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Biomedical subjects

J A Porter

Publications and source records attributed to J A Porter.

At least 19 recordsLinked to original sources
PubMed2005

The effect of density on the properties of short chain fluids.

We incorporate density dependence into continuum Born-Green-Yvon (BGY) theory through calculation of the end-to-end intramolecular correlation function. Whereas in previous studies we had only performed this calculation for the case of an isolated (zero-density) square-well chain of m segments (3</=m</=7), here we consider this single chain to have been placed in a square-well monomeric fluid of variable density. We find that the results obtained by this more sophisticated approach are in good agreement with the predictions of both other theories and simulation concerning the structural properties of short chains. Using a homologous series of n-alkanes as a test case, we also conclude that BGY theory, with the current modifications, is capable of describing fluid properties for heptane (n-C7) through nonadecane (n-C19).

Journal Article↗
PubMed2004

Comparison of lattice and continuum treatments of n-alkanes with experimental data.

Using a homologous series of n-alkanes as a model system, we compare the predictions of a lattice Born-Green-Yvon (BGY) theory and a continuum BGY theory with experimental results. We find that both theories are capable of describing the fluid properties and critical points of alkanes ranging from heptamers (n-C7) to nonadecamers (n-C19). We probe the connection between the lattice and continuum BGY models and extend our discussion to include a sampling of other lattice and continuum treatments.

Journal Article↗
PubMed2003

Comparison of effects of GnRH and prostaglandin in combination, and prostaglandin on conception rates and time to conception in dairy cows.

OBJECTIVE: To assess the effectiveness of a gonadotrophin-releasing hormone (GnRH) / prostaglandin program (GnRH-PG-GnRH, Ovsynch) on conception rates and time to conception of lactating dairy cows compared with a PG program (double prostaglandin injection). DESIGN: A randomised multi-centre cohort study was conducted with 778 cows from nine dairy herds. Cows at different stages of lactation were randomly assigned, after matching for days open at the time of treatment, to either the PG or Ovsynch program. PROCEDURE: Cows on the PG program received two intramuscular injections of prostaglandin (2 mL, Prosolvin) 11 days apart. The Ovsynch program consisted of two intramuscular injections of GnRH (1 mL, Fertagyl) 9 days apart, separated by one injection of prostaglandin 40 h before the second GnRH injection. Milk samples were taken at the time of artificial insemination and assayed for progesterone by radioimmunoassay. RESULTS: The Ovsynch program was not significantly different to PG in achieving conception, with overall conception rates of 37.6% and 41.4%, respectively, for each program. There was, however, a significant interaction between the effects of parity and treatment (P = 0.03), because conception rates were higher in older cows (parity 5 or more) on the PG program than for older cows on the Ovsynch program. There was no significant effect of treatment (P > 0.5) on time to conception after treatment, but older cows were slower to conceive (P < 0.0001). Conception rates differed (P < 0.0001) among herds. CONCLUSION: The median days to conception for both groups was 22 and mean days from treatment to conception were 36.3 +/- 3.3 and 31.6 +/- 2.7 for the Ovsynch and PG programs respectively, indicating that reproductive performance of cows was not significantly different with Ovsynch program or PG program. There appears to be a need to evaluate causes of reproductive failure in older cows.

Aging↗
PubMed1999

Sonic hedgehog protein signals not as a hydrolytic enzyme but as an apparent ligand for patched.

The amino-terminal signaling domain of the Sonic hedgehog secreted protein (Shh-N), which derives from the Shh precursor through an autoprocessing reaction mediated by the carboxyl-terminal domain, executes multiple functions in embryonic tissue patterning, including induction of ventral and suppression of dorsal cell types in the developing neural tube. An apparent catalytic site within Shh-N is suggested by structural homology to a bacterial carboxypeptidase. We demonstrate here that alteration of residues presumed to be critical for a hydrolytic activity does not cause a loss of inductive activity, thus ruling out catalysis by Shh-N as a requirement for signaling. We favor the alternative, that Shh-N functions primarily as a ligand for the putative receptor Patched (Ptc). This possibility is supported by new evidence for direct binding of Shh-N to Ptc and by a strong correlation between the affinity of Ptc-binding and the signaling potency of Shh-N protein variants carrying alterations of conserved residues in a particular region of the protein surface. These results together suggest that direct Shh-N binding to Ptc is a critical event in transduction of the Shh-N signal.

Amino Acid Sequence↗
PubMed1998

Requirement for the NINAC kinase/myosin for stable termination of the visual cascade.

Activation of the Drosophila photoresponse is a rapid process that results in plasma membrane Ca2+ and Na+ conductances. Ca2+ functions in negative feedback regulation of Drosophila vision including deactivation. Protein kinase C (PKC) binds directly to Ca2+ and is required for deactivation. However, the consequences of disrupting phosphorylation of any individual PKC substrate in the Drosophila retina have not been addressed. In the current work, we show that NINAC p174, which consists of a protein kinase domain joined to the head region of myosin heavy chain, is a phosphoprotein and is phosphorylated in vitro by PKC. Mutation of either of two PKC sites in the p174 tail resulted in an unusual defect in deactivation that had not been detected previously for other ninaC alleles or other loci. After cessation of the light stimulus, there appeared to be a transient reactivation of the visual cascade. This phenotype suggests that a mechanism exists to prevent reactivation of the visual cascade and that p174 participates in this process.

Animals↗
PubMed1998

Teratogen-mediated inhibition of target tissue response to Shh signaling.

Veratrum alkaloids and distal inhibitors of cholesterol biosynthesis have been studied for more than 30 years as potent teratogens capable of inducing cyclopia and other birth defects. Here, it is shown that these compounds specifically block the Sonic hedgehog (Shh) signaling pathway. These teratogens did not prevent the sterol modification of Shh during autoprocessing but rather inhibited the response of target tissues to Shh, possibly acting through the sterol sensing domain within the Patched protein regulator of Shh response.

Abnormalities, Drug-Induced↗
PubMed1997

Crystal structure of a Hedgehog autoprocessing domain: homology between Hedgehog and self-splicing proteins.

The approximately 25 kDa carboxy-terminal domain of Drosophila Hedgehog protein (Hh-C) possesses an autoprocessing activity that results in an intramolecular cleavage of full-length Hedgehog protein and covalent attachment of a cholesterol moiety to the newly generated amino-terminal fragment. We have identified a 17 kDa fragment of Hh-C (Hh-C17) active in the initiation of autoprocessing and report here its crystal structure. The Hh-C17 structure comprises two homologous subdomains that appear to have arisen from tandem duplication of a primordial gene. Residues in the Hh-C17 active site have been identified, and their role in Hedgehog autoprocessing probed by site-directed mutagenesis. Aspects of sequence, structure, and reaction mechanism are conserved between Hh-C17 and the self-splicing regions of inteins, permitting reconstruction of a plausible evolutionary history of Hh-C and the inteins.

Amino Acid Sequence↗
PubMed1997

Postabsorption concentration peaks with brand-name and generic verapamil: a double-blind, crossover study in elderly hypertensive patients.

The pharmacokinetic actions, bioequivalence, and cardiovascular effects of two verapamil products were studied in a randomized, double-blind, crossover study in eight elderly hypertensive patients (median age, 69.5 years; range, 60-79 years) given brand-name or generic immediate-release verapamil in 120-mg twice-daily doses for 14 days. Blood pressures, heart rates, P-R intervals; and serum concentrations of R-/S-verapamil and norverapamil were measured multiple times in patients during the last day of each therapy. Median blood pressure decreased more with generic verapamil than with the brand-name drug, with the largest difference occurring at 0.5 hours (137/74 mmHg versus 144.5/80.5 mmHg; P = 0.05 and 0.091, respectively). Pharmacokinetic parameters were not different for the two products (P < 0.01). However, the generic product, compared with the brand-name drug, had mean area under the concentration-time curve (time 0 to 12 hours) ratios (90% CI) of 1.09 (0.78-1.52), 1.16 (0.87-1.55) and 1.11 (0.81-1.52) for R-, S-, and total verapamil. Seventy concentration peaks (31 with the brand-name drug, 39 with the generic drug) appeared between 8 and 24 hours. Median percentages of increase of these peaks, compared with those of previous concentrations, were 48.3% and 36.3% for brand-name and generic drugs, respectively. Fifty of the 70 peaks (71%) were associated with a stereospecific concentration peak of norverapamil and, temporally, with meals. Our findings suggest that whereas the two verapamil products may not be bioequivalent by Food and Drug Administration criteria, the observed differences in effects were not clinically significant in this elderly population. Multiple concentration peaks after absorption were observed in all patients with both verapamil products and were perhaps related to enterohepatic recirculation.

Aged↗
PubMed1997

Splenic rupture from colonoscopy. A report of two cases and review of the literature.

Splenic injury after colonoscopy is rare. Only 15 cases previously have been reported in the English literature. Partial capsular avulsion is the proposed mechanism of injury. Any condition causing increased splenocolic adhesions may be a predisposing factor to splenic injury. Two cases of splenic injury following colonoscopy are reported in addition to a complete review of the literature.

Colonoscopy↗
PubMed1997

Validation of the five-drug "Pittsburgh cocktail" approach for assessment of selective regulation of drug-metabolizing enzymes.

OBJECTIVES: To determine whether the probe drugs caffeine, chlorzoxazone, dapsone, debrisoquin (INN, debrisoquine), and mephenytoin can be simultaneously administered as a metabolic cocktail to estimate in vivo cytochrome P450 (CYP) and N-acetyltransferase enzyme activities. METHODS: Fourteen healthy nonsmoking male volunteers (mean age +/- SD, 21.6 +/- 2.2 years) received 100 mg caffeine, 250 mg chlorzoxazone, 100 mg dapsone, 10 mg debrisoquin, and 100 mg mephenytoin individually and in four and five-drug combinations in a randomized manner using a 7 x 7 Latin square. Each drug or drug combination was given orally after an overnight fast, with a minimum 1-week washout between administrations. In each session, urine was collected from 0 to 8 hours and plasma was obtained at 4 and 8 hours after drug administration. Plasma and metabolite concentrations were used to estimate phenotypic trait measures for the efficiency of each drug's metabolism. RESULTS: The phenotypic indexes determined for caffeine, chlorzoxazone, dapsone, debrisoquin, and mephenytoin were not significantly different when given alone than when given in combination. The median percentage change of the trait measures observed during administration of all five compounds compared with individual administration ranged from -10.7% for the 6-hydroxychlorzoxazone to chlorzoxazone plasma ratio to +2.2% for the debrisoquin recovery ratio. CONCLUSIONS: The results of this study show that caffeine, chlorzoxazone, dapsone, debrisoquin, and mephenytoin in low doses can be simultaneously administered without metabolic interaction. This cocktail approach can thus simultaneously provide independent in vivo phenotypic measures for multiple CYP enzymes and N-acetyltransferase.

Adult↗
PubMed1996

Cholesterol modification of hedgehog signaling proteins in animal development.

Hedgehog (Hh) proteins comprise a family of secreted signaling molecules essential for patterning a variety of structures in animal embryogenesis. During biosynthesis, Hh undergoes an autocleavage reaction, mediated by its carboxyl-terminal domain, that produces a lipid-modified amino-terminal fragment responsible for all known Hh signaling activity. Here it is reported that cholesterol is the lipophilic moiety covalently attached to the amino-terminal signaling domain during autoprocessing and that the carboxyl-terminal domain acts as an intramolecular cholesterol transferase. This use of cholesterol to modify embryonic signaling proteins may account for some of the effects of perturbed cholesterol biosynthesis on animal development.

Animals↗
PubMed1996

Hedgehog patterning activity: role of a lipophilic modification mediated by the carboxy-terminal autoprocessing domain.

Autocatalytic processing mediated by the carboxyterminal domain of the hedgehog (hh) protein precursor (Hh) generates an amino-terminal product that accounts for all known signaling activity. The role of autoprocessing biogenesis of the hh signal has been unclear, since a truncated unprocessed protein lacking all carboxy-terminal domain sequences retains signaling activity. Here, we present evidence that the autoprocessing reaction proceeds via an internal thioester intermediate and results in a covalent modification that increases the hydrophobic character of the signaling domain and influences its spatial and subcellular distribution. We demonstrate that truncated unprocessed amino-terminal protein causes embryonic mispatterning, even when expression is localized to cells that normally express Hh, thus suggesting a role for autoprocessing in spatial regulation of hh signaling. This type of processing also appears to operate in the biogenesis of other novel secreted proteins.

Animals↗
PubMed1996

Angiotensin II receptor antagonists: the prototype losartan.

OBJECTIVE: To describe a new class of antihypertensive agents, the angiotensin II receptor antagonists, with emphasis on the prototype losartan. Pharmacokinetic data and clinical trials are reviewed, as well as adverse reactions, drug interactions, and dosing guidelines. DATA SOURCES: A MEDLINE search of English-language literature published from 1966 through 1995 was performed. In addition, Merck and Co. provided bibliographic data on file for losartan. STUDY SELECTION: Emphasis was placed on clinical and pharmacokinetic studies in humans. Controlled, double-blind studies were evaluated to assess the efficacy and adverse effect profile of losartan. DATA SYNTHESIS: Losartan is a nonpeptide, competitive antagonist of the type I angiotensin II receptor. In comparative clinical trials, losartan appears to have antihypertensive efficacy similar to that of the angiotensin-converting enzyme (ACE) inhibitors. Losartan is well tolerated, with an adverse effect profile similar to that of placebo and a reduced incidence of cough versus that with ACE inhibitors. A combination product consisting of losartan 50 mg and hydrochlorothiazide 12.5 mg has also received approval for the treatment of hypertension. The combination product is not indicated for initial therapy, but is recommended for patients who do not respond adequately to losartan monotherapy. The angiotensin II receptor antagonists are also being investigated for beneficial effects in patients with ventricular hypertrophy, renal disease, and heart failure. CONCLUSIONS: Losartan, the first angiotensin II receptor antagonist to receive approval for use in the US, appears to be an effective new antihypertensive agent with an adverse effect profile similar to that of placebo. Losartan may be an alternative for patients who cannot tolerate ACE inhibitors. However, the effect of losartan on mortality remains to be evaluated. The role of the angiotensin II receptor antagonists in areas such as ventricular hypertrophy, renal function, and heart failure has yet to be determined.

Angiotensin II↗