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Biomedical subjects

D A Lewis

Publications and source records attributed to D A Lewis.

At least 91 records · Page 5Linked to original sources
PubMed2000

Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex.

Microarray expression profiling of prefrontal cortex from matched pairs of schizophrenic and control subjects and hierarchical data analysis revealed that transcripts encoding proteins involved in the regulation of presynaptic function (PSYN) were decreased in all subjects with schizophrenia. Genes of the PSYN group showed a different combination of decreased expression across subjects. Over 250 other gene groups did not show altered expression. Selected PSYN microarray observations were verified by in situ hybridization. Two of the most consistently changed transcripts in the PSYN functional gene group, N-ethylmaleimide sensitive factor and synapsin II, were decreased in ten of ten and nine of ten subjects with schizophrenia, respectively. The combined data suggest that subjects with schizophrenia share a common abnormality in presynaptic function. We set forth a predictive, testable model.

Animals↗
PubMed2000

Description and evaluation of an education and communication skills training course in HIV and AIDS for dental consultants.

A 2-day course was organised for dental hospital consultants as part of a project on raising awareness of dental staff about HIV and AIDS. The course comprised an information update, practical experience in the diagnosis of oral conditions and a "hands-on" exercise in infection control. The 2nd day of the course consisted of experiential communication skills training using rôle-play with actors and video feedback. Evaluation of the course showed that the consultants perceived the course to be valuable. There was a general improvement in dentists' confidence in their knowledge, ability to communicate with HIV-positive patients and in talking to staff who are unwilling to provide treatment. These changes are statistically significant and these skills are still being utilized and maintained 2 years later. Information and training packs prepared by multidisciplinary groups using a variety of teaching methods should be made available to those involved in training dental staff.

Communication↗
PubMed2000

Oral management of patients following oncology treatment: literature review.

Many tumours of the head and neck are treated by clinical oncologists using radiotherapy. This treatment modality is particularly effective in destroying rapidly dividing cells, hence its value in cancer treatment. The tissues of the oral mucosa, the salivary glands and blood vessels can be damaged as the result of radiotherapy treatment. As a result, patients experience unwanted oral effects that have both short and long-term implications. The outlook following treatment for head and neck cancer continues to improve and, as people keep their teeth into later life, dentists will increasingly be expected to address the oral problems that patients experience after radiotherapy. The aim of this article is to review the current literature concerning the implications and management of these oral implications of cancer treatment.

Adult↗
PubMed2000

Chancroid: from clinical practice to basic science.

Chancroid is a sexually transmitted disease caused by the bacterium Haemophilus ducreyi. It usually presents as a genital ulcer and may be associated with regional lymphadenopathy and bubo formation. H. ducreyi infection is predominantly seen in tropical resource-poor regions of the world where it is frequently the most common etiological cause of genital ulceration. Genital ulcer disease has been shown to be an extremely important co-factor in HIV transmission. With the advent of the AIDS epidemic, there has been increased research effort to elucidate those factors involved in the pathogenesis of chancroid. Several putative virulence factors have now been identified and isogenic H. ducreyi mutants constructed by mutagenesis of their encoding genes. This approach has facilitated investigations into the role each of these putative virulence factors may play in H. ducreyi pathogenesis through the use of in vitro and in vivo model systems. One major goal of current chancroid research is to identify antigens which are immunogenic and could form the basis of a vaccine against H. ducreyi infection. Such a vaccine, if shown to be effective in decreasing the prevalence of chancroid, could have the added benefit of slowing down the HIV incidence rates in those populations where chancroid is a major co-factor for HIV transmission.

AIDS-Related Opportunistic Infections↗
PubMed2000

Horizontal synaptic connections in monkey prefrontal cortex: an in vitro electrophysiological study.

In monkey dorsolateral prefrontal cortex (PFC), long-distance, horizontally oriented intrinsic axon collaterals interconnect clusters of pyramidal neurons in the supragranular layers. In order to study the electrophysiological responses mediated by these long-distance projections, an in vitro slice preparation of monkey PFC was used to obtain whole-cell patch clamp recordings from layer 3 pyramidal neurons. Using in vivo tracer injections, we found that long-distance projections were well preserved in PFC slices cut in the coronal plane. Postsynaptic currents were evoked by low-intensity electrical extracellular stimulation applied successively to 20-30 discrete sites located up to 2200 micron lateral to the recorded cell. Several criteria were applied to discriminate between mono- and polysynaptic responses. Long-distance monosynaptic connections were mediated by fibers with relatively slow conduction velocity (0.14 m/s). Excitatory postsynaptic currents (EPSCs) evoked by stimulation of short- or long-distance horizontal connections did not differ in kinetic properties. The majority (77%) of the 35 layer 3 PFC neurons studied were monosynaptic targets of long-distance connections. EPSCs mediated by long-distance connections had amplitudes that were similar or even larger than short-distance EPSCs, suggesting that excitatory input provided by the former was relatively robust. For most neurons (87.5%) in which a full complement of monosynaptic EPSCs was evoked by multisite stimulation, the EPSC amplitude as a function of stimulation distance from the recorded cells exhibited statistically significant peaks. The spacing between peaks was similar to the spacing between interconnected clusters of neurons observed in previous anatomical studies. The results show that long-distance excitatory connections constitute a significant intrinsic pathway of synaptic communication in layer 3 of monkey PFC.

Animals↗
PubMed2000

Dopamine increases excitability of pyramidal neurons in primate prefrontal cortex.

Dopaminergic modulation of neuronal networks in the dorsolateral prefrontal cortex (PFC) is believed to play an important role in information processing during working memory tasks in both humans and nonhuman primates. To understand the basic cellular mechanisms that underlie these actions of dopamine (DA), we have investigated the influence of DA on the cellular properties of layer 3 pyramidal cells in area 46 of the macaque monkey PFC. Intracellular voltage recordings were obtained with sharp and whole cell patch-clamp electrodes in a PFC brain-slice preparation. All of the recorded neurons in layer 3 (n = 86) exhibited regular spiking firing properties consistent with those of pyramidal neurons. We found that DA had no significant effects on resting membrane potential or input resistance of these cells. However DA, at concentrations as low as 0.5 microM, increased the excitability of PFC cells in response to depolarizing current steps injected at the soma. Enhanced excitability was associated with a hyperpolarizing shift in action potential threshold and a decreased first interspike interval. These effects required activation of D1-like but not D2-like receptors since they were inhibited by the D1 receptor antagonist SCH23390 (3 microM) but not significantly altered by the D2 antagonist sulpiride (2.5 microM). These results show, for the first time, that DA modulates the activity of layer 3 pyramidal neurons in area 46 of monkey dorsolateral PFC in vitro. Furthermore the results suggest that, by means of these effects alone, DA modulation would generally enhance the response of PFC pyramidal neurons to excitatory currents that reach the action potential initiation site.

Action Potentials↗
PubMed1999

Uniquely altered DNA replication fidelity conferred by an amino acid change in the nucleotide binding pocket of human immunodeficiency virus type 1 reverse transcriptase.

Arginine 72 in human immunodeficiency virus type 1 reverse transcriptase (RT), a highly conserved residue among retroviral polymerases and telomerases, forms part of the binding pocket for the nascent base pair. We show here that replacement of Arg(72) by alanine strongly alters fidelity in a highly unusual manner. R72A reverse transcriptase is a frameshift and base substitution antimutator polymerase whose increased fidelity results both from increased nucleotide selectivity and from a decreased ability to extend mismatched primer termini. Thus, Arg(72)-substrate interactions in wild-type human immunodeficiency virus type 1 RT can stabilize incorrect nucleotides allowing misinsertion and promoting extension of mismatched and perhaps misaligned template-primers. In contrast to the higher fidelity at most sites, R72A RT is highly error-prone for misincorporations opposite template T in the sequence context: 5'-CTGG. Surprisingly, this results mostly from a 1200-fold increase in the apparent K(m) for correct dAMP incorporation. Thus, Arg(72) interactions with substrate are critical for the stability of the correct T.dAMP base pair when the 5'-CTGG sequence is present in the binding pocket for the nascent base pair. Collectively, the data show that a mutant polymerase may yield higher than normal average replication fidelity, yet paradoxically place specific sequences at very high risk of mutation.

Base Pairing↗
PubMed1999

Altered GABA neurotransmission and prefrontal cortical dysfunction in schizophrenia.

Dysfunction of the dorsolateral prefrontal cortex appears to be a central feature of the pathophysiology of schizophrenia, and this dysfunction may be related to alterations in gamma aminobutyric acid (GABA) neurotransmission. Determining the causes and consequences of altered GABA neurotransmission in schizophrenia, and the relationship of these changes to other abnormalities in prefrontal cortical circuitry, requires an understanding of which of the multiple subpopulations of cortical GABA neurons are affected. The chandelier class of GABA neurons, especially those located in the middle layers of the prefrontal cortex (PFC), have been hypothesized to be preferentially involved in schizophrenia because they 1) receive direct synaptic input from dopamine axons, 2) exert powerful inhibitory control over the excitatory output of layer 3 pyramidal neurons, and 3) undergo substantial developmental changes during late adolescence, the typical age of onset of schizophrenia. Consistent with this hypothesis, the axon terminals of chandelier neurons, as revealed by immunoreactivity for the GABA membrane transporter, are reduced substantially in the middle layers of the PFC in schizophrenic subjects. This alteration appears to be selective for the chandelier class of GABA neurons and for the disease process of schizophrenia. These findings provide insight into the pathophysiologic mechanisms underlying prefrontal cortical dysfunction in schizophrenia, and they reveal new targets for therapeutic intervention in this illness.

Adolescent↗
PubMed1999

Parvalbumin-immunoreactive axon terminals in macaque monkey and human prefrontal cortex: laminar, regional, and target specificity of type I and type II synapses.

In sensory regions of primate neocortex, the calcium-binding protein parvalbumin (PV) is present in axon terminals that form both Gray's type I (asymmetric) and type II (symmetric) synapses. Those terminals forming type I synapses appear to arise from relay nuclei in the thalamus, whereas those forming type II synapses derive from cortical local circuit neurons. However, whether PV is present in both of these two types of terminals in the association regions of the primate prefrontal cortex (PFC) is not known. In the present study, PV-immunoreactive (IR) axon terminals in the superficial layers (layers 2-3a) of monkey PFC area 9 were found to form exclusively type II synapses onto the dendritic spines (44%), shafts (39%), or somata/axon initial segments (17%) of pyramidal neurons. In contrast, in the middle layers (layers 3b-4), 52% of the PV-IR axon terminals formed type I synapses, and 79% of these terminals contacted dendritic spines. However, in the adjacent area 46, only 12% of the PV-IR terminals in the middle layers formed type I synapses. In addition, the PV-IR axon terminals forming type I synapses were 50% larger than those terminals forming type II synapses. Similar to the macaque monkey, in area 9 of the human PFC, PV-IR axon terminals forming type I synapses onto dendritic spines were found in the middle layers. These findings indicate that PV-IR axon terminals in macaque monkey and human PFC are likely to have both intrinsic and extrinsic sources. In addition, the laminar, regional, and target specificity of the labeled terminals forming type I synapses suggests that they arise from PV-IR neurons in the mediodorsal thalamic nucleus.

Adolescent↗
PubMed1999

Syncope in the pediatric patient. The cardiologist's perspective.

The evaluation of syncopal children or adolescents relies heavily on a thorough, detailed history and physical examination. All syncope associated with exercise or exertion must be considered dangerous. The ECG is mandatory, but other laboratory tests are generally of limited value unless guided by pertinent positives or negatives in the history and physical examination. The ECG allows screening for dysrhythmias, such as Wolff-Parkinson-White syndrome, heart block, and long QT syndrome, as well as hypertrophic cardiomyopathies and myocarditis. Tilt table testing can be useful in selecting therapy by demonstrating the physiologic response leading to syncope in an individual patient. The most common type of syncope in otherwise healthy children and adolescents is neurocardiogenic or vasodepressor syncope, which is a benign and transient condition. Because syncope can be a predictor of sudden cardiac death, it must be taken seriously, and appropriate screening must be performed.

Adolescent↗
PubMed1999

Effects of partial dopamine loss in the medial prefrontal cortex on local baseline and stress-evoked extracellular dopamine concentrations.

A reduction in the activity of mesoprefrontal dopamine neurons has been suggested to play a role in the pathophysiology of schizophrenia. Indeed, a recent study indicates that the density of tyrosine hydroxylase-immunoreactive axons is decreased in the deep layers of the prefrontal cortex of schizophrenic subjects [Akil et al., (1999) Am. J. Psychiatry, in press]. To determine the impact of partial loss of prefrontal dopamine axons on the activity of the remaining dopamine axons, we examined the effects of 6-hydroxydopamine lesions of the medial prefrontal cortex on local extracellular dopamine concentrations in the rat. In rats sustaining an average 63% loss of tyrosine hydroxylase-immunoreactive axons and no loss of dopamine-beta-hydroxylase-immunoreactive axons in the medial prefrontal cortex (smaller lesion), the baseline extracellular dopamine concentration was reduced by 63+/-9%. Thirty minutes of tail pressure increased extracellular dopamine in the medial prefrontal cortex by a maximum of 1.28+/-0.28 pg in control rats, but only 0.74+/-0.18 pg in rats with smaller lesions. In rats sustaining an average 80% loss of tyrosine hydroxylase-immunoreactive axons and 25% loss of dopamine-beta-hydroxylase-immunoreactive axons (larger lesion), the baseline extracellular dopamine concentration in the medial prefrontal cortex did not differ from control values. In addition, the maximum stress-evoked increase in dopamine concentration was also similar to that observed in control rats (+1.04+/-0.28 pg). The stress-induced increase in extracellular dopamine in the medial prefrontal cortex of rats sustaining smaller and larger lesions may occur in the absence of a corresponding increase in dopamine synthesis in mesoprefrontal dopamine neurons. This proposal is supported by our observation that stress did not alter tissue or extracellular 3,4-dihydroxyphenylacetic acid concentrations in the medial prefrontal cortex of lesioned rats. These data suggest that moderate loss of tyrosine hydroxylase-immunoreactive axons in the prefrontal cortex is sufficient to reduce extracellular dopamine concentrations in this brain region. In addition, a further reduction in tyrosine hydroxylase-immunoreactive axons in the medial prefrontal cortex, combined with the loss of dopamine-beta-hydroxylase-immunoreactive axons, results in normal extracellular dopamine concentrations in this area. We propose that the latter effect is due to increased neurochemical activity of remaining mesoprefrontal dopamine axons and/or decreased clearance of extracellular dopamine due to loss of both dopamine and norepinephrine transporters.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1999

A natural flavonoid present in unripe plantain banana pulp (Musa sapientum L. var. paradisiaca) protects the gastric mucosa from aspirin-induced erosions.

The active anti-ulcerogenic ingredient was extracted from unripe plantain banana by solvent fractionation and identified by chromatography, spectroscopy and high performance liquid chromatography as the flavonoid leucocyanidin. Dried unripe plantain banana powder, the extracted leucocyanidin and a purified synthetic leucocyanidin demonstrated a significant (P < 0.05) protective effect against aspirin-induced erosions.

Animals↗
PubMed1999

Gender differences and endothelium- and platelet-derived factors in the coronary circulation.

1. Experiments were designed to determine whether or not interactions of platelets with coronary arteries are affected by gender or oestrogen-status. 2. Platelets and right coronary arteries were isolated from sexually mature male, female and ovariectomized pigs. Arteries were suspended in organ chambers for the measurement of isometric force. Responses of rings, with and without endothelium, were evaluated to aggregating platelets and the platelet products 5-hydroxytryptamine (5-HT) and adenosine diphosphate (ADP). 3. Release of 5-HT, thromboxane A2 (TXA2) and prostacyclin were measured from platelets. 4. Platelets caused relaxations of rings with endothelium from all pigs. However, in rings without endothelium, consistent contractions were observed only in rings from male pigs. 5. The release of 5-HT and prostacyclin was greatest from platelets of ovariectomized pigs compared with male and female pigs. Release of TXA2 was greatest from platelets of male pigs. 6. Endothelium-dependent relaxations to ADP and contractions to 5-HT were similar among the three groups. 7. These results suggest that there may be gender-specific differences in vasomotor responses to autogenous platelets but not to the platelet-derived products 5-HT and ADP. Furthermore, there are gender differences in platelets in the release of cyclo-oxygenase metabolites of arachidonic acid and 5-HT. These products could contribute to gender differences in response to injury in the coronary circulation.

Adenosine Diphosphate↗