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Biomedical subjects

M Donoghue

Publications and source records attributed to M Donoghue.

At least 19 recordsLinked to original sources
PubMed2003

How big is the burden of visual loss caused by age related macular degeneration in the United Kingdom?

AIMS: To predict the burden of blindness, partial sight, and visual impairment (binocular visual acuity 6/18 or less) due to late stage age related macular degeneration (AMD) in the ageing population of the United Kingdom. METHODS: A systematic review, followed by a request for data, was used to establish a pooled prevalence of AMD and corresponding visual loss. Prevalence figures were applied to the UK population. Using UK population trends, the future burden of AMD over the coming decade was established. RESULTS: Pooled data from six studies showed that the prevalence of visual loss caused by AMD increased exponentially from the age of 70-85 years of age, with 3.5% (95% CI 3.0 to 4.1) having visual impairment beyond the age of 75 years. The authors estimate that there are currently 214 000 (95% CI 151 000 to 310 000) with visual impairment caused by AMD (suitable for registration). This number is expected to increase to 239 000 (95% CI 168 000 to 346 000) by the year 2011. Currently there are 172 000 (95% CI 106 000 to 279 000) and 245 000 (95% CI 163 000 to 364 000) with geographical and neovascular AMD, respectively. CONCLUSIONS: Estimates of visual impairment agree with official statistics for the number registered partially sighted or blind, caused by AMD, and are well below other figures often cited. Although these estimates are associated with wide confidence intervals (CI) and a number of caveats, they represent the best available data, which can be used to guide health and social care provision for older people in the UK setting. Implications for low vision services are outlined.

Age Distribution↗
PubMed2001

Tissue distribution and functional expression of a cDNA encoding a novel mixed lineage kinase.

Hypertrophy is an adaptive response of the heart to myocardial injury or hemodynamic overload that may progress and contribute to cardiac decompensation and eventually to heart failure. The signaling pathways controlling this response in the cardiac myocyte are poorly understood. A data mining effort of a human failed heart cDNA library was undertaken in an effort to identify novel signaling molecules involved in cardiac hypertrophy. This effort identified a novel kinase (MLK7) homologous to the mixed lineage kinase family of proteins. The mixed lineage kinases are mitogen-activated protein kinase kinase kinases (MAPKKKs) which activate stress activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 kinase pathways. They contain a catalytic domain with homology to both serine/threonine and tyrosine-specific kinases and a dual leucine zipper. MLK7 is identical to leucine zipper and sterile-alpha motif protein kinase (ZAK) through the leucine zipper domain but has a completely divergent COOH-terminus and shares approximately 40% homology with the other MLKs overall. Expression of MLK7 mRNA is most abundant in skeletal muscle and heart, with expression restricted to the cardiac myocyte. The recombinant histidine tagged MLK7 expressed and purified from insect cells exhibited serine/threonine kinase activity in vitro with myelin basic protein as substrate. When expressed in cardiac myocytes, MLK7 activated SAPK/JNK1, and ERK and p38 to a lesser extent. Additionally, MLK7 altered fetal gene expression and increased protein synthesis in cardiac myocytes. These data suggest that MLK7 is a new member of the mixed lineage kinase family that modulates cardiac SAPK/JNK pathway and may play a role in cardiac hypertrophy and progression to heart failure.

Adult↗
PubMed2001

The clinical and pathologic implications of plasmacytic infiltrates in percutaneous renal allograft biopsies.

Plasmacytic infiltrates in renal allograft biopsies are uncommon and morphologically distinctive lesions that may represent variants of acute rejection. This study sought significant clinical and pathologic determinants that might have influenced development of these lesions and assessed their prognostic significance. Renal allograft biopsies (n = 19), from 19 patients, with tubulointerstitial inflammatory infiltrates containing abundant plasma cells, composing 32 +/- 8% of the infiltrating mononuclear cells, were classified using Banff '97 criteria. Clonality of the infiltrates was determined by immunoperoxidase staining for kappa and lambda light chains and polymerase chain reaction for immunoglobulin heavy-chain gene rearrangements, using V(H) gene framework 3 and JH consensus primers. In situ hybridization for Epstein-Barr virus encoded RNA (EBER) was performed in 17 cases. The clinical features, histology, and outcome of these cases were compared with kidney allograft biopsies (n = 17) matched for time posttransplantation and type of rejection by Banff '97 criteria, with few plasma cells (7 +/- 5%). Sixteen of 19 biopsies (84%) with plasmacytic infiltrates had EBER-negative (in 14 cases tested) polyclonal plasma cell infiltrates that were classifiable as acute rejection (types 1A [4], 1B [10], and 2A [2]). These biopsies were obtained between 10 and 112 months posttransplantation. Graft loss from acute and/or chronic rejection was 50% at 1 year and 63% at 3 years, and the median time to graft failure was 4.5 months after biopsy. There was no significant difference in overall survival or time to graft failure compared with the controls. Three of 19 biopsies (16%) had EBER-negative polyclonal plasmacytic hyperplasia, mixed monoclonal and polyclonal polymorphous B cell hyperplasia, and monoclonal plasmacytoma-like posttransplantation lymphoproliferative disease (PTLD) and were obtained at 17 months, 12 weeks, and 7 years after transplantation, respectively. Graft nephrectomies were performed at 1, 19, and 5 months after biopsy, respectively. Plasmacytic infiltrates in renal allografts comprise a spectrum of lesions from acute rejection to PTLD, with a generally poor prognosis for long-term graft survival.

Adult↗
PubMed2000

A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9.

ACE2, the first known human homologue of angiotensin-converting enzyme (ACE), was identified from 5' sequencing of a human heart failure ventricle cDNA library. ACE2 has an apparent signal peptide, a single metalloprotease active site, and a transmembrane domain. The metalloprotease catalytic domains of ACE2 and ACE are 42% identical, and comparison of the genomic structures indicates that the two genes arose through duplication. In contrast to the more ubiquitous ACE, ACE2 transcripts are found only in heart, kidney, and testis of 23 human tissues examined. Immunohistochemistry shows ACE2 protein predominantly in the endothelium of coronary and intrarenal vessels and in renal tubular epithelium. Active ACE2 enzyme is secreted from transfected cells by cleavage N-terminal to the transmembrane domain. Recombinant ACE2 hydrolyzes the carboxy terminal leucine from angiotensin I to generate angiotensin 1-9, which is converted to smaller angiotensin peptides by ACE in vitro and by cardiomyocytes in culture. ACE2 can also cleave des-Arg bradykinin and neurotensin but not bradykinin or 15 other vasoactive and hormonal peptides tested. ACE2 is not inhibited by lisinopril or captopril. The organ- and cell-specific expression of ACE2 and its unique cleavage of key vasoactive peptides suggest an essential role for ACE2 in the local renin-angiotensin system of the heart and kidney. The full text of this article is available at http://www. circresaha.org.

Adult↗
PubMed1999

Low uptake of eye services in rural India: a challenge for programs of blindness prevention.

OBJECTIVES: To investigate service uptake in a rural Indian population served by outreach eye camps and to identify barriers to uptake. PARTICIPANTS AND METHODS: A routine eye camp was conducted within 5 km of each of 48 randomly selected villages of typically Hindu, backward-caste communities. Subsequently, participatory rural appraisal-community mapping, focus groups, matrix ranking, and semistructured interviews-was undertaken to explore community views of eye problems. An eye examination was conducted on persons with eye problems who did not attend the eye camp. Predictors of attendance were identified by multilevel regression analysis. RESULTS: Of 749 adults with an eye problem, 51 (6.8%) attended the eye camp. Independent predictors of attendance were being male (odds ratio = 2.3; 95% confidence interval, 1.2-4.5) and living within 3 km of the camp (odds ratio = 4.5; 95% confidence interval, 1.7-12.5). Of the 552 persons who did not attend the eye camps and had an eye examination, 242 (43.8%) had low vision (visual acuity <6/18 to > or =3/60 in presenting better eye) and 38 (6.9%) were blind in both eyes. Cataract surgery was recommended for 197 (35.8%) of the persons who did not attend the eye camps. Of 109 persons with a previous cataract operation, 42 (38.5%) had low vision and 11 (10.1%) were blind. Fear (principally of eye damage), cost (direct and indirect), family responsibilities, ageism, fatalism, and an attitude of being able to cope (with low or no vision) were the principal barriers to attending the eye camps. CONCLUSIONS: A high proportion of people who could have benefited from eye treatment were not using available services. Poor visual outcomes were observed in surgically treated persons.

Attitude to Health↗
PubMed1999

Association of polymorphisms at the SR-BI gene locus with plasma lipid levels and body mass index in a white population.

The scavenger receptor class B type I (SR-BI) is a lipoprotein receptor that has been shown to be important in high density lipoprotein cholesterol (HDL-C) metabolism in mice. To determine its role in humans, we have characterized the human SR-BI gene and investigated its genetic variation in 489 white men and women. Five variants were demonstrated: 2 in introns (3 and 5) and 3 in exons (1, 8, and 11). Three variants at exons 1 and 8 and intron 5 with allele frequencies >0.1 were used to examine associations with lipid or anthropometric variables. The exon 1 variant was significantly (P<0.05) associated with increased HDL-C and lower low density lipoprotein cholesterol (LDL-C) values in men, but no associations were observed in women. The exon 8 variant was associated in women with lower LDL-C concentrations (3.05+/-0.98 mmol/L and 3.00+/-0.93 mmol/L for heterozygotes and homozygotes, respectively) compared with women homozygous for the common allele (3.39+/-1.09 mmol/L, P=0. 043). No associations for this variant were observed in men. Women carriers of the intron 5 variant showed a higher body mass index (23. 8+/-3.8 kg/m2, P=0.031) than those women homozygous for the common allele (22.4+/-3.4 kg/m2). Similar results were observed after haplotype analysis. Multiple regression analysis using HDL-C, LDL-C, and body mass index as dependent variables and age, sex, and each of the genetic variants as predictors also provided similar results. The associations found with both LDL-C and HDL-C suggest that SR-BI may play a role in the metabolism of both lipoprotein classes in humans.

Adult↗
PubMed1991

Paired MyoD-binding sites regulate myosin light chain gene expression.

The muscle-specific enhancer element located downstream of the myosin light chain (MLC) locus encoding MLC1 and MLC3 contains three binding sites (A, B, and C) for the myogenic determination factor MyoD. A 173-base-pair region of the MLC gene enhancer, including these three sites, retains full enhancer function when transfected into muscle cells. Whereas mutation of either upstream MyoD binding site (A or B) has a mild effect on muscle-specific enhancer activity, mutation of the third MyoD binding site (C) substantially weakens the enhancer, both in muscle cells or in nonmuscle cells cotransfected with a MyoD, myogenin, or myf5 expression vector. Site C is necessary but insufficient, since double mutation of two MyoD binding sites (A plus B) abrogates enhancer activity. Thus, site C requires either site A or B for enhancer function. This study shows a hierarchy of function among the three MyoD binding sites in the MLC enhancer. We propose that a protein-DNA complex is formed with at least two of these sites (A and C or B and C) to effect activation of the locus encoding MLC1/3 during myogenesis.

Animals↗
PubMed1990

A highly conserved enhancer downstream of the human MLC1/3 locus is a target for multiple myogenic determination factors.

A potent muscle-specific enhancer element, originally described in the rat myosin light chain (MLC) 1/3 locus located downstream of the coding region, is found in an analogous position in the human MLC1/3 gene. When linked to a CAT reporter gene and transfected into muscle or non-muscle cells, the human MLC enhancer directs high levels of muscle-specific gene expression from homologous or heterologous promoters, irrespective of position or orientation relative to the CAT transcription unit. A significant degree of sequence homology (over 85%) in the 3'-flanking regions of the two MLC genes is restricted to a 200 bp sequence which lies approximately 1.5 kb downstream of the polyadenylation site in both species. The human enhancer sequence includes binding sites for human myogenic determination factors containing a common basic helix-loop-helix motif, and it can be trans-activated to varying degrees in non-muscle cells by these factors. This study establishes the MLC enhancer as an evolutionarily conserved, integral component of the MLC1/3 locus which constitutes a novel target for the action of myogenic determination factors.

Animals↗
PubMed1989

Myosin light chain enhancer activates muscle-specific, developmentally regulated gene expression in transgenic mice.

The rat myosin light chain (MLC)1/3 gene locus contains a potent muscle-specific enhancer, located downstream of the coding region, greater than 24 kilobases away from the MLC1 transcription start site. To assess the role of this enhancer in the activation of MLC expression during development, transgenic mice were generated carrying multiple copies of a MLC1 promoter-chloramphenicol acetyltransferase (CAT) transcription unit linked to a genomic fragment including the enhancer. CAT expression was detected in four mouse lines, up to 1000-fold higher in skeletal muscles than in other tissues. Activation of endogenous MLC1 transcription in these animals 4 days before birth was reflected in the onset of CAT transgene expression. This study identifies the transcriptional control elements necessary to activate the 21-kilobase MLC1/3 locus at the appropriate fetal stage and indicates that the MLC enhancer is sufficient to induce developmentally regulated expression from the MLC1 promoter exclusively in skeletal muscle cells.

Aging↗
PubMed1988

A muscle-specific enhancer is located at the 3' end of the myosin light-chain 1/3 gene locus.

Two skeletal myosin light chains, MLC1 and MLC3, are generated from a single gene by transcription from two different promoters and alternate splicing of the pre-mRNAs. To define DNA sequences involved in MLC transcriptional control, we constructed a series of plasmid vectors in which segments of the rat MLC locus were linked to a CAT gene and assayed for expression in muscle and nonmuscle cells. Whereas sequences proximal to the two MLC promoters do not appear to contain tissue-specific regulatory elements, a 0.9-kb DNA segment, located greater than 24 kb downstream of the MLC1 promoter, dramatically increases CAT gene expression in differentiated myotubes but not in undifferentiated myoblasts or nonmuscle cells. The ability of this segment to activate gene expression to high levels, in a distance-, promoter-, position-, and orientation-independent way, defines it as a strong muscle-specific enhancer element.

Animals↗
PubMed1982

Nutritional needs of cancer patients.

Individuals with cancer share many similar nutritional problems, regardless of the primary site of the malignant neoplasm. The presence of protein-calorie malnutrition is the most common secondary diagnosis in cancer and is frequently the cause of death. To date, the inability of health care professionals to halt or adequately control the severity of protein-calorie malnutrition in the individual with cancer indicates that the syndrome is more complex than inadequate ingestion of nutrients. The presence and severity of protein-calorie malnutrition in individuals with cancer cannot be attributed to one factor. The disease, treatment modalities, and complications of therapy all contribute to its development.

Diet↗
PubMed1979

Dermatophytoses: a clinical and management review.

The diagnosis and management of dermatophytic fungal infections depends upon a knowledge of the causative organism fungi, the morphological patterns which can be produced and the type, extent and duration of treatment necessary to effect cure.

Dermatomycoses↗