Search PubMed⌕ Search

Biomedical subjects

D Maclean

Publications and source records attributed to D Maclean.

At least 19 recordsLinked to original sources
PubMed2001

The reversed Kenner linker: a new safety-catch linker for the preparation of N-alkyl sulfonamides.

A new strategy for the solid-phase synthesis of sulfonamides is described. The Kenner safety-catch strategy has been modified such that the carboxylic acid component remains attached to the solid support while the sulfonamide portion is released into solution. An initial demonstration of the scope of this strategy is presented, along with an analysis of the cleavage characteristics and extension to more elaborate products via Suzuki reaction and thiazolidinone synthesis. Reaction: see text.

Chemistry, Pharmaceutical↗
PubMed2001

Drugs in pregnancy. Renal disease.

The management of pregnant women with renal impairment presents a major challenge to obstetricians, nephrologists, and ultimately paediatricians. As renal failure progresses there is an increase in both maternal and fetal complications. Often these women have intercurrent medical conditions and, prior to conception, are receiving a broad range of prescribed medications. A successful obstetric outcome relies upon careful pre-pregnancy counselling and planning, obsessive monitoring during pregnancy, and close liaison between different specialist teams. Experience is mounting in the management of pregnant transplant recipients, but the introduction of newer immunosuppressive agents which have great promise in prolonging graft survival present new problems for those recipients of a kidney transplant who are planning to conceive. We review drug prescription for pregnant patients with renal impairment, end-stage renal failure, or a kidney transplant.

Female↗
PubMed2000

Honest assessments of automatic learning algorithm performance.

OBJECTIVE: To compare methods of evaluating probabilistic predictors in systems that learn from examples. STUDY DESIGN: The performance of four automatic learning algorithms, representing current machine learning technology, were assessed using four methodologies in the task of separating normal squamous intermediate cervical cells from all other segmented objects in digital images. Two of the methodologies were carefully constructed to model sources of variation associated with the choice of training and test sets. These assessments were statistically compared with assessments using both standard and a modified version of cross-validation. RESULTS: The investigation illustrates the tradeoffs involved in obtaining statistical rigor as compared with the cost of collecting data. While cross-validation makes frugal use of data, it can produce misleading assessments of algorithm performance in terms of both bias and variance. The modified version produces more reliable assessments but in some cases may also be misleading. CONCLUSION: We suggest that users of learning algorithms should exercise judicious care in evaluating learning algorithm performance in order to avoid unnecessary bias and large variance in their assessments.

Algorithms↗
PubMed1998

Adenosine concentrations in the interstitium of resting and contracting human skeletal muscle.

BACKGROUND: Adenosine has been proposed to be a locally produced regulator of blood flow in skeletal muscle. However, the fundamental questions of to what extent adenosine is formed in skeletal muscle tissue of humans, whether it is present in the interstitium, and where it exerts its vasodilatory effect remain unanswered. METHODS AND RESULTS: The interstitial adenosine concentration was determined in the vastus lateralis muscle of healthy humans via dialysis probes inserted in the muscle. The probes were perfused with buffer, and the dialysate samples were collected at rest and during graded knee extensor exercise. At rest, the interstitial concentration of adenosine was 220+/-100 nmol/L and femoral arterial blood flow (FaBF) was 0.19+/-0.02 L/min. When the subjects exercised lightly, at a work rate of 10 W, there was a markedly higher (1140+/-540 nmol/L; P<0.05) interstitial adenosine concentration and a higher FaBF (2.22+/-0.18 L/min; P<0.05) compared with at rest. When exercise was performed at 20, 30, 40, or 50 W, the concentration of adenosine was moderately greater for each increment, as was the level of leg blood flow. The interstitial concentrations of ATP, ADP, and AMP increased from rest (0.13+/-0.03, 0.07+/-0.03, and 0.07+/-0.02 micromol/L, respectively) to exercise (10 W; 2.00+/-1.32, 2.08+/-1.23, and 1.65+/-0.50 micromol/L, respectively; P<0.05). CONCLUSIONS: The present study provides, for the first time, interstitial adenosine concentrations in human skeletal muscle and demonstrates that adenosine and its precursors increase in the exercising muscle interstitium, at a rate associated with intensity of muscle contraction and the magnitude of muscle blood flow.

Adenosine↗
PubMed1997

Encoded combinatorial chemistry: synthesis and screening of a library of highly functionalized pyrrolidines.

The application of a new encoding technology for drug discovery is described. A combinatorial library of mercaptoacyl pyrrolidines has been prepared on a beaded polymeric support. Each polymer bead carries one library constituent in association with an oligomeric "tag," the structure of which is a record of the specific reagents from which that library member was prepared. After the ligands were solubilized, an array of such beads was screened for angiotensin-converting enzyme inhibitory activity, and the structures of active pyrrolidines were deduced by analysis of the associated tags at sub-picomole levels. Several extremely potent enzyme inhibitors were identified, many from multiple beads. The most potent inhibitor was found to have a Ki of 160 pM, approximately 3-fold more active than captopril in the same assay. Direct comparison with iterative deconvolution shows that the encoded screening strategy is a much more efficient means for extracting information from such compound collections, producing more data on a larger number of active structures.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Substitution of D-Trp32 in NPY destabilizes the binding transition state to the Y1 receptor site in SK-N-MC cell membranes.

The retention rate of the spin label 3-isothiocyanto methyl-2,2,5,5-tetramethyl-1-pyrrolidinyl oxyl spin label (proxyl) attached to the porcine N-acetyl-NPY peptide and the porcine N-acetyl-D-Trp32-NPY peptide at Lys4 was investigated using SK-N-MC neuroblastoma cell membranes containing the Y1 receptor. The release rate of the spin labeled peptides was monitored by electron spin resonance and the KD was determined by a direct radiolabeled NPY displacement binding assay. The analyses show that for the porcine [Ac-Tyr1N epsilon 4-proxyl]-NPY, the KD was 8 x 10(-10) M and koff was 2.7 x 10(-4) sec-1 yielding a value for kon of 3.3 x 10(5) sec-1 M-1. The [Ac-Tyr1, N epsilon 4-proxyl,-D-Trp32]-NPY antagonist ligand had a value of KD equal to 1.35 x 10(-7) M and koff was 1.7 x 10(-4) sec-1 leading to a value for kon of 1.2 x 10(3) sec-1 M-1. The difference in the kon rates of two orders of magnitude is interpreted as demonstrating the N-acetyl-N epsilon 4 proxyl-D-Trp32-NPY ligand binding transition state to be of higher energy then for the unmodified NPY amino acid sequence.

Amino Acid Sequence↗
PubMed1997

Characterization of Y3 receptor-mediated synaptic inhibition by chimeric neuropeptide Y-peptide YY peptides in the rat brainstem.

1. Neuropeptide Y (NPY) and peptide YY (PYY) act at receptors referred to as Y1 and Y2, while the Y3 receptor is specific to NPY and does not recognize PYY. The effects of NPY, its related peptides and a series of newly constructed chimeric NPY-PYY peptides were examined on excitatory and inhibitory postsynaptic currents (e.p.s.cs and i.p.s.cs, respectively) in rat dorsomedial nucleus tractus solitarius (NTS) neurones recorded in coronal brainstem slices. Monosynaptic activity was evoked by electrical stimulation in the region of the tractus solitarius. 2. NPY (5-500 nM) inhibited e.p.s.cs and i.p.s.cs in a concentration-dependent manner. In contrast, PYY (500 nM) failed to affect either e.p.s.cs or i.p.s.cs. The N- and C-terminal parts of a series of chimeric NPY-PYY peptides were joined at positions where NPY and PYY sequences differ. In binding experiments the chimeric peptides were all about equipotent with NPY and PYY in displacing [125I]-PYY from Y1 and Y2 binding sites on SK-N-MC cells and rat hippocampus respectively. 3. In the whole cell voltage clamp recordings of NTS neurones, NPY(1-23)-PYY(24-36) and NPY(1-14)-PYY(15-36) evoked a concentration-dependent inhibition of e.p.s.cs and i.p.s.cs, while NPY(1-7)-PYY(8-36) and NPY(1-3)-PYY(4-36) were inactive. The only differences in amino acid residues between NPY(1-14)-PYY(15-36) and NPY(1-7)-PYY(8-36) reside in positions 13 and 14. 4. Furthermore, [Pro34]NPY (500 nM) was equivalent in potency to NPY itself at inhibiting monosynaptic transmission in NTS, while [Leu31,Pro34]NPY and pancreatic polypeptide (both at 500 nM) failed to affect synaptic transmission. 5. The present study has shown that NPY acts at Y3 receptors to suppress both excitatory and inhibitory currents in the NTS. The different efficacy of the chimeric NPY-PYY peptides suggests that positions 13 and 14 are of great importance for Y3 receptor recognition. Finally, this receptor type readily recognizes [Pro34]NPY, but not [Leu31,Pro34]NPY.

Amino Acid Sequence↗
PubMed1996

Versatile approach to encoding combinatorial organic syntheses using chemically robust secondary amine tags.

Encoded combinatorial organic synthesis has recently emerged as a powerful tool for the discovery of biologically active compounds from complex chemical libraries. This report describes a new encoding methodology that uses chemically robust secondary amines as tags. These amines are incorporated into an N-[(dialkylcarbamoyl)methyl]glycine-coding oligomer through simple chemistry that is compatible with a wide range of polymer-supported transformations useful in combinatorial synthesis. In the decoding process acidic hydrolysis of the tagging polymer regenerates the secondary amines, which after dansylation are resolved and detected at sub-picomole levels by reversed-phase HPLC. The versatility of this strategy is demonstrated here by encoded syntheses of members of several representative heterocyclic compound classes, including beta-lactams, 4-thiazolidinones, and pyrrolidines.

Anti-Bacterial Agents↗
PubMed1996

Combinatorial modification of natural products: preparation of unencoded and encoded libraries of Rauwolfia alkaloids.

We report the preparation of combinatorial libraries which consist of derivatives of the stereoisomeric alkaloids yohimbine and rauwolscine-members of the Rauwolfia genus. The chemistry was performed on solid support using the divide-and-pool method, and involved the derivatization of the E-ring carboxylates and hydroxyls of these alkaloids with 36 amino acids and 22 carboxylic acids, respectively, to afford 792 bifunctionalized derivatives. The rauwolscine library was prepared using an encoding strategy in which the identity of each incorporated amino acid was recorded by cosynthesizing chemically inert tags prior to the pooling step. The general strategy for library synthesis exploits existing functionality present on the natural products, and should be applicable to other families of secondary metabolites.

Chromatography, High Pressure Liquid↗
PubMed1995

A double-blind comparison of bisoprolol and atenolol in patients with essential hypertension.

We compared the beta 1-selective adrenoceptor antagonists bisoprolol and atenolol in a double-blind, randomized crossover study. After 4 weeks placebo phase, 59 patients with essential hypertension received either 10 mg bisoprolol or 50 mg atenolol once daily for 8 weeks, increased if necessary (target BP < or = 150/90 mmHg) to 20 and 100 mg, respectively, after 4 weeks. After a second placebo phase, crossover occurred to the alternative drug. We measured resting systolic and diastolic blood pressures and heart rate at 24 h post-dose baseline and after 4 and 8 weeks treatment. Both drugs significantly lowered systolic and diastolic blood pressures and heart rate at 8 weeks compared to baseline (all p < 0.05). Bisoprolol reduced heart rate significantly more than atenolol (p < 0.01), but systolic and diastolic blood pressure changes were not different between the two drugs. There was no difference in patient acceptability of the drugs as assessed by visual analogue scale. Despite theoretical and circumstantial evidence to suggest superiority of bisoprolol over atenolol, no significant difference between the two was found except for greater heart rate reduction with bisoprolol.

Atenolol↗
PubMed1994

Protein tyrosine phosphatase substrate specificity: size and phosphotyrosine positioning requirements in peptide substrates.

The structural requirements of substrates for two recombinant protein tyrosine phosphatases (PTPases) are probed using various-sized synthetic phosphotyrosine (pY)-containing peptides corresponding to the autophosphorylation site in EGF receptor (EGFR) at Y992. The peptide EGFR988-998 (DADEpYLIPQQG) is chosen as a template due to its favorable kinetic constants. The contribution of individual amino acids on both sides of pY to binding and catalysis was assessed by kinetic analysis using a continuous, spectrophotometric assay. For both Yersinia PTPase and a soluble recombinant mammalian PTPase of 323 amino acid residues (rat PTP1), efficient binding and catalysis required six amino acids including the pY residue, i.e., four residues N-terminal to pY and one residue C-terminal to pY. Thus, PTPase substrate specificity is primarily dictated by residues to the N-terminal side of pY. The pY moiety and the rest of the peptide interact with PTPases in a cooperative manner. The presence of pY in the peptide substrate is necessary but not sufficient for high-affinity binding, since phosphotyrosine and other simple aryl phosphates exhibit weak binding, and dephosphorylated peptides do not bind to PTPases. Two variations on the pY moiety are also examined in order to assess their utility in PTPase inhibitor design. It is demonstrated that the thiophosphoryl analog in which one of the phosphate oxygens is replaced by sulfur can be hydrolyzed by PTPases, whereas the phosphonomethylphenylalanine analog in which the tyrosyl oxygen is replaced by a CH2 group is a competitive and nonhydrolyzable inhibitor, with Ki values of 18.6 and 10.2 microM, respectively, for the Yersinia PTPase and the rat PTP1.

Amino Acid Sequence↗
PubMed1994

Combination therapy with amlodipine and captopril for resistant systemic hypertension.

This study was conducted to assess the therapeutic utility of combining amlodipine with captopril in patients with moderate-to-severe hypertension. Patients had hypertension of WHO grades I-III, with initial mean sitting and standing diastolic blood pressure of 100-119 mm Hg (phase V) after 2-4 weeks on placebo, and had remained uncontrolled (diastolic blood pressure > 95 mm Hg) despite a further 4 weeks on low-dose captopril. Twenty-nine patients entered the computer-randomized, double-blind, placebo-controlled, 2-way crossover comparison of either amlodipine 10 mg once daily or matching placebo added to continued therapy with captopril 25 mg twice daily for 4 weeks. Patients then acted as their own control and received the alternative amlodipine/placebo treatment plus their continued captopril therapy for another 4 weeks. Once-daily amlodipine was shown to be effective when combined with captopril. Mean baseline supine systolic blood pressure decreased from 167 to 149 mm Hg and standing systolic blood pressure from 167 to 144 mm Hg. Mean supine diastolic blood pressure decreased from 105 to 92 mm Hg, and standing diastolic blood pressure decreased from 110 to 96 mm Hg. The placebo-corrected amlodipine differences in mean changes from captopril baseline were -18/-12.2 mm Hg for supine and -20.1/-11.9 mm Hg for standing systolic and diastolic blood pressures, respectively (p < 0.001 for all 4 measurements). The most common side effects encountered with amlodipine were flushing and pedal edema. The combination of amlodipine and captopril was well tolerated, and no patient discontinued therapy. No significant treatment-related effects on biochemical and hematologic parameters were noted.

Adolescent↗
PubMed1994

A survey of magnetic fields in the dental operatory.

Recently, there has been growing concern regarding the biological effects of occupational exposure to weak time-varying magnetic fields, especially those in the extremely low-frequency range (0.1-100.0 Hz). This study examined some potential sources and intensities of 60 Hz magnetic fields produced in the dental environment. A random sample of general dental offices and selected specialty offices was visited, and the magnetic fields associated with ultrasonic scalers, amalgamators, composite light curing units, X-ray view boxes and chair lights were measured. The median 60 Hz field strengths measured at various running speeds (off, standby, low and high) and the distances from the equipment (0, 15 and 30 cm) ranged from 1.2 to 2,225 milligauss (mG). Field strengths fell off quickly with distance, but were less affected by the running speed of the equipment. They also varied among the five types of equipment tested. This was likely due to variations in the make, model and age of the equipment. The 60 Hz magnetic field strengths recorded in the dental operatory were comparable to those reported from measurements of common household appliances. However, in view of recent concerns with respect to the possible effects of magnetic fields, it is suggested that exposures be minimized and the concept of prudent avoidance be employed.

Analysis of Variance↗
PubMed1994

Sequence specificity in the recognition of the epidermal growth factor receptor by the abl Src homology 2 domain.

The transforming activity of the abl gene product requires a functional src homology 2 (SH2) domain. An assay was developed to evaluate this function by examining binding of a bacterially-expressed abl SH2 domain to the activated EGF receptor, used as a surrogate tyrosine phosphorylated protein. The sequence specificity of this interaction has been explored with a series of point mutants of EGF receptor. Analysis of equilibrium binding reveals that substitution of Tyr1086 for Phe in the EGF receptor produced a 10-fold reduced affinity for abl SH2 domain binding as compared to the wildtype receptor. Moreover, a phosphorylated peptide modeled on the sequences surrounding Tyr1086 specifically inhibits abl SH2 binding, with an IC50 of approximately 10 microM. Evaluation of a series of additional peptides, modeled on the Tyr1086 sequence, revealed that the carboxy terminal residues directly next to the phosphotyrosine were particularly critical to this binding. Molecular modeling studies of the pTyr1086 peptide revealed the potential hydrophobic, ionic and hydrogen bonding interactions involved in the functions of the abl SH2 domain.

3T3 Cells↗