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Biomedical subjects

David Mitchell

Publications and source records attributed to David Mitchell.

At least 19 recordsLinked to original sources
PubMed2006

GC content and genome length in Chargaff compliant genomes.

Musto et al. [H. Musto, H. Naya, A. Zavala, H. Romero, F. Alvarez-Valin, G. Bernardi, Genomic GC level, optimal growth temperature, and genome size in prokaryotes, Biochem. Biophys. Res. Commun. 347 (2006) 1-3] recently reported a linear correlation between GC content and genome length. The regression model was heteroscedactic which suggested that the relationship might be more clearly defined. Alternative regression models (R(2)>0.95) were fitted to a set of over 900 sequences compliant with Chargaff's second parity rule. The new models suggest that the relationship between GC content and genome length is more complex than was originally suggested. While similar models can be derived for non-Chargaff compliant genomes, their interpretation is likely to be more difficult.

Base Composition↗
PubMed2006

An investigation of genomic base distribution.

While veritable oceans of ink have been spilled over the base distributions within genes, the literature is virtually silent on large scale intra genomic base distribution. To address this issue, we have examined approximately 3400 chromosomal sequences from approximately 2000 entire genomes-including DNA and RNA, single- and double-stranded, coding and non-coding genomes. For each sequence the mean, variance, skewness, and kurtosis for each base were computed along with the genome base composition. The main findings are: (1) there is no simple relationship between these statistics and the base composition of the genome, (2) in non-viral genomes, base distribution is non-uniform, (3) base distribution in non-eukaryotic genomes obeys a number of simple rules, (4) these rules are not dependent on the presence of coding sequences, (5) bacterial genomes in particular are unusually compliant with these rules, and (6) eukaryotes have a unique pattern of base distribution.

Base Composition↗
PubMed2006

Practical method for transforming alkynes into alpha-diketones.

[reaction: see text] Oxidation of alkynes to alpha-dicarbonyl derivatives through a convenient one-pot procedure via a Brønsted acid-promoted "hydration" and a DMSO-based oxidation sequence has been achieved in high yields. The scope and limitations of the reaction have also been investigated.

Alkynes↗
PubMed2005

A test of Chargaff's second rule.

In 1968, Chargaff and his colleagues discovered a rule in Bacillus subtilis: in single stranded DNA, A=T and C=G. This rule has since been confirmed many times in other bacterial and eukaryotic genomes. To the best of our knowledge, this rule has not been tested before in either single stranded DNA or RNA genomes. Over 3400 genomic sequences were examined here and included for the first time both double and single stranded DNA and RNA genomes. We found that: (1) with the exception of the organellar DNA, this parity rule holds for all types of double stranded DNA genomes and (2) that this rule fails to hold for other types of genomes. The parity rule appears to be a selective force on genome evolution and codon use.

Archaea↗
PubMed2005

Opportunistic screening for iron-deficiency in 6-36 month old children presenting to the Paediatric Emergency Department.

BACKGROUND: The Complete Blood Count (CBC) is a test frequently performed on children presenting to the Pediatric Emergency Department (PED), usually for the evaluation of an infectious illness. The CBC also allows for screening for Iron-deficiency Anemia. This study aims to determine the prevalence of a low Mean Cell Volume (MCV) in children having a CBC performed during a PED visit and whether physicians acted upon the abnormal value. METHODS: We present a retrospective cohort study. We reviewed the PED charts of all children 6-36 months of age who had a CBC performed during a 4-month period and the red blood cell mean cell volume was low. Our main outcome variable was whether or not the possible iron deficiency was addressed through documentation of either iron therapy or further investigation. RESULTS: 938 children had a CBC performed during the two periods. Of these, 78 (8%) had an abnormal MCV or Hemoglobin with no previously identified explanation. Physicians documented either treatment or follow-up investigations in 27 cases (35%, 95% CI: 24-46%). Factors associated with the physician documenting either treatment or investigation plan were the following: hemoglobin level (OR 12.6; 95%CI: 4.0, 39) and age < or = 18 months (OR 4.2; 95%CI: 1.4, 13). CONCLUSION: Children who have had a CBC in the PED can be screened for iron deficiency at no additional cost. Physicians may be under-utilizing this information.

Anemia, Iron-Deficiency↗
PubMed2005

Quantitative high-throughput measurement of gene expression with sub-zeptomole sensitivity by capillary electrophoresis.

Microarray technologies have provided the ability to monitor the expression of whole genomes rapidly. However, concerns persist with regard to quantitation and reproducibility, and the detection limits for individual genes in particular arrays are generally unknown. This article describes a semiautomated PCR-based technology, Q-RAGE, which rapidly provides measurements of mRNA abundance with extremely high sensitivity using fluorescent detection of specific products separated by capillary electrophoresis. A linear relationship between template concentration and fluorescent signal can be demonstrated down to template concentrations in the low aM region, corresponding to approximately 0.04 zmol (24 molecules) per reaction. The technique is shown to be quantitative over five orders of magnitude of template concentration, and average mRNA abundances of approximately 0.01 molecule per cell can be detected. A single predefined set of 320 primers provides 90-95% coverage of all eukaryotic genomes. Analysis of a set of 19 p53-regulated genes in untreated cultures of normal human epithelial cells, derived from three different tissues, revealed a 600-fold range of apparent constitutive expression levels. For most of the genes assayed, good correlations were observed among the expression levels in normal mammary, bronchial, and epidermal epithelial cells.

Bronchi↗
PubMed2005

Complete DiGeorge anomaly in the absence of neonatal hypocalcemia and velofacial and cardiac defects.

We report an atypical case of complete DiGeorge (DG) anomaly that presented initially exclusively as severe combined immunodeficiency (SCID). The child had severe infections at diagnosis, in keeping with the SCID phenotype; however, normal lymphocyte counts and immunoglobulin levels were noted at admission, which delayed diagnosis. Importantly, the child presented without neonatal hypocalcemia or velofacial or cardiac abnormalities at the time of diagnosis, which masked underlying DG. This case outlines the difficulties in making the diagnosis of SCID in a timely manner and illustrates the variation in presentation of the 22q11.2 deletion syndrome. There should be a high index of suspicion for primary immunodeficiency among children with severe infections and, because management may vary, DG anomaly should be considered in the differential diagnosis of T- B+ natural killer+ SCID.

DiGeorge Syndrome↗
PubMed2005

Damage and repair of ancient DNA.

Under certain conditions small amounts of DNA can survive for long periods of time and can be used as polymerase chain reaction (PCR) substrates for the study of phylogenetic relationships and population genetics of extinct plants and animals, including hominids. Because of extensive DNA degradation, these studies are limited to species that lived within the past 10(4)-10(5) years (Late Pleistocene), although DNA sequences from 10(6) years have been reported. Ancient DNA (aDNA) has been used to study phylogenetic relationships of protists, fungi, algae, plants, and higher eukaryotes such as extinct horses, cave bears, the marsupial wolf, the moa, and Neanderthal. In the past few years, this technology has been extended to the study of infectious disease in ancient Egyptian and South American mummies, the dietary habits of ancient animals, and agricultural practices and population dynamics of early native Americans. Hence, ancient DNA contains information pertinent to numerous fields of study including evolution, population genetics, ecology, climatology, medicine, archeology, and behavior. The major obstacles to the study of aDNA are its extremely low yield, contamination with modern DNA, and extensive degradation. In the course of this review, we will discuss the current aDNA literature describing the importance of aDNA studies as they relate to important biological questions and the difficulties associated with extracting useful information from highly degraded and damaged substrates derived from limited sources. In addition, we will present some of our own preliminary and published data on mechanisms of DNA degradation and some speculative thoughts on strategies for repair and restoration of aDNA.

DNA↗
PubMed2004

Reduction in organic contaminant exposure and resultant hepatic hydropic vacuolation in winter flounder (Pseudopleuronectes americanus) following improved effluent quality and relocation of the Boston sewage outfall into Massachusetts Bay, USA: 1987-2003.

Effluent upgrades for metropolitan Boston have included toxicant reduction, primary and secondary treatment and outfall extension. Between 1992 and 2003 winter flounder at five stations were surveyed annually for liver and muscle burden and chronic hepatic sub-lethal impacts of polynuclear and halogenated aromatic hydrocarbons, and metals. Trends in flounder availability and fin condition were also examined. In 1988 12% of the adult winter flounder in Boston Harbor exhibited hepatic neoplasms and up to 80% had hepatic hydropic vacuolation (HV). Tumor prevalence fell to 0-2% and HV to <50% by 1996. Since then tumors have been absent, while a steady prevalence of HV has persisted, consistent with lower hydrocarbon loading and tissue levels. Contaminants and HV also fell with distance from the Boston outfall. After the outfall extension was activated in 2000, there has been no significant change in flounder liver health at the new outfall site.

Animals↗
PubMed2004

In vitro and in vivo metabolism of the anti-cancer agent CI-1040, a MEK inhibitor, in rat, monkey, and human.

PURPOSE: The use of in vitro and in vivo models using both rodent and non-rodent species plays an important role with regard to metabolism during the drug development process. In this study, we compared the metabolism of a MEK inhibitor (CI-1040) using in vitro and in vivo models with that observed in a cancer patient. METHODS: Radiolabeled CI-1040 was assessed for metabolism using rat and monkey liver microsomes and hepatocytes, as well as in Wistar rats and cynomolgus monkeys via oral administration. Human bile and plasma samples were obtained immediately after administration of CI-1040 to a patient with advanced colon cancer. A combination of HPLC-radiochromatography (HPLC-RAM), LC/MS and LC/MS/MS experiments were used to analyze all resulting metabolites. Unlabeled CI-1040 was administered (100 mg/day, QD) for 15 days to a patient suffering from colon cancer. Bile was collected by the insertion of a T-tube directly into the bile duct over a 14-h period. Metabolites were also monitored in the patient's plasma. RESULTS: Analysis of the metabolites in all species using in vitro and animal models demonstrated that CI-1040 undergoes extensive oxidative metabolism (14 metabolites identified) with subsequent glucuronidation of the hydroxylated metabolites. Metabolites were predominantly excreted through the bile in the animal models. CONCLUSIONS: Overall, the in vitro and animal models in combination provided comprehensive coverage for all metabolites observed in human bile and plasma. In conclusion, the results obtained in this study demonstrate the utility of conducting investigations across species in order to gain complete coverage for successfully predicting human metabolites of new compounds in development.

Aged↗
PubMed2004

A competency model for the assessment and delivery of spiritual care.

The delivery of spiritual and religious care has received a high profile in national reports, guidelines and standards since the start of the millennium, yet there is, to date, no recognized definition of spirituality or spiritual care nor a validated assessment tool. This article suggests an alternative to the search for a definition and assessment tool, and seeks to set spiritual care in a practical context by offering a model for spiritual assessment and care based on the individual competence of all healthcare professionals to deliver spiritual and religious care. Through the evaluation of a pilot study to familiarize staff with the Spiritual and Religious Care Competencies for Specialist Palliative Care developed by Marie Curie Cancer Care, the authors conclude that competencies are a viable and crucial first step in 'earthing' spiritual care in practice, and evidencing this illusive area of care.

Attitude of Health Personnel↗
PubMed2003

PEST sequences in the malaria parasite Plasmodium falciparum: a genomic study.

BACKGROUND: Inhibitors of the protease calpain are known to have selectively toxic effects on Plasmodium falciparum. The enzyme has a natural inhibitor calpastatin and in eukaryotes is responsible for turnover of proteins containing short sequences enriched in certain amino acids (PEST sequences). The genome of P. falciparum was searched for this protease, its natural inhibitor and putative substrates. METHODS: The publicly available P. falciparum genome was found to have too many errors to permit reliable analysis. An earlier annotation of chromosome 2 was instead examined. PEST scores were determined for all annotated proteins. The published genome was searched for calpain and calpastatin homologs. RESULTS: Typical PEST sequences were found in 13% of the proteins on chromosome 2, including a surprising number of cell-surface proteins. The annotated calpain gene has a non-biological "intron" that appears to have been created to avoid an unrecognized frameshift. Only the catalytic domain has significant similarity with the vertebrate calpains. No calpastatin homologs were found in the published annotation. CONCLUSION: A calpain gene is present in the genome and many putative substrates of this enzyme have been found. Calpastatin homologs may be found once the re-annotation is completed. Given the selective toxicity of calpain inhibitors, this enzyme may be worth exploring further as a potential drug target.

Amino Acid Sequence↗
PubMed2003

Application of the Dakin-West reaction for the synthesis of oxazole-containing dual PPARalpha/gamma agonists.

An improved method for the preparation of a series of oxazole-containing dual PPARalpha/gamma agonists is described. A synthetic sequence utilizing a Dakin-West reaction was devised that allows for the introduction of the oxazole ring either late in the synthetic sequence via aminomalonate-derived chemistry or in pivotal SAR intermediates derived from aspartic acid.

Aspartic Acid↗