Biomedical subjects
Publications and source records attributed to J Larson.
Malignant melanomas of the female genital tract are uncommon lesions. A patient with multiple cutaneous, vulvar melanomas and a subsequent malignant melanoma of the cervix is described.
Although the standard therapy of vulvar carcinoma remains radical surgery, this approach is accompanied by significant postoperative morbidity and psychological adjustment. Radical hemi-vulvectomy and ipsilateral superficial groin node dissection are increasingly used for patients with "early" or "microinvasive" disease. Two patients with an "early" vulvar carcinoma were treated conservatively and later developed recurrent disease. Despite further surgery and radiotherapy, both patients eventually died of disease. The case histories are described and the pertinent literature is discussed.
The role played by the glycine site associated with the NMDA receptor in inducing long-term potentiation (LTP) in neonatal hippocampus was examined. An antagonist of the glycine site, 7-chlorokynurenic acid (Cl-Kyn), completely blocked both the short-term and the long-term potentiation associated with theta burst stimulation (TBS) linked to NMDA receptor activation in slices from hippocampus at postnatal days 10-16; this effect was reversed by the glycine agonist, D-serine. Analysis of the TBS-evoked responses showed: (1) a developmental alteration in the burst response morphology that may be related to maturation of GABA-mediated inhibition; and (2) that, unlike 2-amino-5-phosphonovalerate (AP5), Cl-Kyn did not reduce any portion of the burst response. These results suggest that stimulation of the glycine site coupled to the NMDA receptor complex is necessary to induce LTP in neonatal tissue and that two NMDA receptor types may be present in the hippocampus.
One of the most fascinating features of the hippocampus is its capacity for plasticity. Long-term potentiation (LTP), a stable facilitation of synaptic potentials after high-frequency synaptic activity, is very prominent in hippocampus and is a leading candidate memory storage mechanism. Here, we discuss the nature and causes of LTP and relate them to endogenous rhythmic neuronal activity patterns and their potential roles in memory. Anatomical studies indicate that LTP is accompanied by postsynaptic structural modifications while pharmacological studies strongly suggest that LTP is not due to an increase in presynaptic transmitter release. In field CA1, LTP induction appears to be triggered by a postsynaptic influx of calcium through NMDA receptor-linked channels. Possible roles of several calcium-sensitive enzyme systems in LTP are discussed and it is argued that activation of a calcium-dependent protease (calpain) could produce the structural changes linked to LTP. Rhythmic bursting activity is highly effective in inducing LTP and it is argued that the endogenous hippocampal theta rhythm plays a role in LTP induction in vivo. Finally, studies indicate that LTP and certain types of memory share a common pharmacology and the use of electrical brain stimulation as a sensory cue suggests that LTP develops when the significance of that cue is learned.
Induction of long-term potentiation (LTP) by asynchronous stimulation of converging afferents was studied in hippocampal slices. Three stimulation electrodes were positioned to activate separate groups of Schaffer-commissural inputs to a population of CA1 pyramidal cells. Patterned stimulation consisted of a single coincident priming pulse to all 3 electrodes followed by a burst of 4 pulses (100 Hz) to the first input (S1) at a delay of 180 ms, to the second (S2) at a delay of 200 ms, and to the third (S3) at a delay of 220 ms. This pattern was repeated 10 times at 5-s intervals. The magnitude of LTP induced (measured 20 min after stimulation) was greatest for the first stimulated input, intermediate for the second, and least for the third. Intracellular recordings indicated that the greatest postsynaptic depolarization occurred during the period of S2 stimulation; thus the magnitude of LTP induced was not simply dependent on the degree of depolarization during afferent activation. Rather, sustained depolarization after synaptic activation could contribute to LTP induction by prolonging the activity of N-methyl-D-aspartate receptor-gated channels. Earlier-arriving bursts may also trigger an inhibitory process that reduces the effectiveness of later bursts for inducing LTP.
The participation of N-methyl-D-aspartate (NMDA) receptors in synaptic transmission before and after induction of long-term potentiation (LTP) was studied in field CA1 of hippocampal slices. NMDA receptor-mediated postsynaptic responses were determined by comparing responses recorded in the presence and absence of the selective antagonist, D-2-amino-5-phosphonopentanoate (D-AP5, 50 microM). In the presence of physiological magnesium concentrations (1 mM), robust D-AP5-sensitive responses could be evoked by high frequency bursts (4 pulses, 100 Hz) when burst stimulation was preceded 200 ms earlier by 'priming' stimulation (2 pulses, 15 ms apart) of a separate input. Induction of LTP resulted in a substantial potentiation (35%) of non-NMDA-mediated responses to primed bursts but not of NMDA-mediated responses. These results suggest that long-term postsynaptic modifications are at least partly responsible for the expression of LTP.
From September 1972 to September 1987, thirty-six patients with stage II carcinoma of the endometrium were treated with external-beam radiotherapy to the pelvis, a single intracavitary application of cesium-137, and extrafascial hysterectomy with adnexectomy. Patients were followed for a median of 54.4 months. Overall 2- and 5-year actuarial survival rates were 83 and 58%, respectively. Survival was analyzed in terms of the independent variables surgical stage, presence of a gross cervical lesion, and residual disease within the myometrium or cervix. Factors contributing to patients survival were analyzed by the log-rank method. The 12 patients with a gross cervical lesion had an adverse prognosis, as compared to those without such a lesion (P less than 0.05). Seven of the twelve patients (58%) with a cervical lesion at clinical staging demonstrated persistent or recurrent disease. The presence of extrauterine disease at surgery was a major prognostic factor in patient survival (P less than 0.01). All six patients with extrauterine disease expired 2.3 to 53.0 months after hysterectomy. Two patients with persistence of disease expired 2.3 and 7.5 months after hysterectomy. Eleven patients developed recurrent disease 2.1 to 56.5 months after hysterectomy. All presented with distant metastases. Four of the thirteen patients with persistent or recurrent disease had no residual tumor within the myometrium.
One hundred fifty-five patients with cervical cancer not amenable to radical surgery underwent selective, paraaortic lymphadenectomy and exploratory laparotomy prior to the initiation of radiotherapy. Fifty-one patients underwent transperitoneal lymphadenectomy; the remainder had the procedure performed using the extraperitoneal approach. Twenty-six patients (17%) were found to have metastatic disease to the paraaortic lymph nodes. The incidence of paraaortic metastases increased with advancing clinical stage. Twenty-four of the 26 patients were treated with extended-field radiotherapy which did not exceed 5100 cGy to the paraaortic region. Twenty-three percent of the patients with positive paraaortic nodes had documented intraperitoneal tumor. Two- and five-year actuarial survival rates for patients with paraaortic metastases were 35 and 27%, respectively. Approximately 4.6% of patients undergoing a selective paraaortic lymphadenectomy derived therapeutic benefit from the information supplied by the procedure. Using a Cox model, tumor histology, status of the paraaortic lymph nodes, tumor size, and presence of intraperitoneal disease were statistically significant prognostic factors in patient survival. Tumor size and presence of intraperitoneal disease were major predictors of patient survival.
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Stimulation of N-methyl-D-aspartate (NMDA) receptors was found to induce proteolysis of brain spectrin in hippocampal slices. The effect was dependent upon extracellular calcium, blocked by the antagonist 2-amino-5-phosphonovalerate (AP5), and was not reproduced by potassium-induced depolarization. These results are consistent with the hypothesis that the involvement of NMDA receptors in plasticity and excitotoxicity is at least partially mediated by calcium-activated proteolysis of cytoskeletal proteins.
Lesions of the rat entorhinal cortex cause extensive synaptic restructuring and perturbation of calcium regulation in the dentate gyrus of hippocampus. Calpain is a calcium-activated protease which has been implicated in degenerative phenomena in muscles and in peripheral nerves. In addition, calpain degrades several major structural neuronal proteins and has been proposed to play a critical role in the morphological changes observed following deafferentation. In this report we present evidence that lesions of the entorhinal cortex produce a marked increase in the breakdown of brain spectrin, a substrate for calpain, in the dentate gyrus. Two lines of evidence indicate that this effect is due to calpain activation: (i) the spectrin breakdown products observed following the lesion are indistinguishable from calpain-generated spectrin fragments in vitro; and (ii) their appearance can be reduced by prior intraventricular in fusion of leupeptin, a calpain inhibitor. Levels of spectrin breakdown products are increased as early as 4 h post-lesion, reach maximal values at 2 days, and remain above normal to some degree for at least 27 days. In addition, a small but significant increase in spectrin proteolysis is also observed in the hippocampus contralateral to the lesioned side in the first week postlesion. At 2 days postlesion the total spectrin immunoreactivity (native polypeptide plus breakdown products) increases by 40%, suggesting that denervation of the dentate gyrus produces not only an increased rate of spectrin degradation but also an increased rate of spectrin synthesis. These results indicate that calpain activation and spectrin degradation are early biochemical events following deafferentation and might well participate in the remodelling of postsynaptic structures. Finally, the magnitude of the observed effects as well as the stable nature of the breakdown products provide a sensitive assay for neuronal pathology.
It has been proposed that activation of a calcium-sensitive protease (calpain) is a crucial step in the induction of long-term potentiation (LTP). To test this hypothesis, we used chronic recording techniques to measure the effects of intraventricular infusion of leupeptin, a calpain inhibitor, on LTP in the hippocampus. Rats implanted bilaterally with stimulating electrodes in the Schaffer-commissural system and one recording electrode in the apical dendrites of field CA1 were fitted with osmotic mini-pumps delivering either leupeptin (20 mg/ml) or saline at a rate of 0.5 microliter/h into the lateral ventricle. Short bursts of high-frequency stimulation with the bursts delivered at 5/s were used to induce LTP in those animals which had stable responses for several days. Rats in the saline group (n = 11) exhibited an immediate LTP effect that remained in place over successive days of testing, while only 3 of 13 leupeptin treated animals showed evidence of LTP 24 h after high-frequency stimulation, and in only one of those was a sizeable effect recorded over several days. The average change in responses at the 24-h test point was +33% for the controls and +4% for the leupeptin group (P less than 0.01). The block of LTP induction was reversible, since high-frequency stimulation applied after disconnecting the pumps led to a robust LTP effect that lasted for several days in 6 of 7 animals tested. There were no detectable differences in baseline responses in the presence and absence of leupeptin.
Short bursts of high frequency stimulation produce maximal long-term potentiation (LTP) at Schaffer-commissural synapses on CA1 neurons in hippocampal slices when the bursts are spaced 200 ms apart. A burst to one input (S1) does not induce LTP but 'primes' the postsynaptic neurons such that 200 ms later the postsynaptic response to a burst to a second input (S2) is greatly enhanced and LTP is induced. The role of N-methyl-D-aspartate (NMDA) receptors in this response enhancement and LTP induction was studied by perfusing slices with the NMDA antagonist, 2-amino-5-phosphonovalerate (AP5). AP5 (100 microM) had no effect on the field excitatory postsynaptic potential evoked by single pulse stimulation, but completely eliminated both the decremental short-term potentiation (lasting less than 10 min) and stable LTP effects elicited by burst stimulation. AP5 reduced the response to a non-primed burst by about 10% and reduced the relative enhancement of a primed burst response by about 35%. These results indicate that part of the postsynaptic response to a primed burst is mediated by NMDA receptors and that this component is necessary for all forms of synaptic potentiation (including LTP) resulting from burst stimulation. The similarity of the short bursts with the complex-spike discharges of hippocampal neurons as well as the 200 ms optimal interval with the period of the hippocampal theta-rhythm suggest links between theta and the NMDA receptor in the induction of hippocampal synaptic plasticity.
The purpose of the study was to investigate the intelligibility of two voice output communication aids. Twenty words and 20 sentences, synthesized with the Personal Communicator and with the SpeechPAC, were presented to 20 listeners. Listener transcriptions of the stimuli were used to compare the intelligibility of the two communication aids. Analysis of variance revealed significantly higher intelligibility scores for the Personal Communicator compared to the SpeechPAC and higher scores for sentences than for words. The implications of these findings for selection of augmentative communication devices is discussed.
In this paper we discuss recent experimental results pertinent to three unresolved issues regarding the long-term potentiation (LTP) effect: the nature of its enduring substrates, the biochemical mechanisms that produce it, and its potential role in memory. LTP appears to be triggered by a postsynaptic influx of calcium and is associated with alterations in the shape of dendritic spines and probably the formation of new synapses. We discuss the possibility that morphological reorganization also modifies membrane surface chemistry of synaptic elements. Evidence is presented that LTP is not associated with changes in presynaptic calcium currents. Activation of protein kinase C is shown to be insufficient for the induction of LTP, although it may play a modulatory role. The hypothesis that activation of a calcium-sensitive protease (calpain) is pivotal to the establishment of LTP is supported by experiments showing that a calpain inhibitor, leupeptin, blocks LTP. Furthermore, activation of NMDA receptors, an event implicated in LTP induction, is accompanied by calcium-sensitive proteolysis of spectrin, a major dendritic cytoskeletal protein. The finding that stimulation patterns designed to mimic naturally-occurring cell discharge patterns are highly effective for LTP induction greatly strengthens the hypothesis that LTP actually occurs during the encoding of information in cortical systems. Potential contributions of LTP to learning are explored using computer simulations of a simple cortical network.
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