Biomedical subjects

P H Kelly

Publications and source records attributed to P H Kelly.

At least 19 recordsLinked to original sources

PubMed1999

Importance of AMPA receptors for hippocampal synaptic plasticity but not for spatial learning.

Gene-targeted mice lacking the L-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor subunit GluR-A exhibited normal development, life expectancy, and fine structure of neuronal dendrites and synapses. In hippocampal CA1 pyramidal neurons, GluR-A-/- mice showed a reduction in functional AMPA receptors, with the remaining receptors preferentially targeted to synapses. Thus, the CA1 soma-patch currents were strongly reduced, but glutamatergic synaptic currents were unaltered; and evoked dendritic and spinous Ca2+ transients, Ca2+-dependent gene activation, and hippocampal field potentials were as in the wild type. In adult GluR-A-/- mice, associative long-term potentiation (LTP) was absent in CA3 to CA1 synapses, but spatial learning in the water maze was not impaired. The results suggest that CA1 hippocampal LTP is controlled by the number or subunit composition of AMPA receptors and show a dichotomy between LTP in CA1 and acquisition of spatial memory.

Action Potentials↗

PubMed1998

Defective inhibition of dream event memory formation: a hypothesized mechanism in the onset and progression of symptoms of schizophrenia.

An average person normally spends at least 90 min to 2 h per night dreaming. Nevertheless, memories of dream events are not retrieved while awake unless the person awoke shortly after a dream. It is hypothesized here that schizophrenic delusions initially arise because a system that normally inhibits the formation of memories of dream events is defective. Therefore, memories of dream events or fragments would be occasionally made and placed in the normal memory store. The only reason that we really know anything happened to us in the past is that we have a memory of it, and having a memory of an event is sufficient to really believe it. Therefore, the schizophrenic would believe that the dream events actually happened. It is proposed that this is the basis of primary delusions. Because memories are represented by strengthened neural connections there will be an accumulation of connections that do not correspond to reality. This accumulation may account for other symptoms of schizophrenia such as thought disorder, loosening of associations, and hallucinations. The brain trying to draw conclusions from several memories may be the basis of secondary delusions. Evidence is presented for the ideas that primary delusions are due to memories of dream events, that a substance, with vasotocin-like bioactivity, is released in the brain during dreaming and inhibits memory formation, that the lateral habenula is a brain area involved in vasotocin actions and is affected by neuroleptics, and that brain mechanisms involved in vasotocin actions show pathological alterations in schizophrenia.

Delusions↗

PubMed1994

The pharmacology of SDZ EAA 494, a competitive NMDA antagonist.

SDZ EAA 494 (D-CPPene) was characterized as a competitive NMDA antagonist, having a pA2 value against NMDA depolarizations in frog spinal cord and rat neocortex of 6.7-6.8 and a pKi of 7.5 in a [3H]CGP39653 binding assay, with no action on other receptors or amine reuptake. The compound was orally active in rodent maximal electroshock models with an ED50 of around 16 mg/kg, was protective in rats even 24 hours after oral application and had an oral therapeutic index of around 8. Muscle relaxation, ataxia, flattened body posture and reduced acquisition of a passive avoidance task, suggesting potential effects on memory formation, occurred at supra-anticonvulsant doses in rodents, with PCP-like stimulatory effects produced only by high i.p. doses or constant i.v. infusions. This favourable profile is discussed in relation to the negative outcome of a recent trial of the compound in patients with intractable epilepsy. The conclusion is drawn that standard models for screening new anticonvulsants are inappropriate to seeking drugs active in patients with a protracted convulsive history. The anti-ischaemic action of SDZ EAA 494 encourages further testing in brain trauma, in which the anticonvulsant action of the compound may be an added benefit.

Animals↗

PubMed1991

Management of dialysis-associated steal syndrome complicating upper extremity arteriovenous fistulas: use of intraoperative digital photoplethysmography.

Dialysis-associated steal syndrome (DASS) occurring after creation of arteriovenous fistulas often necessitates ligation of the fistula. From June 1987 to June 1990, a total of 542 upper extremity arteriovenous fistulas were constructed: radiocephalic fistulas in 182 patients, 325 forearm loop grafts and 32 upper arm loop grafts. We managed 27 patients with DASS including two patients who were referred from other hospitals. DASS developed in two patients (1%) with radiocephalic fistulas and in 23 patients (6.4%) with arteriovenous grafts. Of the 27 patients, the fistula was ligated in nine because of tissue loss, severity of symptoms, or absence of improvement in digital pressure with the fistula occluded. Intraoperative digital photoplethysmography was used to guide the amount of graft narrowing in 16 patients. The goal was to obtain a digital blood pressure of 50 mm Hg or digital to brachial ratio of more than 0.6. Ten of the 16 patients had satisfactory graft function for more than 6 months, and all patients had improvement or resolution of the steal syndrome. We conclude that DASS is an uncommon complication of upper extremity arteriovenous shunts and narrowing of the fistula and that using intraoperative digital photoplethysmography as a guide is a useful method for relieving the steal syndrome and salvaging the shunt.

Adult↗

PubMed1990

Autoradiographic localization of dopamine D 1 and D 2 receptors in the brain of several mammalian species.

Dopamine D 1 and D 2 receptor distributions were studied in the brain of the mouse, rat, guinea pig, cat and monkey by means of in vitro quantitative autoradiography using [3H]SCH 23390 and [3H]CV 205-502 to label D 1 and D 2 subtypes respectively. The distribution of both subtypes of receptors was similar within the basal ganglia of all species investigated. The highest densities for both subtypes were found in the nucleus caudatus, putamen, nucleus accumbens, olfactory tubercle and substantia nigra. Outside of the basal ganglia, differences in the distribution of both receptors were found among the species examined in regions such as cerebellum, cortex, hippocampus, superior colliculus and olfactory bulb. In all species D 1 receptor densities were higher than those of D 2. The absolute amount of both subtypes, however, varied among species. These results indicate that dopamine receptor distribution is well preserved in the basal ganglia during evolution, although differences among species exist in their distribution outside the basal ganglia and their absolute amount.

Aminoquinolines↗

PubMed1990

Experience with the biofragmentable anastomotic ring (BAR) in bowel preoperatively irradiated with 6000 rad.

Previous studies from the authors' laboratory using the biodegradable anastomotic ring (BAR) have demonstrated the safety of this device in animals irradiated preoperatively with the equivalent of 5000 rad; sutured, stapled, and BAR anastomoses all had leak rates of 10 percent or less in this setting. This study was undertaken to assess the safety of the BAR after irradiation with the equivalent of 6000 rad. Thirteen mongrel dogs underwent preoperative irradiation to the rectum and rectosigmoid, receiving 6000 rad according to the nominal standard dose equation. After a three-week rest period, each dog underwent anterior resection of the rectosigmoid and anastomosis with the BAR. The anastomoses were evaluated for early and late healing and anastomotic leaks. The results were compared with previous data from the authors' laboratory using an identical model. Radiographic leaks were found in 7 of 10 sutured anastomoses, 8 of 10 stapled anastomoses, and 3 of 13 BAR anastomoses (P less than 0.01). Comparative clinical leaks were 5 of 10 for sutured, 5 of 10 for stapled, and 3 of 13 for BAR anastomoses. These data suggest that the BAR may offer added safety to an anastomosis after preoperative irradiation. Whether this effect is due to the atraumatic technique of placing the device, improved blood flow to the anastomotic margins, or other factors, is still underdetermined.

Anastomosis, Surgical↗

PubMed1990

Effects of NMDA receptor antagonists on passive avoidance learning and retrieval in rats and mice.

The effects of NMDA antagonists on passive avoidance learning, shock sensitivity and locomotor activity were examined. Pre-training administration of the antagonists 3-((+-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) in mice and rats resulted in impaired performance in a retention test 24 h later. No such impairment resulted from immediate post-training administration of either compound in either species. In addition neither compound, given only before the retention test, reduced the retention latencies of mice. In rats CPP was similarly ineffective whereas MK-801 reduced retention latencies, but only at a dose which significantly elevated locomotor activity at the time of the retention test. As assessed by vocalization threshold in mice and by the proportion of animals vocalizing in response to the passive avoidance training shock, neither compound produced analgesia. The vocalization threshold was, in fact, slightly reduced by both compounds. MK-801, but not CPP, stimulated locomotor activity in mice. These results indicate that in the passive avoidance task activation of NMDA receptors is involved in memory formation, but is not critical for the maintenance of memory or its retrieval.

Animals↗

PubMed1990

Congenital diaphragmatic hernia presenting as massive gastrothorax.

Delayed herniation of abdominal contents through a congenital diaphragmatic hernia may occur beyond the neonatal period. The case of a 29-month-old child with a Bochdalek hernia presenting as acute respiratory failure is presented. Chest radiography showed a tension gastrothorax that was misread as a tension pneumothorax. Tube thoracostomy resulted in clinical improvement by perforating and decompressing the stomach. Nasogastric tube placement confirmed herniation of the stomach into the left chest and is the initial treatment of choice when a tension gastrothorax is identified. A congenital diaphragmatic hernia must be recognized promptly so that rapid gastric decompression and surgical repair of the diaphragmatic defect can be performed.

Child, Preschool↗

PubMed1990

Fibrin glue-antibiotic suspension in the prevention of prosthetic graft infection.

UNLABELLED: The following study was done to assess whether fibrin glue-antibiotic suspension (FGAS) can prevent infection of a PTFE vascular graft in a contaminated wound. METHODS: FGAS was made by combining cryoprecipitate with a mixture of bovine thrombin, aminocaproic acid, and tobramycin (5 mg/cc thrombus). Antibiotic activity was documented by in vitro kinetics which revealed initial elutions to be greater than 8,000 mu gm/cc and elutions at 4 days to be greater than 2 mcg/cc. Twelve dogs had a 1-cm section of infrarenal aorta replaced with a PTFE graft that had been bathed in a 2-cc solution of E. coli 3 x 10(8) CFU/ml and S. aureus 3 x 10(8) CFU/ml. Both organisms were sensitive to tobramycin and cefonicid. Dogs were divided into three groups of four. Group I had a contaminated PTFE graft placed and no further therapy. Group II had a contaminated PTFE graft placed and sealed with fibrin glue. Group III had a contaminated PTFE graft placed and sealed with FGAS. All three groups received daily IV cefonicid. RESULTS: Group I: Four of four dogs were reoperated on the fourth day for suspected sepsis and all four had pseudoaneurysms (one ruptured). Three of four were culture positive for S. aureus and two of four positive for E. coli. Group II: Four of four died of anastomotic disruption by the third day. Four of four were culture positive for S. aureus and E. coli. Group III: All four dogs survived and were sacrificed on Day 17: all anastomoses were normal. Animal survival was significantly associated with the treatment given (p = 0.0025). Three of four tissue cultures of the grafts were weakly positive for S. aureus and one of four for E. coli and Pseudomonas. Serum tobramycin levels were negligible at 12, 24, 72, and 96 hours. CONCLUSIONS: The data show that FGAS was associated with a reduction in vascular graft infection and pseudoaneurysm formation after exposure to a standardized bacterial inoculum. Whether complete eradication of all organisms can be achieved with higher doses of tobramycin is as yet undetermined.

Aneurysm, Infected↗

PubMed1990

Aneurysmal rupture of a femoropopliteal saphenous vein graft.

A case of a nonanastomotic, atheromatous aneurysm in a femoropopliteal saphenous vein graft is presented. This disease is unusual, especially in nonsmokers with normal lipid levels, and, in this case, may be related to mechanical graft failure 22 years after implantation. The aneurysm was excised and the arterial continuity reestablished with a prosthetic graft.

Aged↗

PubMed1987

Discriminative stimulus properties of muscarinic agonists.

In a two-lever, food-reinforced drug-discrimination paradigm separate groups of rats were trained to discriminate either arecoline, pilocarpine or oxotremorine from saline. The discriminative cues of all three agonists were potently blocked by scopolamine, but only by 30-60 fold higher doses of methylscopolamine. The three agonists all suppressed overall response rate. These rate-suppressant effects were not blocked by scopolamine in doses which blocked the discriminative cues. In generalization tests, arecoline elicited selection of the drug-appropriate lever in all groups of trained animals. Pilocarpine was discriminated as drug by all pilocarpine-trained animals and by a majority of oxotremorine-trained animals, but was not significantly discriminated by the arecoline-trained group. Oxotremorine was discriminated by all oxotremorine-trained animals but only by some pilocarpine-trained animals, and was not significantly discriminated by the arecoline-trained group. Morphine, haloperidol, chlordiazepoxide, pentobarbital and nicotine were not generalized to any of the training drugs. The discriminative stimuli produced by the training drugs are therefore specific and exhibit properties indicative of an origin at central muscarinic receptors but may not be identical.

Animals↗

PubMed1987

Is ethylcholine mustard aziridinium ion a specific cholinergic neurotoxin?

The histopathologic effects of different doses of ethylcholine mustard aziridinium ion infused into the caudate-putamen complex or nucleus basalis were evaluated in rats. Although no non-specific tissue damage was observed at the lowest doses of ethylcholine mustard aziridinium ion examined--0.01 nmol in 1-microliter vehicle and 0.02 nmol in 2-, 5-, and 10-microliters vehicle in both the striatum and nucleus basalis--minimal but definite non-selective pathology, characterized by gliosis and loss of all neuronal elements in the region affected by the nitrogen mustard, was observed in both targets at a dose of 0.02 nmol 1 microliter and more severely at all doses containing 0.05 and 0.1 nmol ethylcholine mustard aziridinium ion. At doses of ethylcholine mustard aziridinium ion containing 0.2 nmol of the cytotoxin and greater amounts, non-specific cell loss in intact tissue and extensive cavitation became increasingly the most prominent histologic features of drug action. No statistically significant effects of ethylcholine mustard aziridinium ion on striatal choline acetyltransferase activities were found until doses of 0.4 nmol/1 microliter or greater were injected, concentrations of the cytotoxin at which appreciable non-specific pathology was also observed. Levels of dopamine in the caudate-putamen nucleus were reduced by comparatively greater amounts than choline acetyltransferase at doses of 2.5 nmol/2 microliters, 5.0 nmol/2 microliters and 10 nmol/2 microliters cytotoxin, but a significant effect of ethylcholine mustard aziridinium ion on striatal L-glutamate decarboxylase activity was found only at a dose of 10 nmol/2 microliters. As no dose of ethylcholine mustard aziridinium ion was found that reduced choline acetyltransferase without producing considerable non-specific tissue destruction, the usefulness of the cytotoxin in studying the behavioral and physiological consequences of selective cholinergic hypofunction in the brain must be questioned.

Animals↗

PubMed1985

Role of mesencephalic glycine in locomotor activity.

Microinjection of glycine (20 micrograms) into the ventral mesencephalon of rats caused a stimulation of locomotor activity. Microinjection of haloperidol (5 micrograms) into the nucleus accumbens immediately before the glycine injection did not reduce this locomotor stimulation. In rats with 6-hydroxydopamine-induced destruction of mesolimbic dopamine (DA) terminals the ability of apomorphine (0.1 mg/kg, s.c.) to stimulate locomotor activity was reduced by microinjection of the glycine antagonist strychnine into the ventral mesencephalon. Increased glycinergic activity in the ventral mesencephalon therefore appears to stimulate locomotor activity by a mechanism other than the activation of mesolimbic DA neurons.

Animals↗

PubMed1985

Effects of serotonergic activity in nucleus accumbens septi on drug-induced circling.

The effects of injections of 5-hydroxytryptamine (5-HT) into the nucleus accumbens and lesions of the nucleus accumbens induced by 5,7-dihydroxytryptamine (5,7-DHT) on drug-induced circling were investigated in rats with unilateral nigrostriatal lesions induced by 6-hydroxydopamine (6-OHDA). Injections of 5-HT (60-120 micrograms in 1 microliter; 1 microliter/min) into the nucleus accumbens caused a significant decrease in the circling response to 5.0 mg/kg of d-amphetamine (s.c.). The distribution of radioactivity after intracerebral injections of [3H]5-HT using these parameters showed that although much of the injected material was retained in the nucleus accumbens there was also considerable spread to the frontal cortex. However, in further behavioural experiments, using an injection procedure (0.5 microliter; 0.11 microliter/min) which caused much greater retention of injected material in the nucleus accumbens, with minimal spread to the frontal cortex, the ability of 5-HT injected into the accumbens to block amphetamine-induced circling was not diminished. Moreover, injections of 5-HT into the frontal cortex did not have any effect on amphetamine-induced circling. Lesions of the nucleus accumbens induced by 5,7-DHT caused a significant enhancement of the contralateral circling response to 1.0 mg/kg of apomorphine and a similar but non-significant tendency to increase the circling responses to several other doses of apomorphine and amphetamine. The results provide evidence that serotonergic mechanisms in the nucleus accumbens inhibit circling behaviour generated by unilateral activation of nigrostriatal dopaminergic mechanisms.

5,7-Dihydroxytryptamine↗

PubMed1984

Role of mesencephalic reticular formation in cholinergic-induced catalepsy and anticholinergic reversal of neuroleptic-induced catalepsy.

The present experiments investigate the brain sites involved in the elicitation of catalepsy by cholinergic agonists and neuroleptics. Microinjection of acetylcholine chloride (50 micrograms) in combination with eserine (2.5 micrograms) into the ventral mesencephalic reticular formation (MRF) elicited catalepsy. Microinjection of atropine sulfate (5 micrograms) into the same sites reversed the catalepsy of rats treated with haloperidol (1.5 mg/kg) 2 h earlier, but did not reverse morphine-induced (30 mg/kg, 1 h) catalepsy. Haloperidol (25 micrograms) injected into the nucleus accumbens septi (NAS) resulted in catalepsy as severe as that caused by an identical injection into the caudate nucleus. Catalepsy caused by intraNAS haloperidol occurred with a shorter latency than that resulting from intracaudate haloperidol, and was reversed by systemic scopolamine (0.4 mg/kg). On the basis of these results it is suggested that the ventral MRF is a site for the elicitation of catalepsy by cholinergic agonists and for the reversal of neuroleptic-induced catalepsy by anticholinergics, and that neuroleptic-induced catalepsy involves blockade of dopamine receptors in both the NAS and caudate nucleus.

Acetylcholine↗

PubMed1984

Six-hydroxydopamine induced hyperactivity: neither sex differences nor caffeine stimulation are found.

We investigated possible sex differences in the development of locomotor activity in rats treated neonatally with desmethylimipramine (DMI) followed by intraventricular 6-hydroxydopamine (6-HDA). In addition, the locomotor response to the stimulant caffeine was investigated in the male rats after they had reached adulthood. Both male and female 6-HDA-treated rats exhibited increased activity relative to controls. No sex differences were seen in either the development or magnitude of this effect. Male rats were used to determine the dose effects function for caffeine (0.5, 5, 15, 30 mg/kg) on locomotor activity. Control rats exhibited increased locomotor activity whereas 6-HDA-treated rats showed no increases with any dose of caffeine. Large decreases in the dopamine content of the olfactory tubercle (-88%, -82%), nucleus accumbens (-96%, -95%), and striatum (-99%, -99%) were found in both male and female rats. Choline acetyltransferase and glutamic acid decarboxylase activities were unchanged.

Aging↗

PubMed1984

Effects of intranigral injections of dopamine agonists and antagonists, glycine, muscimol and N-methyl-D,L-aspartate on locomotor activity.

Previously it has been shown that bilateral intranigral injections of dopamine into rats pretreated with a monoamine oxidase inhibitor induced prolonged stimulation of locomotor activity, while bilateral intranigral injections of haloperidol reduced the locomotor stimulation evoked by systemic amphetamine. In the present studies, the role of the substantia nigra in locomotor activity was further investigated using a variety of dopaminergic and other agonists and neuroleptics. Ergometrine, epinine, (+/-)-2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronapthalene hydrobromide (ADTN), 1,2,3,4-tetrahydro-6,7,-dihydroxyisoquinoline hydrochloride (THIQ), muscimol and glycine elicited locomotor activity when injected into the substantia nigra pars reticulata bilaterally. Additionally the non-dopaminergic agonists also elicited a degree of stereotyped behavior. Locomotor activity induced by intranigral ergometrine was blocked by systemic haloperidol but was not affected by intranigral haloperidol. Locomotor activity elicited by systemic amphetamine was blocked by bilateral intranigral alpha-flupenthixol, but that elicited by bilateral intra-accumbens ergometrine was not affected by alpha-flupenthixol or haloperidol injected into the substantia nigra pars reticulata bilaterally. The results provide further evidence that alterations of neurotransmission in the substantia nigra exert effects on locomotor activity.

Amphetamine↗

PubMed1983

Role of nigral dopamine in amphetamine-induced locomotor activity.

Dopamine (100 micrograms) injected into the substantia nigra pars reticulata of rats pretreated with the monoamine oxidase inhibitor, pargyline, resulted in a stimulation of locomotor activity. Bilateral injection of the dopamine antagonist haloperidol (5 micrograms) into the substantia nigra pars reticulata resulted in a reduction of the locomotor activity evoked by a low dose of amphetamine (1.25 mg/kg s.c.). These results suggest that the release of dopamine from nigral dendrites is involved in amphetamine-induced locomotor activity.

Amphetamine↗