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Biomedical subjects

D Johnston

Publications and source records attributed to D Johnston.

At least 163 records · Page 9Linked to original sources
PubMed1994

Autonomously active protein kinase C in the maintenance phase of N-methyl-D-aspartate receptor-independent long term potentiation.

In area CA1 of the hippocampus, the induction of long term potentiation (LTP) requires activation of either N-methyl-D-aspartate receptors (NMDA receptor-dependent LTP) or voltage-gated Ca2+ channels (NMDA receptor-independent LTP). We have investigated biochemical sequelae of NMDA receptor-independent LTP induction. We find that a persistent increase in second messenger-independent protein kinase C activity is associated with the maintenance phase of NMDA receptor-independent LTP. This increase in protein kinase C activity is prevented by blocking LTP with nifedipine, a Ca2+ channel antagonist, or kynurenic acid, a nonselective glutamate receptor antagonist. Additionally, we find an increase in the catalytic fragment of protein kinase C (PKM) in the maintenance phase of NMDA receptor-independent LTP, indicating that proteolytic activation of protein kinase C may account for its autonomous activation. This increase in the catalytic fragment of protein kinase C is also prevented by blocking LTP induction. These results are the first to demonstrate that persistent protein kinase C activation is a possible mechanism for the maintenance of NMDA receptor-independent LTP.

Animals↗
PubMed1994

Role of circumferential margin involvement in the local recurrence of rectal cancer.

Local recurrence after resection for rectal cancer remains common despite growing acceptance that inadequate local excision may be implicated. In a prospective study of 190 patients with rectal cancer, we examined the circumferential margin of excision of resected specimens for tumour presence, to examine its frequency and its relation to subsequent local recurrence. Tumour involvement of the circumferential margin was seen in 25% (35/141) of specimens for which the surgeon thought the resection was potentially curative, and in 36% (69/190) of all cases. After a median 5 years' follow-up (range 3.0-7.7 years), the frequency of local recurrence after potentially curative resection was 25% (95% CI 18-33%). The frequency of local recurrence was significantly higher for patients who had had tumour involvement of the circumferential margin than for those without such involvement (78 [95% CI 62-94] vs 10 [4-16]%). By Cox's regression analysis tumour involvement of the circumferential margin independently influenced both local recurrence (hazard ratio = 12.2 [4.4-34.6]) and survival (3.2 [1.6-6.53]). These results show the importance of wide local excision during resection for rectal cancer, and the need for routine assessment of the circumferential margin to assess prognosis.

Adult↗
PubMed1994

Internal anal sphincter activity after restorative proctocolectomy for ulcerative colitis: a study using continuous ambulatory manometry.

PURPOSE: The aim of this study was to further investigate continuous ambulatory anal manometry which has recently been introduced as a method for studying anorectal activity in ambulant patients, thereby avoiding many of the potential drawbacks of static techniques. METHOD: In this study continuous ambulatory manometry was used to assess the activity of the internal anal sphincter in patients who had undergone restorative proctocolectomy, and, in particular, to compare patients who had undergone conventional mucosal proctectomy with sutured endoanal, ileoanal anastomosis with patients who had undergone restorative proctocolectomy with preservation of the entire anal canal by means of stapled, end-to-end, ileoanal anastomosis without mucosectomy. RESULTS: Evidence of basal internal sphincter activity was found in only 38 percent of patients after mucosal proctectomy with sutured endoanal anastomosis, whereas all patients after restorative proctocolectomy with stapled end-to-end anastomosis and all control individuals showed such activity of the internal sphincter. Similarly, the number of sampling episodes seen in patients after mucosal proctectomy with endoanal anastomosis was significantly less (median, 0.0/hours (0-30/hours)) than the number of sampling episodes observed in patients after end-to-end anastomosis (median, 4.5/hours (1-48/hours)) or in control individuals (median, 5.6/hours (0-31/hours)) (P < 0.001). CONCLUSIONS: These results suggest that the internal anal sphincter is damaged in the course of mucosal proctectomy and endoanal anastomosis. In contrast, after restorative proctocolectomy with stapled, end-to-end anastomosis normal function of the internal sphincter is preserved.

Adult↗
PubMed1994

Stricture at the pouch-anal anastomosis after restorative proctocolectomy.

PURPOSE: The aim of this study was to determine what factors may be responsible for the development of a stricture at the pouch-anal anastomosis after restorative proctocolectomy. METHODS: A consecutive series of 115 patients was studied retrospectively a median of 34 months (range, 4-100 months) after operation or ileostomy closure. The procedure failed in 11 patients (9.6 percent) who subsequently had to have a permanent ileostomy. Another two patients were excluded from the analysis, one of whom was awaiting ileostomy closure, whereas the other had a stricture due to a desmoid tumor. Of the remaining 102 patients, 39 (38 percent) developed an ileoanal anastomotic stricture, which was severe and persistent in 16 percent. RESULTS: The results were analyzed with the aid of multivariate logistic regression analysis. Factors which predisposed significantly to the development of an ileoanal anastomotic stricture were 1) use of the 25-mm (small) diameter stapling gun (P = 0.05), 3) use of a defunctioning ileostomy (P = 0.03), and 4) anastomotic dehiscence and pelvic sepsis (P = 0.03). The single patient whose operation failed because of a stricture had also developed pelvic sepsis associated with an anastomotic dehiscence. CONCLUSIONS: The eventual clinical, functional outcome after dilation of a stricture in the 39 patients who developed a stricture was as good as the outcome in the 63 patients who did not a develop stricture.

Adolescent↗
PubMed1994

Coordinated activity of the new "rectum" and anal sphincter after sphincter-saving resection of the rectum for colitis or carcinoma.

PURPOSE: The aim of this study was to determine whether coordinated activity exists across a stapled enteroanal anastomosis. METHODS: Twenty-nine patients were studied for a median of one year after complete excision of the rectum and stapled enteroanal anastomosis; 12 patients underwent low anterior resection with coloanal anastomosis for carcinoma, and 17 patients underwent restorative proctocolectomy with ileoanal anastomosis. RESULTS: Maximum anal resting pressures were slightly lower after coloanal anastomosis than after ileoanal anastomosis [median range, 56 (11-60) cm H2O, cf 69 (40-107) cm H2O, P = NS]. During distention of the neorectum, anal sphincter pressures at 2.5, 1.5, and 0.5 cm from the anal verge were significantly lower after coloanal anastomosis compared with after ileoanal anastomosis (P < 0.01 at each station). The volume of neorectal distention required to produce maximal inhibition of the anal sphincter was significantly less after coloanal anastomosis at 50 (range, 20-60) ml of air than after ileoanal anastomosis at 240 (range, 100-420) ml of air (P < 0.01). Minor fecal leakage and urgency of bowel action were significantly more common after coloanal anastomosis (P < 0.01). CONCLUSION: Alterations in the dynamic response of the anal sphincter to distention of the neorectum may explain why the clinical results were better after ileal pouch-anal anastomosis than after coloanal anastomosis.

Adult↗
PubMed1994

Decrease in the anorectal pressure gradient after low anterior resection of the rectum. A study using continuous ambulatory manometry.

PURPOSE: Changes in anorectal function after low anterior resection of the rectum (LAR) often lead to symptoms of urgency and frequency of defecation, the anterior resection syndrome. It has been reported that preservation of part of the rectum improves clinical results, but why this should be remains unclear. METHODS: We have carried out continuous ambulatory manometric studies in two groups of patients: 11 patients, a median of 11 (range, 5-96) months after LAR, in whom the median anastomotic level above the anal high-pressure zone was 0 (range, 0-2) cm; 9 patients, a median of 6 (range, 3-12) months after sigmoid colectomy, in whom the rectum remained in situ and who acted as controls. RESULTS: Comparing the LAR group with controls, resting anal pressures were lower, median 68 (range 27-102) cm H2O vs. 95 (45-116) cm H2O (P < 0.05), and neorectal pressures were higher, 25 (0-48) cm H2O vs. 10 (0-10) cm H2O (P < 0.01). Thus the anorectal pressure gradients were less, 34 (0-74) cm H2O vs. 81 (35-113) cm H2O (P < 0.01). Slow-wave activity in the anal sphincter was present in six patients (55 percent) after coloanal anastomosis and eight patients (89 percent) after sigmoid colectomy. Sampling episodes were seen in only two patients (18 percent) after coloanal anastomosis and five patients (56 percent) after sigmoid colectomy. When clinical endpoints were compared (LAR vs. controls), bowel frequency in 24 hours was higher, 5 (3-8) vs. 2 (1-3) (P < 0.01); fecal leakage was more common, affecting seven patients (64 percent) vs. one patient (11 percent) (P < 0.05), and urgency of defecation was also more common. CONCLUSIONS: The inferior clinical results observed after LAR compared with the results after sigmoid colectomy are thus in part because of higher neorectal pressure acting on a weakened sphincter mechanism. These observations lend support to the idea that neorectal capacity should be increased in patients who undergo low anterior resection.

Aged↗
PubMed1994

Dendritic attenuation of synaptic potentials and currents: the role of passive membrane properties.

The dendritic trees of neurons are structurally and functionally complex integrative units receiving thousands of synaptic inputs that have excitatory and inhibitory, fast and slow, and electrical and biochemical effects. The pattern of activation of these synaptic inputs determines if the neuron will fire an action potential at any given point in time and how it will respond to similar inputs in the future. Two critical factors affect the integrative function of dendrites: the distribution of voltage-gated ion channels in the dendritic tree and the passive electrical properties, or 'electrotonic structure', upon which these active channels are superimposed. The authors review recent data from patch-clamp recordings that provide new estimates of the passive membrane properties of hippocampal neurons, and show, with examples, how these properties affect the shaping and attenuation of synaptic potentials as they propagate in the dendrites, as well as how they affect the measurement of current from synapses located in the dendrites. Voltage-gated channels might influence the measurement of 'passive' membrane properties and, reciprocally, passive membrane properties might affect the activation of voltage-gated channels in dendrites.

Animals↗
PubMed1994

The results of modified use of chemotherapy for patients with metastatic breast cancer.

We investigated whether modifying standard chemotherapy with 5-fluorouracil, doxorubicin and cyclophosphamide (FAC) could improve the outcome of patients with advanced breast carcinoma. We changed the conventional FAC treatment as follows: firstly, we administered oestrogens during the delivery of chemotherapy. Secondly, we administered 5-fluorouracil by continuous infusion. Thirdly, we limited chemotherapy treatment to 12 cycles and did not continue treatment during remissions. We evaluated this modified treatment in 63 patients and compared its results to other treatments results given at this institution. We found that the modified treatment improved the quality of life and survival of premenopausal breast cancer patients.

Adult↗
PubMed1994

A comparison of public health care utilization by gay men and intravenous drug users with AIDS in San Francisco.

A group of gay-identified men (n = 81) and intravenous drug users (n = 88) diagnosed with AIDS in San Francisco were surveyed regarding their use and satisfaction with their health care services. The interview contained a mix of qualitative and quantitative questions. The two groups of AIDS patients were not statistically different in terms of age or self-reported level of health during the previous 3 months, although the gay men had been diagnosed with AIDS somewhat longer (20 months) than the group of intravenous drug users (15 months). Analysis of the quantitative data revealed that intravenous drug users receive more medical care for HIV disease than did gay men and were equally satisfied with the care that they did receive. Analysis of the qualitative data showed that considerable agreement exists between the perceptions of both gay men and intravenous drug users of the health care system.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Identification of melanoma cell surface antigens immunogenic in mice.

Active immunization to B16 melanoma cells or vaccines induces anti-melanoma immune responses in syngeneic mice. The immunogenic antigens stimulating immunity to this tumor have not been identified. In this study we detected several B16 melanoma antigens immunogenic in syngeneic mice using as probes antimelanoma antibodies induced by immunization to B16 melanoma vaccines. These antigens were identified by SDS-PAGE and autoradiographic analysis of specific immunoprecipitates. They were cell-surface components with approximate molecular weights of 41, 46, 50, 75, 80, and 104 KD. All these antigens were expressed by syngeneic and xenogeneic melanomas and by some unrelated syngeneic tumors but not by normal syngeneic cells, xenogeneic melanocytes, or by B16 melanoma cells obtained from fresh tumors or grown in defined medium. The antigens were distinct from murine viral antigens expressed by B16 melanoma cells and from components of the culture medium used to grow cells for vaccine production. These results indicate that several B16 melanoma cell-surface antigens are immunogenic in syngeneic mice. Expression of these antigens appears to be related to malignant transformation as they were found on all melanomas studied, and some other cancers, but not on normal cells.

Animals↗
PubMed1994

Digitized slice interposition in forensic dental radiographic identification. An in vitro study.

Traditional methods of comparison involving the presence of missing teeth, dental restorations, and other pathological features may be difficult due to the reduction in dental restorations in today's population. This study demonstrates an alternative method of identification using digitized images. It utilizes anatomical structures such as dental root morphology and spatial relations of teeth roots and their supporting structures on simulated antemortem and postmortem radiographs as the basis for identification. A total of 39 mandibular specimens were used and two radiographs representing the antemortem and postmortem radiographs of each hemimandible were exposed by two operators using different x-ray generators. The radiographs were scanned and digitized. The identities of the antemortem and postmortem radiographs were kept from the operator. Following this, horizontal sections were digitally cut from the antemortem radiographs through the roots approximately halfway between the neck of the tooth and the root apex. This section was manipulated onto the postmortem radiograph by using a computer graphics program and a quantitative comparison of the alignment of normal dental anatomical landmarks was undertaken. The technique enabled perfect matching of all 39 specimens by antemortem and postmortem dental radiographs. The mean number of identifying points was 17.5 and the mean number of nonmatching points was 0.1. The mean concordance was 99.2% between the antemortem and postmortem radiographs.

Forensic Dentistry↗
PubMed1994

Goseki grading in gastric cancer: comparison with existing systems of grading and its reproducibility.

A novel grading method which utilises intra-cellular mucin content and tubular differentiation (the Goseki grade) has been applied to 181 gastric cancers removed in potentially curative resections, and compared to conventional tumour grading (well, moderate, poor differentiation) and the Lauren, Ming and WHO classifications. The Goseki grade is significantly related to patient survival and, unlike the existing approaches, remains so after allowing for tumour stage in multivariate analyses. Potential relationships between the Goseki grade, direct tumour spread, lymph node involvement and survival have been investigated. Prognosis is particularly related to mucin content; 55% of patients with mucin-rich tumours dying within 5 years compared to 29% of those with mucin-poor cancers. A smaller proportion of mucin-poor cancers show lymph node involvement (N1 and N2) than mucin-rich tumours (52% v. 73%) and a smaller proportion of cancers showing good tubular differentiation exhibit widespread lymph node involvement (N2) than tubule-poor cancers (11% v. 28%). However, these differences did not achieve statistical significance. When compared to the existing classification or grading methods, the Goseki grade was found to be highly significantly correlated with the WHO and Lauren classifications and to conventional grading, but not to the Ming classification. These inter-relations are largely dependent upon tubular differentiation. There was no relationship between Goseki grade and the lymphocytic response around the tumour margin. Inter-observer agreement on the WHO type and the Lauren, Ming and Goseki grading methods was tested on 70 randomly selected cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗
PubMed1994

Goseki histological grading of gastric cancer is an important predictor of outcome.

TNM (tumour, node, metastases) staging has thus far been the most important guide to prognosis in patients with gastric cancer. Histological grading, in contrast, has not provided any additional information. Recently a novel grading system based on tubular differentiation and mucus production has been proposed, which was correlated with patterns of tumour spread found at necropsy. This study set out to assess its value as a determinant of survival after gastric resection. In a consecutive series of 211 patients who had potentially curative resection for gastric cancer, five histological grading systems were assessed: the Lauren type, the WHO type, degree of differentiation, the type of tumour border, and the lymphocytic response to the tumour and compared with the Goseki grading (I-IV). When T and N stage were taken into account, using Cox's proportional hazards model, only the Goseki grading added further to the ability to predict survival. The proportional hazards ratios were: node negative v node positive 6.5 T1 v T3 2.45; Goseki I v Goseki IV 3.1. Five year survival of patients with mucus rich (Goseki II and IV) T3 tumours was significantly worse than that of patients with mucus poor (Goseki I and III) T3 tumours (18% v 53%, p < 0.003). Goseki grading identifies subgroups of patients with a poorer prognosis than is predicted by TNM staging alone. It could prove useful in the selection of patients for adjuvant therapy after potentially curative resection for gastric cancer.

Aged↗
PubMed1994

An audit of the treatment of cancer of the oesophagus.

The treatment of cancer of the oesophagus in The General Infirmary at Leeds between the years 1975 and 1988 was reviewed. All cases with histologically proved cancer of the oesophagus were included, data being obtained from case notes, theatre operation books, endoscopy records, pathology records, and the Yorkshire Cancer Registry. Three hundred and sixteen patients were identified. Demographic details, mode of presentation, preoperative investigations, surgical management, methods of palliation, and survival data were entered into a database. The male to female ratio was 3:2 and the median age at presentation was 69 years (range 35-96). Surgical exploration was carried out in 134 of 316 patients (42%). Resection of the tumour, whether curative or palliative, was possible in 106 of 134 patients (79%). Operative (30 day) mortality was 27%. In 22 of 134 patients (16%), only intubation of the tumour was possible, while six patients (5%) had a thoracotomy or laparotomy alone. Median survival of the 106 patients after surgical resection was 292 days (range 0-14.2 years) and seven of them (7%) were still alive five years later. Of the remaining 182 patients (58%) who were not operated upon, 36 patients (11%) had a radical course of radiotherapy with a median survival of 175 days (range 80-453) and 146 patients (46%) either had endoscopic intubation (n = 64) or received no specific treatment (n = 82) with a median survival of 106 days (1-725) and 91 days (1-358) respectively. None of the 182 patients who did not have surgical treatment was alive at five years.

Adenocarcinoma↗
PubMed1994

A model for dendritic Ca2+ accumulation in hippocampal pyramidal neurons based on fluorescence imaging measurements.

1. High-speed fluorescence imaging was used to measure intracellular Ca2+ concentration ([Ca2+]i) changes in hippocampal neurons injected with the Ca(2+)-sensitive indicator fura-2 during intrasomatic and synaptic stimulation. The results of these experiments were used to construct a biophysical model of [Ca2+]i dynamics in hippocampal neurons. 2. A compartmental model of a pyramidal neuron was constructed incorporating published passive membrane properties of these cells, three types of voltage-gated Ca2+ channels characterized from adult hippocampal neurons, voltage-gated Na+ and K+ currents, and mechanisms for Ca2+ buffering and extrusion. 3. In hippocampal pyramidal neurons imaging of Na+ entry during electrical activity suggests that Na+ channels, at least in sufficient density to sustain action potentials, are localized in the soma and the proximal part of the apical dendritic tree. The model, which incorporates this distribution, demonstrates that action potentials attenuate steeply in passive distal dendritic compartments or distal dendritic compartments containing Ca2+ and K+ channels. This attenuation was affected by intracellular resistivity but not membrane resistivity. 4. Consistent with fluorescence imaging experiments, a non-uniform distribution of Ca2+ accumulation was generated by Ca2+ entry through voltage-gated Ca2+ channels opened by decrementally propagating Na+ action potentials. Consequently, the largest increases in [C2+]i were produced in the proximal dendrites. Distal voltage-gated Ca2+ currents were activated by broad, almost isopotential action potentials produced by reducing the overall density of K+ channels. 5. Simulations of subthreshold synaptic stimulation produced dendritic Ca2+ entry by the activation of voltage-gated Ca2+ channels. In the model these Ca2+ signals were localized near the site of synaptic input because of the attenuation of synaptic potentials with distance from the site of origin and the steep voltage-dependence of Ca2+ channel activation. 6. These simulations support the hypotheses generated from experimental evidence regarding the differential distribution of voltage-gated Ca2+ and Na+ channels in hippocampal neurons and the resulting voltage-gated Ca2+ accumulation from action and synaptic potentials.

Animals↗
PubMed1994

Multiple components of calcium current in acutely dissociated dentate gyrus granule neurons.

1. Specific Ca2+ channel blocker were used to isolate and characterize different components of whole cell Ba2+ current in granule neurons acutely dissociated from guinea pig hippocampal slices. 2. Granule cell Ba2+ current peaked around +5 mV, whether elicited by step or ramp commands, and was completely blocked by 100 microM Cd2+. 3. Saturating doses (> or = 5 microM) of the dihydropyridine antagonist, nimodipine, blocked 39% of the total current, and the inhibition was partially reversible. Nimodipine had a greater effect on current at the end of a depolarizing step, suggesting some voltage dependence of its action. 4. Saturating doses (> or = 3 microM) of omega-conotoxin-GVIA irreversibly blocked 21% of the total current and did not occlude subsequent nimodipine inhibition. 5. High concentrations (> or = 100 nM) of omega-agatoxin-IVA irreversibly blocked another 20% of the total current. The effect of omega-Aga-IVA was quite slow, but saturated after several minutes at 200 nM concentration. A high dose (1 microM) produced rapid effects that were used to quantify the magnitude of block. 6. When applied together, all three blockers inhibited nearly the same amount of total current (77%) as would be expected from the sum of each blocker applied individually (80%), suggesting that the three antagonists blocked different channel types. 7. Quantitatively similar results were obtained for the effect of each blocker alone and in combination on currents elicited by depolarizing ramp commands. Ramp currents blocked by each antagonist (difference ramps) all peaked near the same potential as the initial control ramp, indicating very similar activation properties for the three current components. Difference currents elicited by step commands similarly showed little difference among the three components in their kinetics of inactivation during relatively brief (30 ms) depolarizations. With longer steps, however, the omega-CgTX-GVIA-sensitive component showed some inactivation, whereas the omega-Aga-IVA-sensitive current did not inactivate. 8. The component of current resistant to all three blockers (approximately 23% of total current) was not inhibited by omega-conotoxin-MVIIC, but was half blocked by 50 microM Ni2+. This Ni(2+)-sensitive component showed relatively rapid inactivation and peaked at a somewhat lower potential (-10 mV) than the control current. The resistant current was also inactivated by approximately 50% by holding at -60 compared with -80 mV.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Distinctive features of immunoglobulin heavy chain variable region gene rearrangement in multiple myeloma.

We have analysed the rearranged Ig heavy chain (IgH) genes in a series of 28 cases of multiple myeloma (MM), in order to extend the study of Ig heavy chain variable (VH) gene usage in B lymphoid malignancies and to explore the ontogenic compartment from which transformed precursor cells arise in this disease. We were able to amplify 28 rearranged alleles by polymerase chain reaction from 23 of these cases, using a common joining region (JH) amplimer together with a panel of VH family-specific amplimers. The pattern of VH family usage was similar to that reported in normal peripheral blood B cells with infrequent usage of VH5 and VH6 genes. However, nucleotide sequence analysis of 17 IgH alleles revealed rearrangement of other VH family members, closely related to known developmentally regulated VH genes, some of which are known to be associated with autoimmune specificities. In contrast to previous findings on more immature B lineage malignancies, the rearranged genes diverged extensively from consensus germline sequences, consistent with somatic mutation. These findings support the hypothesis that the major proliferating precursor in MM arises at, or following a stage of T cell-dependent germinal centre proliferation in lymphoid follicles.

Base Sequence↗