAMES E. , WOLF MATTHEW B.
Published: January 2010

Objective: To investigate the ability of continuous‐distribution pore models to accurately predict permeability‐surface area product (PS) experimental data in skeletal muscle.

Methods: Models having a water‐only (WO) pathway and continuous distributions of microvascular transport‐pathway sizes were fit to solute reflection‐coefficient (σ) experimental data (∼0.5–16 nm Stokes radii) obtained from skeletal muscle to determine optimal parameter values. Without further modification, these models were used to predict experimental PS values obtained from the literature for small solutes ranging in size from NaCl to inulin and for three proteins, α‐lactalbumin, ovalbumin, and albumin (∼ 0.23–3.7 nm radii). The protein PSs were determined from fluorescent tracer‐diffusion curves and a nonlinear model of tracer diffusion in the cat hindlimb preparation. The model's PS predictions were compared to those of a discrete‐pore model previously developed and a fiber‐matrix (FM) model.

Results: A log‐normal (LN) continuous pore‐size distribution plus WO‐pathway model (three free parameters) fit the σ data to within the 95% confidence intervals of each of eight solutes spanning a 32‐fold size range and was nearly as close to the data as was the two discrete‐pore plus WO‐pathway model (four free parameters). Both models closely described the PS data for nine solutes spanning a 14‐fold size range. The fit of a fiber‐matrix plus WO‐pathway model (three free parameters) to the σ data was much poorer than for the other models.

Conclusions: The LN and two‐discrete‐pore models accurately describe σ and PS experimental data in cat and human skeletal muscle. Therefore, experimental data resulting from complex microvascular transport processes are well characterized by simple pore models.
Potentiation of Pulmonary Arteriolar Vasoconstriction to Endothelin‐1 by Inhibition of Nitric Oxide Synthesis in the Intact Lung
Authors: ROBERTS ANDREW M. , SLAAF DICK W. , JOSHUA IRVING G.
Published: January 2010

Objective: To observe pulmonary arteriolar effects of endothelin‐1 (ET‐1) in the intact lung and determine if constriction to ET‐1 is potentiated by inhibition of nitric oxide (NO) synthesis.

Methods: In anesthetized male Sprague‐Dawley rats with open chest, the lungs were ventilated with air through the lower trachea andin vivoresponses of pulmonary arterioles were examined by video microscopy. Observations were made when the lungs were statically inflated with oxygen to a pressure of approximately 10 cm H2O for brief periods. A lens with a dipping cone was held at the pleural surface. ET‐1 (10−7–10−5 M; approximately 0.1 ml) was applied topically to the fluid layer under the dipping cone.

Results: ET‐1 (10−6 M) constricted parent arterioles 60 ± 5 µm in diameter by 52 ± 12% (range: 20–100%) and branches 45 ± 3 µm in diameter by 36 ± 4% (19–48%). Constriction persisted and there was a dramatic long‐lasting decrease in flow. Alveolar walls quickly became pale, indicating reduced capillary perfusion. A lower concentration of ET‐1 (10−7 M) constricted (p< 0.05) parent arterioles 61 ± 4 µm in diameter by 7 ± 3% initially, and by 13 ± 8% after 14 ± 2 minutes, while smaller branches did not respond. In separate experiments, infusion of the NO synthase inhibitor L‐NAME (1 mg/kg per minute), modestly (10 ± 3%) decreased (p< 0.05) baseline parent arteriolar diameter from 72 ± 7 µm to 64 ± 5 µm. Branch diameter changed insignificantly from 42 ± 7 µm to 38 ± 7 µm. Afterl‐NAME, ET‐1 (10−7 M) constricted (p< 0.05) parent arterioles by 17 ± 4% initially and 40 ± 14% after 14 ± 2 minutes. Concurrently, branches constricted (p< 0.05) by 14 ± 4% and 26 ± 15%.

Conclusions: Arterioles less than 80 µm in diameter were very responsive to ET‐1, which could be a factor in altering pulmonary microvascular resistance. Inhibition of NO synthesis appears to potentiate constriction to ET‐1.
Effect of Reactive Oxygen Metabolites on Endothelial Permeability: Role of Nitric Oxide and Iron
Authors: OKAYAMA NAOTSUKA , GRISHAM MATTHEW B. , KEVIL CHRISTOPHER G. , EPPIHIMER LOIS ANN , WINK DAVID A. , ALEXANDER J. STEVEN
Published: January 2010

Objective: We evaluated the effects of the xanthine oxidase (XO)‐derived reactive oxygen metabolites on the permeability of bovine pulmonary arteryendothelial monolayers and examined how iron and nitric oxide (NO) participate in these changes in permeability.

Methods: Permeability was measured using a cell‐column chromatographic method in which monolayers were exposed to combinations of agents.

Results: Exposure of monolayers to a superoxide/peroxide generator, xanthine (X, 0.1 mM)/XO (25 mU/mL), increased solute permeability after 10 minutes, but the same dose of either X or XO alone did not. Exposure of monolayers to peroxide (0.1 mM) also increased permeability, but only after 70 minutes. This X/XO permeability was attenuated by either catalase, superoxide dismutase, methionine (1 mM), an oxy‐radical scavenger, or desferrioxamine (0.1 mM), an iron chelator. Spermine NONOate (SNO), an NO donor, attenuated X/XO permeability at 0.1 mM, but this protection was not significant at 0.01 or 1 mM. Spermine NONOate (0.1 mM) did not alter the permeability produced by 0.1 mM peroxide. L‐N5‐(1‐iminoethyl)‐ornithine (10 µM), an NO synthase inhibitor, completely blocked peroxide‐, and partially attenuated X/XO‐mediated permeability. However, 3‐morphosynodiomine (SIN‐1, 1 mM) plus catalase (1,000 U/mL), a peroxynitrite generator, did not alter permeability.

Conclusions: Xanthine/Xanthine Oxidase permeability involves peroxide, superoxide, oxy‐radicals, and iron. Endogenous NO may regulate peroxide‐, but not superoxide‐mediated permeability. The protective effects of exogenous NO on the X/XO permeability may represent interactions between superoxide, peroxide, and cell surface‐bound iron.
Ischemia‐Reperfusion: Mechanisms of Microvascular Dysfunction and the Influence of Risk Factors for Cardiovascular Disease
Authors: GRANGER D. NEIL
Published: January 2010

Endothelial cell function in all segments (arterioles, capillaries, and venules) of the microvasculature is compromised in tissues exposed to ischemia and reperfusion (I/R). This endothelial cell dysfunction is manifested as an impaired ability of arterioles to vasodilate, enhanced fluid filtration and leukocyte plugging in capillaries, and leukocyte‐endothelial cell adhesion and increased protein extravasation in venules. An imbalance in the production of reactive oxygen species and nitric oxide contributes to most of these responses. The risk factors for cardiovascular disease, hypercholesterolemia, diabetes, and hypertension all appear to exacerbate the microvascular responses to I/R. A common feature of the deleterious effects of these risk factors is the enhanced oxidant stress experienced by endothelial cells, which appears to promote leukocyte‐endothelial cell adhesion via transcription‐independent (early response) and dependent (late response) processes. The exaggerated endothelial barrier dysfunction elicited by I/R in hypercholesterolemic animals is linked to the enhanced leukocyte recruitment, while the enhanced protein extravasation in postischemic venules of diabetic animals occurs independently of leukocyte recruitment.
Mast Cell Degranulation and Parenchymal Cell Injury in the Rat Mesentery
Authors: COSTA JENNIFER J. , HARRIS ANTHONY G. , DELANO FRANK A. , ZWEIFACH BENJAMIN W. , SCHMID‐SCHÖNBEIN GEERT W.
Published: January 2010

Objective: The objective of this study was to explore the degree of parenchymal cell injury after mast cell degranulation by application of compound 48/80 (CMP 48/80) in the absence of adherent leukocytes in the rat mesentery.

Methods: Rats were rendered leukopenic by injection of an antibody against leukocytes, and the mesentery was superfused with CMP 48/80 during intravital microscopy. The extent of cell injury was determined using a fluorescent cellviability indicator, propidium iodide (PI). In an additional group, mast cell degranulation with CMP 48/80 was prevented by using the mast cell stabilizer Ketotifen.

Results: After a reduction in the number of circulating leukocytes, mast cell degranulation produced a mild increase in parenchymal cell injury. The injury levels significantly increased when individual regions of the mesentery were compared. Stabilization of the mast cells with Ketotifen reduced the injury to below baseline values.

Conclusions: In the absence of leukocyte adhesion to the endothelium, mast cell degranulation contributes to parenchymal cell injury in the mesentery.
A Web‐Based Research Tool for Functional Genomics of the Microcirculation: The Leukocyte Adhesion Cascade
Authors: LEY KLAUS , BREWER KELLY , MOTON ALLEN
Published: January 2010

Objective: Currently, microvascular data are almost exclusively deposited in scholarly journals. With the increasing availability of molecular data and the construction of genomic databases, a need arises to organize physiological data in a more accessible format. The microcirculation is a functional system that spans all organ systems and shares certain characteristics of organization with metabolic pathways, which have successfully been organized around genomic information for several prokaryotes. Here, we present a web‐based research and teaching tool (http:hsc.Virginia.EDUmedicinebasic‐scibiomedley) that covers a small aspect of microcirculatory physiology, the leukocyte adhesion cascade.

Methods: Currently, the site is organized in a flat‐text mode with hypertext links to GenBank, Medline, and online journals where available.

Results: The web‐based research and education tool is useful for graduate student education, and as a research resource for genetic researchers interested in gene function and for physiologists and biomedical engineers interested in the molecular basis of the leukocyte adhesion cascade. Our effort is intended to be a beginning toward a distributed database for the microcirculation (microcirculation physiome, see http:www.bme.jhu.edunewsmicrophys).

Conclusions: We invite all microvascular researchers to provide annotations and comments to make the research and teaching tool more useful to the scientific community.
Microvascular Perfusion and Transport in the Diabetic Heart
Authors: McDONAGH PAUL F. , HOKAMA JASON Y.
Published: January 2010

Diabetes is a chronic disease of metabolic dysfunction that is increasing worldwide. The hyperglycemia associated with diabetes causes significant protein alterations and an oxidative stress. In the heart, all cell types are affected by diabetes; the myocyte, the vasculature and the blood cells. Four out of five diabetics die from ischemic heart disease and stroke, suggesting that the diabetic is quite vulnerable to ischemic injury. It is important to understand the pathophysiologic changes that occur in the diabetic heart in order to develop thoughtful treatments to limit this serious complication. This review focuses on the anatomical and functional alterations that occur in the diabetic circulation of the heart, with emphasis on the coronary microcirculation. Coronary microvascular dysfunction combined with blood cellular alterations are presented to explain the amplified oxidative stress that occurs in the diabetic heart under ischemic conditions.
Propagation of Viral‐Size Particles in Lymph and Blood after Subcutaneous Inoculation
Authors: FOKIN ALEXANDER A. , ROBICSEK FRANCIS , MASTERS THOMAS N. , SCHMID‐SCHÖNBEIN GEERT W. , JENKINS SCERIA H.
Published: January 2010

Objective: We investigated the propagation of viral‐size particles by lymph and blood after subcutaneous injection.

Methods: In the canine model, transport of [99mTc] sulfur colloid particles of different sizes was studied in different settings in venous blood and lymph for 45 minutes after inoculation.

Results: The mean arrival time of particles in the blood was 2.10 ± 0.46 minutes and 8.87 ± 1.72 minutes in the lymph. Lymph flow in the canine leg was 28.79 ± 2.09 µl/min and was increased by leg massage. The particle concentration was 1000 times higher in the lymph fluid than in blood. Particle flux values were comparable in blood and lymph. The accumulation of particles in blood initially rose faster than in lymph. Accumulation in lymph rises slower but continues longer and reaches higher values. Ninety percent of the inoculum remains at the injection site for at least 45 minutes. Particle size matters more in blood distribution. Leg massage enhances particle transport by lymph.

Conclusions: After subcutaneous injection, viral‐size particles initially arrive in the blood and later in the lymph. Accumulation in lymph and blood increases for a prolonged time after inoculation. Results suggest possibilities for limiting the spread of infectious matter by early local antiviral treatment.
Age‐Dependent Cerebral Hemodynamic Effects of Traumatic Brain Injury in Newborn and Juvenile Pigs
Authors: ARMSTEAD WILLIAM M.
Published: January 2010

Traumatic brain injury is one of the major causes of morbidity, mortality, and pediatric intensive care unit admissions of children. Although the effects of traumatic brain injury have been well described for adult animal models, few have investigated these effects in the newborn or have characterized such effects as a function of age using a single model of injury. Using a piglet model of brain injury, recent studies have shown that the cerebral hemodynamic effects and the corresponding mechanisms for such effects of injury vary as a function of age. This review discusses the types of traumatic brain injury, their models, and the role of species in such model choice. This review also describes the effects of brain injury on cerebral blood flow, metabolism, and cerebrovascular regulation as a function of age. Finally, this review presents evidence for potential mechanisms that may contribute to age‐dependent impaired cerebral hemodynamics following brain injury.
Theoretical Simulation of Oxygen Transport to Brain by Networks of Microvessels: Effects of Oxygen Supply and Demand on Tissue Hypoxia
Authors: SECOMB T.W. , HSU R. , BEAMER N.B. , COULL B.M.
Published: January 2010

Objective: Simulations of oxygen delivery by a three‐dimensional network of microvessels in rat cerebral cortex were used to examine how the distribution of partial pressure of oxygen (PO2) in tissue depends on blood flow and oxygen consumption rates.

Methods: Network geometry was deduced from previously published scanning electron micrographs of corrosion casts. A nonlinear least‐squares method, using images obtained at three different angles, was used to estimate vessel locations. The network consisted of 50 segments in a region 140 µm × 150 µm × 160 µm. A Green's function method was used to predict the PO2 distribution. Effects of varying perfusion and consumption were examined, relative to a control state with consumption 10 cm3O2/100 g per min and perfusion 160 cm3/100 g per min.

Results: In the control state, minimum tissue PO2 was 7 mm Hg. A Krogh‐type model with the same density of vessels, but with uniform spacing, predicted a minimum tissue PO2 of 23 mm Hg. For perfusion below 60% of control, tissue hypoxia (PO2 <1 mm Hg) was predicted. When perfusion was reduced by 75%, the resulting hypoxia could be eliminated by a 31% reduction in oxygen consumption rate.

Conclusions: The simulations suggest that tissue hypoxia resulting from a severe decrease in brain perfusion, as can occur in stroke, may be avoided by a moderate decrease in oxygen consumption rate.