Taking the initiative on suicide.
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Adult↗
Biomedical subjects
D Carroll
Publications and source records attributed to D Carroll.
Mike Grace talks to Dennis Carroll.
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Commerce↗
Illegitimate recombination in Xenopus: characterization of end-joined junctions.
When linear DNAs are injected into Xenopus laevis eggs, they are converted into several different kinds of recombination products. Some molecules undergo homologous recombination by a resection-annealing mechanism; some ends are precisely ligated; and some ends are joined by illegitimate means. The homologous and illegitimate products are also generated in nuclear extracts from stage VI Xenopus oocytes. In order to gain insight into the mechanism(s) of illegitimate end joining, we amplified, cloned and sequenced a number of junctions from eggs and from oocyte extracts. The egg junctions fell into three categories: some with no homology at the join point that may have been produced by blunt-end ligation; some based on small, but significant homologies (5-10 bp); and some with matches of only 1 or 2 nucleotides at the joint. Junctions made in oocyte extracts were largely of the latter type. In the extracts, formation of illegitimate joints required the addition of all four deoxyribonucleoside triphosphates and was inhibited by aphidicolin. This indicates that this process involves DNA synthesis, and mechanisms incorporating this feature are considered. The spectrum of recombination products formed in Xenopus eggs is very reminiscent of those produced from DNA introduced into mammalian cells.
Animals↗
Cognitive-behavioural interventions in cardiac rehabilitation.
Evidence pertaining to the efficacy of cognitive-behavioural interventions, broadly defined, in cardiac rehabilitation is reviewed. Primary concerns lie with risk reduction and with the amelioration of psychological distress following myocardial infarction. The available data permit few definitive conclusions. The available data, on balance, suggest that programmes targeted at reducing Type A behaviours, smoking cessation, increasing exercise, or which teach stress management techniques, may be effective in reducing psychological distress and increasing effective coping, although frequently only in the short-term; it is more difficult to point to long-lasting advantage in this context. In addition, psychological interventions of this sort would seem to be associated with positive behavioural change. However, there is, as yet, little concerted evidence that such changes afford benefits in terms of coronary heart disease mortality or morbidity. Nevertheless, the pessimism of these conclusions may reflect shortcomings in study design and the failure to optimally match patients to programmes rather than an intrinsic lack of efficacy of the interventions.
Adaptation, Psychological↗
Identifying the basis for the word frequency effect in recognition memory.
Recent theories of recognition memory have identified two bases on which recognition-memory judgments may be made: recollection, which involves retrieval of contextual information from an earlier episode of stimulus presentation; and familiarity, which is distinguished by a general sense of familiarity in the absence of recollection. Four experiments were conducted to test whether the word frequency effect (WFE) in recognition memory (superior performance with low- in comparison with high-frequency targets) results from recollection-based processes, familiarity-based processes, or both. In two of the experiments, superior memory for aspects of the study context was found for low-frequency in comparison with high-frequency words, suggesting frequency-related differences in recollection. The other two experiments used Jacoby's (1991) inclusion/exclusion paradigm to provide estimates of the contribution of recollection and familiarity to recognition. In both experiments the data suggested that the WFE is primarily a recollection-based phenomenon. These findings suggest that the recognition memory WFE for old items results primarily from the effects of word frequency on recollection. The implications of these findings for theories of recognition memory are discussed.
Adult↗
Distribution of exchanges upon homologous recombination of exogenous DNA in Xenopus laevis oocytes.
Homologous recombination between DNA molecules injected into Xenopus oocyte nuclei was investigated by examining the recovery of information from differentially marked parental sequences. The injected recombination substrate was a linear DNA with terminal direct repeats of 1246 bp; one repeat differed from the other by eight single base-pair substitutions, distributed throughout the region of homology, each of which created or destroyed a restriction enzyme site. Recombination products were recovered and analyzed for their content of the diagnostic sites, either directly by Southern blot-hybridization or after cloning in bacteria. The majority (76%) of the cloned products appeared to be the result of simple exchanges-i.e., there was one sharp transition from sequences derived from one parent to sequences derived from the other. These simple exchanges were concentrated near the ends of the homologous interval and, thus, near the sites of the original molecular ends. Placing marked sites on only one side of the homologous overlap showed that marker recovery was governed largely by the positions of the molecular ends and not by the markers themselves. When a terminal nonhomology was present at one end of the substrate, the yield of recombinants was sharply decreased, but the pattern of exchanges was not affected, suggesting that products from end-blocked substrates arise by the same recombination pathway. Because of considerable evidence supporting a nonconservative, resection-annealing mechanism for recombination in oocytes, we interpret the distribution of exchanges as resulting from long-patch repair of extensive heteroduplex intermediates.
Animals↗
Repair of heteroduplex DNA in Xenopus laevis oocytes.
We have hypothesized that the inheritance of heteroallelic markers during recombination of homologous DNAs in Xenopus oocytes is determined by resolution of a heteroduplex intermediate containing multiple single-base mismatches. To test this idea, we prepared synthetic heteroduplexes carrying 8 separate mispairs in vitro and injected them into oocyte nuclei. DNA was recovered and analyzed directly, by Southern blot-hybridization, and indirectly, by cloning individual repair products in bacteria. Mismatch correction was quite efficient in the oocytes; markers on the same strand were commonly co-corrected, indicating a long-patch mechanism; and the distribution of markers was very similar to that obtained by recombination. This supports our interpretation of the recombination outcome in terms of a resection-annealing mechanism. The injected heteroduplexes carried strand breaks (nicks) as a result of their method of preparation. We tested the idea that mismatch correction might be nick-directed by ligating the strands of the heteroduplex substrate to form covalently closed circles. Repair in oocytes was still efficient, and long patches predominated; but the pattern of recovered markers was quite different than with the nicked substrate. This suggests that nicks, when present, do indeed direct repair, but that, in their absence, recognition of specific mismatches governs repair of the ligated heteroduplexes.
Animals↗
Impact of a health promotion programme on multiple risk factors for CHD: a preliminary evaluation.
Results are reported from a pilot study to evaluate an innovative health promotion programme (Lanark Health Club), in a community where the incidence of CHD is above average. The aim of the programme is to provide multiple risk factor screening and interventions--including an exercise programme--sited in the community and utilising existing resources within primary care and the voluntary sector. Data were returned by 54 respondents after six months' participation on the programme. Subjects' self-reported activity levels increased significantly over time, and there were concomitant significant reductions in weight, SBP and DBP. Reduced levels of self-reported stress were associated with reductions in alcohol intake, and were greater in male subjects. When other measures were controlled for, stress reduction was significantly more likely for those who also lost weight and exhibited a reduction in DBP. Finally, participation in the Health Club appeared to result in cholesterol reduction, particularly for those with relatively high initial cholesterol levels. While this could reflect regression effects, it is certainly worthy of more systematic examination.
Adolescent↗
Self-help and the new health agenda.
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Chronic Disease↗
Inherited prion disease (PrP lysine 200) in Britain: two case reports.
OBJECTIVE: To identify cases of inherited prion diseases in Britain and to assess their phenotypic features. DESIGN: Screening study of patients suspected clinically to have Creutzfeldt-Jakob disease and other neurodegenerative diseases by prion protein gene analysis. SETTING: Biochemical research department. SUBJECTS: Patients suspected to have Creutzfeldt-Jakob disease and other neurodegenerative diseases. RESULTS: Two patients with symptoms characteristic of sporadic Creutzfeldt-Jakob disease were found to have inherited prion protein disease (PrP lysine 200), with a mutation at codon 200 of the prion protein gene. Both were homozygous at codon 129 of the gene. One patient was a man aged 58 of British descent while the other was of Libyan Jewish origin. CONCLUSION: Two foci of inherited prion disease are known, among Libyan Jews and in Slovakia. A separate British focus of the disease may also exist. Heterozygosity at codon 129 may lead to reduced penetrance of the mutation.
Codon↗
Intermediates in extrachromosomal homologous recombination in Xenopus laevis oocytes: characterization by electron microscopy.
Several molecular mechanisms have been proposed to account for nonconservative homologous recombination. This type of recombination is particularly efficient in Xenopus oocytes when appropriate DNA substrates are injected. To distinguish between possible models, we have investigated recombination intermediates from oocytes by direct observation in the electron microscope. Partially recombined DNA was crosslinked with a psoralen derivative after incubation in oocytes to limit the branch migration that might occur during recovery procedures and alter the structures that were initially present. Branched structures, which we interpret as intermediates, represented approximately 10% of the DNA recovered and were readily analyzed. We did not observe any structures with internal loops predicted by invasion mechanisms. The majority of intermediates had one or two single-stranded branches on product-sized molecules, as predicted for incomplete junctions in the resection-annealing mechanism. Detailed length measurements confirmed the expectations of that model. When recovered DNA was not crosslinked, or when annealed junctions were prepared in vitro, we saw branched structures that indicated the occurrence of extensive branch migration. Comparison with the crosslinked sample confirmed the effectiveness of the crosslinking in preserving structures created in the oocytes. Our results strongly support a resection-annealing mechanism of recombination in oocytes.
Animals↗
Isolation of large quantities of functional, cytoplasm-free Xenopus laevis oocyte nuclei.
A procedure is described that facilitates the isolation of large quantities of nuclei (germinal vesicles or GVs) from late stage Xenopus laevis oocytes. The method was developed by modifying techniques described in two published reports (F. Scalenghe et al. (1978) Chromosoma 66, 299-308; I. Ruberti et al. (1989) Anal. Biochem. 180, 177-180). Methods were chosen which optimize yields of GVs and homologous recombination activity. This procedure yields up to 90% of the total GVs present in 70 ml of oocytes. Proteins in the extract made from these GVs are predominantly of nuclear origin; little cytoplasmic contamination is detected as measured by alpha-tubulin content. The extract catalyzes the complete recombination of linear, terminally homologous DNA, as observed in injected oocytes. The extract also performs other nuclear processes including transcription, repair-type DNA synthesis, chromatin assembly, NDP kinase reactions, and dsRNA deamination. Because this procedure greatly increases the yield of GVs over manual isolation protocols, and the resulting extract is capable of carrying out a variety of typical nuclear processes, it should expedite the purification of components found in oocyte GVs, including proteins required for homologous recombination.
Animals↗
A multiple dose comparison of ibuprofen and dihydrocodeine after third molar surgery.
The objectives were to compare the relative merits of ibuprofen 400 mg and dihydrocodeine 30 mg or 60 mg taken up to four times daily for up to 6 days in the treatment of pain after third molar removal. A randomised, double-blind, multiple dose, crossover study was undertaken in 68 patients undergoing two-stage bilateral lower third molar removal. The results showed that ibuprofen produced significantly greater analgesia than either of the dihydrocodeine treatments on the day of surgery. Ibuprofen and dihydrocodeine 60 mg produced significantly greater analgesia than dihydrocodeine 30 mg on the day after surgery, and on days 4 and 5 ibuprofen was again significantly superior to dihydrocodeine 60 mg. Roughly half the patients taking dihydrocodeine stopped the study on the day after surgery, because of adverse effects and/or inadequate relief, compared with 6 out of 44 taking ibuprofen. Dihydrocodeine 60 mg produced four times the number of patients affected by adverse effects compared with ibuprofen, and dihydrocodeine 30 mg three times as many. The principal adverse effects were nausea, vomiting and drowsiness. In conclusion, ibuprofen produced better analgesia than dihydrocodeine with significantly fewer adverse effects and is therefore a better choice for pain relief after oral surgery.
Administration, Oral↗
Single-dose, randomized, double-blind, double-dummy cross-over comparison of extradural and i.v. clonidine in chronic pain.
We studied 10 patients with chronic back pain who had claimed benefit with a previous extradural dose of clonidine 150 micrograms combined with local anaesthetic. We compared a single dose of clonidine 150 micrograms given by either the extradural or i.v. route in a double-blind, randomized, double-dummy and cross-over fashion, with 80% power to detect a difference in the analgesic effect of the two routes. Pain intensity, pain relief, adverse effects, mood, sedation and vital signs were assessed by a nurse observer. I.v. clonidine produced significantly (P < 0.04) greater analgesia than extradural clonidine in one of the five analgesic outcome measures. Clonidine given by either route produced statistically significant sedation and significant decreases in arterial pressure and heart rate. In this study, extradural clonidine had no significant clinical advantages compared with i.v. clonidine; clonidine 150 micrograms by either route produced a high incidence of adverse effects.
Adult↗
Oral bromfenac 10 and 25 mg compared with sublingual buprenorphine 0.2 and 0.4 mg for postoperative pain relief.
The aim of this single-dose, randomized, positive control, double-dummy, double-blind, parallel group study was to compare oral bromfenac 10 and 25 mg with sublingual buprenorphine 0.2 and 0.4 mg for treatment of postoperative pain. We studied 91 patients with moderate or severe pain after general surgical or orthopaedic operations, using pain intensity, pain relief, adverse effect, mood and sedation outcomes. There was a significant analgesic dose-response for buprenorphine, showing study sensitivity, but not for bromfenac. The two bromfenac treatments were significantly superior to the two buprenorphine treatments. Significantly more patients reported nausea with buprenorphine. There was evidence of a ceiling effect for analgesia with bromfenac.
Administration, Oral↗
Dose-response for analgesic effect of amitriptyline in chronic pain.
A randomised, double-blind, multiple dose, crossover study with three 3-week treatment periods was set up to compare the analgesic efficacy and adverse effects of amitriptyline in oral doses of 25, 50 or 75 mg. Patients used diaries to assess their pain, and clinic assessments were made at the end of each treatment period. It was found that in 29 patients with chronic (more than 2 months) pain, amitriptyline 75 mg provided significantly greater efficacy than amitriptyline 25 or 50 mg. There was no significant difference in mood scores between the different doses of amitriptyline, but sleep was judged significantly better with 75 mg compared with 25 mg. The incidence of adverse effects was significantly higher with the 75 mg dose, and the principal adverse effects were dry mouth and drowsiness. In the context of chronic pain, the analgesic effect of amitriptyline was shown to have a dose-response unrelated to mood elevation, but there was a dose-response for the incidence of adverse effects.
Adult↗
Homologous and illegitimate recombination in developing Xenopus oocytes and eggs.
Exogenous DNA is efficiently recombined when injected into the nuclei of Xenopus laevis oocytes. This reaction proceeds by a homologous resection-annealing mechanism which depends on the activity of a 5'-->3' exonuclease. Two possible functions for this recombination activity have been proposed: it may be a remnant of an early process in oogenesis, such as meiotic recombination or amplification of genes coding for rRNA, or it may reflect materials stored for embryogenesis. To test these hypotheses, recombination capabilities were examined with oocytes at various developmental stages. Late-stage oocytes performed only homologous recombination, whereas the smallest oocytes ligated the restriction ends of the injected DNA but supported no homologous recombination. This transition from ligation to recombination activity was also seen in nuclear extracts from these same stages. Exonuclease activity was measured in the nuclear extracts and found to be low in early stages and then to increase in parallel with recombination capacity in later stages. The accumulation of exonuclease and recombination activities during oogenesis suggests that they are stored for embryogenesis and are not present for oocyte-specific functions. Eggs were also tested and found to catalyze homologous recombination, ligation, and illegitimate recombination. Retention of homologous recombination in eggs is consistent with an embryonic function for the resection-annealing mechanism. The observation of all three reactions in eggs suggests that multiple pathways are available for the repair of double-strand breaks during the extremely rapid cleavage stages after fertilization.
Animals↗
Morphine responsiveness of chronic pain: double-blind randomised crossover study with patient-controlled analgesia.
There is controversy about whether the lack of response of some chronic pain to opioid treatment is absolute or relative. It is widely believed that nociceptive pain is responsive to opioids whereas neuropathic pain tends not to be. We have used a method of patient-controlled analgesia (PCA) with simultaneous nurse-observer measurement of analgesia, mood, and adverse effects to address these issues. Ten patients with chronic pain were given morphine at two concentrations (10 and 30 mg/ml) by PCA in two separate sessions in a double-blind randomised crossover study. Before the study a clinical judgment was made as to whether each pain was nociceptive or neuropathic. Seven patients showed good analgesic responses (more than 70 mm pain relief on a visual-analogue scale) of pain at rest, two patients poor responses (less than 30 mm pain relief), and one a moderate response with both concentrations (30-70 mm pain relief). The response to morphine was consistent (greater and faster relief with the higher concentration) in nine patients. Two patients had pain on movement that responded moderately to low-concentration morphine and well to the higher concentration. All patients with pains judged to be nociceptive showed good analgesic responses compared with half of those with neuropathic pain. There was no evidence that analgesic responses in patients with neuropathic pain were due to changes in mood. This PCA method is a quick and efficient tool to determine the consistency of the analgesic response. Such consistency can guide the clinician as to whether continued or higher-dose opioid treatment will produce good analgesia. An inconsistent response points to the use of other pain-relieving strategies.
Adult↗