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Biomedical subjects

E Davidson

Publications and source records attributed to E Davidson.

At least 19 recordsLinked to original sources
PubMed2006

Uncomplicated general anesthesia in the elderly results in cognitive decline: does cognitive decline predict morbidity and mortality?

Elderly surgical patients constitute a unique surgical group. They require special consideration in order to preempt the long term adverse effects of anesthesia. This paper examines the proposition that general anesthesia causes harm to elderly patients with its impact being felt long after the anesthetic agents are cleared from the body. One complication, Postoperative Cognitive Decline (POCD), is associated with the administration of anesthesia and deep sedation. Its' occurrence may herald an increase in morbidity and mortality. Based on both human and animal data, this paper outlines a unitary theoretical framework to explain these phenomena. If this hypothesis proves to be correct, anesthesiologist should consider regional rather than general anesthesia for equivalent surgical procedures to reduce POCD and consequently achieving superior patient outcome.

Aged↗
PubMed2005

Rapid presymptomatic detection of PrPSc via conformationally responsive palindromic PrP peptides.

Structurally unique, synthetic prion peptides provide the basis of a simple assay to serve as both a detection and signal amplification system that distinguishes the normal prion protein, PrPC, from the misfolded prion protein, PrPSc, that is associated with the occurrence of transmissible spongiform encephalopathies (TSE). Proof-of-principle has been shown on brain samples from an experimental scrapie hamster model. The assay demonstrates very sensitive detection of PrPSc in animal brain tissue with potential application for early presymptomatic detection in animal screening. Furthermore, the sensitivity of the assay could enable blood tests for this TSE disease as well as other amyloid and/or misfolded protein diseases.

Animals↗
PubMed2004

Can a health advocate for homeless families reduce workload for the primary healthcare team? A controlled trial.

The objective of the present study was to determine whether provision of health advocacy for homeless patients would reduce the burden of care for a primary healthcare team. The impact of a health advocacy intervention was assessed in a quasi-experimental, three-armed controlled trial. Homeless patients registering at an inner-city health centre were allocated in alternating periods to health advocacy (with or without outreach registration) or 'usual care' over a total intake period of 3 years. The client group were homeless people in hostels or other temporary accommodation in the Liverpool 8 area of the UK. The majority of participants (n = 400) were women (76%) in their twenties (mean age = 26.6 years). Most (63%) were temporarily housed at either one of the women's refuges or Liverpool City Council family hostels, and all were registered with an inner-city health centre. Data on health service utilisation over a 3-month period was collected for all clients recruited to the study and direct health service costs were measured. Homeless adults who were proactively registered by the health advocate on outreach visits to hostels made significantly less use of health centre resources whilst having more contact with the health advocate than patients who registered at the health centre at a time of need. There was no reduction in health centre workload when the offer of health advocacy was made after registration at the health centre. The additional costs of providing health advocacy were offset by a reduction in demand for health-centre-based care. The results demonstrate that health advocacy can alter the pattern of help-seeking by temporarily homeless adults. The intervention was cost-neutral. The short-term health service workload associated with symptomatic homeless patients requiring medication was not reduced, but outreach health advocacy was used successfully to address psycho-social issues and reduce the workload for primary care staff.

Adolescent↗
PubMed2001

Protection against tick-transmitted Lyme disease in dogs vaccinated with a multiantigenic vaccine.

In an effort to develop a safe and effective vaccine for the prevention of Lyme borreliosis that addresses concerns raised over currently available vaccines, dogs were vaccinated twice with a multiantigenic preparation of Borrelia burgdorferi, strain N40, on days 0 and 20 of the experiment. About 70 and 154 days after the first immunization, dogs were challenged by exposing them to field-collected Ixodes scapularis ticks harboring B. burgdorferi. Vaccinated dogs were completely protected from infection by all criteria utilized to assess infection, developed high-titer anti-B. burgdorferi serum antibodies and growth inhibitory activity which persisted for over 200 days, and did not demonstrate any untoward consequence of vaccination. Serum absorption experiments revealed that borreliacidal and most likely protective antibodies in dogs receiving the multiantigenic preparation were not only elicited against the OspA antigen, but were also produced against additional yet to be determined targets on B. burgdorferi organisms. These data demonstrate that a multiantigenic vaccine is effective in preventing Lyme disease transmitted via the natural vector.

Animals↗
PubMed2001

Photoplethysmographic measurement of changes in total and pulsatile tissue blood volume, following sympathetic blockade.

Epidural anaesthesia, used for pain relief, is based on blocking the sensory and the sympathetic nerves in the lower part of the body. Since the sympathetic nervous system regulates blood vessel diameter, the sympathetic block is also associated with several haemodynamic changes. In the current study photoplethysmography (PPG) was measured on toes and fingers of patients undergoing epidural anaesthesia. Three parameters, which are related to the change in total and pulsatile tissue blood volume, were derived from the PPG baseline and amplitude. All parameters showed statistically significant increase in the toes after the sympathetic block, indicating higher arterial and venous blood volume and higher pulsatile increase in the arterial blood volume (higher arterial compliance) in the toe. These haemodynamic changes originate from the lower tonus of the arterial and venous wall muscles after the sympathetic block. In the fingers the PPG parameters based on the change in PPG amplitude decreased after the sympathetic block, indicating lower compliance. The measurement of the haemodynamic changes by PPG enables the assessment of the depth of anaesthesia, and can help control the adverse effects of the blockade on the vascular system.

Algorithms↗
PubMed2001

Isolation of two cDNAs encoding functional human cytoplasmic cysteinyl-tRNA synthetase.

Cysteinyl-tRNA synthetase catalyzes the addition of cysteine to its cognate tRNA. The available eukaryotic sequences for this enzyme contain several insertions that are absent from bacterial sequences. To gain insights into the differences between the bacterial and eukaryotic forms, we previously studied the E. coli cysteinyl-tRNA synthetase. In this study, we sought to clone and express the full-length gene for the human cytoplasmic cysteinyl-tRNA synthetase. Although a gene encoding the human enzyme has been described, the predicted protein sequence, consisting of 638 amino acids, lacks homology with other eukaryotic enzymes in the carboxyl-terminus. This suggested that a further investigation was necessary to obtain the definitive sequence for the human enzyme. Here we report the isolation of a full-length cDNA that encodes a protein of 748 amino acids. The predicted protein sequence shows considerable similarity to other eukaryotic cysteinyl-tRNA synthetases in the carboxyl-terminus. We also found that approximately 20% of the mRNA encoding the cytoplasmic cysteinyl-tRNA synthetase contained an insertion of 8 bases in the 3' coding region of the mRNA. This insertion arises from an alternative splicing between the last two exons of the gene. The alternative splicing alters the reading frame and results in the replacement of the carboxy-terminal 44 amino acids with a novel sequence of 22 amino acids. Expression of the full-length and alternative forms of the enzyme in E. coli generated functional proteins that were active in aminoacylation of human cytoplasmic tRNA(Cys) with cysteine.

Alternative Splicing↗
PubMed2000

Subunit II of cytochrome c oxidase in Chlamydomonad algae is a heterodimer encoded by two independent nuclear genes.

The mitochondrial genomes of Chlamydomonad algae lack the cox2 gene that encodes the essential subunit COX II of cytochrome c oxidase. COX II is normally a single polypeptide encoded by a single mitochondrial gene. In this work we cloned two nuclear genes encoding COX II from both Chlamydomonas reinhardtii and Polytomella sp. The cox2a gene encodes a protein, COX IIA, corresponding to the N-terminal portion of subunit II of cytochrome c oxidase, and the cox2b gene encodes COX IIB, corresponding to the C-terminal region. The cox2a and cox2b genes are located in the nucleus and are independently transcribed into mRNAs that are translated into separate polypeptides. These two proteins assemble with other cytochrome c oxidase subunits in the inner mitochondrial membrane to form the mature multi-subunit complex. We propose that during the evolution of the Chlorophyte algae, the cox2 gene was divided into two mitochondrial genes that were subsequently transferred to the nucleus. This event was evolutionarily distinct from the transfer of an intact cox2 gene to the nucleus in some members the Leguminosae plant family.

Amino Acid Sequence↗
PubMed2000

The human lysyl-tRNA synthetase gene encodes both the cytoplasmic and mitochondrial enzymes by means of an unusual alternative splicing of the primary transcript.

Two cDNAs encoding human lysyl-tRNA synthetase have been identified. One encodes the cytoplasmic form of the enzyme identified previously. The second cDNA contains the same sequence but with a 180-bp insertion at the 5'-end of the mRNA. This results in a predicted protein whose carboxyl 576 amino acids are identical to those of the cytoplasmic enzyme but with a different amino terminus of 49 amino acids that contains a putative mitochondrial targeting sequence. Expression of the two lysyl-tRNA synthetase-green fluorescent protein gene fusions in a human cell line confirmed that the cytoplasmic form was targeted to the cytoplasm and the mitochondrial form to mitochondria. The genomic lysyl-tRNA synthetase gene consisted of 15 exons. The two isoforms were created by alternative splicing of the first three exons of the gene. The cytoplasmic form was created by splicing exon 1 to exon 3. The inclusion of exon 2 between exons 1 and 3 produced an mRNA encoding the mitochondrial isoform with an additional upstream small open reading frame, consisting mainly of a portion of the 5' coding region of the cytoplasmic isoform. This is the first example of mitochondrial targeting sequence being encoded on the second exon of a gene. Ribonuclease protection analysis showed that the mRNA encoding the cytoplasmic isoform makes up approximately 70%, and the mitochondrial isoform approximately 30%, of the mature transcripts from the lysyl-tRNA synthetase gene. The mitochondrial form of the enzyme, purified after expression in Escherichia coli, aminoacylated in vitro transcripts corresponding to both the cytoplasmic and mitochondrial tRNA(Lys), despite the difference in the discriminator base sequence in the acceptor stems of these tRNAs.

Alternative Splicing↗
PubMed2000

Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA.

Two small RNAs regulate the timing of Caenorhabditis elegans development. Transition from the first to the second larval stage fates requires the 22-nucleotide lin-4 RNA, and transition from late larval to adult cell fates requires the 21-nucleotide let-7 RNA. The lin-4 and let-7 RNA genes are not homologous to each other, but are each complementary to sequences in the 3' untranslated regions of a set of protein-coding target genes that are normally negatively regulated by the RNAs. Here we have detected let-7 RNAs of approximately 21 nucleotides in samples from a wide range of animal species, including vertebrate, ascidian, hemichordate, mollusc, annelid and arthropod, but not in RNAs from several cnidarian and poriferan species, Saccharomyces cerevisiae, Escherichia coli or Arabidopsis. We did not detect lin-4 RNA in these species. We found that let-7 temporal regulation is also conserved: let-7 RNA expression is first detected at late larval stages in C. elegans and Drosophila, at 48 hours after fertilization in zebrafish, and in adult stages of annelids and molluscs. The let-7 regulatory RNA may control late temporal transitions during development across animal phylogeny.

Adult↗
PubMed2000

Unusual location of a mitochondrial gene. Subunit III of cytochrome C oxidase is encoded in the nucleus of Chlamydomonad algae.

The algae of the family Chlamydomonadaceae lack the gene cox3 that encodes subunit III of cytochrome c oxidase in their mitochondrial genomes. This observation has raised the question of whether this subunit is present in cytochrome c oxidase or whether the corresponding gene is located in the nucleus. Cytochrome c oxidase was isolated from the colorless chlamydomonad Polytomella spp., and the existence of subunit III was established by immunoblotting analysis with an antibody directed against Saccharomyces cerevisiae subunit III. Based partly upon the N-terminal sequence of this subunit, oligodeoxynucleotides were designed and used for polymerase chain reaction amplification, and the resulting product was used to screen a cDNA library of Chlamydomonas reinhardtii. The complete sequences of the cox3 cDNAs from Polytomella spp. and C. reinhardtii are reported. Evidence is provided that the genes for cox3 are encoded by nuclear DNA, and the predicted polypeptides exhibit diminished physical constraints for import as compared with mitochondrial-DNA encoded homologs. This indicates that transfer of this gene to the nucleus occurred before Polytomella diverged from the photosynthetic Chlamydomonas lineage and that this transfer may have occurred in all chlamydomonad algae.

Amino Acid Sequence↗
PubMed2000

A pathogenic 15-base pair deletion in mitochondrial DNA-encoded cytochrome c oxidase subunit III results in the absence of functional cytochrome c oxidase.

A 15-base pair, in-frame, deletion (9480del15) in the mitochondrial DNA (mtDNA)-encoded cytochrome c oxidase subunit III (COX III) gene was identified previously in a patient with recurrent episodes of myoglobinuria and an isolated COX deficiency. Transmitochondrial cell lines harboring 0, 97, and 100% of the 9480del15 deletion were created by fusing human cells lacking mtDNA (rho(0) cells) with platelet and lymphocyte fractions isolated from the patient. The COX III gene mutation resulted in a severe respiratory chain defect in all mutant cell lines. Cells homoplasmic for the mutation had no detectable COX activity or respiratory ATP synthesis, and required uridine and pyruvate supplementation for growth, a phenotype similar to rho(0) cells. The cells with 97% mutated mtDNA exhibited severe reductions in both COX activity (6% of wild-type levels) and rates of ATP synthesis (9% of wild-type). The COX III polypeptide in the mutant cells, although translated at rates similar to wild-type, had reduced stability. There was no evidence for assembly of COX I, COX II, or COX III subunits in a multisubunit complex in cells homoplasmic for the mutation, thus indicating that there was no stable assembly of COX I with COX II in the absence of wild-type COX III. In contrast, the COX I and COX II subunits were assembled in cells with 97% mutated mtDNA.

DNA, Mitochondrial↗
PubMed2000

Identification of a novel antigenic domain of Plasmodium falciparum merozoite surface protein-1 that specifically binds to human erythrocytes and inhibits parasite invasion, in vitro.

Merozoite surface protein 1 (MSP-1) of Plasmodium falciparum is a promising candidate for vaccine development against malaria. Identification of protective epitopes within MSP-1 is an important step towards the elucidation of mechanisms of parasitic invasion and for the creation of a multi-subunit vaccine. In this study, we show that a 115 amino acid region (p115MSP-1) within the p38 domain of MSP-1 can: (i) specifically bind to human erythrocytes, independent of glycophorin A; (ii) inhibit parasite invasion at significant levels, in vitro; and (iii) be recognized by human sera of individuals from malaria-endemic regions of Africa. More importantly, we also show that polyclonal antibodies specific to this region prevent parasite invasion at levels approaching 90%, in vitro. Our data illustrate that not only is p115MSP-1 involved in parasite recognition/invasion of human erythrocytes, but that this region is highly antigenic, producing high titer antibodies. The delineation of the role of MSP-1 in parasite invasion is an important component of the development of a multi-subunit malaria vaccine, and this study identifies a candidate antigen in this context.

Adolescent↗
PubMed2000

Increase in pulse transit time to the foot after epidural anaesthesia treatment.

Epidurally induced anaesthetic treatment is a routine treatment for pain relief during surgical procedure, based on blocking the sensory and sympathetic fibres that mediate pain. The epidural sympathetic block results in relaxation of the muscle walls in the lower limbs, which can be assessed by the resultant haemodynamic changes. In the current study, the difference tt,f in the transit time of the blood pressure pulses between the toe and the finger is measured by photoplethysmography (PPG). Fifteen patients are administered 10 ml 0.25% of bupivacaine, ten patients are administered 10 ml 0.5%, and 17 patients are administered 40 ml 0.0625%. tt,f decreases as a function of the patient's age and blood pressure, both before and after the sympathetic block, owing to the decrease in arterial compliance with age and blood pressure. The time delay tt,f increases after the epidural treatment by 10.1+/-7.0 and by 16.8+/-10.8 ms for the 0.25% and the 0.5% concentrations, respectively. The time delay increase for the lowest concentration is not statistically significant. The toe-finger time delay change is found to reflect the haemodynamic changes induced by the sympathetic block with higher reliability than the routine methods of skin temperature or arterial blood pressure.

Adult↗
PubMed2000

Rearrangements of human mitochondrial DNA (mtDNA): new insights into the regulation of mtDNA copy number and gene expression.

Mitochondria from patients with Kearns-Sayre syndrome harboring large-scale rearrangements of human mitochondrial DNA (mtDNA; both partial deletions and a partial duplication) were introduced into human cells lacking endogenous mtDNA. Cytoplasmic hybrids containing 100% wild-type mtDNA, 100% mtDNA with partial duplications, and 100% mtDNA with partial deletions were isolated and characterized. The cell lines with 100% deleted mtDNAs exhibited a complete impairment of respiratory chain function and oxidative phosphorylation. In contrast, there were no detectable respiratory chain or protein synthesis defects in the cell lines with 100% duplicated mtDNAs. Unexpectedly, the mass of mtDNA was identical in all cell lines, despite the fact that different lines contained mtDNAs of vastly different sizes and with different numbers of replication origins, suggesting that mtDNA copy number may be regulated by tightly controlled mitochondrial dNTP pools. In addition, quantitation of mtDNA-encoded RNAs and polypeptides in these lines provided evidence that mtDNA gene copy number affects gene expression, which, in turn, is regulated at both the post-transcriptional and translational levels.

Cell Division↗
PubMed1999

Protection from Lyme neuroborreliosis in nonhuman primates with a multiantigenic vaccine.

In an effort to develop an effective and safe vaccine for lyme disease, rhesus macaques were injected with a multiantigenic preparation of Borrelia burgdorferi, strain N40. One month later animals were boosted before intradermal challenge with infectious B. burgdorferi. Challenges were performed at 1 and again at 5 months after the booster vaccination. Vaccinated and control nonvaccinated animals were monitored for development of systemic infection by measurement of serum anti-spirochetal antibodies by ELISA and Western blotting, and neurological involvement was monitored by testing of cerebrospinal fluid (CSF) and PCR analysis of central nervous system (CNS) tissue obtained at necropsy. Two control nonhuman primates (NHPs), given saline injections instead of vaccine and then challenged with B. burgdorferi, developed CSF pleocytosis, PCR positivity of the brain, and high levels of specific anti-B. burgdorferi antibody in the serum and CSF. Necropsy studies revealed widespread invasion of the CNS of one of these animals by the spirochete. In contrast, none of the four vaccinated animals developed evidence of invasion of the CNS after either of two challenge inoculations with infectious B. burgdorferi. In addition to resisting infection, no vaccinated animal demonstrated any untoward consequence of vaccination. These data demonstrate that a multiantigenic vaccine is effective in preventing systemic infection and lyme neuroboreliosis in NHPs and suggest that a successful vaccine could be developed in humans which would prevent lyme disease.

Animals↗
PubMed1998

Dietary supplementation with the inhibitory amino acid taurine suppresses autotomy in HA rats.

Taurine is an inhibitory amino acid in the CNS. When supplied to rats it produces analgesia in some acute pain tests. Here we examined the effect of taurine supplementation on sensitivity to pain in intact rats, and whether perioperative dietary supplementation with taurine in rats would suppress autotomy, a behavior produced by peripheral neurectomy and related to neuropathic pain. Thermal pain sensitivity of intact rats consuming 1% taurine in the drinking solution for 2 weeks was not significantly different from that of control rats. Autotomy levels, determined in rats consuming taurine pre-, post- or perioperatively were significantly lower than in matching control groups. We conclude that taurine plays an important role in the autotomy model, presumably by protecting inhibitory neurons in the CNS against an excitotoxic damage triggered by injury discharge and ectopic input from the severed nerves.

Administration, Oral↗