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Biomedical subjects

G V Williams

Publications and source records attributed to G V Williams.

At least 19 recordsLinked to original sources
PubMed2005

Under the curve: critical issues for elucidating D1 receptor function in working memory.

It has been postulated that spatial working memory operates optimally within a limited range of dopamine transmission and D1 dopamine receptor signaling in prefrontal cortex. Insufficiency in prefrontal dopamine, as in aging, and excessive transmission, as in acute stress, lead to impairments in working memory that can be ameliorated by D1 receptor agonist and antagonist treatment, respectively. Iontophoretic investigations of dopamine's influence on the cellular mechanisms of working memory have revealed that moderate D1 blockade can enhance memory fields in primate prefrontal pyramidal neurons while strong blockade abolishes them. The combined behavioral and physiological evidence indicates that there is a normal range of dopamine function in prefrontal cortex that can be described as an "inverted-U" relationship between dopamine transmission and the integrity of working memory. Both in vivo and in vitro studies have demonstrated a role for dopamine in promoting the excitability of prefrontal pyramidal cells and facilitating their N-methyl-d-aspartate inputs, while simultaneously restraining recurrent excitation and facilitating feedforward inhibition. This evidence indicates that there is a fine balance between the synergistic mechanisms of D1 modulation in working memory. Given the critical role of prefrontal function for cognition, it is not surprising that this balancing act is perturbed by both subtle genetic influences and environmental events. Further, there is evidence for an imbalance in these dopaminergic mechanisms in multiple neuropsychiatric disorders, particularly schizophrenia, and in related nonhuman primate models. Elucidating the orchestration of dopamine signaling in key nodes within prefrontal microcircuitry is therefore pivotal for understanding the influence of dopamine transmission on the dynamics of working memory. Here, we explore the hypothesis that the window of optimal dopamine signaling changes on a behavioral time-scale, dependent upon current cognitive demands and local neuronal activity as well as long-term alterations in signaling pathways and gene expression. If we look under the bell-shaped curve of prefrontal dopamine function, it is the relationship between neuromodulation and cognitive function that promises to bridge our knowledge between molecule and mind.

Animals↗
PubMed2004

The diurnal profile of gastric pepsin activity is reduced with Helicobacter pylori infection.

Both Helicobacter pylori and pepsin are proven mucosal damaging agents and implicated in the aetiology of peptic ulcer disease. Historically studies of pepsin over time have proved methodologically difficult, and as a result little work has been done on the effect of H. pylori on luminal pepsin secretion. Our objectives were to determine pepsin activity over 24 hr in normal human subjects and to examine luminal pepsin activity in relation to H. pylori infection. Twenty-seven healthy volunteers had gastric juice samples aspirated every 2 hr for 24 hr. All subjects had H. pylori status determined by C13 urea breath test and serology. Meals were standardized throughout the study period. Gastric juice samples were measured for pH, diluted, and frozen in acetate buffer pH 4.1 for up to 1 month, conditions shown to cause no loss of activity. Individual samples were measured for pepsin activity by assaying for new N-terminal peptide formation. Mean pepsin activity (microg enzyme/ml) in 21 normal H. pylori-negative subjects ranged from 114 to 1030 microg/ml, with a characteristic diurnal profile of increasing activity to maximum after the evening meal. Mean pepsin activity in subjects with H. pylori was consistently below that for age-matched H. pylori-negative subjects at each time point. Overall mean pepsin activity was significantly lower in those with H. pylori compared to those without (P < 0.001). There is significant pepsin activity in the stomach throughout the 24-hr period, with a trend for the highest activity through the night. Subjects with H. pylori infection have lower luminal pepsin activity.

Adolescent↗
PubMed2000

Magnetic-field-induced low-energy spin excitations in YBa(2)Cu(4)O(8) measured by high field Gd(3+) electron spin resonance.

We have measured the spin susceptibility, chi(s), of the CuO(2) planes in the underdoped high T(c) superconductor, YBa(2)Cu(4)O(8) by Gd(3+) electron spin resonance (ESR) in single crystals and aligned powders in fields up to 15.4 T. At low temperatures and high fields, chi(s) is enhanced slightly in the B parallel c orientation with respect to the B perpendicular c orientation. The enhancement at 15.4 T (approximately equal to 0.15H(c2)) at 16 K (0.2 T(c)) is small: approximately 10% of chi(s)(T(c)), suggesting that the second critical field of superconductivity, H(c2) approximately equal to 100 T, would not suppress the pseudogap. This work demonstrates the potential of high field ESR in single crystals for studying high T(c) superconductors.

Journal Article↗
PubMed2000

Reversal of antipsychotic-induced working memory deficits by short-term dopamine D1 receptor stimulation.

Chronic blockade of dopamine D2 receptors, a common mechanism of action for antipsychotic drugs, down-regulates D1 receptors in the prefrontal cortex and, as shown here, produces severe impairments in working memory. These deficits were reversed in monkeys by short-term coadministration of a D1 agonist, ABT 431, and this improvement was sustained for more than a year after cessation of D1 treatment. These findings indicate that pharmacological modulation of the D1 signaling pathway can produce long-lasting changes in functional circuits underlying working memory. Resetting this pathway by brief exposure to the agonist may provide a valuable strategy for therapeutic intervention in schizophrenia and other dopamine dysfunctional states.

Animals↗
PubMed2000

Destruction and creation of spatial tuning by disinhibition: GABA(A) blockade of prefrontal cortical neurons engaged by working memory.

Local circuit neurons in the dorsolateral prefrontal cortex (dPFC) of monkeys have been implicated in the cellular basis of working memory. To further elucidate the role of inhibition in spatial tuning, we iontophoresed bicuculline methiodide (BMI) onto functionally characterized neurons in the dPFC of monkeys performing an oculomotor delayed response task. This GABA(A) blockade revealed that both putative interneurons and pyramidal cells possess significant inhibitory tone in the awake, behaving monkey. In addition, BMI application primarily resulted in the loss of previously extant spatial tuning in both cell types through reduction of both isodirectional and cross-directional inhibition. This tuning loss occurred in both the sensorimotor and mnemonic phases of the task, although the delay activity of prefrontal neurons appeared to be particularly affected. Finally, application of BMI also created significant spatial tuning in a sizable minority of units that were untuned in the control condition. Visual field analysis of such tuning suggests that it is likely caused by the unmasking of normally suppressed spatially tuned excitatory input. These findings provide the first direct evidence of directional inhibitory modulation of pyramidal cell and interneuron firing in both the mnemonic and sensorimotor phases of the working memory process, and they implicate a further role for GABAergic interneurons in the construction of spatial tuning in prefrontal cortex.

Action Potentials↗
PubMed1999

Isodirectional tuning of adjacent interneurons and pyramidal cells during working memory: evidence for microcolumnar organization in PFC.

Studies on the cellular mechanisms of working memory demonstrated that neurons in dorsolateral prefrontal cortex (dPFC) exhibit directionally tuned activity during an oculomotor delayed response. To determine the particular contributions of pyramidal cells and interneurons to spatial tuning in dPFC, we examined both individually and in pairs the tuning properties of regular-spiking (RS) and fast-spiking (FS) units that represent putative pyramidal cells and interneurons, respectively. Our main finding is that FS units possess spatially tuned sensory, motor, and delay activity (i. e., "memory fields") similar to those found in RS units. Furthermore, when recorded simultaneously at the same site, the majority of neighboring neurons, whether FS or RS, displayed isodirectional tuning, i.e., they shared very similar tuning angles for the sensory and delay phases of the task. As the trial entered the response phase of the task, many FS units shifted their direction of tuning and became cross-directional to adjacent RS units by the end of the trial. These results establish that a large part of inhibition in prefrontal cortex is spatially oriented rather than being untuned and simply regulating the threshold response of pyramidal cell output. Moreover, the isodirectional tuning between adjacent neurons supports a functional microcolumnar organization in dPFC for spatial memory fields similar to that found in other areas of cortex for sensory receptive fields.

Action Potentials↗
PubMed1998

The cerebral cortex: a case for a common site of action of antipsychotics.

Recent evidence from studies of receptor occupancy and regulation in post-mortem brains of patients with neuropsychiatric disorders and in non-human primates is providing new leads in the ongoing quest to understand the pathophysiology and causes of schizophrenia and to develop more effective methods of treatment. These studies suggest that the cerebral cortex may harbour the elusive common sites of action of antipsychotic medications and indicate that chronic treatment with these drugs differentially regulates both families of dopamine receptors in this structure. Upregulation of the cortical dopamine D2 receptors is accompanied by a downregulation of the D1 sites. Balancing the opposing actions of dopamine D1 and D2 receptor regulation may hold the key to optimal drug therapy and to understanding the pathophysiology of schizophrenia. In this article, Michael Lidow, Graham Williams and Patricia Goldman-Rakic review the evidence supporting the cerebral cortex as a pivotal site for these mechanisms underlying the action of antipsychotics.

Animals↗
PubMed1998

Dopaminergic regulation of cerebral cortical microcirculation.

Functional variations in cerebral cortical activity are accompanied by local changes in blood flow, but the mechanisms underlying this physiological coupling are not well understood. Here we report that dopamine, a neurotransmitter normally associated with neuromodulatory actions, may directly affect local cortical blood flow. Using light and electron-microscopic immunocytochemistry, we show that dopaminergic axons innervate the intraparenchymal microvessels. We also provide evidence in an in vitro slice preparation that dopamine produces vasomotor responses in the cortical vasculature. These anatomical and physiological observations reveal a previously unknown source of regulation of the microvasculature by dopamine. The findings may be relevant to the mechanisms underlying changes in blood flow observed in circulatory and neuropsychiatric disorders.

Animals↗
PubMed1997

Analysis of p74, a PDV envelope protein of Autographa californica nucleopolyhedrovirus required for occlusion body infectivity in vivo.

In nature, nuclear polyhedrosis viruses (NPV) are transmitted when susceptible insect larvae ingest viral occlusion bodies (OB). These dissociate in the alkaline environment of the midgut and release encapsulated virions (PDV) which bind to midgut epithelial cells and initiate an infection. A previous study showed that expression of the Autographa californica NPV (AcMNPV) p74 gene during replication is essential for the production of infectious OB. A set of p74 deletion and overexpression recombinants was used for the production and screening of monoclonal antibodies, and for an investigation of gross cytopathology and localization of p74. No differences in virus structure or morphogenesis were observed in infected cells when the p74 gene of AcMNPV was deleted, even though the infectivity of OB harvested from the cells was abolished when they were fed to Trichoplusia ni larvae. Mutant OB released virus particles and degraded insect peritrophic membrane as in infections with wild-type virus; in addition, virions purified from mutant OB were infectious when injected into the haemocoel of T. ni larvae. Western blot analysis confirmed that p74 was associated with the PDV and could not be detected in the budded form virion phenotype. The polypeptide was readily degraded by treatment of purified PDV with proteinase K, in the presence and absence of detergent, and could be extracted from PDV by a non-ionic detergent treatment. The data are consistent with p74 being a structural polypeptide of the PDV phenotype, most probably as a component associated with the outside surface of the virion envelope. Its presence is shown to be essential for primary infection of midgut cells of insect larvae.

Animals↗
PubMed1995

Modulation of memory fields by dopamine D1 receptors in prefrontal cortex.

Dopamine has been implicated in the cognitive process of working memory but the cellular basis of its action has yet to be revealed. By combining iontophoretic analysis of dopamine receptors with single-cell recording during behaviour, we found that D1 antagonists can selectively potentiate the 'memory fields' of prefrontal neurons which subserve working memory. The precision shown for D1 receptor modulation of mnemonic processing indicates a direct gating of selective excitatory synaptic inputs to prefrontal neurons during cognition.

Animals↗
PubMed1994

Genetic analyses of temperature-sensitive mutations in baculovirus late expression factors.

Two temperature-sensitive mutants of Autographa californica nuclear polyhedrosis virus were characterized with respect to late and very late gene expression. Cells infected with ts317 or ts538 at the nonpermissive temperature revealed slightly reduced intracellular levels of late structural gene products including gp64 envelope, vp39 capsid, and p6.9 DNA binding proteins. However, with the exception of gp64, there was a dramatic reduction in extracellular levels of the structural proteins, suggesting that assembly or transport of extracellular virions was impaired. Electron microscopy confirmed the dramatic effect the mutations exhibited on viral morphogenesis. The ts538 mutation was physically mapped to the 60-65 mu region and DNA sequence analysis identified a single nucleotide alteration converting Leu to Phe in amino acid 105 of the late expression factor called lef-4. The mutation was positively correlated with the temperature-sensitive phenotype by analysis of DNA from ts+ revertants generated by marker rescue. Transient expression assays confirmed that lef-4 was required for activation of the late vp39 gene in virus infected cells. The defect in activation of the ts317 and ts538 polyhedrin genes could be overcome by coinfection with helper virus indicating that the mutations affected functions involved in activating the very late class of baculovirus genes as well. These results demonstrated a clear functional differentiation between genes regulating viral DNA replication which was normal in the mutant infected cells and those regulating late gene expression and extracellular virus production which were defective in these same infected cells.

Animals↗
PubMed1994

Colorectal carcinoma: do elderly patients present differently?

A cohort of patients with a histological diagnosis of colorectal carcinoma was enrolled prospectively. All subjects were interviewed by one observer using a structured questionnaire. One hundred and fifty 'young' (under 70 years) and 123 'elderly' (70 years or more) subjects formed the study sample. The elderly patients did not present more frequently as emergencies than the young, but were more often referred to medical or geriatric rather than surgical units (p < 0.01). There was no difference in median overall delay from symptom onset to histological diagnosis between the age groups (19.5 weeks in each). Symptomatic anaemia and nonspecific symptoms were more often the presenting complaint in the elderly subjects (p < 0.05). On direct questioning, there were no differences in symptom reporting with respect to age group for subjects with colonic cancer. For rectal cancer the following symptoms were more common in the young group: tenesmus (odds ratio 4.2; 95% confidence intervals 2.0-10.0), abdominal or rectal pain (4.0; 1.9-10.6), change in flatus production (2.6; 1.3-5.8), passage of mucus per rectum (2.2; 1.1-4.8). Anorexia was more common in the elderly patients (0.4; 0.1-0.8). This study suggests that symptomatic presentation of rectal cancer is different in the elderly but does not necessarily lead to greater delays in diagnosis nor higher rates of non-elective presentation.

Adenocarcinoma↗
PubMed1994

Comparison of gastrointestinal symptoms in colorectal carcinoma patients and community controls with respect to age.

Early diagnosis of colorectal cancer may be delayed by the wide prevalence of gastrointestinal symptoms in the general population. This study assessed, with respect to age, the frequency of gastro-intestinal symptoms in patients with colorectal carcinoma in comparison with community controls and also compared the frequency of such symptoms between 'young' (under 70 years) and 'old' (70 year or over) subjects. Two hundred and seventy three consecutive unselected colorectal cancer patients and 273 age and sex matched community controls were interviewed in a structured manner. Among controls, the 'old' group compared with the 'young' reported abdominal pain (p < 0.05), mucous discharge (p < 0.01), faecal incontinence (p < 0.05), change in flatus production (p < 0.05) significantly more often. There were no significant differences in regularity and frequency of bowel habit by age group. All the symptoms considered were significantly more common in colorectal cancer cases than controls (except abdominal bloating), but the association was less strong in the 'old' group. This study confirms that symptoms attributable to the lower gastrointestinal tract are reported by a clinically important number of community subjects and by a significantly higher proportion of elderly people.

Abdominal Pain↗
PubMed1993

Neuronal responses in the ventral striatum of the behaving macaque.

To analyse the functioning of the ventral striatum, the responses of more than 1,000 single neurons were recorded in a region which included the nucleus accumbens and olfactory tubercle in 5 macaque monkeys. While the monkeys performed visual discrimination and related feeding tasks, the different populations of neurons found included neurons which responded to novel visual stimuli; to reinforcement-related visual stimuli such as (for different neurons) food-related stimuli, aversive stimuli, or faces; to other visual stimuli; in relation to somatosensory stimulation and movement; or to cues which signalled the start of a task. The neurons with responses to reinforcing or novel visual stimuli may reflect the inputs to the ventral striatum from the amygdala and hippocampus, and are consistent with the hypothesis that the ventral striatum provides a route for learned reinforcing and novel visual stimuli to influence behaviour.

Amygdala↗
PubMed1993

The effects of iontophoretic clonidine on neurones in the rat superficial dorsal horn.

Clonidine and glutamate were applied by iontophoresis to cells in the superficial 3 laminae of the spinal cord in the anaesthetised rat. Only cells that were excited by glutamate (up to 150 nA) were studied. Some spontaneously active cells could be excited by clonidine (up to 100 nA). However, when applied to non-spontaneous cells, clonidine had no effect at any dose level. When ejected in a cyclic pattern alternating with glutamate ejection, clonidine powerfully amplified the response of many cells to the glutamate stimulus. This effect was seen only on cells with small-amplitude spikes and low-threshold (LT) receptive fields. The amplification was often sustained and could outlast the clonidine ejection by several minutes. Clonidine had a long-lasting inhibitory effect on the responses to glutamate of cells with high-threshold (HT) or wide-dynamic-range (WDR) receptive fields. Clonidine appeared to selectively decrease the responsiveness of WDR cells to noxious stimulation. It is suggested that an amplification of the response of LT cells to other excitatory inputs could contribute to the analgesic action of clonidine.

Animals↗
PubMed1992

Analysis of polyhedra morphology mutants of Autographa californica nuclear polyhedrosis virus: molecular and ultrastructural features.

Two new mutants of Autographa californica multiple nuclear polyhedrosis virus affected in the morphogenesis of their polyhedra, designated M276 and M934, were investigated. Marker transfer experiments demonstrated that the observed phenotype was due exclusively to alterations in the polyhedrin gene. M276 contained a 229 base insertion near the carboxyl terminus coding region which resulted in synthesis of a truncated protein; M934 had a point mutation substituting phenylalanine for leucine at amino acid 183. Both mutations occurred in highly conserved regions of the protein and prevented the occlusion of virus particles, but did not affect targeting for the intranuclear ring zone. M276 was distinct in that it had prominent cytosolic condensations of polyhedrin, although these were probably due to a decreased protein solubility. M934 polyhedrin condensations associated prematurely with calyx material such that it became incorporated into the condensation rather than at the surface. Results confirm that occlusion size and shape are features inherent to the polyhedrin protein, and suggest that polyhedrin conformation may help regulate the occlusion process.

Amino Acid Sequence↗