Taking heart failure seriously.
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Angiotensin-Converting Enzyme Inhibitors↗
Biomedical subjects
A Clark
Publications and source records attributed to A Clark.
An F-Box/WD40 repeat-containing protein important for Dictyostelium cell-type proportioning, slug behaviour, and culmination.
FbxA is a novel member of a family of proteins that contain an F-box and WD40 repeats and that target specific proteins for degradation via proteasomes. In fruiting bodies formed from cells where the fbxA gene is disrupted (fbxA(-) cells), the spore mass fails to fully ascend the stalk. In addition, fbxA(-) slugs continue to migrate under environmental conditions where the parental strain immediately forms fruiting bodies. Consistent with this latter behaviour, the development of fbxA(-) cells is hypersensitive to ammonia, the signaling molecule that regulates the transition from the slug stage to terminal differentiation. The slug comprises an anterior prestalk region and a posterior prespore region and the fbxA mRNA is highly enriched in the prestalk cells. The prestalk zone of the slug is further subdivided into an anterior pstA region and a posterior pstO region. In fbxA(-) slugs the pstO region is reduced in size and the prespore region is proportionately expanded. Our results indicate that FbxA is part of a regulatory pathway that controls cell fate decisions and spatial patterning via regulated protein degradation.
Amino Acid Motifs↗
Post-transcriptional regulation of pro-inflammatory gene expression.
The cytokine tumour necrosis factor (TNF)alpha is a vital mediator of the innate immune response, and a pleiotropic regulator of cellular function. Its involvement in rheumatoid arthritis is illustrated by the clinical benefits of TNF alpha blockade. Post-transcriptional regulation (the control of mRNA stability and translation) appears to play a critical role in the regulation of TNF alpha expression by mitogen activated protein kinase signal transduction pathways and by anti-inflammatory agents. The aim of this article is to review some recent advances in our understanding of these processes, and to speculate on mechanisms of regulation of TNF alpha and other pro-inflammatory genes.
Humans↗
Preparation of synthetic human islet amyloid polypeptide (IAPP) in a stable conformation to enable study of conversion to amyloid-like fibrils.
Human synthetic islet amyloid polypeptide (hIAPP) is rapidly converted to beta-sheet conformation and fibrils in aqueous media. Optimal solubility conditions for hIAPP were determined by circular dichroism spectroscopy and transmission electron microscopy. hIAPP in trifluoroethanol or hexafluoro-2-isopropanol (HFIP) diluted in water or phosphate buffer (PB) exhibited random structure which was converted to beta-sheet and fibrils with time. hIAPP, solubilised in HFIP, filtered and lyophilised remained in stable random structure for up to 7 days in water; in PB, insoluble aggregates precipitated from which protofilaments and fibrils formed with time. This suggests that amorphous aggregates of hIAPP could initiate islet amyloidosis in vivo.
Amino Acid Sequence↗
Parallel changes of proinsulin and islet amyloid polypeptide in glucose intolerance.
Elevated proinsulin secretion and islet amyloid deposition are both features of Type 2 diabetes but their relationship to beta-cell dysfunction is unknown. To determine if islet amyloid polypeptide (IAPP) secretion is disproportionate with other beta-cell products at any stage of glucose intolerance, 116 subjects were studied. Non-diabetic subjects with equivalent body mass index (BMI) were assigned to three groups, (i) normal fasting glucose, fpg<5.5 mmol l(-1); (ii) intermediate fasting glucose, fpg> or =5.5<6.15 mmol l(-1); (iii) impaired fasting glucose (IFG), fpg> or =6.1<7.0 mmol l(-1). Diabetic subjects were divided according to therapy (9 diet, 19 tablet, and 11 insulin). IAPP, C-peptide and proinsulin were measured fasting and at the end of a 1-h glucose infusion. Fasting C-peptide, IAPP and proinsulin were significantly elevated in the IFG group compared with the other non-diabetic groups (P<0.02); fasting IAPP/C-peptide and proinsulin/C-peptide were 1-2% in all non-diabetic groups. Fasting and 1-h proinsulin and proinsulin/C-peptide were higher in diabetic compared with non-diabetic subjects (P<0.01). IAPP and IAPP/C-peptide in diabetic groups were similar to that in non-diabetic subjects but reduced in the insulin-treated group (P<0.01). Proinsulin was disproportionately increased compared with C-peptide and IAPP in Type 2 diabetes particularly in severe beta-cell failure implying more than one concurrent beta-cell pathology.
Amyloid↗
Physicochemical and biological characterisation of an antisense oligonucleotide targeted against the bcl-2 mRNA complexed with cationic-hydrophilic copolymers.
The aim of this study was to evaluate the use of cationic-hydrophilic copolymers for self-assembly with antisense oligonucleotides targeted to the bcl-2 mRNA in order to improve their biocompatibility and modulation of their pharmacokinetics for greater therapeutic usefulness. Examination of the ability of poly(trimethylammonioethyl methacrylate chloride)-poly[N-(2-hydroxypropyl)methacrylamide] (pHPMA-b-pTMAEM) block copolymers to condense the oligonucleotide by fluorescence and electrophoresis techniques showed that complexes were formed more efficiently than with copolymers containing poly(ethylene glycol) blocks grafted onto the backbone of poly(L-lysine) (pLL-g-pEG). In addition, the copolymer pTMAEM-b-pHPMA produced oligonucleotide complexes with the most favourable physicochemical properties appropriate for in vivo applications. The complexes were small (approximately 36 nm in diameter), with low surface charge as measured by zeta potential, relatively stable to physiological salt conditions and could be formed at a DNA concentration of 500 microg/ml. Complex formation with the copolymer pTMAEM-b-pHPMA or pLL-g-pEG reduced the urinary clearance of the oligonucleotide after intravenous injection into mice. However after 30 min, the oligonucleotide complexes were cleared from the bloodstream. These results indicate that for the systemic delivery of oligonucleotides the polymer-derived complexes are not stable enough for prolonged circulation. Instead, these complexes may be more suitable for localised in vivo applications.
Animals↗
Investigations into pharmacological antagonism of general anaesthesia.
The effects of convulsant drugs, and of thyrotropin releasing hormone (TRH), were examined on the general anaesthetic actions of ketamine, ethanol, pentobarbitone and propofol in mice. The aim was to investigate the possibility of selective antagonism, which, if seen, would provide information about the mechanism of the anaesthesia. The general anaesthetic effects of ketamine were unaffected by bicuculline; antagonism was seen with 4-aminopyridine and significant potentiation with 300 mg kg(-1) NMDLA (N-methyl-DL-aspartate). The calcium agonist, Bay K 8644, potentiated the anaesthesia produced by ketamine and antagonism of such anaesthesia was seen with TRH. A small, but significant, antagonism of the general anaesthesia produced by ethanol was seen with bicuculline, and a small, significant, potentiation with 4-aminopyridine. There was an antagonist effect of TRH, but no effect of NMDLA. Potentiation of the anaesthetic effects of pentobarbitone was seen with NMDLA and with 4-aminopyridine and the lower dose of bicuculline (2.7 mg kg(-1)) also caused potentiation. There was no significant change in the ED(50) value for pentobarbitone anaesthesia with TRH. Bicuculline did not alter the anaesthetic actions of propofol, while potentiation was seen with NMDLA and 4-aminopyridine. TRH had no significant effect on propofol anaesthetic, but Bay K 8644 at 1 mg kg(-1) significantly potentiated the anaesthesia. These results suggest that potentiation of GABA(A) transmission or inhibition of NMDA receptor-mediated transmission do not appear to play a major role in the production of general anaesthesia by the agents used.
Anesthesia, General↗
The antimalarial agent mefloquine inhibits ATP-sensitive K-channels.
The aim of this study was to determine whether antimalarial agents inhibit ATP-sensitive potassium (K(ATP)) channels and thereby contribute to the observed side-effects of these drugs. Mefloquine (10 - 100 microM), but not artenusate (100 microM), stimulated insulin release from pancreatic islets in vitro. Macroscopic K(ATP) currents were studied in inside-out patches excised from Xenopus oocytes expressing cloned K(ATP) channels. Mefloquine (IC(50) approximately 3 microM), quinine (IC(50) approximately 3 microM), and chloroquine inhibited the pancreatic beta-cell type of K(ATP) channel Kir6.2/SUR1. Artenusate (100 microM) was without effect. Mefloquine and quinine also blocked a truncated form of Kir6.2 (Kir6. 2DeltaC36) when expressed in the absence of SUR1. The extent of block was similar to that observed for Kir6.2/SUR1 currents. Our results suggest that inhibition of the beta-cell K(ATP) channel accounts for the ability of quinoline-based antimalarial drugs to stimulate insulin secretion, and thereby produce hypoglycaemia. The results also indicate that quinoline-based antimalarial agents inhibit K(ATP) channels by interaction with the Kir6.2 subunit. This subunit is common to beta-cell, neuronal, cardiac, skeletal muscle, and some smooth muscle K(ATP) channels suggesting that K(ATP) channel inhibition may contribute to the other side effects of these drugs, which include cardiac conduction abnormalities and neuropsychiatric disturbances.
Adenosine Triphosphate↗
Processing of synthetic pro-islet amyloid polypeptide (proIAPP) 'amylin' by recombinant prohormone convertase enzymes, PC2 and PC3, in vitro.
Islet amyloid polypeptide (IAPP), amylin, is the constituent peptide of pancreatic islet amyloid deposits which form in islets of Type 2 diabetic subjects. Human IAPP is synthesized as a 67-residue propeptide in islet beta-cells and colocalized with insulin in beta-cell granules. The mature 37-amino acid peptide is produced by proteolysis at pairs of basic residues at the C- and N-termini of the mature peptide. To determine the enzymes responsible for proteolysis and their activity at the potential cleavage sites, synthetic human proIAPP was incubated (0.5-16 h) with recombinant prohormone convertases, PC2 or PC3 at appropriate conditions of calcium and pH. The products were analysed by MS and HPLC. Proinsulin was used as a control and was cleaved by both recombinant enzymes resulting in intermediates. PC3 was active initially at the N-terminal-IAPP junction and later at the C-terminus, whereas initial PC2 activity was at the IAPP-C-terminal junction. Processing at the basic residues within the C-terminal flanking peptide rarely occurred. There was no evidence for substantial competition for the processing enzymes when the combined substrates proinsulin and proIAPP were incubated with both PC2 and PC3. As proinsulin cleavage is sequential in vivo (PC3 active at the B-chain-C-peptide junction, followed by PC2 at A chain-C-peptide junction), these data suggest that proteolysis of proIAPP and proinsulin is coincident in secretory granules and increased proinsulin secretion in diabetes could be accompanied by increased production of proIAPP.
Amyloid↗
Profiles of cognitive performance associated with reading disability in temporal lobe epilepsy.
92 patients with temporal lobe epilepsy (TLE) were classified into reading deficient (RD; N = 41) and non-reading deficient (no-RD; N = 51) groups. A cutoff of 80 was used to further classify patients as having low average or better (AVG: IQ > 79) or below average (LOW: 69 < IQ < 80) intellectual ability. Differences between RD-AVG and no-RD-AVG patients in profiles of performance on cognitive tests were specific to verbal and non-verbal memory and verbal abilities, but not visuoconstructional and executive abilities. RD-LOW patients exhibited globally reduced abilities. Profiles of performance on cognitive tests were sensitive to side of seizure onset in the no-RD AVG group, but not the RD-AVG or RD-LOW groups. These data suggest that a group of patients with TLE and reduced academic achievement exhibit cognitive deficits suggestive of a language learning disability, and that cognitive tests are less sensitive to side of seizure onset in this group.
Adolescent↗
Emergency medicine resident documentation: results of the 1999 american board of emergency medicine in-training examination survey.
OBJECTIVES: To assess how emergency medicine (EM) residents perform medical record documentation, and how well they comply with Health Care Financing Administration (HCFA) Medicare charting guidelines. In addition, the study investigated their abilities and confidence with billing and coding of patient care visits and procedures performed in the emergency department (ED). Finally, the study assessed their exposure to both online faculty instruction and formal didactic experience with this component of their curriculum. METHODS: A survey was conducted consisting of closed-ended questions investigating medical record documentation in the ED. The survey was distributed to all EM residents, EM-internal medicine, and EM-pediatrics residents taking the 1999 American Board of Emergency Medicine (ABEM) In-Training examination. Five EM residents and the Society for Academic Emergency Medicine (SAEM) board of directors prevalidated the survey. Summary statistics were calculated and resident levels were compared for each question using either chi-square or Fisher's exact test. Alpha was 0.05 for all comparisons. RESULTS: Completed surveys were returned from 88.5% of the respondents. A small minority of the residents code their own charts (6%). Patient encounters are most frequently documented on free-form handwritten charts (38%), and a total of 76% of the respondents reported using handwritten forms as a portion of the patient's final chart. Twenty-nine percent reported delays of more than 30 minutes to access medical record information for a patient evaluated in their ED within the previous 72 hours. Twenty-five percent "never" record their supervising faculty's involvement in patient care, and another 25% record that information "1-25%" of the time. Seventy-nine percent are "never" or "rarely" requested by their faculty to clarify or add to medical records for billing purposes. Only 4% of the EM residents were "extremely confident" in their ability to perform billing and coding, and more than 80% reported not knowing the physician charges for services or procedures performed in the ED. CONCLUSIONS: The handwritten chart is the most widely used method of patient care documentation, either entirely or as a component of a templated chart. Most EM residents do not document their faculty's participation in the care of patients. This could lead to overestimation of faculty noncompliance with HCFA billing guidelines. Emergency medicine residents are not confident in their knowledge of medical record documentation and coding procedures, nor of charges for services rendered in the ED.
Adult↗
Langhans' giant cells in the gills of an Atlantic salmon.
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Animals↗
Relationship between psychotic disorders in adolescence and criminally violent behaviour. A retrospective examination.
BACKGROUND: The interaction between psychosis and violence in adults is an important area of research receiving attention. To date there is little available data examining this relationship in adolescence. AIMS: To investigate the possible relationships between criminally violent types of behaviour, and psychopathology and social factors, among adolescents suffering from a psychotic disorder. METHOD: A retrospective case note study of 39 in-patients diagnosed as having a psychotic disorder and admitted to one of two adolescent psychiatry units (one secure, one open). Cases were divided into a 'violent' and a 'non-violent' group, and these two groups were then compared for social and psychopathological variables. RESULTS: There was no association between recorded psychopathology and criminally violent behaviour. Criminally violent behaviour was associated with a history of emotional or physical abuse, contact with social or mental health services, and previous criminal behaviour. CONCLUSIONS: These findings fail to echo results of studies in adult schizophrenia; they suggest that violent behaviour in psychosis is associated more closely with social factors than with specific symptoms of the psychotic illness. Potential explanations are discussed.
Adolescent↗
Urinary kallikrein excretion in normotensive and hypertensive pregnancies: 8 years later.
In a previous longitudinal study of urinary kallikrein (UK) excretion in pregnancy we reported that women with low inactive UK (IUK) to creatinine ratio (IUK:Cr), measured at 16-20 weeks gestation, were at increased risk of developing pregnancy induced hypertension. In this study, 8 years later, we have recalled 14 women who had an IUK:Cr < or = 170 (Gp1) and became hypertensive in late pregnancy and 14 women who had IUK:Cr > 170 and remained normotensive (Gp2). Resting blood pressure (BP) and BP response following application of cutaneous cold to assess vasoconstrictor reactivity were measured. A timed urine sample was also collected for measurements of components of the kallikrein kinin system (KKS): IUK, active UK (AUK), kininogen (UKg), urinary kinins (UKi). Urinary creatinine (UCr) was also measured. The correlation between IUK:Cr during the 1989-1990 study and current measurement was r2 = 0.52, p < 0.0001. Although resting BP was higher in Gp1 than Gp2 this was not significantly different. However, there was a greater change in diastolic BP in Gp1 than in Gp2 in response to the cold pressor test (p < 0.04). Excretion rates of IUK, UKg and UKi were significantly lower in Gp1, p < 0.006, p < 0.003, p < 0.03, respectively. AUK was also reduced in Gp1 but did not reach statistical significance. Women with reduced activity of the renal KKS combined with increased sympathetic drive may be at increased risk of developing hypertension.
Adult↗
Progesterone metabolite and spontaneous myometrial contractions in vitro.
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20-alpha-Dihydroprogesterone↗
Designing conditions for in vitro formation of amyloid protofilaments and fibrils.
We have been able to convert a small alpha/beta protein, acylphosphatase, from its soluble and native form into insoluble amyloid fibrils of the type observed in a range of pathological conditions. This was achieved by allowing slow growth in a solution containing moderate concentrations of trifluoroethanol. When analyzed with electron microscopy, the protein aggregate present in the sample after long incubation times consisted of extended, unbranched filaments of 30-50 A in width that assemble subsequently into higher order structures. This fibrillar material possesses extensive beta-sheet structure as revealed by far-UV CD and IR spectroscopy. Furthermore, the fibrils exhibit Congo red birefringence, increased fluorescence with thioflavine T and cause a red-shift of the Congo red absorption spectrum. All of these characteristics are typical of amyloid fibrils. The results indicate that formation of amyloid occurs when the native fold of a protein is destabilized under conditions in which noncovalent interactions, and in particular hydrogen bonding, within the polypeptide chain remain favorable. We suggest that amyloid formation is not restricted to a small number of protein sequences but is a property common to many, if not all, natural polypeptide chains under appropriate conditions.
Acid Anhydride Hydrolases↗
The evidence for beta blockers in heart failure.
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Adrenergic beta-Antagonists↗