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Biomedical subjects

David Richardson

Publications and source records attributed to David Richardson.

At least 19 recordsLinked to original sources
PubMed2006

Mutation analysis of 24 known cancer genes in the NCI-60 cell line set.

The panel of 60 human cancer cell lines (the NCI-60) assembled by the National Cancer Institute for anticancer drug discovery is a widely used resource. The NCI-60 has been characterized pharmacologically and at the molecular level more extensively than any other set of cell lines. However, no systematic mutation analysis of genes causally implicated in oncogenesis has been reported. This study reports the sequence analysis of 24 known cancer genes in the NCI-60 and an assessment of 4 of the 24 genes for homozygous deletions. One hundred thirty-seven oncogenic mutations were identified in 14 (APC, BRAF, CDKN2, CTNNB1, HRAS, KRAS, NRAS, SMAD4, PIK3CA, PTEN, RB1, STK11, TP53, and VHL) of the 24 genes. All lines have at least one mutation among the cancer genes examined, with most lines (73%) having more than one. Identification of those cancer genes mutated in the NCI-60, in combination with pharmacologic and molecular profiles of the cells, will allow for more informed interpretation of anticancer agent screening and will enhance the use of the NCI-60 cell lines for molecularly targeted screens.

Cell Line, Tumor↗
PubMed2006

Mutations in the gene encoding the Sigma 2 subunit of the adaptor protein 1 complex, AP1S2, cause X-linked mental retardation.

In a systematic sequencing screen of the coding exons of the X chromosome in 250 families with X-linked mental retardation (XLMR), we identified two nonsense mutations and one consensus splice-site mutation in the AP1S2 gene on Xp22 in three families. Affected individuals in these families showed mild-to-profound mental retardation. Other features included hypotonia early in life and delay in walking. AP1S2 encodes an adaptin protein that constitutes part of the adaptor protein complex found at the cytoplasmic face of coated vesicles located at the Golgi complex. The complex mediates the recruitment of clathrin to the vesicle membrane. Aberrant endocytic processing through disruption of adaptor protein complexes is likely to result from the AP1S2 mutations identified in the three XLMR-affected families, and such defects may plausibly cause abnormal synaptic development and function. AP1S2 is the first reported XLMR gene that encodes a protein directly involved in the assembly of endocytic vesicles.

Adaptor Protein Complex sigma Subunits↗
PubMed2006

A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy.

Malignant gliomas have a very poor prognosis. The current standard of care for these cancers consists of extended adjuvant treatment with the alkylating agent temozolomide after surgical resection and radiotherapy. Although a statistically significant increase in survival has been reported with this regimen, nearly all gliomas recur and become insensitive to further treatment with this class of agents. We sequenced 500 kb of genomic DNA corresponding to the kinase domains of 518 protein kinases in each of nine gliomas. Large numbers of somatic mutations were observed in two gliomas recurrent after alkylating agent treatment. The pattern of mutations in these cases showed strong similarity to that induced by alkylating agents in experimental systems. Further investigation revealed inactivating somatic mutations of the mismatch repair gene MSH6 in each case. We propose that inactivating somatic mutations of MSH6 confer resistance to alkylating agents in gliomas in vivo and concurrently unleash accelerated mutagenesis in resistant clones as a consequence of continued exposure to alkylating agents in the presence of defective mismatch repair. The evidence therefore suggests that when MSH6 is inactivated in gliomas, alkylating agents convert from induction of tumor cell death to promotion of neoplastic progression. These observations highlight the potential of large scale sequencing for revealing and elucidating mutagenic processes operative in individual human cancers.

Aged↗
PubMed2006

Location and removal of non-palpable Implanon implants with the aid of ultrasound guidance.

BACKGROUND: Implanon insertion appears to be an easy procedure, but in a small minority of cases difficulties have been encountered with removal if the rod is impalpable. METHODS: Patients were referred to the contraceptive and sexual health service with non-palpable Implanon. Following a clinical assessment and examination of the arm where the implant had been inserted, an ultrasound examination was carried out to identify and locate the implant. These implants were subsequently removed, some under general anaesthesia and others under local anaesthesia. RESULTS: Twenty-seven patients were referred to the unit with impalpable Implanon rods. In four cases the rods were palpable and were removed in the clinic setting without the need for further intervention. Positive identification of the implants was achieved in 21 of the remaining 23 cases using ultrasound. No implant was detected in two cases and etonogestrel was not demonstrated serologically in either woman, suggesting non-insertion. All 21 Implanon rods identified by ultrasound were successfully removed. In just over 52% of women a previous attempt at removal had been undertaken prior to referral. CONCLUSIONS: It is possible to identify and locate impalpable Implanon rods with the aid of ultrasound, facilitating their subsequent safe removal. Although previous reports have identified the position of 'lost' implants using ultrasound, this is the first case series to discuss measuring the skin/implant depth. This parameter, together with the precise position of the implant (in muscle or fat), aids removal. All health professionals inserting and removing contraceptive implants should have been appropriately trained.

Adult↗
PubMed2005

Nitrate reduction by Desulfovibrio desulfuricans: a periplasmic nitrate reductase system that lacks NapB, but includes a unique tetraheme c-type cytochrome, NapM.

Many sulphate reducing bacteria can also reduce nitrite, but relatively few isolates are known to reduce nitrate. Although nitrate reductase genes are absent from Desulfovibrio vulgaris strain Hildenborough, for which the complete genome sequence has been reported, a single subunit periplasmic nitrate reductase, NapA, was purified from Desulfovibrio desulfuricans strain 27774, and the structural gene was cloned and sequenced. Chromosome walking methods have now been used to determine the complete sequence of the nap gene cluster from this organism. The data confirm the absence of a napB homologue, but reveal a novel six-gene organisation, napC-napM-napA-napD-napG-napH. The NapC polypeptide is more similar to the NrfH subgroup of tetraheme cytochromes than to NapC from other bacteria. NapM is predicted to be a tetra-heme c-type cytochrome with similarity to the small tetraheme cytochromes from Shewanella oneidensis. The operon is located close to a gene encoding a lysyl-tRNA synthetase that is also found in D. vulgaris. We suggest that electrons might be transferred to NapA either from menaquinol via NapC, or from other electron donors such as formate or hydrogen via the small tetraheme cytochrome, NapM. We also suggest that, despite the absence of a twin-arginine targeting sequence, NapG might be located in the periplasm where it would provide an alternative direct electron donor to NapA.

Amino Acid Sequence↗
PubMed2005

A practitioner-focused approach to the provision of psychological support in soccer: adopting action research themes and processes.

In this review, we explore a practitioner-focused approach to the provision of psychological support in soccer. Support is depicted to be a collaborative exercise and is associated with action research themes and processes. Various procedures and perspectives that are associated with action research are outlined. The ideas presented suggest that many soccer-based practitioners (coaches, managers and physiotherapists) have the capacity to influence how sport psychology practice might be experienced by players. The sport scientist is depicted here as someone who acts as a critical friend to those practitioners who are interested in developing aspects of their own working practice. Having established these ideas, the review provides an illustration of how a combination of action research themes and qualitative research techniques has been used to influence and support heads of education and welfare in UK soccer academies across the north-west of England.

Focus Groups↗
PubMed2005

Molecular epidemiology of simian T-cell lymphotropic virus type 1 in wild and captive sooty mangabeys.

A study was conducted to evaluate the prevalence and diversity of simian T-cell lymphotropic virus (STLV) isolates within the long-established Tulane National Primate Research Center (TNPRC) colony of sooty mangabeys (SMs; Cercocebus atys). Serological analysis determined that 22 of 39 animals (56%) were positive for STLV type 1 (STLV-1). A second group of thirteen SM bush meat samples from Sierra Leone in Africa was also included and tested only by PCR. Twenty-two of 39 captive animals (56%) and 3 of 13 bush meat samples (23%) were positive for STLV-1, as shown by testing with PCR. Nucleotide sequencing and phylogenetic analysis of viral strains obtained demonstrated that STLV-1 strains from SMs (STLV-1sm strains) from the TNPRC colony and Sierra Leone formed a single cluster together with the previously reported STLV-1sm strain from the Yerkes National Primate Research Center. These data confirm that Africa is the origin for TNPRC STLV-1sm and suggest that Sierra Leone is the origin for the SM colonies in the United States. The TNPRC STLV-1sm strains further divided into two subclusters, suggesting STLV-1sm infection of two original founder SMs at the time of their importation into the United States. STLV-1sm diversity in the TNPRC colony matches the high diversity of SIVsm in the already reported colony. The lack of correlation between the lineage of the simian immunodeficiency virus from SMs (SIVsm) and the STLV-1sm subcluster distribution of the TNPRC strains suggests that intracolony transmissions of both viruses were independent events.

Animals↗
PubMed2005

Detection and partial characterization of simian immunodeficiency virus SIVsm strains from bush meat samples from rural Sierra Leone.

Human immunodeficiency virus type 2 (HIV-2) originated from simian immunodeficiency viruses (SIVs) that naturally infect sooty mangabeys (SMs; Cercocebus atys). In order to further investigate the relationship between HIV-2 and SIVsm, the SIV specific to the SM, we characterized seven new SIVsm strains from SMs sold in Sierra Leone markets as bush meat. The gag, pol, and env sequences showed that, while the viruses of all seven SMs belonged to the SIVsm-HIV-2 lineage, they were highly divergent viruses, in spite of the fact that most of the samples originated from the same geographical region. They clustered in three lineages, two of which have been previously reported. Two of the new SIVsm strains clustered differently in gag and env phylogenetic trees, suggesting SIVsm recombination that had occurred in the past. In spite of the fact that our study doubles the number of known SIVsm strains from wild SMs, none of the simian strains were close to the groups in which HIV-2 was epidemic (groups A and B).

Animals↗
PubMed2005

Management of craniofacial abnormalities.

A number of congenital and acquired conditions can affect the skull, face and jaws resulting in a wide range of craniofacial abnormalites that commonly present at birth or in early infancy. This article aims to outline the aetiology, pathogenesis, diagnosis and principles of management of those conditions that commonly present to a craniofacial unit namely the craniosynostoses.

Adolescent↗
PubMed2004

Plutonium-related work and cause-specific mortality at the United States Department of Energy Hanford Site.

BACKGROUND: Health effects of working with plutonium remain unclear. Plutonium workers at the United States Department of Energy (US-DOE) Hanford Site in Washington State, USA were evaluated for increased risks of cancer and non-cancer mortality. METHODS: Periods of employment in jobs with routine or non-routine potential for plutonium exposure were identified for 26,389 workers hired between 1944 and 1978. Life table regression was used to examine associations of length of employment in plutonium jobs with confirmed plutonium deposition and with cause specific mortality through 1994. RESULTS: Incidence of confirmed internal plutonium deposition in all plutonium workers was 15.4 times greater than in other Hanford jobs. Plutonium workers had low death rates compared to other workers, particularly for cancer causes. Mortality for several causes was positively associated with length of employment in routine plutonium jobs, especially for employment at older ages. At ages 50 and above, death rates for non-external causes of death, all cancers, cancers of tissues where plutonium deposits, and lung cancer, increased 2.0 +/- 1.1%, 2.6 +/- 2.0%, 4.9 +/- 3.3%, and 7.1 +/- 3.4% (+/-SE) per year of employment in routine plutonium jobs, respectively. CONCLUSIONS: Workers employed in jobs with routine potential for plutonium exposure have low mortality rates compared to other Hanford workers even with adjustment for demographic, socioeconomic, and employment factors. This may be due, in part, to medical screening. Associations between duration of employment in jobs with routine potential for plutonium exposure and mortality may indicate occupational exposure effects.

Adult↗
PubMed2004

The effect of rate denominator source on US fatal occupational injury rate estimates.

BACKGROUND: The Current Population Survey (CPS) is often used as a source of denominator information for analyses of US fatal occupational injury rates. However, given the relatively small sample size of the CPS, analyses that examine the cross-classification of occupation or industry with demographic or geographic characteristics will often produce highly imprecise rate estimates. The Decennial Census of Population provides an alternative source for rate denominator information. We investigate the comparability of fatal injury rates derived using these two sources of rate denominator information. METHODS: Information on fatal occupational injuries that occurred between January 1, 1983 and December 31, 1994 was obtained from the National Traumatic Occupational Fatality surveillance system. Annual estimates of employment by occupation, industry, age, and sex were derived from the CPS, and by linear interpolation and extrapolation from the 1980 and 1990 Census of Population. Fatal injury rates derived using these denominator data were compared. RESULTS: Fatal injury rates calculated using Census-based denominator data were within 10% of rates calculated using CPS data for all major occupation groups except farming/forestry/fishing, for which the fatal injury rate calculated using Census-based denominator data was 24.69/100,000 worker-years and the rate calculated using CPS data was 19.97/100,000 worker-years. The choice of denominator data source had minimal influence on estimates of trends over calendar time in the fatal injury rates for most major occupation and industry groups. CONCLUSIONS: The Census offers a reasonable source for deriving fatal injury rate denominator data in situations where the CPS does not provide sufficiently precise data, although the Census may underestimate the population-at-risk in some industries as a consequence of seasonal variation in employment.

Accidents, Occupational↗
PubMed2004

Effects of data limitations when modeling fatal occupational injury rates.

BACKGROUND: Occupational fatal injury rate studies are often based upon uncertain and variable data. The numerator in rate calculations is often obtained from surveillance systems that can understate the true number of deaths. Worker-years, the denominator in many occupational rate calculations, are frequently estimated from sources that exhibit different amounts of variability. METHODS: Effects of these data limitations on analyses of trends in occupational fatal injuries were studied using computer simulation. Fatality counts were generated assuming an undercount. Employment estimates were produced using two different strategies, reflecting either frequent but variable measurements or infrequent, precise estimates with interpolated estimates for intervening years. Poisson regression models were fit to the generated data. A range of empirically motivated fatality rate and employment parameters were studied. RESULTS: Undercounting fatalities resulted in biased estimation of the intercept in the Poisson regression model. Relative bias in the trend estimate was near zero for most situations, but increased when a change in fatality undercounting over time was present. Biases for both the intercept and trend were larger when small employment populations were present. Denominator options resulted in similar rate and trend estimates, except where the interpolated method did not capture true trends in employment. CONCLUSIONS: Data quality issues such as consistency of conditions throughout the study period and the size of population being studied affect the size of the bias in parameter estimation.

Accidents, Occupational↗
PubMed2004

Time-related aspects of the healthy worker survivor effect.

PURPOSE: Health is important for continued employment and therefore continued accrual of occupational exposure; furthermore, steady employment can benefit health. Consequently, bias can occur in estimates of cumulative exposure-mortality associations. This has been called the healthy worker survivor effect (HWSE). The processes associated with the HWSE tend to lead to variation in mortality rates with time-since-termination of employment, most notably a peak in mortality shortly after termination of employment. We use simulations and an empirical example to demonstrate that time-since-termination can be a confounding factor in analyses of occupational-exposure-mortality associations. METHODS: Simulation data were generated for 20,000 workers followed for 40 years under a model of no effect of employment duration (a proxy for cumulative exposure) on mortality. Proportional hazards regression methods were used to quantify exposure-mortality associations and evaluate methods to control for the HWSE. Results were derived after 100 iterations of the simulation. Relationships between employment duration and mortality were also investigated in a cohort of 122,247 male utility workers with adjustments for time since termination. RESULTS: Simulation data show a peak in mortality rates in the first year after termination of employment which declined in magnitude with continued time since termination of employment; average employment duration also declined with time since termination of employment. This led to confounding of cumulative-exposure-mortality associations, with spurious evidence of a positive association between cumulative exposure and mortality in the post-termination period. Adjustment for time-since-termination eliminated this spurious association; in contrast, adjustment for a binary indicator of employment status led to positively-biased relative rate estimates. A similar pattern was observed in analyses of utility worker data. The log relative rate of all cancer mortality is -0.12+/-0.03 per decade of employment without adjustment for time-since-termination, and -0.01+/-0.03 with adjustment for time-since-termination of employment. CONCLUSIONS: The HWSE can lead to temporal variation in mortality rates that is correlated with cumulative exposure. Under these conditions, adjusting for time-since-termination of employment may reduce bias in estimates of cumulative-exposure-mortality trends more effectively than the commonly-used method of adjusting for a binary indicator of employment status.

Adolescent↗
PubMed2004

Architecture of NarGH reveals a structural classification of Mo-bisMGD enzymes.

The structure of the catalytic and electron-transfer subunits (NarGH) of the integral membrane protein, respiratory nitrate reductase (Nar) has been determined to 2.0 A resolution revealing the molecular architecture of this Mo-bisMGD (molybdopterin-guanine-dinucleotide) containing enzyme which includes a previously undetected FeS cluster. Nar, together with the related enzyme formate dehydrogenase (Fdh-N), is a key enzyme in the generation of proton motive force across the membrane in Escherichia coli nitrate respiration. A comparative study revealed that Nar and Fdh-N employ different approaches for acquiring substrate, reflecting different catalytic mechanisms. Nar uses a very narrow and nonpolar substrate-conducting cavity with a nonspecific substrate binding site, whereas Fdh-N accommodates a wider, positively charged substrate-conducting cavity with a more specific substrate binding site. The Nar structure also demonstrates the first example of an Asp side chain acting as a Mo ligand providing a structural basis for the classification of Mo-bisMGD enzymes.

Amino Acid Sequence↗
PubMed2003

Breakfast reduces declines in attention and memory over the morning in schoolchildren.

Twenty-nine schoolchildren were tested throughout the morning on 4 successive days, having a different breakfast each day (either of the cereals Cheerios or Shreddies, glucose drink or No breakfast). A series of computerised tests of attention, working memory and episodic secondary memory was conducted prior to breakfast and again 30, 90, 150 and 210 min later. The glucose drink and No breakfast conditions were followed by declines in attention and memory, but the declines were significantly reduced in the two cereal conditions. This study provides objective evidence that a typical breakfast of cereal rich in complex carbohydrates can help maintain mental performance over the morning.

Adolescent↗
PubMed2003

Conservative management of otitis media in cleft palate.

AIMS: Eustachian tube dysfunction affects nearly all children with cleft palate but its management is controversial. Some units perform routine prophylactic grommet insertion at the time of palate repair, whilst others are more conservative, inserting grommets only when signs and symptoms of otitis media with effusion are present. This study aims to present outcome data from one cleft team practising a conservative approach. DESIGN: This is a retrospective study in which consecutive palate repairs over 10 years are analysed and compared with previously published data. The spectrum of clefting and severity (LAHSHAL), otological and speech outcomes were recorded. Patients were excluded if incomplete data was available, and if sensorineural deafness or syndromic clefting was present. RESULTS: Data is presented for 72 of 109 consecutive patients and the 37 excluded patients are discussed. Following a conservative approach to otitis media with effusion, 29% of cases required grommets. The use of grommets seemed to be more common in those with more severe clefting. Despite this, the group receiving grommets had better speech results than those who did not, although this improvement was not statistically significant. CONCLUSIONS: There is no evidence of poor overall otological outcome in this series. The data demonstrates that those receiving grommets had better results despite more severe clefting.

Child, Preschool↗