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Biomedical subjects

P Lawlor

Publications and source records attributed to P Lawlor.

At least 37 records · Page 2Linked to original sources
PubMed1997

Dose ratio between morphine and hydromorphone in patients with cancer pain: a retrospective study.

Morphine (M) and hydromorphone (HM) are commonly used opioid analgesics for cancer pain. Opioid rotation is often necessary in the event of toxicity and/or inadequate analgesia. Equianalgesic reference tables based on single dose comparisons are possibly inadequate for patients on chronic treatment and developing tolerance. This retrospective study of opioid rotation involving M and HM sought to determine the equianalgesic dose ratio for 91 rotations in 74 consecutively evaluable cancer pain patients. Only rotations involving subcutaneous (s.c.-s.c.) and oral (p.o.-p.o.) routes were evaluated. There were 44 rotations from M-HM (34: s.c.-s.c., 10: p.o.-p.o.) and 47 rotations from HM-M (35: s.c.-s.c., 12: p.o.-p.o.). Expressing all ratios as M/HM, the median dose ratios (lower-upper quartiles) for s.c. and p.o. rotations were 4.92 (4.1-5.9) vs. 5.76 (4.9-5.8) for M-HM (P = 0.28, NS) and 4.0 (3.1-4.8) vs. 3.45 (2.8-4.2) for HM-M (P = 0.4, NS), respectively. Pain intensity, as measured on a visual analogue scale (VASP), showed no significant difference between mean values pre- and post-rotation. A unified overall median dose ratio of 4.29 (3.3-5.3, lower-upper quartiles) was calculated by expressing all of the HM-M dose ratios as M/HM and combining them with the dose ratios for all of the M-HM rotations. This suggests a potency ratio of approximately 4.3:1 between M and HM. When expressed as M/HM for dose ratio comparison, the median dose ratio for all HM-M rotations was 3.7 (2.9-4.5, lower-upper quartiles) vs. 5 (4.2-5.9) for M-HM rotations (P = 0.0001), suggesting that the opioid to which rotation is taking place is more potent than our proposed unified overall median dose ratio of 4.29:1 would predict. Our data suggests that HM is 5 times more potent than M when given second (M-HM), but is only 3.7 times more potent when given first (HM-M). We therefore recommend a ratio of 5 for M/HM in rotating from M to HM and ratio of 3.7 for M/HM when rotating from HM to M in patients exposed to chronic dosing of these opioids. There was no correlation observed between M-HM and HM-M dose ratios and the level of previous opioid dose, in contrast to HM to methadone rotation where the dose ratio was higher in patients receiving higher doses of HM.

Aged↗
PubMed1997

Severe opioid toxicity and somatization of psychosocial distress in a cancer patient with a background of chemical dependence.

A case of severe opioid toxicity is described in a 52-year-old cancer patient. The patient presented with classical clinical features of central hyperexcitability associated with opioid toxicity: delirium, myoclonus, hallucinations, hyperalgesia, and a possible seizure. This patient had a background of severe psychosocial distress and somatization in addition to a history of benzodiazepine dependence and alcohol abuse. The occurrence of opioid toxicity in this patient highlights the risks of a unidimensional approach to cancer pain, which ignores the non-organic components of pain, such as psychosocial distress, which will not respond to escalating doses of opioid medication.

Alcoholism↗
PubMed1997

Cancer pain management.

Pain occurs in more than 80% of cancer patients before death. Because of the increase in the frequency of cancer deaths worldwide, it is imperative to address cancer pain as a public health problem. Until recently, educational efforts were focused on treatment issues rather than adequate assessment. The approach to pain intensity as a multidimensional construct has helped in focusing treatments and identifying prognostic factors. Valid tools have been developed that allow multidisciplinary assessment of these prognostic factors and their complex interrelationship with the analgesic response. As a result of increased opioid exposure, patients are currently developing newer toxicities, mostly central excitability including delirium, myoclonus, grand mal seizures, and hyperalgesia. The observation that more than 80% of patients will require alternate routes for opioid delivery before death led to the development of a number of novel and effective alternate routes for delivery. Finally, in recent years it has become evident that some specific pain syndromes need to be addressed using specific assessment and management techniques. Incidental pain, somatization, neuropathic pain, and cancer pain in patients with alcoholism and drug addiction are some of these syndromes.

Analgesics, Opioid↗
PubMed1997

Cholecystectomy-induced gastroesophageal reflux: is it reduced by the laparoscopic approach?

OBJECTIVE: The incidence of gastroesophageal reflux and esophagitis increases significantly following cholecystectomy. Laparoscopic technique minimizes the metabolic and mechanical disturbances of cholecystectomy, but there has been no study of its effects on gastroesophageal reflux. The aim of this study was to examine the effect of laparoscopic cholecystectomy on the indices of gastroesophageal reflux. METHODS: A prospective study was carried out on patients scheduled for cholecystectomy. Informed consent was obtained. Preoperative 24-h pH studies and manometry were performed. Studies were repeated 3 months after surgery. Pathological acid reflux was defined in terms of the DeMeester acid score. RESULTS: Pre- and postoperative studies were carried out on 28 patients who had open cholecystectomy and on 22 patients who had laparoscopic cholecystectomy. The mean (SEM) DeMeester acid score increased from 14.8 (2.4) to 34.0 (6.7) following open cholecystectomy (p = 0.006) and from 13.9 (2.5) to 28.9 (4.3) following laparoscopic cholecystectomy (p = 0.002). Decrease in mean lower esophageal sphincter pressure in both groups was not significant. CONCLUSIONS: A significant increase in the incidence of gastroesophageal reflux occurred within 3 months after surgery in both study groups. Despite the less invasive nature of laparoscopic cholecystectomy, the type of surgery did not influence the degree of esophageal dysfunction.

Adult↗
PubMed1996

Temporal relationship between the expression of fos, jun and krox-24 in the guinea pig vestibular nuclei during the development of vestibular compensation for unilateral vestibular deafferentation.

Immediately following unilateral vestibular deafferentation (UVD), expression of the c-fos protein increased in both vestibular nucleus complexes (VNCs). By 10 h post-UVD, c-fos proteins were more evident in the bilateral medial vestibular nuclei (MVN), but their expression had decreased in the bilateral superior vestibular nuclei (SVN) and lateral vestibular nuclei (LVN) compared to immediately post-UVD. At 50 h post-UVD, c-fos protein expression was still evident in the bilateral VNC, but had decreased relative to immediately post-UVD. Immediately post-UVD, c-jun protein expression increased in the bilateral VNC, but was more noticeable at 10 h post-UVD. By 50 h post-UVD, c-jun protein expression had decreased markedly throughout the bilateral VNC. The krox-24 protein could not be seen anywhere in the immediate post-UVD condition. However, it was expressed at a low level in the bilateral MVN at 10 h post-UVD; by 50 h post-UVD, this expression had decreased. No evidence of apoptosis was observed following UVD.

Adaptation, Physiological↗
PubMed1996

Trk receptor alterations in Alzheimer's disease.

The expression of trk receptors in postmortem normal, Huntington's disease and Alzheimer's disease human brains was investigated using immunohistochemistry, in-situ hybridisation and Western blotting. Alzheimer's disease hippocampi displayed an increase in trkA receptor levels in astrocytes in the CA1 region, some of which were associated with beta-amyloid-positive plaques. Truncated trkB receptors were found in high levels in senile plaques, while the full-length receptor was expressed in glial-like cells in the hippocampus of Alzheimer's disease brains. In-situ hybridisation studies indicated that trk receptor mRNA was also elevated in Alzheimer's. The appearance of trkA and trkB receptors in astrocytes and plaques in Alzheimer's disease might be related to beta-amyloid deposition and could be implicated in the development of Alzheimer's disease.

Adult↗
PubMed1995

In situ evidence for DNA fragmentation in Huntington's disease striatum and Alzheimer's disease temporal lobes.

To test the hypothesis that apoptosis is involved in human brain neurodegenerative disorders, we investigated whether DNA fragmentation occurs in Alzheimer's disease (AD). Huntington's disease (HD) and Parkinson's disease, as well as in temporal lobe epilepsy, using neurologically normal post-mortem human brain tissue as a control. Using in situ end labelling of DNA, we found evidence of DNA fragmentation in cells in temporal cortex and hippocampus from patients with AD and in striatum from those with HD. In contrast, only scattered DNA fragmentation positive cells were detected in the pial surfaces of some of the neurologically normal human brains. Thus, cells in the HD striatum and AD temporal cortex exhibited DNA fragmentation, suggesting that apoptosis may be involved in these disorders.

Adult↗
PubMed1995

Ambulatory oesophageal bile reflux monitoring in Barrett's oesophagus.

Bile reflux has been implicated in the pathogenesis of Barrett's oesophagus but evaluation remains difficult. Bilitec 2000 is an ambulatory system that detects bilirubin based on its spectrophotometric properties. Oesophageal bile exposure was evaluated in three groups of patients. Group 1 (n = 11) were normal controls, group 2 (n = 13) were patients with uncomplicated gastro-oesophageal reflux and group 3 (n = 12) were patients with Barrett's oesophagus. Bile reflux was greater in patients with Barrett's mucosa than in controls or those with uncomplicated reflux. This difference was seen in the supine and interdigestive periods. The percentage of time at which gastric pH was greater than 4 and oesophageal pH was above 7 did not differ between the groups. Bilitec 2000 detects greater bile reflux in patients with Barrett's oesophagus. No corresponding gastric or oesophageal alkaline shift is found. This ambulatory bile reflux monitoring system may be a useful tool in clinical practice.

Adolescent↗
PubMed1995

Krox20 may play a key role in the stabilization of long-term potentiation.

Long-term potentiation-inducing stimulation of the perforant path was followed in dentate gyrus granule cells by a dramatic increase of mRNA and protein for Krox20, a zinc-finger-containing transcription factor. Induction of Krox20 required stimulation sufficient to induce LTP and was prevented by NMDA antagonists CPP and MK-801, which block LTP induction. Krox20 protein increased within 20 min of tetanization, was maximal between 1 and 8 h, and was still significantly elevated at 24 h after LTP induction. This prolonged appearance is in striking contrast with the more transient induction of the related molecule, Krox24. The elevation in the mRNA for Krox20 and Krox24 was of similar duration, suggesting that the Krox20 protein has a greater stability and may play a key role in the stabilization of long-term potentiation.

Animals↗
PubMed1995

Clusterin accumulates in dying neurons following status epilepticus.

Clusterin is a protein that has been implicated in cell death and remodelling in a number of different tissues. To further investigate the role of clusterin in nerve cell death its expression was measured in the rat brain at various times after status epilepticus (SE) induced by 1 h of hippocampal stimulation, by using in situ hybridization, immunocytochemistry, and immunoblotting. SE lead to a dramatic time-dependent increase in clusterin mRNA in non-nerve cells resembling astrocytes in the hippocampus beginning after 24 h. There was also an earlier induction of clusterin mRNA in dentate granule cells, that survive SE. Only a low mRNA signal was observed over the CA1 pyramidal cells, which die after SE. In contrast to these mRNA results, massive clusterin-like immunoreactivity was observed in CA1 pyramidal cells and dentate hilar neurons (and both of these neuronal populations die after SE), but not in dentate granule cells. We speculate that astrocytes produce clusterin after SE and that the clusterin is then secreted and taken up by hippocampal neurons destined to die. Thus, the role of clusterin in nerve cell death/ regeneration warrants further investigation.

Animals↗
PubMed1994

Immediate early gene expression associated with the persistence of heterosynaptic long-term depression in the hippocampus.

Long-term depression (LTD) of synaptic efficacy is likely to be as important in memory processing as the more well-known long-term potentiation (LTP). The case for LTD serving as a memory mechanism, however, requires that it be shown to persist across days or weeks at least. Here we examined the persistence of heterosynaptic LTD in the medial and lateral perforant path inputs to the dentate gyrus in awake rats and correlated this persistence with the degree of immediate early gene expression as assessed immunohistochemically. Rats were chronically implanted with separate stimulating electrodes in the medial and lateral perforant paths and an extracellular field potential recording electrode in the dentate hilus. After recovery from surgery, either the medial or the lateral perforant path was tetanized with 400-Hz trains, and homosynaptic LTP and heterosynaptic LTD were followed across time. Heterosynaptic LTD was shown to occur readily in awake animals and to persist across days or weeks, depending on the stimulation protocol. The persistence of LTD and LTP was highly correlated within animals. Additional animals, given the same tetanization protocols, showed that the greatest immediate early gene expression occurred following that protocol which consistently gave the longest-lasting LTP and LTD. These data support the proposed role of LTD in memory processing but question whether immediate early genes are important for the persistence of LTP, LTD, or both.

Animals↗
PubMed1994

Neuronal rescue with transforming growth factor-beta 1 after hypoxic-ischaemic brain injury.

Transforming growth factor-beta 1 (TGF-beta 1) mRNA is induced from 5 h to 3 days following hypoxic-ischaemic brain injury. Cell death also develops during this time suggesting that extracellular accumulation of this peptide may be involved in the processes that regulate cell loss. We examined the effect of rhTGF-beta 1 (0,2.5, 10,50 ng) injected into the cerebral lateral ventricle of rats 2 h after severe hypoxic-ischaemic brain injury. Histological outcome and B4-isolectin histochemistry were assessed 5 and 2 days, respectively following hypoxia. Treatment with 10 ng TGF-beta 1 reduced the microglia reaction (p < 0.05), the magnitude of neuronal loss (p < 0.01) and the area of cortical infarction (p < 0.05). Exogenous TGF-beta 1 given soon after hypoxic-ischaemic brain injury may have therapeutic potential and act by inhibiting the microglial reaction.

Animals↗
PubMed1994

c-fos antisense reduces expression of Krox 24 in rat caudate and neocortex.

1. The aim of this study was to investigate the neurochemical effects and measure the anatomical spread of infusion of c-fos antisense (AS) DNA into the striatum. 2. Rats were anesthetized and infused in opposing striata with c-fos AS and c-fos sense (S) DNA. Ten hours later they were injected with apomorphine (2 mg/kg, i.p.) and 20 min later they were overdosed with sodium pentobarbital and their brains either perfused or frozen. Vibratome-cut sections were immunostained for the detection of c-fos, JunB, Krox 24, somatostatin, substance P, dynorphin, tyrosine hydroxylase, and enkephalin. Cryostat-cut sections from the caudate were immunostained for the detection of c-fos, JunB, and Krox 24, as well as in situ hybridization for proenkephalin mRNA. Sections from the globus pallidus were used for the autoradiographic localization of D2 dopamine and A2a adenosine receptors. Sections from the substantia nigra were used for the autoradiographic localization of D1 dopamine and cannabinoid receptors. A second group of rats were injected in opposing striata with biotin-labeled c-fos AS DNA and c-fos S DNA. Ten hours later they were challenged with apomorphine (2 mg/kg, i.p.) and 20 min later brains were either perfused or frozen. Sections from these brains were cut throughout the rostral-caudal extent of the forebrain and the biotin labeled AS DNA was localized. 3. Krox 24 was expressed at high levels on the sense side of the brain in the striatum and overlying neocortex. However, on the AS-injected side there was a reduction in Krox 24 expression in striatum and overlying cortex. The biotin-labeled AS studies confirmed that the striatal infusion spread throughout the dorsal striatum as well as the overlying neocortex. We did not detect any changes in neurotransmitter receptors, neuropeptides, or tyrosine hydroxylase in AS/S-injected rat brains. 4. These results demonstrate that c-fos AS reduces Krox 24 expression in striatal and neocortical neurons but does not change the expression of a number of other proteins involved in basal ganglia function. Whether this effect is due to nonspecific actions of c-fos AS or to its effects on a component of the transduction pathway responsible for basal Krox 24 expression (NMDA receptors?) is unknown.

Animals↗
PubMed1994

Immediate-early gene protein expression in neurons undergoing delayed death, but not necrosis, following hypoxic-ischaemic injury to the young rat brain.

A unilateral hypoxia-ischaemia (HI) 21-day-old rat preparation was used to assess the effects of HI on the expression of the immediate-early gene proteins (IEGPs) c-Fos/FRAs, Fos B, c-Jun, Jun B, Jun D, Krox 20, Krox 24, and on the mRNA for the neurotrophic factor, brain-derived neurotrophic factor (BDNF). Moderate HI (15 min hypoxia) produced delayed, selective neuronal death and was associated with a rapid induction of c-Fos, Fos B, Jun B, Jun D, and c-Jun proteins, but not Krox 20 protein or BDNF mRNA, in neurons on the side of HI and also a delayed expression of c-Jun (and to a lesser extent c-Fos/FRA's and Fos B) 24-48 h after HI in neurons that underwent delayed neuronal death. Krox 24 showed an initial induction followed by a long-lasting suppression of its expression in regions undergoing cell loss. Severe HI (60 min hypoxia) resulted in seizures and rapid neuronal loss and infarction (necrotic cell death) on the side of HI, and was associated with early induction of c-Fos, Fos B, c-Jun, Jun B, Jun D, Krox 20 and Krox 24 protein and BDNF mRNA in neurons on the non-ligated side of the brain. Fos, c-Jun, Jun B, Jun D and Krox 24, but not Krox 20, Fos B, or BDNF mRNA, were also induced in non-nerve cells on the damaged side of the brain after both moderate and severe HI, and many of these cells appeared to be dividing. Thus, moderate HI induces IEGP's in neurons and non-nerve cells in damaged regions, whereas severe HI induces IEGP's and BDNF in non-damaged regions. c-Jun (and to a lesser extent c-Fos/FRA's) showed a prolonged expression in neurons undergoing delayed, but not necrotic, cell death suggesting that they may be involved in the biochemical cascade that causes selective delayed neuronal death. BDNF was not induced by HI, and therefore, does not appear to play an endogenous neuroprotective role in the CNS.

Animals↗
PubMed1993

c-fos antisense generates apomorphine and amphetamine-induced rotation.

Sodium pentobarbital anaesthetized rats were injected ipsilaterally with an antisense oligonucleotide to c-fos and contralaterally with a sense of oligonucleotide to c-fos in the striatum. Ten hours later they were injected with amphetamine or apomorphine and their behaviour was observed for a further 2 h at which time they were overdosed with anaesthetic and their brains were removed, frozen and processed for Fos and Jun B immunohistochemistry. Rats showed amphetamine- and apomorphine-induced rotation towards the antisense injected striatum. The antisense oligonucleotide also strongly inhibited the amphetamine-induced expression of c-Fos and Jun B in striatal neurones. These results suggest that antisense to c-fos produces a biochemical change in the injected striatum that then, 10 h later, blocks amphetamine- and apomorphine-induced behavioural and biochemical effects.

Amphetamine↗