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PubMed2006

The impact of early childhood lead exposure on brain organization: a functional magnetic resonance imaging study of language function.

OBJECTIVES: The purpose of this work was to assess the long-term impact of childhood lead exposure on the neurosubstrate of language function and brain organization. METHODS: Young adults from the Cincinnati Lead Study were recruited to undergo functional magnetic resonance image scanning while performing a verb generation task. These subjects have been followed from birth through early childhood with extensive documentation of lead exposure, neuropsychology, and behavior. Forty-two subjects provided useful imaging data. The locale, strength, and the correlation between brain language activation and childhood blood lead concentration were studied. RESULTS: After adjusting for potential confounders, the activation in left frontal cortex, adjacent to Broca's area, and left middle temporal gyrus, including Wernicke's area, were found to be significantly associated with diminished activation in subjects with higher mean childhood blood lead levels, whereas the compensatory activation in the right hemisphere homolog of Wernicke's area was enhanced in subjects with higher blood lead levels. CONCLUSION: This study indicates that childhood lead exposure has a significant and persistent impact on brain reorganization associated with language function.

Adult↗

PubMed1995

Functional human hepatocytes: isolation from small liver biopsy samples and primary cultivation with liver-specific functions.

Morphologically and functionally intact human hepatocytes were isolated from small liver biopsy samples weighing about 1-2 g by initial digestion with collagenase followed by repeated digestions with trypsin. The usual yield of hepatocytes was greater than 1 x 10(7) cells per g of liver sample and cell viability, as judged by dye exclusion test, was routinely over 90%. The isolated human hepatocytes showed intact morphology under scanning electron microscope. Formation of membrane protrusions upon phalloidin addition demonstrated that the actin in isolated hepatocytes was maintained with its structural integrity. The cultured human hepatocytes retained a variety of liver-specific functions which were similarly exhibited by rat hepatocytes isolated using the same procedure. The cultured human hepatocytes exhibited a specific cytochrome P-450 related enzyme activity, and active amino acid uptake that increased upon addition of hormones like glucagon and dexamethasone. Additionally, the cultured human hepatocytes synthesized DNA actively and, human serum albumin, and was found to be responsive to modulation by growth modulating hormones, cytokines and hepatotoxic agents. Based on the profile of activity described above, the presently established conditions for isolation and culturing of human hepatocytes demonstrate that functional liver cells can be obtained from small biopsied liver samples.

Albumins↗

PubMed2005

Functional MR cholangiography: diagnosis of functional abnormalities of the gallbladder and biliary tree.

OBJECTIVE: Our objective was to describe the technique and utility of functional MR cholangiography (fMRC) in the evaluation of the gallbladder and biliary tree. CONCLUSION: FMRC has the potential to provide a comprehensive examination for the anatomic and functional assessment of the gallbladder and biliary tree. Complex anatomic abnormalities and functional disorders can be shown by fMRC, including biliary obstruction and extravasation.

Biliary Tract↗

PubMed1998

Longitudinal observation of pulmonary function decline in male Japanese workers: design, baseline results, and methodological considerations of handling pulmonary function data.

To investigate the possible work-relatedness of obstructive lung disorders, 402 male Japanese employees who had continued to work in two natural mineral fiber processing factories (97% of the total number of employees) were first surveyed in 1985 and 1986. Follow-up surveys were repeated essentially annually until 1995. The surveys included forced spirometry and questionnaires concerning respiratory status. Pulmonary function in 328 workers could be examined acceptably for three years or more with at least three acceptable survey results. Correlation analyses clearly indicated that second-order height proportional values should be used to standardize conventional spirometric indices for subjects' body size difference. No consistent association was observed between pulmonary function values and room temperature at the time of measurement. Within-subject coefficient of variations of forced expiratory volume in one second and forced vital capacity were as low as 2% to 3% for data one year apart. Those coefficients of variations were almost constant throughout the entire study period. It seems critically important to minimize the measurement error of forced expiration maneuvers and keep it constant throughout all of the surveys, by striving to control the quality of pulmonary function data.

Adult↗

PubMed1995

The contributions of proprioceptive deficits, muscle function, and anatomic laxity to functional instability of the ankle.

Functional instability is a common complication following an acute ankle sprain. Three potential contributing factors underlying the ankle which chronically gives way are proprioceptive deficits, muscle weakness, and ligamentous laxity. This study's purpose was to document the presence or absence of these concerns in a sample of subjects with unilateral functional ankle instability. Both ankles of 42 subjects were randomly assessed for passive movement sense into inversion and generation of peak torque by the evertors isokinetically. Thirty-four subjects were available for documentation of talar tilt of both ankles through inversion stress radiographs. Analysis found significantly greater mean values for passive movement sense and talar tilt for the involved ankles compared with the uninvolved, while no significant strength differences in peak torque of the evertors were present. Fifty-eight percent of the sample demonstrated clinical impairments in at least one of these three categories. In conclusion, deficits in passive movement sense and anatomic stability are greater concerns than strength deficits when managing the ankle with functional instability.

Adolescent↗

PubMed2005

Disability and walking capacity in patients with lumbar spinal stenosis: association with sensorimotor function, balance, and functional performance.

STUDY DESIGN: One-group, prospective, cross-sectional study. OBJECTIVES: To determine how sensorimotor function, balance, and physical performance are associated with disability and walking capacity in patients with lumbar spinal stenosis. BACKGROUND: Disability and limited walking capacity are often reported by patients with lumbar spinal stenosis. Identification of associated factors could provide information for future investigations leading to better prevention and intervention strategies. METHODS AND MEASURES: Fifty patients with lumbar spinal stenosis answered questions regarding symptom intensity, disability, and walking capacity. Muscle strength and vibration sense were assessed to represent sensorimotor function. Balance ability was measured by single-leg stance time and basic physical performance was tested by the up-and-go (UG) test. Regression analyses, entering demographics and symptom intensity as control variables, and sensory, strength, balance, and physical performance as additional independent variables, were conducted separately for disability and walking capacity. RESULTS: Symptom intensity, vibration sense at the big toe, and UG test time were significantly correlated with disability. The final regression model showed that the control variables explained 20% of the variance, while vibration sense and UG test time explained an additional 20% of the variance. Walking capacity was significantly correlated with vibration sense at the big toe and UG test time. No significant regression model emerged for walking capacity. CONCLUSIONS: A moderate amount of variance in disability could be explained by sensory function at the big toe and physical performance. These factors should be considered in future research.

Aged↗

PubMed1994

Effects of indomethacin on renal function in normotensive patients with chronic glomerulonephritis with preserved renal function.

Thirteen normotensive patients with biopsy verified chronic glomerulonephritis (GN) with preserved renal function and 12 healthy control subjects (CS) were studied before and during prostaglandin synthesis inhibition by indomethacin. Glomerular filtration rate (GFR), renal plasma flow (RPF), urinary output (V), sodium excretion (UNa V), fractional lithium excretion (FELi), plasma levels of angiotensin II (Ang II), aldosterone (Aldo), atrial natiuretic peptide (ANP), arginine vasopressin (AVP) and endothelin (ir-ET) and urinary excretion rates of PGE2, mean blood pressure (MBP) and heart rate (HB) were determined on two separate occasions at least 7 days apart. During basal conditions without indomethacin administration no significant differences were found between the two groups. Indomethacin administration (100 mg 12 h and 1 h before clearance investigations) resulted in significant and almost identical decreases in GFR, RPF, V, UNa V, FELi and HR and increases in MBP in both the GN group and the CS group. It is concluded that normotensive patients with a biopsy verified chronic glomerulonephritis but with preserved renal function and without nephrotic syndrome have no increased risk of acute deterioration of renal function during administration of a non-steroidal anti-inflammatory drug compared with healthy control subjects.

Adult↗

PubMed1993

Functional dyspepsia versus other functional gastrointestinal disorders: a practical approach in Belgian general practices.

This paper identifies the symptom profile associated with the four main diagnoses of functional digestive disorders (dyspepsia, gastro-oesophageal reflux disease (GORD), gastritis, and constipation) made by general practitioners in Belgium. Results are also presented from a multicentre study in which the effects of cisapride, administered as an oral tablet or suspension, were evaluated in patients with these functional digestive disorders. Analysis of symptom patterns revealed that early satiety and postprandial abdominal bloating were the most prominent symptoms, followed by eructation (belching), heartburn, regurgitation, postprandial epigastric burning or discomfort, and nausea. These symptoms occurred in all diagnostic groups. However, different symptom patterns were associated with each of the disorders; for example, heartburn and regurgitation were the core symptoms in patients diagnosed as having GORD, early satiety and abdominal bloating were characteristic of patients diagnosed with dyspepsia, and fasting or postprandial pain were characteristic of patients given the diagnosis of gastritis. Therefore, it appears that these diagnoses used by general practitioners in Belgium closely correspond to reflux-like, dysmotility-like and ulcer-like dyspepsia, as defined by an international working party. Cisapride improved the core symptoms in about 80% of patients with GORD or dyspepsia, relieved all epigastric symptoms in about 80% of patients with gastritis, and significantly decreased the use of laxatives and increased stool frequency in constipated patients. Cisapride was well tolerated and thus appears to be a useful option in the treatment of functional digestive disorders in a general practice setting.

Adult↗

PubMed1985

Deterioration of renal function during angiotensin converting enzyme inhibition in hypertensive patients with a poorly functioning solitary kidney.

During treatment with the angiotensin converting enzyme inhibitor, Captopril, glomerular filtration rate (GFR) decreased in three unilaterally nephrectomized hypertensive patients with a poorly functioning remaining kidney. The fall in GFR was not related to changes in the blood pressure, and was reversed when Captopril was stopped. In a fourth nephrectomized patient the initially normal GFR was not affected by captopril. These observations point to a functional reduction in GFR due to a withdrawal of an intrarenal action of angiotensin II. Maintenance of GFR may become critically dependent on a functioning renin-angiotensin system when renal perfusion pressure is reduced to a certain degree. Inhibition of angiotensin II formation may lead to a decrease in GFR in patients with renal hypertension and pre-existing renal insufficiency.

Aged↗

PubMed1994

Distinctive electrophysiological characteristics of functionally discrete brain areas: a tenable approach to functional localization.

The direct cortical response (DCR), an electrical potential recorded in the immediate vicinity of a surface cortical stimulus, shows a configuration in the primary sensory areas of animals that is different from the one observed in association cortex. This suggested the possibility that systematic study of the DCR in the human brain might reveal a profile of configurations in which the form of the response provides functional information about the gyri being tested. Studies were carried out in subhuman primates and in patients undergoing surgery for tumors, occult vascular malformations, and epilepsy. In the animals, DCR's from somatosensory, motor, and association cortex are distinguishable; however, there are no differences in configuration between motor and premotor responses, or between association responses from prefrontal and parietal cortex. In patients with epilepsy due to nonspace-occupying pathology, the responses did not show distinguishing features. In contrast, in the patients with tumors or occult vascular malformations, DCR's from somatosensory, motor, and premotor cortex could be readily distinguished from each other. Responses along the mid and posterior sylvian fissure of the dominant hemisphere also had distinctive features, but more data are needed before the significance of this finding with respect to language function can be assessed. The accumulating results suggest that analysis of DCR's may prove to be a useful method for functional localization in individuals with focal space-taking pathology.

Animals↗

PubMed2001

Localization of human frontal eye fields: anatomical and functional findings of functional magnetic resonance imaging and intracerebral electrical stimulation.

OBJECT: The goal of this study was to investigate the anatomical localization and functional role of human frontal eye fields (FEFs) by comparing findings from two independently conducted studies. METHODS: In the first study, 3-tesla functional magnetic resonance (fMR) imaging was performed in 14 healthy volunteers divided into two groups: the first group executed self-paced voluntary saccades in complete darkness and the second group repeated newly learned or familiar sequences of saccades. In the second study, intracerebral electrical stimulation (IES) was performed in 38 patients with epilepsy prior to surgery, and frontal regions where stimulation induced versive eye movements were identified. These studies showed that two distinct oculomotor areas (OMAs) could be individualized in the region classically corresponding to the FEFs. One OMA was consistently located at the intersection of the superior frontal sulcus with the fundus of the superior portion of the precentral sulcus, and was the OMA in which saccadic eye movements could be the most easily elicited by electrical stimulation. The second OMA was located more laterally, close to the surface of the precentral gyrus. The fMR imaging study and the IES study demonstrated anatomical and stereotactic agreement in the identification of these cortical areas. CONCLUSIONS: These findings indicate that infracentimetric localization of cortical areas can be achieved by measuring the vascular signal with the aid of 3-tesla fMR imaging and that neuroimaging and electrophysiological recording can be used together to obtain a better understanding of the human cortical functional anatomy.

Adult↗

PubMed2004

Searching for motor functions in dysgenic cortex: a clinical transcranial magnetic stimulation and functional magnetic resonance imaging study.

OBJECT: Cortical motor organization/reorganization was studied in patients with malformation of cortical development (MCD) by applying two noninvasive motor mapping techniques: transcranial magnetic stimulation (TMS) and functional magnetic resonance (fMR) imaging. METHODS: Eight patients (age range 6-22 years), all suffering from congenital hemiparesis of similar severity, were included. Underlying lesions were schizencephalies in four cases, nonschizencephalic polymicrogyria in one, and complex hemispheric malformations in three. All MCDs involved rolandic cortex of the hemisphere contralateral to the hemiparesis. Transcranial magnetic stimulation was used to search, in both hemispheres, for brain regions with corticospinal projections to the paretic hand, and cortical activation during simple repetitive movements of the paretic hand was monitored using fMR imaging. Transcranial magnetic stimulation identified abnormal ipsilateral corticospinal projections from the contralesional hemisphere to the paretic hand in six of eight patients, in all of whom fMR imaging activation of the contralesional hand area was demonstrated during paretic hand movement. In two patients with schizencephaly in this subgroup, additional activation was shown in the affected hemisphere, located in dysgenic cortex lining the schizencephalic clefts but without TMS evidence for corticospinal projections originating from these sites. Corticospinal projections to the paretic hand originating in the MCD were identified in the remaining two patients, one with (nonschizencephalic) polymicrogyria and one with a complex hemispheric malformation. CONCLUSIONS: Malformations of cortical development can show various degrees of participation in motor functions, ranging from corticospinal ("primary") motor control, to putative participation as "nonprimary" motor areas, to absence of evidence for any functional participation. This information can be obtained, noninvasively, using a combination of TMS and fMR imaging.

Adolescent↗

PubMed2006

Amino acid residues affecting drug pump function in Candida albicans--C. albicans drug pump function.

Membrane-located drug transporters are important components in the multidrug resistance of microbial cells and human tissues. In fungi, clinically important resistance to antifungal drugs most often results from the over-expression of efflux pump proteins in the plasma membrane of the resistant cell. This review describes studies of the ATP binding cassette (ABC) family of membrane efflux pumps in the opportunistic human pathogen Candida albicans and, in particular, examines how changes in the polypeptide sequence can affect pump function. The identification of amino acid residues affecting pump function can provide new insights into efflux pump mechanisms and the relationship between structure and function. Such information will be important for the design of pump inhibitors which could supplement existing antifungal drugs.

ATP-Binding Cassette Transporters↗

PubMedDate not supplied

Functional neuroanatomy in depressed patients with sexual dysfunction: blood oxygenation level dependent functional MR imaging.

OBJECTIVE: To demonstrate the functional neuroanatomy associated with sexual arousal visually evoked in depressed males who have underlying sexual dysfunction using Blood Oxygenation Level Dependent-based fMRI. MATERIALS AND METHODS: Ten healthy volunteers (age range 21-55: mean 32.5 years), and 10 depressed subjects (age range 23-51: mean 34.4 years, mean Beck Depression Inventory score of 39.6+/-5.9, mean Hamilton Rating Scale Depression (HAMD)-17 score of 33.5+/-6.0) with sexual arousal dysfunction viewed erotic and neutral video films during functional magnetic resonance imaging (fMRI) with 1.5 T MR scanner (GE Signa Horizon). The fMRI data were obtained from 7 oblique planes using gradient-echo EPI (flip angle/TR/TE= 90 degrees /6000 ms/50 ms). The visual stimulation paradigm began with 60 sec of black screen, 150 sec of neutral stimulation with a documentary video film, 30 sec of black screen, 150 sec of sexual stimulation with an erotic video film followed by 30 sec of black screen. The brain activation maps and their quantification were analyzed by SPM99 program. RESULTS: There was a significant difference of brain activation between two groups during visual sexual stimulation. In depressed subjects, the level of activation during the visually evoked sexual arousal was significantly less than that of healthy volunteers, especially in the cerebrocortical areas of the hypothalamus, thalamus, caudate nucleus, and inferior and superior temporal gyri. On the other hand, the cerebral activation patterns during the neutral condition in both groups showed no significant differences (p < 0.01). CONCLUSION: This study is the first demonstration of the functional neuroanatomy of the brain associated with sexual dysfunction in depressed patients using fMRI. In order to validate our physiological neuroscience results, further studies that would include patients with other disorders and sexual dysfunction, and depressed patients without sexual dysfunction and their treatment response are needed.

Adult↗

PubMed2000

Exclusive Th2 primary effector function in spleens but mixed Th1/Th2 function in lymph nodes of murine neonates.

Recent studies have shown that neonatal mice are competent to develop mature, Ag-specific Th1 function in situ. However, under many conditions, Th2 responses dominate in the neonate, while Th1 responses are more prevalent in adults. To compare further the immune responses of neonates and adults, we used the enzyme-linked immunospot method to measure the frequencies of primary Th1/Th2 effectors generated in situ in the spleens and lymph nodes. As assessed by the detection of IFN-gamma- or IL-4-producing cells, adults developed mixed Th1/Th2 responses in both organs. Neonatal lymph nodes contained mature frequencies of IFN-gamma- and IL-4-producing cells. In striking contrast, while mature frequencies of Th2 cells developed in neonatal spleens, virtually no IFN-gamma-secreting cells were detected. Exclusive Th2 function was observed in both BALB/c and C57BL/6 neonates, strains in which the Th2 and Th1 lineages, respectively, are favored in adults. Although Th1 effectors were virtually undetectable, the addition of rIL-12 boosted the frequency of IFN-gamma-secreting cells to adult levels. Therefore, Th1 effectors apparently developed in situ, but Th1 effector function either was not promoted or was inhibited upon subsequent exposure to the Ag in culture. Together, these results indicate that the quality of a primary Th response in neonates is strongly dependent on the site of initial Ag exposure; responses initiated in the lymph nodes are mixed Th1/Th2, whereas responses occurring in the spleen are heavily Th2 biased.

Animals↗

PubMed2003

Variations in eosinophil chemokine responses: an investigation of CCR1 and CCR3 function, expression in atopy, and identification of a functional CCR1 promoter.

We previously showed in a small group of donors that eosinophils from a subgroup of individuals responded equipotently to CC chemokine ligand (CCL)11/eotaxin and CCL3/macrophage-inflammatory protein-1alpha in assays of eosinophil shape change (CCL3/macrophage-inflammatory protein-1alpha-highly responsive (MHR) donors). In this study, we investigated the functional role of CCL3 in eosinophil responses in 73 donors. MHR donors, identified by their eosinophil shape change responses, represented approximately 19% of the donor pool. Eosinophils from these donors showed increased eosinophil CCR1 expression and also underwent CCL3-mediated chemotaxis and up-regulation of CD11b. All MHR donors gave a history of atopy-associated diseases. In a further study, we prospectively recruited 110 subjects, subdivided into nonatopics or atopics, and investigated expression of CCR1 and CCR3 on eosinophils, basophils, monocytes, and neutrophils. Eosinophil CCR1 expression was non-normally distributed in atopics, although higher CCR1 expression levels were not predictive of a diagnosis of atopy or atopic disease. We identified the CCR1 promoter and investigated its function. We found a minimal promoter within 177 bp of the transcription start site, and an upstream enhancer region that facilitated expression in leukocyte cell lines. Collectively, these data demonstrate that MHR individuals form an important subgroup that, when associated with a diagnosis of allergic disease, may require tailored therapy to modulate eosinophil recruitment. Identification of a functional CCR1 promoter will facilitate the study of possible genetic determinants underlying this potentially important clinical phenotype.

Adolescent↗

PubMed2006

Structural basis of inducible costimulator ligand costimulatory function: determination of the cell surface oligomeric state and functional mapping of the receptor binding site of the protein.

Inducible costimulator (ICOS) ligand (ICOSL), a B7-related transmembrane glycoprotein with extracellular IgV and IgC domains, binds to ICOS on activated T cells and delivers a positive costimulatory signal for optimal T cell function. Toward determining the structural features of ICOSL crucial for its costimulatory function, the present study shows that ICOSL displays a marked oligomerization potential, resembling more like B7-1 than B7-2. Use of ICOSL constructs lacking either the IgC or IgV domain demonstrates that receptor binding is mediated solely by the IgV domain but requires the IgC domain for maintaining the structural integrity of the protein. To map further the receptor recognition surface on ICOSL, a homology-based protein structure model of the ICOS:ICOSL complex was constructed. Based on predictions from the model, a series of mutations were generated targeting the potential receptor binding surface on ICOSL, and the mutants were tested for their biological function in terms of ICOS binding and T cell costimulation ability. The results provide experimental validation of the model and show that the receptor binding site on ICOSL is constituted chiefly by aromatic/hydrophobic residues. Critical ICOSL residues essential for ICOS binding map to the GFCC'C'' beta-sheet face of the IgV domain and approximately overlap with the B7-1/B7-2 motif(s) that recognize CD28/CTLA-4. Altogether, similar structural features of ICOSL and B7 isoforms suggest a close evolutionary relationship between these costimulatory ligands, yet differences at the same time explain their unique specificity for the cognate binding partners, ICOS and CD28/CTLA-4, respectively.

Amino Acid Sequence↗

PubMedDate not supplied

Associations between static and functional measures of joint function in the foot and ankle.

Clinicians have traditionally assessed range of motion of the first metatarsophalangeal and ankle joints in a static position. It is unclear, however, if these measurements accurately reflect functional sagittal plane limitations of these joints during gait. For 50 patients (100 feet), we assessed available dorsiflexion at the first metatarsophalangeal and ankle joints, as well as the presence of pinch callus. We then compared these findings with 11 functional gait parameters, as measured using a pressure sensor system. After adjusting for age, weight, smoking status, glycosylated hemoglobin, and insensitivity to monofilament, we found that patients with pinch callus demonstrated statistically significant compensatory gait patterns in 7 of 11 measures. Hallux limitus and equinus patients demonstrated six and three statistically significant associations, respectively. Pinch callus seems to be as predictive of functional gait alterations as static first metatarsophalangeal joint and ankle dorsiflexion.

Aged↗