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Biomedical subjects

David Saunders

Publications and source records attributed to David Saunders.

16 recordsLinked to original sources
PubMed2006

Common inheritance of chromosome Ia associated with clonal expansion of Toxoplasma gondii.

Toxoplasma gondii is a globally distributed protozoan parasite that can infect virtually all warm-blooded animals and humans. Despite the existence of a sexual phase in the life cycle, T. gondii has an unusual population structure dominated by three clonal lineages that predominate in North America and Europe, (Types I, II, and III). These lineages were founded by common ancestors approximately10,000 yr ago. The recent origin and widespread distribution of the clonal lineages is attributed to the circumvention of the sexual cycle by a new mode of transmission-asexual transmission between intermediate hosts. Asexual transmission appears to be multigenic and although the specific genes mediating this trait are unknown, it is predicted that all members of the clonal lineages should share the same alleles. Genetic mapping studies suggested that chromosome Ia was unusually monomorphic compared with the rest of the genome. To investigate this further, we sequenced chromosome Ia and chromosome Ib in the Type I strain, RH, and the Type II strain, ME49. Comparative genome analyses of the two chromosomal sequences revealed that the same copy of chromosome Ia was inherited in each lineage, whereas chromosome Ib maintained the same high frequency of between-strain polymorphism as the rest of the genome. Sampling of chromosome Ia sequence in seven additional representative strains from the three clonal lineages supports a monomorphic inheritance, which is unique within the genome. Taken together, our observations implicate a specific combination of alleles on chromosome Ia in the recent origin and widespread success of the clonal lineages of T. gondii.

Animals↗
PubMed2006

Phase resetting and coupling of noisy neural oscillators.

A number of experimental groups have recently computed Phase Response Curves (PRCs) for neurons. There is a great deal of noise in the data. We apply methods from stochastic nonlinear dynamics to coupled noisy phase-resetting maps and obtain the invariant density of phase distributions. By exploiting the special structure of PRCs, we obtain some approximations for the invariant distributions. Comparisons to Monte-Carlo simulations are made. We show how phase-dependence of the noise can move the peak of the invariant density away from the peak expected from the analysis of the deterministic system and thus lead to noise-induced bifurcations.

Action Potentials↗
PubMed2006

Genetic analysis of the capsular biosynthetic locus from all 90 pneumococcal serotypes.

Several major invasive bacterial pathogens are encapsulated. Expression of a polysaccharide capsule is essential for survival in the blood, and thus for virulence, but also is a target for host antibodies and the basis for effective vaccines. Encapsulated species typically exhibit antigenic variation and express one of a number of immunochemically distinct capsular polysaccharides that define serotypes. We provide the sequences of the capsular biosynthetic genes of all 90 serotypes of Streptococcus pneumoniae and relate these to the known polysaccharide structures and patterns of immunological reactivity of typing sera, thereby providing the most complete understanding of the genetics and origins of bacterial polysaccharide diversity, laying the foundations for molecular serotyping. This is the first time, to our knowledge, that a complete repertoire of capsular biosynthetic genes has been available, enabling a holistic analysis of a bacterial polysaccharide biosynthesis system. Remarkably, the total size of alternative coding DNA at this one locus exceeds 1.8 Mbp, almost equivalent to the entire S. pneumoniae chromosomal complement.

Bacterial Capsules↗
PubMed2006

Prospective longitudinal proton magnetic resonance spectroscopic imaging in adult traumatic brain injury.

PURPOSE: To investigate whether longitudinal magnetic resonance proton spectroscopic imaging (MRSI) demonstrates regional metabolite abnormalities after traumatic brain injury (TBI) that predict long-term neurologic outcome. MATERIALS AND METHODS: Two-dimensional-MRSI (point resolved spectroscopy sequence [PRESS]; TR/TE = 3000/144 msec; 10 mm) was acquired prospectively in 42 adults with severe TBI through the level of the corpus callosum 7 +/- 4 days after injury. Measurements were repeated in 31 patients six to 12 months after injury. Regional and pooled (all regions combined) mean ratios were compared with control values and then used to predict long-term (six- to -12-month) neurologic outcome (good vs. poor) using a logistic regression model. RESULTS: Initial pooled mean N-acetylaspartate (NAA) ratios were lower (P < 0.01) and choline (Cho)/creatine (Cr) ratios higher (P < 0.01) in all TBI patients compared to controls. Ratios from the corpus callosum region were affected most and predicted long-term dichotomized outcome with 83% accuracy. When repeated at six to 12 months after injury, pooled mean NAA/Cr remained lower (P = 0.03) and Cho/Cr remained higher (P = 0.01) in patients with poor outcomes. CONCLUSION: The NAA/Cr ratio from the corpus callosum was most useful for outcome prediction. Chronic alterations of metabolite ratios are likely due to neuronal loss and glial proliferation long after injury.

Adolescent↗
PubMed2006

Substance abuse and dependence in anaesthetists.

The incidence of substance abuse amongst anaesthetists in the United Kingdom is unknown. In the interests of patient safety, it is essential that the dependent doctor is identified and entered into a treatment regime. No national strategy is in place to treat and, where possible, return the anaesthetist in recovery to work. It is important therefore, that individual employers have a standing operating procedure to deal with the addicted doctor. It is essential that the initial approach is made by a competent panel, each of whom has experience of dealing with dependent doctors. This is an extremely stressful time for the doctor involved; it is therefore essential that active support is given. It is not always necessary to suspend the doctor from work whilst treatment is undertaken. In the dependent doctor sudden withdrawal of the substance of addiction can be life-threatening. It is therefore essential that the supervising physician has specialist knowledge of the treatment of addiction. Residential care probably provides the greatest hope of success. In the United States, Canada, Australia and New Zealand 'impaired physician' programmes are in place which allow some doctors to return to work, initially under strict supervision. Registration with a self-help organisation is essential; a list of such groups in the United Kingdom is appended.

Anesthesiology↗
PubMed2006

The older anaesthetist.

It is not possible to generalise about the way in which increasing years affect the performance of an individual anaesthetist. Physical and mental deterioration occurs as we age; most anaesthetists will be able to reach the normal retirement age of 65 years without that deterioration affecting their clinical practice. In some, however, decreasing competence and an unwillingness to embrace a continuing education regime may offer a direct threat to patient safety. Stress and 'burnout' are common in anesthetists; clinical depression can often be one of the factors involved. Continuing involvement in the on-call rota is a potent stressor. Airline pilots are required to retire at 60 years; the feasibility and desirability of applying this process to anaesthetists are discussed. Employers have a duty to provide employees with adequate and achievable demands in relation to their agreed hours of work and to have in place policies and procedures to offer adequate support.

Aged↗
PubMed2006

Neuraxial drug administration: a review of treatment options for anaesthesia and analgesia.

Neuraxial drug administration describes techniques that deliver drugs in close proximity to the spinal cord, i.e. intrathecally into the CSF or epidurally into the fatty tissues surrounding the dura, by injection or infusion. This approach was initially developed in the form of spinal anaesthesia over 100 years ago. Since then, neuraxial drug administration has evolved and now includes a wide range of techniques to administer a large number of different drugs to provide anaesthesia, but also analgesia and treatment of spasticity in a variety of acute and chronic settings. This review concentrates on the pharmacological agents used and the clinical basis behind currently utilised approaches to neuraxial drug administration. With regard to local anaesthetics, the main focus is on the development of the enantiomer-specific compounds ropivacaine and levobupivacaine, which provide similar efficacy to bupivacaine with a reduced risk of severe cardiotoxicity. Opioids are the other group of drugs widely used neuraxially, in particular to provide analgesia alone or more commonly in combination with other agents. The physicochemical properties of the various opioids explain the main differences in efficacy and safety between these drugs when used intrathecally, of which morphine, fentanyl and sufentanil are most commonly used. Another group of drugs including clonidine, dexmedetomidine and epinephrine (adrenaline) provide neuraxial analgesia via alpha-adrenergic receptors and are used mainly as adjuvants to local anaesthetics and opioids. Furthermore, intrathecal baclofen is in routine clinical use to treat spasticity in a number of neurological conditions. Beside these established approaches, a wide range of other drugs have been assessed for neuraxial administration to provide analgesia; however, most are in various early stages of investigation and are not used routinely. These drugs include neostigmine, ketamine, midazolam and adenosine, and the conotoxin ziconotide. The latter is possibly the most unusual compound here; it has recently gained registration for intrathecal use in specific chronic pain conditions.

Adrenergic alpha-2 Receptor Agonists↗
PubMed2005

Genomic sequence of the pathogenic and allergenic filamentous fungus Aspergillus fumigatus.

Aspergillus fumigatus is exceptional among microorganisms in being both a primary and opportunistic pathogen as well as a major allergen. Its conidia production is prolific, and so human respiratory tract exposure is almost constant. A. fumigatus is isolated from human habitats and vegetable compost heaps. In immunocompromised individuals, the incidence of invasive infection can be as high as 50% and the mortality rate is often about 50% (ref. 2). The interaction of A. fumigatus and other airborne fungi with the immune system is increasingly linked to severe asthma and sinusitis. Although the burden of invasive disease caused by A. fumigatus is substantial, the basic biology of the organism is mostly obscure. Here we show the complete 29.4-megabase genome sequence of the clinical isolate Af293, which consists of eight chromosomes containing 9,926 predicted genes. Microarray analysis revealed temperature-dependent expression of distinct sets of genes, as well as 700 A. fumigatus genes not present or significantly diverged in the closely related sexual species Neosartorya fischeri, many of which may have roles in the pathogenicity phenotype. The Af293 genome sequence provides an unparalleled resource for the future understanding of this remarkable fungus.

Allergens↗
PubMed2005

Mitochondrial DNA and survival after sepsis: a prospective study.

BACKGROUND: Human genome evolution has been shaped by infectious disease. Although most genetic studies have focused on the immune system, recovery after sepsis is directly related to physiological reserve that is critically dependent on mitochondrial function. We investigated whether haplogroup H, the most common type of mitochondrial DNA (mtDNA) in Europe, contributes to the subtle genetic variation in survival after sepsis. METHODS: In a prospective study, we included 150 individuals who were sequentially admitted to the intensive care unit in a hospital in Newcastle upon Tyne, UK. After clinical data were obtained, patients underwent mtDNA haplotyping by analysis with PCR and restriction fragment length polymorphism. As endpoints, we used death during the 6-month period or survival at 6 months. FINDINGS: Follow-up was complete for all study participants, although the haplotype of two patients could not be reliably determined. On admission to the intensive care unit, the frequency of mtDNA haplogroup H in study patients did not differ between study patients admitted with severe sepsis and 542 age-matched controls from the northeast of England. MtDNA haplogroup H was a strong independent predictor of outcome during severe sepsis, conferring a 2.12-fold (95% CI 1.02-4.43) increased chance of survival at 180 days compared with individuals without the haplogroup H. INTERPRETATION: Although haplogroup H is the most recent addition to the group of European mtDNA, paradoxically it is also the most common. Increased survival after sepsis provides one explanation for this observation. MtDNA haplotyping offers a new means of risk stratification of patients with severe infections, which suggests new avenues for therapeutic intervention.

APACHE↗
PubMed2005

The genome of the kinetoplastid parasite, Leishmania major.

Leishmania species cause a spectrum of human diseases in tropical and subtropical regions of the world. We have sequenced the 36 chromosomes of the 32.8-megabase haploid genome of Leishmania major (Friedlin strain) and predict 911 RNA genes, 39 pseudogenes, and 8272 protein-coding genes, of which 36% can be ascribed a putative function. These include genes involved in host-pathogen interactions, such as proteolytic enzymes, and extensive machinery for synthesis of complex surface glycoconjugates. The organization of protein-coding genes into long, strand-specific, polycistronic clusters and lack of general transcription factors in the L. major, Trypanosoma brucei, and Trypanosoma cruzi (Tritryp) genomes suggest that the mechanisms regulating RNA polymerase II-directed transcription are distinct from those operating in other eukaryotes, although the trypanosomatids appear capable of chromatin remodeling. Abundant RNA-binding proteins are encoded in the Tritryp genomes, consistent with active posttranscriptional regulation of gene expression.

Animals↗
PubMed2005

Genome of the host-cell transforming parasite Theileria annulata compared with T. parva.

Theileria annulata and T. parva are closely related protozoan parasites that cause lymphoproliferative diseases of cattle. We sequenced the genome of T. annulata and compared it with that of T. parva to understand the mechanisms underlying transformation and tropism. Despite high conservation of gene sequences and synteny, the analysis reveals unequally expanded gene families and species-specific genes. We also identify divergent families of putative secreted polypeptides that may reduce immune recognition, candidate regulators of host-cell transformation, and a Theileria-specific protein domain [frequently associated in Theileria (FAINT)] present in a large number of secreted proteins.

Amino Acid Motifs↗
PubMed2004

Insight into the genome of Aspergillus fumigatus: analysis of a 922 kb region encompassing the nitrate assimilation gene cluster.

Aspergillus fumigatus is the most ubiquitous opportunistic filamentous fungal pathogen of human. As an initial step toward sequencing the entire genome of A. fumigatus, which is estimated to be approximately 30 Mb in size, we have sequenced a 922 kb region, contained within 16 overlapping bacterial artificial chromosome (BAC) clones. Fifty-four percent of the DNA is predicted to be coding with 341 putative protein coding genes. Functional classification of the proteins showed the presence of a higher proportion of enzymes and membrane transporters when compared to those of Saccharomyces cerevisiae. In addition to the nitrate assimilation gene cluster, the quinate utilisation gene cluster is also present on this 922 kb genomic sequence. We observed large scale synteny between A. fumigatus and Aspergillus nidulans by comparing this sequence to the A. nidulans genetic map of linkage group VIII.

Aspergillus fumigatus↗
PubMed2004

Orbital cellulitis after phacoemulsification and intraocular lens implantation.

We report a case of orbital cellulitis after uneventful phacoemulsification and intraocular lens implantation under peribulbar injection. The eyelid skin was prepared with chlorhexidine gluconate before the peribulbar injection, and the eyelid and conjunctival cul-de-sac were prepared with povidone-iodine before phacoemulsification. Five days postoperatively, the patient presented with reduced visual acuity and lid swelling. Ocular examination showed signs of orbital cellulitis, which was confirmed by a computed tomography scan. Oral erythromycin and metronidazole were given, after which the symptoms improved with successful outcomes.

Anti-Infective Agents↗
PubMed2003

Comparative analysis of the genome sequences of Bordetella pertussis, Bordetella parapertussis and Bordetella bronchiseptica.

Bordetella pertussis, Bordetella parapertussis and Bordetella bronchiseptica are closely related Gram-negative beta-proteobacteria that colonize the respiratory tracts of mammals. B. pertussis is a strict human pathogen of recent evolutionary origin and is the primary etiologic agent of whooping cough. B. parapertussis can also cause whooping cough, and B. bronchiseptica causes chronic respiratory infections in a wide range of animals. We sequenced the genomes of B. bronchiseptica RB50 (5,338,400 bp; 5,007 predicted genes), B. parapertussis 12822 (4,773,551 bp; 4,404 genes) and B. pertussis Tohama I (4,086,186 bp; 3,816 genes). Our analysis indicates that B. parapertussis and B. pertussis are independent derivatives of B. bronchiseptica-like ancestors. During the evolution of these two host-restricted species there was large-scale gene loss and inactivation; host adaptation seems to be a consequence of loss, not gain, of function, and differences in virulence may be related to loss of regulatory or control functions.

Base Sequence↗