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Reduction of infarct size by systemic amino acid supplementation during reperfusion.

The amino acids aspartate and glutamate, in combination, were evaluated as a means of reducing infarct size and improving cardiac function during reperfusion in an intact pig having an acute anteroseptal infarct. Three groups of 6 pigs each were randomly studied in a blinded manner: control (no amino acids), aspartate/glutamate 3 mmol/L, and aspartate/glutamate 13 mmol/L. The left anterior descending coronary artery was occluded distal to its first diagonal branch for 60 minutes followed by reperfusion for 6 hours. Aspartate and glutamate were administered systemically immediately before reperfusion. The following parameters were measured: infarct size and percent area at risk, global metabolic function, global and regional myocardial function, and tissue parameters of metabolic function. The results clearly showed a significant decrease in infarct size from 60% of the area at risk in control pigs to 37% in both 3 mmol/L and 13 mmol/L amino acid groups. Cardiac output, coronary blood flow, and global oxygen consumption were not significantly affected by the use of amino acids relative to the control group. Global left ventricular mechanical function was also not adversely affected by the infarct and was not altered by amino acid administration. Regional function, however, was significantly decreased by occlusion of the left anterior descending coronary artery in all groups to near 20% and only significantly recovered to 64% in the 13 mmol/L amino acid group. Adenosine triphosphate and acetyl coenzyme A measurements documented significant increases in the 13 mmol/L amino acid group relative to the control group. The conclusions of this study strongly support aspartate/glutamate supplementation for stunned, reperfused myocardium. It is apparent that the effect of amino acid supplementation on glycolysis is directly translated into improved regional function and reduced infarct size.

Animals↗

[Towards the development of a global index of functional disability based on the O.E.C.D. questionnaire. Items in a Swiss survey (author's transl)].

This study is based on a sample of 1500 persons, representative of the general population aged 65 years and over in Geneva and the central Valais region. The questions used to evaluate the level of disability are those selected by the OECD working group. They were included in a self-administered questionnaire. A global score of disability is created by using both an endogenous and an exogenous approach. The endogenous approach attempts to isolate a limited number of factors (factorial analysis) and to order the disability items (Guttman Scale). The exogenous approach adopts as criteria a global assessment of the health of each individual. The discussion of different systems of scoring is based on the distribution of different scores and their intercorrelations.

Activities of Daily Living↗

Regional and global left ventricular function during intra-aortic balloon counterpulsation in patients with acute myocardial infarction shock.

We evaluated the improvement in hemodynamic and left ventricular (LV) function in 15 patients with acute myocardial infarction and cardiogenic shock, who were treated with intraaortic balloon counterpulsation (IABP). They were studied by flow-directed right heart catheterization and nuclear angiography. IABP decreased LV end-diastolic volume from 134 to 114 ml and LV end-systolic volume from 100 to 72 ml. LV stroke volume increased from 34 to 42 ml and cardiac output from 3.0 to 3.6 L/min. Global LV ejection fraction increased from 27.6% to 36.1%, and this was due to improvement in regional ejection fraction in ischemic areas. Pulmonary capillary wedge pressure and pulmonary blood volume decreased. Right ventricular ejection fraction also increased significantly. IABP improved LV function in acute myocardial infarction.

Adult↗

Recovery of semantic word processing in global aphasia: a functional MRI study.

One important issue concerning the recovery of higher cognitive functions-such as word comprehension in aphasia-is to what extent impairments can be compensated for by intact parts of the network of areas normally involved in a closely related function ("redundancy recovery"). In a previous functional MRI investigation, we were able to show that left hemispheric redundancy recovery within a distributed system of related lexical-semantic functions was the most probable basis of recovery of comprehension from transcortical sensory aphasia. The question remained, however, whether redundancy recovery may play a more general role in the recovery of comprehension after large left hemispheric lesions and severe aphasia. We had the possibility, using the same fMRI paradigm, to study seven cases with left middle cerebral artery (MCA) infarction and partial recovery of comprehension > or =6 months after presentation with global aphasia on acute assessment. Lateralization of activation did not differ significantly between patients and controls. The most consistent regions of activation included the left extrasylvian posterior temporal and the right posterior parietal cortex. Recovery of language comprehension was associated predominantly with activations in regions, which were also activated in several normal subjects. We suggest that a redundancy recovery mechanism within multiple representations of closely related functions was more important than take-over of function by previously unrelated areas (vicariation) as the basis of recovery of word comprehension in our patients in spite of extensive left hemispheric damage. We conclude that redundancy within the lexical-semantic system seems to make an important contribution to recovery of comprehension even in severe aphasia.

Acoustic Stimulation↗

Effect of cardiopulmonary support on regional and global left ventricular function during transient coronary occlusion.

The ability of extracorporeal cardiopulmonary support (CPS) to unload the left ventricle and reduce ischemic dysfunction during transient coronary occlusion was studied in 10 anesthetized dogs. Three serial 60-second circumflex coronary artery occlusions were performed with CPS initiated only during the second occlusion. CPS significantly reduced preocclusion systolic blood pressure, blood pressure x heart rate double-product, circumflex blood flow, left ventricular end-diastolic pressure (LVEDP), peak negative dP/dt, and left ventricular systolic thickening. Circumflex occlusion caused changes in LVEDP and left ventricular wall thickening that were similar regardless of the presence or absence of CPS. These data suggest that CPS unloads the left ventricle during myocardial ischemia but does not prevent regional or global myocardial dysfunction.

Angioplasty, Balloon, Coronary↗

From tropics to tundra: global convergence in plant functioning.

Despite striking differences in climate, soils, and evolutionary history among diverse biomes ranging from tropical and temperate forests to alpine tundra and desert, we found similar interspecific relationships among leaf structure and function and plant growth in all biomes. Our results thus demonstrate convergent evolution and global generality in plant functioning, despite the enormous diversity of plant species and biomes. For 280 plant species from two global data sets, we found that potential carbon gain (photosynthesis) and carbon loss (respiration) increase in similar proportion with decreasing leaf life-span, increasing leaf nitrogen concentration, and increasing leaf surface area-to-mass ratio. Productivity of individual plants and of leaves in vegetation canopies also changes in constant proportion to leaf life-span and surface area-to-mass ratio. These global plant functional relationships have significant implications for global scale modeling of vegetation-atmosphere CO2 exchange.

Journal Article↗

Quantification of global and regional ventricular function in cardiac magnetic resonance imaging.

One of the strong assets of cardiac magnetic resonance (CMR) is its ability to assess myocardial anatomy, structure, function, flow, and perfusion within a single examination. Quantification of global and regional function from magnetic resonance imaging (MRI) studies was shown to be accurate and reproducible in experimental and clinical research studies. With the advent of high-performance MRI scanners and newly developed pulse sequences, image acquisition times have been reduced considerably in recent years. However, the clinical use of CMR remains limited for various reasons. Among these limitations is that the amount of images obtained in a typical cardiac examination is so large that visual and especially quantitative image analysis is tedious and time consuming. There is an urgent need for optimized dedicated software tools featuring highly automated contour detection and optimized display capabilities to present the quantitative results to the physician in an orderly fashion, thus facilitating clinical decision making. This article focuses on the state of the art in CMR postprocessing techniques for quantitative assessment of global and regional function.

Female↗

Quantitative gated single photon emission computed tomography imaging: a counts-based method for display and measurement of regional and global ventricular systolic function.

BACKGROUND: Gated single photon emission computed tomography imaging allows simultaneous determination of myocardial perfusion and function. Quantitative perfusion measurements can be based on regional tracer uptake, but function measurements ordinarily require endocardial and epicardial edge detection, which is problematic because of the inherently low spatial resolution and image noise in single photon emission computed tomography images. This article presents methods for quantification of both function and perfusion that do not require edge detection. METHODS AND RESULTS: In SPECT imaging the partial volume effect causes changes in myocardial wall thickness to be reflected as changes in pixel counts in pixels representing the myocardial wall. This effect allows an estimation of changes in myocardial wall thickness by comparing pixel counts in end-systolic images with corresponding pixel counts in end-diastolic images. This article first describes a standard method to quantify myocardial perfusion by sampling myocardial tracer activity at rest and stress. The same method is then used to sample tracer activity in diastolic and systolic images. A new method is developed to convert the diastolic and systolic samples into quantitative estimates of regional wall thickening. A method is then developed to convert the regional wall thickening fractions into a global left ventricular ejection fraction. A normal database is presented. Receiver operating characteristic analysis is used to establish normal limits. CONCLUSION: This method requires no edge detection or geometric boundary estimates. Computer results are presented in a simple and intuitive format, which is uniform for parameters of both perfusion and function. The method is robust and produces relatively few false-positive results.

Databases as Topic↗

Family functioning in bipolar I disorder.

In a sample of 62 patients with Bipolar I disorder, the authors used a repeated measures longitudinal design to examine whether global family functioning was associated with the presence of a concurrent bipolar episode as well as whether global family functioning was associated with the presence of manic and depressive episodes in the following 3 months. Participants were recruited for a randomized clinical trial examining the efficacy of family treatments combined with pharmacotherapy for bipolar disorder. Global family functioning was repeatedly measured with both clinician-rated and patient-rated assessment instruments over the 28-month study period. Results indicated that mood episodes were associated with concurrent global family functioning within individuals, but global family functioning was not associated with episode status in the subsequent 3 months. The repeated measures nature of these results suggests that global family functioning and bipolar episodes may fluctuate in concert with each other but that global family functioning is not associated with subsequent change in episode status.

Adult↗

Hypertrophic cardiomyopathy in pediatric patients: effect of verapamil on regional and global left ventricular diastolic function.

OBJECTIVE: To assess the effects of treatment with verapamil on regional and global left ventricular (LV) diastolic function in paediatric patients with hypertrophic cardiomyopathy (HCM). DESIGN: Twelve patients (age range 5.1 to 12.3 years, median 8.6) with HCM were evaluated during ongoing chronic oral treatment with verapamil (4 mg/kg/day) and four days after withdrawal of therapy. Twelve age- and body surface area-matched normal children served as controls. In an echocardiographic study, global LV diastolic function was evaluated by assessing isovolumic relaxation time (IVRT) and mitral flow indexes, including peak filling rate normalized to mitral stroke volume (PFR/SV). In addition, regional LV diastolic function was assessed by pulsed-wave Doppler tissue imaging at the subendocardial portion of the middle region of the anterior and posterior interventricular septum, and anterolateral and inferior walls to measure the peak velocities and the velocity-time integrals of myocardial excursion in both early diastole and atrial systole. In addition, as an index of diastolic asynchrony (AsyI), the variation in time to peak filling rate, measured as the time from the peak of the R wave on the electrocardiogram to the peak of the regional E wave, among the four myocardial regions was defined by subtracting the smallest value from the greatest and expressing the difference as a percentage of the smallest value. RESULTS: Compared with the controls, patients with HCM without therapy showed a longer IVRT (P<0.01) and a decrease in PFR/SV (P<0.01) without a compensatory increase in filling during atrial systole. Oral administration of verapamil induced a significant shortening of the IVRT (P=0.003) and an increase in PFR/SV (P=0.02). Furthermore, patients with HCM without therapy showed a significantly longer time to peak filling rate (P<0.01) associated with a decreased peak velocity in early diastole without a concomitant increase in peak velocity during atrial systole in each of the myocardial regions. Furthermore, the AsyI was higher in the HCM group than in controls (19% versus 6%, respectively), and this index was inversely correlated with the PFR/SV (r=-0.86, P<0.001). The regional diastolic velocity of the myocardium at each of the four analyzed regions was not significantly different with verapamil, but the AsyI was significantly lower (P<0.05). CONCLUSIONS: Children with HCM show abnormalities of both global and regional LV diastolic function. In these patients, chronic administration of verapamil plays a crucial role in the improvement in global LV filling and, as a consequence, in clinical manifestations. The beneficial effects of verapamil seem to be related to a reduction in diastolic asynchrony more than to significant changes in diastolic velocities of the myocardial fibres.

Calcium Channel Blockers↗

Virus infection and the interferon response: a global view through functional genomics.

The primary focus of this chapter is on providing an overview of how we use the tools of functional genomics to study virus infection, the interferon response, and the mechanisms by which viruses attenuate or evade this response to ensure successful replication. We provide examples of the types of analyses we perform, experimental design considerations, and the tools and techniques we use for data processing and mining. We have not attempted to provide detailed protocols for performing microarray or proteomics experiments because even individual components of such analyses, for example, techniques for the isolation and amplification of ribonucleic acid, could easily be the subject of an entire chapter. Rather, our goal is to show how data obtained from global gene expression and protein profiling can be used to gain new insights into virus-host interactions, with particular emphasis on the interferon response and its modulation by virus infection.

Animals↗

Unscheduled DNA synthesis: a functional assay for global genomic nucleotide excision repair.

The unscheduled DNA synthesis (UDS) assay measures a cell's ability to perform global genomic nucleotide excision repair (NER). This chapter provides instructions for the application of this technique in living cells by creating 6-4 photoproducts and pyrimidine dimers using UVC irradiation, then allowing for their repair. Repair is quantified by the amount of radioactive thymidine incorporated after this insult, and the length of time allowed for this incorporation is specific for repair of particular lesions. Radioactivity is evaluated by grain counting after autoradiography. The results are used to diagnosis repair-deficient disorders clinically and provide a basis for investigation of repair deficiency in human tissues or tumors. At the present time, no other functional assay is available that directly measures the capacity to perform NER on the entire genome without the use of specific antibodies. Since live cells are required for this assay, explant culture techniques must be previously established. Host cell reactivation, as discussed in Chapter 28, is not an equivalent technique, as it specifically measures transcription-coupled repair at active genes, a subset of total NER.

Autoradiography↗

Identification and functional clustering of global gene expression differences between human age-related cataract and clear lenses.

PURPOSE: Age-related cataract is a multi-factorial disease with a poorly understood etiology. Numerous studies provide evidence that the human eye lens has evolved specific regulatory and protective systems to ameliorate lens damage associated with cataract. Other studies suggest that the presence of cataract is associated with the altered expression of specific genes including metallothionein IIa, osteonectin, transglutaminase 2, betaig-h3, multiple ribosomal proteins, ADAM9, and protein phosphatase 2A. Here, we sought to identify further gene expression changes that are associated with cataract and to cluster the identified genes into specific biological pathways. METHODS: Oligonucleotide microarray hybridization was used to analyze the full complement of gene expression differences between lens epithelia isolated from human age-related cataract relative to clear lenses. The expression levels of a subset of the identified genes were further evaluated by semi-quantitative RT-PCR. The identified genes were functionally clustered into specific categories and the probability of over-representation of each category was determined using the computer program EASE. RESULTS: 412 transcripts were observed to be increased and 919 transcripts were observed to be decreased by 2 fold or more in lens epithelia isolated from age-related cataract relative to clear lenses. Of these, 74 were increased and 241 were decreased at the 5 fold level or greater. Seventeen genes selected for further confirmation exhibited similar trends in expression when examined by RT-PCR using both the original and separately prepared clear and cataract RNA populations. Functional clustering of the identified genes using the EASE bioinformatics software package revealed that, among others, transcripts increased in cataract are associated with transcriptional control, chromosomal organization, ionic and cytoplasmic transport, and extracellular matrix components while transcripts decreased in cataract are associated with protein synthesis, defense against oxidative stress, heat-shock/chaperone activity, structural components of the lens, and cell cycle control. CONCLUSIONS: These data suggest that cataract is associated with multiple previously identified and novel changes in lens epithelial gene expression and they point to numerous pathways likely to play important roles in lens protection, maintenance, and age-related cataract.

Aged↗

Global analysis of gene function in yeast by quantitative phenotypic profiling.

We present a method for the global analysis of the function of genes in budding yeast based on hierarchical clustering of the quantitative sensitivity profiles of the 4756 strains with individual homozygous deletion of nonessential genes to a broad range of cytotoxic or cytostatic agents. This method is superior to other global methods of identifying the function of genes involved in the various DNA repair and damage checkpoint pathways as well as other interrogated functions. Analysis of the phenotypic profiles of the 51 diverse treatments places a total of 860 genes of unknown function in clusters with genes of known function. We demonstrate that this can not only identify the function of unknown genes but can also suggest the mechanism of action of the agents used. This method will be useful when used alone and in conjunction with other global approaches to identify gene function in yeast.

Cluster Analysis↗

Working memory and executive functions in transient global amnesia.

Transient global amnesia (TGA) is usually considered to produce a profound impairment of long-term episodic memory, while at the same time sparing working memory. However, this neuropsychological dissociation has rarely been examined in detail. While a few studies have assessed some components of working memory in TGA, the results that have been obtained are far from conclusive. To clarify this issue, we carried out a comprehensive investigation of working memory in 10 patients during a TGA attack. In the first study, we report the results from three patients examined with a battery of neuropsychological tests designed to assess each of the three subcomponents of Baddeley's model of working memory. In a second study, seven different patients underwent neuropsychological investigations that focused specifically on the central executive system, using a protocol derived from a study by Miyake and colleagues. Our findings showed that subcomponents of working memory, such as the phonological loop and visuo-spatial sketch pad, were spared in TGA patients. Specific executive functions that entailed inhibitory control, dual task performance, updating and shifting mechanisms were also found to be normal. However, we found significantly impaired performance for the Brown-Peterson test, and that TGA patients were significantly impaired in the recollection of their episodic memories. They also made reduced numbers of 'remember' compared with 'know' judgments in the episodic memory test several days after TGA. On the basis of our findings, it would appear that the episodic memory deficit during TGA is not related to elementary aspects of executive functioning. Our data also highlight the nature of the cognitive mechanisms involved in the Brown-Peterson task, which may well depend on long-term memory (such as the process of semantic encoding). Lastly, the selective deficit in recollective episodic memories observed in TGA may be principally related to medial temporal lobe abnormalities that have been reported in this syndrome.

Aged↗

Pindolol and propranolol in patients with angina pectoris and normal or near-normal ventricular function. Lack of influence of intrinsic sympathomimetic activity on global and segmental left ventricular function assessed by radionuclide ventriculography.

To investigate the role of intrinsic sympathomimetic activity on left ventricular (LV) function during antianginal therapy with beta-adrenoreceptor antagonists, 23 patients with chronic, exercise-induced angina pectoris and normal or near normal LV function underwent radionuclide ventriculography at rest and during exercise, during 3 randomly allocated periods: (a) treatment with oral propranolol, a drug without intrinsic sympathomimetic activity, 40 to 80 mg 4 times a day; (2) treatment with pindolol, a drug with marked intrinsic sympathomimetic activity, 5 to 10 mg 2 times a day; and (3) a control period. During the control period, the LV ejection fraction decreased from rest (58.9 +/- 8.2%) to exercise (54.3 +/- 10.7%), and the wall motion score decreased from 0.57 +/- 1.08 at rest to 2.39 +/- 2.10 during exercise, p less than 0.001. After propranolol, the ejection fraction did not change significantly at rest (57.2 +/- 8.1%) but improved during exercise (56.8 +/- 11.8%), compared with control values. After pindolol, the ejection fraction did not change at rest (57.9 +/- 8.6%) but improved during exercise (56.9 +/- 8.1%), compared with control values. Similarly, the wall motion score after administration of both agents did not change significantly at rest, but improved during exercise (p less than 0.001). The number of anginal episodes, nitroglycerin tablets consumed, and magnitude of S-T segment depression decreased significantly with both pindolol and propranolol. With both drugs, a similar improvement in exercise tolerance and a similar decrease in exercise heart rate and blood pressure were obtained. It is concluded that pindolol and propranolol, beta-adrenoreceptor antagonists with and without intrinsic sympathomimetic activity, respectively, have similar effects on global and regional LV function in patients with angina pectoris, at doses producing equal suppression of exercise heart rate and similar antianginal effect.

Adult↗

Regional and global left ventricular function in infants with anomalous origin of the left coronary artery from the pulmonary trunk: preoperative and postoperative assessment.

Anomalous origin of the left coronary artery from the pulmonary trunk (ALCA) remains a diagnostic as well as a therapeutic problem. The purposes of this study were: (1) to analyze left ventricular mechanics, including regional wall motion, in infants with ALCA, (2) to determine if the pattern of wall motion in infants with ALCA distinguishes these patients from those with congestive cardiomyopathy of other causes, and (3) to evaluate the potential for recovery of left ventricular function after successful restoration of a dual coronary artery system. Left ventricular mechanics were studied before and serially after surgery in six infants (2 to 13 months old) with ALCA. Fifteen age-matched normal subjects and seven age-matched patients with idiopathic congestive cardiomyopathy were also studied for comparison. Preoperatively, the end-diastolic volume in infants with ALCA was about four times larger than normal and did not differ from that in infants with CM; the myocardial volume was also about three times larger than normal, similar to that in the patients with CM. The myocardial volume/end-diastolic volume ratio was extremely low in patients with ALCA and in those with CM. The infants with ALCA did not exhibit specific segmental wall motion abnormalities but rather had global hypokinesis indistinguishable from that in the patients with CM. After successful repair, end-diastolic volume index rapidly decreased, reaching near normal values by 7 to 22 months after surgery, while myocardial volume index decreased at a slower rate, leading to an early phase of "overshoot hypertrophy," but reaching normal values by 7 to 22 months after surgery.+

Cardiomyopathy, Dilated↗

Left ventricular performance after coronary artery bypass surgery. Prediction of functional benefit.

Global left ventricular performance (ejection fraction) and regional function were studied by rest-exercise radionuclide ventriculography in 36 patients before and after (23 +/- 8.5 wk) they had coronary artery bypass surgery for stable angina pectoris. The exercise ejection fraction was less than the resting ejection fraction before surgery (n = 36,p = 0.006), but not after surgery. The degree of postoperative improvement correlated with the degree of preoperative dysfunction (r = 0.55, n = 36, p less than 0.001). Improvement was most likely to occur if exercise-induced dysfunction was present preoperatively (n = 15,p = 0.001), even with old myocardial infarction. Regional dysfunction during preoperative exercise was also likely to improve postoperatively (n = 18, p = 0.001). Protocol design is important in determining the results and their interpretation. Matching postoperative exercise loads to preoperative loads and using regional analysis with two imaging projections improved judgment of the results. Regional dysfunction was commoner than global dysfunction and was less sensitive to workloads than was ejection fraction. This study shows that coronary artery bypass surgery can improve left ventricular performance on exercise if preoperative tests indicate the presence of ischemia-induced dysfunction.

Adult↗