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Biomedical subjects

A Potter

Publications and source records attributed to A Potter.

At least 19 recordsLinked to original sources
PubMed2001

Permeability and route of entry for lipid-insoluble molecules across brain barriers in developing Monodelphis domestica.

1. We have studied the permeability of blood-brain barriers to small molecules such as [(14)C]sucrose, [(3)H]inulin, [(14)C]L-glucose and [(3)H]glycerol from early stages of development (postnatal day 6, P6) in South American opossums (Monodelphis domestica), using a litter-based method for estimating steady-state cerebrospinal fluid (CSF)/plasma and brain/plasma ratios of markers that were injected I.P. 2. Steady-state ratios for L-glucose, sucrose and inulin all showed progressive decreases during development. The rate of uptake of L-glucose into the brain and CSF, in short time course experiments (7-24 min) when age-related differences in CSF production can be considered negligible also decreased during development. These results indicate that there is a significant decrease in the permeability of brain barriers to small lipid-insoluble molecules during brain development. 3. The steady-state blood/CSF ratio for 3000 Da lysine-fixable biotin-dextran following I.P. injection was shown to be consistent with diffusion from blood to CSF. It was therefore used to visualise the route of penetration for small lipid-insoluble molecules across brain barriers at P0-30. The proportion of biotin-dextran-positive cells in the choroid plexuses declined in parallel with the age-related decline in permeability to the small-molecular-weight markers; the paracellular (tight junction) pathway for biotin-dextran appeared to be blocked, but biotin-dextran was easily detectable in the CSF. A transcellular route from blood to CSF was suggested by the finding that some choroid plexus epithelial cells contained biotin-dextran. 4. Biotin-dextran was also taken up by cerebral endothelial cells in the youngest brains studied (P0), but in contrast to the CSF, could not be detected in the brain extracellular space (i.e. a significant blood-brain barrier to small-sized lipid-insoluble compounds was already present). However, in immature brains (P0-13) biotin-dextran was taken up by some cells in the brain. These cells generally had contact with the CSF, suggesting that it is likely to have been the source of their biotin-dextran. Since the quantitative permeability data suggest that biotin-dextran behaves similarly to the radiolabelled markers used in this study, it is suggested that these markers in the more immature brains were also present intracellularly. Thus, brain/plasma ratios may be a misleading indicator of blood-brain barrier permeability in very immature animals. 5. The immunocytochemical staining for biotin-dextran in the CSF, in contrast to the lack of staining in the brain extracellular space, together with the quantitative permeability data showing that the radiolabelled markers penetrated more rapidly and to a much higher steady-state level in CSF than in the brain, suggests that lipid-insoluble molecules such as sucrose and inulin reach the immature brain predominantly via the CSF rather than directly across the very few blood vessels that are present at that time.

Algorithms↗
PubMed2001

Environmental sources and transmission of Escherichia coli O157 in feedlot cattle.

A study was conducted in 2 feedlots in southern Alberta to identify environmental sources and management factors associated with the prevalence and transmission of Escherichia coli O157:H7. Escherichia coli O157:H7 was isolated in preslaughter pens of cattle from feces (0.8%), feedbunks (1.7%), water troughs (12%), and incoming water supplies (4.5%), but not from fresh total mixed rations. Fresh total mixed rations did not support the growth of E. coli O157:H7 and E. coli from bovine feces following experimental inoculation. Within a feedlot, the feces, water troughs, and feedbunks shared a few indistinguishable subtypes of E. coli O157:H7. A few subtypes were repeatedly isolated in the same feedlot, and the 2 feedlots shared a few indistinguishable subtypes. The prevalence of E. coli O157:H7 in water troughs of preslaughter cattle in 1 feedlot was associated with season, maximum climatic temperatures the week before sampling; total precipitation the week before sampling, and coliform and E. coli counts in the water trough.

Alberta↗
PubMed2000

Randomised controlled trial of midwife led debriefing to reduce maternal depression after operative childbirth.

OBJECTIVE: To assess the effectiveness of a midwife led debriefing session during the postpartum hospital stay in reducing the prevalence of maternal depression at six months postpartum among women giving birth by caesarean section, forceps, or vacuum extraction. DESIGN: Randomised controlled trial. SETTING: Large maternity teaching hospital in Melbourne, Australia. PARTICIPANTS: 1041 women who had given birth by caesarean section (n= 624) or with the use of forceps (n= 353) or vacuum extraction (n= 64). MAIN OUTCOME MEASURES: Maternal depression (score >/=13 on the Edinburgh postnatal depression scale) and overall health status (comparison of mean scores on SF-36 subscales) measured by postal questionnaire at six months postpartum. RESULTS: 917 (88%) of the women recruited responded to the outcome questionnaire. More women allocated to debriefing scored as depressed six months after birth than women allocated to usual postpartum care (81 (17%) v 65 (14%)), although this difference was not significant (odds ratio=1.24, 95% confidence interval 0.87 to 1.77). They were also more likely to report that depression had been a problem for them since the birth, but the difference was not significant (123 (28%) v 94 (22%); odds ratio=1. 37, 1.00 to 1.86). Women allocated to debriefing had poorer health status on seven of the eight SF-36 subscales, although the difference was significant only for role functioning (emotional): mean scores 73.32 v 78.98, t= -2.31, 95% confidence interval -10.48 to -0.84). CONCLUSIONS: Midwife led debriefing after operative birth is ineffective in reducing maternal morbidity at six months postpartum. The possibility that debriefing contributed to emotional health problems for some women cannot be excluded.

Adult↗
PubMed2000

Fetuin in the developing neocortex of the rat: distribution and origin.

Immunocytochemical distribution of the fetal protein fetuin in the neocortex of developing rat brain and the presence of its mRNA, as detected by using reverse transcriptase-polymerase chain reaction analysis, was studied in fetuses at embryonic day 15 (E15) through E22, in neonates at postnatal day 0 (P0) through P20, and in adults. Quantitative estimates of fetuin in cerebrospinal fluid (CSF) and plasma were obtained over the same period. Exogenous (bovine) fetuin injected intraperitoneally into fetal and postnatal rats was used to study the uptake of fetuin into CSF and brain and its distribution compared with endogenous fetuin; bovine albumin was used as a control. Fetuin was identified immunocytochemically in the cortical plate and subplate cells of the developing neocortex. In the rat fetus, fetuin first was apparent at E17, mainly in cell processes, but a few subplate cells also were positive. By E18, there was strong staining in subplate neurons and in inner cells of the cortical plate. At E21, these inner cells of the cortical plate were beginning to differentiate into layer VI neurons, many of which were positive for fetuin. By P0-P1, more layer VI neurons and some layer V neurons had become positive for fetuin. Fetuin immunoreactivity generally was weaker at P1, and, by P2-P3, it had disappeared from all of the layers of the developing neocortex. Bovine fetuin (but not albumin), probably taken up through CSF over the neocortical dorsal surface, had a cytoplasmic distribution; endogenous rat fetuin was both cytoplasmic and membrane bound. Thus, much of this fetuin can be accounted for by uptake, although the presence of fetuin mRNA indicates that in situ synthesis may also contribute.

Animals↗
PubMed2000

Identification of two new Pmp22 mouse mutants using large-scale mutagenesis and a novel rapid mapping strategy.

Mouse mutants have a key role in discerning mammalian gene function and modelling human disease; however, at present mutants exist for only 1-2% of all mouse genes. In order to address this phenotype gap, we have embarked on a genome-wide, phenotype-driven, large-scale N-ethyl-N--nitrosourea (ENU) mutagenesis screen for dominant mutations of clinical and pharmacological interest in the mouse. Here we describe the identification of two similar neurological phenotypes and determination of the underlying mutations using a novel rapid mapping strategy incorporating speed back-crosses and high throughput genotyping. Two mutant mice were identified with marked resting tremor and further characterized using the SHIRPA behavioural and functional assessment protocol. Back-cross animals were generated using in vitro fertilization and genome scans performed utilizing DNA pools derived from multiple mutant mice. Both mutants were mapped to a region on chromosome 11 containing the peripheral myelin protein 22 gene (Pmp22). Sequence analysis revealed novel point mutations in Pmp22 in both lines. The first mutation, H12R, alters the same amino acid as in the severe human peripheral neuropathy Dejerine Sottas syndrome and Y153TER in the other mutant truncates the Pmp22 protein by seven amino acids. Histological analysis of both lines revealed hypo-myelination of peripheral nerves. This is the first report of the generation of a clinically relevant neurological mutant and its rapid genetic characterization from a large-scale mutagenesis screen for dominant phenotypes in the mouse, and validates the use of large-scale screens to generate desired clinical phenotypes in mice.

Animals↗
PubMed1999

Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following anti-TNF-alpha therapy in rheumatoid arthritis.

Treatment with a chimeric mAb to TNF-alpha has been shown to suppress inflammation and improve patient well-being in rheumatoid arthritis (RA), but the mechanisms of action of such treatment have not been fully explored. Here we show that in vivo administration of anti-TNF-alpha Ab, using a longitudinal analysis, results in the rapid down-regulation of a spectrum of cytokines, cytokine inhibitors, and acute-phase proteins. Marked diurnal variation in the serum levels of some of these were detected. These results were consistent with the concept of a cytokine-dependent cytokine cascade, and the degree of clinical benefit noted after anti-TNF-alpha therapy is probably due to the reduction in many proinflammatory mediators apart from TNF-alpha, such as IL-6, which reached normal levels within 24 h. Serum levels of cytokine inhibitors such as soluble p75 and p55 TNFR were reduced as was IL-1 receptor antagonist. Reductions in acute-phase proteins occurred after serum IL-6 fell and included serum amyloid A, haptoglobin, and fibrinogen. The latter reduction could be of importance, as it is a risk factor for atherosclerosis, which is augmented in RA patients.

Acute-Phase Proteins↗
PubMed1999

Apoptotic human lymphocytes have diminished CD4 and CD8 receptor expression.

We used quantitative multiparameter flow cytometric assays to simultaneously detect viable, apoptotic, and necrotic human peripheral blood mononuclear cells (PBMC) and immunophenotyped lymphocyte subsets within the PBMC. Apoptosis was induced by a spectrum of treatments, including camptothecin, cisplatin, dexamethasone, hyperthermia, staurosporine, and etoposide in anti-CD3 mAb-stimulated cells and by cyclohexamide in both quiescent and stimulated cells; apoptosis in the latter was augmented by anti-fas mAb. We found that CD4(+) and CD8(+) cells were significantly underrepresented in the apoptotic PBMC and that the percentage of CD4(+) and CD8(+) PBMC each markedly decreased as apoptosis increased. This suggested that surface expression of these receptors was lessened on apoptotic CD4(+) and CD8(+) cells. This was directly confirmed by observation of sorted CD4(+) PBMC. This analysis of a wide variety of apoptotic stimuli demonstrates that diminished CD4 and CD8 surface receptor expression is a common feature of human T lymphocyte apoptosis.

Apoptosis↗
PubMed1999

Acute effects of the selective cholinergic channel activator (nicotinic agonist) ABT-418 in Alzheimer's disease.

To explore further the potential for cognitive enhancement utilizing nicotinic stimulation in Alzheimer's disease (AD), six otherwise healthy subjects with moderate AD received placebo and three doses (6, 12, and 23 mg) of the novel selective cholinergic channel activator (ChCA) (nicotinic agonist) ABT-418 over 6 h in a double-blind, within-subjects, repeated-measures design. Subjects showed significant improvements in total recall and a decline in recall failure on a verbal learning task. Qualitatively similar improvements were seen in non-verbal learning tasks such as spatial learning and memory, and repeated acquisition. No significant behavioral, vital sign, or physical side effects were seen. These results confirm that stimulating central nicotinic receptors has acute cognitive benefit in AD patients. These findings suggest that selective ChCAs have a potential therapeutic role in dementing disorders, and that further studies with this or similar agents in AD and/or Parkinson's disease are warranted.

Aged↗
PubMed1999

Midwives in Victoria, Australia: a survey of current issues and job satisfaction.

OBJECTIVE: To describe demographic and work profiles of registered practising midwives, to assess their job satisfaction and their knowledge of and attitudes to the 1990 Victorian Birthing Services review. DESIGN: A questionnaire posted in 1995 to a population-based random sample of registered midwives. PARTICIPANTS: Two hundred and forty midwives currently using their midwifery skills in their work. SETTING: One thousand names and addresses were randomly selected from a database of midwives registered to practise in Victoria, Australia in 1993. FINDINGS: There was a 72% response rate to the postal questionnaire. Two hundred and forty practising midwives returned completed questionnaires. Seventy-three per cent were in full time employment, 49% lived in rural Victoria, 80% were born in Australia, more than half were aged 40 or more years and 72% had at least one child. Twenty-six per cent worked in postnatal wards, 9% in each the labour ward and the neonatal nursery, 2% in birthing centres and 12% in out of hospital settings. Eighty per cent were satisfied with their work and interactions with women were the most important aspect. Satisfaction was associated with working in a labour ward, feeling adequately prepared by midwifery education and training, nursing for more than 15 years and having continuing education. Neonatal and rotating positions were significantly associated with dissatisfaction. Less than one-half of the midwives had read some of the Birthing Services Review, and of these only one-half had changed their attitudes or practice. One-third knew little of the imminent changes to the Midwifery Regulations. CONCLUSION: Although most midwives enjoyed their work there was little evidence of increasing autonomy or involvement in change.

Adult↗
PubMed1998

Is baby too warm? The use of infant clothing, bedding and home heating in Victoria, Australia.

Overheating of infants has been associated with a raised risk for sudden infant death syndrome (SIDS). Data on the use of heating, bedding and clothing and other measures affecting the thermal environment of 4 week old infants were collected at a home interview for infants of women born in Australia (Anglo-Celtic background), in Southern Europe, in Asia and of women who had a planned out-of-hospital birth. These groups have different risks of SIDS not explained by the classic social and perinatal risk factors nor associated with the currently promoted 'new' risk factors. Thermal insulation of the infant's bedding and clothing and excess thermal insulation (for any observed room temperature) were calculated. Bed sharing differed significantly between the groups as did the use of a sheepskin, tucking in firmly, the closing of doors and windows and the use of heating in the infant's room. After stratifying by bed sharing practice and season of interview, it was found that bed sharing infants had more thermal insulation than those sleeping alone irrespective of season of interview. Infants sleeping alone in the Asian-born and Southern European-born groups were kept warmer than infants in the other two groups. Cultural factors appear to affect the thermal environment in which infants are raised. Some bed sharing infants in all four groups were inappropriately warm, particularly in colder weather, but this was more likely in the Asian-born (low risk) group than in the home birth (high risk) group. These results do not explain the differences in SIDS incidence between the groups.

Adult↗
PubMed1998

Development of walking, swimming and neuronal connections after complete spinal cord transection in the neonatal opossum, Monodelphis domestica.

Development of coordinated movements was quantitatively assessed in adult opossums (Monodelphis domestica) with thoracic spinal cords transected by (1) crushing 7-8 d after birth [postnatal days 7-8 (P7-P8)]; at 2-3 years of age, systematic behavioral tests (e.g., climbing, footprint analysis, and swimming) showed only minor differences between control (n = 5) and operated (n = 10) animals; and (2) cutting on P4-P6; at 1 month these opossums exhibited coordinated walking movements but were unable to right themselves from a supine position, unlike controls (n = 6). When tested at 2 or 6 months, they could right themselves and showed remarkable coordination, albeit with more differences from controls than after a crush. No animals with spinal cords that were crushed at P14-18 survived because of cannibalism by the mother. Morphological studies (n = 10) 3 months-3 years after crush at 1 week showed restoration of structural continuity and normal appearance at the lesion site. Animals with cut rather than crushed cords showed continuity but greater morphological deficits. That lesions were complete was demonstrated by examining morphology and nerve impulse conduction immediately after crushing or cutting the spinal cord in controls. After lumbar spinal cord injection of 10 kDa dextran amine, retrogradely labeled cells were found rostral to the lesion in hindbrain and midbrain nuclei. Conduction was restored across the site of the lesion. Thus complete spinal cord transection in neonatal Monodelphis was followed by development of coordinated movements and repair of the spinal cord, a process that included development of functional connections by axons that crossed the lesion.

Animals↗
PubMed1998

Advantages of impact testing over hardness testing in determining physical integrity of tablets.

An investigation of four different tablet strength tests was carried out on four different placebo formulations (differing in Avicel: Pharmatose ratios). The results analysis compared fatigue failure, work of failure, and impact failure to diametrical compression measurements (hardness). The impact results clearly show how different formulations can have the same hardness, yet their impact resistance can vary by as much as 200%. The impact test used in this work and other tests described are useful in tablet development to understand, compare, and mitigate tablet breakage during subsequent unit operations.

Cellulose↗
PubMed1997

TGF-beta receptor type II and fetuin in the developing sheep neocortex.

Fetuin shows a characteristic pattern of distribution in the developing neocortex in many mammalian species. Its expression is confined to early-appearing cortical-plate and later subplate neurons. A short 19 amino-acid sequence of fetuin shows a degree of homology to an 18 amino-acid sequence of the TGF-beta type II receptor (TbetaR-II) and in vitro fetuin binds to members of the TGF-beta family of cytokines. It has been suggested that fetuin is the biologically significant antagonist of these cytokines. We have compared, using immunocytochemistry, the distribution pattern of TbetaR-II and fetuin in the developing neocortex of foetal sheep. TbetaR-II immunoreactivity first appears at around 40 days of gestation in the fetal sheep (E40, term in sheep is 150 days from conception), localised in two discreet bands: one just outside the cortical plate in the inner part of the marginal zone and one deep in the cortical plate in what becomes the transient subplate zone. By E70-E80, TbetaR-II is prominent in a population of subplate cells, whereas, by E120 only small patches of TbetaR-II-positive cells are visible, principally in pyramidal cells in layer VI. The developmental sequence of the staining pattern for TbetaR-II in the neocortex is complementary to that for fetuin, rather than overlapping with it. Double-labelling of fetuin and TbetaR-II shows some cellular co-localisation, especially at E60, but most fetuin-positive cells are not immunoreactive for TbetaR-II. Thus, fetuin's proposed role as an antagonist of TGF-beta cytokines and mimic of TbetaR-II is not consistent with the observed distribution of these two molecules in the developing neocortex of the foetal sheep.

Animals↗
PubMed1997

Cytogenetic abnormalities and their prognostic significance in idiopathic myelofibrosis: a study of 106 cases.

The prognostic significance of cytogenetic abnormalities was determined in 106 patients with well-characterized idiopathic myelofibrosis who were successfully karyotyped at diagnosis. 35% of the cases exhibited a clonal abnormality (37/106), whereas 65% (69/106) had a normal karyotype. Three characteristic defects, namely del(13q) (nine cases), del(20q) (eight cases) and partial trisomy 1q (seven cases), were present in 64.8% (24/37) of patients with clonal abnormalities. Kaplan-Meier plots and log rank analysis demonstrated an abnormal karyotype to be an adverse prognostic variable (P<0.001). Of the eight additional clinical and haematological parameters recorded at diagnosis, age (P<0.01), anaemia (haemoglobin < or = 10 g/dl: P<0.001), platelet (< or = 100 x 10(9)/l, P<0.0001) and leucocyte count (> 10.3 x 10(9)/l; P=0.06) were also associated with a shorter survival. In contrast, sex, spleen and liver size, and percentage blast cells were not found to be significant. Multivariate analysis, using Cox's regression, revealed karyotype, haemoglobin concentration, platelet and leucocyte counts to retain their unfavourable prognostic significance. A simple and useful schema for predicting survival in idiopathic myelofibrosis has been produced by combining age, haemoglobin concentration and karyotype with median survival times varying from 180 months (good-risk group) to 16 months (poor-risk group).

Adult↗
PubMed1997

Genomic variation and gene conversion in spinal muscular atrophy: implications for disease process and clinical phenotype.

Autosomal recessive spinal muscular atrophy (SMA) is classified, on the basis of age at onset and severity, into three types: type I, severe; type II, intermediate; and type III, mild. The critical region in 5q13 contains an inverted repeat harboring several genes, including the survival motor neuron (SMN) gene, the neuronal apoptosis inhibitory protein (NAIP) gene, and the p44 gene, which encodes a transcription-factor subunit. Deletion of NAIP and p44 is observed more often in severe SMA, but there is no evidence that these genes play a role in the pathology of the disease. In > 90% of all SMA patients, exons 7 and 8 of the telomeric SMN gene (SMNtel) are not detectable, and this is also observed in some normal siblings and parents. Point mutations and gene conversions in SMNtel suggest that it plays a major role in the disease. To define a correlation between genotype and phenotype, we mapped deletions, using pulsed-field gel electrophoresis. Surprisingly, our data show that mutations in SMA types II and III, previously classed as deletions, are in fact due to gene-conversion events in which SMNtel is replaced by its centromeric counterpart, SMNcen. This results in a greater number of SMNcen copies in type II and type III patients compared with type I patients and enables a genotype/phenotype correlation to be made. We also demonstrate individual DNA-content variations of several hundred kilobases, even in a relatively isolated population from Finland. This explains why no consensus map of this region has been produced. This DNA variation may be due to a midisatellite repeat array, which would promote the observed high deletion and gene-conversion rate.

Centromere↗
PubMed1997

Anaemia of chronic disease in rheumatoid arthritis: in vivo effects of tumour necrosis factor alpha blockade.

Anaemia of chronic disease (ACD) is a common feature of active rheumatoid arthritis (RA). Inflammatory cytokines, particularly tumour necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1) and interleukin-6 (IL-6), are thought to contribute to the pathogenesis of ACD, possibly by inhibiting erythropoietin (EPO) production. In this study, we examined the in vivo effects of TNF-alpha blockade with a chimeric monoclonal antibody, cA2, on erythropoiesis in RA patients with ACD. Administration of cA2 led to a dose-dependent increase in haemoglobin levels compared to placebo and these changes were accompanied by a reduction in both EPO and IL-6 levels. The data support the notion that TNF-alpha is important in the causation of ACD, but suggest a mechanism independent of EPO suppression. Instead, TNF-alpha may act directly on bone marrow red cell precursors.

Anemia↗