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Biomedical subjects

S Smith

Publications and source records attributed to S Smith.

At least 217 records · Page 12Linked to original sources
PubMed2000

Analysis of ovariectomy and estrogen effects on body composition in rats by X-ray and magnetic resonance imaging techniques.

Resistance of bone to fracture--bone strength--has been shown to depend on both the amount of bone and its architectural spatial organization. In vivo magnetic resonance (MR) techniques have the capability of imaging bone tissue, including the trabecular microarchitecture and the marrow composition. We have applied in vivo and ex vivo MR methods to the tibia in an ovariectomized rat model of osteoporosis. Specifically, in vivo high-resolution three-dimensional MR imaging and localized MRS were facilitated by specialized coils and high field magnets, resulting in enhanced sensitivity of detection. As a result, in vivo and ex vivo differences in marrow composition were found between sham-ovariectomized, ovariectomized, and ovariectomized animals treated with 17-beta-estradiol. Estrogen effects were detected in vivo 7 days after surgery (3 days into treatment) as a decrease in the tibial fat signal level. The in vivo effects of ovariectomy were observed 56 days after surgery as an increase in MR image fat signal level and spectral fat/water ratio in the proximal tibia. Ex vivo measurements of tibial marrow water signal discriminated clearly between the sham and ovariectomized groups and showed increased individual variations in the treatment group. Imaging further showed that the highest fat content is observed in the epiphysis. Computed tomography confirmed ovariectomy-induced loss of bone in the proximal tibial metaphysis compared with the sham group. This loss of cancellous bone with ovariectomy is consistent with the MR observations of increases in both fat and water in the metaphysis. These data showed that MR techniques complement X-ray techniques in the bone, water, and fat compositional analysis of the appendicular skeleton in response to ovariectomy and pharmacological treatment.

Adipose Tissue↗
PubMed2000

Evaluation of infants with subdural hematoma who lack external evidence of abuse.

OBJECTIVE: Advances in radiologic technique have increased the recognition of subdural hematoma. No study to date has addressed the role of child protective investigation into the cause and management of subdural hematoma in children who lack other indicators of abuse. METHODS: Medical records, radiology studies, and social service notes for all infants and children referred for child abuse investigation who had any form of intracranial hemorrhage were reviewed. The study covered the 12 months of 1997. All referrals were to the Suncoast Child Protection Team (St Petersburg, FL). RESULTS: There were 19 investigations because of subdural hematoma. Eight children had retinal hemorrhage as well as other major findings of trauma, such as bruises and/or fractures; all 8 were victims of child abuse. Two infants had tiny subdurals adjacent to accidental linear skull fractures. Nine infants were investigated for the possibility of abuse that had no findings of trauma apart from the subdural hematoma. These 9 cases form the basis for this study. The age range was 11 days to 15 months. Inflicted cerebral trauma was the medical diagnosis in 8 of the 9 cases; 1 case had a final diagnosis of possible inflicted injury in a high-risk setting. CONCLUSIONS: Infants with subdural hematoma but no other findings of abuse present a difficult challenge to child protection workers. Investigation by a medically oriented team can uncover the circumstances of the trauma in most instances and can usefully direct protective efforts. The high incidence of severe sequelae in infants with inflicted cerebral trauma warrants a vigorous approach.

Battered Child Syndrome↗
PubMed2000

Decreased insulin receptor tyrosine kinase activity and plasma cell membrane glycoprotein-1 overexpression in skeletal muscle from obese women with gestational diabetes mellitus (GDM): evidence for increased serine/threonine phosphorylation in pregnancy and GDM.

The cellular mechanisms for the insulin resistance of pregnancy and gestational diabetes mellitus (GDM) are unknown. The membrane protein plasma cell membrane glycoprotein-1 (PC-1) has been identified as an inhibitor of insulin receptor tyrosine kinase (IRTK) activity. We investigated insulin receptor function and PC-1 levels in muscle from three groups of obese subjects: women with GDM, pregnant women with normal glucose tolerance, and nonpregnant control subjects. Subjects (n = 6 for each group) were similar in age and degree of obesity (body fat >30%). IRTK activity, insulin receptor tyrosine phosphorylation, and protein levels of membrane glycoprotein PC-1 were determined in rectus abdominus muscle biopsies obtained at the time of either elective cesarean section or gynecological surgery. No significant differences were evident in basal insulin receptor tyrosine phosphorylation or IRTK activity in the three groups. After maximal insulin (10(-7) mol/l) stimulation, IRTK activity measured with the artificial substrate poly(Glu,Tyr) increased in all subjects but was lower in women with GDM by 25% (P < 0.05) and 39% (P < 0.001) compared with pregnant and nonpregnant control subjects, respectively. Similarly, insulin receptor tyrosine phosphorylation was significantly decreased in subjects with GDM (P < 0.05) compared with pregnant and nonpregnant control subjects. Treatment of the insulin receptors with alkaline phosphatase to dephosphorylate serine/threonine residues increased insulin-stimulated IRTK activity significantly in pregnant control and GDM subjects (P < 0.05), but these rates were still lower compared with nonpregnant control subjects (P < 0.05). PC-1 content in muscle from GDM subjects was increased by 63% compared with pregnant control subjects (P < 0.05) and by 206% compared with nonpregnant control subjects (P < 0.001). PC-1 content was negatively correlated with insulin receptor phosphorylation (r = -0.55, P < 0.05) and IRTK activity (r = -0.66, P < 0.05). These results indicate that pregnant control and GDM subjects had increased PC-1 content and suggest excessive phosphorylation of serine/threonine residues in muscle insulin receptors and that both may contribute to decreased IRTK activity. These changes worsen in women with GDM when controlling for obesity. These postreceptor defects in insulin signaling may contribute to the pathogenesis of GDM and the increased risk for type 2 diabetes later in life.

Alkaline Phosphatase↗
PubMed2000

Neural transplantation cannula and microinjector system: experimental and clinical experience. Technical note.

The authors present a simple, reliable, and safe system for performing neural transplantation in the human brain. The device consists of a transplantation cannula and microinjector system that has been specifically designed to reduce implantation-related trauma and to maximize the number of graft deposits per injection. The system was evaluated first in an experimental rat model of Parkinson's disease (PD). Animals in which transplantation with this system had been performed showed excellent graft survival with minimal trauma to the brain. Following this experimental stage, the cannula and microinjector system were used in eight patients with PD enrolled in the Halifax Neural Transplantation Program who received bilateral putaminal transplants of fetal ventral mesencephalic tissue. A total of 16 transplantation operations and 64 trajectories were performed in the eight patients, and there were no intraoperative or perioperative complications. Magnetic resonance imaging studies obtained 24 hours after surgery revealed no evidence of tissue damage or hemorrhage. Transplant survival was confirmed by fluorodopa positron emission tomography scans obtained 6 and 12 months after surgery. As neural transplantation procedures for the treatment of neurological conditions evolve, the ability to deliver viable grafts safely will become critically important. The device presented here has proved to be of value in maximizing the number of graft deposits while minimizing implantation-related trauma to the host brain.

Animals↗
PubMed2000

Quantitative pathological evidence for axonal loss in normal appearing white matter in multiple sclerosis.

We assessed axonal loss in the normal appearing white matter of the corpus callosum in postmortem brains of patients with multiple sclerosis, using quantitative measures of both axonal density and white matter atrophy. The calculated total number of axons was reduced significantly (mean +/- SD, 5.4 x 10(7) +/- 3.1 x 10(7)) compared with normal controls (11.6 x 10(7) +/- 2.2 x 10(7), p = 0.001) with a reduction both in axonal density (median, 34%; range, 16-56%; p = 0.004) and area (mean +/- SD: multiple sclerosis, 584 +/- 170 mm2; controls, 871 +/- 163 mm2; p = 0.004). These results confirm substantial axonal loss in the normal appearing white matter and demonstrate that measures of both axonal density and white matter volume are necessary to appreciate the full extent of axonal loss.

Adult↗
PubMed2000

The motor cortex shows adaptive functional changes to brain injury from multiple sclerosis.

Although multiple sclerosis (MS) is an inflammatory demyelinating disease, there can be substantial axonal injury and loss. We therefore hypothesized that adaptive cortical changes may contribute to limiting functional impairment, particularly in the early stages of the disease. To test our hypothesis, we used functional magnetic resonance imaging (MRI) to characterize the localization and volumes of activation in the motor cortex during simple flexion-extension finger movements. There were differences in the patterns of cortical activation with movement between the 12 MS patients and the 12 normal controls. All patients showed greater relative supplementary motor area activation than did the normal controls. The relative hemispheric lateralization of sensorimotor cortex (SMC) activation decreased in direct proportion to the total cerebral T2-weighted MRI hyperintense lesion load. This appeared to be due primarily to increases in ipsilateral SMC activation with increasing lesion load in white matter of the hemisphere contralateral to the limb moved. The center of activation in the contralateral SMC was shifted a mean of 8.8 mm posterior in patients relative to controls, providing additional evidence for cortical adaptive responses to injury. The magnitude of this posterior shift in the SMC activation increased with greater T2 lesion loads. These observations demonstrate that cortical recruitment for simple finger movements can change both quantitatively and qualitatively in the SMCs of MS patients, suggesting that cortical reorganization or "unmasking" of latent pathways can contribute to functional recovery. These adaptive changes are another factor potentially limiting the strength of the relationship between MRI measures of pathology and clinical measures of disability.

Adaptation, Physiological↗
PubMed1999

Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis.

BACKGROUND: Multiple sclerosis results from T-cell-dependent inflammatory demyelination of the central nervous system. Our objective was long-term suppression of inflammation with short-term monoclonal antibody treatment. METHODS: We depleted 95% of circulating lymphocytes in 27 patients with multiple sclerosis by means of a 5-day pulse of the humanised anti-CD52 monoclonal antibody, Campath-1H. Clinical and haematological consequences of T-cell depletion, and in-vitro responses of patients' peripheral-blood mononuclear cells were analysed serially for 18 months after treatment. FINDINGS: Radiological and clinical markers of disease activity were significantly decreased for at least 18 months after treatment. However, a third of patients developed antibodies against the thyrotropin receptor and carbimazole-responsive autoimmune hyperthyroidism. The depleted peripheral lymphocyte pool was reconstituted with cells that had decreased mitogen-induced proliferation and interferon gamma secretion in vitro. INTERPRETATION: Campath-1H causes the immune response to change from the Th1 phenotype, suppressing multiple sclerosis disease activity, but permitting the generation of antibody-mediated thyroid autoimmunity.

Adult↗
PubMed1999

Early switch from intravenous to oral antibiotics and early hospital discharge: a prospective observational study of 200 consecutive patients with community-acquired pneumonia.

UNLABELLED: To determine the proportion of patients who can be treated with early switch to oral antibiotics and early discharge, to evaluate clinical outcome and patient satisfaction for patients treated with early switch and early discharge, and to define the factors that interfere with early discharge for some of the patients who underwent early switch to oral antibiotic therapy. DESIGN: Prospective study. PARTICIPANTS: Two hundred consecutive hospitalized patients with community-acquired pneumonia. MAIN OUTCOME MEASURES: Number of days needed to switch to oral therapy and length of hospital stay. Clinical outcome and satisfaction with care were evaluated for those patients treated with early switch and early discharge. RESULTS: Early switch to oral antibiotics (within the first 3 days of hospitalization) was performed in 133 patients (67%). Clinical failure was documented in 1 patient. Early switch and early discharge was performed in 88 patients (44%). The mean length of hospital stay for this group was 3.4 days. The most common reason for prolonged hospitalization after the switch to oral antibiotics was the need for diagnostic workup. More than 95% of patients were satisfied with the care they had received. CONCLUSIONS: Using simple clinical and laboratory criteria, a significant proportion of hospitalized patients with community-acquired pneumonia (44%) can be treated with early switch and early discharge. This model did not affect patient outcome, decreased the length of hospitalization, and was associated with a high level of patient satisfaction.

Administration, Oral↗
PubMed1999

The orienting response in schizophrenia and mania.

We examined skin conductance (SCR) and finger pulse amplitude response (PULSE) in 53 schizophrenic, 30 manic, and 28 control subjects to provide information on orienting response (OR) dysfunction in severe psychiatric disorders. SCR and PULSE to neutral and task-relevant tones were measured in acutely ill inpatients and normal control subjects on two occasions separated by a 3-week interval. There were no significant group differences in proportions of SCR and PULSE non-responders to neutral tones. PULSE frequency to task-relevant tones in both the schizophrenic and manic patients was lower than that for the control subjects in both OR sessions, but did not differ significantly between patient groups. Although PULSE frequency was inversely related to neuroleptic dose in the schizophrenia sample, reanalysis of unmedicated patients did not change our results. OR frequency to task-relevant but not to neutral tones exhibited test-retest reliability. Certain aspects of OR dysfunction may overlap in schizophrenia and bipolar disorder. Our failure to demonstrate excessive OR non-responding to neutral tones in schizophrenia patients is inconsistent with many previous studies but may be due to a high proportion of OR non-responders among the control subjects.

Acoustic Stimulation↗
PubMed1999

Cellular localization of dopamine-releasing protein (DARP) in rat C6 glioma and primary mesencephalic cell cultures.

Dopamine-releasing protein (DARP) is a multisubunit protein shown to have dramatic effects on development, recovery, and function of the rat catecholaminergic (CA) system. This study details efforts to determine if glial cells are responsible for the production of DARP in the central nervous system (CNS). Enzyme-linked immunosorbent assays (ELISA), Western blotting, and immunocytochemical techniques were employed to measure DARP levels and identify DARP immunoreactive proteins in rat C6 glioma cells and medium, respectively. ELISA analysis of serum-free C6 culture media revealed a maximal concentration of DARP by culture day 1. However, ELISA analysis of C6 cultures grown in F-12K/serum medium revealed that maximal levels of DARP were detected on culture day 6 with a 108% increase in DARP immunoreactivity from culture day 1. These values were determined using a polyclonal antibody generated against DARP-36aa (anti-DARP-36aa), a synthetic peptide with dopamine (DA) releasing activity, and anti-DARP B9-B10, a monoclonal antibody generated against partially purified DARP. Western blot analysis revealed that anti-DARP B9-B10 recognized proteins of approximately 60, 50, and 45 kDa in C6 cell homogenates while anti-DARP-36aa had immunoreactivity with the 60-kDa protein alone. Immunocytochemical studies demonstrated that anti-DARP-36aa and anti-DARP B9-B10 had strong immunoreactivity with proteins throughout the cytosol and in several processes of C6 cells. These results reveal that DARP is detected in glioma cells and secreted in a time-dependent fashion during culture. Primary rat mesencephalic cultures were also examined using immunocytochemistry. Incubation with DARP antibodies and antisera against glial fibrillary acidic protein (GFAP) revealed that DARP and GFAP immunoreactivity co-localized in primary mesencephalic cultures. However, the majority of DARP immunoreactivity was localized to cells without GFAP staining. These findings reveal that DARP is detected in astrocytes although the majority of DARP immunoreactivity is found in non-astrocyte type cells.

Animals↗
PubMed1999

Conversion of a beta-ketoacyl synthase to a malonyl decarboxylase by replacement of the active-site cysteine with glutamine.

beta-Ketoacyl synthases involved in the biosynthesis of fatty acids and polyketides exhibit extensive sequence similarity and share a common reaction mechanism, in which the carbanion participating in the condensation reaction is generated by decarboxylation of a malonyl or methylmalonyl moiety; normally, the decarboxylation step does not take place readily unless an acyl moiety is positioned on the active-site cysteine residue in readiness for the ensuing condensation reaction. Replacement of the cysteine nucleophile (Cys-161) with glutamine, in the beta-ketoacyl synthase domain of the multifunctional animal fatty acid synthase, completely inhibits the condensation reaction but increases the uncoupled rate of malonyl decarboxylation by more than 2 orders of magnitude. On the other hand, replacement with Ser, Ala, Asn, Gly, and Thr compromises the condensation reaction without having any marked effect on the decarboxylation reaction. The affinity of the beta-ketoacyl synthase for malonyl moieties, in the absence of acetyl moieties, is significantly increased in the Cys161Gln mutant compared to that in the wild type and is similar to that exhibited by the wild-type beta-ketoacyl synthase in the presence of an acetyl primer. These results, together with modeling studies of the Cys --> Gln mutant from the crystal structure of the Escherichia coli beta-ketoacyl synthase II enzyme, suggest that the side chain carbonyl group of the Gln-161 can mimic the carbonyl of the acyl moiety in the acyl-enzyme intermediate so that the mutant adopts a conformation analogous to that of the acyl-enzyme intermediate. Catalysis of the decarboxylation of malonyl-CoA requires the dimeric form of the Cys161Gln fatty acid synthase and involves prior transfer of the malonyl moiety from the CoA ester to the acyl carrier protein domain and subsequent release of the acetyl product by transfer back to a CoA acceptor. These results suggest that the role of the Cys --> Gln beta-ketoacyl synthases found in the loading domains of some modular polyketide synthases likely is to act as malonyl, or methylmalonyl, decarboxylases that provide a source of primer for the chain extension reactions catalyzed by associated modules containing fully competent beta-ketoacyl synthases.

3-Oxoacyl-(Acyl-Carrier-Protein) Synthase↗
PubMed1999

Functional analysis of the N-terminal CXXC metal-binding motifs in the human Menkes copper-transporting P-type ATPase expressed in cultured mammalian cells.

The Menkes protein (MNK) is a copper-transporting P-type ATPase, which has six highly conserved metal-binding sites, GMTCXXC, at the N terminus. The metal-binding sites may be involved in MNK trafficking and/or copper-translocating activity. In this study, we report the detailed functional analysis in mammalian cells of recombinant human MNK and its mutants with various metal-binding sites altered by site-directed mutagenesis. The results of the study, both in vitro and in vivo, provide evidence that the metal-binding sites of MNK are not essential for the ATP-dependent copper-translocating activity of MNK. Moreover, metal-binding site mutations, which resulted in a loss of ability of MNK to traffick to the plasma membrane, produced a copper hyperaccumulating phenotype. Using an in vitro vesicle assay, we demonstrated that the apparent K(m) and V(max) values for the wild type MNK and its mutants were not significantly different. The results of this study suggest that copper-translocating activity of MNK and its copper-induced relocalization to the plasma membrane represent a well coordinated copper homeostasis system. It is proposed that mutations in MNK which alter either its catalytic activity or/and ability to traffick can be the cause of Menkes disease.

Adenosine Triphosphatases↗