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PubMed1985

The separate profile structures of the functional calcium pump protein and the phospholipid bilayer within isolated sarcoplasmic reticulum membranes determined by X-ray and neutron diffraction.

The detailed profile structure of the isolated sarcoplasmic reticulum membrane was studied utilizing a combination of X-ray and neutron diffraction. The water and lipid profile structures within the sarcoplasmic reticulum membrane were determined at 28 A resolution directly by neutron diffraction and selective deuteration of the water and lipid components. The previously determined electron density profile structure of the sarcoplasmic reticulum membrane at 12 A resolution was subjected to model refinement analysis constrained by the neutron diffraction results, thereby providing unique higher resolution calculated lipid and protein profile structures. It was found that the lipid bilayer profile structure of the isolated sarcoplasmic reticulum membrane is asymmetric, primarily the result of more lipid residing in the inner versus the outer monolayer of the sarcoplasmic reticulum lipid bilayer. The asymmetry in the lipid composition was necessarily coincident with a complimentary asymmetry in the protein mass distribution between the two monolayers in order to preserve the overall cross-sectional area of lipid and protein throughout the lipid bilayer region of the sarcoplasmic reticulum membrane profile structure. Approximately 50% of the mass of the total protein was found to be localized externally to the sarcoplasmic reticulum membrane lipid bilayer protruding from the outer lipid monolayer into the extravesicular medium. The structural features of the protein protrusion appear to be rather variable depending upon the environment of the sarcoplasmic reticulum membrane. This highly asymmetric structural organization of the sarcoplasmic reticulum membrane profile is consistent with its primary function of unidirectional calcium transport.

Animals↗
PubMed2002

(+)-(10R)-Germacrene A synthase from goldenrod, Solidago canadensis; cDNA isolation, bacterial expression and functional analysis.

Profiling of sesquiterpene hydrocarbons in extracts of goldenrod, Solidago canadensis, by GC-MS revealed the presence of both enantiomers of germacrene D and lesser amounts of germacrene A, alpha-humulene, and beta-caryophyllene. A similarity-based cloning strategy using degenerate oligonucleotide primers, based on conserved amino acid sequences in known plant sesquiterpene synthases and RT-PCR, resulted in the isolation of a full length sesquiterpene synthase cDNA. Functional expression of the cDNA in E. coli, as an N-terminal thioredoxin fusion protein using the pET32b vector yielded an enzyme that was readily purified by nickel-chelate affinity chromatography. Chiral GC-MS analysis of products from of (3)H- and (2)H-labelled farnesyl diphosphate identified the enzyme as (+)-(10R)-germacrene A synthase. Sequence analysis and molecular modelling was used to compare this enzyme with the mechanistically related epi-aristolochene synthase from tobacco.

Alkyl and Aryl Transferases↗
PubMed1999

Validity of the PULSES profile compared with the Functional Independence Measure for measuring disability in a stroke rehabilitation setting.

OBJECTIVES: To test the validity of the PULSES profile for measuring the disability of stroke rehabilitation patients and to compare it with the Functional Independence Measure (FIM); and to determine the ability of the PULSES score to predict discharge home from a stroke rehabilitation setting. STUDY DESIGN: Retrospective cohort. SETTING: A tertiary stroke rehabilitation unit. PATIENTS: One hundred ninety-seven patients admitted consecutively to a stroke rehabilitation unit from September 1992 to April 1995. METHODS: The PULSES profile was tested for internal consistency. Criterion validity was evaluated by comparing with the FIM. Construct validity was tested using the multimethod-multitrait matrix method and by performing logistic regression to determine if admission PULSES score was predictive of discharge home. RESULTS: Internal consistency of the PULSES profile was supported with a Cronbach's alpha of .74. There was a high correlation between the PULSES and FIM admission and discharge scores of -.82 and -.88, respectively. The multimethod-multitrait matrix correlations demonstrated good convergent and divergent validity for the correlation of the PULSES profile items and the FIM subcategories. Multivariate logistic regression determined the admission PULSES total score to be an independent variable in the model to predict discharge home. CONCLUSIONS: The PULSES profile is a valid measure for assessing disability in the stroke rehabilitation setting. The PULSES profile correlates highly with the FIM. The admission PULSES total score is predictive of discharge home from a stroke rehabilitation program.

Activities of Daily Living↗
PubMed1992

Assessment of spatial and temporal velocity profiles distal of normally functioning Björk-Shiley prosthesis by the Doppler method.

By Doppler echocardiography, the performance of heart valve prostheses is assessed with the aid of maximal transprosthetic velocities, which, however, may not be representative for the full spatial velocity profile in the vicinity of mechanical valve substitutes due to flow separation by the open occluder. The purpose of this study was to determine characteristics of velocity profiles downstream of a normally functioning Björk-Shiley prosthesis. In a pulsatile flow apparatus, different flow rates of 6.3 and 8.4 l/min were delivered. Using a spatially and temporally resolving ultrasonic Doppler method, velocity profiles 20 and 30 mm distal from the prosthesis were registered and displayed in a three-dimensional grid. The spatial velocity profile was found to deviate substantially from a flat profile at these transducer positions at the two flow conditions. Distal to the minor orifice, velocities measured only 70 and 80% of those downstream of the major orifice. In between, a region of relatively slow moving flow was present. The shape of the profiles remained essentially unchanged during acceleration and deceleration of flow. Thus, spatially resolved velocity profiles downstream of mechanical prostheses can be registered by an ultrasonic Doppler device. These findings may be useful for the detection of beginning malfunction both in the experimental and the clinical setting.

Blood Flow Velocity↗
PubMed2002

Functional tyrosine kinase inhibitor profiling: a generally applicable method points to a novel role of platelet-derived growth factor receptor-beta in tuberous sclerosis.

Tumors often exhibit activation of specific tyrosine kinases, which may allow targeting of therapy through inhibition of tyrosine kinase signaling. This strategy has been used successfully in the development of STI571 (gleevec), an inhibitor of bcr-abl tyrosine kinase that has been used successfully in the treatment of chronic myelogenous leukemia. STI571 also shows activity against c-kit and platelet-derived growth factor receptor-beta (PDGFRbeta) tyrosine kinase signaling, thus potentially expanding the number of tumors that may respond to it. We describe a simple and rapid method to assess functional activity of tyrosine kinase signaling that is broadly applicable to tumor types. As proof of principle, we have applied it to cells that serve as models of the autosomal-dominant tumor syndrome tuberous sclerosis (TS). We found that TS model cells derived from tuberin heterozygous mice and from a human renal angiomyolipoma are highly sensitive to PDGFR antagonists and that these cells express PDGFRbeta. Given that PDGFRbeta signaling is inhibited by STI571, we found that SV7tert human angiomyolipoma cells are sensitive to STI571. Thus, we describe a novel but simple method of determining the functional tyrosine kinase profile of a neoplastic cell and our results suggest that STI571 might be useful in the treatment of neoplasms commonly seen in patients with TS.

Benzamides↗
PubMed2003

Altered corticogenesis and neuronal morphology in irradiation-induced cortical dysplasia: a Golgi-Cox study.

Cortical dysplasia has a strong clinical association with epilepsy and mental retardation, but the relationship between alterations in cortical structure and function in dysplasia-related disorders is poorly understood. The cerebral cortex of irradiated rats, an experimental model of cortical dysplasia, was studied using cresyl violet-stained sections and the Golgi-Cox method. The irradiated cortex is characterized by reductions in size, volume, and number of neurons and fibers reflecting the original lethal injury to neuronal precursors. Consequently, only neurons that survived this injury were able to continue their, albeit altered, development. The result is an altered corticogenesis characterized by neuronal, fiber circuitry, and microvascular alterations. Abnormal aggregates (nodules) of excitatory pyramidal neurons with altered dendritic profiles and functional territories are found between 200 and 400 microm from the pial surface. Their horizontal dendritic profiles and functional territories contrast with the vertical (columnar) dendritic profiles and functional territories of normal pyramidal neurons. This horizontal concentration of spiny dendrites and, hence, of excitatory synaptic contacts suggests a response to the presence of an abnormal horizontal plexus of afferent fibers terminals. Stellate neurons, some morphologically compatible with inhibitory basket cells, are also essential components of these nodules. Some neuronal nodules are characterized by a rich plexus of anastomotic capillaries that contrasts with the sparser vasculature of surrounding gray matter tissue. The presence of well-vascularized aggregates of altered pyramidal and inhibitory neurons suggests a high level of metabolic activity. Well-vascularized deep heterotopias are also found. We propose that the functional activity of well-vascularized neuronal nodules and heterotopias could play a role in the abnormal cortical function in this model.

Aging↗
PubMed2003

Heterogeneity of non-insulin-dependent diabetes expressed as variability in insulin sensitivity, beta-cell function and cardiovascular risk profile.

AIMS: The present study investigated the variability in insulin sensitivity and beta-cell function and their relationship to anti-glutamic acid decarboxylase (GAD) positivity and the metabolic syndrome in a group of patients with non-insulin-dependent diabetes mellitus (NIDDM). METHODS: Fifty-four subjects aged 59.5 +/- 6.1 (mean +/- SD) years with NIDDM for 7.9 +/- 3.9 years referred to hospital due to poor glycaemic control, were investigated. Insulin sensitivity was determined by the euglycaemic hyperinsulinaemic glucose clamp technique as the glucose disposal rate relative to the insulin level obtained (GDRI), and also estimated with the homeostasis model assessment (HOMA-S). beta-cell function was measured by assaying the fasting and glucagon-stimulated C-peptide levels and with the HOMA-B. RESULTS: The insulin sensitivity varied 18-fold between subjects when estimated with the clamp and six-fold when estimated with HOMA-S, and was lower the more criteria for the metabolic syndrome present (P = 0.0001 by anova). The beta-cell function varied four-fold when measured as stimulated C-peptide, and eight-fold when estimated with the HOMA-B. The levels of fasting C-peptide and HOMA-B values tended to be lower in anti-GAD+ (n = 11) than in anti-GAD-subjects (P = 0.06 and P = 0.08, respectively). From previously published coronary risk charts, we estimated the 10-year risk of a coronary heart disease (CHD) event to be > 20% in 17 of 39 patients free from cardiovascular disease at the time of study, 16 of whom qualified for a diagnosis of the metabolic syndrome. CONCLUSIONS: The wide variations in insulin sensitivity and beta-cell function found among subjects with NIDDM support the notion that the disorder is highly heterogeneous. Reduced insulin sensitivity was clearly related to the metabolic syndrome and an increased risk for CHD.

Adult↗
PubMed2003

Pulmonary artery vasoactivity in broiler and Leghorn chickens: an age profile.

Vascular function plays a preponderant role in the pulmonary changes that occur with maturation, during birth, and in the development of pulmonary hypertension. This study was designed to characterize the changes in vasoactivity occurring in broiler and Leghorn chickens from late embryonic life to 5 wk of age. Pulmonary arteries were isolated from 19- and 20-d-old embryos, hatchlings, and 1-, 2-, 3-, 4- and 5-wk-old chickens of both lines and subjected to KCl (45.4 mM)- and endothelin-1 (10(-7.5) M)-induced vasoconstrictions followed by acetylcholine (ACh; 10(-5), 10(-6) and 10(-7) M)- and papaverine (10(-4) M)-induced vasodilations. Vasoconstrictions were greatest at hatch and rapidly declined thereafter, whereas vasodilations were greatest in 20-d-old embryos except with 10(-7) M ACh. Broilers grew faster than Leghorns and had lower vasodilation responses to all concentrations of ACh at 2 and 5 wk of age. Broilers also had greater right-to-total ventricular weight ratios at 5 wk of age, whereas ratios were greater in Leghorn embryos at 20 d of incubation and at hatch. Thus, for a brief period before hatch there is a significant increase in pulmonary endothelium-dependent vasodilation capacity in the chicken embryo, which may aid in the transition from chorioallantoic to pulmonary respiration. The absence of differences in vasodilator capacity between broilers and Leghorns before hatch suggests that the differences in pulmonary artery relaxation capacity and pulmonary hypertension observed after hatch in broilers are not necessarily acquired during incubation but may be related to rapid growth of the broiler chicken.

Acetylcholine↗
PubMedDate not supplied

Effects of alcohol and prescription and over-the-counter drug use on liver enzyme profiles.

Liver function tests are commonly ordered during routine checkups or in an effort to identify the cause of underlying disease. Elevated liver enzymes usually indicate a disease or an insult to the liver, the main causes of which can be hepatitis (caused by virus infection or chemical exposures) or cirrhosis of the liver due to alcohol abuse. Results from the Metropolitan Life Insurance Testing Laboratory confirm national data showing a slow rise in the percentage of "free-living" persons with elevated liver enzymes. The percentage of "abnormal" results increased despite unchanged analytic methods or quality control measures during the data gathering period. In addition, the proportions of abnormal enzyme levels have increased while U.S. per capita alcohol consumption has decreased and sales of over-the-counter medications that elevate liver enzymes have increased. Thus, it is increasingly more difficult to determine the true cause of elevated liver enzymes. As more Americans self-medicate and as more prescription drugs become available over-the-counter, which can have subtle or overt effects on liver enzyme secretion, the causes for abnormal enzyme levels will remain difficult to interpret. Continued monitoring of liver enzyme levels and the prevalence of drug and alcohol use are necessary to determine if the noted rise in abnormal levels is associated with increased morbidity or adverse outcome.

Drug Interactions↗
PubMed2006

Associating functional recovery with neurocognitive profiles identified using partially ordered classification models.

Neurocognitive deficits are a core feature of schizophrenia and a significant cause of functional disability. However, targeting these deficits with new treatment approaches will only yield functional improvements if those cognitive operations that are responsible for different dimensions of functional recovery can be identified. A major challenge is that conventional neuropsychological tests, the most practical tools for broadly sampling cognitive functions in treatment trials, are polyfactorial, so that task performance is influenced by multiple cognitive operations. Hence, it is difficult to pinpoint exactly for which cognitive operations a low scoring subject may have poor functionality. We have previously applied in a neuropsychological test battery administered to 220 patients having schizophrenia or schizoaffective disorder, Bayesian statistical methods (yielding partially ordered sets, or posets) designed to mimic the expert analysis of a neuropsychologist by classifying patients into discrete groupings or "states" each having a unique cognitive profile. Here, we report on the association of attributes describing these states (viz. working memory, capacity for divergent thinking, cognitive flexibility and psychomotor speed) with two domains of functional outcome (work/education and residential functioning) rated up to 18 months later. After multiplicity correction, only working memory was associated with work/education outcome. While working memory was not associated with residential outcome, the remaining three attributes were. These findings suggest that different neurocognitive operations may be responsible for different outcome domains. Findings support the use of the poset methodology for clarifying patterns of relationships between discrete neurocognitive attributes and domains of functional outcome.

Adolescent↗
PubMed2005

Exploring trafficking GTPase function by mRNA expression profiling: use of the SymAtlas web-application and the Membrome datasets.

Despite complete sequencing of the human and mouse genomes, functional annotation of novel gene function still remains a major challenge in mammalian biology. Emerging strategies to help elucidate unknown gene function include the analysis of tissue-specific patterns of mRNA expression. A recent study investigated the steady-state mRNA expression profiling of the vast majority of protein-encoding human and mouse genes across a panel of 79 human and 61 mouse nonredundant tissues. The microarray data from this study constitutes the Genomics Institute of Novartis Foundation (GNF) Human and Mouse Gene Atlases and is publicly available for exploration through the SymAtlas web-application (http://symatlas.gnf.org/). We have recently reported the use of these data and hierarchical clustering algorithms to generate a global overview of the distribution of Rabs, SNAREs, and coat machinery components, as well as their respective adaptors, effectors, and regulators. This systems biology approach led us to propose Rab-centric protein activity hubs as a framework for an integrated coding system, the membrome network, which orchestrates the dynamics of specialized membrane architecture of differentiated cells. Here, we describe the use of the SymAtlas web-application and the Membrome datasets to help explore trafficking GTPase function. The human and mouse membrome datasets are available through the Membrome homepage (http://www.membrome.org/) and correspond to subsets of the SymAtlas content restricted to known membrane trafficking components. Considering the fragmentary nature of the current reductionist approaches in elucidating trafficking component functions, the membrome datasets provide a more focused systems biology perspective that not only complements our current understanding of transport in complex tissues but also provides an integrated perspective of Rab activity in controlling membrane architecture.

Animals↗
PubMed2004

Conversion from cyclosporine to tacrolimus improves quality-of-life indices, renal graft function and cardiovascular risk profile.

Long-term use of cyclosporine after renal transplantation results in nephrotoxicity and an increased cardiovascular risk profile. Tacrolimus may be more favorable in this respect. In this randomized controlled study in 124 renal transplant patients, the effects of conversion from cyclosporine to tacrolimus on renal function, cardiovascular risk factors, and perceived side-effects were investigated after a follow-up of 2 years. After conversion from cyclosporine to tacrolimus renal function remained stable, whereas continuation of cyclosporine was accompanied by a rise in serum creatinine from 142 +/- 48 micromol/L to 157 +/- 62 micromol/L (p < 0.05 comparing both groups). Conversion to tacrolimus resulted in a sustained reduction in systolic and diastolic blood pressure, and a sustained improvement in the serum lipid profile, leading to a reduction in the Framingham risk score from 5.7 +/- 4.3 to 4.8 +/- 5.3 (p < 0.05). Finally, conversion to tacrolimus resulted in decreased scores for occurrence of and distress due to side-effects. In conclusion, conversion from cyclosporine to tacrolimus in stable renal transplant patients is beneficial with respect to renal function, cardiovascular risk profile, and side-effects. Therefore, for most renal transplant patients tacrolimus will be the drug of choice when long-term treatment with a calcineurin inhibitor is indicated.

Blood Glucose↗
PubMed2005

Neuropsychological functioning and MMPI-2 profiles in chronic neck pain: a comparison of whiplash and non-traumatic groups.

We measured the neuropsychological functioning in 42 patients with chronic neck pain, 21 with a whiplash trauma and 21 without previous trauma. Subjectively, the whiplash group was more forgetful and had more concentration difficulties compared with the non-traumatic group. The neuropsychological tests did not reveal any differences between the two groups and a reference group of healthy individuals. Thus, chronic neck pain did not seem to interfere with neuropsychological functioning. The personality traits assessed with MMPI-2 in our 42 patients with chronic neck pain differed significantly from the normals on several scales. We also found that the whiplash group had more divergent test results than the non-traumatic group on the MMPI-2 test. Thus, it seems that the health status in those with chronic neck pain is closely linked to separate personality traits. It is concluded that the subjective complaints and poor performance in patients with chronic neck pain may be associated to somatization and inadequate coping, especially in chronic whiplash patients.

Adult↗
PubMed2005

A comparative profile analysis of neuropsychological function in men and women with schizotypal personality disorder.

The purpose of this study was to compare the cognitive profiles of men and women with clinically defined schizotypal personality disorder (SPD). We examined the neuropsychological profile of SPD in 26 right-handed females and 31 right-handed males who met DSM-IV criteria for SPD, and matched comparison subjects. Cognitive performance was assessed on measures of abstraction, verbal and spatial intelligence, learning and memory, language, attention, and motor skills. Neuropsychological profiles were constructed by standardizing test scores based on the means and standard deviations of comparison groups matched for sex, age, handedness, ethnicity and parental SES. Overall, SPD subjects showed mild, general decrements in performance in most cognitive domains. However, unlike male SPD subjects, female SPDs did not show relative deficits in verbal learning and abstraction. The results suggest a less severe pattern of cognitive deficits in women with SPD compared to men, consistent with hypotheses of gender differences in cognitive function in schizophrenia.

Adult↗
PubMed2004

Phydbac2: improved inference of gene function using interactive phylogenomic profiling and chromosomal location analysis.

Phydbac (phylogenomic display of bacterial genes) implemented a method of phylogenomic profiling using a distance measure based on normalized BLAST scores. This method was able to increase the predictive power of phylogenomic profiling by about 25% when compared to the classical approach based on Hamming distances. Here we present a major extension of Phydbac (named here Phydbac2), that extends both the concept and the functionality of the original web-service. While phylogenomic profiles remain the central focus of Phydbac2, it now integrates chromosomal proximity and gene fusion analyses as two additional non-similarity-based indicators for inferring pairwise gene functional relationships. Moreover, all presently available (January 2004) fully sequenced bacterial genomes and those of three lower eukaryotes are now included in the profiling process, thus increasing the initial number of reference genomes (71 in Phydbac) to 150 in Phydbac2. Using the KEGG metabolic pathway database as a benchmark, we show that the predictive power of Phydbac2 is improved by 27% over the previous version. This gain is accounted for on one hand, by the increased number of reference genomes (11%) and on the other hand, as a result of including chromosomal proximity into the distance measure (16%). The expanded functionality of Phydbac2 now allows the user to query more than 50 different genomes, including at least one member of each major bacterial group, most major pathogens and potential bio-terrorism agents. The search for co-evolving genes based on consensus profiles from multiple organisms, the display of Phydbac2 profiles side by side with COG information, the inclusion of KEGG metabolic pathway maps the production of chromosomal proximity maps, and the possibility of collecting and processing results from different Phydbac queries in a common shopping cart are the main new features of Phydbac2. The Phydbac2 web server is available at http://igs-server.cnrs-mrs.fr/phydbac/.

Artificial Gene Fusion↗
PubMed1985

[Estimation of operative risk in cirrhotic patients, from the aspects of both functional reserve and morphological findings in the liver].

In order to evaluate the operative risk in cirrhotic patients, the total risk is measured from the multivariant analyses of 10 useful liver function tests, such as ICG Rmax, LCAT and normotest, etc, and this is very useful on selection of the appropriate operative procedures and on evaluation of the prognosis. In the cases of hepatectomy, however, it is very useful on evaluation of the prognosis, if the functional reserve of the remnant liver could be estimate preoperatively. ICG Rmax of the remnant liver, estimated by our own method using Emission CT, may be the most valuable parameter of the functional reserve of the remnant liver. If ICG Rmax of the remnant liver is over 0.4 mg/kg/min, any types of hepatectomy could be performed with good results. Furthermore, if ICG Rmax of unit liver volume is over 0.8 microgram/kg/min/cm3, the remnant liver regenerates well with good recovering of the functional reserve, following long-term survival. The function of coagulation and reticuloendothelial system, and morphological findings of the liver are also significantly related to the operative results. Therefore, in surgery for cirrhotic patients, especially in hepatectomy, it is necessary to estimate the exact operative risk preoperatively, based on not only hepatic function tests but also coagulation profiles, RES function and morphological findings of the liver, and to select the adequate operative procedures, depending on the operative risk, in order to the excellent operative results.

Humans↗
PubMed1995

A comparison of demographic variables, symptom profiles, and measurements of functioning in symptomatic volunteers and an outpatient clinical population.

There is consistent concern about the generalizability of research findings generated by clinical trials. There are several reasons for concern about these findings: (1) most clinical trials involve symptomatic volunteers who are recruited by means of advertisements rather than patients recruited from general clinical populations; (2) most clinical trials have restrictive criteria for admission into the study; and (3) the design of most trials is not representative of prescribing practices in the community. These methodological issues require investigators to question whether results from trials adequately model what will be seen in a general clinical situation. This report begins to evaluate the representativeness of initial samples by studying the demographic characteristics, symptom profiles, and measurements of functional disability for clinical outpatients and symptomatic volunteers recruited for clinical trials. We found that symptomatic volunteers were statistically more likely to be older than outpatients, were less likely to be single, and reported using more alcohol and cigarettes than outpatients. The two groups had similar levels of functional impairment and similar ages at onset of symptoms, but symptomatic volunteers reported more symptoms of depression and anxiety than outpatients. However, we believe the differences identified in this study did not seem to be clinically significant.

Adult↗