bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Hematocrit Variations on Cerebral Blood Flow and Oxygen Transport in Ischemic Cerebrovascular Disease
Authors: Kusunoki Masahito , Kimura Kazufumi , Nakamura Masaichi , Isaka Yoshinari , Yoneda Shotaro , Abe Hiroshi
Published: April 2011

The contribution of hematocrit (Ht) changes on cerebral blood flow (CBF) and brain oxygenation in ischemic cerebrovascular disease is still controversial. In the present study, effects of Ht variations on CBF and oxygen delivery were investigated in patients with ischemic cerebrovascular disease. CBF was measured by the Xe-133 intracarotid injection method in 27 patients, whose diagnoses included completed stroke, reversible ischemic neurological deficit, and transient ischemic attack. Ht values in the patients ranged from 31 to 53%. There was a significant inverse correlation between CBF and Ht in these Ht ranges. Oxygen delivery, i.e., the product of arterial oxygen content and CBF, increased with Ht elevation and reached the maximum level in the Ht range of 40–45% and then declined. The CBF-Ht and oxygen transport-Ht relations observed in our study were similar to those in the glass-tube model studies by other workers rather than to those in intact animal experiments. From these results, it is conceivable that in ischemic cerebrovascular disease, the vasomotor adjustment was impaired in such a manner that the relations among Ht, CBF, and oxygen delivery were different from those in healthy subjects. Further, an “optimal hematocrit” for brain oxygenation was also discussed.
The Electroencephalogram, Blood Flow, and Oxygen Uptake in Rabbit Cerebrum
Authors: Pearce William J. , Scremin Oscar U. , Sonnenschein Ralph R. , Rubinstein Eduardo H.
Published: April 2011

In the present study, the relationships among electroencephalographic (EEG) amplitude shifts, cerebral blood flow (CBF), and cerebral oxygen uptake (CMRO2) have been characterized in halothane-anesthetized rabbits. CBF was measured by timed collection of venous effluent from the superior sagittal sinus. CMRO2 was calculated as the product of CBF and the arteriovenous difference in oxygen content. The depth of anesthesia in the first series of experiments was maintained at a constant level that was characterized by spontaneous EEG shifts from high- to low-voltage states (HV-LV shifts). These shifts were associated with transient decreases in mean arterial pressure (MAP), which averaged 23 ± 2 mm Hg ( n = 17). Ninety seconds after spontaneous HV-LV shifts, MAP had returned to its original value, CBF had increased by 26 ± 7% ( n = 8), and CMRO2 had increased 22 ± 4% ( n = 7). In a second series of experiments, HV-LV shifts were induced by a 90-s application of a standardized nociceptive stimulus ( n = 13). Following these stimulation-induced HV-LV shifts, CBF increased 28 ± 5% and CMRO2 increased 27 ± 4%. Under scopolamine (0.35 mg/kg, i.v., n = 8), no change in CBF was observed following HV-LV shifts induced by 90-s of stimulation, although CMRO2 increased significantly by 14 ± 3%. After 300 s of post-scopolamine stimulation, however, both CBF and CMRO2 had significantly increased by 12 ± 3 and 15 ± 3% ( n = 8) of control, respectively. These results demonstrate that HV-LV shifts, whether spontaneous or stimulation-induced, are associated with significant increases in both CBF and CMRO2. Because the early (90-s) increases in CBF but not those in CMRO2 could be blocked by scopolamine, we suggest that the cerebral vasodilatation that occurs during the early phase of HV-LV shifts involves cholinergic mechanisms. Because scopolamine could not block the increase in CBF observed after 300 s of stimulation, we suggest that the final value of CBF obtained after an HV-LV shift is determined by a combination of both cholinergic and noncholinergic factors.
Histamine H1- and H2-Receptors are Differentially and Spatially Distributed in Cerebral Vessels
Authors: Gross Paul M.
Published: April 2011

Receptor sites for neurotransmitters may be spatially oriented within cerebral vascular walls. The direction from which neurohumoral stimuli arise (e.g., perivascular or intravascular) and the location and type of receptor activated may therefore determine the nature of vascular response. I review a series of studies that examined cerebrovascular responses to histamine and suggest that histamine receptors are differentially and spatially organized in two profiles within the cerebral circulation. A transmural distribution is suggested from the following results: increases in permeability of the blood-brain barrier (endothelial cells) to intra-arterial infusion of histamine were mediated by H2-receptors; increases in blood flow to intra-arterial infusion of histamine occurred only after the blood-brain barrier was disrupted and were the result of stimulation of both H1- and H2-receptors. These responses probably occur within inner layers of arterial smooth muscle; dilatation of pial arterioles to local microapplication of histamine and its receptor agonists indicates that H2-receptors are the predominant type in outer layers of arterial smooth muscle. A segmental profile of histamine receptors within the cerebrovascular bed is suggested as follows: since both H1- and H2-receptors could mediate dilatation of arterioles and arteries, it may be concluded that both types of receptor are present in resistance vessels; in the capillary bed, H2-receptors are the predominant type; capacitance vessels (pial veins) did not respond to perivascular application of histamine or its agonists. These studies suggest that receptors for histamine may be sparsely populated or absent in cerebral venous smooth muscle.
Effect of Ischemia on Quantification of Local Cerebral Glucose Metabolic Rate in Man
Authors: Hawkins Randall A. , Phelps> Michael E. , Huang Sung-Cheng , Kuhl David E.
Published: April 2011

The model for quantifying local cerebral glucose metabolic rates originally developed by Sokoloff et al. and modified by Phelps, Huang and co-workers was applied to humans with cerebral ischemia (i.e., stroke). Rate constants for fluorodeoxyglucose were measured in ischemic and nonischemic regions with positron computed tomography. Using measured rate constants for ischemia, the model generates more accurate estimates of local cerebral glucose metabolism as compared to the use of rate constants from normal young adults, because the local metabolic rate is significantly underestimated, and temporal instability of the model is observed when normal values are applied to ischemic regions. A method was also developed to test the stability of the local lumped constant. The estimates of the lumped constant showed no or only small variations between ischemic and nonischemic types. Thus, errors introduced in the calculated local cerebral glucose metabolism by inappropriate rate constants appear to be more significant than those caused by any potential change in the lumped constant in ischemia.
Hypoglycemic Brain Injury: Metabolic and Structural Findings in Rat Cerebellar Cortex during Profound Insulin-Induced Hypoglycemia and in the Recovery Period following Glucose Administration
Authors: Agardh C.-D. , Kalimo H. , Olsson Y. , Siesjö B. K.
Published: April 2011

Previous results have shown that severe, prolonged hypoglycemia leads to neuronal cell damage in, among other structures, the cerebral cortex and the hippocampus but not the cerebellum. In order to study whether or not this sparing of cerebellar cells is due to preservation of cerebellar energy stores, hypoglycemia of sufficient severity to abolish spontaneous EEG activity was induced for 30 and 60 min. At the end of these periods of hypoglycemia, as well as after a 30 min recovery period, cerebellar tissue was sampled for biochemical analyses or for histopathological analyses by means of light and electron microscopy. After 30 min of hypoglycemia, the cerebellar energy state, defined in terms of the phosphocreatine, ATP, ADP, and AMP concentrations, was better preserved than in the cerebral cortex. After 60 min, gross deterioration of cerebellar energy state was observed in the majority of animals, and analyses of carbohydrate metabolites and amino acids demonstrated extensive consumption of endogenous substrates. In spite of this metabolic disturbance, histopathologic alterations were surprisingly discrete. After 30 min, no clear structural changes were observed. After 60 min, only small neurons in the molecular layer (basket cells) were affected, while Purkinje cells and granule cells showed few signs of damage. The results support our previous conclusion that the pathogenesis of cell damage in hypoglycemia is different from that in hypoxia-ischemia and indicate that other mechanisms than energy failure must contribute to neuronal cell damage in the brain.
Regulation of Extra- and Intracellular pH in the Brain in Severe Hypoglycemia
Authors: Pelligrino Dale , Siesjö Bo K.
Published: April 2011

Severe hypoglycemia is associated with a marked curtailment of cerebral glucose supply and with consumption of endogenous carbohydrate metabolites and amino acids, many of which exist as anions of acids. Since metabolic control of intracellular pH in acute hypo- and hypercapnia seems to be dependent on the production and consumption of metabolic acids, it must be suspected that intracellular pH in the brain is poorly regulated in hypoglycemic animals. We induced hypocapnia (Paco2 about 15 mm Hg) and hypercapnia (Paco2 about 90 mm Hg) in insulin-injected animals in “precoma” (EEG pattern of slow waves, polyspikes) and “coma” (cessation of EEG activity) and measured CSF and intracellular acid-base changes using the CO2 method.

The induced hypoglycemia did not measurably alter CSF acid-base changes from the normal during hypercapnia, but it did impair CSF pH regulation in hypocapnia. Animals in precoma showed an unchanged cerebral energy state during both hypo- and hypercapnia. Regulation of intracellular pH was not measurably affected in hypercapnia but was reduced in hypocapnia. These results could be accounted for by a reduced ability of the hypoglycemic animals to produce metabolic acids in response to the decrease in Pco2, while the capacity to “consume” acids was largely retained.

In comatose animals, cerebral energy state was held at normocapnic levels during hypercapnia but deteriorated during hypocapnia. In the latter condition, the reduction in adenylate energy charge correlated to a decrease in blood pressure. The capacity to alter metabolic acid levels was abolished. In spite of this, hypocapnia was associated with a marked rise in intracellular pH, in some animals to values of about 7.7 (control, 7.0), and hypercapnia caused only very moderate reduction in intracellular pH. It is proposed that the excessive increase in intracellular pH during hypocapnia was due to hypotension-induced energy failure with subsequent depolarization of cells and passive equilibration of HCO3− (or H+) across the cell membranes. In hypercapnia, the influx of HCO3− into cells was unrelated to further deterioration of cerebral energy state but could possibly have been caused by CO2-induced depolarization and/or increased cell membrane permeability to HCO3−/H+ ions.

It is concluded that severe hypoglycemia disrupts intracellular pH regulation in the brain and that hypocapnia combined with moderate hypotension leads to an excessive intracellular alkalosis of potential importance for the development of cell damage.
A Simplified in vivo Autoradiographic Strategy for the Determination of Regional Cerebral Blood Flow by Positron Emission Tomography: Theoretical Considerations and Validation Studies in the Rat
Authors: Ginsberg Myron D. , Lockwood Alan H. , Busto Raul , Finn Ronald D. , Butler Cathy M. , Cendan Ignacio E. , Goddard John
Published: April 2011

A simplified mathematical model is described for the measurement of regional cerebral blood flow by positron emission tomography in man, based on a modification of the autoradiographic strategy originally developed for experimental animal studies. A modified ramp intravenous infusion of radiolabeled tracer is used; this results in a monotonically increasing curvilinear arterial activity curve that may be accurately described by a polynomial of low degree (= z). Integrated cranial activity C̄ B is measured in regions of interest during the latter portion of the tracer infusion period (times T1 to T2). It is shown that

[Formula: see text]

where each of the terms A x is a readily evaluated function of the blood flow rate constant k, the brain:blood partition coefficient for the tracer, the cranial activity integration limits T1 and T2, the coefficients of the polynomial describing the arterial curve, and an iteration factor n that is chosen to yield the desired degree of precision. This relationship permits generation of a table of C̄ B vs. k, thus facilitating on-line computer solution for blood flow. This in vivo autoradiographic paradigm was validated in a series of rats by comparing it to the classical autoradiographic strategy developed by Kety and associates. Excellent agreement was demonstrated between blood flow values obtained by the two methods: CBF in vivo = CBFclassical X 0.99 − 0.02 (units in ml g−1 min−1; correlation coefficient r = 0.966).
Measurement of Local Blood Flow and Distribution Volume with Short-Lived Isotopes: A General Input Technique
Authors: Huang Sung-Cheng , Carson Richard E. , Phelps Michael E.
Published: April 2011

A new technique for measuring local blood flow and distribution volume is proposed. The technique uses short-lived isotopes but is different from the equilibrium method in that no constant input is necessary, and no assumption about distribution volume is needed. The theoretical basis of the technique is developed, and the results of a computer-simulation study are presented to show the potential of the technique. The technique is expected to be easier to perform and to give more accurate flow values than the equilibrium method.
Cat Pial Venoconstriction by Topical Microapplication of Norepinephrine
Authors: Ulrich K. , Auer L. M. , Kuschinsky W.
Published: April 2011

Pial venous reactions to perivascular microapplication of norepinephrine (10−9 10−3 M) were investigated. The sample of 26 pial venous portions with resting diameters between 80 and 498 μm exhibited a significant constriction with 10−6−10−3 M norepinephrine solutions. The mean percentage constriction with 10−3 M norepinephrine solution was 22% from resting diameter.
Reflectometric Mapping of Microregional Blood Flow and Blood Volume in the Brain Cortex
Authors: Eke Andras
Published: April 2011

A reflectometric indicator-dilution method has been developed for mapping the parenchymal minute volume flow and blood content over tiny superficial areas of the brain cortex at 625 or 2500 locations, respectively. About 0.4 ml dextran-saline solution was used as nondiffusible indicator and injected into the feline cerebral circulation for each measurement. The subsequent cerebrocortical transit of the hemodiluted bolus was detected as a temporary change in the tissue optical density [OD( t)] and interpreted as indicator dilution, C( t). This gave the data necessary to calculate the microregional blood volume (mrCBV), mean transit time of the bolus (mrMTT), and the microregional blood flow (mrCBF = mrCBV/mrMTT). A two-dimensional record of the OD( t) function was made on Kodak SO 115 film by 16-mm cinematography, as a reflectometric tool, over an exposed area of the brain cortex during the bolus perfusion. Later, the microregional OD( t) functions were retrieved for analysis in a square array from the developed film by computer-controlled, frame-by-frame scanning densitometry. Maps of mrCBF, mrCBV, and mrMTT were presented as square arrays of gray-scaled pixels. The maximal spatial and temporal resolution of the method was 0.015 mm2 (mrCBF), 0.004 mm2 (mrCBV), 6 maps/min (mrCBF), and 600 maps/min (mrCBV).
Quantitative Airway Artefact Compensation at Regional Cerebral Blood Flow Measurements with Radioactive Gases
Authors: Nilsson B. G. , Ryding E. , Ingvar D. H.
Published: April 2011

An algorithm is described for detection and correction of airway contamination of clearance curves recorded extracranially during regional cerebral blood flow measurements with inert radioactive gases, mainly xenon-133.
Effect of Topically Administered Epinephrine, Norepinephrine, and Acetylcholine on Cerebrocortical Circulation and the NAD/NADH Redox State
Authors: Dóra Eörs , Kovách Arisztid G. B.
Published: April 2011

We investigated the effects of topically administered catecholamines and acetylcholine (ACh) on the cerebrocortical microcirculation and NAD/NADH redox state in chloralose-anesthetized cats. NADH fluorescence of the brain cortex and the volume of small intracortical vessels were measured by fluororeflectometry, and in most of the experiments the pial vessels were photographed simultaneously through a cranial window. Cerebrocortical vascular volume (CVV) and the diameter of the pial vessels were decreased, and NADH was oxidized by concentrations of epinephrine and norepinephrine as low as 3 × 10−8 M. Pial veins constricted approximately twice as much as pial arteries. ACh dilatated pial arteries, slightly constricted pial veins, and increased CVV, but had no effect on the NAD/NADH redox state. Since pial and intracortical vessels were constricted markedly by catecholamines, and since these vascular reactions appeared at a lower concentration than is presumed to occur in the synaptic cleft, our results support the regulating role of these substances in cerebral circulation. NADH oxidation, obtained with catecholamines, was interpreted to be due to enhanced tissue respiration. The finding that ACh dilatated pial arteries and increased CVV, but failed to influence the NAD/NADH redox state, might indicate that the brain cortices of normal animals are bioenergetically nonhypoxic. If cortical microregions where the oxygen tension is close to zero were biochemically hypoxic, NADH oxidation should have occurred during ACh administration.
Local Cerebral Blood Flow in the Recovery Period following Complete Cerebral Ischemia in the Rat
Authors: Kågström Erik , Smith Maj-Lis , Siesjö Bo K.
Published: April 2011

This study examines reflow patterns in the recirculation period following complete, global ischemia. Cerebrospinal fluid (CSF) compression ischemia was induced in ventilated rats for 5–30 min, and local cerebral blood flow (CBF) was measured autoradiographically after 5, 60, and 90 min of recirculation, Ischemia of 15 min duration was induced by four-vessel occlusion combined with arterial hypotension in two additional groups, with recovery periods of 5 or 60 min, In the immediate recirculation period (5 min), following 15 min of ischemia, local CBF was markedly heterogeneous, Thus, whereas most structures gave clear evidence of “reactive hyperemia,” others showed perfusion defects of the “no-reflow” type, Typically these defects affected the striatum, thalamus, and hippocampus, as well as the frontal, sensorimotor, and parietal cortices. Areas of no-reflow appeared after 10 min, were more extensive after 15 min, and occupied a major part of the brain after 30 min of ischemia. When recirculation was instituted for 60 or 90 min, following 15 min of ischemia, flow returned in previously unperfused areas. However, a delayed hypoperfusion developed, which differed widely between structures (range of CBF values, 20–80% of control). When the ischemic period was prolonged to 30 min, some perfusion defects remained, even after 90 min of recirculation.
Ischemia Reduces Blood-to-Brain Glucose Transport in the Gerbil
Authors: Betz A. Lorris , Iannotti Fausto , Hoff Julian T.
Published: April 2011

The effect of carotid occlusion on cerebral blood flow (CBF), brain plasma volume for sucrose ( Vplsuc), and unidirectional transport of glucose from blood to brain was measured in four regions of gerbil brain. Unilateral common carotid artery occlusion caused a variable decrease in CBF to the ipsilateral cerebral cortex and basal ganglia, with no change in CBF to the contralateral structures, cerebellum, or brainstem. One hour of bilateral carotid artery occlusion reduced flow to near zero in the cerebral cortex and to 30% of control in the basal ganglia, while increasing CBF to the cerebellum and brainstem. There was a significant decrease in the Vplsuc of the cerebral cortex and basal ganglia after 1 h of ischemia, perhaps due to compression of the intravascular space by edema fluid. Blood-to-brain glucose transport, 1 min after release from 1 h of bilateral carotid occlusion, was decreased in the cerebral cortex and basal ganglia, but not in the cerebellum or brainstem. These data indicate that 1 h of complete or incomplete ischemia reduces the rate of unidirectional glucose transport from blood to brain.
Effects of Bradykinin on Pial Arteries and Arterioles in vitro and in situ
Authors: Wahl Michael , Young Alan R. , Edvinsson Lars , Wagner Franz
Published: April 2011

The effect of bradykinin on cerebrovascular resistance vessels was investigated by the use of in vitro and in situ preparations. Bradykinin, in the range of 10−10 to 10−5 M, elicited a concentration-dependent vasodilatation on both feline and human pial arteries in vitro; the half-maximal response was found to be approximately at 2.8 × 10−7 M and 1.3 × 10−8 M (EC50), respectively. This dilatatory effect of bradykinin in vitro was found only in arteries preconstricted with prostaglandin F2α or 5-hydroxytryptamine. In order to determine the effects of bradykinin on the diameter of cat pial arteries in situ, perivascular microapplication was employed. The dose-response curves obtained showed vasodilatation; the EC50 and the maximal response (EAm) were 4.4 × 10−7 M and 45.5% at 10−5 M, respectively. Statistically significant (p < 0.01) reactions were observed at 10−7 M and higher concentrations of bradykinin. The observed effects were independent of initial vessel size (80–260 μm). These in situ findings are very similar to those found in vitro. The isolated guinea pig ileum was used to check the stability of the bradykinin solutions. In this instance, a concentration-dependent contraction was found when “freshly prepared” or “5 hours stored” bradykinin was applied, indicating no measurable degradation of bradykinin. We conclude that bradykinin is a powerful vasodilator of both human and feline pial arteries.
Regional Brain Blood Flow, Blood Volume, and Haematocrit Values in the Adult Rat
Authors: Cremer Jill E. , Seville Malcolm P.
Published: April 2011

Measurements of red cell volume, plasma volume, and tissue haematocrit (Hct) were made in 14 brain regions in adult rats using 51Cr-tagged red cells and 125I-labeled human serum albumin. The mean large vessel (systemic artery) Hct was 41.8, total body Hct was 35.3, and of the brain regions, the lowest value (septal nucleus) was 25.91 and the highest (visual cortex) was 32.05. The lowest blood volume was 6.29 μl g−1 (caudate putamen) and the highest was 14.44 μl g−1 (inferior colliculus). There was a significant difference between regions in both blood volume and tissue blood Hct. When brain regions were ranked in order of blood volume, this did not coincide with the order for blood flow.
Delayed Hypoperfusion after Incomplete Forebrain Ischemia in the Rat. The Role of Polymorphonuclear Leukocytes
Authors: Grøgaard Bjarne , Schürer Ludwig , Gerdin Bengt , Arfors Karl E.
Published: April 2011

The role of polymorphonuclear leukocytes (PMNLs) in postischemic delayed hypoperfusion in the rat brain was investigated. Cerebral ischemia was accomplished by reversible bilateral occlusion of the common carotid arteries for 15 min combined with bleeding to an MABP of 50 mm Hg. The animals of one group were depleted of their circulating PMNLs by intraperitoneal injections of an antineutrophil serum (ANS) prior to the experiment. All animals included in this group had fewer than 0.2 × 109 circulating PMNLs/L at the start of the experiments. In another group ANS was injected intravenously for 5 min starting 2 min after the ischemic insult. After 4 min of recirculation, the number of circulating PMNLs in this group was below 10% of the normal. Control animals were injected with the same amount of normal sheep serum or were not treated at all. Sixty minutes after termination of ischemia, the local blood flow in previously ischemic cerebral structures was 40–50% of the normal as measured with the [14C]iodoantipyrine technique. In animals treated with ANS prior to the ischemic insult, the postischemic blood flow in the frontal, sensorimotor, and parietal cortex as well as caudoputamen and thalamus was significantly higher than that in non-ANS-treated animals. Treatment with ANS immediately after the ischemic period caused no improvement of the local CBF. It is concluded that PMNLs are involved in the cerebral postischemic flow derangements seen in this model. Their effects seem to be exerted during ischemia or immediately upon reinstitution of blood flow.
Assessment of Postischemic Cerebral Energy Metabolism in Cat by 31P NMR: The Cumulative Effects of Secondary Hypoxia and Ischemia
Authors: Alger J. R. , Brunetti A. , Nagashima G. , Hossmann K.-A.
Published: April 2011

The sensitivity of cerebral energy metabolism to ischemic and hypoxic stresses following global cerebral ischemia was evaluated in a cat model using 31P nuclear magnetic resonance (NMR) spectroscopic methods. Complete global cerebral ischemia of 5 to 10 min in length was produced at 1 h intervals by reversible arterial occlusion, permitting continuous monitoring of NMR and EEG. Ischemia appeared to produce slightly more severe energy failure in animals that had previously experienced an ischemic injury. Preischemic hypoxia (5% O2 for 5 min) resulted in minor changes in the levels of phosphocreatine and intracellular inorganic phosphate, which were slightly amplified in animals that previously experienced ischemia.
A Cerebral Vasoconstrictive Effect of Some Adenosine Analogues. A Study of Adenosine Analogues on Local Cerebral Blood Flow and Glucose Utilisation in the Rat
Authors: McBean Douglas E. , Grome John J. , Harper A. Murray
Published: April 2011

Local CBF (LCBF) in the rat was determined using [14C]iodoantipyrine autoradiography. Adenosine and 5'-( N-ethyl)carboxamidoadenosine in a 15-min infusion had no significant effect on LCBF, although there was a tendency to increase. N6-Cyclohexyladenosine (CHA) and 2-chloroadenosine (2-CADO) significantly decreased LCBF in a number of brain regions. Laser-Doppler experiments using CHA confirmed that CHA decreased CBF and that this change was monophasic. Further experiments involving the use of [14C]2-deoxyglucose autoradiography showed that the unexpected vascular effects of CHA and 2-CADO were not a consequence of a decreased metabolic demand. The available data do not allow us to identify the mechanism of action by which the known vasodilators CHA and 2-CADO were able to cause a vasoconstriction and a decrease in LCBF.
P Wave Indices, Obesity, and the Metabolic Syndrome: The Atherosclerosis Risk in Communities Study
Authors: Magnani Jared W. , Lopez Faye L. , Soliman Elsayed Z. , Maclehose Richard F. , Crow Richard S. , Alonso Alvaro
Published: April 2011

Atrial fibrillation and obesity are increasing in prevalence and are interrelated epidemics. There has been limited assessment of how obesity and the metabolic syndrome impact P wave indices, established electrocardiographic predictors of atrial fibrillation. We conducted a cross‐sectional analysis to determine the association of obesity and the components of the metabolic syndrome with P wave indices in the population‐based Atherosclerosis Risk in Communities (ARIC) study. Analyses were adjusted for demographic, anthropometric and clinical variables, and cardiovascular diseases and risk factors. Following relevant exclusions, 14,433 subjects were included (55% women and 24.7% black). In multivariable analyses, we identified significant, progressive increases in PR interval, P wave maximum duration, and P wave terminal force with BMI 25–30 kg/m2 and BMI ≥30 kg/m2 compared to the reference group <25 kg/m2 (P < 0.0001 for trend for all P wave indices). These effects were present in both blacks and whites. Presence of metabolic syndrome was also associated with longer P wave indices. When components of the metabolic syndrome were examined separately, hypertension resulted in significant (P < 0.001) augmentation of the three P wave indices. Similarly, waist circumference was associated with greater P wave maximum duration in both races (P < 0.001). We concluded that P wave indices are significantly associated with obesity and particularly with hypertension and waist circumference. P wave indices may comprise intermediate markers, independent of age and cardiovascular risk, of the pathway linking obesity and with the risk of atrial fibrillation (AF).
Fat Redistribution Following Suction Lipectomy: Defense of Body Fat and Patterns of Restoration
Authors: Hernandez Teri L. , Kittelson John M. , Law Christopher K. , Ketch Lawrence L. , Stob Nicole R. , Lindstrom Rachel C. , Scherzinger Ann , Stamm Elizabeth R. , Eckel Robert H.
Published: April 2011

No randomized studies in humans have examined whether fat returns after removal or where it returns. We undertook a prospective, randomized‐controlled trial of suction lipectomy in nonobese women to determine if adipose tissue (AT) is defended and if so, the anatomic pattern of redistribution. Healthy women with disproportionate AT depots (lower abdomen, hips, or thighs) were enrolled. Baseline body composition measurements included dual‐energy X‐ray absorptiometry (DXA) (a priori primary outcome), abdominal/limb circumferences, subcutaneous skinfold thickness, and magnetic resonance imaging (MRI) (torso/thighs). Participants (n = 32; 36 ± 1 year) were randomized to small‐volume liposuction (n = 14, mean BMI: 24 ± 2 kg/m2) or control (n=18, mean BMI: 25 ± 2) following baseline. Surgery group participants underwent liposuction within 2–4 weeks. Identical measurements were repeated at 6 weeks, 6 months, and 1 year later. Participants agreed not to make lifestyle changes while enrolled. Between‐group differences were adjusted for baseline level of the outcome variable. After 6 weeks, percent body fat (%BF) by DXA was decreased by 2.1% in the lipectomy group and by 0.28% in the control group (adjusted difference (AD): −1.82%; 95% confidence interval (CI): −2.79% to −0.85%; P = 0.0002). This difference was smaller at 6 months, and by 1 year was no longer significant (0.59% (control) vs. −0.41% (lipectomy); AD: −1.00%; CI: −2.65 to 0.64; P = 0.23). AT reaccumulated differently across various sites. After 1 year the thigh region remained reduced (0.77% (control) vs. −1.83% (lipectomy); AD: −2.59%; CI: −3.91 to −1.28; P = 0.0001), but AT reaccumulated in the abdominal region (0.64% (control) vs. 0.42% (lipectomy); AD: −0.22; CI: −2.35 to 1.91; P = 0.84). Following suction lipectomy, BF was restored and redistributed from the thigh to the abdomen.
Randomized Trial of a Video‐Based Patient Decision Aid for Bariatric Surgery
Authors: Arterburn David E. , Westbrook Emily O. , Bogart T. Andy , Sepucha Karen R. , Bock Steven N. , Weppner William G.
Published: April 2011

The decision to have bariatric surgery should be based on accurate information on possible risks and benefits of all treatment options. The goal of this study was to determine whether a video‐based bariatric decision aid intervention results in superior decision quality compared to an educational booklet. We conducted a prospective, randomized controlled trial among adult patients in a single health plan who met standard criteria for bariatric surgery. Patients were randomly assigned to review either a video‐based decision aid (intervention) or an educational booklet on bariatric surgery (control). Changes in patient decision quality were assessed using bariatric‐specific measures of knowledge, values, and treatment preference after 3 months. Of 152 eligible participants, 75 were randomly assigned to the intervention and 77 to the control. The 3‐month follow‐up rate was 95%. Among all participants, significant improvements were observed in knowledge (P < 0.001), values concordance (P = 0.009), decisional conflict (P < 0.001), decisional self‐efficacy (P < 0.001), and in the proportion who were “unsure” of their treatment choice (P < 0.001). The intervention group had larger improvements in knowledge (P = 0.03), decisional conflict (P = 0.03), and outcome expectancies (P = 0.001). The proportion of participants choosing bariatric surgery did not differ significantly between groups, although there was a trend toward decreased surgical choice in the intervention group (59% booklet vs. 42% video at 3 months; P = 0.16). The use of bariatric surgery decision aids was followed by improved decision quality and reduced uncertainty about treatment at 3 months. The video‐based decision aid appeared to have a greater impact than the educational booklet on patient knowledge, decisional conflict, and outcome expectancies.
The Association Between Abdominal Body Composition and Vascular Calcification
Authors: Jensky Nicole E. , Criqui Michael H. , Wright C. Michael , Wassel Christina L. , Alcaraz John E. , Allison Matthew A.
Published: April 2011

Subclinical cardiovascular disease (CVD) may be associated with both adipose and skeletal muscle tissues in the abdomen. Accordingly, we examined whether subcutaneous, intermuscular, and visceral adipose tissue, as well as abdominal lean muscle, were associated with the presence and extent of vascular calcification in multiple vascular beds. Three hundred and ninety four patients (58.1% men) underwent electron beam computed tomography (EBCT) scans as part of routine health maintenance screening. The coronary and carotid calcium scores were analyzed at the time of the scan, whereas the other calcium scores, as well as the body composition analyses, were analyzed retrospectively. Mean age was 55.2 ± 11.1 years and BMI was 26.9 ± 4.2. The prevalence of any calcification in the carotids, coronaries, thoracic aorta, abdominal aorta, and iliacs was 30.1, 60.1, 39.8, 55.7, and 56.8%, respectively. Compared to those with calcification in different vascular beds, those without vascular calcification generally had significantly more lean muscle and less adipose tissue. In separate multivariable logistic models, a 1 s.d. increment in the ratio of abdominal and visceral fat to total area of each corresponding compartments was significantly associated with an increased odds for the presence of thoracic aortic calcium (odds ratio (OR) = 1.6, 1.5, respectively; P = 0.01 for both). Conversely, increases in abdominal lean muscle were associated with significantly decreased odds of thoracic aortic calcification (OR = 0.34; P ≤ 0.01). A similar pattern of associations existed among the other vascular beds. Also, the association between lean muscle and vascular calcification was independent of visceral adipose tissue. In conclusion, adipose tissue was positively and lean body mass inversely associated with prevalent aortic calcification.
Assessing mitochondrial dysfunction in cells
Authors: Brand Martin D. , Nicholls David G.
Published: April 2011

Assessing mitochondrial dysfunction requires definition of the dysfunction to be investigated. Usually, it is the ability of the mitochondria to make ATP appropriately in response to energy demands. Where other functions are of interest, tailored solutions are required. Dysfunction can be assessed in isolated mitochondria, in cells or in vivo, with different balances between precise experimental control and physiological relevance. There are many methods to measure mitochondrial function and dysfunction in these systems. Generally, measurements of fluxes give more information about the ability to make ATP than do measurements of intermediates and potentials. For isolated mitochondria, the best assay is mitochondrial respiratory control: the increase in respiration rate in response to ADP. For intact cells, the best assay is the equivalent measurement of cell respiratory control, which reports the rate of ATP production, the proton leak rate, the coupling efficiency, the maximum respiratory rate, the respiratory control ratio and the spare respiratory capacity. Measurements of membrane potential provide useful additional information. Measurement of both respiration and potential during appropriate titrations enables the identification of the primary sites of effectors and the distribution of control, allowing deeper quantitative analyses. Many other measurements in current use can be more problematic, as discussed in the present review.
Targeting the regulation of CFTR channels
Authors: Eckford Paul D.W. , Bear Christine E.
Published: April 2011

In this issue of the Biochemical Journal, Zhang et al. reveal a new strategy for modifying the regulated function of CFTR (cystic fibrosis transmembrane conductance regulator) on the apical surface of epithelial cells. Simply stated, these authors tested the idea that the cAMP-dependent channel activity of CFTR could be effectively enhanced by disruption of a protein–protein interaction which is normally inhibitory for the production of cAMP. This particular protein–protein interaction [between the PDZ motif of LPA2 (type 2 lysophosphatidic acid receptor) and the scaffold protein Nherf2 (Na+/H+ exchanger regulatory factor 2)] is localized in the CFTR interactome on the apical membrane of epithelial cells. Hence disruption of the LPA2–Nherf2 interaction should lead to a localized elevation in cAMP and, consequently, increased cAMP-dependent CFTR activity on the surface of epithelial cells. Zhang et al. confirmed these expectations for a small-molecule compound targeting the LPA2–Nherf2 interaction using relevant cultures and tissues thought to model the human respiratory epithelium. The success of this strategy depended on previous knowledge regarding the role for multiple PDZ-motif-mediated interactions in signalling (directly or indirectly) to CFTR. Given the number and diversity of such PDZ-mediated interactions, future structural and computational studies will be essential for guiding the design of specific pharmacological interventions.
The Residential Context and the Division of Household and Childcare Tasks
Authors: de Meester Edith , Zorlu Aslan , Mulder Clara H
Published: April 2011

This paper reports a study of the division of household and childcare tasks between partners from a time–space perspective. Data from the 2005 Netherlands Kinship Panel Study and the 2004 ABF Real Estate Monitor are used. The impact of the residential context on the division of household and childcare tasks is studied, taking into account the endogeneity of time spent in paid work for the division of unpaid tasks. The findings suggest that the residential context is an important factor explaining the intrahousehold allocation of unpaid tasks. We found an indirect effect of living in a large city and of job access on the division of household tasks, running via the number of hours worked by the female partner: women living in large cities work more hours, and this leads to a greater likelihood of a nontraditional division of household tasks. There is also a direct effect of living in a large city on the likelihood of a nontraditional division of household tasks, but not on the likelihood of a nontraditional division of childcare tasks.
Incorporating Jurisdiction Issues into Regional Carbon Accounts under Production and Consumption Accounting Principles
Authors: Turner Karen , Munday Max , McIntyre Stuart , Jensen Christa D
Published: April 2011

Despite increased public interest, policy makers have been slow to enact targets based on limiting emissions under full consumption accounting measures (such as carbon footprints). We argue that this may be due to the fact that policy makers in one jurisdiction do not have control over production technologies used in other jurisdictions. We use a regional input–output framework and data derived on carbon dioxide emissions by industry (and households) to examine regional accountability for emissions generation. In so doing, we consider two accounting methods which permit greater accountability of regional private and public (household and government) final consumption as the main driver of regional emissions generation, while retaining focus on the local production technology and consumption decisions which fall under the jurisdiction of regional policy makers. We propose that these methods permit an attribution of emissions generation that is likely to be of more use than a full global footprint analysis to regional policy makers.
Solution structure of the Zβ domain of human DNA-dependent activator of IFN-regulatory factors and its binding modes to B- and Z-DNAs
Authors: Kim Kyungmin , Khayrutdinov Bulat I. , Lee Chung-Kyung , Cheong Hae-Kap , Kang Sung Wook , Park Hyejin , Lee Sangho , Kim Yang-Gyun , Jee JunGoo , Rich Alexander , Kim Kyeong Kyu , Jeon Young Ho
Published: April 2011

The DNA-dependent activator of IFN-regulatory factors (DAI), also known as DLM-1/ZBP1, initiates an innate immune response by binding to foreign DNAs in the cytosol. For full activation of the immune response, three DNA binding domains at the N terminus are required: two Z-DNA binding domains (ZBDs), Zα and Zβ, and an adjacent putative B-DNA binding domain. The crystal structure of the Zβ domain of human DAI (hZ
β
DAI
) in complex with Z-DNA revealed structural features distinct from other known Z-DNA binding proteins, and it was classified as a group II ZBD. To gain structural insights into the DNA binding mechanism of hZ
β
DAI
, the solution structure of the free hZ
β
DAI
was solved, and its bindings to B- and Z-DNAs were analyzed by NMR spectroscopy. Compared to the Z-DNA–bound structure, the conformation of free hZ
β
DAI
has notable alterations in the α3 recognition helix, the “wing,” and Y145, which are critical in Z-DNA recognition. Unlike some other Zα domains, hZ
β
DAI
appears to have conformational flexibility, and structural adaptation is required for Z-DNA binding. Chemical-shift perturbation experiments revealed that hZ
β
DAI
also binds weakly to B-DNA via a different binding mode. The C-terminal domain of DAI is reported to undergo a conformational change on B-DNA binding; thus, it is possible that these changes are correlated. During the innate immune response, hZ
β
DAI
is likely to play an active role in binding to DNAs in both B and Z conformations in the recognition of foreign DNAs.
Dynamics of molecules in extreme rotational states
Authors: Yuan Liwei , Teitelbaum Samuel W. , Robinson Allison , Mullin Amy S.
Published: April 2011

We have constructed an optical centrifuge with a pulse energy that is more than 2 orders of magnitude larger than previously reported instruments. This high pulse energy enables us to create large enough number densities of molecules in extreme rotational states to perform high-resolution state-resolved transient IR absorption measurements. Here we report the first studies of energy transfer dynamics involving molecules in extreme rotational states. In these studies, the optical centrifuge drives CO
2
molecules into states with J ∼ 220 and we use transient IR probing to monitor the subsequent rotational, translational, and vibrational energy flow dynamics. The results reported here provide the first molecular insights into the relaxation of molecules with rotational energy that is comparable to that of a chemical bond.
Alternative mechanisms of receptor editing in autoreactive B cells
Authors: Kalinina Olga , Doyle-Cooper Colleen M. , Miksanek Jennifer , Meng Wenzhao , Prak Eline Luning , Weigert Martin G.
Published: April 2011

Pathogenic anti-DNA antibodies expressed in systemic lupus erythematosis bind DNA mainly through electrostatic interactions between the positively charged Arg residues of the antibody complementarity determining region (CDR) and the negatively charged phosphate groups of DNA. The importance of Arg in CDR3 for DNA binding has been shown in mice with transgenes coding for anti-DNA VHregions; there is also a close correlation between arginines in CDR3 of antibodies and DNA binding. Codons for Arg can readily be formed by V(D)J rearrangement; thereby, antibodies that bind DNA are part of the preimmune repertoire. Anti-DNAs in healthy mice are regulated by receptor editing, a mechanism that replaces κ light (L) chains compatible with DNA binding with κ L chains that harbor aspartic residues. This negatively charged amino acid is thought to neutralize Arg sites in the VH. Editing by replacement is allowed at the κ locus, because the rearranged VJ is nested between unrearranged Vs and Js. However, neither λ nor heavy (H) chain loci are organized so as to allow such second rearrangements. In this study, we analyze regulation of anti-DNA H chains in mice that lack the κ locus, κ-/κ- mice. These mice show that the endogenous preimmune repertoire does indeed include a high frequency of antibodies with Arg in their CDR3s (putative anti-DNAs) and they are associated mainly with the editor L chain λx. The editing mechanisms in the case of λ-expressing B cells include L chain allelic inclusion and VHreplacement.
Efficient targeted gene disruption in the soma and germ line of the frog
Xenopus tropicalis
using engineered zinc-finger nucleases
Authors: Young John J. , Cherone Jennifer M. , Doyon Yannick , Ankoudinova Irina , Faraji Farhoud M. , Lee Andrew H. , Ngo Catherine , Guschin Dmitry Y. , Paschon David E. , Miller Jeffrey C. , Zhang Lei , Rebar Edward J. , Gregory Philip D. , Urnov Fyodor D. , Harland Richard M. , Zeitler Bryan
Published: April 2011

The frog
Xenopus
, an important research organism in cell and developmental biology, currently lacks tools for targeted mutagenesis. Here, we address this problem by genome editing with zinc-finger nucleases (ZFNs). ZFNs directed against an eGFP transgene in
Xenopus tropicalis
induced mutations consistent with nonhomologous end joining at the target site, resulting in mosaic loss of the fluorescence phenotype at high frequencies. ZFNs directed against the
noggin
gene produced tadpoles and adult animals carrying up to 47% disrupted alleles, and founder animals yielded progeny carrying insertions and deletions in the
noggin
gene with no indication of off-target effects. Furthermore, functional tests demonstrated an allelic series of activity between three germ-line mutant alleles. Because ZFNs can be designed against any locus, our data provide a generally applicable protocol for gene disruption in
Xenopus
.