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PubMed2000

Near-infrared spectroscopy: does it function in functional activation studies of the adult brain?

Changes in optical properties of biological tissue can be examined by near-infrared spectroscopy (NIRS). The relative transparency of tissues including the skull to near-infrared light is the prerequisite to apply the method to brain research. We describe the methodology with respect to its applicability in non-invasive functional research of the adult cortex. A summary of studies establishing the 'typical' response in NIRS vascular parameters, i.e. changes in the concentration of oxygenated and deoxygenated haemoglobin, over an activated area is followed by the validation of changes in the cytochrome-oxidase redox state in response to a visual stimulus. Proceeding from these findings a rough mapping of this metabolic response over the motion-sensitive extrastriate visual area is demonstrated. NIRS measures concentration changes in deoxygenated haemoglobin [deoxy-Hb] which are assumed to be the basis of fMRI BOLD contrast (blood oxygenation level-dependent). The method is therefore an excellent tool to validate assumptions on the physiological basis underlying the fMRI signal, due to its high specificity as to the parameters measured. Questions concerning the concept of 'activation'/'deactivation' and that of the linearity of the vascular response are discussed. To challenge the method we finally present results from a complex single-trial motor paradigm study testing the hypothesis, that premotor potentials (contingent negative variation) can be examined by functional techniques relying on the vascular response. Some of the work described here has been published elsewhere.

Adult↗

PubMed2003

Functional specialization within the anterior medial prefrontal cortex: a functional magnetic resonance imaging study with human subjects.

This study investigated the functional neuroanatomy of the anterior medial prefrontal cortex (aMPFC). Previous studies have shown that the aMPFC is involved in evaluative judgment and self-referential processes. Specifically, different sections of the aMPFC are differentially influenced by attention demanding processes. Whereas the dorsal section is supposed to be involved in self-referential processes, the ventral section is assumed to be attenuated during attention demanding processes. The present study investigates the involvement of the dorsal and ventral aMPFC in evaluative judgment by using functional magnetic resonance imaging with spin-echo echo-planar-imaging. Processes involved in evaluative judgment are attention-demanding, self-referential and activate regions in the dorsal and ventral section of the aMPFC. Attention demanding tasks do not necessarily lead to an attenuation of the ventral section of the aMPFC, a region mainly involved in emotional and affective processing.

Adult↗

PubMed1996

The functional basis of ocular dominance: functional MRI (fMRI) findings.

Changes in cortical metabolism and cerebral perfusion may be recorded non-invasively with functional magnetic resonance imaging (fMRI). In pilot experiments, using fMRI with photic stimulation, we found differences between activated areas when the left or the right eye was stimulated separately. In this study we investigated whether this could be explained by ocular dominance. We studied 26 healthy volunteers (mean age 23.3 +/- 3.5 years). Ocular dominance was determined by means of the near-far alignment test. fMRI-measurements consisted of a double-slice gradient echo sequence. Slices were acquired placed parallel on either side of the calcarine fissure. Visual stimulation was done with goggles with two LED matrices (red light, 8 Hz); each in front of one eye. In each subject, the left and right eye were stimulated separately and together, in a randomly alternating order. Twenty-two subjects showed activation, of whom eight subjects had a dominant left eye and 14 a dominant right eye. In general the size of the activated area was bigger upon stimulation of the dominant eye. The difference with the area upon stimulation of the non-dominant eye was statistically significant in the right eye dominant group. These results indicate that the dominant eye actually activates a larger area of the primary visual cortex than the non-dominant eye. This provides for the first time a functional basis for the concept of ocular dominance.

Adult↗

PubMed1983

Atrial transport function in coronary artery disease: relation to left ventricular function.

The atrial contribution to ventricular stroke volume was evaluated in 50 patients with coronary artery disease and found to be related to left ventricular function. All patients underwent complete hemodynamic and angiographic studies. Angiographic volume studies were utilized to determine atrial contribution to the stroke volume, end-systolic volume and ejection fraction. In 11 patients without heart disease, atrial contribution to stroke volume was (mean value +/- standard deviation) 9.3 +/- 6 ml/m2 compared with 13.5 +/- 6 ml/m2 in the patients with coronary disease (probability [p] less than 0.05). The percent of atrial contribution to stroke volume was 20 +/- 7 and 33 +/- 11%, respectively, in normal subjects and patients with coronary disease (p less than 0.05). The combination of congestive heart failure and cardiomegaly was the only clinical aspect associated with a significantly higher (p less than 0.05) atrial contribution to stroke volume than that in the remaining patients with coronary disease (46 versus 31%). Relating the atrial contribution to stroke volume to the left ventricular end-diastolic pressure, stroke volume, end-systolic volume and ejection fraction revealed correlation coefficients of 0.30, -0.44, 0.56 and -0.64, respectively. No patient with a normal ejection fraction (greater than 0.50) had an atrial contribution greater than 40% of stroke volume. The ratio of peak left ventricular systolic pressure/end-systolic volume (mm Hg/ml) was 2.7 +/- 1.5 in patients (n = 14) with an atrial contribution greater than 40% of stroke volume compared with 5.3 +/- 3.4 in patients having an atrial contribution of 40% or less (p less than 0.01). These findings indicate that atrial contribution to stroke volume is inversely related to left ventricular function.

Adult↗

PubMed1986

Reciprocal functional interaction of adjacent myocardial segments during regional ischemia: an intraventricular loading phenomenon affecting apparent regional contractile function in the intact heart.

The mechanism of the increase in function in myocardial segments adjacent to those subjected to regional ischemia is not known. To investigate the hypothesis that changes in regional loading are an important causative factor of this phenomenon, 17 dogs were instrumented with segmental shortening sonomicrometers in the left anterior descending and circumflex artery distributions, circumflex coronary flow probes and cuff occluders, as well as circumflex coronary pressure catheters. Additionally, the animals had aortic pressure catheters and ventricular pressure micromanometers. This animal model allowed modulation of regional inotropic state with regional ischemia or isoproterenol administration. With circumflex coronary bed ischemia, segmental shortening in the circumflex distribution decreased from 11.9 to 6.3% (p = 0.001) whereas left anterior descending regional shortening increased from 11.6 to 13.4% (p less than 0.001). These reciprocal changes occurred in the absence of changes in global afterload or heart rate. Systemic beta-receptor blockade did not change this response, suggesting that it was not reflex- or catecholamine-mediated. Infusing isoproterenol into the circumflex coronary artery resulted in an increase in circumflex regional shortening from 12.5 to 17.4% (p less than 0.02) whereas left anterior descending regional shortening decreased from 13.5 to 8.3% (p less than 0.001), again without change in heart rate or left ventricular or aortic pressure. These data suggest that reciprocal functional interaction between adjacent myocardial segments is a result of changes in regional afterload for the most part, with changes in local preload and timing of ejection also contributing to the observed effect.

Animals↗

PubMed1986

[Functional cramps or functional dystonias in writers and musicians].

The clinical evaluation in the "dystonies of function" or "impaired dexterity" reveals certain physical anomalies which either appear spontaneously or are triggered by specific tests: abnormal postures involving the trunck, head, and upper limb. During the professional gesture the physiological "pulley effect" on flexor tendons is accompanied with an interference effect produced by the displacement of the segments; this, adds up to an unbalance of the digital kinetic chain, building a locked functional system. The antagonist muscles begin to supply the deficiency of the agonist muscles. In addition, patients with a characteristic psychological ground suffer a more acute "disorganization" or a performing career.

Dystonia↗

PubMed1992

Identification of a processed pseudogene related to the functional gene encoding the GM2 activator protein: localization of the pseudogene to human chromosome 3 and the functional gene to human chromosome 5.

The GM2 activator protein is an essential substrate cofactor for the hydrolysis of GM2 ganglioside by lysosomal beta-hexosaminidase A (EC 3.2.1.52). There have been conflicting reports as to the chromosomal localization of the gene encoding the activator. We demonstrate here that these conflicts were caused by the presence of a previously unidentified processed activator-pseudogene on chromosome 3, and we confirm a previous ELISA-based localization of the functional activator gene to chromosome 5. Our data indicate that the functional activator locus can still be considered a candidate site for defects causing some forms of spinal muscular atrophy.

Animals↗

PubMed2002

The functional neuroanatomy of Tourette's syndrome: an FDG PET study III: functional coupling of regional cerebral metabolic rates.

Functional coupling of regional cerebral metabolic rates for glucose measured with [18F]-Fluoro-2-deoxy-D-glucose PET was compared in 18 drug-free patients with Tourette's Syndrome (TS) and 16 age- and sex-matched control subjects. Pearson product-moment correlation matrices containing correlations between metabolic rates in regions sampled throughout the brain were generated independently for TS patients and controls and compared. Significant differences between Z-transformed correlation coefficients were used to identify group differences, and revealed that the connectivity of the ventral striatum was most severely affected in TS. Changes in the coupling of other brain areas-primary motor areas, somatosensory association areas, and insula-also appeared to differentiate TS patients and controls. Evaluation of interrelationships between cortico-striato-thalamo-cortical circuits revealed the existence of functional connections between the motor and lateral orbitofrontal circuits in both groups, however, a reversal in the pattern of these interactions differentiated TS patients and controls. In controls, activity in these circuits appeared to be negatively correlated-i.e. increased activity in one is associated with relative inactivity the other. In TS patients, on the other hand, activity in the motor and lateral orbitofrontal circuits appears to be positively coupled. These results lend further credence to the hypothesis that altered limbic-motor interactions represent a pathophysiological hallmark of this disease.

Adult↗

PubMedDate not supplied

The Prosthetic Upper Extremity Functional Index: development and reliability testing of a new functional status questionnaire for children who use upper extremity prostheses.

The Prosthetic Upper Extremity Functional Index (PUFI) was developed by the authors' clinical research group to evaluate the extent to which a child actually uses a prosthetic limb for daily activities, the comparative ease of task performance with and without the prosthesis, and its perceived usefulness. The PUFI's test-retest and interrater reliability were evaluated with 24 children. Intraclass coefficients (ICCs) were calculated for each of four subscales of the PUFI--specifically, method of performance, ease of prosthetic use, usefulness of the prosthesis, and ease of performance without the prosthesis. The ICCs were greater than 0.65, indicating good test-retest reliability for the older-child respondents (n = 10) and fair to good reliability (ICCs, 0.40 to 0.84) for the parent respondents overall (n= 21). Interrater (child-parent) reliability was lower, with ICCs from 0.30 to 0.77. This finding was not unexpected, since a child and parent may rate in the context of different functional environments. The prosthesis was used 53% of the time by older children and more than 75% of the time by younger children. The results provide evidence that the PUFI has good test-retest reliability overall as a measure of a child's ability to perform upper extremity activities with a prosthesis.

Activities of Daily Living↗

PubMed1996

Engineering new functions and altering existing functions.

Structural and mechanistic information, sequence comparisons, and site-directed mutagenesis data continue to provide a basis for the rational design of new protein functions and the alteration of existing functions. Random mutagenesis and 'directed evolution' approaches, however, are making significant headway in solving protein engineering problems, proving highly practical for tuning properties such as enzyme substrate specificity.

Binding Sites↗

PubMed2003

Involvement of multiple functionally distinct cerebellar regions in visual discrimination: a human functional imaging study.

We investigated the contribution of the human cerebellum to cerebral function during visual discrimination using PET and fMRI. The cognitive task was a successive discrimination of shades of brown with a parametric variation of the stimulus presentation rate and a constant task difficulty. The successive color discrimination task was contrasted to a dimming detection control task, with identical retinal input but with double the number of motor responses. Three sets of activated cerebellar and cerebral regions were observed: rate-dependent and rate-independent color discrimination networks and a motor-and-detection network. The rate-dependent color discrimination network included both an anterior and a posterior activation site in lobule-VI of the two lateral cerebellar hemispheres, whereas the rate-independent network involved a bilateral activation site in lateral Crus-I. Cerebellar sites of the motor-and-detection network were located in medial lobule-V bilaterally, in the vermis, and in posterior left Crus-I and right Crus-II. An additional fMRI study was performed to control for differences in motor output and response timing between the tasks. In this control study, the cerebellar activation sites of the rate-dependent and rate-independent color discrimination networks remained unaltered. The motor-and-detection network included cerebellar activations in posterior left Crus-I and right Crus-II, but none in lobule-V or the vermis. Thus, cerebellar activation sites of the motor-and-detection network could be subdivided into those related to a motor network and those belonging to a dimming detection network. We conclude that successive color discrimination activates multiple, functionally distinct cerebellar regions.

Adult↗

PubMed2003

Cutaneous sympathetic function and cardiovascular function in patients with progressive supranuclear palsy and Parkinson's disease.

Some procedures, such as deep inspiration, increase sweat output (SSwR; sympathetic sweat response) and reduce cutaneous blood flow (SVR; skin vasomotor reflex) on the palm. We investigated SSwR, SVR, and cardiovascular function in 12 patients with progressive supranuclear palsy (PSP), 13 patients with Parkinson's disease (PD), and 9 healthy subjects. In the PSP patients, SSwR was severely diminished, whereas SVR was maintained and cardiovascular function was well preserved. In the PD patients, SSwR was relatively preserved, SVR was maintained, and some patients showed cardiovascular hypofunction. A combination of skin sympathetic and cardiovascular tests may be useful for distinguishing between PD and PSP.

Aged↗

PubMedDate not supplied

Does aging influence pancreatic response in the ultrasound secretin test by impairing hydrokinetic exocrine function or sphincter of Oddi motor function?

BACKGROUND: Secretin administration induces a brief distinct dilatation of the main pancreatic duct in healthy persons, visible at ultrasonography. Several investigations have indicated that sonographic duct measurements before and after secretin injections are a useful tool in the diagnostic screening for pancreatic disease. AIMS: Aim of this study was to evaluate the influence of aging on the test results. METHODS: We examined prospectively two groups of patients with distinctly different mean age, measuring the pancreatic duct diameter sonographically before, 2, 4, 6 and 10 minutes after intravenous injection of 1 CU secretin per kilogram body weight. The examination was performed in all patients on account of abdominal complaints, and pancreatic disease could be excluded by further diagnostic procedures. Group 1 consisted of 22 patients, median age 30.5 years, Group 2: 21 patients, median age 68 years. RESULTS: The younger patients (Group 1) had a mean basal pancreatic duct diameter of 1.6 mm. After secretin injection they showed dilatation reading 3. 1 mm, corresponding to 94% of the basal duct diameter. The older patients (Group 2), with a basal diameter of 1.9 mm, showed a duct enlargement of about 84% to 3.5 mm. There was no statistically significant difference between the two groups concerning extent and temporal development of secretin-induced pancreatic duct dilatation. CONCLUSIONS: The underlying mechanisms of response to secretin stimulation - hydrokinetic pancreatic function, sphincter of Oddi motor function, and extensibility of Wirsung's duct--do not seem to be impaired by aging. Thus, the ultrasound secretin test should be suitable for application in older patients.

Adolescent↗

PubMed2002

Finding genes for bipolar disorder in the functional genomics era: from convergent functional genomics to phenomics and back.

Psychiatric genetics, while promising to unravel the mechanisms of psychiatric disorders, has proven to be a challenging field. Psychiatric disorders, like other common genetic traits, are complex and heterogeneous. Psychiatric genetics has also suffered from a lack of quantifiable, biology-based phenotypes. However, the field is currently at an opportune moment. The work of various investigators is on the verge of paying rich dividends. Efforts at positional cloning are being greatly accelerated by the fruits of the Human Genome Project. New tools of functional genomics, such as expression profiling and proteomics, are being applied to animal models. These two methods can complement each other in an approach we have termed convergent functional genomics. Lastly, improvements in the measurement of biologically distinct endophenotypes--or phenomic--will lead to a better understanding of the mapping of genes to phenotypes in both animal and human systems.

Journal Article↗

PubMed1993

Modularity of protein function: chimeric interleukin 1 beta s containing specific protease inhibitor loops retain function of both molecules.

Although it is widely recognized that many proteins contain discrete functional domains, it is less certain whether smaller, less obviously discrete, units of structure will retain their specific function when transplanted into a different context. The observation that the potent inflammatory cytokine human interleukin 1 beta has the same overall structure as soybean trypsin inhibitor (STI) (Kunitz) prompted us to replace a tight turn in the cytokine sequence with the large loop in soybean trypsin inhibitor that binds to the active site of trypsin. Wild-type interleukin 1 beta (IL-1 beta) is highly resistant to proteolysis, but the chimeric STI/IL is specifically cleaved by trypsin, apparently in the inserted loop. Other chimeric interleukins have also been constructed, by replacing the same tight turn with inhibitory loops from other protein protease inhibitors: turkey ovomucoid inhibitor (TOI), a chymotrypsin inhibitor, and alpha 1-antitrypsin (AT), an elastase inhibitor. Although these loops come from proteins not related structurally to interleukin 1, they confer specific protease sensitivity or inhibition on the chimeric cytokine. The cytokine properties of these chimeric interleukins have also been evaluated. The chimeras formed from human IL-1 beta and all inhibitory loops tested bind to the interleukin 1 receptor with reasonable affinity. The typical cellular effects of IL-1, however, are not observed with all the recombinant proteins, thus confirming that receptor binding and signal transduction can be uncoupled. When these results are taken together with the results of site-directed mutagenesis of IL-1, reported in this paper and elsewhere, they allow the receptor and intracellular transduction sites on the protein to be mapped in detail.

Amino Acid Sequence↗

PubMed1986

In vivo function of Escherichia coli pyruvate oxidase specifically requires a functional lipid binding site.

The pyruvate oxidase of Escherichia coli is a peripheral membrane flavoprotein that is dramatically activated by lipids. The enzyme strongly binds to phospholipid vesicles in vitro. In vivo, in addition to enzyme activation, binding is thought to be important to provide access of the enzyme to ubiquinone dissolved in the lipid bilayer. It was unclear if both or either of these attributes is needed for enzyme function in vivo. To differentiate between activation and lipid binding, we have constructed, using recombinant DNA techniques, a mutant gene that produces a truncated protein. The truncated protein lacks the last 24 amino acids of the C-terminus of the oxidase (due to introduction of a translation termination codon) and thus is closely analogous to the activated species produced in vitro by limited chymotrypsin cleavage [Recny, M.A., Grabau, C., Cronan, J.E., Jr., & Hager, L.P. (1985) J. Biol. Chem. 260, 14287-14291]. The truncated protein (like the protease-derived species) is fully active in vitro in the absence of lipid, and its activity is not further increased by addition of lipid activators. Moreover, the truncated enzyme fails to bind Triton X-114, a detergent that binds to and activates the wild-type oxidase. Strains producing the truncated protein were devoid of oxidase activity in vivo. This result indicates that binding to membrane lipids is specifically required for function of the oxidase in vivo; activation alone does not suffice.

Amino Acid Sequence↗

PubMed1990

Regulation of the function of eukaryotic DNA topoisomerase I: analysis of the binding step and of the catalytic constants of topoisomerization as a function of DNA topology.

It was previously observed that two steps of the reaction of eukaryotic DNA topoisomerase I (topoisomerization and cleavage) depend upon the conformation of the DNA substrate: in both instances the supercoiled form is a more efficient substrate than the relaxed one. This paper reports the analysis of two other steps of the reaction: the binding of DNA topoisomerase I to DNA and the catalytic constants (Kcs) of topoisomerization as a function of the topology of the substrate. Binding. Competition assays show that supercoiled DNA binds the enzyme with even slower kinetics than the relaxed form. Therefore, the preferential topoisomerization of supercoiled DNA is not due to the binding step. Additional evidence that the rate-limiting step of the topoisomerization reaction is not the binding of the enzyme to DNA is provided by the fact that the kinetics of relaxation is first order. Catalysis. The Kcs of the topoisomerization reaction have been calculated and it was shown that they do not vary as a function of the topology of the substrate or of its size. Taken together, the data on binding, cleavage, topoisomerization, and Kcs suggest that the preferential topoisomerization of torsionally strained DNA is due to the higher availability, on this topological form, of DNA sites that allow the onset of the reaction.

Animals↗

PubMed2004

Protein functional cycle viewed at atomic resolution: conformational change and mobility in nitrophorin 4 as a function of pH and NO binding.

The blood-sucking insect Rhodnius prolixus uses nitrophorin 4, a heme protein, to deliver nitric oxide (NO) to a victim, causing vasodilation and improved feeding. Binding of NO occurs at a ferric heme and is modulated by pH. NO binding at lower pH induces a large conformational change involving loops A-B and G-H that leads to distal pocket desolvation and protection of the nitrosyl heme complex. We have determined the crystal structures of Rhodnius nitrophorin 4 to ultrahigh resolution in four functional states: +/-NO at pH = 7.4 and +/-NO at pH = 5.6. The structure with NO at pH 7.4 (1.08 A) is newly determined while the other complexes have been modeled to resolutions much greater than previously reported (1.0-0.85 A). The ultrahigh resolution allowed us to resolve multiple conformers in binding-site loops, leading to a detailed description of the dynamics involved with storing NO in the insect salivary gland at low pH, and releasing NO in response to the increased pH of a victim's tissue. Strikingly, features for both the "open" and "closed" conformers exist under all conditions, suggesting that the flexible loops can transition with relative ease between conformational states. Yet, release of NO from rNP4 is much slower than found for other ferric heme proteins. The structures suggest that highly mobile loops can limit diffusion of diatomic molecules into and out of a protein cavity, a result with implications for the role of protein dynamics in function.

Animals↗