Biomedical subjects

A R Martin

Publications and source records attributed to A R Martin.

At least 19 recordsLinked to original sources

PubMed1995

Prognostic value of cellular proliferation and histologic grade in follicular lymphoma.

The clinical usefulness of histologic grading in follicular lymphoma (FL) is controversial and is further compromised by the subjective nature and poor reproducibility of most systems in current use. Therefore, we decided to objectively evaluate the importance of cellular proliferation in FL, along with the current grading systems. We studied 106 patients with FL who were uniformly staged and aggressively treated. A proliferative index (PI) was determined quantitatively using an automated image analyzer and a new Ki-67 antibody that stains archival paraffin tissues. The cases were also subclassified according to the Berard, Rappaport, Luke-Collins, and Jaffe methods, and survival analysis was performed. Patients with a low PI (< 40%) had a significantly longer overall survival (OS) than those with a high PI (> or = 40%), but the PI did not predict failure-free survival (FFS). The mean PI correlated well with the subgroups in each of the various classifications. All four of the classification methods were predictive of OS, but only the Berard method appeared to predict FFS and suggest that a proportion of patients with FL may be curable. In multivariate analysis, histologic classification was the only independent predictor of OS (Berard method: relative risk, 3.1) and the International Prognostic Index was the only independent predictor of FFS (relative risk, 2.3). We conclude that the Berard method for grading of FL is clinically useful and, along with the International Prognostic Index, should be included in future clinical studies of FL. The measurement of cellular proliferation does not appear to add additional useful information in FL.

Adult↗

PubMed1995

(R)-11-hydroxy- and (R)-11-hydroxy-10-methylaporphine: synthesis, pharmacology, and modeling of D2A and 5-HT1A receptor interactions.

(R)-11-Hydroxyaporphine (2) and (R)-11-hydroxy-10-methylaporphine (3) were synthesized from natural morphine by using new, short, and efficient synthetic sequences. The dopaminergic and serotonergic effects of 2 and 3 were evaluated by use of in vitro and in vivo test systems. The results indicate that 3 is a potent, selective, and efficacious 5-HT1A receptor agonist. In contrast, 2 is a partial 5-HT1A receptor agonist of low potency which has affinity also for central D1 and D2A receptors. The differences in pharmacological profiles were rationalized by modeling of ligand-receptor interactions using homology-based receptor models of the 5-HT1A and D2A receptor binding site. The selective and pronounced serotonergic effects of 3 appear to be due to the C10-methyl group, which is accommodated by a lipophilic pocket in the 5-HT1A receptor. In contrast, the C10-methyl group of 3 is not accommodated by the binding site model of the D2A receptor.

Adenylyl Cyclases↗

PubMed1995

Immunization compliance outside the health plans. A non-HMO report card.

PURPOSE: To assess the rate of completed immunizations by age 24 months in children cared for by a private medical practice. METHODS: A chart review of all children born between January 1, 1990, and June 30, 1992, and seen by a provider in this private medical practice at least once between ages 15 months and 24 months. RESULTS: Overall, 77% of children received four DTP immunizations, 78% received at least three OPV immunizations, and 82% at least one MMR by 24 months of age. Seventy-two percent received the recommended combination of one MMR, three OPV, and four DTP immunizations by age 2. Rates were about 5% to 10% higher in children delivered by physicians of the group practice where the study occurred. The presence of a serious medical problem did not statistically significantly change the rates of completed immunizations. The rate of missed opportunities was almost three times as high in those not completing the basic DTP, OPV, MMR immunization series by age 24 months. CONCLUSIONS: Rates of immunizations are high in this private group practice and comparable to those reported by HMOs that care exclusively for children with insurance. However, the rate of missed opportunities is also high, with three to four visits for each child who did not complete the basic immunization series by age 24 months. This private practice report card will be used to improve immunization practices in our medical group.

Child, Preschool↗

PubMed1995

Aggressive natural killer cell lymphoma of the small intestine.

We report a case of aggressive non-Hodgkin's lymphoma of the small cell type arising in the small intestine and having a natural killer cell phenotype. Immunophenotyping of frozen tissue sections revealed a lack of reactivity with the pan-T-cell markers CD3 and CD5, and no reaction with B-cell markers. Positive staining was obtained with antibodies to CD2, CD7, and CD56. Molecular studies were negative for clonal T gamma, T beta and immunoglobulin heavy-chain gene rearrangements. Natural-killer-cell-associated cytotoxin was demonstrated by positive staining with an antibody to perforin, a protein present in the granules of large granular lymphocytes. Despite its indolent histologic appearance, the aggressive nature of this neoplasm was suggested by the expression of the activation markers CD38 and CD71, and the nuclear proliferation marker Ki67, and confirmed clinically by its rapid recurrence with extensive involvement of the pelvic organs, resistance to chemotherapy, and the short survival of the patient. Distinct from many Asian cases, Epstein-Barr virus genome was not detectable in the tumor. This case emphasizes the importance of recognizing non-Hodgkin's lymphomas with a natural killer cell phenotype as a distinct entity, both biologically and clinically.

Biomarkers, Tumor↗

PubMed1994

Health care costs.

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Academic Medical Centers↗

PubMed1994

Proliferative activity and aneuploidy in pleomorphic adenomas of the salivary glands.

We used flow cytometry in a retrospective study of pleomorphic adenoma and carcinoma arising in pleomorphic adenoma, using paraffin-embedded tissue, to assess the relationship among proliferative activity, ploidy, and recurrence or malignant transformation. Twenty-four specimens obtained from 22 tumors were acceptable for analysis (co-efficient of variation, < or = 7.0), including multiple samples from two tumors. Fourteen tumors (13 benign and one malignant) were diploid. Six tumors were aneuploid: four benign pleomorphic adenomas and two carcinomas arising in pleomorphic adenoma. Two tetraploid tumors were malignant recurrences from the same patient. Of the recurrent tumors (nine benign and four malignant), 54% were aneuploid. The highest S-phase fractions were observed in recurrent and malignant pleomorphic adenomas. Immunostaining with p105, a nuclear proliferation antigen, revealed increased proliferative activity in a majority of pleomorphic adenomas. Increased proliferative activity and aneuploidy occurred in benign pleomorphic adenomas.

Adenoma, Pleomorphic↗

PubMed1993

Effect of cytoplasmic chloride concentration on open-state preference of glycine-activated chloride channels in cultured spinal cord cells.

1. Glycine was bath-applied to outside-out patches taken from cultured mouse spinal cord neurons. Glycine-activated chloride channels had at least six open states with permeabilities of 40 (A), 68 (B), 100 (C), 145 (D), 180 (E), and 250 (F) al/s (1 attoliter = 10(-18) liter). Usually no more than two such states were seen in any given patch. The usual extracellular chloride concentration was 157 mM; chloride concentration in the electrode (on the cytoplasmic face of the patch) was varied between 7 and 170 mM, replaced at lower concentrations with either of the inert anions gluconate or methane sulphonate. 2. With normal (7 mM) chloride concentration in the electrode, openings to state D were the most probable, and the average permeability of all openings was 115 al/s. When the cytoplasmic chloride concentration was 20 mM, the most probable open state was the lower-permeability state (C), and the average permeability was 92 al/s. In symmetrical 170 mM chloride, the most probable open state was B and the mean permeability 77 al/s. 3. The glycine-activated channels had a vanishingly small permeability to fluoride. However, in experiments in which 150 mM gluconate in the pipette was replaced by fluoride, the most probable open state was B, as in the high-chloride solution. Thus the two halides had similar effects on open state preference. 4. With external and internal chloride concentrations of 7 and 157 mM, respectively, single-channel current-voltage relations could be fit with constant field relations appropriate to one or more of the permeability states.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

The dependence of calcium-activated potassium currents on membrane potential.

Previous experiments on cholinergic synapses in chick cochlear hair cells have shown that calcium entering through acetylcholine-activated synaptic channels in turn activates calcium-dependent potassium currents, resulting in synaptic inhibition. In voltage-clamp experiments such currents would be expected to increase with depolarization (as the driving force for potassium entry is increased) and then decrease towards zero as the membrane approaches the calcium equilibrium potential (when calcium entry is suppressed). In the hair cells, however, such currents approached zero at about +20 mV, more than 170 mV negative to the calcium equilibrium potential. Another feature of the synapse is its post-junctional morphology: a uniform 20 nm cleft is formed between the postsynaptic membrane and the outermost membrane of an underlying cisterna. Here we present a model in which synaptic activation results in calcium influx into the subsynaptic cleft and thence into the bulk of the cytoplasm. The model suggests that the voltage dependence of the calcium-activated potassium current can be accounted for by only two basic assumptions: (i) entry of calcium through the activated synaptic channels by simple diffusion; and (ii) activation of the potassium channels by the cooperative action of four calcium ions. In addition, the model suggests that during activation the calcium concentration in the restricted subsynaptic space can reach levels adequate to activate the potassium channels, without requiring additional, more complicated, considerations (for example, secondary calcium release from the cisterna).

Animals↗

PubMed1992

Principles of neuromuscular transmission.

Activation of skeletal muscles, small and large alike, occurs when spinal cord neurons send action potentials to groups of fibers. The central role of acetylcholine and its receptors in this activation is well established. The mechanisms involved and the implications for understanding neuromuscular disorders and for rationalizing and improving therapy are discussed.

Acetylcholine↗

PubMed1992

Causes of mortality and parasites and incidental lesions in harbour porpoises (Phocoena phocoena) from British waters.

Detailed post mortem examinations were carried out on 41 harbour porpoises (Phocoena phocoena) found dead on the coast of the United Kingdom. The commonest causes of death were entanglement in fishing gear, and parasitic and bacterial pneumonia. Among the non-fatal conditions parasitoses of various organs were common and there was a very wide variety of other conditions. In total 295 diseases and other lesions were found, an average of 7.2 per animal.

Animals↗

PubMed1992

Flow cytometric DNA analysis of ovarian Brenner tumors and transitional cell carcinomas.

Flow cytometry has been previously used as a method of obtaining prognostic information about ovarian carcinomas using ploidy, DNA index, and S-phase fraction. DNA content has also been assessed in ovarian tumors of low malignant potential. Brenner tumor variants such as metaplastic, proliferating, and low malignant potential, recently designated as intermediate Brenner tumors, and malignant Brenner tumors are unusual tumors that present classification problems. Their histological appearance may not accurately reflect biological activity. We used flow cytometry to analyze paraffin-embedded tissue for DNA content and S-phase in 34 Brenner tumors, three ovarian transitional cell (urothelial) carcinomas (TCCs), and nine normal control ovaries. We correlated histological and clinical features with DNA analysis. Twenty-five Brenner tumors and three ovarian TCCs were acceptable for histogram analysis (coefficient of variation less than 7.0). Thirteen typical, three metaplastic (extensive mucinous or glandular metaplasia), and two proliferating (papillary formation with increased cellularity) Brenner tumors were diploid. One proliferating tumor was tetraploid. The single Brenner tumor of low malignant potential was diploid but had an increased S-phase. Four of five malignant Brenner tumors were aneuploid, and one was diploid. All the TCCs were aneuploid. S-phase was elevated in intermediate and malignant Brenner tumors and TCC. Limited numbers of cases available preclude prognostic prediction based on ploidy in malignant Brenner tumors or primary ovarian TCCs. DNA ploidy and S-phase reflect the intermediate status of metaplastic, proliferating, and low malignant potential Brenner tumors.

Adult↗

PubMed1990

Comparison of two different arterial tissues suggests possible 5-hydroxytryptamine2 receptor heterogeneity.

A comparison of activities and affinities of several known and novel compounds in the isolated rat thoracic aorta (RA) and the rabbit femoral artery (RFA) was undertaken to evaluate these two tissues for use in screening for functional 5-hydroxytryptamine2 (5-HT2) receptor activity. Affinities for 5-HT and for ketanserin against 5-HT-elicited contractions in both vascular tissues suggested the presence of homogeneous 5-HT2 receptors with values consistent with other reported 5-HT2 receptor preparations. However, further studies showed compounds which exhibited either partial agonism in the RFA and competitive antagonism of 5-HT in the RA, or antagonism of 5-HT in both arteries with different affinities. Affinity constants calculated from the isolated vascular tissue studies were compared with affinity constants calculated for inhibition of [3H]ketanserin binding in the frontal cortices of both the rat and the rabbit. There were no significant differences between the pKi values in the rat and the rabbit cortical membranes or between these pKi's in either species and the pA2 values in the RA. Several of the affinities for both the partial agonists and the antagonists in the RFA were significantly different from the binding pKi and the pA2 values in the RA. These findings suggest identity between the [3H]ketanserin binding site in the cortices of both species and the 5-HT2 receptor in the RA; however, the contractile 5-HT receptor in the RFA, although showing some characteristics of a 5-HT2 receptor, is significantly different. We suggest that there may be functional subtypes of the vascular 5-HT receptor.

Animals↗

PubMed1989

MDL 73005EF: partial agonist at the 5-HT1A receptor negatively linked to adenylate cyclase.

MDL 73005EF has been recently described as a potent, highly selective 5-HT1A ligand. Although proposed to act predominantly as an antagonist (M. Hibert, A.K. Mir, G. Maghioros, P. Moser, D.N. Middlemiss, M.D. Trickleband and J.R. Fozard, 1988, The Pharmacological properties of MDL 73005EF: a potent and selective ligant at 5-HT1A receptors, Br. J. Pharmacol. 93, 2P), we have demonstrated that MDL 73005EF also acts as a highly efficacious partial agonist at the 5HT1A receptor, based on its ability to inhibit forskolin-stimulated adenylate cyclase in rat hippocampal membranes. Compared with two structurally related 5-HT1A partial agonists, the rank order of potency of MDL 73005EF in the FSC assay was comparable to affinity calculated by radioligand binding.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1989

Presynaptic calcium currents recorded from calyciform nerve terminals in the lizard ciliary ganglion.

Electron microscopic examination of ciliary ganglion from Anolis carolinensis shows large calyciform presynaptic nerve terminals ending on ganglion cells. Intracellular records were obtained from the terminals, and membrane currents were recorded with the single-electrode voltage clamp technique. After block of Na+ currents with tetrodotoxin, depolarization of the terminals produced inward currents that disappeared when extracellular Ca2+ was removed, and increased in magnitude and duration when competing outward currents were blocked by intracellular Cs+. Thus it is possible, with this preparation, to record and characterize Ca2+ currents presumably associated with neurotransmitter release.

Animals↗

PubMed1989

3-(1-Methyl-1,2,3,6-tetrahydropyrid-4-yl)indole.

C14H16N2, Mr = 212.3, orthorhombic, Pca2(1), a = 19.424 (3), b = 6.770 (1), c = 8.899 (1) A, V = 1170.2 (3) A3, Z = 4, Dx = 1.20 g cm-3, Mo K alpha, lambda = 0.71073 A, mu = 0.7 cm-1, F(000) = 456, T = 296 K, final R = 0.043 for 1162 observed reflections. The pi systems in the title compound (1), a serotonin mimic, are in a 'near-planar' conformation (actually twisted 21 degrees from the transoid conformation) as has been postulated to be essential for activity. Molecular-mechanics calculations indicate that the inactive 2-methyl derivative of (1) has near-planar forms of much higher energy in accordance with expectation.

Carbolines↗

PubMed1989

Potassium channels activated by sodium.

Na+-activated K+ currents have been reported in snail neurones, crayfish giant motoneurones, cardiac myocytes, and in ganglion cells and brain stem cells from chick embryos. Such currents are seen in voltage-clamp experiments, following depolarization-induced Na+ influx. A variety of experiments have shown that the currents through the conductance pathways are indeed carried by K+ ions and that they are quantitatively dependent upon Na+ influx into the cells. Theoretical calculations indicate that such currents must make a substantial contribution to action potential repolarization. The conductances are activated by Li+ in invertebrate neurones, but not in the embryonic vertebrate neurones. Single-channel recordings from vertebrate brain stem cells reveal channels with conductances of about 50 pS, activated by Na+ concentrations in the 10-100 mM range.

Animals↗

PubMed1989

A Na+-activated K+ current in cultured brain stem neurones from chicks.

1. Patch-clamp techniques were used to study the properties of a Na+-activated K+ current (IK(Na) in neurones cultured from embryonic chick brain stem. 2. With whole-cell clamp, a depolarizing voltage command evoked an inward current that was followed by an outward current with two components, the first transient, the second sustained. 3. Tetrodotoxin (TTX, 1 microM) eliminated the inward current and the transient component of the outward current, without affecting the sustained outward current. In addition, the transient outward current was attenuated when all external Na+ was replaced by Li+, suggesting that it was activated specifically by Na+ entry into the cell. 4. The time course of the transient outward current was obtained by subtracting records obtained in Li+ solution from those obtained in Na+ solution. There was significant overlap between the decay of the inward current and the onset of the transient outward current. 5. When just after the peak of the transient outward current, the membrane was stepped to progressively more hyperpolarized levels, the tail currents associated with the current reversed polarity near the calculated K+ equilibrium potential. 6. 4-Aminopyridine (4-AP, 4 mM) abolished the transient outward current and approximately half of the sustained late current. Tetraethylammonium (TEA, 2 mM) had no effect on the transient current, but reduced the sustained current slightly. 7. Inside-out patches, made in LiCl bathing solutions, contained channels that were activated by exposing the cytoplasmic face of the patch to Na+. Channel activity continued as long as Na+ was present. 8. The single-channel currents reversed at the K+ equilibrium potential, and were associated with a main conductance that depended upon K+ concentration (about 50 pS with [K+]o = 15 mM, [K+]i = 5 mM, and 100 pS when [K+]i was increased to 75 mM). 9. The open probability of the channels increased with increasing cytoplasmic Na+ concentration. At [Na+]i = 150 mM (the maximum concentration tested), channels were open almost continuously. Open probability was considerably less at 50 mM, and still measureable at 20 mM. 10. The magnitude of IK(Na) and its overlap with the inward Na+ current indicate that these channels contribute significantly to the repolarizing phase of the action potential. In addition, the relation between channel activity and Na+ concentration suggests that the channels may make a measurable contribution to membrane conductance at resting intracellular Na+ concentrations.

Animals↗

PubMed1988

Serotonergic properties of spiroxatrine enantiomers.

The neuroleptic drug spiperone (1) has proven very useful in the characterization of putative serotonin (5-hydroxytryptamine, 5-HT) receptors. Thus, 5-HT1 receptors have been divided into subtypes based on their affinities for 1: 5-HT1A sites have high affinity, while 5-HT1B sites have low affinity. However, the usefulness of 1 for the pharmacological characterization of 5-HT1A sites is limited because of its high affinity for 5-HT2 (as well as D2-dopaminergic) receptors. A close analogue of 1, (+/-)-spiroxatrine (2), has much higher affinity for 5-HT1A receptors and much lower affinity for 5-HT2 receptors. We report here the stereospecific synthesis of (R)-(+)- and (S)-(-)-spiroxatrine enantiomers and their evaluation at several 5-HT receptors and D2-dopaminergic and alpha 1-adrenergic receptors.

Animals↗