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J O'Keefe

Publications and source records attributed to J O'Keefe.

At least 55 records · Page 3Linked to original sources
PubMed1996

Geometric determinants of the place fields of hippocampal neurons.

The human hippocampus has been implicated in memory, in particular episodic or declarative memory. In rats, hippocampal lesions cause selective spatial deficits, and hippocampal complex spike cells (place cells) exhibit spatially localized firing, suggesting a role in spatial memory, although broader functions have also been suggested. Here we report the identification of the environmental features controlling the location and shape of the receptive fields (place fields) of the place cells. This was done by recording from the same cell in four rectangular boxes that differed solely in the length of one or both sides. Most of our results are explained by a model in which the place field is formed by the summation of gaussian tuning curves, each oriented perpendicular to a box wall and peaked at a fixed distance from it.

Animals↗
PubMed1996

Neuronal computations underlying the firing of place cells and their role in navigation.

Our model of the spatial and temporal aspects of place cell firing and their role in rat navigation is reviewed. The model provides a candidate mechanism, at the level of individual cells, by which place cell information concerning self-localization could be used to guide navigation to previously visited reward sites. The model embodies specific predictions regarding the formation of place fields, the phase coding of place cell firing with respect to the hippocampal theta rhythm, and the formation of neuronal population vectors downstream from the place cells that code for the directions of goals during navigation. Recent experiments regarding the spatial distribution of place cell firing have confirmed our initial modeling hypothesis, that place fields are formed from Gaussian tuning curve inputs coding for the distances from environmental features, and enabled us to further specify the functional form of these inputs. Other recent experiments regarding the temporal distribution of place cell firing in two-dimensional environments have confirmed our predictions based on the temporal aspects of place cell firing on linear tracks. Directions for further experiments and refinements to the model are outlined for the future.

Animals↗
PubMed1995

Medial septal control of theta-correlated unit firing in the entorhinal cortex of awake rats.

The present study investigated whether the medial septal nucleus controls theta-correlated unit activity in the entorhinal cortex (EC), as it does in the hippocampus. Single neurones were recorded from the medial EC of rats as they ran on a linear track or chased food pellets on a small platform. The most prominent pattern of cell activity observed was burst firing occurring near the peaks of the ongoing dentate gyrus theta rhythm. This rhythmic unit activity was abolished by microinjections of lignocaine into the medial septal nucleus, but was resistant to cholinergic blockade.

Animals↗
PubMed1995

Comparison of in-hospital outcome in men versus women treated by either thrombolytic therapy or primary coronary angioplasty for acute myocardial infarction.

At 12 centers, 395 patients, including 288 men (73%) and 107 women (27%) with acute myocardial infarction (AMI), were prospectively randomized to treatment with tissue plasminogen activator (t-PA) or primary percutaneous transluminal coronary angioplasty (PTCA). Compared with men, women were older (65.7 vs 57.7 years, p < 0.0001), more often had diabetes mellitus (19% vs 10%, p = 0.03), systemic hypertension (54% vs 39%, p = 0.005), prior congestive heart failure (5% vs 0%, p = 0.002), and presented later after symptom onset (229 vs 174 minutes, p = 0.0004). The in-hospital mortality in women was 3.3-fold higher than men (9.3% vs 2.8%, p = 0.005). After adjustment for comorbid baseline characteristics, however, only advanced age independently correlated with mortality. Among t-PA-treated patients, mortality was significantly higher in women than in men (14.0% vs 3.5%, p = 0.006). Intracranial hemorrhage after t-PA was also more common in women than in men (5.3% vs 0.7%, p = 0.037). In contrast, women and men had similar in-hospital mortality after primary PTCA (4.0% vs 2.1%, respectively, p = 0.46). No intracranial bleeding occurred in PTCA-treated patients. A univariate trend was present for reduced in-hospital mortality in women treated with PTCA rather than t-PA (4.0% vs 14.0%, p = 0.07). By multiple logistic regression analysis of 15 clinical variables, treatment with PTCA rather than t-PA, as well as younger age, were independently predictive of in-hospital survival in women.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1995

Predictors of in-hospital and 6-month outcome after acute myocardial infarction in the reperfusion era: the Primary Angioplasty in Myocardial Infarction (PAMI) trail.

OBJECTIVES: This study examined the predictors of in-hospital and 6-month outcome after different reperfusion strategies in acute myocardial infarction. BACKGROUND: Thrombolytic therapy and primary angioplasty are both widely applied as reperfusion modalities in patients with myocardial infarction. Although it is accepted that restoration of early patency of the infarct-related artery can reduce mortality and salvage myocardium, the optimal reperfusion strategy remains controversial, and the predictors of outcome in the reperfusion era have been incompletely characterized. METHODS: At 12 centers, 395 patients presenting within 12 h of onset of acute transmural myocardial infarction were prospectively randomized to receive tissue-type plasminogen activator (t-PA) or undergo primary angioplasty without antecedent thrombolysis. Sixteen clinical variables were examined with univariate and multiple logistic regression analysis to identify the predictors of clinical outcome. RESULTS: By univariate analysis, in-hospital mortality was increased in the elderly, women, patients with diabetes and in patients treated with t-PA as opposed to angioplasty. Only advanced age and treatment by t-PA versus angioplasty independently correlated with increased in-hospital mortality (6.5% vs. 2.6%, respectively, p = 0.039 by multiple logistic regression analysis). Similarly, the only variables independently related to in-hospital death or nonfatal reinfarction were advanced age and treatment by t-PA versus angioplasty (12.0% vs. 5.1%, p = 0.02). The reduction in in-hospital death or reinfarction with angioplasty versus t-PA was particularly marked in patients > or = 65 years of age (8.6% vs. 20.0%, p = 0.048). Furthermore, primary management with angioplasty versus t-PA was the most powerful multivariate correlate of freedom from recurrent ischemic events (10.3% vs. 28.0%, p = 0.0001). The independent beneficial effect of angioplasty on freedom from death or reinfarction was maintained at 6-month follow-up (8.2% vs. 17.0%, p = 0.02). CONCLUSIONS: In the reperfusion era, the two most powerful determinants of freedom from death, reinfarction and recurrent ischemia after myocardial infarction are young age and treatment by primary angioplasty.

Age Factors↗
PubMed1995

Implications of recurrent ischemia after reperfusion therapy in acute myocardial infarction: a comparison of thrombolytic therapy and primary angioplasty.

OBJECTIVES: The purpose of this study was to examine the incidence and implications of recurrent ischemia after different reperfusion strategies in acute myocardial infarction. BACKGROUND: The rates and effects of recurrent ischemia after reperfusion with thrombolytic therapy and with primary percutaneous transluminal coronary angioplasty have not been compared. METHODS: At 12 centers 395 patients presenting within 12 h of the onset of acute myocardial infarction were prospectively randomized to receive recombinant tissue-type plasminogen activator (rt-PA) or primary coronary angioplasty. Sixteen clinical variables were examined by using univariate and multiple logistic regression analysis to identify the predictors of recurrent ischemia. The relation of recurrent ischemic events to patient outcome was analyzed. RESULTS: Recurrent ischemia developed in 76 patients (19.2%) before hospital discharge, resulting in reinfarction in 18 patients (4.6%) and death in 5 (2.6%). Recurrent ischemia occurred in 56 patients (28.0%) after rt-PA but in only 20 patients (10.3%) after coronary angioplasty (p < 0.0001), directly contributing to a higher rate of death or reinfarction (7.5% vs. 3.1%, p = 0.05), catheterization and revascularization procedures and prolonged hospital stay after thrombolysis. By multivariate analysis, treatment with coronary angioplasty rather than rt-PA was the strongest predictor of freedom from recurrent ischemia. Although the incidence of recurrent ischemia after angioplasty and after rt-PA was similar within the 1st 2 days of admission (9.2% vs. 14.5%, p = 0.11), after hospital day 2 recurrent ischemia occurred in only 2 patients who received primary angioplasty compared with 27 patients who received rt-PA (1.1% vs. 13.5%, p < 0.0001). CONCLUSIONS: The development of recurrent ischemia adversely affects patient outcome, increasing morbidity, mortality and resource utilization. The much lower rate of recurrent ischemia after primary coronary angioplasty than after rt-PA results in improved survival without reinfarction and allows a shorter, less complicated hospital stay. Given the extremely low rate of recurrent ischemia after hospital day 2, safe early discharge on day 3 after primary coronary angioplasty should be feasible in selected patients with acute myocardial infarction.

Angioplasty, Balloon, Coronary↗
PubMed1995

Quantitative myocardial SPECT for infarct sizing: feasibility of a multicenter trial evaluated using a cardiac phantom.

UNLABELLED: This study determined the feasibility of performing a multicenter trial using quantitative SPECT myocardial perfusion imaging in patients with acute myocardial infarction. The feasibility was assessed by a cardiac phantom. METHODS: Twenty-two gamma camera systems in 19 laboratories were evaluated. Each laboratory performed nine studies on the cardiac phantom and performed quality control tests of system uniformity, collimator quality and gantry alignment on their gamma camera system. Defects simulating "hypoperfused" myocardium of differing amounts were placed in the myocardium for eight of the nine studies. Measured defect size was compared to true defect size. RESULTS: A total of 198 studies from 22 systems were analyzed. Three studies were technically inadequate. For all 22 systems, the average correlation coefficient between true and measured defect size was 0.992 +/- 0.009, with a range from 1.00 to 0.97. Three systems were rejected due to slopes of the regression line outside the limits 1.00 +/- 0.10 and mean errors > 5% in estimating defect size. The remaining systems had a correlation coefficient of 0.995 + 0.008 with an average slope of 1.00 +/- 0.04 and an intercept of 0.11% +/- 1.57%. The mean error in estimating defect size was 2.08% +/- 0.69%. CONCLUSION: The small interlaboratory variation and the close correlation with true defect size observed in a cardiac phantom indicate the feasibility of quantitative myocardial SPECT as a useful tool in multicenter trials evaluating therapy in acute myocardial infarction. Preliminary objective testing is required, however, to identify systems with technical deficiencies.

Feasibility Studies↗
PubMed1995

A pilot smoking cessation program involving dental offices in the borough of East York, Ontario: an initial evaluation.

A Change Of Heart (ACOH)--a heart-health promotion project based in the Toronto borough of East York--devised a tobacco-cessation counselling program for use in dental offices. This protocol was implemented on a pilot basis in dental offices in East York during 1993. Four practices (seven dentists) agreed to incorporate the program into their office routine. The initial evaluation of the program was carried out in a telephone survey one month later. After one month, none of the dentists had incorporated the program into their office routine, citing lack of time, fear of alienating patients and a preference for their own protocol. All respondents indicated they were happy with the contents of the program and expressed a desire for further education about tobacco-cessation counselling. If dentists are to become more involved in tobacco-cessation counselling, it must be perceived by the profession and the public to be a legitimate activity for dentists. To this end, organized dentistry must actively promote continuing education activities related to cessation counselling, incorporate tobacco-cessation counselling into the undergraduate dental curriculum, and collaborate with other interested agencies to raise the public awareness of tobacco as an oral health issue.

Attitude of Health Personnel↗
PubMed1994

Primary coronary angioplasty for acute myocardial infarction (the Primary Angioplasty Registry).

During a 14-month period, 6 experienced centers prospectively enrolled 271 patients into a registry in which percutaneous transluminal coronary angioplasty was the primary treatment for acute myocardial infarction. Patients age > 18 years who presented with ST-segment elevation on the 12-lead electrocardiogram were enrolled if symptom duration was < 12 hours and there was no proclivity for bleeding. An independent core angiographic laboratory processed the angiographic data. Of 271 patients giving informed consent, 245 (90%) were deemed anatomically suitable and underwent angioplasty therapy. Upon leaving the catheterization laboratory 98% of patients had achieved reperfusion; 92% had a residual visual stenosis < or = 50%. Emergency bypass surgery was required in 14 patients (5%) for either failed angioplasty (n = 3) or presumed life-threatening anatomy (n = 11). The in-hospital mortality rate was 4%, whereas the reinfarction rate was 3% and the stroke rate was 1%, with 1 intracranial hemorrhage and 2 embolic events. Bleeding requiring > or = 2 units of blood occurred in 46 patients (18%); 14 of these transfusions were related to coronary artery bypass surgery. Primary angioplasty is associated with a high reperfusion rate, low in-hospital mortality and few recurrent myocardial ischemic events. These results point to the need for a large-scale trial comparing angioplasty with thrombolytic therapy in the setting of acute myocardial infarction.

Aged↗
PubMed1994

Six-month clinical and angiographic follow-up after direct angioplasty for acute myocardial infarction. Final results from the Primary Angioplasty Registry.

BACKGROUND: After direct angioplasty in the setting of acute myocardial infarction, patients were followed clinically and angiographically for 6 months at six experienced centers to evaluate outcomes. METHODS AND RESULTS: Of 258 patients with 6-month follow-up after surviving initial hospitalization, 5 (2%) died, 8 (3%) had nonfatal infarctions, 56 (22%) had chest pain, of whom 25 (10%) required hospitalization, and 42 (16%) patients needed repeat angioplasty. Of 203 eligible patients, 154 (76%) had angiographic follow-up. The infarct-related artery remained patent (defined as TIMI 2 or 3 flow) in 87%, while 13% developed reocclusion (TIMI 0 or 1 flow) by 6 months after discharge. Patients with reocclusion were more likely to have adverse events, including 35% with clinically evident reinfarction and 59% requiring repeat angioplasty. The median ejection fraction improvement from acute to follow-up study was 6%, with no improvement in patients with a reoccluded infarct-related artery and an 8% improvement in patients with a patent infarct-related artery. CONCLUSIONS: The positive clinical outcomes recorded immediately after direct angioplasty persisted through 6 months of follow-up. Although the incidence of clinical end points was equivalent to or lower than thrombolytic therapy trials, restenosis is a substantial problem. These findings provide evidence beyond the initial hospitalization that direct angioplasty is a reasonable choice for the treatment of acute myocardial infarction.

Aged↗
PubMed1994

Disparate temporal expression of the prothrombin and thrombin receptor genes during mouse development.

The protease thrombin is a potent agonist for platelet aggregation, mesenchymal cell proliferation, and endothelial production of growth factors and adhesion molecules. Thrombin also modulates neurite outgrowth in neuronal cultures. These apparently disparate responses to thrombin appear to be largely mediated by the recently cloned thrombin receptor. In the adult, thrombin is generated from its zymogen prothrombin at sites of vascular injury when circulating coagulation factors meet extravascular tissue factor. In this context thrombin's varied actions may mediate responses to wounding. Whether thrombin's actions on cells may also play a role in development is unknown. We examined the expression of thrombin receptor, prothrombin, and tissue factor by in situ hybridization in mouse development. Thrombin receptor mRNA was expressed widely in mesenchymal cell populations during early organogenesis (E9.5) and was particularly abundant in developing heart and blood vessels. Robust receptor expression was also noted in the germinal epithelium of the hindbrain. Thrombin receptor expression became more restricted with time and by the fetal growth stage (E16.5) was most readily detected in certain neurons, endocardial and endothelial cells, and within lung and liver. In contrast to the thrombin receptor, prothrombin mRNA was limited to the embryonic liver and was not detected until E12.5, well after the onset of receptor expression. mRNA for tissue factor, one important trigger for thrombin generation in the adult, was detected in embryonic epithelia from E9.5-12.5. In several instances, tissue factor-expressing epithelia were surrounded by thrombin receptor-expressing mesenchyme. These data suggest a possible role for the thrombin receptor in development. The finding of robust thrombin receptor expression before prothrombin mRNA was detected raises the question of whether other proteases or peptide ligands can activate the thrombin receptor.

Animals↗
PubMed1993

A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction. The Primary Angioplasty in Myocardial Infarction Study Group.

BACKGROUND: The success of thrombolytic therapy for acute myocardial infarction is limited by bleeding complications, the impossibility of reperfusing all occluded coronary arteries, recurrent myocardial ischemia, and the relatively small number of patients who are appropriate candidates for this therapy. We hypothesized that these problems could be overcome by the use of immediate percutaneous transluminal coronary angioplasty (PTCA), without previous thrombolytic therapy. METHODS: At 12 clinical centers, 395 patients who presented within 12 hours of the onset of myocardial infarction were treated with intravenous heparin and aspirin and then randomly assigned to undergo immediate PTCA (without previous thrombolytic therapy, 195 patients) or to receive intravenous tissue plasminogen activator (t-PA, 200 patients) followed by conservative care. Radionuclide ventriculography was performed to assess ventricular function within 24 hours and at six weeks. RESULTS: Among the patients randomly assigned to PTCA, 90 percent underwent the procedure; the success rate was 97 percent, and no patient required emergency coronary-artery bypass surgery. The in-hospital mortality rates in the t-PA and PTCA groups were 6.5 and 2.6 percent, respectively (P = 0.06). In a post hoc analysis, the mortality rates in the subgroups classified as "not low risk" were 10.4 and 2.0 percent, respectively (P = 0.01). Reinfarction or death in the hospital occurred in 12.0 percent of the patients treated with t-PA and 5.1 percent of those treated with PTCA (P = 0.02). Intracranial bleeding occurred more frequently among patients who received t-PA than among those who underwent PTCA (2.0 vs. 0 percent, P = 0.05). The mean (+/- SD) ejection fractions at rest (53 +/- 13 vs. 53 +/- 13 percent) and during exercise (56 +/- 13 vs. 56 +/- 14 percent) were similar in the t-PA and PTCA groups at six weeks. By six months, reinfarction or death had occurred in 32 patients who received t-PA (16.8 percent) and 16 treated with PTCA (8.5 percent, P = 0.02). CONCLUSIONS: As compared with t-PA therapy for acute myocardial infarction, immediate PTCA reduced the combined occurrence of nonfatal reinfarction or death, was associated with a lower rate of intracranial hemorrhage, and resulted in similar left ventricular systolic function.

Adult↗
PubMed1993

Phase relationship between hippocampal place units and the EEG theta rhythm.

Many complex spike cells in the hippocampus of the freely moving rat have as their primary correlate the animal's location in an environment (place cells). In contrast, the hippocampal electroencephalograph theta pattern of rhythmical waves (7-12 Hz) is better correlated with a class of movements that change the rat's location in an environment. During movement through the place field, the complex spike cells often fire in a bursting pattern with an interburst frequency in the same range as the concurrent electroencephalograph theta. The present study examined the phase of the theta wave at which the place cells fired. It was found that firing consistently began at a particular phase as the rat entered the field but then shifted in a systematic way during traversal of the field, moving progressively forward on each theta cycle. This precession of the phase ranged from 100 degrees to 355 degrees in different cells. The effect appeared to be due to the fact that individual cells had a higher interburst rate than the theta frequency. The phase was highly correlated with spatial location and less well correlated with temporal aspects of behavior, such as the time after place field entry. These results have implications for several aspects of hippocampal function. First, by using the phase relationship as well as the firing rate, place cells can improve the accuracy of place coding. Second, the characteristics of the phase shift constrain the models that define the construction of place fields. Third, the results restrict the temporal and spatial circumstances under which synapses in the hippocampus could be modified.

Action Potentials↗