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Biomedical subjects

P A Rose

Publications and source records attributed to P A Rose.

At least 19 recordsLinked to original sources
PubMed2000

Inhibitors of abscisic acid 8'-hydroxylase.

Structural analogues of the phytohormone (+)-abscisic acid (ABA) have been synthesized and tested as inhibitors of the catabolic enzyme (+)-ABA 8'-hydroxylase. Assays employed microsomes from suspension-cultured corn cells. Four of the analogues [(+)-8'-acetylene-ABA, (+)-9'-propargyl-ABA, (-)-9'-propargyl-ABA, and (+)-9'-allyl-ABA] proved to be suicide substrates of ABA 8'-hydroxylase. For each suicide substrate, inactivation required NADPH, increased with time, and was blocked by addition of the natural substrate, (+)-ABA. The most effective suicide substrate was (+)-9'-propargyl-ABA (K(I) = 0.27 microM). Several analogues were competitive inhibitors of ABA 8'-hydroxylase, of which the most effective was (+)-8'-propargyl-ABA (K(i) = 1.1 microM). Enzymes in the microsomal extracts also hydroxylated (-)-ABA at the 7'-position at a low rate. This activity was not inhibited by the suicide substrates, showing that the 7'-hydroxylation of (-)-ABA was catalyzed by a different enzyme from that which catalyzed 8'-hydroxylation of (+)-ABA. Based on the results described, a simple model for the positioning of substrates in the active site of ABA 8'-hydroxylase is proposed. In a representative physiological assay, inhibition of Arabidopsis thaliana seed germination, (+)-9'-propargyl-ABA and (+)-8'-acetylene-ABA exhibited substantially stronger hormonal activity than (+)-ABA itself.

Abscisic Acid↗
PubMed2000

Anthracenone ABA analogue as a potential photoaffinity reagent for ABA-binding proteins.

An anthracenone analogue of abscisic acid (ABA) was synthesized as a potential photoaffinity reagent and tested for biological activity. Reaction between 10,10'-dimethoxy-9-anthrone with two equivalents of the lithiated dianion of cis-3-methylpent-2-en-4-yn-1-ol afforded an acetylenic alcohol key intermediate. Subsequent reduction of the triple bond, functional group manipulation of the side chain alcohol and deprotection of the dimethoxy protected anthrone provided anthracenone ABA analogue 7 as a potential photoaffinity reagent for ABA-binding proteins. The effect of natural ABA and the potential photoaffinity anthracenone ABA 7 on corn cell growth was determined at various concentrations. The results show that anthracenone ABA 7 is perceived as ABA-like, although producing less inhibition than ABA itself. For example, 7 at 33 microM produces approximately the same inhibition as ABA at 10 microM.

Abscisic Acid↗
PubMed1999

Safety profile of Lansoprazole: the US clinical trial experience.

OBJECTIVE: Lansoprazole has undergone extensive clinical evaluation for the treatment of acid-peptic diseases. The aim of this study was to define the safety profile of lansoprazole and compare it to that of other therapeutic agents evaluated in the same controlled trials. METHODS: The clinical safety profile of lansoprazole and comparative agents (placebo, ranitidine and omeprazole) was reviewed for 3281 patients who participated in short term (up to 8 weeks) and long term (up to 56 months) clinical trials conducted in the US. Adverse events, laboratory value changes and gastric biopsy changes that occurred during treatment were compared statistically for differences between treatments. RESULTS: The incidence of adverse events and number of patients discontinuing treatment because of adverse events was similar for lansoprazole and comparative agents. Other than elevated serum gastrin levels, a known effect of proton pump inhibitors, no trends in laboratory changes were observed. Median values for gastrin levels remained within the normal range; about 2% of patients had gastrin levels >400 pg/ml at any time, while <1% had 2 or more gastrin values >500 pg/ml. Values returned to baseline levels after therapy was discontinued. No significant changes in gastric endocrine cell growth from baseline to final visit were observed, nor was there evidence of dysplasia or neoplasia. CONCLUSION: Lansoprazole is well tolerated for both short and long term treatment of acid-related disease. The tolerability of lansoprazole is comparable to that of ranitidine, omeprazole and placebo in the treatment of these diseases.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1997

Tight clustering of extracellular BP180 epitopes recognized by bullous pemphigoid autoantibodies.

Bullous pemphigoid is a blistering skin disease associated with autoantibodies against the BP180 antigen, a transmembrane component of the hemidesmosome. Anti-BP180 antibodies have been demonstrated to be pathogenic in a passive transfer mouse model. One extracellular site on human BP180 (MCW-1) was previously shown to be recognized by 50-60% of bullous pemphigoid sera. To facilitate the identification of additional autoantibody-reactive epitopes, recombinant forms of the BP180 ectodomain were generated using both bacterial and mammalian expression systems. One recombinant protein, sec180e, that was expressed in COS-1 cells and that contained the entire BP180 ectodomain, provided us with a tool to detect conformational epitopes. Bullous pemphigoid sera immunoadsorbed against the major noncollagenous NC16A domain no longer reacted with sec180e, indicating that autoantibody reactivity to the BP180 ectodomain is restricted to the NC16A region. Immunoblot analysis of bullous pemphigoid sera immunoadsorbed with a series of recombinant NC16A peptides revealed the presence of three novel autoantigenic sites that, along with the MCW-1 epitope, are clustered within the N-terminal 45 amino acid stretch of NC16A. All 15 bullous pemphigoid sera tested reacted with a recombinant protein containing this BP180 segment. No disease-associated epitopes were detectable within the remaining 28 amino acids of NC16A. Thus, bullous pemphigoid patient autoantibodies react with a set of epitopes on the BP180 ectodomain that are highly clustered. This autoantibody-reactive region on human BP180 shows overlap with the corresponding murine BP180 site that is targeted by antibodies that are pathogenic in the mouse model of bullous pemphigoid. These findings suggest new directions for the development of diagnostic and therapeutic tools for this disease.

Amino Acid Sequence↗
PubMed1997

A highly sensitive enzyme-linked immunosorbent assay for the detection of circulating anti-BP180 autoantibodies in patients with bullous pemphigoid.

The BP180 antigen, a component of the epidermal anchoring complex, has been identified as one of the major antigenic targets of autoantibodies associated with the blistering skin disease, bullous pemphigoid. Our research group has recently demonstrated that reactivity of bullous pemphigoid autoantibodies to the BP180 ectodomain is almost entirely restricted to a set of four antigenic sites clustered within the membrane-proximal noncollagenous stretch (NC16A). Using a passive transfer mouse model, antibodies to the corresponding noncollagenous region of murine BP180 were shown to trigger an inflammatory subepidermal blistering disease that closely mimics bullous pemphigoid. We now report the development of an enzyme-linked immunoabsorbent assay system that is extremely sensitive in detecting disease-specific autoantibodies in the sera of bullous pemphigoid patients. The target antigen in this assay is a recombinant form of the BP180 NC16A domain that contains all four of the well-defined bullous pemphigoid-associated antigenic sites. Of 50 randomly selected bullous pemphigoid sera tested, 47 (94%) were positive in this assay, whereas no specific reactivity was detected in any of the 107 controls. Interestingly, all three of the bullous pemphigoid sera that were negative in this assay had been obtained from patients who were already undergoing treatment. The NC16A enzyme-linked immunosorbent assay is more sensitive than any of the standard techniques for detecting circulating bullous pemphigoid autoantibodies, including other enzyme-linked immunosorbent assays, immunoblotting, and indirect immunofluorescence. Finally, the NC16A enzyme-linked immunosorbent assay provides immunologic information that cannot be obtained from direct immunofluorescence studies of skin biopsies, and that may well be relevant in the diagnosis and treatment of bullous pemphigoid.

Autoantibodies↗
PubMed1996

Simultaneous transmission/emission myocardial perfusion tomography. Diagnostic accuracy of attenuation-corrected 99mTc-sestamibi single-photon emission computed tomography.

BACKGROUND: The purpose of the present study was to assess the diagnostic performance of attenuation-corrected (AC) stress 99mTc-sestamibi cardiac single-photon emission computed tomography (SPECT) for the identification of coronary heart disease (CHD). METHODS AND RESULTS: With a triple-detector SPECT system with a 241Am transmission line source, simultaneous transmission/emission tomography (TCT/ECT) was performed on 60 patients with angiographic coronary disease and 59 patients with < or = 5% likelihood of CHD. Iteratively reconstructed AC stress 99mTc-sestamibi perfusion images were compared with uncorrected (NC) filtered-backprojection images. Normal database polar maps were constructed from AC and NC images for quantitative analyses. From the low-likelihood patients, the visual and quantitative normalcy rates increased from 0.88 and 0.76 for NC to 0.98 and 0.95 for AC (P < .05). For the detection of CHD, the receiver operating characteristic curves for the AC images demonstrated improved discrimination capacity (P < .05), and sensitivity/specificity values increased from 0.78/0.46 (NC) to 0.84/0.82 (AC) with visual analysis and from 0.84/0.46 (NC) to 0.88/0.82 (AC) with quantitative analysis. For localization of stenosed vessels, visual and quantitative sensitivity values were 0.51 and 0.63 for NC and 0.64 and 0.78 for AC images (P < .05), respectively. CONCLUSIONS: TCT/ECT myocardial perfusion imaging significantly improves the diagnostic accuracy of cardiac SPECT for the detection and localization of CHD. Clinical use of TCT/ECT imaging deserves serious consideration.

Coronary Angiography↗
PubMed1995

The meaning of critical illness to families.

Critical illness creates stress in patients and their families. However, families' reactions vary and suggest that having a loved one in an intensive care unit (ICU) may not be a crisis for all families. The purpose of this study was to explore and describe the meanings that families ascribe to an ICU experience. In-depth unstructured interviews took place with 18 family members from eight families of ICU patients. Interviews were analyzed qualitatively and revealed five categories of meanings that the ICU experience had for families: "it could go either way," "everything is good," "going upstairs," "like living on a roller-coaster," and "there is no hope." All eight families described an initial period of uncertainty during which they were unsure whether the patient would survive. The subsequent trajectory of critical illness followed one of two paths: positive or negative. The results of this study are of interest to nurses who seek to broaden their understanding of the impact of critical illness on the family.

Adaptation, Psychological↗
PubMed1994

Current results of coronary bypass surgery after failed angioplasty.

Percutaneous Transluminal Coronary Angioplasty (PTCA) is a technique in continuous development. Since its introduction indications, number, quality of stenosis amenable to treatment and device employed have evolved leading to a change in the population undergoing treatment. Therefore surgical results obtained in the early 80's may not apply to the beginning of the 90's. This reason prompted us to review our recent experience. In the last 4 years (1989-1992) among 2563 PTCA procedures performed in our Institution, 114 patients (4.3%, CL 3.5%-5%) underwent urgent surgical revascularization because of failed angioplasty. Thirty-four patients (30%, CL 21%-38%) were older than 65 years; 68 patients (60%, CL 50%-68%) had multiple vessel disease; 63 patients (55%, CL 46%-64%) had previous Myocardial Infarction (M.I.); 20 patients (17%, CL 10%-24%) had already undergone a PTCA and 3 patients (2%, CL 0%-6%) had had coronary surgery. In 21 patients (18%, CL 11%-25%) the left ventricular Ejection Fraction (EF%) was below < 50%. Complete revascularization was always performed with an average of 2.2 +/- 1 graft/patient. A Left Internal Mammary Artery (LIMA) was implanted in 20 patients (17%, CL 10%-25%) of the patients and in 52% of cases requiring LAD grafts in the last two years. There were 2 deaths (1.7%, CL 0%-4%), both patients were in cardiac arrest before surgery (p < 0.001), 2 patients required a LVAD to be weaned from ECC and 7 patients (6%, CL 1%-10%) had an IABP inserted at the moment of surgery. Twenty-five patients (21%, CL 14%-29%) showed evidence of a new myocardial infarction.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

The bovine mannose 6-phosphate/insulin-like growth factor II receptor. The role of arginine residues in mannose 6-phosphate binding.

The extracytoplasmic region of the bovine cation-independent mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF-II receptor) consists of 15 homologous repeating domains, each of which is approximately 147 residues in length. The receptor contains two high affinity mannose 6-phosphate (Man-6-P) binding sites and our recent studies (Westlund, B., Dahms, N. M., and Kornfeld, S. (1991) J. Biol. Chem. 266, 23233-23239) have localized these two binding sites to domains 1-3 and 7-11. To further define the location of the Man-6-P binding sites and to determine the role of specific arginine residues in Man-6-P binding, site-directed mutagenesis was utilized to create truncated soluble forms of the M6P/IGF-II receptor in conjunction with either conservative (Lys) or nonconservative (Ala) replacement of arginine residues. These mutants were expressed transiently in COS-1 cells and assayed for their ability to bind phosphomannosyl residues by affinity chromatography. Analysis of the ligand binding activity of carboxyl-terminal truncated forms of the receptor's extracytoplasmic region demonstrated that the second Man-6-P binding site is contained within domains 7-9. Substitution of Arg435 in domain 3 of the amino-terminal binding site and Arg1334 in domain 9 of the second binding site results in a dramatic loss of ligand binding activity. However, substitutions at positions 435 and/or 1334 did not affect the secretion, glycosylation, or immunoreactivity of these truncated proteins. Taken together, these results indicate that Arg435 and Arg1334 are essential components of the M6P/IGF-II receptor's high affinity Man-6-P binding sites.

Amino Acid Sequence↗
PubMed1992

Optically pure abscisic Acid analogs-tools for relating germination inhibition and gene expression in wheat embryos.

We report an examination of the structural requirements of the abscisic acid (ABA) recognition response in wheat dormant seed embryos using optically pure isomers of ABA analogs. These compounds include permutations to the ABA structure with either an acetylene or a trans bond at C-4 C-5, and either a single or double bond at the C-2' C-3' double bond. (R)-ABA and the three isomers with the same configuration at C-1' as natural ABA were found to be effective germination inhibitors. The biologically active ABA analogs exhibited differential effects on ABA-responsive gene expression. All the ABA analogs that inhibited germination induced two ABA-responsive genes, wheat group 3 lea and dhn (rab). However, (R)-ABA and (S)-dihydroABA were less effective in inducing the ABA-responsive gene Em within the time that embryonic germination was inhibited.

Journal Article↗
PubMed1991

Mutations in the thymidine kinase gene that allow expression of the enzyme in quiescent (G0) cells.

Thymidine kinase (TK) is a nucleotide salvage pathway enzyme whose activity is highly dependent on the growth state and cell cycle phase of a cell. Cells in the resting or quiescent (G0) phase express very low levels of TK mRNA and protein. When quiescent cells are stimulated to enter the cell cycle by the addition of serum, TK mRNA, activity and polypeptide increase coordinately after about 10-15 h, at the beginning of S phase. When growth-independent heterologous promoters are substituted for the natural TK promoter, TK mRNA can be expressed in quiescent cells. Despite the presence of TK mRNA in such G0 cells, there is little expression of TK polypeptide; the normal increase in enzyme at S phase is observed following serum stimulation. Deletion of the introns and 3' untranslated sequences does not affect the expression of the TK gene in serum stimulation experiments. In contrast, deletion of the C-terminal 40 amino acids or fusion of a small segment of a beta-galactosidase to the C-terminus overcomes the block to expression of the TK polypeptide in G0 cells. These C-terminal alterations are the same as those which lead to constitutive expression of TK during the cell cycle of proliferating cells, suggesting that mechanisms which control the levels of TK in cycling cells may also operate in quiescent cells.

Animals↗
PubMed1988

Effect of arterial pressure on drinking and urinary responses to angiotensin II.

To investigate the relationship between angiotensin II (ANG II) and mean arterial pressure (MAP) in the control of drinking in rats, we infused ANG II intravenously at constant rates (either 50 or 100 ng.kg-1.min-1 for 90 min) and varied MAP by intravenous injections of diazoxide (5-20 mg/kg). Rats were pretreated with captopril to block the endogenous synthesis of ANG II. When given alone, low and high doses of ANG II increased MAP approximately 30 and 50 mmHg, respectively. The low but not the high dose significantly increased water intake above control levels. Both doses caused such a large diuresis and natriuresis that the net effect was fluid loss. Reducing MAP toward normal greatly increased the drinking response to the high but not the low dose of ANG II and reduced the urinary solute and water loss to both doses. These results support the hypothesis that water intake and net fluid gain are inhibited when MAP is above normal. When MAP was reduced below normal in rats given constant infusions of ANG II the amount of water drunk and net fluid gain was proportional to the dose of ANG II but not the dose of diazoxide, the degree of hypotension, or urinary losses. This is consistent with previous reports that ANG II is essential for the drinking response to hypotension. Furthermore, it demonstrates that ANG II is not merely permissive but probably the signal controlling water intake when arterial pressure is reduced below normal.

Angiotensin II↗
PubMed1987

Evidence for reorganization of the neuroendocrine centres regulating pulsatile LH secretion in rats receiving neonatal monosodium-L-glutamate treatment.

Previous research has shown that the combination of anterior hypothalamic deafferentation (AHD) and electrolytic lesions of the anterior part of the arcuate nuclei blocks pulsatile LH secretion in ovariectomized rats, but that neither lesion alone was effective. Furthermore, the combination of AHD with arcuate lesions produced by neonatal treatment with monosodium-L-glutamate (MSG) does not block pulsatile LH release. To distinguish between the various possible reasons for this result, AHD and electrolytic lesions of the arcuate nuclei were combined in rats which had been treated neonatally with MSG or saline of equal osmolarity. One week after brain surgery, venous catheters were installed and blood samples taken at 5-min intervals for up to 3 h for assay of plasma LH. Rats treated with MSG and bearing AHD and electrolytic lesions of the arcuate nuclei continued to show pulsatile secretion of LH. Where the electrolytic lesions were posterior and dorsal to the anterior arcuate nuclei, however, LH release was blocked whether AHD was performed or not, but only in rats treated with MSG. None of the lesion combinations blocked pulsatile LH secretion in rats treated with saline. These results suggest that neonatal MSG treatment leads to a reorganization of the hypothalamus such that the role normally played by the arcuate nuclei in the regulation of pulsatile LH secretion is taken over by other hypothalamic structures.

Animals↗
PubMed1986

Effects of anterior hypothalamic deafferentation and neonatal monosodium-L-glutamate treatment on pulsatile LH secretion in the castrated rat.

Previous research has shown that electrolytic lesions of the anterior arcuate nuclei combined with anterior hypothalamic deafferentation (AHD) blocked pulsatile luteinizing hormone (LH) release in the ovariectomized rat, but that neither lesion was sufficient by itself. This led to the hypothesis that two separate neural pathways were capable of effecting pulsatile LH secretion, which was tested in another way in the present study. Newborn rats were injected with monosodium glutamate (MSG), a treatment which damages the arcuate nuclei, or NaCl of the same osmolarity as a control. As adults, the rats were gonadectomized and 2 weeks later, AHD or sham AHD was performed. One week after that, the rats were catheterized, and small blood samples were taken every 5 min for 3 h. Plasma was assayed for LH by radioimmunoassay. Neither MSG alone, AHD alone, nor the combination affected the number of animals with pulsatile LH patterns. In female rats, MSG treatment slightly decreased pulse frequency, while AHD depressed mean LH levels in male rats. No differences were seen in LH pulse amplitude. These results suggest either that MSG spares those neurons of the arcuate nuclei which are important for LH secretion, that electrolytic lesions of the arcuate nuclei destroy fibres of passage which are important for LH release, or that functional reorganization of the systems controlling LH release occurs following neonatal MSG treatment.

Afferent Pathways↗
PubMed1986

Hyperresponsiveness to the inhibitory action of dopamine agonists on luteinizing hormone secretion in the monosodium-L-glutamate-treated, orchidectomized rat.

The tuberoinfundibular (A12) dopaminergic pathway, which originates in the arcuate and periventricular nuclei, is thought to play an inhibitory role in the regulation of episodic luteinizing hormone (LH) secretion. Neonatal treatment of rats with the neurotoxin monosodium-L-glutamate (MSG) causes extensive damage to the arcuate nuclei and up to 60% depletion of dopamine (DA) in the mediobasal hypothalamus. We hypothesized that such DA depletion should result in a hyperresponsiveness to subsequent administration of a DA agonist. To test this hypothesis, male rats were treated neonatally with MSG. Control rats received injections of equiosmotic saline. As adults the rats were orchidectomized and fitted with indwelling venous catheters. Blood samples were taken from these unanesthetized, unrestrained rats at 5-min intervals for a 1-hour period, at which time the animals received an intraperitoneal injection of one of the following drugs: apomorphine (0.8 mg/kg, a DA receptor agonist), bromocriptine (8.0 mg/kg, a DA receptor agonist), 0.9% saline (vehicle for apomorphine) or 95% ethanol (vehicle for bromocriptine). Blood sampling was continued for a further 2-2.5 h. Plasma LH was measured by RIA. Both apomorphine and bromocriptine produced striking inhibition of circulating LH levels in MSG-treated rats. Neither of the control treatments altered pulsatile LH secretion patterns. Administration of exogenous gonadotropin-releasing hormone produced LH peaks in all animals so treated, including those whose endogenous LH secretion had been inhibited by the DA agonists. These findings suggest that the depletion of DA induced by neonatal MSG treatment results in a supersensitivity to DA agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1977

Afterdischarge thresholds and kindling rates in dorsal and ventral hippocampus and dentate gyrus.

Electrodes were implanted to dorsal hippocampus (CA1), ventral CA1, DOrsal dentate gyrus or ventral dentate gyrus. Epileptiform afterdischarge (AD) thresholds were lower in dorsal areas than in ventral areas. Dorsal areas, however, required a greater number of stimulations to develop ("kindle") a fully generalized convulsion than did ventral areas. Thresholds and kindling rates in the dentate gyrus were intermediate between dorsal and ventral CA1, except for the ventral dentate which had higher AD thresholds than ventral CA1. Secondary sites within the hippocampus subsequently kindled within a few stimulations following completion of kindling in the primary site, regardless of which hippocampal area served as the primary site.

Animals↗
PubMed1973

Studies on the sulphation of 3,4-dihydroxyphenylethylamine (dopamine) and related compounds by rat tissues.

The formation of sulpho-conjugates of 3,4-dihydroxyphenylethylamine (dopamine) and related compounds was examined in preparations of rat tissues. Liver high-speed-supernatant preparations readily transferred sulphate from adenosine 3'-phosphate 5'-sulphato-phosphate to dopamine under standard conditions. The main product was identified as the 3-O-sulphate. The preparation also sulphated the 3- and 4-methoxy derivatives but to a lesser extent (44% and 95% respectively) relative to dopamine. Brain preparations possessed only half the activity of liver but formed both the 3- and 4-O-sulphates in the molar ratio of 1.7:1. l-3,4-Dihydroxyphenylalanine (l-dopa) in both tissue preparations did not yield any significant amount of sulpho-conjugate when the dopa decarboxylase present was inhibited. The sulphotransferase activity of preparations was doubled in the presence of dithiothreitol and it was concluded that l-tyrosine methyl ester sulphotransferase was the enzyme involved. A method for the preparation of authentic dopamine 3-O-sulphate and 4-O-sulphate was developed.

Animals↗