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Biomedical subjects

A Michael

Publications and source records attributed to A Michael.

At least 19 recordsLinked to original sources
PubMed2000

Glycogen synthase kinase-3beta is a negative regulator of cardiomyocyte hypertrophy.

Hypertrophy is a basic cellular response to a variety of stressors and growth factors, and has been best characterized in myocytes. Pathologic hypertrophy of cardiac myocytes leads to heart failure, a major cause of death and disability in the developed world. Several cytosolic signaling pathways have been identified that transduce prohypertrophic signals, but to date, little work has focused on signaling pathways that might negatively regulate hypertrophy. Herein, we report that glycogen synthase kinase-3beta (GSK-3beta), a protein kinase previously implicated in processes as diverse as development and tumorigenesis, is inactivated by hypertrophic stimuli via a phosphoinositide 3-kinase-dependent protein kinase that phosphorylates GSK-3beta on ser 9. Using adenovirus-mediated gene transfer of GSK-3beta containing a ser 9 to alanine mutation, which prevents inactivation by hypertrophic stimuli, we demonstrate that inactivation of GSK-3beta is required for cardiomyocytes to undergo hypertrophy. Furthermore, our data suggest that GSK-3beta regulates the hypertrophic response, at least in part, by modulating the nuclear/cytoplasmic partitioning of a member of the nuclear factor of activated T cells family of transcription factors. The identification of GSK-3beta as a transducer of antihypertrophic signals suggests that novel therapeutic strategies to treat hypertrophic diseases of the heart could be designed that target components of the GSK-3 pathway.

Animals↗
PubMed1999

A rare coding variant within the wolframin gene in bipolar and unipolar affective disorder cases.

A recent report has shown that Wolfram syndrome carriers (heterozygotes) are 26-fold more likely to require psychiatric hospitalization compared with non-carriers, and that Wolfram syndrome heterozygotes may constitute approximately 25% of individuals hospitalized with depression and suicide attempts. We analyzed a His611Arg polymorphism of the wolframin gene by the polymerase chain reaction (PCR) and HhaI restriction digestion, in 158 bipolar I and 163 unipolar major affective disorder cases, and 316 controls. Statistical analyses of allele or genotype frequencies do not support a major role for wolframin in affective disorder. HhaI restriction digestion and sequencing of PCR products from four affective disorder cases showed a heterozygous Ala559Thr change. The Ala559Thr variant was not detectable in 382 controls tested. Thus, the rare wolframin 559Thr allele deserves consideration as a risk allele for affective disorder.

Alleles↗
PubMed1999

Emotional bias and inhibitory control processes in mania and depression.

BACKGROUND: Despite markedly different clinical presentations, few studies have reported differences in neuropsychological functioning between mania and depression. The disinhibited behaviour characteristic of mania and evidence that subgenual prefrontal cortex is differentially activated in mania and depression both suggest that dissociable deficits will emerge on tasks that require inhibitory control and are subserved by ventromedial prefrontal cortex. METHODS: Manic patients and controls undertook computerized neuropsychological tests of memory and planning ability. In addition, manic and depressed patients were directly compared with controls on a novel affective shifting task that requires inhibitory control over different components of cognitive and emotional processing. RESULTS: Manic patients were impaired on tests of memory and planning. Importantly, affective shifting performance of manic patients differed from that of depressed patients. Manic patients were impaired in their ability to inhibit behavioural responses and focus attention, but depressed patients were impaired in their ability to shift the focus of attention. Depressed patients exhibited an affective bias for negative stimuli, and we believe this to be the first demonstration of an affective bias for positive stimuli in manic patients. CONCLUSIONS: Observed impairments on tests of memory and planning suggest a global pathology for mania consistent with previous profiles for this disorder and similar to established profiles for depression. The results on the affective shifting task demonstrate the presence of mood-congruent bias and dissociable components of inhibitory control in mania and depression. Against a background of memory and planning impairments in the two groups, these findings are consistent with a role for the ventromedial prefrontal cortex in mediating mood-cognition relationships.

Adult↗
PubMed1999

Identification and characterization of cDNA clones encoding hydroxycinnamoyl-CoA:tyramine N-hydroxycinnamoyltransferase from tobacco.

The sequences of three cDNA clones that include the complete coding region of hydroxycinnamoyl-CoA:tyramine N-hydroxycinnamoyltransferase (THT) from tobacco are reported. The three cDNAs were isolated by antibody screening of a cDNA expression library produced from poly(A)+RNA purified from tobacco leaves (Nicotiana tabacum cv. Bottom Special), previously infiltrated with an incompatible strain of Ralstonia solanacearum. The identity of these clones was confirmed by the detection of THT activity in extracts of transformed Escherichia coli and by matching the translated polypeptides with tryptic enzyme sequences. cDNA clones tht4 and tht11 differ only by their 5' leader and 3' UTRs and therefore encode the same protein, whereas tht10 and tht11 exhibit 95 and 99% sequence identity at the DNA and deduced amino acid levels, respectively. The three clones encode proteins of 226 amino acids with calculated molecular masses of 26 kDa. The deduced amino acid sequences show no similarity with the sequence of anthranilate hydroxycinnamoyl/benzoyltransferase from Dianthus caryophyllus, the only enzyme exhibiting hydroxycinnamoyltransferase activity to be cloned so far in plants. In contrast, comparison of the THT amino acid sequence with protein sequence databases revealed substantial homology with mammalian diamine acetyltransferases. The THT clones hybridized to a 0.95-kb mRNA from elicited tobacco cell-suspension cultures and also to a mRNA of similar size from wound-healing potato tubers. The messengers for THT were also found to be expressed at relatively high levels in tobacco root tissues. Southern hybridization of tobacco genomic DNA with THT cDNA suggests that several copies of the THT gene occur in the tobacco genome. Inhibition experiments using amino-acid-specific reagents demonstrated that both histidyl and cysteyl residues are required for THT activity. In the course of these experiments THT was also found to be inhibited by (2-hydroxyphenyl) amino sulfinyl acetic acid 1,1-dimethylethyl ester, an irreversible inhibitor of cinnamyl alcohol dehydrogenase.

Acyltransferases↗
PubMed1999

Aetiology and clinical signs of bacterial meningitis in children admitted to Goroka Base Hospital, Papua New Guinea, 1989-1992.

Children aged 1-59 months admitted to Goroka Base Hospital with signs suggestive of meningitis were recruited to determine what proportion of such children have clinical or bacterial meningitis and to investigate the bacterial aetiology. A laboratory classification of definite, probable, possible, indeterminate and no meningitis was established. Thirty per cent of 697 children had a final clinical diagnosis of meningitis, 12% had culture-proven bacterial meningitis (case fatality rate 34%) and 10% had probable or possible meningitis. Inability to feed, vomiting, drowsiness, "staring eyes" and haemoglobin < 9 g/dl in addition to the classical signs of meningitis were associated with increased mortality. Isolates from cerebrospinal fluid were 62 pneumococci, 22 Haemophilus influenzae type b (Hib) and one Neisseria meningitidis. Including blood culture-proven and antigen-proven Hib disease, Hib and pneumococci accounted for 44% and 46% of bacterial meningitis, respectively, and 23% of pneumococci were intermediately resistant to penicillin. Inability to feed, bulging fontanelle, convulsions in young children, neck stiffness, fever and "staring eyes" were all independently associated with bacterial meningitis. Conjugate Hib vaccine must be given to infants as early as possible. Conjugate pneumococcal vaccines, maternal immunization with 23-valent vaccine and pneumococcal protein vaccines are under investigation for prevention of pneumococcal disease.

Age Distribution↗
PubMed1999

Bacterial and viral etiology of severe infection in children less than three months old in the highlands of Papua New Guinea.

OBJECTIVE: Determine the bacterial and viral etiology of severe infection in young Papua New Guinean infants as part of a multicenter study in four developing countries aimed at improving case management guidelines. METHODS: Between March, 1991, and April, 1993, children aged <3 months were recruited at the outpatient department of Goroka Base Hospital, Papua New Guinea (PNG). Children with pre-defined inclusion criteria were enrolled, a history was taken and clinical examination was performed. Blood and urine were collected from children with signs suggestive of severe disease together with eye, umbilical and pernasal swabs as appropriate. Nasopharyngeal aspirates (NPAs) were collected from children with and without signs of severe disease for identification of viruses and Chlamydia trachomatis by direct fluorescent antibody staining. RESULTS: 3280 infants were triaged and 2168 enrolled, among whom 968 had signs suggestive of severe disease. Group A Streptococcus (Streptococcus pyogenes) and Staphylococcus aureus were the most important bacterial pathogens isolated from children < 1 month old with severe infections, and Streptococcus pneumoniae, S. pyogenes and Staphylococcus aureus were most important in older children. Of 292 eye swabs 19 (7%) grew Neisseria gonorrhoeae. Of 116 umbilical swabs 51 (44%) grew S. pyogenes and 45 (39%) grew Staphylococcus aureus. Respiratory syncytial virus was the most important viral cause of acute lower respiratory infection. CONCLUSIONS: S. pyogenes, S. pneumoniae and Staphylococcus aureus are important causes of severe infection in young children in the PNG highlands. It is necessary to improve access to clean water, promote hand-washing in the hospital and at home and investigate further the use of maternal immunization for the prevention of severe disease in young infants.

Bacteria↗