Biomedical subjects

Keith Williams

Publications and source records attributed to Keith Williams.

At least 19 recordsLinked to original sources

PubMed2006

Comparative studies of anthraquinone- and anthracene-tetraamines as blockers of N-methyl-D-aspartate receptors.

Anthraquinone spermine [N1-(anthraquinone-2-carbonyl)spermine; AQ343], anthraquinone homospermine [N1-(anthraquinone-2-carbonyl; AQ444], anthracene spermine [N1-(9-anthracenylmethyl)spermine; Ant343], and anthracene homospermine [N1-(9-anthracenylmethyl)homospermine; Ant444] were found to be potent antagonists of recombinant N-methyl-D-aspartate (NMDA) receptors (NRs). The effects of both anthraquinone (AQ)- and anthracene (Ant)-tetraamines were reversible and voltage-dependent. Results of experiments using mutant NR1 and NR2B subunits of NMDA receptor identified residues that influence block by AQ- and Ant-tetraamines. The results indicate that the polyamine tail is crucial for block by AQ- and Ant-tetraamines. Residues in the outer vestibule of the NR1 subunit were more strongly involved in block by AQ-and Ant-tetraamines than residues in the corresponding region of NR2B. Several amino acid residues in the inner vestibule, below the level of the selectivity filter of NR1 and NR2B, affected block by AQ444, Ant343, and Ant444, but they did not affect block by AQ343. AQ-tetraamines could permeate the channel at very negative membrane potentials when the narrowest constriction of the channel was expanded by replacing the Asn residue at Asn616 of NR1 and NR2B with Gly, whereas Ant-tetraamines did not easily pass through the channel, apparently because of differences in the relative position of the head groups on AQ- and Ant-polyamines.

Animals↗

PubMed2005

Dendritic BC1 RNA in translational control mechanisms.

Translational control at the synapse is thought to be a key determinant of neuronal plasticity. How is such control implemented? We report that small untranslated BC1 RNA is a specific effector of translational control both in vitro and in vivo. BC1 RNA, expressed in neurons and germ cells, inhibits a rate-limiting step in the assembly of translation initiation complexes. A translational repression element is contained within the unique 3' domain of BC1 RNA. Interactions of this domain with eukaryotic initiation factor 4A and poly(A) binding protein mediate repression, indicating that the 3' BC1 domain targets a functional interaction between these factors. In contrast, interactions of BC1 RNA with the fragile X mental retardation protein could not be documented. Thus, BC1 RNA modulates translation-dependent processes in neurons and germs cells by directly interacting with translation initiation factors.

3' Flanking Region↗

PubMed2005

Human high mobility group box transcription factor 1 affects thymocyte development and transgene variegation.

It has been shown previously that a human CD2 (hCD2) disabled locus control region (LCR) transgene is unable to establish an open chromatin configuration in all the T cells, and this leads to position effect variegation of the transgene. In this study we show that thymus-specific overexpression of human high mobility group box transcription factor 1 (HBP1), a transcription factor that binds a specific sequence within the hCD2 LCR, affects thymus cellularity as well as the number of CD8(+) thymocytes in two independent transgenic mouse lines and increases the proportion of T cells that fully activate the transgenic locus in hCD2 variegating mice in a sequence-specific dependent manner. This finding suggests that overexpression of HBP1 can affect lineage commitment and can relieve the suppressive influence of heterochromatin, allowing thymocytes to express the variegating target locus more efficiently. These effects could be the result of direct HBP1 action on LCR activity. Alternatively, the extra HBP1 molecules may sequester repressive elements away from the LCR, thus allowing transcription permissive states to form on the transgene locus.

Animals↗

PubMed2005

Food preferences and factors influencing food selectivity for children with autism spectrum disorders.

Although clinicians and parents widely accept that children with autism spectrum disorder exhibit more feeding problems than their typically developing peers, little information is available concerning the characteristic food items accepted by these children or the possible factors contributing to these feeding problems. This article used an informant-based questionnaire to survey parents of children with autism spectrum disorders (N=138) to determine: (a) the types of feeding problems their children typically exhibit, (b) the food items their children prefer, (c) the relationship of feeding problems to family eating preferences, and (d) the relationship of the diagnostic characteristics of autism to feeding behavior. Results indicated that the children preferred fewer types of food items within groups than their families; however, family food preferences appeared to influence food selection more than the diagnostic characteristics of autism.

Autistic Disorder↗

PubMed2004

Anthraquinone polyamines: novel channel blockers to study N-methyl-D-aspartate receptors.

The effects of various anthraquinone polyamines (AQP) were studied at recombinant N-methyl-d-aspartate (NMDA) receptors expressed in Xenopus laevis oocytes. The AQP derivatives had different numbers of methylene groups between the NH(2) (or NH) groups in their spermidine-like tail. Thus, we termed these derivatives AQ33, AQ34, etc. All AQP derivatives inhibited responses of NR1/NR2 receptors in oocytes voltage-clamped at -70 mV, with IC(50) values between 4 and 22 microM. The block was strongly voltage-dependent. AQ34 and AQ33b inhibited responses of NR1/NR2 receptors but did not inhibit responses of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors expressed from GluR1 or GluR2(Q), indicating that AQ34 and AQ33b are preferential NMDA antagonists. Results of experiments using mutant NR1 and NR2 subunits identified residues that influence block by AQ34 and AQ33b. These residues are located in the outer vestibule at the selectivity filter/narrowest constriction of the channel and in the inner vestibule below the level of the selectivity filter. The results with mutant NR1 and NR2 subunits are consistent with the idea that NR1(Asn616) and NR2B(Asn616), but not NR2B(Asn615), make the narrowest constriction of NMDA channel.

Amino Acids↗

PubMed2004

A comparison of eating behaviors between children with and without autism.

Although clinicians typically assume that feeding problems co-exist with a diagnosis of autism, no previous research has compared the eating behavior of children with autism to typically developing children. This study compared caregiver report of eating problems of children with and without autism on a standardized questionnaire. The questionnaire included items pertaining to food refusal and acceptance patterns as well as food presentation requirements. Caregivers were also asked to complete a food inventory that indicated the number of foods eaten within each food group for both the child and the family. Results indicated children with autism have significantly more feeding problems and eat a significantly narrower range of foods than children without autism.

Autistic Disorder↗

PubMed2004

Vascular reactivity in preeclampsia assessed noninvasively using maternal brachial artery hyperemic response.

OBJECTIVE: To estimate if women with preeclampsia had measurable differences in the brachial artery waveforms after blood flow occlusion. METHODS: In a cross-sectional study, 14 preeclamptic and 28 matched normotensive women were assessed. Hemolysis, elevated liver enzymes, low platelets syndrome patients were excluded. All patients had baseline brachial Doppler flow velocities while resting in the left lateral position and after a 60-second forearm occlusion. Doppler waveforms were analyzed from the brachial artery 30-45 seconds after the release of the blood pressure cuff. We analyzed the classical Doppler waveform parameters of systolic diastolic, mean velocity and pulsatility index, time taken to achieve peak systolic velocity, systolic acceleration time, the percentage of time in each cycle to achieve peak systolic velocity, and systolic acceleration from 3 waveforms. Comparison of the percentage change in each of these parameters between the groups was done using t tests. RESULTS: Before brachial artery occlusion, systolic acceleration time was significantly less in the preeclamptic group (77.5 +/- 14.4 milliseconds versus 93.2 +/- 11.7 milliseconds; (P < .001). After occlusion, the percentage change in the systolic acceleration and systolic acceleration time was increased in the normotensive group (P < .001). CONCLUSION: There was significantly increased impedance to blood flow downstream assessed by Doppler waveform analysis after a period of forearm ischemia (blood pressure occlusion) in the women with preeclampsia. LEVEL OF EVIDENCE: II-1.

Brachial Artery↗

PubMed2003

Testing the nematophagous biological control strain Paecilomyces lilacinus 251 for paecilotoxin production.

Paecilomyces lilacinus is a nematophagous fungus currently developed as a biological control agent. In order to evaluate potential toxin production, culture extract and concentrated culture supernatant of P. lilacinus strain 251 were tested against Gram-negative and Gram-positive bacteria. High-performance liquid chromatography analysis was carried out to compare the chromatograms of P. lilacinus strain 251 with the chromatogram of known paecilotoxin. It was found that the 251 strain of P. lilacinus did not produce detectable levels of paecilotoxin or other toxins with antimicrobial activity.

Animals↗

PubMed2003

Propofol suppresses the sleep state-dependent P13 midlatency auditory evoked potential in the rat.

Propofol (2,6-diisopropylphenol) is a widely used anesthetic agent, but its mechanisms of action are poorly understood. In this report, the effects of three dose levels of propofol (5, 7.5, and 10mg/kg) on the amplitude of the vertex-recorded, sleep state-dependent P13 midlatency evoked potential were investigated. The P13 potential is generated, at least in part, by the ascending cholinergic reticular activating system (RAS). The RAS is known to be affected by anesthetic agents. Intravenous injections of propofol were found to reduce the amplitude of the P13 potential in a dose- and time-dependent manner. At 2min post-injection, the mean P13 amplitude was suppressed to 40% of its pre-injection level by the lowest dose, but was suppressed to 10% of pre-injection levels by the two higher doses of propofol. The duration of the suppression of mean P13 potential amplitude was also dose-dependent such that complete recovery occurred by 5min using 5mg/kg, by 15min using 7.5mg/kg and by 30min using 10mg/kg of propofol. Using a paired stimulus paradigm, transient effects on habituation of the P13 potential were observed but only after the highest dose. Thus, one of the mechanisms of propofol may be to affect portions of the RAS which modulate the level of arousal. It may only transiently affect higher systems known to modulate the degree of habituation of responses by the RAS (i.e. processes which modulate habituation and may participate in sensory gating and distractibility).

Analysis of Variance↗

PubMed2003

Delayed discharge. Home truths.

The Department of Health wants to turn home improvement agencies into key players in provision of services to older people discharged from hospital. 104 clients have been referred to the project: 55 related to hospital discharge and 49 to admission prevention. Having a single point of contact for a range of home improvement services has made referrals easier.

Aftercare↗

PubMed2003

Pharmacology of delta2 glutamate receptors: effects of pentamidine and protons.

The properties of delta2 receptors, which have homology to glutamate receptors but are not gated by glutamate, were studied using the constitutively active Lurcher mutant delta2(A654T) expressed in Xenopus oocytes. The macroscopic current through delta2(A654T) channels in voltage-clamped oocytes was defined as the difference between the holding current measured in the presence of extracellular Na(+) and that in the presence of the large impermeant cation N-methyl-d-glucamine. A-to-T mutations in the delta1 subunit and in NMDA (N-methyl-d-aspartate) receptor subunits, at positions equivalent to delta2(A654T), did not produce constitutively active channels. The current through delta2(A654T) channels was reduced by pentamidine and 9-tetrahydroaminoacridine, antagonists that also inhibit NR1/NR2B NMDA receptors but not AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors. Block of delta2(A654T) currents by these two antagonists was incomplete and weakly voltage-dependent, in contrast to the block of NR1/NR2B receptors, which was complete and strongly voltage-dependent. Pentamidine inhibited a constitutively active NR1(T648A)/NR2B NMDA receptor in a manner similar to its inhibition of a glutamate-gated wild-type NMDA receptor, but different from its inhibition of constitutively active delta2(A654T) receptors. Currents gated by delta2(A654T) were sensitive to the extracellular pH, being smaller at acidic than at alkaline pH, with a pH IC(50) value of 7.47 and a maximum inhibition of 70%. It is concluded that delta2(A654T) channels have some properties in common with NMDA channels but also have characteristics that are different from these receptors. Compounds such as pentamidine may be useful for studies of native delta2 receptors.

Algorithms↗

PubMed2003

Transgenic mice with hematopoietic and lymphoid specific expression of Cre.

Bacteriophage P1 Cre/loxP based systems can be used to manipulate the genomes ofmice in vivo and in vitro, allowing the generation of tissue-specific conditional mutants. We have generated mouse lines expressing Cre recombinase in hematopoietic tissues using the vav regulatory elements, or in lymphoid cells using the hCD2 promoter and locus control region (LCR). The R26R-EYFP Cre reporter mouse line was used to determine the pattern of Cre expression in each line and enabled the assessment of Cre activity at a single-cell level. Analysis showed that the vav promoter elements were able to direct Cre-mediated recombination in all cells of the hematopoietic system. The hCD2 promoter and LCR on the other hand were able to drive Cre-mediated recombination only in T cells and B cells, but not in other hematopoietic cell types. Furthermore, in the appropriate tissues, deletion of the floxed target was complete in all cells, thereby excluding the possibility of variegated expression of the Cre transgene. Both of these Cre-transgenic lines will be useful in generating tissue-specific gene deletions within all the cells of hematopoietic or lymphoid tissues.

Animals↗

PubMed2003

Beta-elimination: an unexpected artefact in proteome analysis.

Two persistent myths, ingrained in the electrophoretic literature of the last thirty years, namely carbamylation and deamidation, have been recently dispelled (Herbert et al., J. Proteome Res. 2002, in press). We report here, for the first time, a noxious and unexpected artefact in proteome analysis: beta-elimination (or desulfuration), which results on the loss of an H(2)S group (34 Da) from cysteine (Cys) residues for protein focusing in the alkaline pH region. With such an elimination event, a dehydro alanine residue is generated at the Cys site. In turn, the presence of a double bond in this position elicits lysis of the peptide bond, generating a number of peptides of fairly large size from an intact protein. The first process seems to be favored by the electric field, probably due to the continuous harvesting of the SH(-) anion produced. The only remedy found to this noxious degradation pathway is the reduction and alkylation of all Cys residues prior to their exposure to the electric field. Alkylation appears to substantially reduce both beta-elimination and the subsequent amido bond lysis.

Alkylation↗

PubMed2003

Purification and characterization of a serine protease and chitinases from Paecilomyces lilacinus and detection of chitinase activity on 2D gels.

The filamentous fungus Paecilomyces lilacinus is currently developed as a biocontrol agent against plant parasitic nematodes. Nematode eggs and cuticles are the infection sites for biocontrol agents that penetrate by the production of lytic enzymes. P. lilacinus was cultured in liquid media and proteases and chitinases were induced by the introduction of egg yolk and chitin, respectively. A serine protease was purified from a culture medium using Sepharose-bacitracin affinity column. The protease occurred in three forms, two of which were C-terminally truncated. Chitinase activity was also observed in the culture supernatant, and after separation by isoelectric focusing six proteins were detected that showed activity. Chitinase activity was further confirmed on non-denaturing one-dimensional (1D) and two-dimensional (2D) gels using a sandwich assay with glycol chitin as a substrate. Two of the proteins had similarities with endochitinases as shown by their N-terminal amino acid sequences.

Amino Acid Sequence↗

PubMed2003

Preparation and biological assessment of hydroxycinnamic acid amides of polyamines.

Many plants contain hydroxycinnamic acid conjugates of polyamines that are remarkably similar in general structure to the acylated polyamines found in spider and wasp toxins. In an effort to determine whether these compounds might play a role in the chemical defense of plants against arthropod pests we synthesized a variety of analogues of the coumaric (4-hydroxycinnamic) acid conjugates of di-, tri-, and tetraamines using common protection and acylation strategies. N(1)- and N(8)-coumaroyl spermidine were tested in feeding trials with insect larvae including the European corn borer (Ostrinia nubilalis), the tobacco budworm (Heliothis verescens) and the oblique banded leaf roller (Choristoneura rosaceana). Antifeedant assays with the rice weevil Sitophilus oryzae were also performed. Neither the naturally occurring coumaric acid conjugates of polyamines nor their analogues showed notable toxicity towards insects, despite precautions to maintain these easily oxidized materials in the wet diet. However, more direct bioassays of these compounds on glutamate dependent neuroreceptors including the deep abdominal extensor muscles of crayfish, or mammalian NMDA, delta2, and AMPA receptors, clearly showed that these compounds were inhibitory. N(1)-Coumaoryl spermine, a dodecyl and a cyclohexyl analogue were especially active at NMDA NR1/NR2B receptors. The latter had an IC(50) of 300 microM in the crayfish. N(1)-Coumaroyl spermine had an IC(50) in the crayfish preparation of 70-300 microM and against the mammalian NR1/NR2B receptor of 38 nM. Structure-activity variations show similar trends of length and hydrophobicity as has been seen previously with analogues of spider toxins. We conclude from this work that while the coumaric acid polyamine conjugates are active when directly applied to neuroreceptors, they show no overt toxicity when ingested by insect larvae.

Acylation↗

PubMed2003

Hybrid vigor.

Explore the source record for details and available documents.

Australia↗

PubMed2003

Polyamine transport, accumulation, and release in brain.

Cycling of polyamines (spermine and spermidine) in the brain was examined by measuring polyamine transport in synaptic vesicles, synaptosomes and glial cells, and the release of spermine from hippocampal slices. It was found that membrane potential-dependent polyamine transport systems exist in synaptosomes and glial cells, and a proton gradient-dependent polyamine transport system exists in synaptic vesicles. The glial cell transporter had high affinities for both spermine and spermidine, whereas the transporters in synaptosomes and synaptic vesicles had a much higher affinity for spermine than for spermidine. Polyamine transport by synaptosomes was inhibited by putrescine, agmatine, histidine, and histamine. Transport by glial cells was also inhibited by these four compounds and additionally by norepinephrine. On the other hand, polyamine transport by synaptic vesicles was inhibited only by putrescine and histamine. These results suggest that the polyamine transporters present in glial cells, neurons, and synaptic vesicles each have different properties and are, presumably, different molecular entities. Spermine was found to be accumulated in synaptic vesicles and was released from rat hippocampal slices by depolarization using a high concentration of KCl. Polyamines, in particular spermine, may function as neuromodulators in the brain.

Animals↗

PubMed2003

Emergency department use of persons with comorbid psychiatric and substance abuse disorders.

STUDY OBJECTIVE: This study assesses the relationship between substance abuse comorbidity and emergency department use among patients with psychiatric disorders in a large academic medical center. METHODS: Data were obtained from an administrative database including every patient visit to the ED of a large, academically affiliated county hospital from January 1994 through June 1998. This study focuses on 12,212 patients who were given a diagnosis of a primary psychiatric disorder in the ED. Diagnoses, assigned during ED visits, were made according to the Diagnostic and Statistical Manual of Mental Disorders III-R or IV. RESULTS: Primary psychiatric patients with substance use comorbidity had a significantly higher mean number of ED visits across the span of the study (mean 5.2; SD 7.4) than primary psychiatric patients without substance use comorbidity (mean 2.8; SD 3.9). In multiple logistic regression analyses predicting several categorizations of heavier use of the ED (either 4+, 8+, 12+, 16+, or 20+ visits over the span of the study), psychiatric patients with a comorbid substance use disorder had adjusted odds ratios of 2.8 to 4.9 (reference group was defined as patients with a psychiatric disorder but no substance use disorder; models controlled for age, race, and sex). CONCLUSION: Substance use comorbidity among patients presenting to an ED with a psychiatric disorder is associated with substantially increased ED service use. Improved detection, referral, and treatment of substance use disorders in this population could result in decreased ED use and improved patient outcomes.

Academic Medical Centers↗