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Biomedical subjects

David Jones

Publications and source records attributed to David Jones.

At least 19 recordsLinked to original sources
PubMed2006

Utility of serum Campylobacter specific antibodies in determining prior Campylobacter infection in neurological disease.

Campylobacter jejuni has been implicated in the pathogenesis of Guillain-Barre syndrome (GBS); however, little information exists on the utility of Campylobacter serology in determining recent infection in the patient population. C. jejuni specific antibodies (CAs) were measured in 420 blood donors (controls), 99 patients with recent C. jejuni infection, 34 patients with central nervous system disorders (neurology controls), and 44 patients with peripheral nervous system (PNS) disorders: 18 with GBS, 12 with MND and 14 with chronic inflammatory neuropathies. Elevated CA titres consistent with recent C. jejuni infection were found in six of the 44 patients with PNS disorders (three with GBS, two with neuropathy, and one with MND, only one of whom had a history of recent C. jejuni infection), compared with two of 454 controls (p = 0.00001). Therefore, we conclude that CAs are often raised in patients with PNS disorders who do not have a history of recent C. jejuni gastroenteritis, so Campylobacter serology may be an unreliable marker of recent infection in this patient group.

Acute Disease↗
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

Combined liquid chromatography-tandem mass spectrometry as an analytical method for high throughput screening for X-linked adrenoleukodystrophy and other peroxisomal disorders: preliminary findings.

Utilizing combined liquid chromatography-tandem mass spectrometry (LC-MS/MS) as the analytical method, we have demonstrated a ten to sixtyfold excess of lysophosphatidyl choline containing hexacosanoic acid (26:0) in dried blood spots on a filter paper matrix from 25 male patients with X-linked adrenoleukodystrophy and nine patients with peroxisome biogenesis disorders compared to 19 controls. There was no overlap between normal subjects versus affected subjects.

Adrenoleukodystrophy↗
PubMed2006

PONGO: a web server for multiple predictions of all-alpha transmembrane proteins.

The annotation efforts of the BIOSAPIENS European Network of Excellence have generated several distributed annotation systems (DAS) with the aim of integrating Bioinformatics resources and annotating metazoan genomes (http://www.biosapiens.info). In this context, the PONGO DAS server (http://pongo.biocomp.unibo.it) provides the annotation on predictive basis for the all-alpha membrane proteins in the human genome, not only through DAS queries, but also directly using a simple web interface. In order to produce a more comprehensive analysis of the sequence at hand, this annotation is carried out with four selected and high scoring predictors: TMHMM2.0, MEMSAT, PRODIV and ENSEMBLE1.0. The stored and pre-computed predictions for the human proteins can be searched and displayed in a graphical view. However the web service allows the prediction of the topology of any kind of putative membrane proteins, regardless of the organism and more importantly with the same sequence profile for a given sequence when required. Here we present a new web server that incorporates the state-of-the-art topology predictors in a single framework, so that putative users can interactively compare and evaluate four predictions simultaneously for a given sequence. Together with the predicted topology, the server also displays a signal peptide prediction determined with SPEP. The PONGO web server is available at http://pongo.biocomp.unibo.it/pongo.

Humans↗
PubMed2006

Prediction of summation in incompletely fused tetanic contractions of rat muscle.

Summation is the accumulating contractile force resulting from sequential activations applied to a muscle without sufficient interval to permit complete relaxation. The purpose of this study was to evaluate summation in the rat medial gastrocnemius muscle, and to determine if the contractile responses during summation could be predicted from the relationship between force and activation pattern. In the first part of this study, the consistency of summation in the rat gastrocnemius muscle was assessed and prediction equations were derived. The second part compared predicted summation with actual contractions obtained in a new set experiments. Summation was assessed by calculation of the contractile response, per stimulation, for up to five stimulating pulses at these frequencies: 20, 40, 60 and 80Hz. This was done by subtraction of the force transient for j-1 pulses of stimulation (where j=1-5 pulses) from the force response with j pulses of stimulation. Each of these force differences was evaluated for peak rate of force development, contraction time and half-relaxation time. Contraction and half-relaxation times changed by only a small magnitude from values obtained for the twitch. Peak rate of force development was proportional to the active force for all force transients obtained by subtraction. The force per activation increased from the first to the fifth stimulus, and was dependent on interpulse delay. In the second series of experiments, the predicted force was related to the actual force for brief tetanic contractions at 40, 50 and 60Hz (r(2)=0.875). These experiments demonstrate that the force response to sequential activations is consistent and predictable. Summation can be predicted, knowing only the amplitude of the twitch contraction and the relationship between delay and force for each activating stimulus.

Animals↗
PubMed2006

Economic burden associated with breast cancer recurrence: findings from a retrospective analysis of health system data.

BACKGROUND: The economics of breast cancer recurrence are poorly understood. For this retrospective cohort study, the authors evaluated the economic burden of breast cancer recurrence by using data from a large Midwestern healthcare system. METHODS: Women with Stage I or II breast cancer (according to the American Joint Commission on Cancer staging criteria) were identified from the tumor registry of the Henry Ford Health System. The economic burden of breast cancer recurrence was estimated from patient charges (adjusted to 2003 U.S. dollars). RESULTS: From 1996 to 2002, 1616 patients with early breast cancer were identified, including 192 patients who had recurrent tumors. Patients with recurrence had significantly greater charges in the 6-month and 12-month postrecurrence periods (45,855 U.S. dollars and 79,253 U.S. dollars, respectively) compared with the 6-month and 12-month prerecurrence periods (10,715 U.S. dollars and 12,344 U.S. dollars, respectively; both P <.001). This was evident for all recurrence types (locoregional, contralateral breast, and distant), but it was most evident for distant recurrences. In a regression analysis that was adjusted for baseline characteristics, the mean monthly charges were significantly greater for patients with recurrence versus patients without recurrence (P <.001), and this was true for each recurrence type. For women with recurrence (n = 74 patients), the mean charges during the 6-month postrecurrence period were significantly greater than mean charges during the initial 6-month period after diagnosis (50,355 U.S. dollars vs. 38,254 U.S. dollars; P <.01). Quarterly charges for continuing care postrecurrence were significantly greater than prerecurrence charges (4934 U.S. dollars vs. 1825 U.S. dollars; P <.001). The mean charges for terminal care were significantly greater (P <.01) for women with recurrence (n = 27 patients, 63,434 U.S. dollars) versus women without recurrence (n = 65 patients, 53,872 U.S. dollars). CONCLUSIONS: Patients with early breast cancer who experienced recurrence required more costly care than patients who did not develop recurrent disease. Therapies that reduce the risk of recurrence may reduce costs significantly.

Adult↗
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

Sequence analysis of the protein kinase gene family in human testicular germ-cell tumors of adolescents and adults.

The protein kinase gene family is the most frequently mutated in human cancer. Previous work has documented activating mutations in the KIT receptor tyrosine kinase in testicular germ-cell tumors (TGCT). To investigate further the potential role of mutated protein kinases in the development of TGCT and to characterize the prevalence and patterns of point mutations in these tumors, we have sequenced the coding exons and splice junctions of the annotated protein kinase family of 518 genes in a series of seven seminomas and six nonseminomas. Our results show a remarkably low mutation frequency, with only a single somatic point mutation, a K277E mutation in the STK10 gene, being identified in a total of more than 15 megabases of sequence analyzed. Sequencing of STK10 in an additional 40 TGCTs revealed no further mutations. Comparative genomic hybridization and LOH analysis using SNP arrays demonstrated that the 13 TGCTs mutationally screened through the 518 protein kinase genes were uniformly aneuploid with consistent chromosomal gains on 12p, 8q, 7, and X and losses on 13q, 18q, 11q, and 4q. Our results do not provide evidence for a mutated protein kinase implicated in the development of TGCT other than KIT. Moreover, they demonstrate that the general prevalence of point mutations in TGCT is low, in contrast to the high frequency of copy number changes.

Adolescent↗
PubMed2006

Fatigue in primary biliary cirrhosis is associated with excessive daytime somnolence.

A significant proportion of patients with primary biliary cirrhosis (PBC) suffer from severe fatigue. The aim of this study was to characterize patterns of daytime sleep in patients with PBC (using both objective and subjective assessment approaches) and to study the association between sleep abnormality and fatigue severity. Fatigue severity was assessed in 48 female subjects with PBC (using a disease-specific quality of life instrument (the PBC-40) and a generic fatigue measure (Fatigue Impact Scale [FIS]) as well as 48 case-matched normal controls. All participants also completed the Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale (ESS, which assesses daytime hypersomnolence). Objective sleep assessment was performed using accelerometry over 7 days. Global sleep quality assessed by the PSQI was significantly lower in the PBC group compared to controls (P < .0001). ESS scores were significantly higher in patients with PBC than controls (P = .0001), suggesting significantly greater daytime somnolence in the patients with PBC. Objective sleep assessment confirmed that subjects with PBC were sleeping on average almost twice as long as controls during the daytime. Both degree of daytime somnolence (ESS) and actual daytime sleep activity (accelerometry) correlated strongly with fatigue severity in the patient group (r2 = 0.5, P < .0001 and r2 = 0.2, P < .01, respectively). In conclusion, Sleep abnormality, in the form of excessive daytime somnolence, is present in a significant proportion of patients with PBC, with the degree of daytime somnolence correlating strongly with the degree of fatigue. Existing agents effective at reducing daytime somnolence (such as modafinil) hold potential for the treatment of fatigue in PBC.

Cognition↗
PubMed2006

Negatively oriented personality and perceived negative job characteristics as predictors of future psychological and physical symptoms: a meta-analytic structural modelling approach.

OBJECTIVES: There is evidence that perceptions of negative job characteristics (e.g., lack of control) and negatively oriented personality (e.g., negative affect) both predict symptom reporting. However, the relative contribution of these factors is rarely examined. This paper uses meta-analytic structural equation modelling (MA-SEM) to explore their relative contribution. METHODS: A meta-analysis of recent longitudinal studies was conducted. Eight studies covering 10 separate samples met the inclusion criteria (N=2104) and were used in the MA-SEM. Meta-correlations were used to construct structural equations models in which perceived negative job characteristics (PNJC) and negatively oriented personality (NOP) at baseline were used to predict concurrent and future symptom reporting, controlling for symptom reporting at baseline. RESULTS: The results indicated that a model based solely on NOP offered a more parsimonious account for baseline and future symptom reporting than did PNJC. CONCLUSIONS: The evidence indicates interventions should focus on both individuals and organizations, and not just organizational-level interventions.

Affect↗
PubMed2006

Post-streptococcal uveitis.

PURPOSE: To describe the clinical features of post-streptococcal uveitis (PSU) and examine management strategies in the treatment of this under-recognized condition. METHODS: Patients were identified from the world literature using the Pubmed search engine. We examined two new cases of post-streptococcal intermediate uveitis. The epidemiology, immune mechanisms, clinical features, investigations, treatments and visual outcomes were examined and recorded. RESULTS: We reviewed 11 patients including our own two cases. There was a statistically significant seasonal difference in antistreptolysin-O titres (ASOT), and age-related ASOT was identified. Of the 11 patients, eight (72.7%) had anterior uveitis, two (18.2%) had intermediate uveitis and one (9.1%) had panuveitis. Their ages ranged from 5 to 56 years (mean 17 years). The majority of cases had significantly elevated ASOT; most patients were treated with topical steroids and oral antibiotics and four cases underwent adenotonsillectomy. The visual prognosis was good in most cases. CONCLUSIONS: Uveitis may be the sole presenting clinical feature, or it may occur in combination with other features of post-streptococcal infection. Ophthalmologists should be aware of the clinical features of PSU and maintain a high level of suspicion, particularly in childhood uveitis.

Adolescent↗
PubMed2005

Assessing the potential to induce respiratory hypersensitivity.

Acute and repeat dose inhalation studies have been an important part of the safety assessment of drugs, chemicals, and other products throughout the world for many years. It is known that damage to the respiratory tract can be triggered either by nonspecific irritation or by specific immune-mediated pathogenesis, and it is acknowledged that traditional inhalation studies are not designed to address fully the impact of the latter. It is also recognized that different types of immune-mediated responses can be triggered by different classes of compounds and that some immune reactions in the lung are life threatening. As such, it is important to understand as fully as possible the basis for the immune-mediated damage to the lung in order to characterize adequately the risks of individual chemicals or proteins. It is against this background that a review of the methods used to assess the potential for immune-mediated respiratory hypersensitivity was conducted. The primary objectives of this review are to discuss appropriate methods for identifying and characterizing respiratory hypersensitivity hazards and risks; and to identify key data gaps and related research needs with respect to respiratory hypersensitivity testing. The following working definition of respiratory hypersensitivity was formulated: a hypersensitivity response in the respiratory tract precipitated by a specific immune response, mediated by multiple mechanisms, including IgE antibody. Because of the importance played by various classes of compounds, the subsequent sections of this review will consider protein-specific, chemical-specific, and drug-specific aspects of respiratory hypersensitivity.

Drug Hypersensitivity↗
PubMed2005

Long-acting inhaled bronchodilators for COPD--lack of logic continues.

Long acting inhaled bronchodilators - beta agonists and anti-cholinergic--can improve symptoms, enhance quality of life, increase exercise ability, and reduce exacerbation rates in patients with COPD. PHARMAC needs to change policy so that these patients have easy access to this effective group of drugs.

Administration, Inhalation↗
PubMed2005

Somatic mutations of the protein kinase gene family in human lung cancer.

Protein kinases are frequently mutated in human cancer and inhibitors of mutant protein kinases have proven to be effective anticancer drugs. We screened the coding sequences of 518 protein kinases (approximately 1.3 Mb of DNA per sample) for somatic mutations in 26 primary lung neoplasms and seven lung cancer cell lines. One hundred eighty-eight somatic mutations were detected in 141 genes. Of these, 35 were synonymous (silent) changes. This result indicates that most of the 188 mutations were "passenger" mutations that are not causally implicated in oncogenesis. However, an excess of approximately 40 nonsynonymous substitutions compared with that expected by chance (P = 0.07) suggests that some nonsynonymous mutations have been selected and are contributing to oncogenesis. There was considerable variation between individual lung cancers in the number of mutations observed and no mutations were found in lung carcinoids. The mutational spectra of most lung cancers were characterized by a high proportion of C:G > A:T transversions, compatible with the mutagenic effects of tobacco carcinogens. However, one neuroendocrine cancer cell line had a distinctive mutational spectrum reminiscent of UV-induced DNA damage. The results suggest that several mutated protein kinases may be contributing to lung cancer development, but that mutations in each one are infrequent.

Adenocarcinoma↗