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Biomedical subjects

P Moran

Publications and source records attributed to P Moran.

At least 55 records · Page 3Linked to original sources
PubMed1999

A human antibody that binds to the gamma-carboxyglutamic acid domain of factor IX is a potent antithrombotic in vivo.

10C12, a human antibody F(ab')2, which specifically binds to the Gla domain of factor IX, interfered with all known coagulation processes that involve factor IX/IXa. These include the function of the intrinsic Xase complex and the activation of zymogen factor IX by factor XIa and by the tissue factor:factor VIla complex. Furthermore, 10C12 potently inhibited activated partial thromboplastin clotting times (APTT) in plasma of guinea pig and rat, thus enabling in-vivo evaluation. In guinea pigs, a bolus administration of 10C12 (10 microg/kg) prevented cyclic flow variations in damaged carotid arteries without affecting coagulation or bleeding parameters. At a 100-fold higher dose, 10C12 had no effect on normal hemostasis as assessed by the cuticle bleeding time. At this dose, 10C12 was also efficacious in a rat arterial thrombosis model, substantially reducing clot weight and duration of vessel occlusion while prolonging ex-vivo APTT only 1.2-fold. The dose of heparin required to produce comparable antithrombotic effects prolonged the APTT by 12-fold and increased the tail bleeding time (TBT) by 8-fold. In contrast, 10C12 had no effect on TBT. However, rat tails showed a tendency for rebleeding which 10C12 exacerbated. In conclusion, the antithrombotic potency of the 10C12 antibody in two species provides evidence for an important role of F.IX, and its Gla domain in particular, during thrombogenesis under arterial flow conditions. The relative safety at effective doses of this fully human antibody suggests that it may have therapeutic value for treatment of thrombotic disorders.

1-Carboxyglutamic Acid↗
PubMed1998

Seasonal influences on admissions in schizophrenia and affective disorder in Ireland.

Although the seasonal patterns of admissions of affective disorder have been extensively studied, less attention has been given to the seasonal admission patterns of schizophrenia. The traditional method of aggregating the data over a study period, rather than analysing by year of admission may obscure potentially relevant fluctuations in the seasonal pattern. We examined the year-to-year variation in the admission patterns of schizophrenia and affective disorder in Ireland. Using the National Psychiatric Inpatient Reporting System (NPIRS), individuals admitted with an ICD-9/10 diagnosis of a first episode of schizophrenia or affective disorder during the 6-year period 1989-1994 were identified. Seasonal variations in their admission patterns were examined statistically and graphically. There was a significant seasonal variation in the monthly admission patterns of both schizophrenia and affective disorder. This pattern was more marked for individuals with affective disorder. However, the seasonal pattern was not constant from year to year, particularly for schizophrenia.

Humans↗
PubMed1998

Regulation of hippocampal synaptic plasticity by the tyrosine kinase receptor, REK7/EphA5, and its ligand, AL-1/Ephrin-A5.

The Eph-related tyrosine kinase receptor, REK7/EphA5, mediates the effects of AL-1/Ephrin-A5 and related ligands and is involved in the guidance of retinal, cortical, and hippocampal axons during development. The continued expression of REK7/EphA5 in the adult brain, in particular in areas associated with a high degree of synaptic plasticity such as the hippocampus, raises the question of its function in the mature nervous system. In this report we examined the role of REK7/EphA5 in synaptic remodeling by asking if agents that either block or activate REK7/EphA5 affect synaptic strength in hippocampal slices from adult mouse brain. We show that a REK7/EphA5 antagonist, soluble REK7/EphA5-IgG, impairs the induction of long-term potentiation (LTP) without affecting other synaptic parameters such as normal synaptic transmission or paired-pulse facilitation. In contrast, perfusion with AL-1/Ephrin-A5-IgG, an activator of REK7/EphA5, induces a sustained increase in normal synaptic transmission that partially mimics LTP. The sustained elevation of normal synaptic transmission could be attributable to a long-lasting binding of the AL-1/Ephrin-A5-IgG to the endogenous REK7/EphA5 receptor, as revealed by immunohistochemistry. Furthermore, maximal electrical induction of LTP occludes the potentiating effects of subsequent treatment with AL-1/Ephrin-A5-IgG. Taken together these results implicate REK7/EphA5 in the regulation of synaptic plasticity in the mature hippocampus and suggest that REK7/EphA5 activation is recruited in the LTP induced by tetanization.

Animals↗
PubMed1998

Protein targeting in the analysis of learning and memory: a potential alternative to gene targeting.

Gene targeting using homologous recombination in embryonic stem (ES) cells offers unprecedented precision with which one may manipulate single genes and investigate the in vivo effects of defined mutations in the mouse. Geneticists argue that this technique abrogates the lack of highly specific pharmacological tools in the study of brain function and behavior. However, by now it has become clear that gene targeting has some limitations too. One problem is spatial and temporal specificity of the generated mutation, which may appear in multiple brain regions or even in other organs and may also be present throughout development, giving rise to complex, secondary phenotypical alterations. This may be a disadvantage in the functional analysis of a number of genes associated with learning and memory processes. For example, several proteins, including neurotrophins--cell-adhesion molecules--and protein kinases, that play a significant developmental role have recently been suggested to be also involved in neural and behavioral plasticity. Knocking out genes of such proteins may lead to developmental alterations or even embryonic lethality in the mouse, making it difficult to study their function in neural plasticity, learning, and memory. Therefore, alternative strategies to gene targeting may be needed. Here, we suggest a potentially useful in vivo strategy based on systemic application of immunoadhesins, genetically engineered fusion proteins possessing the Fc portion of the human IgG molecule and, for example, a binding domain of a receptor of interest. These proteins are stable in vivo and exhibit high binding specificity and affinity for the endogenous ligand of the receptor, but lack the ability to signal. Thus, if delivered to the brain, immunoadhesins may specifically block signalling of the receptor of interest. Using osmotic minipumps, the protein can be infused in a localized region of the brain for a specified period of time (days or weeks). Thus, the location and timing of delivery are controlled. Here, we present methodological details of this novel approach and argue that infusion of immunoadhesins will be useful for studying the role particular receptors play in behavioral and neural plasticity.

Animals↗
PubMed1998

Predicting depression in women: the role of past and present vulnerability.

BACKGROUND: A prospective study, covering just over a 1-year period, sought to confirm an earlier finding that around 40% of women who experience a severe life event in the presence of two ongoing psychosocial vulnerability factors, (negative close relationships and low self-esteem) will develop a major depressive episode. Distal risk factors were examined to see if they improved prediction. METHODS: A population sample of 105 mainly working-class mothers with vulnerability and without depression were interviewed three times over a 14-month period to date the occurrence of severe life events and onset of major depression. Degree of vulnerability was assessed at first contact together with distal risk in terms of childhood neglect/abuse and any earlier episodes of depression. RESULTS: Thirty-seven per cent of these vulnerable women became depressed in the study period. The majority experienced a severe life event, and of these, 48% had onsets. Contrary to expectation, risk was only a little less among those with just one of the two vulnerability factors. Two-thirds of women with an onset had been depressed in previous years. Although this was associated with increased risk, the effect was greatest for those who had experienced an episode before age 20. A relationship between childhood neglect/abuse and onset was entirely accounted for by such early depression. CONCLUSION: An aetiological model of depression outlined in earlier research was confined with a new factor of teenage depression shown to increase risk of onset.

Adolescent↗
PubMed1997

Physical localization and characterization of the BglI element in the genomes of Atlantic salmon (Salmo salar L.) and brown trout (S. trutta L.).

This work describes chromosomal localization, fine physical mapping, and population variation of the BglI element in the genome of Atlantic salmon (Salmo salar L.) and a similar sequence in the genome of brown trout (S. trutta L.). Results from a variety of complementary approaches, clearly demonstrate that the BglI element does not occur as a satellite-like repetitive DNA in these species but is part of the rDNA cistron as suggested by Goodier and Davidson (1993). Coincident hybridization of BglI clones with rDNA loci in both single and double-probe fluorescence in situ hybridization (FISH) experiments demonstrated physical linkage between the BglI element and rDNA loci. Fine physical mapping by Southern analysis and PCR amplification showed the BglI element to be located approximately 1.6 kb upstream of the 18S gene. The BglI element was used to screen for population-specific markers by Southern analysis. Population-specific banding patterns were only observed in brown trout, allowing identification of individual populations of this species. Sequence comparisons revealed sequences similar to the BglI element present in the rDNA cistron of other salmonids. This result suggests the presence of this sequence in the genome of the salmonid tetraploid ancestor.

Animals↗
PubMed1997

Lerk2 (ephrin-B1) is a collapsing factor for a subset of cortical growth cones and acts by a mechanism different from AL-1 (ephrin-A5).

The transmembrane (TM) subfamily of Eph ligands and their receptors have been implicated in axon pathfinding and in pattern formation during embryogenesis. These functions are thought to involve repulsive interactions but this has not been demonstrated directly. In this study we used a growth cone collapse assay to determine if the TM ligands Lerk2 and HtkL have repellant guidance activity. We show that Lerk2, but not HtkL, is a collapsing factor for a subset of embryonic cortical neurons. Analysis of the effects of Lerk2 on both the morphology and the cytoskeleton of cortical neurons suggests a mechanism of action different from that of AL-1, a GPI-linked Eph ligand having similar repellant activity. Treatment with Lerk2 disrupts the organization of both the actin cytoskeleton and the microtubules and induces the formation of swellings in the center of the growth cone and along the axon. Measurement of the relative F-actin concentrations in the neurites and soma indicated that F-actin levels in the neurites decrease while those in the soma increase, with the net F-actin content of the neuron remaining unchanged. In contrast, we show that prolonged treatment with AL-1 leads to a net loss of F-actin, consistent with the hypothesis that AL-1 acts by perturbing actin polymerization. These results provide evidence that the ectodomain of Lerk2 functions as a repellant guidance cue and show that, despite overlapping specificities in vitro, the biological activities of related ligands are not necessarily overlapping. Further, TM and GPI-linked Eph ligands appear to exert repellant activity by different mechanisms, opening up the possibility that they may have different effects on growth cones in vivo.

Actins↗
PubMed1997

AL-1-induced growth cone collapse of rat cortical neurons is correlated with REK7 expression and rearrangement of the actin cytoskeleton.

Previous experiments identified AL-1 as a glycosylphosphatidylinositol (GPI)-linked ligand for the Eph-related receptor, REK7, and showed that a REK7-IgG fusion protein blocks axon bundling in co-cultures of cortical neurons on astrocytes, suggesting a role for REK7 and AL-1 in axon fasciculation. Subsequent identification of RAGS, the chick homologue of AL-1, as a repellent axon guidance molecule in the developing chick visual system led to speculation that AL-1, expressed on astrocytes, provides a repellent stimulus for cortical axons, inducing them to bundle as an avoidance mechanism. Using a growth cone collapse assay to test this hypothesis, we show that a soluble AL-1-IgG fusion protein is a potent collapsing factor for embryonic rat cortical neurons. The response is strongly correlated with REK7 expression, implicating REK7 as a receptor mediating AL-1-induced collapse. Morphological collapse is preceded by an AL-1-IgG-induced reorganization of the actin cytoskeleton that resembles the effects of cytochalasin D. This suggests a pathway whereby REK7 activation by AL-1 leads to perturbation of the actin cytoskeleton, possibly by an effect on actin polymerization, followed by growth cone collapse. We further show that AL-1-IgG causes collapse of rat hippocampal neurons and rat retinal ganglion cells. These data suggest a role for REK7 and AL-1 in the patterning of axonal connections in the developing cortex, hippocampus and visual system.

Actins↗
PubMed1997

Increased rate of psychosis among African-Caribbeans in Britain is not due to an excess of pregnancy and birth complications.

BACKGROUND: It has been suggested that the increased rate of psychotic illness among African-Caribbeans living in Britain is due to an excess of pregnancy and birth complications (PBCs). METHOD: We therefore compared the frequency of PBCs in a group of White psychotic patients (n = 103) and a comparable group of patients of African-Caribbean origin (n = 61); the latter consisted of 30 first-generation (born in the Caribbean) and 31 second-generation (born in Britain) individuals. RESULTS: White psychotic patients were more than twice as likely to have a history of PBCs as their African-Caribbean counterparts (odds ratio = 2.34, 95% confidence interval (CI) 0.88-6.47, P = 0.062). The same trend was observed among patients with a DSM-III diagnosis of schizophrenia (odds ratio = 1.65, 95% CI 0.56-4.97, P = 0.32). The rate of PBCs was similar among the first- and second-generation Caribbean psychotic patients. CONCLUSIONS: The increased rate of psychotic illness that has been reported among the African-Caribbean population in Britain is not due to an increased prevalence of PBCs.

Adult↗
PubMed1997

Prospective study of Entamoeba dispar infection in a cohort of mothers and their infants: relationship to serum antibody response.

The sera of cohorts of newborn infants and their mothers, characterized as cyst passers of Entamoeba with nonpathogenic zymodemes (E. dispar) and seropositive for amoebic antigens, were analyzed. Both cohorts were followed for a period of 12 months by microscopic examination of feces and determination of serum anti-amoebic antibody titers using the indirect hemagglutination assay. Control groups (noncyst passer mothers and their infants) were included and followed. To characterize antigens involved in the induction of IgG and IgA antibody responses, Western blots of serum from all participants were tested and immunoplots of the frequency of antigenic recognition were constructed. Results of clinical follow-up and microscopic examination of feces showed that during the 12-month period none of the cyst passer mothers had episodes of diarrhea attributable to E. histolytica invasion; five of 21 children of cyst passer mothers became infected during the study, five of five infected children developed serum antiamebic antibodies (titers 1:64-1:128); none of the cohort of children from cyst passer mothers had diarrhea due to E. histolytica. Western blot analysis showed that there are antigenic fractions that induce serum antibodies of the IgG and IgA classes against E. dispar very early in the host-parasite relationship. Our results suggest that mechanisms of antibody induction different from intestinal invasion may be operating in amebic infection. Intestinal absorption of antigen, systemic reflection of secretory antibody response, and priming of newborns by maternal anti-idiotypic antibody transfer are discussed.

Adult↗
PubMed1997

Contamination of traditional drinking water sources during a period of extreme drought in the Zvimba communal lands, Zimbabwe.

OBJECTIVES: Diarrhoeal disease is a significant public health concern in Zimbabwe, particularly for the population living in rural settings. The present study was undertaken to investigate the quality of water in a rural area of Zimbabwe during a period of extreme drought. DESIGN AND SETTING: A cross sectional survey study design was used. During the month of July 1995, water samples were collected from various actively used sources in the Zvimba communal lands, Zimbabwe. MAIN OUTCOME MEASURES: The level of contamination was estimated by use of the membrane filtration technique to detect the presence of Escherichia coli. RESULTS: Mean concentrations of E. coli found in boreholes and piped water were 9.3 and zero colonies per 100 ml, respectively. Using standardized criteria to define suitable drinking water quality, borehole and piped sources were determined to be more likely to provide satisfactory drinking water. CONCLUSIONS: Water samples collected from semi-protected and unprotected wells, which serve the majority of the population in the study area, were found to be unsatisfactory for drinking (range from two to 1,960 colonies of E. coli per 100 ml). Included are suggestions on how to efficiently utilize available water.

Cross-Sectional Studies↗
PubMed1996

Sex chromosome linkage of 5S rDNA in rainbow trout (Oncorhynchus mykiss).

The karyotype of the rainbow trout is characterized by a primitive XX/XY sex-determining chromosomal system. (Thorgaard et al., 1977). In the present study using FISH we have physically linked the 5S rRNA genes to the partially undifferentiated X chromosome pair. PCR amplified 5S rDNA was used for FISH and hybridization signals indicated that the genes were duplicated, present in one acrocentric and one metacentric pair of chromosomes. After analyzing several individuals, the female metaphases showed four fluorescent signals whereas males presented only three signals. Two of the three signals obtained in males corresponded to the metacentric pair whereas the single signal was mapped to the heterochromatin that cytologically differentiates the X chromosome from the Y chromosome. Double FISH experiments demonstrated that the 5S rDNA which is not sex linked is located at the NOR bearing arm close to the major ribosomal RNA genes (5.8S, 18S and 28S), similar to the situation observed in Atlantic salmon (Pendas et al., 1994a).

Animals↗
PubMed1996

Morbid risk of schizophrenia in first-degree relatives of white and African-Caribbean patients with psychosis.

BACKGROUND: The high rate of schizophrenia among the second-generation African-Caribbean population in Britain has prompted much concern and speculation. Sugarman and Craufurd have reported that the morbid risk in the siblings of second-generation African-Caribbean schizophrenic patients was unusually high compared with that of the siblings of White patients. METHOD: We sought to replicate these findings by comparing the morbid risk for schizophrenia in the first-degree relatives of 111 White and 73 African-Caribbean psychotic probands. The latter comprised 35 first-generation (born in the Caribbean) and 38 second-generation (born in Britain) probands. RESULTS: The morbid risk for schizophrenia was similar for the parents and siblings of White and first-generation African-Caribbean patients, and for the parents of the second-generation African-Caribbean probands. However, the siblings of second-generation African-Caribbean psychotic probands had a morbid risk for schizophrenia that was seven times that of their White counterparts (P = 0.007); similarly, the siblings of second-generation African-Caribbean schizophrenic probands had a morbid risk for schizophrenia that was four times that of their White counterparts (P = 0.05). CONCLUSIONS: These findings replicate those of the earlier report of Sugarman and Craufurd, and suggest either that the second-generation African-Caribbean population in Britain is particularly vulnerable to some environmental risk factors for schizophrenia, or that some environmental factors act selectively on this population in Britain.

Adult↗