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PubMed1999

Expression and function of lymphocyte function associated antigen-3 (LFA-3) at the blood-brain barrier.

Lymphocyte function associated antigen-3 (LFA-3) is a cell surface glycoprotein involved in antigen independent T-cell activation and proliferation. The expression and function of LFA-3 at the blood-brain barrier were studied in an in vitro model consisting of primary cultures of human brain microvessel endothelial cells (HBMEC). Surface expression of LFA-3 was detected by immunogold silver staining and the presence of RNA by reverse transcriptase-polymerase chain reaction (RT-PCR). Unstimulated HBMEC in primary culture constitutively express LFA-3 on their surface. Expression is only marginally upregulated following stimulation with tumor necrosis factor-alpha (TNF-alpha) or interferon-gamma (IFN-gamma). Similarly, LFA-3 RNA is present constitutively in unstimulated HBMEC with minimal increase after co-incubation with TNF-alpha and IFN-gamma. The function of LFA-3 as a costimulatory molecule on HBMEC was investigated by incubating purified CD4+ T-lymphocytes with resting or IFN-gamma treated HBMEC monolayers. Proliferation of alpha-CD3 activated CD4+ T-cells was significantly increased upon incubation with resting or activated endothelial cells. Monoclonal antibodies to LFA-3 consistently blocked the proliferative response by 64-76%. The ability of the cerebral endothelium to express LFA-3 and provide secondary signals for T-cell proliferation suggests that cerebral EC may be important in the initiation of inflammatory responses in the human central nervous system.

Antibodies, Monoclonal↗

PubMed1999

A comparative study of the usefulness of the Bath Ankylosing Spondylitis Functional Index and the Dougados Functional Index in the assessment of ankylosing spondylitis.

To determine whether the Bath Ankylosing Spondylitis Functional Index (BASFI, score 0-10) or Dougados Functional Index (DFI, score 0-40) is superior in measuring physical function in ankylosing spondylitis (AS) we studied 191 consecutive outpatients with AS in the Netherlands, France, and Belgium. The participating centers are secondary and tertiary referral centers. The external criterion for disease activity (DA) was: both patient and physician assessment of disease activity on a visual analog scale (VAS) and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). The external criterion for damage was 2 radiological scores of the spine; BASRI-s (Bath Ankylosing Spondylitis Radiology Index-spine) and a modified SASSS (Stoke Ankylosing Spondylitis Spine Score). Median scores for BASFI and DFI were 2.5 (range 0-10) and 8.5 (range 0-35), respectively. Spearman correlation coefficient between both indexes was 0.89. The average correlation with disease activity variables was 0.42 for BASFI and 0.41 for DFI. For both BASFI and DFI the correlation with BASRI-s was 0.42 and with SASSS 0.36. When distinguishing between patients with high and low disease activity, sensitivity for both indexes was between 76 and 94%, while specificity was between 66 and 87% for all 3 DA measures. Average misclassification between BASFI, DFI and DA was 23 and 27%, respectively. Both BASFI and DFI correlate equally well with disease activity and damage.

Adolescent↗

PubMed1999

Does the functional assessment measure (FAM) extend the functional independence measure (FIM) instrument? A rasch analysis of stroke inpatients.

Adding the items of the Functional Assessment Measure (FAM) to the Functional Independence Measure (FIM instrument) has been proposed as a method to extend the range of the FIM, particularly when assessing functional status in rehabilitation patients with brain injury, including stroke. It has been proposed that this approach is especially helpful in ameliorating ceiling effects when brain-injured patients have reached the end of their inpatient rehabilitation stay or are being seen in outpatient settings. In the present study, 376 consecutive stroke patients on a Canadian inpatient rehabilitation unit were concurrently administered the FIM and the FAM. Rasch analysis was used to evaluate how well the FAM items extended the difficulty range of the FIM for both the Motor and Cognitive domains. Within the Motor domain, only the FAM item assessing Community Access was found to be more difficult than extant FIM items, and this item showed some tendency to misfit with the other motor items. In the Cognitive domain, the only FAM item with a higher difficulty level than the FIM items was that assessing Employability. Notably, strict adherence to scoring guidelines for these two FAM items requires taking patients out into the community to evaluate their actual performances, a practice unlikely in the typical inpatient stroke rehabilitation unit. Results indicate that use of the entire FAM as an adjunct to the FIM reduces test efficiency while providing only minimal additional protection against ceiling effects.

Activities of Daily Living↗

PubMed1976

Renal pelvic function following total alloplastic replacement of ureter in pigs. Electrophysiology, renal function and morphology.

Total replacement of one ureter was under-taken in pigs. After an observation period of 2-3 months further studies were made. Pelvic peristaltic activity as reflected by pelvic pressure waves and electrical activity was indistinguishable from that in normal pigs. In particular, retrograde activity was not observed. It appears that ureteric peristalsis is not a prerequisite of normal pelvic function. Providing only that the calibre is sufficient, function of a ureteric prosthesis is satisfactory, and no changes in kidney or pelvis function and morphology are apparent.

Action Potentials↗

PubMed1975

Long-term functional results of surgery for coronary artery disease in patients with poor ventricular function.

Thirty-two patients with coronary artery disease and an ejection fraction (EF) below 0.40 had coronary bypass and/or left ventricular aneurysm (LVA) resection. Twenty-four patients had a previous infarction, 12 had congestive heart failure (CHF), and left ventricular end-diastolic pressure averaged 15 mm. Hg. Nineteen patients had three-vessel involvement and there was an average of 2.4 vessels involved per patient. Bypass was accomplished on 87 per cent of vessels; 11 patients had resection of LVA; 11 had coronary endarterectomy. There were no hospital deaths, 63 per cent of the patients were improved, and 56 per cent were able to return to work or full activity. There were five late deaths (16 per cent). There was good functional improvement in 83 per cent of the survivors, followed 1 to 4 years. We believe that patients with poor ventricular function due to severe coronary artery disease should not categorically be denied surgery, and that operation can be done with a low hospital mortality rate and good functional results.

Adult↗

PubMed2000

Absence of functional lymphatics within a murine sarcoma: a molecular and functional evaluation.

Despite a clinically recognized association between the lymphatics and metastasis, the biology of tumor-lymphatic interaction is not clearly understood. We report here that functional lymphatic capillaries are absent from the interior of a solid tumor, despite the presence within the tumor of the lymphangiogenic molecule vascular endothelial growth factor (VEGF)-C and endothelial cells bearing its receptor, VEGF receptor 3. Functional lymphatics, enlarged and VEGF receptor 3 positive, were detected in some tumors only at the tumor periphery (within 100 microm of the interface with normal tissue). We conclude that although lymphangiogenic factors are present, formation of functional lymphatic vessels is prevented, possibly due to collapse by the solid stress exerted by growing cancer cells.

Animals↗

PubMed2000

Assessment of bone marrow stem cell reserve and function and stromal cell function in patients with autoimmune cytopenias.

To investigate whether bone marrow (BM) stem cell compartment and/or BM microenvironment are affected by the immune insult in autoimmune cytopenias (AICs), BM stem cell reserve and function and BM stromal function were studied in 15 AIC patients. Stem cells were evaluated by means of flow cytometry, clonogenic progenitor cell assays, long-term BM cultures (LTBMCs), and limiting dilution assay for quantification of long-term-culture initiating cells (LTC-ICs). Stromal cell function was assessed with the use of preformed irradiated LTBMCs from patients and normal controls, recharged with normal CD34(+) cells. AIC patients exhibited a high number of CD34(+), CD34(+)/CD38(+), and CD34(+)/CD38(-) cells; high frequency of granulocyte-macrophage colony forming units in the BM mononuclear cell fraction; high colony recovery in LTBMCs; and normal LTC-IC frequency. Patient BM stromal layers displayed normal hematopoietic-supporting capacity and increased production of granulocyte-colony stimulating factor. Data from this study support the concept that AIC patients with severe, resistant disease might be appropriate candidates for autologous stem cell transplantation.

ADP-ribosyl Cyclase↗

PubMed1975

[Breath rate as a function of parameters of pulmonary function in body plethysmography (author's transl)].

Parameters of pulmonary function were measured at resting breathing rates (mean 15-17/min) and at breathing rates of 20-40/min in 238 subjects (79 normals, 44 patients with normal pulmonary function in spite of lung disease, and 115 patients, most of whom had obstructive-emphysematous lesions) in a constantvolume body plethysmograph with a respiratory bag. In the subjects with normal pulmonary function the resistance increased significantly by 25 and 45 percent, resp., with more rapid respiration (p smaller than 0,01). Nevertheless it is assumed that this rarely accounts for false interpretations in everyday routine practice. No relationship of breathing rate to respiratory passage resistance was observed in patients with increased total resistance. By way of contrast, ventilation work of breathing (pV diagram) and the index of ventilation work of breathing (defined Vp ratio) showed a close correlation to breathing rate in all 3 groups. This leads us to conclude that these parameters provide more exact information on the breathing mechanism than does total resistance. Studies on ventilation work of breathing must be conducted under clearly defined breathing rates and consideration of the respiratory volume. intrathoracic gas volume was not correlated to the breath rate.

Adult↗

PubMed2000

Mutant p53: "gain of function" through perturbation of nuclear structure and function?

Mutant p53 not simply is an inactivated tumor suppressor, as at least some mutant p53 proteins exhibit oncogenic properties. Mutant p53 thus is the most commonly expressed oncogene in human cancer. Accordingly, the expression of mutant p53 in tumors often correlates with bad prognosis, and expression of mutant p53 in p53-negative tumor cells enhances their transformed phenotype. The molecular basis for this "gain of function" is not yet understood. However, the finding that mutant p53 tightly associates with the nuclear matrix in vivo, and with high affinity binds to nuclear matrix attachment region (MAR) DNA in vitro, suggests that these activities are connected and may result in perturbation of nuclear structure and function in tumor cells. MAR-binding of mutant p53 most likely is due to conformation-selective DNA binding by mutant p53, i.e. the specific interaction of a given mutant p53 protein with regulatory or structural genomic DNA elements that are able to adopt specific non-B-DNA conformations. In support to this assumption, human mutant p53 (Gly(245)-->Ser) was shown to bind to repetitive DNA elements in vivo that might be part of MAR elements. This further supports a model according to which mutant p53, by interacting with key structural components of the nucleus, exerts its oncogenic activities through perturbation of nuclear structure and function. J. Cell. Biochem. Suppl. 35:115-122, 2000.

Animals↗

PubMed2002

Functional interactions between estrogen and insulin-like growth factor-I in the regulation of alpha 1B-adrenoceptors and female reproductive function.

The ovarian hormone estradiol (E(2)) and insulin-like growth factor-I (IGF-I) interact in the CNS to regulate neuroendocrine function and synaptic remodeling. Previously, our laboratory showed that 2 d E(2) treatment induces alpha(1B)-adrenoceptor expression and promotes IGF-I enhancement of alpha(1)-adrenoceptor potentiation of cAMP accumulation in the preoptic area (POA) and hypothalamus (HYP). This study examined the hypothesis that E(2)-dependent aspects of female reproductive function, including alpha(1B)-adrenoceptor expression and function in the POA and HYP, are mediated by brain IGF-I receptors (IGF-IRs) in female rats. Ovariohysterectomized rats were implanted with a guide cannula aimed at the third ventricle and treated in vivo with vehicle or E(2) daily for 2 d before experimentation. Intracerebroventricular infusions of JB-1, a selective IGF-IR antagonist, were administered every 12 hr beginning 1 hr before the first E(2) injection. Administration of JB-1 during E(2) priming completely blocks hormone-induced luteinizing hormone release and partially inhibits hormone-dependent reproductive behavior. Reproductive behavior is restored by intracerebroventricular infusion of 8-bromo-cGMP, the second messenger implicated in alpha(1)-adrenergic facilitation of lordosis. In addition, blockade of IGF-IRs during E(2) priming prevents E(2)-induced increases in alpha(1B)-adenoceptor binding density and abolishes acute IGF-I enhancement of NE-stimulated cAMP accumulation in HYP and POA slices. These data document the existence of a novel mechanism by which IGF-I participates in the remodeling of noradrenergic receptor signaling in the HYP and POA after E(2) treatment. These events may help coordinate the timing of ovulation with the expression of sexual receptivity.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed2002

Effect of metabolic disorders accompanying gastroenteritis on the pancreatic exocrine function in piglets. B. Disturbances of the pancreatic exocrine function in piglets with gastroenteritis.

The study was performed on 90 piglets of both sexes, aged from 21 to 42 days. The control group consisted of 30 healthy piglets, the experimental one included 60 piglets with symptoms of gastroenteritis. Clinical and biochemical tests were performed on all the animals at the age of 21 and 35 days, and 7 days after weaning. Biochemical examinations allowed to determine the total serum activity of amylase and lipase, and the amylase salivary and pancreatic fractions. The total activity of amylase and lipase was also determined in pancreatic homogenates. A biochemical feces analysis (pH and fat content) and a D-xylose test were made in 20 piglets from each of the groups. The results obtained revealed failure of the pancreatic exocrine function in the piglets with gastroenteritis. A decrease in the total amylase activity, resulting from hypoactivity of its pancreatic fraction, was observed in the experimental animals. It was also found that indirect function tests cannot be applied to evaluate the pancreatic exocrine function in piglets with diarrhea.

Aging↗

PubMed2002

Functional heterogeneity in human olfactory cortex: an event-related functional magnetic resonance imaging study.

Studies of patients with focal brain injury indicate that smell perception involves caudal orbitofrontal and medial temporal cortices, but a more precise functional organization has not been characterized. In addition, although it is believed that odors are potent triggers of emotion, support for an anatomical association is scant. We sought to define the neural substrates of human olfactory information processing and determine how these are modulated by affective properties of odors. We used event-related functional magnetic resonance imaging (fMRI) in an olfactory version of a classical conditioning paradigm, whereby neutral faces were paired with pleasant, neutral, or unpleasant odors, under 50% reinforcement. By comparing paired (odor/face) and unpaired (face only) conditions, odor-evoked neural activations could be isolated specifically. In primary olfactory (piriform) cortex, spatially and temporally dissociable responses were identified along a rostrocaudal axis. A nonhabituating response in posterior piriform cortex was tuned to all odors, whereas activity in anterior piriform cortex reflected sensitivity to odor affect. Bilateral amygdala activation was elicited by all odors, regardless of valence. In posterior orbitofrontal cortex, neural responses evoked by pleasant and unpleasant odors were segregated within medial and lateral segments, respectively. The results indicate functional heterogeneity in areas critical to human olfaction. They also show that brain regions mediating emotional processing are differentially activated by odor valence, providing evidence for a close anatomical coupling between olfactory and emotional processes.

Adolescent↗

PubMed2003

Hand function in children with hemiplegic cerebral palsy: prospective follow-up and functional outcome in adolescence.

The aim of this prospective study was to determine the outcome of affected hand impairment and disability in a group of 31 children (16 males, 15 females) with hemiplegic cerebral palsy who were referred consecutively to our rehabilitation service and followed from a mean age of 2 years and 7 months to a mean age of 12 years and 9 months. The hand function assessment protocol consisted of video-recorded procedures: one to assess grip and the other to assess the extent of spontaneous use of the affected hand. Assessments at outset and at latest follow-up showed that the series as a whole had greater hand impairment in spontaneous manipulation than in gripping tasks. Comparison of hand function before age 4 years with the latest assessment over age 11 years revealed a non-significant improvement in grip, whereas spontaneous hand use remained stable. All but one of the children who had good grip and hand use scores at first assessment maintained them over time unless they were not treated for hand dysfunction. Among the children with low scores at outset, the improvement over time was more marked in grip than spontaneous hand use and occurred mainly in the early years. These results suggest that to evaluate the real disability of the affected hand in children with hemiplegia, grip assessment is insufficient and that an instrument assessing spontaneous hand use in bilateral manipulation is required. Furthermore, intensive treatment focused on hand function should be planned in the early years for children with more severe hand impairment, whereas regular follow-up is sufficient for less affected children.

Activities of Daily Living↗

PubMedDate not supplied

Translation, cross-cultural adaptation, and validation of the Bath Ankylosing Spondylitis Functional Index (BASFI), the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Dougados Functional Index (DFI) in a Spanish speaking population with spondyloarthropathies.

OBJECTIVES: The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Bath Ankylosing Spondylitis Functional Index (BASFI) and the Dougados Functional Index (DFI) are the most commonly used instruments to measure disease activity and functioning in ankylosing spondylitis (AS). The aim of this study was to translate, adapt and validate these instruments into the Spanish language. METHODS: The BASDAI, BASFI, and DFI questionnaires were translated into Spanish by three independent bilingual physicians who were familiar with the medical aspects of AS and by one professional translator. Two rheumatologists familiar with instrument validation, and who were aware of the purpose of the study, examined semantic, idiomatic and conceptual issues and produced by consensus unified versions of each instrument. English back-translations from the Spanish were done by a professional translator unaware of the original version. Both English versions were compared, and where needed, modifications to the Spanish versions were made. The Spanish versions were administered to 61 ambulatory patients with AS and to 80 patients with undifferentiated spondyloarthropathy for validation purposes. Reliability and responsiveness were measured in 28 patients participating in a physiotherapy program. RESULTS: Reliability showed an acceptable 24-hour test-retest intraclass correlation coefficient (ICC)--BASFI ICC: 0.68, 95% CI: 0.29-0.85; BASDAI ICC: 0.74, 95% CI: 0.52-0.88 and DFI ICC: 0.87, 95% CI: 0.73-0.94. The construct validity of the instruments was evaluated, and BASDAI was correlated with disease activity measured by the total enthesis count (rs: 0.34); general well being in the last week (rs: 0.7); spinal pain (rs: 0.53) and duration of morning stiffness (rs: 0.64). BASFI correlated with Schöber's test (rs: -0.4); occipital-wall distance (rs: 0.38) and thoracic expansion (rs: -0.3). DFI correlated with Schöber's test (rs: -0.36); occipital-wall distance (rs: 0.29) and chest expansion (rs: -0.3). The correlation among DFI and BASFI was rs: 0.83. All instruments showed clinical responsiveness in the physiotherapy program (baseline and end of program; mean +/- SD): BASDAI: 6.25 +/- 1.97 and 3.07 +/- 2.04 (p = 0.0001); BASFI: 5.68 +/- 2.29 and 2.88 +/- 1.77 (p = 0.0001); DFI: 16 +/- 7.6 and 8.0 +/- 5.5 (p = 0.001) with effect sizes and standardized effect sizes > 1. CONCLUSIONS: The Mexican Spanish versions of the BASDAI, BASFI, and DFI showed adequate reliability, validity and responsiveness to clinical change. These instruments can be used in the clinical evaluation of Spanish-speaking patients with AS.

Activities of Daily Living↗

PubMedDate not supplied

[Search for functional domain boundaries and localization of functional sites based on oligopeptide vocabularies].

A new method based on the analysis of oligopeptide composition of the amino acid sequences from different protein families is presented. We assume, that any protein family can be characterized by the set of oligopeptides (oligopeptides vocabulary). We demonstrate, that oligopeptides vocabulary comparison can distinguish different families from each other and from random sequences. It should be noted, that this comparison can be successfully performed on the set of only 25 dipeptides and without preliminary alignment. We demonstrate, that characteristic peptides are localized in the regions of functional significance, as shown on the example of GTP-binding domain of translation elongation factors. We suggest how to use this method to localize the boundaries of functional domains in amino sequences. On the example of few functional domains we demonstrate, that the average error of prediction does not exceed 3-4 amino acid residue.

Amino Acid Sequence↗

PubMed2003

Functional magnetic resonance imaging (fMRI) and effects of L-dopa on visual function in normal and amblyopic subjects.

PURPOSE: To evaluate the effects of a single dose of levodopa on visual cortex, based on functional MRI (fMRI), and on visual function, based on psychophysical tests, in amblyopic and normal subjects. METHOD: A prospective, randomized trial of a single dose of levodopa (2 mg/kg body weight) was undertaken in an institutional setting in nine normal and six amblyopic subjects, who were assessed at baseline and 90 minutes after levodopa ingestion. fMRI of occipital visual cortex was undertaken with a 1.5T GE MRI scanner utilizing the BOLD contrast technique. fMRI stimuli were two gratings (0.5, 2.0 cycles/degree of visual angle) that counterphased at 4 Hz. fMRI parameters for analysis included AREA and LEVEL of activation and a SUMMED score (AREA x LEVEL). Psychophysical tests included visual acuity, contrast sensitivity, stereoacuity, and binocular fusion. RESULTS: At baseline, AREA of activation (P = .05) and SUMMED score (P = .05) were significantly less in the amblyopic compared to the dominant eyes. Psychophysically, visual acuity and contrast sensitivity were significantly worse in the amblyopic eye. Following levodopa ingestion, there was significant decrease in LEVEL of activation in the amblyopic eye, even though visual acuity showed significant improvement (P = .03). Also, amblyopes showed a significant increase and normals showed some decrease in interocular difference in LEVEL of activation (P = .04). CONCLUSION: Unique information was obtained when fMRI was utilized to assess visual cortical function. While levodopa improved visual acuity in the amblyopic eye, it decreased the LEVEL of activation based on fMRI, a counterintuitive finding. The results highlight the value of utilizing fMRI to assess amblyopia and provide new directions for research.

Adult↗

PubMed2003

Gene duplication, the evolution of novel gene functions, and detecting functional divergence of duplicates in silico.

Duplication of genes increases the amount of genetic material on which evolution can work and has been considered of major importance for the development of biological novelties or to explain important transitions that have occurred during biological evolution. Recently, much research has been devoted to the study of the evolutionary and functional divergence of duplicated genes. Since the majority of genes are part of gene families, there is considerable interest in predicting differences in function between duplicates and assessing the functional redundancy of genes within gene families. In this review, we discuss the strengths and limitations of both older and novel approaches to investigate the evolution of duplicated genes in silico.

Algorithms↗

PubMed2004

The ER function BiP is a master regulator of ER function.

The endoplasmic reticulum (ER) is a command center of the cell that is second only to the nucleus in terms of the breadth of its influence on other organelles and activities. It is a major site of protein synthesis, contains the cellular calcium stores that are an essential component of many signaling pathways, and is the proximal site of a signal transduction cascade that responds to cellular stress conditions and serves to maintain homeostasis of the cell. All eucaryotic cells possess an ER, which can comprise nearly 50% of the membranes of a cell. Its functions can be divided into those that occur on the cytosolic side of the membrane (where protein translation and signal transduction cascades occur) and the luminal space (where most other ER functions take place). Our studies during the past several years have revealed that the ER molecular chaperone BiP is a master regulator of ER function. It is responsible for maintaining the permeability barrier of the ER during protein translocation, directing protein folding and assembly, targeting misfolded proteins for retrograde translocation so they can be degraded by the proteasome, contributing to ER calcium stores, and sensing conditions of stress in this organelle, to activate the mammalian unfolded protein response.

Adaptation, Physiological↗