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Biomedical subjects

P Nichols

Publications and source records attributed to P Nichols.

At least 19 recordsLinked to original sources
PubMed2006

Course and outcome of acute limbic encephalitis with negative voltage-gated potassium channel antibodies.

BACKGROUND: Limbic encephalitis is a potentially treatable immunological condition. The presence of voltage-gated potassium channel antibodies (VGKC-Ab) in the cerebrospinal fluid (CSF) and serum of patients with the condition is a marker of the disease associated with a non-paraneoplastic form and good response to treatment. Recent work has highlighted absent serum VGKC-Ab and distinct immunology in patients with the paraneoplastic form of limbic encephalitis. METHODS: The cases of four patients with the typical clinical presentation, neuropsychological features and brain imaging of acute limbic encephalitis, in the absence of any evidence for associated cancer during a follow-up of at least 18 months are described here. RESULTS: All patients had negative testing for VGKC-Ab measured during their acute presentation. All patients made some recovery, although they were left with marked cognitive deficits and persistent seizures. CONCLUSION: These cases demonstrate that the absence of VGKC-Ab in limbic encephalitis does not necessarily imply a paraneoplastic form. Further work is required to establish the immunological basis for the disorder in these patients, and the optimal treatment regimen.

Acute Disease↗
PubMed2004

The distributions of mitochondria and sodium channels reflect the specific energy requirements and conduction properties of the human optic nerve head.

AIM: To study the normal distributions of mitochondria and voltage gated Na+ channels in the human optic nerve head in order to gain insight into the potential mechanisms of optic nerve dysfunction seen in the inherited optic neuropathies. METHODS: Five fresh frozen human optic nerves were studied. Longitudinally orientated, serial cryosections of optic nerve head were cut for mitochondrial enzyme histochemistry and immunolabelling for cytochrome c oxidase (COX) subunits and voltage gated Na+ channel subtypes (Na(v) 1.1, 1.2, 1.3, and 1.6). RESULTS: A high density of voltage gated Na+ channels (subtypes Na(v) 1.1, 1.3, and 1.6) in the unmyelinated, prelaminar, and laminar optic nerve was found. This distribution co-localised both with areas of high COX activity and strong immunolabelling for COX subunits I and IV. CONCLUSIONS: Increased numbers of mitochondria in the prelaminar optic nerve have previously been interpreted as indicating a mechanical hold up of axoplasmic flow at the lamina cribrosa. These results suggest that this increased mitochondrial density serves the higher energy requirements for electrical conduction in unmyelinated axons in the prelaminar and laminar optic nerve and is not a reflection of any mechanical restriction. This could explain why optic neuropathies typically occur in primary inherited mitochondrial diseases such as Leber's hereditary optic neuropathy, myoclonic epilepsy with ragged red fibres (MERRF), and Leigh's syndrome. Secondary mitochondrial dysfunction has also been reported in dominant optic atrophy, Friedreich's ataxia, tobacco alcohol amblyopia, Cuban epidemic optic neuropathy, and chloramphenicol optic neuropathy. These diseases are rare but these findings challenge the traditional theories of optic nerve structure and function and may suggest an alternative approach to the study of commoner optic neuropathies such as glaucoma.

Adult↗
PubMed2002

Achieving river integrity through natural resource management and integrated catchment management legislative frameworks.

This paper reports on a project which further refines a model legislative framework first identified in a Land and Water Australia project in 1999. This framework is benchmarked against legislative excerpts from within Australian jurisdictions, as well as the major policy initiatives of the Council of Australian Governments (COAG) water reform agenda, the Commonwealth's National Action Plan on Salinity and Water Quality, and others. The model framework has been heavily influenced by current thinking on ecological systems, good governance, and organisational management. Another important product of the report is a statement of model statutory objectives and principles, suitable for use in water resource legislation.

Australia↗
PubMed2001

Wound botulism in drug addicts in the United Kingdom.

Clostridium novyi has recently been identified as the causative organism responsible for the deaths of 35 heroin addicts who had injected themselves intramuscularly. We present two heroin addicts who developed C. botulinum infection following intramuscular or subcutaneous injection of heroin. Like C. novyi, this grows under anaerobic conditions and clinical presentation may be similar; however, descending motor or autonomic signs are invariably present in botulism. The prognosis is good if the diagnosis is made early and appropriate treatment commenced.

Adult↗
PubMed2000

Leptomeningeal glioblastoma presenting with multiple cranial neuropathies and confusion.

Glioblastoma multiforme (GBM) is the commonest primary malignant neoplasm of the CNS. Usually, patients present with seizures and headache but in the elderly, confusion and generalised cognitive decline are more frequently the initial features. Multiple cranial nerve lesions as a manifestation of leptomeningeal meningitis is a rare presentation of GBM. The diagnosis is not often suggestive on either brain computed tomography (CT) or magnetic resonance imaging (MRI) and is usually confirmed by cerebrospinal fluid (CSF) cytology or histology. We describe the case of an 80-year-old man, who presented with multiple cranial nerve palsies and confusion secondary to leptomeningeal gliomatosis, in whom GBM was detected along the intra-ventricular lining of the left lateral ventricle at ventriculoscopy, in the absence of a distinct parenchymal lesion.

Age Factors↗
PubMed2000

Microbial ecology of the leach bed anaerobic digestion of unsorted municipal solid waste.

The microbial ecology of the sequential, leach-bed, mesophilic anaerobic digestion of unsorted, coarse municipal solid waste (MSW) was examined over 80 days. The methane yield was approximately 75% of the ultimate biochemical methane potential (BMP) of the waste loaded into the digesters. The operational strategy involved a sequence of two digesters containing fresh and anaerobically stabilised MSW respectively. Cell wall phospholipid fatty acid (PLFA) and ether lipid (PLEL) analysis was used to monitor changes in microbial biomass. Both Bacterial and Archaeal biomass were heavily influenced by pH during the two-week start up period. Archaeal biomass peaked just before the methane production rate reached a maximum whereas Bacterial biomass peaked at a later stage. Changes in the phylogenetic diversity of the population were monitored by denaturing gradient gel electrophoresis (DGGE). An analysis of the changes in DGGE banding patterns suggested that rapid start-up of a new reactor was effected by inoculation as well as the provision of buffering capacity from the mature reactor leachate.

Archaea↗
PubMed1999

Comparison of standard and alternative prehospital resuscitation in uncontrolled hemorrhagic shock and head injury.

BACKGROUND: Recently acquired data suggest that prehospital fluid resuscitation may worsen outcome of patients with penetrating torso trauma. In patients with head injury, delayed resuscitation (DR) could lead to secondary cerebral ischemia. We hypothesized that standard prehospital resuscitation (SPR) with lactated Ringer's solution or diaspirin cross-linked hemoglobin would reduce secondary cerebral ischemia compared with DR. METHODS: Anesthetized swine were randomized to receive SPR, diaspirin cross-linked hemoglobin, or DR after cryogenic brain injury and uncontrolled hemorrhagic shock and studied for 70 minutes after the combined insults. RESULTS: Hemorrhage volume was lowest in the DR group (p<0.05). There were no significant differences between the groups in systemic or cerebral oxygen delivery. Intracranial pressure was lower and cerebral perfusion pressure higher in the diaspirin cross-linked hemoglobin group compared with SPR (p<0.05). Lesion size was greatest in the SPR group, but the difference was not significant. CONCLUSION: In this model, SPR leads to secondary cerebral ischemia. DR is no worse and may be superior to conventional prehospital resuscitation with lactated Ringer's solution.

Animals↗
PubMed1999

Mutation of the acetylcholine receptor epsilon-subunit promoter in congenital myasthenic syndrome.

Congenital myasthenic syndrome comprises a heterogeneous group of inherited disorders of neuromuscular transmission. Acetylcholine receptor (AChR) deficiency is the most common form of congenital myasthenic syndrome and in most cases results from mutations within the coding region of the AChR epsilon subunit. However, studies in mice have established that synapse-specific expression of AChR is dependent on a sequence contained within the AChR-subunit promoter regions, termed an N-box. We describe a consanguineous family in which 2 of 7 siblings had clinical and electromyographic features consistent with AChR deficiency. Muscle biopsy demonstrated low AChR numbers, establishing the disorder as postsynaptic. Single-strand conformational polymorphism analysis identified an abnormal conformer in the AChR epsilon-subunit gene promoter of the patients. DNA sequence and restriction endonuclease analysis shows that the disorder cosegregates with recessive inheritance of a single point mutation, a transition (C-->T) in the N-box of the epsilon-subunit promoter. Analysis of an intercostal biopsy from 1 of the patients showed a dramatic reduction in epsilon-subunit mRNA levels compared with disease and normal controls. This is the first evidence in humans that an N-box mutation can lead to disruption of epsilon-subunit transcription, resulting in the loss of adult AChR synthesis and the clinical phenotype of AChR-deficiency congenital myasthenic syndrome.

Adult↗
PubMed1998

Delayed fluid resuscitation of head injury and uncontrolled hemorrhagic shock.

OBJECTIVE: To evaluate the effects of delayed vs early fluid resuscitation on cerebral hemodynamics after severe head injury and uncontrolled hemorrhagic shock. DESIGN: Prospective, randomized, controlled experimental trial. SETTING: Surgical research laboratory. PARTICIPANTS: Immature swine (N=16) weighing 40 to 50 kg. INTERVENTIONS: Twelve swine were subjected to cryogenic brain lesion and hemorrhage to maintain a mean arterial pressure (MAP) of 50 mm Hg. Animals were randomized to receive 1 L of Ringer lactate solution in 20 minutes, starting 20 minutes after injury and hemorrhage, followed by 1 L of Ringer lactate solution in 30 minutes (ER group) (n=6), or no fluid resuscitation (DR group) (n=6). The 4 control animals underwent instrumentation only. The study ended 70 minutes after head injury and hemorrhage. MAIN OUTCOME MEASUREMENTS: Measurements of MAP, bilateral regional cerebral blood flow, serum hemoglobin level, systemic and regional cerebral oxygen delivery, and intracranial pressure performed at baseline and 20 (phase 1), 50 (phase 2), and 70 minutes (phase 3) after head injury and hemorrhage. Lesion size (percentage of ipsilateral cortex) was measured post mortem. RESULTS: All animals survived the experimental period. Systemic cerebral oxygen delivery in the DR group was significantly lower at phase 3 compared with that of the ER group (31.5% vs 53.1% at baseline) (P=.03). However, bilateral regional cerebral oxygen delivery was significantly greater in the DR group at phase 3 compared with that of the ER group (71.5% vs 47.0% at baseline in the injured side; 72.9% vs 48.4% at baseline in the noninjured side) (P=.02). Bilateral cerebral blood flow was similar in all groups at all times. The ER group showed a trend toward a greater intracranial pressure elevation (6.8 vs -0.25) (P=.07) and lesion size (37.0% vs 28.6%) (P=.07). Hemoglobin level became significantly lower in the ER group at phase 2 (7.0 vs 10.7) (P=.03) and remained lower at phase 3 (6.9 vs 11.7) (P=.01). CONCLUSIONS: Early fluid resuscitation with Ringer lactate solution following head injury and uncontrolled hemorrhagic shock worsens cerebral hemodynamics. Cerebral pressure autoregulation is sufficiently intact following head injury to maintain regional cerebral oxygen delivery without asanguineous fluid resuscitation.

Animals↗
PubMed1998

Weakness of sympathetic neural control of human pial compared with superficial temporal arteries reflects low innervation density and poor sympathetic responsiveness.

BACKGROUND AND PURPOSE: The primary goal of these studies was to understand and investigate the capacity of perivascular nerves to influence the tone of human pial arteries and to compare them with other human cephalic arteries, the superficial temporal and middle meningeal. METHODS: Responses to electrical activation of intramural nerves and related features of fresh segments of human cephalic arteries-the pial (PA; 478+/-34 microm ID), middle meningeal (MMA; 540+/-41 microm ID), and superficial temporal (STA; 639+/-49 microm ID)-obtained from patients aged 15 to 82 years during surgical procedures were studied on a resistance artery myograph. RESULTS: The PA segment responses to electrical nerve activation and to norepinephrine (NE; 10[-5] mol/L) were 1% and 21% of tissue maximum, respectively, compared with 6% and 34% for the MMA and 14% and 90% for the STA. Tissue maximum was defined as the force increase to 127 mmol/L KCl plus arginine vasopressin (1 microm). All arteries dilated well to acetylcholine. Possible explanations for the PA marginal neurogenic responses were assessed. NE ED50 was 5.4+/-2.2 X 10(-7) mol/L and did not vary with age or diameter. NE responsiveness did not increase in vessels with spontaneous or raised potassium-induced tone. Relaxation to isoproterenol was variable and propranolol did not increase the neurogenic response. Neither N(G)-monomethyl-L-arginine, N(G)-nitro-L-arginine methyl ester, endothelium removal, nor indomethacin consistently influenced the contractions to NE or neurogenic reactivity. The weak PA neurogenic response is in keeping with its poor innervation. As determined by catecholamine histofluorescence, innervation in the PA is sparse, with density increasing in the order PA, MMA, and STA. The incidence of nerve structures in the PA adventitio-medial junction was only 3% of those in the STA, and these were situated more than 3 microm from the closest smooth muscle cell. CONCLUSIONS: We conclude that the weak neurogenic response of adult human pial artery reflects its poor innervation and responsiveness to NE, implying that these features are not important in the regulation of its diameter.

Acetylcholine↗
PubMed1998

Responsiveness of human infant cerebral arteries to sympathetic nerve stimulation and vasoactive agents.

Responses of segments of basilar and middle cerebral arteries of eight human infants to activation of perivascular nerves and to vasoactive drugs were studied using a resistance artery myograph. The infants ages ranged from 23 wk of gestation to 34 postnatal days. Neurogenic vasoconstriction occurred in all segments and at 8 Hz was 12.7 +/- 3.5% (11%) of tissue maximum and was blocked by phentolamine (10(-6) M). There was no evidence of a neurogenic dilator response. Catecholamine histofluorescence was seen in nerves in the adventitia at all ages studied. Norepinephrine ED50 was 7.6 +/- 1.8 x 10(-7) M, and its maximum effect was 43.1 +/- 5.7% of tissue maximum. Both neural and norepinephrine responses were greater than those of the proximal parts of adult human middle cerebral arteries obtained postmortem and surgically removed adult human pial arteries. Electron microscopy demonstrated that neural density at the adventitiomedial junction in the infant vessels was greater than in the pial arteries. Constrictor responses to serotonin and prostaglandin F2 alpha were minimal in the two infants of 23 and 24 wk of gestation but were clearly present in the older infants. Histamine and acetylcholine were potent vasodilators. Indomethacin potentiated agonist-induced contraction. In a limited number of trials angiotensin II, neuropeptide Y, caused contraction and bradykinin, relaxation. It is concluded that there is a quantitative similarity between the studied responses of infant cerebral artery segments and human pial arteries of similar diameter. However, sympathetic nerves may potentially play a more important role in the regulation of cerebrovascular tone in the infant compared with the adult, and during the gestational period examined these vessels possess an indomethacin-sensitive system that buffers agonist tone.

Acetylcholine↗
PubMed1996

Effects of hypertension and propranolol upon aneurysm expansion in the Anidjar/Dobrin aneurysm model.

Propranolol has been suggested to slow aortic aneurysm (AAA) expansion by a mechanism independent of simple blood pressure (BP) reduction. To investigate this hypothesis, we designed a series of experiments to examine the effects of hypertension and propranolol upon AAA expansion. Using an established animal model, we induced AAA in normotensive and genetically hypertensive rats by perfusion of the isolated infrarenal aorta with elastase for two hours. Systolic tail BP was monitored with a plethysmograph. AAA size was measured directly with a micrometer on postoperative days 7 and 14. All data are expressed as the mean +/- standard deviation (SD). BP (mmHg) was significantly higher in hypertensive rats: 164 +/- 15 versus 119 +/- 7 (p < 0.001). AAA were also significantly larger in hypertensive rats with a mean expansion rate (mm/day) nearly twice that of normotensive animals: 0.13 +/- 0.09 versus 0.07 +/- 0.03. In a second series of animals, propranolol treatment was compared to placebo. In those animals, hypertensive propranolol-treated rats had significantly smaller AAA than placebo-treated controls (p < 0.05). There was no difference in normotensive animals but these rats had an unexplained paradoxical rise in BP with treatment. In this model, hypertension increases the expansion rate of AAA. Propranolol reduced the size of AAA in hypertensive animals, at least in part because of a decrease in BP. Other possible mechanisms of propranolol's action may be operative and require further study.

Adrenergic beta-Antagonists↗
PubMed1996

Hemodynamic and biochemical characteristics of the aorta in the WKY, SHR, WKHT, and WKHA rat strains.

This study was designed to characterize the hemodynamic and biochemical properties of the abdominal aorta in four genetically related inbred rat strains that express genetic hypertension and hyperactive behavior in varying combinations. These include (1) the spontaneously hypertensive rat (SHR), which is hypertensive, hyperactive, and hyperreactive to stress; (2) Wistar-Kyoto (WKY) rats, which express none of these traits; (3) WKHT rats, which are hypertensive but not hyperactive; and (4) WKHA rats, which are hyperactive and hyperreactive to stress, but normotensive. Together, these four strains allowed us to examine the structural and functional changes in the aorta in the hypertensive SHR, the most widely used animal model of genetic hypertension, while controlling for the variables of hyperactivity and hyperreactivity that are also expressed in the SHR. Four groups of animals of both sexes were studied: (1) WKY, n = 101, (2) WKHA, n = 33, (3) WKHT, n = 91, and (4) SHR, n = 28. Blood pressure (BP) was determined by tail plethysmography as well as direct intraarterial monitoring under anesthesia. Fixed specimens were prepared for histologic analysis and the wall thickness determined morphometrically. Quantification of soluble tissue protein, elastin, and collagen in the aortic tissue was determined by measuring leucine (leu), hydroxyproline (HP/leu), and desmosine (DES/leu). The hypertensive strains (SHR and WKHT) had significantly higher tail BP than the normotensive strains (WKY and WKHA)-WKY: 128.7 +/- 22.3; WKHA: 126.7 +/- 14.6; WKHT: 162.8 +/- 21.2; SHR: 164.2 +/- 36.1 (p < 0.0001). Additionally, intraaortic diastolic BP and mean BP were higher in SHR rats than in WKHT. Morphometric studies showed the media thickness in the SHR rats was significantly greater than in the WKY and WKHA rats and no different than in the WKHT rats. Significantly less of the aortic wall protein was present as elastin in the hypertensive rats (SHR and WKHT), as well as the hyperactive rats (WKHA), compared to rats that had neither trait (WKY). These studies provide new information regarding aortic structure and function in genetic hypertension using inbred strains to control for the hyperactivity/hyperreactivity traits that coexist with hypertension in the SHR. They reveal that hypertensive aortas have altered matrix proteins that cannot be explained simply on the basis of blood pressure alone.

Amino Acids↗
PubMed1996

Anti-CD 18 monoclonal antibody slows experimental aortic aneurysm expansion.

PURPOSE: Inflammation has been implicated as a contributing factor in the expansion of abdominal aortic aneurysms (AAA). To test this hypothesis, we examined the effects of a monoclonal antibody (MAB) to the leukocyte CD18 adhesion molecule on the expansion of experimental AAA. METHODS: Aneurysms were induced by perfusion of an isolated segment of the infrarenal aorta with elastase in 22 normotensive (WKY) and 17 genetically hypertensive (WKHT) rats. Animals of both strains were randomly allocated to control or MAB-treated groups (MAB, 5 microgram/100 gm body weight intraperitoneally, daily, beginning on the operative day for a total of four doses). The activity of the MAB against rat leukocytes had first been determined by in vitro immunofluorescence flow cytometry. Aortic size was directly measured initially and on day 14. At that time, a segment of aorta was stained with hematoxylin and eosin and mononuclear leukocytes and neutrophils were counted in each of 10 microscopic fields (400X). RESULTS: The initial aortic size in all animals was 1.11+/-0.15 mm. All groups developed aneurysms significantly larger than the initial aortic size (p<0.01). However, the MAB-treated animals had significantly smaller aneurysms than the untreated controls (mm): WKY: 3.63+/-1.26, WKY-MAB: 2.08+/-0.30, WKHT: 4.54+/-1.86, WKHT-MAB: 2.37+/-0.40, p<0.0001. There also were significantly fewer monocytes in the MAB-treated normotensive rats: WKY:35.5+/-29.9, WKHT:40.6+/-28.8, WKY-MAB: 8.9+/-8.5, WKHT-MAB: 32.3+/-25.7, p=0.03. Neutrophil counts did not differ significantly between the groups. CONCLUSIONS: Treatment with anti-CD18 monoclonal antibody slows the expansion of AAA in this experimental model. The associated inflammatory process at day 14, as indicated by monocyte infiltration, is reduced, but this effect may be opposed by the presence of hypertension. Further evaluation of the role of leukocytes and adhesion molecules in the expansion of AAA is warranted.

Animals↗
PubMed1995

Use of the stress-inducible grp78/BiP promoter in targeting high level gene expression in fibrosarcoma in vivo.

Current advances in human gene therapy open up new frontiers for molecular therapies of cancer. However, one major limitation in cancer gene therapy is the lack of a general tumor-specific promoter which allows stringent and high level expression of the therapeutic reagent in malignantly transformed but not normal tissues. Hallmark features of solid tumors such as glucose deprivation, chronic anoxia, and acidic pH induce the glucose-regulated proteins, in particular, GRP78/BiP, a M(r) 78,000 endoplasmic reticulum-localized protein with chaperone and calcium-binding properties. We report here that a truncated rat grp78 promoter with most of the distal basal elements removed can be utilized as a potent internal promoter in a retroviral vector to drive high level expression of a reporter gene in a murine fibrosarcoma model system. The stress-inducible grp78 promoter offers a novel approach for gene delivery systems targeting transcription in tumorigenic cells.

3T3 Cells↗