Biomedical subjects

D C Williams

Publications and source records attributed to D C Williams.

At least 37 records · Page 2Linked to original sources

PubMed2000

The evolution of ADHD: a disorder of communication?

Attention deficit hyperactivity disorder (ADHD) is the most commonly diagnosed psychiatric condition. Many believe that the central disability is impaired inhibition, which leads to reduced abilities in social skills, self-control, organization and time management. The behaviors identified by clinicians as problematic--inattention, hyperactivity and impulsivity--have been incorporated into several evolutionary models as selectively adaptive cognitive skills for surviving the challenges of a variable Pleistocene environment. We propose that the "disabilities" exhibited by individuals with ADHD are maladaptive, and we concur with Barkley that there is a central impairment in the behavioral inhibition system. The underlying neural anatomy and physiology support the possibility that neurotransmitter pathology may have an impact on other interlinked systems (including language), and may also account for the frequent comorbidity of aggression, anxiety, depression, and learning disabilities (many of which are language-related). Language skills compete with other cognitive activities for the attentional system, and thus the evolution of language could not in fact be independent of the evolution of attention. If language represents the ultimate expression of the attentional system, and some individuals with ADHD are seriously impaired in the coordination of interlinked neural systems (including language), then ADHD fits Jerome Wakefield's definition of "harmful dysfunction," and communication impairments should be investigated more thoroughly by clinicians.

Adaptation, Physiological↗

PubMed2000

Isolation, cultivation, and characterization of Borrelia burgdorferi from rodents and ticks in the Charleston area of South Carolina.

Twenty-eight Borrelia burgdorferi isolates from the Charleston, S.C., area are described. This represents the first report and characterization of the Lyme disease spirochete from that state. The isolates were obtained from December 1994 through December 1995 from the tick Ixodes scapularis, collected from vegetation, and from the rodents Peromyscus gossypinus (cotton mouse), Neotoma floridana (eastern wood rat), and Sigmodon hispidus (cotton rat). All isolates were screened immunologically by indirect immunofluorescence with monoclonal antibodies to B. burgdorferi-specific outer surface protein A (OspA) (antibodies H5332 and H3TS) and B. burgdorferi-specific OspB (antibodies H6831 and H614), a Borrelia (genus)-specific antiflagellin antibody (H9724), Borrelia hermsii-specific antibodies (H9826 and H4825), and two polyclonal antibodies (one to Borrelia species and another to B. burgdorferi). Six of the isolates were analyzed by exposing Western blots to monoclonal antibodies H5332, H3TS, H6831, and H9724. All isolates were also analyzed by PCR with five pairs of primers known to amplify selected DNA target sequences specifically reported to be present in the reference strain, B. burgdorferi B-31. The protein profiles of six of the isolates (two from ticks, one from a cotton mouse, two from wood rats, and one from a cotton rat) also were compared by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. We conclude that the 28 Charleston isolates are B. burgdorferi sensu stricto based on their similarities to the B. burgdorferi B-31 reference strain.

Animals↗

PubMed2000

Inhibition of myogenesis by ouabain: effect on protein synthesis.

Ouabain, a specific inhibitor of the sodium- and potassium-activated adenosine triphosphatase, causes reversible inhibition of the fusion of myoblasts to form myotubes. We further examined this observation to investigate whether control of Na/K-ATPase activity may normally contribute to the regulation of myogenesis. In control cultures, fusion was preceded by a small decrease in intracellular sodium concentration, but intracellular sodium and potassium increased significantly during fusion. Levels of ouabain that produce prolonged inhibition of fusion (400 microM) virtually eliminated sodium and potassium gradients. However, lower ouabain levels (10-100 microM) also produced significant changes in intracellular potassium and/or sodium along with little apparent decrease in the eventual extent of fusion. The effect of ouabain on protein synthesis was also examined. Low levels of ouabain (<50 microM) that did not affect myogenesis also did not affect incorporation of radiolabeled amino acids, while higher concentrations produced a decline in protein synthesis that paralleled decreases in the rate of myoblast fusion. Levels of metabolic labeling were reduced 90% in cultures treated with 400 microM ouabain. Inhibition of protein synthesis would prevent membrane remodeling required for fusion and other events in myogenesis. Thus, our results do not support any specific role for the sodium- and potassium-activated adenosine triphosphatase in regulating myogenesis.

Animals↗

PubMed2000

Stimulus control and generalization of point-loss punishment with humans.

Two experiments demonstrated stimulus control and generalization of conditioned punishment with humans. In both studies, responses first were reinforced with points exchangeable for money on a variable-interval schedule in the presence of one line length (S(D)). Next, a second line length was introduced, and point loss followed every response in the presence of that line (S(D)p). In the final training condition, points were deducted at session end. Response rate was lower in the presence of the S(D)p despite equal rates of points for money in the presence of both stimuli. In generalization testing for Experiment 1, the two lines were included in a 10-line continuum; S(D)p fell in the middle and the trained SD was at one end. Lines were presented randomly, and point delivery and loss contingencies were as in training but with points available in the presence of all lines. For all subjects, response rates were lowest around S(D)p and increased towards the SD end of the continuum. Because testing included only one or two lines beyond S(D), this pattern did not rule out S(D) generalization. Thus, in Experiment 2, stimuli beyond S(D) were added to generalization tests. Response rates did not decrease as a function of distance from S(D), clarifying the demonstration of punishment generalization.

Adult↗

PubMed2000

Pyrrolo-1,5-benzoxazepines induce apoptosis in HL-60, Jurkat, and Hut-78 cells: a new class of apoptotic agents.

Some, but not all, of a series of novel pyrrolo-1,5-benzoxazepines (PBOXs) induce apoptosis as shown by cell shrinkage, chromatin condensation, and DNA fragmentation in three human cell lines, HL-60 promyelocytic, Jurkat T lymphoma, and Hut-78 s.c. lymphoma cells. This chemical selectivity, together with the lack of apoptotic activity against rat Leydig cells, argues against a general cell poisoning effect. PBOX-6, a potent member of the series, caused activation of a member of the caspase-3 family of proteases. In addition, the caspase-3-like inhibitor z-DEVD-fmk, but not the caspase-1-like inhibitor z-YVAD-fmk prevented PBOX-6-induced apoptosis, suggesting that caspase 3-like proteases are involved in the mechanism by which PBOX compounds induce apoptosis. The release of cytochrome c into the cytosol in HL-60 cells in response to PBOX-6 suggests that this cellular response may be important in the mechanism by which PBOX-6 induces apoptosis. However, reactive oxygen intermediates do not play a key role in PBOX-6-induced apoptosis because neither the free radical scavenger TEMPO nor the antioxidant N-acetylcysteine had any effect on PBOX-6-induced apoptosis. The apoptotic induction seems independent of the mitochondrial peripheral-type benzodiazepine receptor (PBR) that binds these pyrrolobenzoxazepines with high affinity, due to the lack of correlation between their affinities for the receptor and their apoptotic potencies, their high apoptotic activity in PBR-deficient cells such as Jurkats, and their lack of apoptotic induction in PBR-rich rat Leydig cells. These PBOXs also can overcome nuclear factor-kappaB-mediated resistance to apoptosis. This suggests an important potential use of these compounds in drug-resistant cancers.

Animals↗

PubMed2000

Utilization review: a practical approach for physicians.

Rhode Island has rules and regulations for UR, as well as an appeals process. When the appeals process is used, it is more often than not successful. (Table 1) If questions arise concerning the UR Act, the UR process, the appeals process, the rights of patients, physicians, and reviewers, or the authority of the HEALTH, please contact OMCR. For a copy of the Rules and Regulations for the Utilization Review of Health Care Services (R23-17.12-1-UR), please write: Rhode Island Department of Health Office of Managed Care Regulation 3 Capitol Hill Cannon Building, Room 410 Providence, RI 02908.

Certification↗

PubMed1999

In vitro pharmacology of cryptophycin 52 (LY355703) in human tumor cell lines.

PURPOSE: Cryptophycin 52 (LY355703) is a new member of the cryptophycin family of antitumor agents that is currently undergoing clinical evaluation for cancer chemotherapy. The mechanism of action of the cryptophycin class of compounds is associated with an action on microtubules. This report details the pharmacological profile of this new clinical compound in a panel of human tumor cell lines. METHODS: Antiproliferative effects of cryptophycin 52 were measured indirectly by detection of the metabolic reduction of alamarBlue. Cytoxicity was assessed by enzymatic dye activation (calcein AM) combined with dye exclusion (ethidium homodimer) and by clonogenicity assay. Cell cycle effects were evaluated using flow cytometry and fluorescence microscopy. RESULTS: Both antiproliferative and cytotoxic effects of cryptophycin 52 were concentration- and time-dependent. IC50 values for antiproliferative activity in both solid and hematologic tumor cell lines were in the low picomolar range, and without exception, were significantly below values for the antimitotic agents paclitaxel and vinblastine. Flow cytometry and microscopic examination of tumor cells treated with cryptophycin 52 indicated that they accumulated in the mitotic phase of the cell cycle. Cryptophycin 52 was tested for its sensitivity to multidrug-resistance in several paired cell lines in which a sensitive parental line was matched with a multidrug-resistant derivative line. The resistant lines have been shown to over express Pgp and/or MRP multidrug-resistance transport factors. Compared to other antimitotic agents (paclitaxel, vinblastine, vincristine), the potency of cryptophycin 52 was shown to be minimally affected in multidrug-resistant cells compared to their sensitive parental lines. CONCLUSION: Cryptophycin 52 has potent antimitotic, antiproliferative and cytotoxic activity in in vitro human tumor cell models. It is significantly more potent and less sensitive to multidrug resistance mechanisms than other antimitotic antitumor agents currently used in cancer therapy. These characteristics may translate into therapeutic advantages for the clinical use of cryptophycin 52 in cancer chemotherapy.

Antineoplastic Agents↗

PubMed1999

Effect of combined immunosuppressive drug therapy on small intestinal nutrient transport in the rat.

OBJECTIVE: Prevention of rejection and preservation of graft function remain as obstacles to clinical small intestinal transplantation (SIT). This study evaluated the effects of combined immunosuppressive agents (FK506, Rapamycin, and Mycophenolate Mofetil) on intestinal function and animal well being. METHODS: Screening for additive toxicity was done in experiment one (D1, n = 10); doses were: FK506 0.3 mg/kg/d, Rapamycin 2 mg/kg/d, and Mycophenolate Mofetil 20 mg/kg/d, orally once daily. Control animals (C1, n = 10) received equivalent vehicle. In the second phase of the experiment, the effect of an additional parenteral treatment phase was investigated, with drug treated animals (D2, n = 6) received FK506 0.3 mg/kg, Rapamycin 1 mg/kg, and Mycophenolate Mofetil 10 mg/kg sq q12h for 1 week followed by FK506 3 mg/kg, Rapamycin 1 mg/kg, and Mycophenolate Mofetil 10 mg/kg p.o. q12h for 4 weeks. Control animals (C2, n = 6) received equivalent vehicle. Parameters followed were weight gain, nutrient absorption, drug levels and nutrient transport in vitro. RESULTS: Controls grew normally, while weight gain was significantly reduced in drug treated animals: This was paralleled by a reduction in dietary fat absorption. Drug levels were low to therapeutic for all drugs in both experiments; FK506 appeared to affect Rapamycin and Mycophenolate Mofetil metabolism, increasing levels of both as FK506 doses increased. Nutrient transport was either not effected (D1) or increased (D2). CONCLUSIONS: We conclude that low dose combination immunosuppressive therapy inhibits weight gain, without affecting absorption of dietary energy, or adversely affecting glucose transport. We postulate a systemic metabolic cause, which requires additional investigation at the cellular level; additional studies are also required to determine if the additive immunosuppression outweigh the side effects for SIT.

3-O-Methylglucose↗

PubMed1999

Novel naphthoquinones from a Streptomyces sp.

Cdc25A assay-guided fractionation of a fermentation broth derived from a Streptomyces sp. resulted in the isolation of four novel naphthoquinones 1-4. Structures of these compounds were deduced by NMR and mass spectrometry. Two of them, 3 and 4, incorporate a modified cysteine residue which is observed for the first time in this class of natural products. Naphthoquinones 1-4 showed weak activity against cdc25A phosphatase.

Chromatography, High Pressure Liquid↗

PubMed1999

Ticks of South Carolina (Acari: Ixodoidea).

County and host records are reported for 19 species of ticks from South Carolina: Amblyomma americanum, Amblyomma maculatum, Amblyomma tuberculatum, Aponomma latum, Boophilus annulatus, Boophilus microplus, Dermacentor albipictus, Dermacentor variablis, Haemaphysalis leporispalustris, Ixodes affinis, Ixodes brunneus, Ixodes cookei, Ixodes marxi, Ixodes minor, Ixodes scapularis, Ixodes texanus, Ixodes woodi, Rhipicephalus sanguineus, and Ornithodoros capensis. Ixodes woodi is recorded from South Carolina for the first time. Boophilus annulatus and Boophilus microplus probably no longer exist in South Carolina, and Aponomma latum is an exotic species that is not established in South Carolina. Brief notes follow each species.

Animals↗

PubMed1998

Sanger DNA-sequencing reactions performed in a solid-phase nanoreactor directly coupled to capillary gel electrophoresis.

A miniaturized, solid-phase nanoreactor was developed to prepare Sanger DNA-sequencing ladders which was directly interfaced to a capillary gel electrophoresis system. A biotinylated fragment of the rat brain actin gene (1 kbp) was amplified by PCR and attached to the interior wall of an (aminoalkyl)silane-derivatized fused-silica capillary tube via a biotin/streptavidin/biotin linkage. Coverage of the capillary wall with the biotinylated DNA averaged 77 +/- 10%. Stability of the anchored template under pressure (33 nL/s) and electroosmotic flows (11.3 nL/s) were favorable, requiring rinsing for > 150 h to reduce the surface coverage by only 50%. In addition, the immobilized template was stable toward temperatures required for preparing sequencing ladders, even under cycling conditions. Standard Sanger dideoxynucleotide termination performed in a large-volume (approximately 8 microL) solid-phase reactor using the thermally stable polymerase enzymes Taq and Vent and the polymerases T7 and Bst with off-line slab gel electrophoresis and autoradiographic detection indicated that acceptable fragment generation was achieved only in the case of the thermally stable polymerases. Banding was not apparent for T7 and Bst since all reagents were inserted into the column in a single plug at the beginning of the reaction. A small volume reactor (volume approximately 62 nL) was then used to perform DNA polymerase reactions and was coupled directly to a capillary gel column for separation. The capillary reactor was placed inside a thermocycler to control the temperature during chain extension and was directly connected to the gel column via zero dead volume fused-silica connectors. The complementary DNA fragments generated (C-track only) in the reactor were denatured using heat and directly injected onto the gel-filled capillary for size separation with detection accomplished using near-IR laser-induced fluorescence. Extension and single-base separation resolution of the C-track, which was directly injected onto the gel column, was estimated to be > 450 bases from the primer annealing site with plate numbers ranging from 1 x 10(6) to 2 x 10(6)/m.

Actins↗

PubMed1998

Truncation of limonene synthase preprotein provides a fully active 'pseudomature' form of this monoterpene cyclase and reveals the function of the amino-terminal arginine pair.

The monoterpene cyclase limonene synthase transforms geranyl diphosphate to a monocyclic olefin and constitutes the simplest model for terpenoid cyclase catalysis. (-)-4S-Limonene synthase preprotein from spearmint bears a long plastidial targeting sequence. Difficulty expressing the full-length preprotein in Escherichia coli is encountered because of host codon usage, inclusion body formation, and the tight association of bacterial chaperones with the transit peptide. The purified preprotein is also kinetically impaired relative to the mixture of N-blocked native proteins produced in vivo by proteolytic processing in plastids. Therefore, the targeting sequence, that precedes a tandem pair of arginines (R58R59) which is highly conserved in the monoterpene synthases, was removed. Expression of this truncated protein, from a vector that encodes a tRNA for two rare arginine codons (pSBET), affords a soluble, tractable 'pseudomature' form of the enzyme that is catalytically more efficient than the native species. Truncation up to and including R58, or substitution of R59, yields enzymes that are incapable of converting the natural substrate geranyl diphosphate, via the enzymatically formed tertiary allylic isomer 3S-linalyl diphosphate, to (-)-limonene. However, these enzymes are able to cyclize exogenously supplied 3S-linalyl diphosphate to the olefinic product. This result indicates a role for the tandem arginines in the unique diphosphate migration step accompanying formation of the intermediate 3S-linalyl diphosphate and preceding the final cyclization reaction catalyzed by the monoterpene synthases. The structural basis for this coupled isomerization-cyclization reaction sequence can be inferred by homology modeling of (-)-4S-limonene synthase based on the three-dimensional structure of the sesquiterpene cyclase epi-aristolochene synthase [Starks, C. M., Back, K., Chappell, J., and Noel, J. P. (1997) Science 277, 1815-1820].

Amino Acid Sequence↗

PubMed1998

Loss of estrogen upregulates osteoblastogenesis in the murine bone marrow. Evidence for autonomy from factors released during bone resorption.

Loss of sex steroids causes an increase in both the resorption and formation of bone, with the former exceeding the latter. Based on evidence that the increased bone resorption after estrogen loss is due to an increase in osteoclastogenesis, we hypothesized that estrogen loss also stimulates osteoblastogenesis. We report that the number of mesenchymal osteoblast progenitors in the murine bone marrow was increased two- to threefold between 2 and 8 wk after ovariectomy and returned to control levels by 16 wk. Circulating osteocalcin, as well as osteoclastogenesis and the rate of bone loss, followed a very similar temporal pattern. Inhibition of bone resorption by administration of the bisphosphonate alendronate led to a decrease of the absolute number of osteoblast progenitors; however, it did not influence the stimulating effect of ovariectomy on osteoblastogenesis or osteoclastogenesis. These observations indicate that the increased bone formation that follows loss of estrogen can be explained, at least in part, by an increase in osteoblastogenesis. Moreover, they strongly suggest that unlike normal bone remodeling, whereby osteoblast development is stimulated by factors released from the bone matrix during osteoclastic resorption, estrogen deficiency unleashes signals that can stimulate the differentiation of osteoblast progenitors in a fashion that is autonomous from the need created by bone resorption, and therefore, inappropriate.

Alendronate↗

PubMed1998

Antiproliferative action of pyrrolobenzoxazepine derivatives in cultured cells: absence of correlation with binding to the peripheral-type benzodiazepine binding site.

Three novel peripheral-type benzodiazepine binding site (PBBS) ligands, NF 182, 213 and 262, along with the classically used PBBS ligands, PK 11195 and Ro5-4864, were found to inhibit, at micromolar concentrations and in dose-dependent manner, the proliferation of rat C6 glioma and human 1321N1 astrocytoma, without being cytotoxic. This antiproliferative effect is mediated by arrest in the G1 phase of the cell cycle and does not appear to be mediated by a specific interaction of these ligands with the peripheral-type benzodiazepine binding site.

Animals↗

PubMed1998

Interictal paroxysmal discharges in the electroencephalograms of epileptic dogs.

Paroxysmal discharges (PD) consisting of spikes, multiple spike complexes, sharp waves, multiple sharp-wave complexes, and spike-and-slow-wave complexes can be recorded in the interictal electroencephalograms of sedated epileptic dogs. With appropriate methods, focal PD can be detected and the hemisphere of origin and rostrocaudal location of their sources identified. Electrode montages that permit ready recognition of so-called instrumental phase reversal are especially helpful. PD that are presumably generalized can be recorded from dogs with signalments suggesting inherited/"idiopathic" epilepsy. These PD are described as "presumably" generalized because of the lack of recordings from ventral and ventrolateral cerebral regions. Further study is necessary, attempting to correlate types of PD with types of epilepsy.

Animals↗

PubMed1998

The serotonin transporter: a primary target for antidepressant drugs.

The serotoninergic system is known to modulate mood, emotion, sleep and appetite and thus is implicated in the control of numerous behavioural and physiological functions. Decreased serotoninergic neurotransmission has been proposed to play a key role in the aetiology of depression. The concentration of synaptic serotonin is controlled directly by its reuptake into the pre-synaptic terminal and, thus, drugs blocking serotonin transport have been successfully used for the treatment of depression. In addition to tricyclic antidepressants (TCAs; e.g. imipramine) which also block noradrenaline reuptake, highly specific serotonin reuptake inhibitors (SSRIs) such as fluoxetine and paroxetine have been developed, which are increasingly prescribed for depressed patients. The mode of action of these antidepressant drugs on their direct target, the serotonin transport protein, and possible regulatory mechanisms with respect to long-term alleviation of depression, although having been investigated both neurobiologically and clinically over the last years, are not yet understood. The cloning of the cDNA encoding the serotonin transporter has allowed a more precise characterization of this protein at the molecular level. This will show how antidepressants act at this target, thereby affecting the biochemical, pharmacological and electrophysiological properties of the serotoninergic system and give an introduction of how they might exert their therapeutic effect. This review gives an overview of the recent developments in this field, discusses mechanisms of antidepressant action on this target, and also possible interactions with other components of serotoninergic neurotransmission.

Antidepressive Agents↗

PubMed1998

Conditional versus trial-unique delayed matching-to-sample.

We compared performance on conditional and trial-unique delayed identity matching-to-sample procedures. In Experiment 1, participants with moderate to severe mental retardation were exposed to both procedures under a single, brief delay value. Three of 5 subjects showed higher accuracy in the trial-unique sessions. In Experiment 2, participants with mild mental retardation were exposed to delay values of 0, 2, 4, 8, and 16 seconds, randomized within each session. For 3 of 4 subjects, accuracy was highest with trial-unique, and lowest on the conditional matching-to-sample, at longer delays. Across the two studies, 6 of 9 subjects showed lower delayed matching accuracy when fewer rather than more stimuli were included in a session.

Adolescent↗

PubMed1998

Flit-gun sprayer characteristics.

Six flit-gun sprayers were tested for possible use in mosquito adulticide programs where inexpensive nonmotorized application technology may be required. An analysis of variance for differences in droplets < or = 24 microns (mu), droplets > or = 48 mu, droplets/cm2, volume median diameters, and mosquito mortality is provided. As shown by these data, good results can be achieved with this equipment.

Analysis of Variance↗