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Biomedical subjects

K Hughes

Publications and source records attributed to K Hughes.

At least 91 records · Page 5Linked to original sources
PubMed1995

Diet and coronary heart disease--a review.

Few topics have aroused more scientific controversy than the relationship of diet and coronary heart disease (CHD), yet it is still not fully resolved largely due to the difficulties in measuring diet, particularly over a long-term period. Studies have established that low density lipoprotein cholesterol (LDL-C) is a major risk factor for CHD and that a diet, high in saturated fatty acids (SFAs) and cholesterol and low in polyunsaturated fatty acids (PUFAs) and monounsaturated fatty acids (MUFAs) increases LDL-C. However, the evidence directly linking dietary lipids and CHD is less definite. In particular, trials on dietary change have been inconclusive with some showing no effect and others some benefits. Marine PUFAs have been found in some studies to be associated with reduced CHD mortality. Antioxidants (e.g. vitamins E and C) reduce oxidation of LDL and hence possibly atherosclerosis and some studies have shown their protective effect. There is some evidence that high dietary fibre is associated with lower CHD risk but there has been no real evidence as yet, for a similar effect for minerals. Moderate alcohol intake is protective. It is recommended that total fat intake should not constitute more than 30% of calories (approximately equally divided between SFAs, PUFAs and MUFAs) and cholesterol intake not more than 300 mg per day (similar to the United States National Cholesterol Education Program Step I Diet). Regular fatty fish consumption and a high intake of fresh fruits and vegetables is recommended. For persons with high LDL-C and particularly also with CHD, the Step II Diet is recommended.

Animals↗
PubMed1995

Lipoprotein (a) levels and clinical correlations in CAPD patients.

Dyslipidemia is an important risk factor for atherosclerotic vascular disease. Serum lipoprotein (a) [Lp(a)] has been implicated as an independent atherogenic risk factor. We measured serum (Lp(a) levels in our patients and studied its correlations with other lipoproteins and clinical parameters. All stable patients on continuous ambulatory peritoneal dialysis (CAPD) for more than one month were enrolled in the study. Fasting serum Lp(a), total cholesterol, triglycerides, LDL-cholesterol, HDL-cholesterol, apolipoprotein-A and apolipoprotein-B levels were measured on entering the CAPD program and at 3 monthly intervals. One hundred and nine patients (M/F: 65/44, mean age +/- SD: 59.5 +/- 12.0 years) were studied. Fifty-two patients had diabetes mellitus. Age- and sex-matched normals were used as controls. Serum Lp(a) levels were raised in 54.5% of CAPD patients compared to 18.6% of controls (p < 0.01). There was no significant change in Lp(a) levels over time. Serum Lp(a) levels showed positive and negative correlations with LDL-cholesterol and triglycerides, respectively, but not with age, sex, diabetic status, and serum total cholesterol and albumin levels. Thirty-six of 54 (66.7%) patients with serum Lp(a) levels greater than 30 mg/dL had either coronary, cerebral, and/or peripheral vascular disease compared to 30/55 (54.5%) of patients with serum Lp(a) levels less than 30 mg/dL (p = NS). In conclusion, serum Lp(a) levels were raised in a significant proportion of CAPD patients, but there was no significant association with vascular disease.

Aged↗
PubMed1994

PHF-tau from Alzheimer's brain comprises four species on SDS-PAGE which can be mimicked by in vitro phosphorylation of human brain tau by glycogen synthase kinase-3 beta.

Extensive in vitro phosphorylation of a purified preparation of control human brain tau consistently produces four rather than, as previously believed, three tau species on SDS-PAGE. The species thus generated are shifted on SDS-PAGE to positions that match those of PHF-tau isolated from Alzheimer's disease brain. A mixture of recombinant human tau isoforms phosphorylated by GSK-3 beta gave similar results to those obtained with control human brain tau. In vitro phosphorylation of the individual recombinant isoforms by GSK-3 beta showed that the four bands of PHF-tau are likely to consist of isoforms 3R,0 alone; 4R,0 with 3R,29; 4R,29 with 3R,58 and 4R,58 alone.

Alzheimer Disease↗
PubMed1994

Parathyroidectomy in chronic renal failure.

BACKGROUND: A subset of patients who are being maintained on dialysis for end-stage renal disease develop severely symptomatic secondary hyperparathyroidism that cannot be controlled medically. The relative merits of two alternative surgical approaches--subtotal parathyroidectomy versus total parathyroidectomy with autotransplantation--have not been clearly elucidated. METHODS: The records of 77 patients who had renal failure and underwent parathyroid surgery between 1982 and 1993 were retrospectively reviewed. RESULTS: Fifty-three patients (69%) underwent subtotal parathyroidectomy and 24 (31%) underwent total resection with auto-transplantation into forearm musculature. The incidences of postoperative hypocalcemia and tetany were similar in both groups, as was the recurrence rate (7%) of clinically significant hyperparathyroidism. CONCLUSIONS: Subtotal parathyroidectomy can be performed without mortality or morbidity and provides good control of hyperparathyroidism secondary to chronic renal failure. Total parathyroidectomy with autotransplantation offers no additional advantage in this difficult patient population. Most patients will require postoperative intravenous calcium replacement. We observed a significant incidence of continued hyperparathyroidism following successful renal transplantation.

Adult↗
PubMed1994

Nuclear onco-protein targets of signal transduction pathways.

Irradiation of mammalian cells with ultraviolet light (200-400 nm) results in the activation of a number of genes, the so-called "UV response" (Herrlich et al., Rev. Physiol. Biochem. Pharmacol., 119:187-223, 1992). Many of the UV responsive genes are also transcriptionally activated by growth factors and mitogens. Two transcription factors have been demonstrated to acutely respond to these stimuli, namely AP-1 and NF-kappa B. Whereas NF-kappa B proteins are primarily controlled via proteolysis of regulatory domains which prevent nuclear translocation, the AP-1 proteins are regulated at several levels including transcription and posttranslational modification. Here, we discuss progress in the identification of the components of pathways acutely regulating these transcription factors.

Animals↗
PubMed1993

Modulation of the glycogen synthase kinase-3 family by tyrosine phosphorylation.

Glycogen synthase kinase-3 (GSK-3) is a protein serine kinase implicated in the cellular response to insulin. The enzyme is the mammalian homologue of the zeste-white3 (shaggy) homeotic gene of Drosophila melanogaster and has been implicated in the regulation of the c-Jun/AP-1 transcription factor. In mammals this protein serine kinase is encoded by two related genes termed GSK-3 alpha and beta. Here, we demonstrate that these two proteins and the fruit fly protein are phosphorylated on tyrosine in vivo. Moreover, GSK-3 beta activity and function are shown to be dependent on tyrosine phosphorylation. The modified tyrosine residue is conserved in all members of the GSK-3 family and is equivalent to that required for activity by mitogen-activated protein (MAP) kinases. However, unlike MAP kinases, GSK-3 is highly phosphorylated on tyrosine and thus active in resting cells.

Amino Acid Sequence↗
PubMed1993

Relationships between cigarette smoking, blood pressure and serum lipids in the Singapore general population.

In a cross-sectional random survey of the whole of Singapore (2143 subjects aged 18-69 years), cardiovascular risk factors were measured by standardized techniques. For the analysis in the 18-69 year age group there was adjustment for ethnic group, age, body mass index, alcohol consumption and physical activity. Among serum lipids, high density lipoprotein (HDL-) cholesterol and fasting triglyceride were inversely related with partial correlation coefficients (r) of males -0.34 (P < 0.001) and females -0.26 (P < 0.001). There were no relationships between blood pressure and serum lipids except for direct ones with fasting triglyceride, being males (systolic r = 0.06, P = 0.066 and diastolic r = 0.12, P < 0.001) and females (systolic r = 0.11, P < 0.001 and diastolic r = 0.13, P < 0.001). Cigarette smoking, in males, was related to systolic blood pressure (inversely), with, compared to non-smokers, a reduction of 1.3 mm Hg (1.1%) in light smokers, 3.8 mm Hg (3.1%) in moderate smokers and 4.6 mm Hg (3.7%) in heavy smokers; there was no clear relation with diastolic blood pressure. Cigarette smoking, in males, was related to HDL-cholesterol (inversely), even after further adjustment for fasting triglyceride, with compared to non-smokers reductions of 0.03 mmol/l (3.4%) in light smokers, 0.09 mmol/l (10.3%) in moderate smokers and 0.12 mmol/l (13.8%) in heavy smokers. Cigarette smoking was related to fasting triglyceride (directly) but this was removed by further adjustment for HDL-cholesterol. Cigarette smoking was not related to low density lipoprotein cholesterol. These results are compared to those of other surveys.

Adolescent↗
PubMed1993

Effect of weekend physical therapy treatment on postoperative length of stay following total hip and total knee arthroplasty.

Postoperative length of stay (LOS) may be affected by more intensive physical therapy following surgery. This study was designed to assess whether LOS could be affected by weekend physical therapy following surgery in patients who had undergone total hip arthroplasty (THA) or total knee arthroplasty (TKA). Weekend coverage for these patients was made possible by increased staffing in the Physical Therapy Department. The study group consisted of 84 patients who had undergone THA or TKA and had physical therapy treatment the weekend following surgery. The Control group consisted of 53 patients who had undergone THA or TKA prior to the implementation of the weekend intervention program. A retrospective chart audit was used to obtain pertinent information about control group patients. In the total sample mean LOS following weekend therapy (10.84 days) was significantly different (p < 0.05) from mean LOS prior to implementation of the study (12.28 days). Significant decreases in postoperative LOS were also found within the two subgroups of patients who had undergone THA and TKA. The results indicate that physical therapy treatment the weekend following THA or TKA significantly decreases postoperative LOS when physical therapy resources are increased to accommodate this increase in coverage.

Adolescent↗
PubMed1993

Co-purification of mitogen-activated protein kinases with phorbol ester-induced c-Jun kinase activity in U937 leukaemic cells.

Phorbol esters, such as phorbol myristate acetate (PMA), cause differentiation of U937 human monomyelocytic cells along the macrophage pathway. Within 15 min of PMA treatment DNA binding of the c-jun transcription factor is increased and is accompanied by rapid changes in the phosphate content of the c-jun protein. Phorbol esters stimulate phosphorylation of serines 63 and 73 located within the A1 transactivation domain of c-Jun that have previously been shown to positively regulate activity. A protein kinase activity is detectable in extracts of phorbol ester-treated U937 cells that specifically targets these two serines. Using novel assays, the protein kinase activity has been purified over 1000-fold. The major portion of protein kinase activity co-chromatographs over three columns with pp42/44 mitogen-activated protein kinases as judged by immunological methods. The significance of these results with respect to mitogen-induced transcription of AP-1-responsive genes is discussed.

Base Sequence↗
PubMed1992

Glycogen synthase kinase-3: functions in oncogenesis and development.

Study of GSK-3 had an inauspicious beginning rooted in intermediary metabolism. However, owing to the fortuitous convergence of several disparate areas of biology, the enzyme now offers unique opportunities for study of the control of a variety cellular processes. While at first sight a role in transcriptional regulation appears unlikely for a protein first identified as acting on glycogen synthase, it is even more surprising that the same protein should be functionally interchangeable with a fruit fly homeotic gene. Such understandable scepticism, however, is based on teleological bias. Glycogen synthase is a critical enzyme regulating glucose storage. The c-Jun oncoprotein may have the potential to transform cells but this does not excuse it from similar mechanisms of control to glycogen synthase. Likewise, homeotic genes play a crucial role in setting up the body plan of an embryo but must also be subject to control. The main difference is that when such control is lost, the result is rather graphic. It is, therefore, only to be expected that regulatory protein kinases will surface in superficially quite unrelated areas and that many of their targets will be 'housekeeping' proteins. Perhaps the most difficult aspect of protein phosphorylation research is the linking of physiological substrates with particular protein kinases, hence reconstructing pathways. No matter how compelling in vitro data appear, there must be demonstration that the protein is targeted by the specific protein kinase in cells, an extremely difficult process. Most progress in this respect has been made using genetic analysis in lower organisms, especially yeast. Here another problem arises: demonstration of biochemical linkages underlying genetic interactions which requires function to be ascribed to genes identified by a gross effect. The challenge is to co-ordinate these two approaches, a strategy currently being employed to further unravel the biological role of GSK-3.

Amino Acid Sequence↗
PubMed1992

Glycogen synthase kinase-3 induces Alzheimer's disease-like phosphorylation of tau: generation of paired helical filament epitopes and neuronal localisation of the kinase.

Glycogen synthase kinase-3 (GSK-3) reduced the mobility of human tau on SDS-PAGE, prevented binding of the monoclonal antibody (mAb), Tau.1, and induced binding of the mAb 8D8. Recombinant tau phosphorylated by GSK-3 aligned on SDS-PAGE with the abnormally phosphorylated tau (PHF-tau) associated with the paired helical filaments in Alzheimer's disease brain. Phosphorylated serine396 (numbering of the largest human brain tau isoform) was identified as a binding site on tau for mAb 8D8. The localisation of GSK-3 within granular structures in pyramidal cells indicates that GSK-3 alpha and GSK-3 beta may have a role in the production of PHF-tau in Alzheimer's disease.

Alzheimer Disease↗
PubMed1992

Identification of multifunctional ATP-citrate lyase kinase as the alpha-isoform of glycogen synthase kinase-3.

Multifunctional ATP-citrate lyase kinase (ACLK) exhibits several properties that are similar to glycogen-synthase kinase-3 (GSK-3). The molecular cloning of two distinct mammalian GSK-3 cDNAs and a Drosophila melanogaster (fruitfly) homologue, zeste-white3sgg, has established the existence of a GSK-3 subfamily. A multifunctional protein kinase first identified as an ACLK has recently been shown to exhibit several similarities to the alpha- and beta-forms of GSK-3. Here we have used immunological and biochemical analyses to directly compare these enzymes. Thus purified preparations of ACLK isolated from brain and liver preferentially cross-react with anti-GSK-3 alpha antisera and phosphorylate previously defined substrates of GSK-3 at identical sites. Conversely, both alpha- and beta-forms of GSK-3 phosphorylated ATP-citrate lyase at the same site(s) targeted by ACLK. These, and other similarities, demonstrate ACLK to be identical with, or highly related to, GSK-3 alpha, the implications of which are discussed.

Animals↗
PubMed1992

Differential regulation of glycogen synthase kinase-3 beta by protein kinase C isotypes.

In cells, stimulation of protein kinase C (PKC) results in the dephosphorylation of specific residues proximal to the DNA binding domain of c-Jun, a major component of the AP-1 transcription factor. Since phosphorylation of this region of c-Jun inhibits interaction with DNA, this pathway may contribute to PKC activation of AP-1. To determine the mechanism(s) underlying this pathway, possible interactions between PKC and proteins implicated in c-Jun regulation are being investigated. Here it is shown that glycogen synthase kinase-3 beta (GSK-3 beta), a serine/threonine kinase that specifically targets the inhibitory c-Jun phosphorylation sites, is phosphorylated in vitro by particular forms of PKC (alpha, beta 1, gamma greater than beta 2; not epsilon). By contrast, the related GSK-3 alpha is not a substrate for any of these PKC isotypes. Phosphorylation of GSK-3 beta by PKC results in its specific inactivation. These results are consistent with a model in which activation of PKC stimulates c-Jun DNA binding by inhibiting its phosphorylation by GSK-3 beta.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1992

Baculovirus-mediated expression and characterisation of rat glycogen synthase kinase-3 beta, the mammalian homologue of the Drosophila melanogaster zeste-white 3sgg homeotic gene product.

Molecular cloning of glycogen synthase kinase-3 (GSK-3) has demonstrated the existence of a novel form, termed GSK-3 beta, which is highly related to the well characterised GSK-3 alpha protein but derived from a distinct gene. The cDNA cloning also revealed a striking degree of amino acid identity between the two GSK-3 proteins, particularly the beta-form, and the zeste-white3/shaggy (zw3sgg) homeotic gene of Drosophila melanogaster. Abrogation of zw3sgg causes pleiotropic effects on fruitfly development affecting segmental organisation and cell fate determination. In view of the potential importance of GSK-3 beta in mammalian development and the lack of previous characterisation, we have expressed this protein in insect cells using recombinant baculovirus. A rapid purification scheme has been developed yielding essentially pure GSK-3 beta protein in three chromatographic steps. The protein has autonomous protein kinase activity and similar, but not identical, substrate preferences to GSK-3 alpha. Both GSK-3 proteins activate the MgATP-dependent form of protein phosphatase-1 and thus display 'factor A' activity. Since GSK-3 beta exhibits an identical site specificity to GSK-3 alpha with respect to phosphorylation of the proto-oncogene/transcription factors c-jun and c-myc, it is likely that the Drosophila zw3sgg protein kinase has a similar specificity for such transcription factors which may underlie the pleiotropic phenotypes observed when the Drosophila homologue is mutationally inactivated.

Animals↗