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John Martin

Publications and source records attributed to John Martin.

At least 19 recordsLinked to original sources
PubMed2005

Investigating hookworm genomes by comparative analysis of two Ancylostoma species.

BACKGROUND: Hookworms, infecting over one billion people, are the mostly closely related major human parasites to the model nematode Caenorhabditis elegans. Applying genomics techniques to these species, we analyzed 3,840 and 3,149 genes from Ancylostoma caninum and A. ceylanicum. RESULTS: Transcripts originated from libraries representing infective L3 larva, stimulated L3, arrested L3, and adults. Most genes are represented in single stages including abundant transcripts like hsp-20 in infective L3 and vit-3 in adults. Over 80% of the genes have homologs in C. elegans, and nearly 30% of these were with observable RNA interference phenotypes. Homologies were identified to nematode-specific and clade V specific gene families. To study the evolution of hookworm genes, 574 A. caninum/A. ceylanicum orthologs were identified, all of which were found to be under purifying selection with distribution ratios of nonsynonymous to synonymous amino acid substitutions similar to that reported for C. elegans/C. briggsae orthologs. The phylogenetic distance between A. caninum and A. ceylanicum is almost identical to that for C. elegans/C. briggsae. CONCLUSION: The genes discovered should substantially accelerate research toward better understanding of the parasites' basic biology as well as new therapies including vaccines and novel anthelmintics.

Ancylostoma↗
PubMed2005

An expressed sequence tag analysis of the life-cycle of the parasitic nematode Strongyloides ratti.

14,761 expressed sequence tags (ESTs) were generated, representing five stages during the parasitic and free-living phases of the life-cycle of the parasitic nematode Strongyloides ratti. These ESTs formed 4152 clusters, of which 97% contained 10 or fewer ESTs and 66% were singletons. These 4152 clusters are likely to represent approximately 20% of S. ratti's genes. The clusters' consensus sequences were used to assign each cluster to one of three databases: (i) Caenorhabditis elegans and C. briggsae sequences; (ii) other nematode sequences; (iii) non-nematode sequences. This approach has identified putative nematode-specific genes, that may be targets for developing approaches for parasitic nematode control. Approximately 25% of the clusters have no significant alignments and may therefore represent novel genes. The EST representation between the libraries was used to analyse stage-specific or -biased expression in silico. This showed that 81% of clusters are present in only one library and 12% are present in any two libraries, indicating substantial stage-specificity of gene expression. The 30-most abundantly expressed clusters were analysed in further detail. Many of these have significantly different parasitic- or free-living-specific or -biased expression. Many of the parasitic-specific genes are, as yet, uncharacterised: one of these represents 25% of all ESTs obtained from the parasitic stage.

Animals↗
PubMed2005

Treatments for mild-to-moderate recalcitrant plaque psoriasis: expected clinical and economic outcomes for first-line and second-line care.

The cost effectiveness of treatments for psoriasis has been evaluated previously by several different investigators. Such evaluations should be updated as new products or data become available. To this end, a comparison of expected treatment-related clinical and economic outcomes is undertaken from the payer perspective using a disease-intervention model, decision analyses, and newly emergent information. The model is based on academy guidelines and recommended clinical practice. Model inputs (clinical and cost data) are culled from the medical literature and advisory clinical assessment surveys. Comparable therapies are various topical pharmacotherapies and phototherapies, including the 308-nm excimer laser (XTRAC, PhotoMedex, Montgomeryville, PA). Analytic results indicate that clinical and economic outcomes are influenced by treatment selections but are muted by the rotational nature of treatment regimens. Multiple analyses are required to reveal individual product performance. On the basis of these analyses, the addition of the 308-nm excimer laser to the rotational mix of treatments commonly utilized as second-line therapies for mild-to-moderate plaque psoriasis is expected to add incremental clinical benefit for patients without incremental cost for payers, because the laser can replace both more costly and less costly alternatives for appropriately selected patients who require a different therapeutic modality to maintain or improve their responsiveness.

Administration, Topical↗
PubMed2004

A transcriptomic analysis of the phylum Nematoda.

The phylum Nematoda occupies a huge range of ecological niches, from free-living microbivores to human parasites. We analyzed the genomic biology of the phylum using 265,494 expressed-sequence tag sequences, corresponding to 93,645 putative genes, from 30 species, including 28 parasites. From 35% to 70% of each species' genes had significant similarity to proteins from the model nematode Caenorhabditis elegans. More than half of the putative genes were unique to the phylum, and 23% were unique to the species from which they were derived. We have not yet come close to exhausting the genomic diversity of the phylum. We identified more than 2,600 different known protein domains, some of which had differential abundances between major taxonomic groups of nematodes. We also defined 4,228 nematode-specific protein families from nematode-restricted genes: this class of genes probably underpins species- and higher-level taxonomic disparity. Nematode-specific families are particularly interesting as drug and vaccine targets.

Animals↗
PubMed2004

Vascular endothelial growth factor gene transfer inhibits neointimal macrophage accumulation in hypercholesterolemic rabbits.

OBJECTIVE: This study aims to determine the effects of periadventitial vascular endothelial growth factor (VEGF) gene transfer on neointima formation and macrophage accumulation induced by collar placement around the carotid artery in hypercholesterolemic rabbits. METHODS AND RESULTS: Collar placement around the carotid artery in cholesterol-fed rabbits induced intimal thickening with increased neointimal macrophage content. Liposome-mediated VEGF gene transfer, confirmed by transgene-specific RT-PCR, caused a marked inhibition of both intimal thickening and macrophage accumulation compared with a lacZ control gene. VEGF gene transfer was not accompanied by a significant increase in adventitial neovascularization. Collaring of carotid arteries in hypercholesterolemic rabbits also upregulated endothelial VCAM-1 expression. Inhibition of neointimal macrophage infiltration in VEGF-transduced, collared arteries was associated with decreased endothelial VCAM-1. CONCLUSIONS: VEGF gene transfer inhibits collar-induced intimal thickening, macrophage accumulation, and VCAM-1 expression in cholesterol-fed rabbits. These findings support the concept that low-level VEGF expression can exert arterioprotective effects in the presence of high blood cholesterol.

Animals↗
PubMed2004

Identification and analysis of the promoter region of the human hyaluronan synthase 2 gene.

Hyaluronan (HA) is a linear glycosaminoglycan of the vertebrate extracellular matrix that is synthesized at the plasma membrane by the HA synthase (HAS) enzymes HAS1, -2 and -3. The regulation of HA synthesis has been implicated in a variety of extracellular matrix-mediated and pathological processes, including renal fibrosis. We have recently described the genomic structures of each of the human HAS genes. In the present study, we analyzed the HAS2 promoter region. In 5'-rapid amplification of cDNA ends analysis of purified mRNA from human renal epithelial proximal tubular cells, we detected an extended sequence for HAS2 exon 1, relocating the transcription initiation site 130 nucleotides upstream of the reference HAS2 mRNA sequence, GenBank accession number NM_005328. A luciferase reporter gene assay of nested fragments spanning the 5' terminus of NM_005328 demonstrated the constitutive promoter activity of sequences directly upstream of the repositioned transcription initiation site but not of the newly designated exonic nucleotides. Using reverse transcription-PCR, expression of this extended HAS2 mRNA was demonstrated in a variety of human cell types, and orthologous sequences were detected in mouse and rat kidney. Alignment of human, murine, and equine genomic DNA sequences upstream of the repositioned HAS2 exon 1 provided evidence for the evolutionary conservation of specific transcription factor binding sites. The location of the HAS2 promoter will facilitate analysis of the transcriptional regulation of this gene in a variety of pathological contexts as well as in developmental models in which HAS2 null animals have an embryonic lethal phenotype.

Animals↗
PubMed2004

Multicenter pivotal trial results of the Lifepath System for endovascular aortic aneurysm repair.

PURPOSE: This study was undertaken to assess the results of endovascular aortic aneurysm repair with the Lifepath abdominal aortic aneurysm (AAA) graft system. METHOD: In a prospective clinical trial, 23 centers used the Lifepath System balloon-expandable, modular bifurcated stent graft for elective endovascular aortic aneurysm repair. Stent grafts were sized according to computed tomographic angiography-based diameter measurements. All repairs were performed in the operating room through bilateral surgically exposed femoral arteries. Results were assessed with contrast agent-enhanced computed tomography scans and plain abdominal x-ray films at 1, 6, 12, 24, 36, and 48 months postoperatively. RESULTS: Over 52 months (mean follow-up, 11 months), 227 patients (206 men, 21 women) were enrolled. Technical implant success rate was 98.7%. There were five (2.2%) conversions to open surgery: two emergently because of aortic perforation; to treat refractory endoleak, immediate in one and at 12 months in one; and to replace a device with wireform fractures that had migrated at 12 months, resulting in a proximal endoleak. The perioperative mortality rate was 1.3%. There was one operative death during a secondary procedure to repair perforation of the aorta. There were two perioperative deaths, from postoperative myocardial infarction (n = 1) and pulmonary embolus (n = 1). There were 12 late deaths, from coronary artery disease (n = 4), cancer (n = 2), respiratory failure (n = 2), sepsis (n = 1), or unknown cause (n = 3). Median length of stay was 2 days (mean, 4 days). There have been no AAA ruptures after successful implantation of the device, no graft limb thromboses, and no limb dislocations. At the time of operation endoleak was noted in 43 (19%) patients, but by 6 months this was reduced to 8 (5.9%) patients (type I, n = 1; type II, n = 7). There were no type III or type IV endoleaks. Secondary interventions to treat endoleaks included open conversion (n = 2), placement of extension cuffs (n = 4), repeated balloon dilation (n = 3), and coil embolization (n = 6). The two remaining secondary interventions were emergent treatment of postoperative bleeding from a groin incision, and a colon resection because of postoperative colonic ischemia, for a 12-month secondary intervention rate of 7.5%. Wireform fractures were noted in the first generation Lifepath device in 37 of 79 (47%) patients. Graft migration (>10 mm) was observed in five patients (2.2%), each of whom also had two or more fractures of the proximal anchoring wireforms. Migration resulted in a proximal attachment endoleak in one patient. In response to wireform fractures, the device was modified after the initial 79 patients were enrolled. Wireform fracture has been observed in six patients since this modification (4%), and in only one patient did this involve fracture of a proximal anchoring wireform; none of these patients has had endoleak or graft migration. By 12 months, mean aneurysm diameter was noted to decrease by 9 mm (P <.0001), and mean aneurysm volume by 42 mL (P <.0001) from the preoperative visit. CONCLUSION: The Lifepath System demonstrates a low endoleak and secondary intervention rate and high sac regression rate, compared with other devices. The unique balloon-expandable design offers the advantages of precise placement and high radial force. The device appears to be highly resistant to limb thrombosis and modular component separation. Patients were protected from AAA rupture after successful device implantation, and demonstrated significant reduction in AAA diameter and volume. Fractures of the wireforms of the main body of the device have been observed. Careful long-term follow-up is necessary.

Adult↗
PubMed2004

Gene discovery in the adenophorean nematode Trichinella spiralis: an analysis of transcription from three life cycle stages.

Expressed sequence tags (ESTs) were produced from cDNA libraries for immature L1, mature muscle larva and adult stages of the adenophorean nematode Trichinella spiralis. 10,130 ESTs were grouped into 3454 gene clusters. The clusters represent a conservative estimate of 3262 unique genes. Interspecific comparisons of the predicted proteins support an ancient divergence of clade I nematodes from other nematodes in the phylum Nematoda. Furthermore, apparent clade I or Trichocephalida-specific proteins were identified, which may include molecular determinants important in the evolution of these species. Similarity matches identified 463 C. elegans genes homologs that confer phenotypes by RNA interference. Classification of predicted proteins suggested diverse cellular, metabolic and extracellular functions, significantly expanding the dataset of T. spiralis proteins with prospective, and potentially critical, functions. Several lines of evidence suggested stage-specific expression of certain genes beyond those previously identified. Evidence was obtained for the existence of large gene families encoding isoforms of known secreted proteins, such as p43 and TspE1. Unexpectedly, diverse isoforms of the muscle larva p43 gene appear to be expressed by immature L1. Proteinases, kinases, antioxidant proteins and enzymes involved in glycan synthesis are implicated in T. spiralis interactions with its hosts. Numerous genes were identified that encode predicted proteins in these categories. The genes discovered, when put into context of functional classification, stage of expression, and biology of the parasite, should substantially enhance experimental potential for research on this parasite.

Animals↗
PubMed2004

A knowledge-based clustering algorithm driven by Gene Ontology.

We have developed an algorithm for inferring the degree of similarity between genes by using the graph-based structure of Gene Ontology (GO). We applied this knowledge-based similarity metric to a clique-finding algorithm for detecting sets of related genes with biological classifications. We also combined it with an expression-based distance metric to produce a co-cluster analysis, which accentuates genes with both similar expression profiles and similar biological characteristics and identifies gene clusters that are more stable and biologically meaningful. These algorithms are demonstrated in the analysis of MPRO cell differentiation time series experiments.

Algorithms↗
PubMed2004

Comparative genomics of gene expression in the parasitic and free-living nematodes Strongyloides stercoralis and Caenorhabditis elegans.

Although developmental timing of gene expression is used to infer potential gene function, studies have yet to correlate this information between species. We analyzed 10,921 ESTs in 3311 clusters from first- and infective third-stage larva (L1, L3i) of the parasitic nematode Strongyloides stercoralis and compared the results to Caenorhabditis elegans, a species that has an L3i-like dauer stage. In the comparison of S. stercoralis clusters with stage-specific expression to C. elegans homologs expressed in either dauer or nondauer stages, matches between S. stercoralis L1 and C. elegans nondauer-expressed genes dominated, suggesting conservation in the repertoire of genes expressed during growth in nutrient-rich conditions. For example, S. stercoralis collagen transcripts were abundant in L1 but not L3i, a pattern consistent with C. elegans collagens. Although a greater proportion of S. stercoralis L3i than L1 genes have homologs among the C. elegans dauer-specific transcripts, we did not uncover evidence of a robust conserved L3i/dauer 'expression signature.' Strikingly, in comparisons of S. stercoralis clusters to C. elegans homologs with RNAi knockouts, those with significant L1-specific expression were more than twice as likely as L3i-specific clusters to match genes with phenotypes. We also provide functional classifications of S. stercoralis clusters.

Animals↗
PubMed2004

Myopathy and hepatic lipidosis in weaned lambs due to vitamin E deficiency.

A sheep flock experienced losses in weaned lambs from myopathy and hepatic lipidosis. Investigation revealed painful ambulation, illthrift, and unexpected death in lambs with normal selenium levels, deficient vitamin E levels, and elevated muscle and liver enzyme levels. Vitamin E deficiency should be considered when investigating myopathy and illthrift in lambs.

Animals↗
PubMed2003

Connectivity of the turtle accessory optic system.

Recent whole-cell recordings show that there are multiple synaptic inputs to the accessory optic system of the pond turtle Pseudemys scripta elegans (the basal optic nucleus, BON), suggesting a complex role in visual processing. The BON outputs have now been investigated using transport of diI, rhodamine-conjugated and biotinylated dextrans. Although transport was primarily anterograde, contralateral retinal ganglion cells were labeled retrogradely, confirming that the injection site was a retinal target. Other retrogradely labeled neurons were found ipsilateral to the injection site, in the pretectum, the ventral tegmentum, the dorsal nucleus of the posterior commissure and the lateral habenular nucleus. However, other data indicate that the habenular cells were labeled by spread of the tracer from the BON to the adjacent fasciculus retroflexus and interpeduncular nucleus. Anterogradely labeled fibers projected from BON following three paths, a lateral bundle to the ipsilateral dorsal midbrain, an intermediate bundle to the ipsilateral pretectal area or the posterior commissure and a ventral fiber bundle to the tegmentum bilaterally. Some of these fibers projected caudally through the tegmentum and cerebellar peduncle to terminate just below the Purkinje cell layer of the cerebellar cortex. Fibers that coursed via the intermediate bundle to the posterior commissure were also seen reaching the contralateral pretectal area and the contralateral BON. Injections of the retrograde tracer Fluorogold were also made in the BON to confirm the reciprocal connectivity of both basal optic nuclei. The pathways revealed by these experiments indicate the existence of multiple afferent and efferent connections of the BON, supporting the view that the accessory optic system is more than a simple relay of retinal signals into the brainstem for optokinetic reflexes.

Animals↗
PubMed2003

Analysis and functional classification of transcripts from the nematode Meloidogyne incognita.

BACKGROUND: Plant parasitic nematodes are major pathogens of most crops. Molecular characterization of these species as well as the development of new techniques for control can benefit from genomic approaches. As an entrée to characterizing plant parasitic nematode genomes, we analyzed 5,700 expressed sequence tags (ESTs) from second-stage larvae (L2) of the root-knot nematode Meloidogyne incognita. RESULTS: From these, 1,625 EST clusters were formed and classified by function using the Gene Ontology (GO) hierarchy and the Kyoto KEGG database. L2 larvae, which represent the infective stage of the life cycle before plant invasion, express a diverse array of ligand-binding proteins and abundant cytoskeletal proteins. L2 are structurally similar to Caenorhabditis elegans dauer larva and the presence of transcripts encoding glyoxylate pathway enzymes in the M. incognita clusters suggests that root-knot nematode larvae metabolize lipid stores while in search of a host. Homology to other species was observed in 79% of translated cluster sequences, with the C. elegans genome providing more information than any other source. In addition to identifying putative nematode-specific and Tylenchida-specific genes, sequencing revealed previously uncharacterized horizontal gene transfer candidates in Meloidogyne with high identity to rhizobacterial genes including homologs of nodL acetyltransferase and novel cellulases. CONCLUSIONS: With sequencing from plant parasitic nematodes accelerating, the approaches to transcript characterization described here can be applied to more extensive datasets and also provide a foundation for more complex genome analyses.

Animals↗
PubMed2003

The need for resources for clinical research: proceedings of a policy conference held at the European Heart House, 27-28 June 2002: executive summary.

The medical profession, in particular cardiologists, acknowledge the fact that during the last 30 years, much of the progress made in the field of medicine has resulted from fruitful and close collaboration between academia and the pharmaceutical industry. However, during the last decade, this relationship has changed considerably. The industry increasingly carries out its own research, development of drugs and trials, according to its own agenda. As a result, academia has lost its influence. This has led to a dramatic increase in the cost of clinical randomised trials. In the meantime, academic careers and research have become less attractive to physicians. Funding for research is increasingly devoted to basic science, in particular genomics, and little is left for clinical research. As a result, many important clinical trials in various areas of medicine, including cardiology, remain unfunded.

Cardiology↗
PubMed2003

Limited contribution of the SPINK1 N34S mutation to the risk and severity of alcoholic chronic pancreatitis: a report from the United States.

Mutations in the SPINK1 gene (e.g. N34S) have been reported in patients with idiopathic, familial, tropical, and alcoholic pancreatitis. The prevalence of SPINK1 N34S differs between different patient populations, and its contribution to the risk and the severity of alcoholic chronic pancreatitis has not been defined in the United States. Mutational analysis of the exon 3 was performed in 32 patients with alcoholic chronic pancreatitis, 39 patients with nonalcoholic chronic pancreatitis or recurrent acute pancreatitis, and 190 previously studied healthy controls. The course of alcoholic chronic pancreatitis with and without N34S was compared in age of onset- and sex-matched patients. All SPINK1 gene sequence variations were heterozygous. SPINK1 N34S was present in 3/190 (1.6%) and P55S was found in 2/190 (1.1%) of controls. In alcoholics, the N34S mutation was identified in 2/32 patients (6.3%, P > 0.05). In nonalcoholics, N34S and P55S were identified in 6/39 patients (15.4%, P < 0.005, N34S N = 4, P55S N = 1, N34S/P55S N = 1). The clinical course of alcoholic chronic pancreatitis was similar between patients with and without the N34S mutation. The N34S mutation is uncommon in patients with alcoholic chronic pancreatitis in the United States; its prevalence is similar to other countries and appears not to alter the onset or the severity of alcoholic chronic pancreatitis.

Adult↗
PubMed2003

Longitudinal validation of a risk calculator for periodontal disease.

BACKGROUND: Risk assessment and utilization of the results are important components of prevention, diagnosis and treatment of periodontal diseases. Risk assessment is relatively new to dentistry. Currently risk is assessed by subjective evaluation and results vary widely among clinicians. We have developed a computer-based risk assessment tool, the Periodontal Risk Calculator (PRC), for objective, quantitative assessment of risk. The purpose of the study reported here was to evaluate the accuracy and validity of this tool. METHODS: Clinical records and radiographs of 523 subjects enrolled in the VA Dental Longitudinal Study of Oral Health and Disease, covering a period of 15 years, were used. Information from baseline examinations was entered into the risk calculator and a risk score on a scale of l-5 for periodontal deterioration was calculated for each subject. Actual periodontal status in terms of alveolar bone loss determined using digitized radiographs, and tooth loss determined from the clinical records, was assessed at years 3, 9 and 15. The strength of the association between risk prediction and actual outcome was determined statistically. RESULTS: The risk scores were strong predictors of future periodontal status measured as worsening severity and extent of alveolar bone loss and tooth loss, especially loss of periodontally affected teeth. Over the entire 15-year period, risk scores consistently ranked groups from least to most bone loss and tooth loss. Risk groups differed greatly from one another. By year 3, the incidence rate of bone loss of group 5 was 3.7-fold greater than for group 2, and by year 15, the loss of periodontally affected teeth was 22.7-fold greater than for group 2 (p<0.001). By year 15, 83.7% of subjects in risk group 5 had lost one or more periodontally affected teeth compared to 20.2% of subjects in group 2. CONCLUSIONS: Risk scores calculated using the PRC and information gathered during a standard periodontal examination predict future periodontal status with a high level of accuracy and validity. Use of the risk assessment tool over time may be expected to result in more uniform and accurate periodontal clinical decision-making, improved oral health, reduction in the need for complex therapy and reduction in health-care cost.

Adult↗