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Biomedical subjects

M Daly

Publications and source records attributed to M Daly.

At least 19 recordsLinked to original sources
PubMed1992

Insertions/deletions in the antithrombin gene: 3 mutations associated with non-expression.

We have investigated the molecular basis of antithrombin deficiency in 3 individuals, 2 of whom had a proven family history of thromboembolic disease. An approximate 50% reduction in functional and immunologic levels of antithrombin was detected in plasma from the propositi indicating an allelic deficiency of antithrombin. In each case direct sequencing of amplified DNA revealed a novel mutation involving single bases: two being insertions, of a T in codon 48 and an A in codon 208, and the third being the deletion of an A in codon 370. The three mutations, which were confirmed by cloning and sequencing the normal and variant alleles, all caused frameshifts leading to premature termination of protein translation. In no case could a truncated antithrombin be detected in plasma from the propositus suggesting either that it fails to be secreted, or is rapidly degraded.

Adult↗
PubMed1992

Specific expression of the annexin VIII gene in acute promyelocytic leukemia.

Since the translocation breakpoint t(15;17) (q22;q21) in acute promyelocytic leukemia (APL) occurs within the retinoic acid receptor-alpha (RARA) gene, the expression of many genes normally regulated by RARA may be affected by this translocation. To identify genes that may be aberrantly expressed in APL, a subtraction cDNA library of an APL patient with t(15;17) was constructed. A cDNA, pRD1, specifically expressed in APL was identified. DNA sequence analysis of pRD1 showed that this gene is similar to the DNA sequence of annexin VIII, a gene which encodes a vascular anticoagulant. The annexin VIII gene was assigned to chromosome 10, which indicates that specific expression of this gene in APL is not directly involved in the t(15;17) breakpoint region. We have analyzed the expression of annexin VIII gene in nine t(15;17)-positive APL patients and one APL patient with a chromosome 17q-abnormality. We found that all APL samples expressed high levels of the annexin VIII gene. Expression of the annexin VIII gene in all other leukemias, including acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and acute lymphoblastic leukemia, was undetectable, except in one patient with acute myelogenous leukemia in which a very low level of expression was detected. Annexin VIII is highly expressed in the APL cell line, NB4. Its expression was significantly reduced after 8 hours of all-trans retinoic acid (ATRA) treatment, whereas the expression of RARA increased several-fold within 4 hours postinduction. Thus, increased expression of RARA preceded the downregulation of annexin VIII after ATRA induction, suggesting an inverse relationship between RARA and annexin VIII expression. Since increased expression of the fusion transcript was seen after ATRA induction and an APL without a t(15;17) translocation expressed high levels of annexin VIII, it appears that increased expression of annexin VIII in APL is not related to the fusion transcript. Therefore, dysregulation of the RARA gene may be related to the overexpression of annexin VIII in APL.

Amino Acid Sequence↗
PubMed1992

Recurrence of myomas after myomectomy in women pretreated with leuprolide acetate depot or placebo.

The recurrence of myomas and myoma-related symptoms was evaluated in women participating in a randomized, double-blind, P-controlled study of the efficacy of LA depot before myomectomy. After 27 to 38 months of follow-up, the recurrence of myomas was found to be greater when at least four myomas were resected. Myoma recurrence was not associated with pretreatment or preoperative uterine volume, resected myoma mass, or preoperative medical therapy.

Adult↗
PubMed1992

Powerlessness in acute spinal cord injury patients: a descriptive study.

The purpose of this study was to describe the frequency and characteristics of the nursing diagnosis, powerlessness, in an acute spinal cord injury (SCI) population. This descriptive study had a sample of 50 SCI patients admitted during the acute phase of injury to a model systems SCI center. Patients with a length of stay of greater than or equal to 15 days experienced a significantly higher (p less than .01) occurrence of powerlessness than did those with hospitalization of less than 15 days. Powerlessness was not found to cluster or occur in any pattern but was random throughout hospitalization. There was a statistically significant relationship (p less than .01) between the occurrence of powerlessness and patient acuity, with the occurrence increasing as acuity increased in severity. Quadriplegics and patients over the age of 60 years had a higher occurrence of powerlessness (p less than .05). This study demonstrated powerlessness was a commonly occurring diagnosis in acute SCI.

Adolescent↗
PubMed1992

The influence of antidepressants in overdose on the increased suicide rate in Ireland between 1971 and 1988.

There has been almost a threefold increase in the incidence of suicide in Ireland during the past 20 years. When each case occurring between 1971 and 1988 was reviewed, the major causes of death were found to be drowning and hanging. Deliberate overdoses with tricyclic antidepressants accounted for less than 4% of all suicides, over the 17 years studied, and during this time, overdose with tricyclics has made a proportionately smaller contribution to the total number of suicides. Greater attention should be paid to identifying and treating the majority of suicidal patients who are at risk by other methods.

Adolescent↗
PubMed1991

The complex genetic locus polyhomeotic in Drosophila melanogaster potentially encodes two homologous zinc-finger proteins.

Differential expression of the homeotic gene complexes, ANT-C and BX-C, of Drosophila melanogaster is partly controlled by trans-regulating factors located outside the two complexes. The complex genetic locus, polyhomeotic (ph), is one of these trans regulators required during development for correct expression of the homeotic selector genes. The ph locus comprises two genetically independent units whose functions are largely redundant. There are two duplicated sequences arranged as a tandem repeat in the ph region, defining two molecular ph units. Sequence analysis of the 28.6 kb of DNA comprising the locus shows varying degrees of sequence conservation between these two molecular units. Long open reading frames with a high degree of conservation have been localized in each tandem repeat. Putative protein products encoded by both the proximal and the distal unit contain several identical or practically identical protein domains: a zinc-finger-forming motif, an alpha-helix motif, a domain rich in serine and threonine residues and stretches of glutamine residues. The presence of these protein domains supports the hypothesis that ph encodes a transcription factor that may function as part of a protein complex. Possible molecular mechanisms leading to the particular structure of the locus are discussed.

Amino Acid Sequence↗
PubMed1991

Antithrombin Cambridge II, 384 Ala to Ser. Further evidence of the role of the reactive centre loop in the inhibitory function of the serpins.

Four unrelated individuals have been identified with an identical antithrombin variant, associated in one of them with episodes of recurrent venous thromboses. In each case, the plasma antithrombin concentration was normal and the only function abnormality was a minor but consistent decrease in the heparin-induced thrombin inhibition suggesting a mutation at or near the reactive centre of the molecule. Amplification and direct sequencing of exon 6 showed a G----T mutation at nucleotide 1246, which corresponds to a substitution of a serine for an alanine at residue 384. This is one of a series of conserved alanines that form the stalk to the reactive centre loop. The observed changes in this variant are compatible with recent structural studies that infer that mobility of this stalk with partial re-entry into the A-sheet of the molecule is necessary for optimal inhibitory activity.

Aged↗
PubMed1991

Identification of bile duct stones in patients undergoing laparoscopic cholecystectomy.

To identify patients with common bile duct stones, all patients considered for laparoscopic cholecystectomy in this unit undergo intravenous cholangiography (IVC) with tomography and, more recently, operative cholangiography. To date 100 consecutive patients with symptomatic gallstones have undergone laparoscopic cholecystectomy with no specific exclusion criteria. Eight patients of 100 were found to have duct stones on IVC with one false-positive. These IVC data were compared with data from 52 patients who also had operative cholangiograms performed. One stone was detected on operative cholangiography that was not identified on IVC. No additional information was gained from operative cholangiography. These data suggest that preoperative IVC is adequate for the detection of duct stones in patients considered for laparoscopic cholecystectomy.

Adolescent↗
PubMed1991

Asymptomatic primary hyperparathyroidism.

Of 118 consecutive white patients referred for asymptomatic primary hyperparathyroidism, the diagnosis was clinically confirmed in 100, of whom 85 adults had a serum calcium less than 3.0 mM (12 mg/dl) and no skeletal, rheumatic, or significant neuropsychiatric symptoms, azotemia, or other significant illnesses. Among these 85, 68 had both asymptomatic and medically uncomplicated hyperparathyroidism, whereas 17 had historical, radiographic, or ultrasonic evidence of renal stone disease. The 20% with past or present renal calculi concentrated their urine significantly better than the 68 others (p = 0.05), but these two groups were otherwise not distinguished by the tests we performed, so all 85 patients were analyzed together. Systolic and diastolic blood pressures were normal, but premature osteopenia and/or impaired renal function were present in 29-36% of the patients. Micrometer measurements of metacarpal radiographs and 125I photon absorptiometry at the shaft of the radius revealed cortical osteopenia. Osteopenia was equally significant in the distal radius (cortical plus trabecular bone). These quantitative measurements were superior to routine bone radiography, and ROC analysis showed that 125I absorptiometry at either site was superior (p less than 0.01) to metacarpal cortex measurements for detecting premature osteopenia, which was present in more than a third of these patients. Creatinine clearances (24 h) and maximum urine concentrating capacity (overnight dehydration plus the synthetic vasopressin analog DDAVP) were each significantly reduced, despite all patients' normal BUN and serum creatinine levels. Sequential performance of a 24 h creatinine clearance and a urine concentration test revealed abnormalities in the renal function of 27 of 74 patients (36%), with a specificity of 95% and a higher sensitivity than either test alone (27-29%).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

The incidence of dysfunctional antithrombin variants: four cases in 210 patients with thromboembolic disease.

210 patients, with a history of venous thrombosis, have undergone prothrombotic investigations. In nine cases a consistent deficiency of antithrombin was identified. In five there was a reduction in the plasma antigenic concentration of antithrombin and in a further four cases deficiency was due to the presence of a dysfunctional antithrombin variant. The variants have all been characterized by DNA analysis and in three the mutations have been confirmed by peptide sequencing (antithrombin Basel (41 Pro to Leu). Hamilton (382 Ala to Thr). Cambridge I (384 Ala to Pro) and Cambridge II (384 Ala to Ser). The incidence of antithrombin deficiency in patients with a history of venous thrombosis has previously been quoted at between 2% and 3%: there is no published data available on the incidence of antithrombin variants. In our series 5% of patients who presented before the age of 40 years had antithrombin deficiency, and 2% of the total number of patients investigated had a dysfunctional variant. Our figures indicate that a significant number of cases of antithrombin deficiency are due to dysfunctional variants and that the true incidence of antithrombin deficiency in patients with a history of venous thrombosis is in the order of 5%.

Adult↗
PubMed1991

Screening for heparin binding variants of antithrombin.

A chromogenic assay for use as a screening test for the identification of antithrombin deficiency is described. The heparin concentration and the incubation time in the assay were optimised specifically to permit the detection of heparin binding defects of antithrombin. The sensitivity of antithrombin assays for the detection of this type of variant was significantly impaired when an incubation time of more than 30 seconds was used. Several commercially available assays recommend a longer incubation time than 30 seconds and therefore some patients with heparin binding defects of antithrombin may not be identified. The assay described here allows heparin binding variants of antithrombin to be identified and distinguished from other types of antithrombin deficiency in a simple two stage procedure.

Antithrombins↗
PubMed1990

Antithrombin Dublin (-3 Val----Glu): an N-terminal variant which has an aberrant signal peptidase cleavage site.

Antithrombin Dublin is an electrophoretically fast variant of antithrombin which has normal heparin affinity. Direct sequencing of amplified exon 2 revealed a Val----Glu substitution at position -3. N-terminal sequencing of antithrombin from two individuals, heterozygous for the Dublin mutation, showed the presence of a truncated antithrombin in which the N-terminal dipeptide is absent. We propose that the prepeptide mutation redirects signal peptidase cleavage to a site two amino acids downstream into the mature protein.

Adult↗
PubMed1990

Are primary alloresponses truly primary?

Proliferative T cell responses against major histocompatibility complex (MHC) incompatible stimulator cells in the mixed lymphocyte reaction are conventionally regarded as primary. However, it is generally accepted that the recognition of allogeneic MHC products results from a cross-reaction by self-MHC-restricted cells. These two assumptions were tested by examining the contribution of previously primed and naive T cells to 'primary' alloresponses. Peripheral blood T cells were separated into LFA-3+, memory, and LFA-3-, naive, populations by fluorescence-activated cell sorting. In contrast, to recall antigen responses to Candida albicans which were almost entirely confined to the LFA-3+, memory, population, the proliferative response to MHC incompatible stimulator cells, including HLA-DR-expressing mouse L cell transfectants, was equally distributed between the two T cell subsets in 5 day assays. Furthermore, limiting dilution analysis showed that the frequency of alloreactive T cells did not differ significantly between the two populations. The kinetics of proliferation in the two populations differed but were consistent with their naive and memory phenotype, in that after 3 days of culture the LFA-3+ cells proliferated more strongly to MHC alloantigens. These results show that a substantial proportion of 'primary' alloresponses are contributed by previously primed cells. In addition, the evidence for the cross-reactive hypothesis is supported and extended from the clonal to the population level.

Animals↗
PubMed1990

Is parent-offspring conflict sex-linked? Freudian and Darwinian models.

Freud's Oedipal theory sees parent-offspring conflict as a within-gender rivalry, whereas most modern evolutionary models interpret it as a gender-blind disagreement about resource allocation. New analyses of family homicides and a critical review of prior evidence do not support the central Freudian claim of a same-sex contingency in parent-offspring antagonism during the Oedipal phase. Several errors of fact and interpretation in psychoanalytic theorizing about family relations are discussed. We argue that psychoanalysts mistake substantive conflicts between nonrelatives for symbolic manifestations of family conflicts.

Conflict, Psychological↗