Biomedical subjects
R Hicks
Publications and source records attributed to R Hicks.
Potentiation of etoposide-induced cytotoxicity and DNA damage in CCRF-CEM cells by pretreatment with non-cytotoxic concentrations of arabinosyl cytosine.
Pretreatment of the human lymphoblastoid cell line CCRF-CEM with 0.02 microM arabinosyl cytosine (ara C) enhances both the cytotoxic and the DNA-damaging effects of etoposide. This concentration of ara C is itself non-cytotoxic and results in no detectable DNA damage as measured by alkaline elution. Ara C pretreatment results in the synchronisation of cells, a 24-h pretreatment resulting in the accumulation of cells in the early S phase. The sensitivity of cells to etoposide-induced cytotoxicity was increased 2.5 times and DNA damage was enhanced 1.66 times by this pretreatment. Maximal potentiation of etoposide-induced DNA damage (2.06-fold increase) was observed after 48 h continuous treatment with ara C, but no further enhancement of cytotoxicity occurred. Cell-cycle analysis demonstrated that 48 h ara C treatment resulted in the accumulation of cells in the late S/G2M phase. Cells returned to a normal cell-cycle distribution within 24 h of the removal of ara C, and the potentiation of etoposide activity was then reduced to a 1.3- to 1.4-fold level. DNA damage induced by etoposide following ara C pretreatment was qualitatively identical to that produced by etoposide alone, suggesting a mechanism involving topoisomerase II. To investigate this possibility, we measured topoisomerase II protein levels by immunoblotting. Measurement of topoisomerase II levels in whole-cell lysates of ara C-pretreated cells showed a 3- to 5-fold increase in topoisomerase levels relative to total protein content. This suggests that elevated enzyme levels may be responsible for the increased sensitivity of ara C-pretreated cells to etoposide.
Assessment of corticospinal and somatosensory conduction simultaneously during scoliosis surgery.
The function of descending motor pathways and that of ascending sensory pathways in the spinal cord were monitored at the same time in 120 patients undergoing surgery for scoliosis. Transcranial electrical stimulation of the motor cortex was performed simultaneously with stimulation of the tibial nerves in the popliteal fossae, and the descending and ascending volleys were recorded from the spinal cord at two levels using epidural electrodes. Stable recordings of both volleys have been obtained in all neurologically normal patients and in many with pre-existing neurological deficits. The experimental conditions which resulted in reliable recordings were explored in select patients and include: a vertex-anode/lateral cathode montage for transcranial stimulation, epidural recording of evoked corticospinal and somatosensory volleys at two spinal levels, a high-pass filter of 500 Hz, and stable anaesthesia. The epidural recording allows full muscle relaxation and the use of volatile anaesthetics; recording at two levels allows a deterioration in function to be identified quickly and distinguished from an artifactual change.
Anodal and cathodal stimulation of the upper-limb area of the human motor cortex.
In 18 neurologically normal subjects the corticofugal volleys evoked by anodal and cathodal electrical stimulation of the motor cortex were recorded using epidural electrodes at the high-thoracic and low-thoracic regions of the spinal cord during surgery for scoliosis. At and just above threshold, anodal and cathodal stimulation of the upper-limb area and motor cortex produced a D wave that propagated to the low-thoracic region. The stimulus intensity required to produce D waves was significantly lower with anodal stimulation. I waves were recorded at higher stimulus intensities than the D wave but not more readily with cathodal stimulation. There was no significant difference in the extent to which stimulus intensity had to be increased above D-wave threshold to produce I waves with the two stimulus polarities, and the number of I waves was the same when the stimulus was increased by the same amount above D-wave threshold. After withdrawal of isoflurane, I waves could not be recorded when the stimulus intensity was below D-wave threshold with either stimulus polarity. Anodal stimulation over the upper-limb area remained more effective than cathodal stimulation in producing both D and I waves. These results indicate that, at threshold, regardless of anaesthesia, anodal and cathodal stimuli access upper-limb corticospinal neurons directly at a similar site, the anodal stimuli being more effective. In addition, the results suggest that some corticospinal neurons in the upper-limb area of motor cortex have projections to lumbar segments.
Corticospinal volleys evoked by electrical stimulation of human motor cortex after withdrawal of volatile anaesthetics.
1. In twenty-two neurologically normal patients undergoing surgery for scoliosis, corticospinal volleys to transcranial electrical stimulation of the motor cortex were recorded from the spinal cord using epidural electrodes. While anaesthesia was maintained by nitrous oxide and narcotics, volatile anaesthetics were withdrawn to determine whether such agents had a depressant effect on the evoked corticospinal volley. 2. Profound changes were documented in liminal D waves, there being an increase in amplitude averaging 392% following withdrawal of the volatile anaesthetic. There was a proportionately smaller increase (averaging 26%) in supraliminal D waves; these had a complex bifid or trifid shape indicating that some corticofugal axons were being activated deep to cortex. In general the effect on the D wave of withdrawing the anaesthetic agent was similar to that of increasing stimulus intensity. 3. Withdrawal of isoflurane dramatically increased the number of I waves and their mean amplitude. In the absence of isoflurane, I3 (mean latency 3.5 ms after the D wave) became the dominant I wave. The amplitude of I2 (mean latency 2.2 ms) became slightly smaller. The change in I waves could not be likened to an increase in stimulus intensity, because I waves invariably increase in, or remain of the same, amplitude as stimulus intensity is increased. 4. These findings indicate that changes in motor cortex excitability can result in major changes in the corticospinal volley produced by transcranial electrical stimulation, affecting both the D wave and I waves. They caution against identifying a cortical action solely on the basis of a change in the responses to magnetic stimulation of motor cortex but no such change to electrical stimulation.
'Tooth bleaching is vital'.
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Identification of murine thymocyte populations capable of extensive proliferation in serially passaged thymic organ cultures.
Using the approach of titrating precursor cells into mouse thymus organ cultures and serial passage, we have sought to compare the proliferative capacities of cells derived from adult and embryonic thymus and related haemopoietic tissues. We find that cells derived from the liver and thymus of day 14 embryos are capable of extensive proliferation in such cultures (surviving for at least 12 weeks) whereas cells derived from adult sources (blood and thymus) display a much more restricted lifespan and potential for division. Analysis of sequentially passaged thymic lobes shows that cells lacking CD4 and CD8 (CD4- and CD8-) and a subset of single CD8 positives are selectively expanded in these cultures. A preliminary study of the CD4-CD8- populations in these lobes suggest that these include cells expressing surface CD3 (in association with either TCR alpha beta or TCR gamma delta) and a subset of CD4-CD8-CD3-. These findings suggest that sequential passage of thymocytes in organ culture may be a useful alternative strategy for characterising cells with high proliferative potential, resident in the thymus and also for probing their lineage relationships.
Loss of the first permanent molar and caries experience of adjacent teeth.
The caries experience of the occlusal and distal surfaces of the second premolars and the occlusal and mesial surfaces of the second permanent molars was examined in four groups of subjects aged 19-20 years. Group 1 comprised subjects with first permanent molars present, Group 2 subjects with early loss of the first permanent molar (before the age of 11-12 years), Group 3 subjects with late loss of the first permanent molar (after 11-12 years but before 15-16 years) and Group 4 included a combination of Group 2 and Group 3. Loss of the first permanent molar was associated with increased caries or restorations in the occlusal surfaces of adjacent teeth, but reduced caries or restorations in the proximal surfaces of adjacent teeth. Early loss of the first molar was associated with significantly greater caries or restoration experience in proximal surfaces than late loss, but no difference was detected for occlusal surfaces.
The expression of MHC class II (Ia) antigens on mouse keratinocytes following epicutaneous application of contact sensitizers and irritants.
The expression of MHC class II (Ia) antigens on mouse keratinocytes was studied following both the induction and elicitation of contact sensitivity, and after primary irritant reactions. IA+ and IE+ keratinocytes were detected, using an indirect immunofluorescence assay on epidermal sheets, only after the induction and elicitation of contact sensitivity with the sensitizers oxazalone, picryl chloride and 2,4-dinitrochlorobenzene but not with formaldehyde. Ia+ keratinocytes were not detected after epicutaneous application of the non-sensitizing irritants croton oil, SDS and anthralin, or following attempted sensitization of nude mice, suggesting that the expression of Ia antigen on keratinocytes during contact sensitivity reactions is T-cell mediated. Because Ia antigen expression on keratinocytes could be detected only several days after induction or elicitation of contact sensitivity, and contact sensitization could also be demonstrated to occur independently of aberrant Ia expression, Ia+ keratinocytes cannot be involved in the initiation of these reactions. However, they might be important in exerting an immunomodulatory influence during the later stages of the responses to certain sensitizers.
Auto- and polyreactivity of IgM from CD5+ and CD5- cord blood B cells.
The presence of the CD5 (67 kDa) molecule on the surface of B cells has been considered a marker for cells producing auto- and polyreactive antibodies. Cord blood B lymphocytes (rich in CD5+ B cells) have been sorted into CD5 positive and negative populations by flow cytometry using monoclonal antibodies to CD20 and CD5. Clones of these populations were obtained by immortalization with Epstein-Barr virus. Clones derived from both CD5+ and CD5- B cells produced IgM which was auto- and polyreactive with a higher frequency of these specificities in the CD5+ population. These data indicate that expression of surface CD5 on cord blood B cells is not a definitive marker of an auto/polyreactive population.
Contact sensitivity (allergic contact dermatitis) to bis(tri-n-butyltin) oxide in mice.
Contact sensitivity (allergic contact dermatitis) to bis(tri-n-butyltin) oxide (TBTO) was demonstrated in the mouse. TBTO (in an acetone:olive olive oil vehicle) or acetone:olive oil alone (as a control) were applied to the shaved flank under an occlusive patch and animals were challenged on the dorsum of the ear 6 days later. Ear swelling was then measured using an engineer's micrometer, 2, 24, 48 or 72 h thereafter. Significant differences in ear swelling between control and TBTO-sensitized animals were found 24 h after challenge: thereafter the elicitation reaction declined rapidly whilst irritant swelling in control animals increased. Maximal elicitation of TBTO sensitivity could only be elicited by concentrations of TBTO that caused irritation. In a separate experiment, a single application of TBTO to the ears of naive animals provoked increase in auricular lymph node weight, cell yield and proliferation of lymph node cells during overnight culture. These data support the conclusion that TBTO is a contact sensitizer and illustrate the potential usefulness of the quantitative methods of contact sensitivity assessment which have been developed in the mouse.
The impact of curriculum-based suicide prevention programs for teenagers: an 18-month follow-up.
In a long-term follow-up of a study designed to assess the impact of school-based suicide prevention curricula on high school students, a group of 174 students from two high schools who were exposed to a prevention program were compared with a group of 207 control students from two additional high schools who were not exposed to the curriculum. A questionnaire, designed to measure the effects of the prevention program on actual help-seeking behaviors and suicide morbidity during the follow-up period, was administered 18 months after delivery of the program. The study failed to find convincing evidence of any program effect.
The clinical role of metabolic imaging of the heart by positron emission tomography.
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Abnormal neuroendocrine responsivity to acute i.v. clomipramine challenge in depressed patients.
The neuroendocrine responsivity to an acute serotonergic challenge with low-dose i.v. clomipramine was studied in seven drug-free depressed patients and seven age-matched healthy control subjects. The depressed patients had higher baseline prolactin concentrations than the healthy subjects, and their prolactin response to clomipramine, assessed as either the percent of baseline or the log-transformed concentration, was significantly different (delayed and blunted peak response) compared to healthy controls. The growth hormone response was exaggerated in the depressed patients, and there were also trends toward blunting in their cortisol and adrenocorticotropic hormone responses. These results are consistent with previous findings of altered neuroendocrine responses to a variety of putative serotonin agonists in depressed patients.
Factors influencing the initiation of carious lesions in specific tooth surfaces over a 4-year period in children between the ages of 11-12 years and 15-16 years.
An analysis of factors influencing the initiation of carious lesions on specific tooth surfaces over a 4-year period in children between the ages of 11-12 years and 15-16 years is presented. Approximately 1000 children, resident in the County of South Glamorgan, Wales, were assessed for caries status and oral cleanliness in 1980 when aged 11-12 years and again in 1984 when aged 15-16 years. On both occasions, the children completed detailed questionnaires on dental health-related topics. Surfaces which were sound when the children were 11-12 years were identified and subsequently awarded a score of zero if they remained sound at 15-16 years or a score of one if they had developed carious lesions or had been filled. For each child, a mean mouth caries initiation score was computed for specific groups of surfaces, namely pit and fissure surfaces in posterior teeth, approximal surfaces in posterior teeth, buccal and lingual smooth surfaces of all teeth and approximal surfaces of anterior teeth. One-way analysis of variance and multiple regression techniques revealed that a number of factors had a significant influence on the initiation of caries. The factors and their level of significance varied between the surfaces. However, relatively little (less than 6 per cent) of the total variance in caries initiation score could be explained by the identified factors. Overall, more lesions developed in pit and fissure surfaces in posterior teeth than in the other surfaces included in the analyses.
Factors influencing the caries experience of a group of children at the ages of 11-12 and 15-16 years: results from an ongoing epidemiological survey.
An analysis of factors influencing the caries experience of adolescents in South Wales is presented. Approximately 1000 children were assessed for caries status and oral cleanliness in 1980 when aged 11-12 years and again in 1984 when aged 15-16 years. In addition, on both occasions, the children completed detailed questionnaires on dental health-related topics. When aged 11-12 years, the observed mean DMFT, DMFS and DFS scores of the children were 4.0, 6.7 and 5.5 respectively. The corresponding scores at age 15-16 years were 6.5, 11.8 and 10.2. A preliminary analysis using conventional multiple regression techniques revealed that a number of factors had a significant influence on the caries experience of the children. The significance of the factors depended on the sex of the population subgroup, the age of the children and the particular caries index studied. However, at both ages the factors of most significance were the number of erupted teeth, total mean plaque score and the reported amount of money spent on sweets per week. A further evaluation using analysis of covariance with the number of erupted teeth and surfaces as the covariates confirmed the significant influence of the total mean plaque score and amount of money spent on sweets. In addition, both analyses indicated that toothbrushing frequency and social class had a significant influence on the caries experience of boys.
Epstein-Barr virus and other herpesvirus infections in Kawasaki syndrome.
Epstein-Barr virus (EBV), a possible cause of Kawasaki syndrome (KS), is not pathenogenically associated with KS in Hawaii. The prevalence of EBV capsid antibody in KS patients was found not to differ significantly from that in controls, and the antibody response in those infected with EBV was the same as that in other children similarly infected. No EBV was isolated from acute-phase patients. All patients with capsid antibody at the onset of KS also had Epstein-Barr nuclear antigen antibody: 36 patients developed antibody within 3 months after onset of KS; in 10, EBV infection could have been coincidental with the disease. Cytomegalovirus (CMV) was isolated from 9 patients with KS and 10 controls. A similar number of controls and patients had antibody to human herpesvirus 6 (HHV6); one patient seroconverted. None of the herpes viruses (EBV, CMV, HHV6, varicella-zoster virus, or herpes simplex virus) plays a unique or dominant role in the etiology or pathogenesis of KS in Hawaii.
Regional heterogeneity of cardiac substrate metabolism?
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