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Biomedical subjects

P Fogarty

Publications and source records attributed to P Fogarty.

At least 19 recordsLinked to original sources

Epidemiology of the most frequent diseases in the European a-symptomatic post-menopausal women. Is there any difference between Ireland and the rest of Europe?

Osteoporosis, cardiovascular disease, breast cancer and genitourinary diseases are some of the most frequently diagnosed diseases in a-symptomatic post-menopausal women. There is a marked European geographic distribution of osteoporosis. Rates are higher in Scandinavia than in the Southern European countries. The possible reasons for this higher incidence of osteoporotic fractures in the Northern European countries is associated with the climate, which limits physical activity and exposure to sunlight and increases the risk of falls. During the next two decades, the number of hip fractures for European women over 65 years is expected to nearly double. Despite these figures, osteoporosis prevention has not yet been adopted in many European countries. There is a devastating impact and a huge financial burden on the European economy and health care system. Breast cancer is the most common cancer in females in Europe. The regions of highest incidence are Western and Northern Europe, while Southern and Eastern Europe have lower incidence rates. The causes of differences in breast cancer incidences between Northern and Southern Europe are not known, but the average 5-year survival of women with breast cancer has increased in Europe in the last three decades. Studies have revealed marked differences in cardiovascular diseases across Europe, showing cardiovascular death rates as highest among the Eastern and Central European countries and lowest in the Mediterranean countries. Cardiovascular disease is the major cause of mortality in European women. However, in North European countries, there are more ischaemic heart diseases in women than in Mediterranean countries. In Mediterranean countries, on the other hand, there are more strokes than in Northern Europe. These strokes events occur 10 years later than the ischaemic heart attacks.

Breast Neoplasms↗

Pulmonary presentations of amyloidosis.

Respiratory tract involvement with amyloid is rare. We report eight cases of lower respiratory tract amyloidosis including a case of isolated pulmonary interstitial amyloidosis treated with chemotherapy, two cases of recurrent endobronchial amyloid with airway obstruction successfully treated with laser therapy and three cases of localized nodular pulmonary amyloidosis. The subjects with endobronchial and nodular amyloid demonstrated good long-term survival, while those with systemic or interstitial pulmonary amyloid had progressive disease and poor survival. Circulating monoclonal immunoglobulins were identified in five of the eight cases as the likely cause of the amyloid.

Adult↗

D1S80 allele frequencies in Hasidic and non-Hasidic New York City Jewish populations.

Allele frequencies were determined for the VNTR locus D1S80 in Hasidic and non-Hasidic Ashkenazi New York City Jewish subpopulations. Samples were amplified via the polymerase chain reaction and underwent genotyping using polyacrylamide gel electrophoresis. In the Hasidic population 14 alleles were observed as opposed to 19 alleles in the non-Hasidic community. Both populations were tested for Hardy-Weinberg equilibrium. The frequency data obtained can be used for comparison to other populations and for allele and genotype frequency estimates in genetic marker profiling of evidentiary specimens.

Alleles↗

Absence of linkage of the epithelial sodium channel to hypertension in black Caribbeans.

Hypertensives of African origin have low-renin, sodium-sensitive blood pressure and respond poorly to treatment with angiotensin converting enzyme inhibitors. The epithelial sodium channel may be important in the pathogenesis of essential hypertension in this population. This is supported by the identification of mutations within this channel, which lead to excess sodium reabsorption and hypertension in Liddle's syndrome. In this study we tested whether there was linkage of the genes encoding the three subunits of the epithelial sodium channel to essential hypertension in 63 affected sibling pairs of West African origin from St. Vincent and the Grenadines. We found no support for linkage of the epithelial sodium channel to essential hypertension in this population. However, further studies will be needed in larger populations of African ancestry to exclude a contribution of the genes encoding the epithelial sodium channel to hypertension.

Aged↗

Nuclear-fallout, a Drosophila protein that cycles from the cytoplasm to the centrosomes, regulates cortical microfilament organization.

nuclear fallout (nuf) is a maternal effect mutation that specifically disrupts the cortical syncytial divisions during Drosophila embryogenesis. We show that the nuf gene encodes a highly phosphorylated novel protein of 502 amino acids with C-terminal regions predicted to form coiled-coils. During prophase of the late syncytial divisions, Nuf concentrates at the centrosomes and is generally cytoplasmic throughout the rest of the nuclear cycle. In nuf-derived embryos, the recruitment of actin from caps to furrows during prophase is disrupted. This results in incomplete metaphase furrows specifically in regions distant from the centrosomes. The nuf mutation does not disrupt anillin or peanut recruitment to the metaphase furrows indicating that Nuf is not involved in the signaling of metaphase furrow formation. These results also suggest that anillin and peanut localization are independent of actin localization to the metaphase furrows. nuf also disrupts the initial stages of cellularization and produces disruptions in cellularization furrows similar to those observed in the metaphase furrows. The localization of Nuf to centrosomal regions throughout cellularization suggests that it plays a similar role in the initial formation of both metaphase and cellularization furrows. A model is presented in which Nuf provides a functional link between centrosomes and microfilaments.

Actin Cytoskeleton↗

The Drosophila grapes gene is related to checkpoint gene chk1/rad27 and is required for late syncytial division fidelity.

BACKGROUND: Cell cycle checkpoints maintain the fidelity of the somatic cell cycle by ensuring that one step in the cell cycle is not initiated until a previous step has been completed. The extent to which cell cycle checkpoints play a role in the initial rapid embryonic divisions of higher eukaryotes is unclear. The initial syncytial divisions of Drosophila embryogenesis provide an excellent opportunity to address this issue as they are amenable to both genetic and cellular analysis. In order to study the relevance of cell cycle checkpoints in early Drosophila embryogenesis, we have characterized the maternal-effect grapes (grp) mutation, which may affect feedback control during early syncytial divisions. RESULTS: The Drosophila grp gene encodes a predicted serine/threonine kinase and has significant homology to chk1/rad27, a gene required for a DNA damage checkpoint in Schizosaccharomyces pombe. Relative to normal embryos, embryos derived from grp-mutant mothers exhibit elevated levels of DNA damage. During nuclear cycles 12 and 13, alignment of the chromosomes on the metaphase plate was disrupted in grp-derived embryos, and the embryos underwent a progression of cytological events that were indistinguishable from those observed in normal syncytial embryos exposed to X-irradiation. The mutant embryos also failed to progress through a regulatory transition in Cdc2 activity that normally occurs during interphase of nuclear cycle 14. CONCLUSION: We propose that the primary defect in grp-derived embryos is a failure to replicate or repair DNA completely before mitotic entry during the late syncytial divisions. This suggests that wild-type grp functions in a developmentally regulated DNA replication/damage checkpoint operating during the late syncytial divisions. These results are discussed with respect to the proposed function of the chk1/rad27 gene.

Amino Acid Sequence↗

Obstructive sleep apnoea. The clinical consequences.

Obstructive sleep apnoea (OSA) results in a variety of clinical consequences and is associated with a number of important common diseases. This article outlines the clinical features and pathophysiology of OSA and explores its protean manifestations.

Adult↗

Linkage of the angiotensinogen gene locus to human essential hypertension in African Caribbeans.

The renin-angiotensin system regulates blood pressure and sodium balance. The angiotensinogen gene which encodes the key substrate within this system has been linked to essential hypertension in White Europeans. It has been suggested that people of West African ancestry may have a different genetic basis for hypertension. In this study we have tested whether there is linkage of the angiotensinogen gene to essential hypertension in African Caribbeans from St. Vincent and the Grenadines. DNA from 63 affected sibling pairs with hypertension was tested for linkage by analyzing whether there was excess allele sharing among siblings genotyped using an angiotensinogen dinucleotide repeat sequence. There was significant support for linkage (T = 3.07, P = 0.001) and association of this locus to hypertension (chi 2 = 50.2, 12 degrees of freedom, P << 0.001). A DNA polymorphism which alters methionine to threonine at position 235 (M235T) within the angiotensinogen peptide has been associated previously with hypertension. However, we found no association of this variant with hypertension in this study. These findings provide support for linkage and association of the angiotensinogen locus to hypertension in African Caribbeans and suggest some similarities in the genetic basis of essential hypertension in populations of different ethnicity.

Adult↗

The Drosophila maternal-effect mutation grapes causes a metaphase arrest at nuclear cycle 13.

grapes (grp) is a second chromosome (36A-B) maternal-effect lethal mutation in Drosophila melanogaster. We demonstrate that the syncytial nuclear divisions of grp-derived embryos are normal through metaphase of nuclear cycle 12. However, as the embryos progress into telophase of cycle 12, the microtubule structures rapidly deteriorate and midbodies never form. Immediately following the failure of midbody formation, sister telophase products collide and form large tetraploid nuclei. These observations suggest that the function of the midbody in the syncytial embryo is to maintain separation of sister nuclei during telophase of the cortical divisions. After an abbreviated nuclear cycle 13 interphase, these polyploid nuclei progress through prophase and arrest in metaphase. The spindles associated with the arrested nuclei are stable for hours even though the microtubules are rapidly turning over. The nuclear cycle 13 anaphase separation of sister chromatids never occurs and the chromosomes, still encompassed by spindles, assume a telophase conformation. Eventually neighboring arrested spindles begin to associate and form large clusters of spindles and nuclei. To determine whether this arrest was the result of a disruption in normal developmental events that occur at this time, both grp-derived and wild-type embryos were exposed to X-irradiation. Syncytial wild-type embryos exhibit a high division error rate, but not a nuclear-cycle arrest after exposure to low doses of X-irradiation. In contrast, grp-derived embryos exhibit a metaphase arrest in response to equivalent doses of X-irradiation. This arrest can be induced even in the early syncytial divisions prior to nuclear migration. These results suggest that the nuclear cycle 13 metaphase arrest of unexposed grp-derived embryos is independent of the division-cycle transitions that also occur at this stage. Instead, it may be the result of a previously unidentified feedback mechanism.

Animals↗

Delays in anaphase initiation occur in individual nuclei of the syncytial Drosophila embryo.

The syncytial divisions of the Drosophila melanogaster embryo lack some of the well established cell-cycle checkpoints. It has been suggested that without these checkpoints the divisions would display a reduced fidelity. To test this idea, we examined division error frequencies in individuals bearing an abnormally long and rearranged second chromosome, designated C(2)EN. Relative to a normal chromosome, this chromosome imposes additional structural demands on the mitotic apparatus in both the early syncytial embryonic divisions and the later somatic divisions. We demonstrate that the C(2)EN chromosome does not increase the error frequency of the late larva neuroblast divisions. However, in the syncytial embryonic nuclear divisions, the C(2)EN chromosome produces a 10-fold increase in division errors relative to embryos with a normal karyotype. During late anaphase of the neuroblast divisions, the sister C(2)EN chromosomes cleanly separate from one another. In contrast, during late anaphase of the syncytial divisions in C(2)EN-bearing nuclei, large amounts of chromatin often lag on the metaphase plate. Live analysis of C(2)EN-bearing embryos demonstrates that individual nuclei in the syncytial population of dividing nuclei often delay in their initiation of anaphase. These delays frequently lead to division errors. Eventually the products of the nuclei delayed in anaphase sink inward and are removed from the dividing population of syncytial nuclei. These results suggest that the Drosophila embryo may be equipped with mechanisms that monitor the fidelity of the syncytial nuclear divisions. Unlike checkpoints that rely on cell cycle delays to identify and correct division errors, these embryonic mechanisms rely on cell cycle delays to identify and discard the products of division errors.

Anaphase↗

Mutations affecting the cytoskeletal organization of syncytial Drosophila embryos.

Cytoplasmic organization, nuclear migration, and nuclear division in the early syncytial Drosophila embryo are all modulated by the cytoskeleton. In an attempt to identify genes involved in cytoskeletal functions, we have examined a collection of maternal-effect lethal mutations induced by single P-element transposition for those that cause defects in nuclear movement, organization, or morphology during the syncytial embryonic divisions. We describe three mutations, grapes, scrambled, and nuclear-fallout, which define three previously uncharacterized genes. Females homozygous for these mutations produce embryos that exhibit extensive mitotic division errors only after the nuclei migrate to the surface. Analysis of the microfilament and microtubule organization in embryos derived from these newly identified mutations reveal disruptions in the cortical cytoskeleton. Each of the three mutations disrupts the actin-based pseudocleavage furrows and the cellularization furrows in a distinct fashion. In addition to identifying new genes involved in cytoskeletal organization, these mutations provide insights into cytoskeletal function during early Drosophila embryogenesis.

Animals↗

Prophylactic oophorectomy in Northern Ireland.

A postal questionnaire was sent to all gynaecological consultants and senior registrars (n = 50) in Northern Ireland to establish the prevalence of prophylactic oophorectomy. Forty three (84%) replied. 72% performed prophylactic oophorectomy (28% unilateral), 28% did not. With reference to the world literature, there appears to be no benefit from the unilateral procedure but a consensus that bilateral oophorectomy is an option which should be considered in certain cases where there is a high risk of ovarian cancer.

Adult↗

Spontaneous rupture of the spleen in Legionnaires' disease.

A case of Legionnaires' disease is described in a 63 year old man who presented with pneumonia and confusion. Eleven days after admission he became acutely hypotensive and attempts at resuscitation failed. Post-mortem examination revealed spontaneous splenic rupture and massive hepatocellular necrosis--an outcome that has not previously been associated with Legionnaires' disease.

Humans↗