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Biomedical subjects

A B Smith

Publications and source records attributed to A B Smith.

At least 19 recordsLinked to original sources
PubMed1998

A genome-wide search for schizophrenia susceptibility genes.

We completed a systematic genome-wide search for evidence of loci linked to schizophrenia using a collection of 70 pedigrees containing multiple affected individuals according to three phenotype classifications: schizophrenia only (48 pedigrees; 70 sib-pairs); schizophrenia plus schizoaffective disorder (70 pedigrees; 101 sib-pairs); and a broad category consisting of schizophrenia, schizoaffective disorder, paranoid or schizotypal personality disorder, psychosis not otherwise specified (NOS), delusional disorder, and brief reactive psychosis (70 pedigrees; 111 sib-pairs). All 70 families contained at least one individual affected with chronic schizophrenia according to DSM-III-R criteria. Three hundred and thirty-eight markers spanning the genome were typed in all pedigrees for an average resolution of 10.5 cM (range, 0-31 cM) and an average heterozygosity of 74.3% per marker. The data were analyzed using multipoint nonparametric allele-sharing and traditional two-point lod score analyses using dominant and recessive, affecteds-only models. Twelve chromosomes (1, 2, 4, 5, 8, 10, 11, 12, 13, 14, 16, and 22) had at least one region with a nominal P value <0.05, and two of these chromosomes had a nominal P value <0.01 (chromosomes 13 and 16), using allele-sharing tests in GENEHUNTER. Five chromosomes (1, 2, 4, 11, and 13) had at least one marker with a lod score >2.0, allowing for heterogeneity. These regions will be saturated with additional markers and investigated in a new, larger set of families to test for replication.

Chromosome Mapping↗
PubMed1998

Evidence for linkage to psychosis and cerebral asymmetry (relative hand skill) on the X chromosome.

The hypothesis that psychosis arises as a part of the genetic diversity associated with the evolution of language generates the prediction that illness will be linked to a gene determining cerebral asymmetry, which, from the evidence of sex chromosome aneuploidies, is present in homologous form on the X and Y chromosomes. We investigated evidence of linkage to markers on the X chromosome in 1) 178 families multiply affected with schizophrenia or schizoaffective disorder with a series of 16 markers spanning the centromere (study 1), and 2) 180 pairs of left-handed brothers with 14 markers spanning the whole chromosome (study 2). In study 1, excess allele-sharing was observed in brother-brother pairs (but not brother-sister or a small sample of sister-sister pairs) over a region of approximately 20 cM, with a maximum LOD score of 1.5 at DXS991. In study 2, an association between allele-sharing and degree of left-handedness was observed extending over approximately 60 cM, with a maximum lod score of 2.8 at DXS990 (approximately 20 cM from DXS991). Within the overlap of allele-sharing is located a block in Xq21 that transposed to the Y chromosome in recent hominid evolution and is now represented as two segments on Yp. In one of two XX males with psychosis we found that the breakpoint on the Y is located within the distal region of homology to the block in Xq21. These findings are consistent with the hypothesis that an X-Y homologous determinant of cerebral asymmetry carries the variation that contributes to the predisposition to psychotic illness.

Female↗
PubMed1998

Modulation of receptor and receptor subtype affinities using diastereomeric and enantiomeric monosaccharide scaffolds as a means to structural and biological diversity. A new route to ether synthesis.

We show that carbohydrates constitute an attractive source of readily available, stereochemically defined scaffolds for the facile attachment of side chains contained in genetically encoded and other amino acids. beta-D- and beta-L-glucose, L-mannose, and the 6-deoxy-6-N-analogue of beta-D-glucose have been employed to synthesize peptidomimetics that bind the SRIF receptors on AtT-20 mouse pituitary cells, five cloned human receptor subtypes (hSSTRs), and the NK-1 receptor. The affinity profile of various sugar-based ligands at the hSSTRs is compared with that of SRIF. Compound 19 bound hSSTR4 with a Ki of 100 nM. Subtle structural changes affect affinities. Evidence is presented that suggests that one compound (8) binds both the AtT-20 cell receptors and the five hSSTRs via a unique mode. The SARs of the glycosides at SRIF receptors differ markedly from those at the NK-1 receptor. For example a 4-benzyl substituent is important for SRIF receptor binding, but the 4-desbenzyl analogue 27 was highly potent (IC50 of 27 nM) at the NK-1 receptor. A new, nonbasic method for the synthesis of base-sensitive ethers from primary and secondary alcohols is also described.

Animals↗
PubMed1998

What does palaeontology contribute to systematics in a molecular world?

Palaeontology provides the only direct record for morphological and genetic change through time and uniquely contributes to systematics in two ways: by providing access to denser taxon sampling than is otherwise possible and by dating divergence times. Claims that ancient DNA has survived millions of years in certain fossils suggested the possibility that palaeontology could contribute directly to molecular systematic studies. Unfortunately, none of the supposed geologically ancient DNA records stands up to detailed scrutiny and fossils therefore contribute primarily through the morphological information they preserve. Denser taxon sampling can improve the accuracy of phylogenetic estimates primarily through allowing better discrimination of homoplasy from homology. This in turn leads to more accurate hypotheses of character transformation. Denser taxon sampling also offers the opportunity for more accurate rooting, since more characters can be polarized by reference to a stem-group taxon than to an extant sister-group taxon. Missing data can be a problem for fossils, but is not crippling. Finally the temporal order of clade appearances in the fossil record can provide ancillary evidence for selecting a working phylogeny from among a number of equally most parsimonious cladograms.

Animals↗
PubMed1998

Transport characteristics of peptidomimetics. Effect of the pyrrolinone bioisostere on transport across Caco-2 cell monolayers.

PURPOSE: To compare the permeation characteristics of amide bond-containing HIV-1 protease inhibitors and their pyrrolinone-containing counterparts across Caco-2 cell monolayers, a model of the intestinal mucosa. METHODS: Transepithelial transport and cellular uptake of three pairs of amide bond-containing and pyrrolinone-based peptidomimetics were assessed in the presence and absence of cyclosporin A using the Caco-2 cell culture model. The potential of the peptidomimetics to interact with biological membranes was estimated by IAM chromatography. RESULTS: In the absence of cyclosporin A, apical (AP) to basolateral (BL) flux of all compounds studied was less than the flux determined in the opposite direction (i.e., BL-to-AP). The ratio of the apparent permeability coefficients (Papp) calculated for the BL-to-AP and AP-to-BL transport (P(BL-->AP)/P(AP-->BL)) varied between 1.7 and 36.2. When individual pairs were ompared, P(BL-->AP)/P(AP-BL) ratios of the pyrrolinone-containing compounds were 1.5 to 11.5 times greater than those determined for the amide bond-containing analogs. Addition of 25 microM cyclosporin A to the transport buffer reduced the P(BL-->AP)/P(AP-->BL) ratios for all protease inhibitors to a value close to unity. Under these conditions, the amide bond-containing peptidomimetics were at least 1.6 to 2.8 times more able to permeate Caco-2 cell monolayers than were the pyrrolinone-containing compounds. The intrinsic uptake characteristics into Caco-2 cells determined in the presence of 25 microM cyclosporin A were slightly greater for the amide bond-containing protease inhibitors than for the pyrrolinone-containing analogs. These uptake results are consistent with the transepithelial transport results determined across this in vitro model of the intestinal mucosa. CONCLUSIONS: The amide bond-containing and pyrrolinone-based peptidomimetics are substrates for apically polarized efflux systems present in Caco-2 cell monolayers. The intrinsic permeabilities of the amide bond-containing protease inhibitors are slightly greater than the intrinsic permeabilities of the pyrrolinone-based analogs through Caco-2 cell monolayers.

Biological Transport↗
PubMed1998

Omega-conotoxin GVIA-resistant neurotransmitter release from postganglionic sympathetic nerves in the guinea-pig vas deferens and its modulation by presynaptic receptors.

1 Intracellular recording techniques were used to study neurotransmitter release mechanisms in postganglionic sympathetic nerve terminals in the guinea-pig isolated vas deferens. 2 Recently, a component of action potential-evoked release which is insensitive to high concentrations of the selective N-type calcium channel blocker omega-conotoxin GVIA termed 'residual release' has been described. Under these conditions, release of the neurotransmitter ATP evoked by trains of low frequency stimuli is abolished, but at higher frequencies a substantial component of release is revealed. 3 'Residual release' was studied with trains of 5 or 10 stimuli at stimulation frequencies of 10, 20 and 50 Hz. The alpha2-adrenoceptor agonist clonidine (30-100 nM) inhibited 'residual release', the degree of inhibition being most marked at the beginning of a train. 4 The alpha2-adrenoceptor antagonist yohimbine (1 microM) induced a marked increase in 'residual release' which was dependent on both the frequency of stimulation and the number of stimuli in a train. 5 Prostaglandin E2 (30 nM) and neuropeptide Y (100 nM) caused a rapid inhibition of 'residual release' at all stimulation frequencies examined. 6 4-Aminopyridine (100 microM) induced a powerful potential of 'residual release' and could reverse the inhibition of omega-conotoxin GVIA. 7 'Residual release' was modulated through presynaptic alpha2-adrenoceptors suggesting that (i) residual release of ATP is subject to alpha-autoinhibition through the co-release of noradrenaline, (ii) noradrenaline release can be triggered by calcium channels other than the N-type and (iii) when presynaptic receptors are activated, inhibition of transmitter release can occur by mechanisms other than modulation of calcium-entry through N-type calcium channels in postganglionic sympathetic nerves. Prostaglandin E2 and neuropeptide Y also modulated neurotransmitter release.

4-Aminopyridine↗
PubMed1997

Problems of reproducibility--does geologically ancient DNA survive in amber-preserved insects?

Apparently ancient DNA has been reported from amber-preserved insects many millions of years old. Rigorous attempts to reproduce these DNA sequences from amber- and copal-preserved bees and flies have failed to detect any authentic ancient insect DNA. Lack of reproducibility suggests that DNA does not survive over millions of years even in amber, the most promising of fossil environments.

Amber↗
PubMed1997

Multiple calcium channels control neurotransmitter release from rat postganglionic sympathetic nerve terminals.

1. Intracellular recording techniques were used to study neurotransmitter release mechanisms in postganglionic sympathetic nerve terminals of the rat isolated anococcygeus muscle. 2. Low concentrations of the N-type calcium channel blocker omega-conotoxin GVIA (omega-CgTX GVIA) irreversibly abolished excitatory junction potentials (EJPs) evoked by trains of < or = five stimuli at 10 Hz. When the frequency of stimulation was increased (10-50 Hz) trains of stimuli evoked EJPs even in the presence of 1 microM omega-CgTX GVIA. We have termed this omega-CgTX GVIA-resistant release 'residual release'. EJP amplitude in the presence of omega-CgTX GVIA depended on both the frequency and number of stimuli in a train. 3. Residual release was inhibited by the P-type calcium channel blocker omega-agatoxin IVA (100 nM). However, even in the presence of both toxins, longer trains of stimuli could still evoke neurotransmitter release. 4. Residual release was abolished by omega-conotoxin MVIIC and by the non-specific calcium channel antagonist omega-grammotoxin SIA. Therefore, it would appear that a heterogeneous population of calcium channels is involved in mediating neurotransmitter release from these sympathetic nerve terminals.

Animals↗
PubMed1997

Special considerations for WEB-based clinical database applications.

The Hospital Information System at the University of Missouri-Columbia Veterinary Medical Teaching Hospital is implementing a web-based interface to the existing Hospital Information System. The "stateless" nature of HTML forms introduces a number of special considerations that, though not immediately obvious, nevertheless apply to any multi-user database application. Problems including identifying sessions and users, dealing with abandoned sessions or use of the "Back" arrow on the browser, record locking across multiple forms, state variables, and flow through "utility" forms. General solutions to each of these problems have been devised and are presented here.

Animals↗
PubMed1997

Bringing a WEB-based interface to a hospital information system.

The Hospital Information System at the MU Veterinary Medical Teaching Hospital is a "home-grown" system written in MUMPS. The system has a "roll-and-scroll" user interface typical of terminal based systems from the 1970s and early 1980s. We are now introducing a new user interface that uses World Wide Web technology (HTML forms). Computers connected to the hospital's intranet can access the hospital system using the Web browser of the user's choice. The new user interface can run in parallel with the older interface (even on the same computer), and uses the same underlying database. This allows a smooth migration to the new interface which minimizes both user and programmer anguish. User acceptance has been good, and the ease and speed of development has been very promising.

Animals↗
PubMed1997

Data model development as a prelude to implementing a hospital information system.

We developed a data model for use in a veterinary teaching hospital using modern object oriented database diagramming. Since we deal with more than one species and often with herds or flocks, the problem became even more complex than the situation in human medicine. We chose to follow, insofar as possible, standards set forth by the HL7 consortium and the American Society for Testing and Materials (ASTM), two organizations deeply involved in setting standards for the health care record. Some modifications became necessary in order to fit the veterinary medical record to these standards but these were straightforward and did not disrupt the overall model. As a first step in constructing a hospital information system we have developed, and present herein, a data model which adequately addresses our needs in both the clinical and financial arenas and which conforms to appropriate standards as completely as possible.

Animals↗
PubMed1996

Ryanodine-sensitive calcium stores involved in neurotransmitter release from sympathetic nerve terminals of the guinea-pig.

1. Intracellular and focal extracellular recording techniques were used to study neurotransmitter release mechanisms in postganglionic sympathetic nerve terminals in the guinea-pig isolated vas deferens. 2. High concentrations of the selective N-type calcium channel blocker omega-conotoxin GVIA abolished the release of the neurotransmitter ATP evoked by trains of low-frequency stimuli. However, in the presence of high concentrations of the blocker, a 'residual release' persisted at higher frequencies. 3. Residual release was dependent on calcium entry through a pharmacologically distinct voltage-dependent calcium channel. 4. Residual release was inhibited by ryanodine in a use- and time-dependent manner and this inhibitory effect was potentiated by caffeine. The inhibitory effect of ryanodine on residual release was reversed by 4-aminopyridine. 5. These findings indicate that calcium-induced calcium released from intraneuronal stores plays an important role in action potential-evoked neurotransmitter release mechanisms in postganglionic sympathetic nerve terminals.

Adenosine Triphosphate↗
PubMed1996

Chromosome 18 translocation (18;21) (p11.1;p11.1) associated with psychosis in one family.

In the course of recruiting families with 2 schizophrenic siblings for genome screening and linkage studies, a family was found with mental retardation, schizophrenia, and/or other related psychotic illnesses in individuals who also had an unbalanced or balanced translocation between chromosomes 21-18 [t(18;21)(p11.1;p11.1)]. The pericentric region of chromosome 18 has already been noted as a possible location of a gene for bipolar psychosis. The family described here provides further evidence that this region should be examined for a candidate psychosis gene.

Adult↗
PubMed1996

Synthesis of potent cyclic hexapeptide NK-1 antagonists. Use of a minilibrary in transforming a peptidal somatostatin receptor ligand into an NK-1 receptor ligand via a polyvalent peptidomimetic.

The endogenous peptides somatostatin (SRIF) and substance P comprise very different structures. Although both bind G-protein-coupled receptors, the SRIF receptors (SSTR 1-5) recognize SRIF and related peptides which retain its beta-turn such as the potent cyclic hexapeptide SRIF agonist L-363,301 (6a), but not substance P. Conversely the NK-1 receptor binds substance P but not the above ligands. In contrast, the beta-D-glucosides 1 and 2, designed to mimic the beta-turn of 6a, bind both receptors. This observation led us to attempt the conversion of 6a into the first potent, selective cyclic hexapeptide ligand for the NK-1 receptor. To this end, we combined design with a minilibrary approach. The goal was accomplished with surprising ease, leading to the NK-1 receptor antagonist 9 (IC50 2.0 +/- 0.4 nM). This demonstrates that peptidomimetics, incorporating in this case the promiscuous beta-D-glucose scaffold, can provide valuable clues about receptor similarities not revealed by their endogenous ligands. In addition, this work suggests that the use of libraries and rational design need not be mutually exclusive approaches to lead discovery.

Amino Acid Sequence↗
PubMed1996

Acute and chronic liver toxicity resulting from exposure to chlorinated naphthalenes at a cable manufacturing plant during World War II.

Historical records were used to reconstruct an outbreak of chlorance and acute liver toxicity due to chlorinated naphthalene exposure at a New York State plant which manufactured "Navy cables" during World War II. A cohort mortality study was conducted of the population (n = 9,028) employed at the plant from 1940 to 1944. Vital status was followed through December 31, 1985. The study found an excess of deaths from cirrhosis of the liver [observed (OBS) = 150; standardized mortality ratio (SMR) = 1.84; 95% confidence interval (CI) = 1.56-2.16]; cirrhosis deaths were elevated to a similar degree in the 460 individuals who had chlorance (OBS = 8; SMR = 1.51; CI = 0.65-2.98). The SMR for "non-alcoholic cirrhosis" (OBS = 83; SMR = 1.67; CI = 1.33-2.07) was similar to the SMR for "alcoholic cirrhosis" (OBS = 59; SMR = 1.96; CI = 1.49-2.53). There was no evidence for increased alcoholism in the overall cohort based on mortality from alcohol-related causes of death other than cirrhosis (SMR for esophageal cancer = 1.01 and for deaths from alcoholism = 0.99). We conclude that the excess mortality from cirrhosis of the liver observed in this cohort is due to the chronic effect of chlorinated naphthalene exposure.

Acute Disease↗