Continental doctors take leadership in British medicine.
Explore the source record for details and available documents.
Emigration and Immigration↗
Biomedical subjects
John Martin
Publications and source records attributed to John Martin.
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↗
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↗
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↗
A see-through in vitro tendon repair model.
Explore the source record for details and available documents.
Humans↗
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↗
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↗
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↗
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↗
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↗
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↗
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↗
Monocyte adhesion to mesangial matrix modulates cytokine and metalloproteinase production.
BACKGROUND: Monocytes migrate into the glomerular mesangium during acute inflammatory renal disease, differentiate into macrophages, and may play a key role in the development and progression of glomerular scarring. Treatment strategies that inhibit monocyte infiltration ameliorate glomerular injury in animal models. Mesangial matrix contains several potential monocyte-binding domains that may contribute to monocyte entrapment and modulate cell activation. METHODS: Adhesion of peripheral blood-derived monocytes to matrix synthesized by human mesangial cells and to individual matrix proteins was assessed by colorimetry of nuclear staining with crystal violet. Monoclonal antibodies were used to identify the cell-surface integrins and matrix ligands involved. Monocyte proliferation was assessed by 3H-thymidine incorporation and cytokine production using enzyme-linked immunosorbent assay (ELISA). Secretion of metalloproteinases and their inhibitors was determined by zymography and ELISA, respectively. RESULTS: Monocytes bound to matrix synthesized by mesangial cells. Prestimulation of mesangial cells with tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta) enhanced matrix fibronectin content (P < 0.001) and monocyte binding (P < 0.001). Blocking antibodies to fibronectin, as well as to the integrins very late antigen-4 (VLA-4) and VLA-5, reduced monocyte adhesion to mesangial matrix by approximately 50%. Incubation of monocytes with matrix, fibronectin, laminin and collagen IV enhanced production of interleukin-1beta (IL-1beta), interleukin-6 (IL-6), TNF-alpha and metalloproteinase-9 (MMP-9) when compared to cells incubated in plastic wells. However, there was no apparent difference in proliferation rate and no change in production of metalloproteinase inhibitors. CONCLUSION: Monocyte activation within the glomerulus may be mediated by binding to mesangial matrix components, particularly fibronectin. Matrix-mediated activation enhances production of inflammatory cytokines and matrix-degrading enzymes.
Cell Adhesion↗
Gene discovery in the apicomplexa as revealed by EST sequencing and assembly of a comparative gene database.
Large-scale EST sequencing projects for several important parasites within the phylum Apicomplexa were undertaken for the purpose of gene discovery. Included were several parasites of medical importance (Plasmodium falciparum, Toxoplasma gondii) and others of veterinary importance (Eimeria tenella, Sarcocystis neurona, and Neospora caninum). A total of 55192 ESTs, deposited into dbEST/GenBank, were included in the analyses. The resulting sequences have been clustered into nonredundant gene assemblies and deposited into a relational database that supports a variety of sequence and text searches. This database has been used to compare the gene assemblies using BLAST similarity comparisons to the public protein databases to identify putative genes. Of these new entries, approximately 15%-20% represent putative homologs with a conservative cutoff of p < 10(-9), thus identifying many conserved genes that are likely to share common functions with other well-studied organisms. Gene assemblies were also used to identify strain polymorphisms, examine stage-specific expression, and identify gene families. An interesting class of genes that are confined to members of this phylum and not shared by plants, animals, or fungi, was identified. These genes likely mediate the novel biological features of members of the Apicomplexa and hence offer great potential for biological investigation and as possible therapeutic targets.
Animals↗
Assessing periodontal disease risk: a comparison of clinicians' assessment versus a computerized tool.
BACKGROUND: The authors conducted a study to compare risk scores assigned by subjective expert clinician opinion with quantitative scores generated for the same subjects using the Periodontal Risk Calculator, or PRC. METHODS: The authors assembled a group of 107 subjects and performed standard periodontal examinations. The authors entered the resulting information into the PRC and calculated risk scores for two and four years, assuming no treatment would be performed. Using the same subject records, three groups of expert clinicians assigned risk scores for years 2 and 4. The authors analyzed the data to reveal the extent of interevaluator variation and the level of agreement between expert clinician scores and PRC scores. RESULTS: The extent of variation among scores assigned by individual expert clinicians was greater than the authors had expected. Expert clinicians consistently assigned more subjects to PRC risk group 2 and fewer to risk group 5 than did the PRC. The authors observed very high heterogeneity in the risk scores expert clinicians assigned to patients in each of the PRC-assigned groups. Thus, expert clinicians varied greatly in evaluating risk and, relative to the PRC, they appeared to underestimate periodontitis risk, especially for high-risk patients. CONCLUSIONS AND PRACTICE IMPLICATIONS: The authors' observations suggest that use of risk scores generated for individual patients by subjective expert clinician opinion about risk in periodontal clinical decision making could result in the misapplication of treatment for some patients and support the use of an objective tool such as the PRC. Use of the PRC 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 costs.
Adult↗
The need for resources for clinical research: the European Society of Cardiology calls for European, international collaboration.
Explore the source record for details and available documents.
Biomedical Research↗
The role of ADAM 15 in glomerular mesangial cell migration.
Mesangial cells (MC) occupy the core of the renal glomerulus and are surrounded by a mesangial matrix. In certain diseases, MC migrate through this matrix into the pericapillary space. The mechanisms involved, however, are poorly understood. Members of the ADAM (A Disintegrin And Metalloproteinase) family of membrane proteins have the potential to be key modulators of cell-matrix interactions through the activities of their constituent domains. We have studied the possible role of ADAM 15 in human (H) MC migration in vitro. HMC ADAM 15 was expressed at low levels in serum-free medium but was increased during migration. Antibodies to the individual domains of ADAM 15 and the incorporation of antisense ADAM 15, (but not control oligonucleotide) inhibited this migration. Furthermore, inhibition of migration by the broad spectrum metalloproteinase inhibitor BB3103, demonstrated that metalloproteinase activity was essential for migration. ADAM 15, extracted from HMC membranes, was an active metalloproteinase, which degraded both type IV collagen and gelatin prepared from fibrillar collagen. Activity was inhibited by EDTA but not by phenylmethylsulfonyl fluoride. This is the first report of the potential of ADAM 15 for involvement in the restructuring of the mesangial matrix and in the migration of MC in disease.
ADAM Proteins↗
A polymeric sealant inhibits anastomotic suture hole bleeding more rapidly than gelfoam/thrombin: results of a randomized controlled trial.
HYPOTHESIS: An experimental polymeric sealant (CoSeal [Cohesion Technologies, Palo Alto, Calif]) provides equivalent anastomotic sealing to Gelfoam (Upjohn, Kalamazoo, Mich)/thrombin during surgical placement of prosthetic vascular grafts. DESIGN: Randomized controlled trial. SETTING: Nine university-affiliated medical centers. PATIENTS: One hundred forty-eight patients scheduled for implantation of polytetrafluoroethylene grafts, mainly for infrainguinal revascularization procedures or the creation of dialysis access shunts, who were treated randomly with either an experimental intervention (n = 74) or control (n = 74). INTERVENTION: Following polytetrafluoroethylene graft placement, anastomotic suture hole bleeding was treated intraoperatively in all control subjects with Gelfoam/thrombin. Subjects in the experimental group had the polymeric sealant applied directly to the suture lines without concomitant manual compression. MAIN OUTCOME MEASURES: Primary treatment success was defined as the proportion of subjects in each group that achieved complete anastomotic sealing within 10 minutes. The proportion of subjects that achieved immediate sealing and the time required to fully inhibit suture hole bleeding also were compared between treatment groups. RESULTS: Overall 10-minute sealing success was equivalent (86% vs 80%; P =.29) between experimental and control subjects, respectively. However, subjects treated with CoSeal achieved immediate anastomotic sealing at more than twice the rate of subjects treated with Gelfoam/thrombin (47% vs 20%; P<.001). Consequently, the median time needed to inhibit bleeding in control subjects was more than 10 times longer than for experimental subjects (16.5 seconds vs 189.0 seconds; P =.01). Strikingly similar findings for all comparisons were observed separately for subgroups of subjects having infrainguinal bypass grafting and for those undergoing placement of dialysis access shunts. CONCLUSIONS: The experimental sealant offers equivalent anastomotic sealing performance compared with Gelfoam/thrombin, but it provides this desired effect in a significantly more rapid time frame.
Anastomosis, Surgical↗