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Biomedical subjects

T Carr

Publications and source records attributed to T Carr.

At least 19 recordsLinked to original sources
PubMed2000

Donor bone marrow from a sibling with inborn error of metabolism for treatment of acute leukaemia - clinical and biochemical consequences in the non-affected recipient.

Bone marrow transplantation (BMT) is increasingly used in an attempt to correct inborn errors of metabolism (IEM). However, little is known about effects of BMT from patients with IEM donating for non-affected recipients. We present data from a 8.5-year-old girl who underwent BMT in second remission for relapsed acute lymphoblastic leukaemia (ALL) at the age of 7 years from her HLA-identical brother who was severely affected by Hunter syndrome (Mucopolysaccharidosis type II, iduronate-2-sulphatase (IDS) deficiency). After BMT not only leukocyte but also plasma activity of IDS was absent. Mixing experiments and immunoadsorption suggest antibody-mediated enzyme inhibition. However, her urinary glycosaminoglycan excretion has not increased post BMT and clinical signs of mucopolysaccharidosis are absent 20 months after BMT. We conclude that patients with white cell enzyme deficiencies and other IEMs do not have to be excluded from bone marrow donation. Antibody production by the graft may occur and be reflected by a marked reduction in plasma enzyme levels but not tissue activity. Similar antibody responses resulting in enzyme inactivation might also affect other enzyme replacement strategies for individuals with IEM.

Acute Disease↗
PubMed1999

Culture of human renal tubular cells: positive selection of kallikrein-containing cells.

Human renal tubular cells derived from nephrectomy specimens were maintained in culture and grown to confluence. Immunocytochemistry, using a panel of antibodies selected for their ability to bind to different cell types within the nephron, showed the cells to be predominantly of epithelial origin with no significant contamination by fibroblasts or cells of endothelial origin. Ten to thirty percent of the cells expressed the putative distal marker, epithelial membrane antigen (EMA), a finding confirmed by flow cytometry. Cells expressing EMA were positively selected from mixed cultures by magnetic activated cell sorting (MACS). Kallikrein activity, expressed as mU/10(6) cells, in the EMA +ve cells, was increased fourfold to sixfold when compared with that in the EMA -ve cells. Cultures of characterized human renal tubular cells and sub-populations enriched with distal cells should prove useful in studies of synthesis and release of parameters of the kallikrein kinin system (KKS) to physiological stimuli. Furthermore, a better understanding of the toxic effect on the KKS of clinically useful drugs, particularly those used for immunosuppression, may lead to therapeutic interventions to lessen unwanted effects.

Cell Culture Techniques↗
PubMed1999

A 1H-decoupled 31P chemical shift imaging study of medicated schizophrenic patients and healthy controls.

BACKGROUND: Current 31P spectroscopy research in schizophrenia has examined phospholipid metabolism by measuring the sum of phosphomonoesters and the sum of phosphodiester-containing molecules. Proton decoupling was implemented to measure the individual phosphomonoester and phosphodiester components. This is the first study employing this technique to examine schizophrenic patients. METHODS: Multivoxel two-dimensional chemical shift in vivo phosphorous-31 magnetic resonance spectroscopy with proton decoupling was used to examine a 50-cm3 volume in prefrontal, motor, and parieto-occipital regions in the brain. Eleven chronic medicated schizophrenic patients were compared to 11 healthy controls of comparable gender, education, parental education, and handedness. RESULTS: A significant increase in the mobile phospholipid peak area and its full width at half maximum was observed in the medicated schizophrenic patients compared to the healthy controls in the prefrontal region. Inorganic orthophosphate and phosphocholine were lower in the schizophrenic group in the prefrontal region. CONCLUSIONS: The increased sum of phosphodiester [mobile phospholipid + glycerol-3-phosphoethanolamine (GPEth) + glycerol-3-phosphocholine (GPCh)] in schizophrenic patients, measured in earlier studies, arises from the phospholipid peak (MP) and not the more mobile phosphodiesters (GPEth, GPCh) as was originally suspected. A decrease in the phosphocholine component of the phosphomonoesters was also observed in the schizophrenic patients. These findings are consistent with an abnormality in membrane metabolism in the prefrontal region in schizophrenics.

Adult↗
PubMed1997

Peptide aldehyde inhibitors of cathepsin K inhibit bone resorption both in vitro and in vivo.

We have shown previously that cathepsin K, a recently identified member of the papain superfamily of cysteine proteases, is expressed selectively in osteoclasts and is the predominant cysteine protease in these cells. Based upon its abundant cell type-selective expression, potent endoprotease activity at low pH and cellular localization at the bone interface, cathepsin K has been proposed to play a specialized role in osteoclast-mediated bone resorption. In this study, we evaluated a series of peptide aldehydes and demonstrated that they are potent cathepsin K inhibitors. These compounds inhibited osteoclast-mediated bone resorption in fetal rat long bone (FRLB) organ cultures in vitro in a concentration-dependent manner. Selected compounds were also shown to inhibit bone resorption in a human osteoclast-mediated assay in vitro. Chz-Leu-Leu-Leu-H (in vitro enzyme inhibition Ki,app = 1.4 nM) inhibited parathyroid hormone (PTH)-stimulated resorption in the FRLB assay with an IC-50 of 20 nM and inhibited resorption by isolated human osteoclasts cultured on bovine cortical bone slices with an IC-50 of 100 nM. In the adjuvant-arthritic (AA) rat model, in situ hybridization studies demonstrated high levels of cathepsin K expression in osteoclasts at sites of extensive bone loss in the distal tibia. Cbz-Leu-Leu-Leu-H (30 mg/kg, intraperitoneally) significantly reduced this bone loss, as well as the associated hind paw edema. In the thyroparathyriodectomized rat model, Cbz-Leu-Leu-Leu-H inhibited the increase in blood ionized calcium induced by a 6 h infusion of PTH. These data indicate that inhibitors of cathepsin K are effective at reducing osteoclast-mediated bone resorption and may have therapeutic potential in diseases of excessive bone resorption such as rheumatoid arthritis or osteoporosis.

Aldehydes↗
PubMed1997

Italo-Canadian mothers' beliefs surrounding cause and treatment/cure of childhood disabilities.

A qualitative design was used to explore Italo-Canadian beliefs about the cause and treatment/cure of childhood disabilities. A convenience sample of eight second-generation Italo-Canadian mothers of children with moderate to severe disabilities was recruited through a pediatric rehabilitation centre in Southern Ontario. The mothers were interviewed using open-ended questions that served as probes to stimulate their thoughts and feelings. Data analysis proceeded concomitantly with data collection, and consisted of content analysis. Three major categories of traditional causation beliefs were identified: (a) punishment for past wrongdoing, (b) "bad blood" caused by intermarriage or a family curse, and (c) supernatural forces such as mal'occhio (the evil eye). The major category identified for cure of childhood disability was magico-religious healing. These traditional beliefs were described by the mothers to be strongest among first-generation Italo-Canadians, especially grandparents. The mothers themselves expressed their acceptance of some of these beliefs, but only minimal acceptance of or resistance to others. Based on this study, it would be premature to formulate implications for practice; however, several directions for future research are identified.

Adult↗
PubMed1996

Molecular analysis of HLA-DQB1 alleles in childhood common acute lymphoblastic leukaemia.

Epidemiological studies suggest that childhood common acute lymphoblastic leukaemia (c-ALL) may be the rare outcome of early post-natal infection with a common infectious agent. One of the factors that may determine whether a child succumbs to c-ALL is how it responds to the candidate infection. Since immune responses to infection are under the partial control of (human leucocyte antigen) HLA genes, an association between an HLA allele and c-ALL could provide support for an infectious aetiology. To define the limit of c-ALL susceptibility within the HLA region, we have compared HLA-DQB1 allele frequencies in a cohort of 62 children with c-ALL with 76 newborn controls, using group-specific polymerase chain reaction (PCR) amplification, and single-strand conformation polymorphism (SSCP) analysis. We find that a significant excess of children with c-ALL type for DQB1*05 [relative risk (RR): 2.54, uncorrected P=0.038], and a marginal excess with DQB1*0501 (RR: 2.18; P=0.095). Only 3 of the 62 children with c-ALL have the other susceptibility allele, DPB1*0201 as well as DQB1*0501, whereas 15 had one or the other allele. This suggests that HLA-associated susceptibility may be determined independently by at least two loci, and is not due to linkage disequilibrium. The combined relative risk of the two groups of children with DPB1*0201 and/or DQB1*0501 is 2.76 (P=0.0076). Analysis of amino acids encoded by exon 2 of DQB1 reveal additional complexity, with significant (P<0.05) or borderline-significant increases in Gly26, His30, Val57, Glu66-Val67 encoding motifs in c-ALL compared with controls. Since these amino acids are not restricted to DQB1*0501, our results suggest that, as with DPB1, the increased risk of c-ALL associated with DQB1 is determined by specific amino acid encoding motifs rather than by an individual allele. These results also suggest that HLA-associated susceptibility to c-ALL may not be restricted to the region bounded by DPB1 and DQB1.

Alleles↗
PubMed1995

Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein.

Alzheimer's disease (AD) is the most common cause of progressive intellectual failure in aged humans. AD brains contain numerous amyloid plaques surrounded by dystrophic neurites, and show profound synaptic loss, neurofibrillary tangle formation and gliosis. The amyloid plaques are composed of amyloid beta-peptide (A beta), a 40-42-amino-acid fragment of the beta-amyloid precursor protein (APP). A primary pathogenic role for APP/A beta is suggested by missense mutations in APP that are tightly linked to autosomal dominant forms of AD. A major obstacle to elucidating and treating AD has been the lack of an animal model. Animals transgenic for APP have previously failed to show extensive AD-type neuropathology, but we now report the production of transgenic mice that express high levels of human mutant APP (with valine at residue 717 substituted by phenylalanine) and which progressively develop many of the pathological hallmarks of AD, including numerous extracellular thioflavin S-positive A beta deposits, neuritic plaques, synaptic loss, astrocytosis and microgliosis. These mice support a primary role for APP/A beta in the genesis of AD and could provide a preclinical model for testing therapeutic drugs.

Alzheimer Disease↗
PubMed1995

Preliminary evidence of an association between HLA-DPB1*0201 and childhood common acute lymphoblastic leukaemia supports an infectious aetiology.

It has been suggested that childhood leukaemia may be the abnormal outcome of a common infection. Rare events caused by common environmental events such as infections are likely to be influenced by host genetic susceptibility. We have therefore investigated whether immunogenetic susceptibility contributes to the risk of childhood common ALL (c-ALL). In this preliminary study, we report that children with c-ALL (n = 63) carry the HLA-DPB1 locus allele *0201 twice and nearly three times more frequently than adult (n = 92; relative risk (RR) = 2.9, P < 0.05) or infant controls (n = 82; RR = 2.1). Moreover, children with c-ALL are 3-4 times more likely than controls to be heterozygous for DPB1*0201/*0301, /*0401 and /*0402 (RRadult controls = 3.9; RRinfant controls = 2.8). These results suggest that HLA-DPB1*0201 either alone or with other DPB1 alleles contributes to the risk of childhood c-ALL, possibly by increasing susceptibility to an infectious agent.

Adolescent↗
PubMed1994

Systolic anterior motion of the mitral valve after valve repair without an annular ring.

A 78-year-old woman underwent mitral reconstruction, consisting of a quadrangular posterior leaflet resection without a concomitant annular ring, for symptomatic mitral regurgitation. Postoperatively she became hypotensive while being treated with dopamine. Transesophageal echocardiography revealed systolic anterior motion of the mitral valve with significant mitral regurgitation. With discontinuation of the dopamine regimen, institution of phenylephrine administration, and volume loading of the ventricle the systolic anterior motion disappeared as did the mitral regurgitation. The patient recovered uneventfully.

Aged↗
PubMed1994

An intron-containing tRNAArg gene within a large cluster of human tRNA genes.

The insert within lambda Ht363, a recombinant selected from a bank of human genomic DNA cloned in lambda Ch4A, is described. Southern blot hybridization with a mixed tRNA[32P]pCp probe revealed the presence of four tRNA genes, which were shown to represent further copies of genes previously identified as a solitary tRNAGly gene and as a three gene cluster on two different recombinants. In vitro transcription of a fragment containing the three gene cluster revealed the presence of a further pol III gene, which was shown to be that for a tRNAArgTCT. This gene contains a 15 bp intron, the presence of which presumably prevented its detection on Southern blots by tRNA hybridisation. The gene is present in the previously reported cluster and occurs in higher copy number (> 7) in other arrangements in the genome. Most of the copies of the gene have related intron sequences.

Base Sequence↗
PubMed1993

The conformation of tRNA genes. Chemical modification studies.

It has been suggested that eukaryotic tRNA genes might adopt a higher order stem and loop structure to facilitate transcription by interaction of their variably spaced intragenic promoter blocks. Using sodium bisulphite, which reacts specifically with cytosine residues in single-stranded nucleic acids, no deamination of C in the TTCGAA sequence of the 3' ICR of a tRNA(Leu) gene could be detected under conditions which caused 60% deamination of cytosine residues within the loop region of a synthetic cruciform cloned in the same negatively supercoiled plasmid vector. We conclude that, under these conditions, such structures occur in tRNA genes very rarely, if at all.

DNA, Superhelical↗
PubMed1993

Control-related beliefs and self-reported depressive symptoms in late childhood.

Research thus far links depressive symptoms in children to one type of control-related belief: low levels of perceived personal competence. However, child research, unlike adult research, has not supported a linkage between depressive symptoms and another theoretically important control-related belief: perceived noncontingency of outcomes. Here we reexamined the issue, adjusting for limitations in previous methodology by using (a) psychometrically stronger measures of control beliefs, and (b) a general population sample rather than children being treated in mental health clinics. In contrast to previous results, we found that both perceived incompetence and perceived noncontingency were strongly related to children's depression, together accounting for 40% of the variance in Child Depression Inventory scores. We also found, as in previous research, that depressive symptoms were correlated with uncertainty as to the causes of outcomes, especially successes. The findings suggest that children may be susceptible to both "personal helplessness" and "universal helplessness" forms of depression.

Child↗
PubMed1992

Frontal, temporal, and striatal proton relaxation times in schizophrenic patients and normal comparison subjects.

Spin-lattice (T1) and spin-spin (T2) magnetic resonance relaxation times were examined in frontal, temporal, and striatal regions of 24 patients with schizophrenia and 10 normal comparison subjects. The schizophrenic patients had more prolonged T2 values than did the comparison subjects, particularly in the left temporal cortex and white matter, suggesting tissue pathology.

Adult↗